RNA CONSTRUCT

The present invention relates to RNA constructs, and particularly, although not exclusively, to mRNA constructs and saRNA replicons and to nucleic acids and expression vectors encoding such RNA constructs. The invention extends to the use of such RNA constructs in therapy, for example in treating diseases and/or in vaccine delivery. The invention extends to pharmaceutical compositions comprising such RNA constructs, and methods and uses thereof.

Messenger RNA (mRNA) is a promising tool for biotherapeutics. However, while mRNA therapeutics have been shown to be highly effective in small animals, the outcomes do not scale linearly when these formulations are translated in dose-escalation studies in humans. Furthermore, adverse events associated with the induction of interferon responses have been rate-limiting with respect to the increased doses of RNA likely to be effective in humans. The reason for this inconsistency is unclear, but the inventors hypothesize that inherent differences in human innate sensing pose a barrier to the translation of RNA therapeutics from the lab to the clinic.

Furthermore, innate sensing of RNA has been associated with the inhibition of protein expression. To date, the main approach to overcoming the innate recognition of exogenous RNA has been to use modified ribonucleotides that are less detectable by innate sensing mechanisms. However, modified mRNA is not completely undetectable, and still results in some induction of interferon production, protein silencing and reduced tolerability for human use (see FIG. 2).

Another approach has been the use of self-amplifying or saRNA vectors, which are typically based on an alphavirus backbone that have the capacity to self-amplify their own RNA by encoding polymerase activity within their non-structural proteins. Prior art methods have involved replacing the structural proteins of these vectors by a gene of interest (GOI), for example encoding an antigen of interest be it a vaccine construct, or encoding a therapeutic protein. Other versions of saRNA have been based on picornaviruses, flaviviruses, and coronaviruses. When saRNA is taken up into the cytoplasm of target cells, this leads to amplification of the RNA by the encoded polymerase machinery and very high expression levels of the GOI. As a consequence, saRNA has been shown to induce immune responses with lower doses of saRNA than mRNA (10- to 100-fold lower) and results in prolonged protein expression for up to 60 days in mice.

However, as shown in FIG. 3, a drawback with saRNA is that it is also sensed by innate sensing pattern recognition receptors, triggering antiviral (interferon) responses that limit protein expression and self-amplification of these prior art saRNAs. Innate sensing of saRNA differs to that of mRNA due to its large size (typically >5000 bases) and profound secondary structure, including double stranded regions (dsRNA). Long and double stranded RNA triggers innate responses through amongst other sensors, the MDA5 ((Melanoma Differentiation-Associated protein 5) pathway. This is facilitated by the binding of PACT (PKR activating protein) to long and dsRNA RNA promoting the oligomerization of MDA5 and subsequent triggering of a down-stream signalling cascade that inhibits replication and expression of saRNA.

Accordingly, there is a need in the art to produce new means by which RNA therapeutics, be they mRNA- or saRNA-based, can be delivered and expressed in patients, such that they are able to overcome the innate immune system sensing.

The inventors have developed novel RNA constructs (saRNA and mRNA) that advantageously overcome the innate immune system which senses RNA, by expressing viral immune inhibitor proteins that block or reduce the activity of immune system machinery, resulting in improved translation (in the case of mRNA) and increased self-amplification and subsequent translation (in the case of saRNA systems), and therefore greater protein expression levels of the gene of interest, such as an antigen, in a host cell.

Accordingly, in a first aspect of the invention, there is provided an RNA construct encoding: (i) at least one therapeutic biomolecule; and (ii) at least one viral innate inhibitor protein (IIP).

RNA constructs, such as mRNA and saRNA replicons, have been postulated to be potential tools for the delivery and expression of genes of interest for vaccines and therapeutics. However, single stranded mRNA (ssRNA) and double stranded RNA (dsRNA) is detected intracellularly by innate sensing mechanisms that trigger responses, which inhibit protein translation. As a consequence, expression of genes of interest encoded by the RNA construct is significantly impaired and thus the immunogenic or therapeutic potential of RNA constructs, including saRNA and mRNA, is limited. Advantageously, the RNA constructs of the invention overcome this problem because they encode one or more viral innate inhibitor protein (IIP), which reduces or ablates the downstream innate inhibition of transgene expression within the host cell.

The induction of interferon is one downstream consequence of innate recognition, but it will be appreciated that other molecules and pathways can and are induced, as discussed below, and any of these will be inhibited by the one or more viral innate immunity inhibitor protein that is harboured on the RNA construct. Preferably, therefore, the at least one innate inhibitor protein (IIP) is capable of inhibiting the innate immune response to RNA in a subject treated with the RNA construct of the invention. The IIP can therefore be described as an inhibitor of innate immunity. It may also be described as an interferon inhibiting molecule in some embodiments.

One previously published approach to ablating the interferon response with saRNA used interferon inhibiting proteins from the vaccinia virus, E3, K3 and B18. However, in that study, the interferon inhibiting proteins were delivered and formulated as separate mRNA molecules that were combined with the saRNA. This requires the manufacture of both saRNA and mRNA, and necessitated the use of at least 3-6 times as much vaccinia mRNA as the saRNA replicon construct according to the invention to provide any observable enhancement in protein expression.

Advantageously, the presence, in the RNA construct of the first aspect, of one or more viral innate inhibitor protein, enables dual protein expression with the biotherapeutic molecule, i.e. a peptide or protein of interest. As opposed to delivering two different strands of RNA as described in the prior art, one encoding the peptide/protein of interest and one encoding the innate modulatory protein, when using the RNA construct of the invention, only one single strand is delivered to the target cell, thereby ensuring colocalization of the RNA molecule and the viral immune inhibitor protein.

The viral immune inhibitor protein inhibits the innate sensing of RNA in the host cell, thereby enabling higher protein expression and translation, and the viral immune inhibitor protein expression itself is co-expressed and translated from the same RNA molecule as the therapeutic biomolecule.

As described in the examples, the RNA constructs of the invention (also known as “Stealthicons”) encoding luciferase or VEGF-A (as a GOI) have surprisingly been shown to increase luciferase or VEGF-A protein expression levels by up to 12-fold in a human cell line with intact innate sensing systems in vitro. The skilled person would readily appreciate that the luciferase reporter is truly representative of the therapeutic biomolecule described herein (i.e. the GOI), because it proves that the RNA construct is able to express the gene harboured on the RNA molecule of the invention. As such, the luciferase provides robust evidence of the proof of concept that the RNA construct of the invention can be used to express any therapeutically active biomolecule. In addition, VEGF-A (see FIG. 11) represents an alternative exemplar to luciferase as the GOI.

The RNA construct of the first aspect may be single-stranded RNA or double-stranded RNA.

The RNA construct may comprise a mRNA molecule or a saRNA molecule.

In one embodiment, the RNA construct comprises mRNA. FIG. 1 (right hand side) illustrates various embodiments of the RNA construct as a mRNA molecule.

In a preferred embodiment, however, the RNA construct comprises self-amplifying RNA (saRNA). FIG. 1 (left hand side) illustrates various embodiments of the RNA construct as a saRNA molecule. The skilled person would understand that such an RNA construct can also be referred to as a self-replicating RNA virus vector, or an RNA replicon.

Preferably, the saRNA construct comprises or is derived from a positive stranded RNA virus selected from the group of genus consisting of: alphavirus; picornavirus; flavivirus; rubivirus; pestivirus; hepacivirus; calicivirus and coronavirus.

Preferably, the RNA construct comprises or is derived from an alphavirus. Suitable wild-type alphavirus sequences are well-known. Representative examples of suitable alphaviruses include Aura, Bebaru virus, Cabassou, Chikungunya virus, Eastern equine encephalomyelitis virus, Fort Morgan, Getah virus, Kyzylagach, Mayaro, Mayaro virus, Middleburg, Mucambo virus, Ndumu, Pixuna virus, Ross River virus, Semliki Forest, Sindbis virus, Tonate, Triniti, Una, Venezuelan equine encephalomyelitis, Western equine encephalomyelitis, Whataroa, and Y-62-33. Preferably, therefore, the RNA construct comprises or is derived from any of these alphaviruses.

Preferably, the RNA construct comprises or is derived from a virus selected from the group of species consisting of: Venezuelan Equine Encephalitis Virus (VEEV); enterovirus 71; Encephalomyocarditis virus; Kunjin virus; and Middle East respiratory syndrome virus. In one preferred embodiment, the RNA construct comprises or is derived from Kunjin virus. Preferably, the RNA construct comprises or is derived from VEEV.

Preferably, the RNA construct comprises a nucleotide sequence, which encodes the at least one innate inhibitor protein (IIP), which is capable of reducing, ablating or blocking the innate immune response to RNA. The IIP is, therefore, an inhibitor of innate immunity, and can therefore be described as a viral innate immunity inhibitor protein. The IIP may also be an inhibitor of interferon signalling.

The reduction, ablation or blocking of the innate immune response to RNA in a host cell transformed with that RNA molecule (i.e. non-endogenously produced RNA) may be achieved by the IIP regulating interferon production, inhibiting innate signalling pathways, and/or inhibiting RNA recognition. It will be appreciated that regulation of interferon production could be described as inhibiting innate signalling. Therefore, innate sensing and innate signalling systems include: (a) RNA recognition systems, (b) pathways leading to interferon production and resulting in stimulation of interferon-stimulated genes, and (c) interferon signalling systems.

The IIP may, therefore, fall into any of the following four broad categories:—

- (i) Category 1: Inhibitors of interferon regulatory factor activity;
- (ii) Category 2: Inhibitors of pathways leading to interferon production and resulting in stimulation of interferon-stimulated genes;
- (iii) Category 3: Inhibitors of interferon signalling; and/or
- (iv) Category 4: Inhibitors of RNA recognition systems.

It will be appreciated that some IIPs may have multiple actions. For instance, a Category 4 IIP may also be classified as a Category 2 IIP (e.g. IRF3, IRF7) and a Category 3 IIP (e.g. IRF9).

In one embodiment, the reduction, ablation or blocking of the innate immune response to RNA is preferably achieved by the IIP by reducing or preventing the recognition of cytosolic RNA by pattern recognition receptors leading to activation of interferon regulatory factor 3 and 7 (IRF3 and IRF7) and NF-κB transcription factors, directly triggering a range of antiviral genes (e.g. IFIT1-3, Mx1, Mx2 known to suppress RNA expression), proinflammatory genes whose products orchestrate the innate immune response, and direct activation of canonically IFN-stimulated genes (ISGs) upstream of any interferon dependent cascade. These pathways may be enhanced by the induction of type I & III interferons that provide a positive feedback loop further amplifying many antiviral responses.

The at least one IIP may be derived from a herpes simplex virus. The IIP may be derived from a hepatitis virus, optionally a hepatitis C virus. The IIP may be derived from a vaccinia virus. The IIP may be derived from a coronavirus, optionally Middle East Respiratory Syndrome (MERS) virus or Severe Acute Respiratory Syndrome (SARS) virus. The SARS virus may be SARS-Cov or SARS-CoV-2. The IIP may be derived from a Karposi's sarcoma-associated herpesvirus (KSHV). The IIP may be derived from an Ebola virus.

The at least one innate inhibitor protein (IIP) may be selected from a group of viral IIPs consisting of: HPV16 E6; HSV ICP34.5; HCV E2; HCV NS5a; VACV E3L; VACV K3L; MERS ORF8B; KSHV ORF52; EBOV VP35; SARS-2 ORF3b and VACV C6 or an orthologue thereof. It will be appreciated that these IIPs can bring about inhibition of innate signalling systems leading to IFN production.

In one embodiment, the at least one IIP may be HPV16 E6 (human papillomavirus E6; NP_041325.1; Accession Number—NCBI Reference Sequence: NC_001526.4; UniProtKB—P03126 (VE6_HPV16)), or an orthologue thereof. This protein is believed to prevent the establishment of a cellular antiviral state by acting on multiple proteins within the innate signalling cascade including PKR, IRF3 and IRF9. Westrich J A, Warren C J, Pyeon D. (2017). Evasion of host immune defenses by human papillomavirus. Virus Res. 2017 231, 21-33. doi: 10.1016/j.virusres.2016.11.023. Noguchi T, Satoh, S, Noshi T, Hatada E, Fukuda R, Kawai A, Ikeda S, Hijikata M. Shimotohno K (2001), Effects of Mutation in Hepatitis C Virus Nonstructural Protein 5A on Interferon Resistance Mediated by Inhibition of PKR Kinase Activity in Mammalian Cells, Microbiol. Immunol., 45-840. doi: 10.1111/j.1348-0421.2001.tbo1322.x.).

One embodiment of the HPV16 E6 polypeptide sequence is represented herein as SEQ ID No: 1, as follows:

[SEQ ID No: 1]

MHQKRTAMFQDPQERPRKLPQLCTELQTTIHDIILECVYCKQQLLRR

EVYDFAFRDLCIVYRDGNPYAVCDKCLKFYSKISEYRHYCYSLYGTT

LEQQYNKPLCDLLIRCINCQKPLCPEEKQRHLDKKQRFHNIRGRWTG

RCMSCCRSSRTRRETQL

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 1, or a variant or fragment thereof.

In one embodiment, the HPV16 E6 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 2, as follows:

[SEQ ID No: 2]

ATGCACCAAAAGAGAACTGCAATGTTTCAGGACCCACAGGAGCGACC

CAGAAAGTTACCACAGTTATGCACAGAGCTGCAAACAACTATACATG

ATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGACGT

GAGGTATATGACTTTGCTTTTCGGGATTTATGCATAGTATATAGAGA

TGGGAATCCATATGCTGTATGTGATAAATGTTTAAAGTTTTATTCTA

AAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACA

TTAGAACAGCAATACAACAAACCGTTGTGTGATTTGTTAATTAGGTG

TATTAACTGTCAAAAGCCACTGTGTCCTGAAGAAAAGCAAAGACATC

TGGACAAAAAGCAAAGATTCCATAATATAAGGGGTCGGTGGACCGGT

CGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCA

GCTG

Accordingly, preferably the HPV16 E6 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 2, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 3, as follows:

[SEQ ID No: 3]

AUGCACCAAAAGAGAACUGCAAUGUUUCAGGACCC

ACAGGAGCGACCCAGAAAGUUACCACAGUUAUGCA

CAGAGCUGCAAACAACUAUACAUGAUAUAAUAUUA

GAAUGUGUGUACUGCAAGCAACAGUUACUGCGACG

UGAGGUAUAUGACUUUGCUUUUCGGGAUUUAUGCA

UAGUAUAUAGAGAUGGGAAUCCAUAUGCUGUAUGU

GAUAAAUGUUUAAAGUUUUAUUCUAAAAUUAGUGA

GUAUAGACAUUAUUGUUAUAGUUUGUAUGGAACAA

CAUUAGAACAGCAAUACAACAAACCGUUGUGUGAU

UUGUUAAUUAGGUGUAUUAACUGUCAAAAGCCACU

GUGUCCUGAAGAAAAGCAAAGACAUCUGGACAAAA

AGCAAAGAUUCCAUAAUAUAAGGGGUCGGUGGACC

GGUCGAUGUAUGUCUUGUUGCAGAUCAUCAAGAAC

ACGUAGAGAAACCCAGCUG

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 3, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 1 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 4, as follows:

[SEQ ID No: 4]

ATGCACCAGAAACGGACCGCCATGTTCCAGGATCC

TCAAGAGAGGCCCAGAAAGCTGCCTCAGCTGTGTA

CCGAGCTGCAGACCACCATCCACGACATCATCCTG

GAATGCGTGTACTGCAAGCAGCAGCTCCTGCGGAG

AGAGGTGTACGATTTCGCCTTCCGGGACCTGTGCA

TCGTGTACAGAGATGGCAACCCCTACGCCGTGTGC

GACAAGTGCCTGAAGTTCTACAGCAAGATCAGCGA

GTACCGGCACTACTGCTACAGCCTGTACGGCACCA

CACTGGAACAGCAGTACAACAAGCCCCTGTGCGAC

CTGCTGATCCGGTGCATCAACTGCCAGAAACCTCT

GTGCCCCGAGGAAAAGCAGCGGCACCTGGACAAGA

AGCAGCGGTTCCACAACATCAGAGGCCGGTGGACC

GGCAGATGCATGAGCTGTTGTCGGAGCAGCAGAAC

CAGACGGGAAACCCAGCTGTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 4, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 4 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 5, as follows:

[SEQ ID No: 5]

AUGCACCAGAAACGGACCGCCAUGUUCCAGGAUCC

UCAAGAGAGGCCCAGAAAGCUGCCUCAGCUGUGUA

CCGAGCUGCAGACCACCAUCCACGACAUCAUCCUG

GAAUGCGUGUACUGCAAGCAGCAGCUCCUGCGGAG

AGAGGUGUACGAUUUCGCCUUCCGGGACCUGUGCA

UCGUGUACAGAGAUGGCAACCCCUACGCCGUGUGC

GACAAGUGCCUGAAGUUCUACAGCAAGAUCAGCGA

GUACCGGCACUACUGCUACAGCCUGUACGGCACCA

CACUGGAACAGCAGUACAACAAGCCCCUGUGCGAC

CUGCUGAUCCGGUGCAUCAACUGCCAGAAACCUCU

GUGCCCCGAGGAAAAGCAGCGGCACCUGGACAAGA

AGCAGCGGUUCCACAACAUCAGAGGCCGGUGGACC

GGCAGAUGCAUGAGCUGUUGUCGGAGCAGCAGAAC

CAGACGGGAAACCCAGCUGUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 5, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be HSV ICP34.5 (Herpes simplex virus ICP34.5; YP_009137073.1; Accession Number—NCBI Reference Sequence: NC_001806.2; UniProtKB—P36313 (ICP34_HHV11)), or an orthologue thereof. HSV ICP34.5 has been shown to sequester TBK1 and interfere with the interaction between TBK1 and IRF3, ultimately leading to the inactivation of IRF3. Zhu H, Zheng C (2020).

The race between host antiviral innate immunity and the immune evasion strategies of Herpes simplex virus 1. Microbiol Mol Biol Rev., 84(4): e00099-20. One embodiment of the HSV ICP34.5 polypeptide sequence is represented herein as SEQ ID No:6, as follows:

[SEQ ID No: 6]

MARRRRHRGPRRPRPPGPTGAVPTAQSQVTSTPNS

EPAVRSAPAAAPPPPPAGGPPPSCSLLLRQWLHVP

ESASDDDDDDDWPDSPPPEPAPEARPTAAAPRPRP

PPPGVGPGGGADPSHPPSRPFRLPPRLALRLRVTA

EHLARLRLRRAGGEGAPEPPATPATPATPATPATP

ARVRFSPHVRVRHLVVWASAARLARRGSWARERAD

RARFRRRVAEAEAVIGPCLGPEARARALARGAGPA

NSV

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 6, or a variant or fragment thereof.

In one embodiment, the HSV ICP34.5 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 7, as follows:

[SEQ ID No: 7]

ATGGCCCGCCGCCGCCGCCATCGCGGCCCCCGCCG

CCCCCGGCCGCCCGGGCCCACGGGCGCCGTCCCAA

CCGCACAGTCCCAGGTAACCTCCACGCCCAACTCG

GAACCCGCGGTCAGGAGCGCGCCCGCGGCCGCCCC

GCCGCCGCCCCCCGCCGGTGGGCCCCCGCCTTCTT

GTTCGCTGCTGCTGCGCCAGTGGCTCCACGTTCCC

GAGTCCGCGTCCGACGACGACGATGACGACGACTG

GCCGGACAGCCCCCCGCCCGAGCCGGCGCCAGAGG

CCCGGCCCACCGCCGCCGCCCCCCGGCCCCGGCCC

CCACCGCCCGGCGTGGGCCCGGGGGGCGGGGCTGA

CCCCTCCCACCCCCCCTCGCGCCCCTTCCGCCTTC

CGCCGCGCCTCGCCCTCCGCCTGCGCGTCACCGCG

GAGCACCTGGCGCGCCTGCGCCTGCGACGCGCGGG

CGGGGAGGGGGCGCCGGAGCCCCCCGCGACCCCCG

CGACCCCCGCGACCCCCGCGACCCCCGCGACCCCC

GCGCGGGTGCGCTTCTCGCCCCACGTCCGGGTGCG

CCACCTGGTGGTCTGGGCCTCGGCCGCCCGCCTGG

CGCGCCGCGGCTCGTGGGCCCGCGAGCGGGCCGAC

CGGGCTCGGTTCCGGCGCCGGGTGGCGGAGGCCGA

GGCGGTCATCGGGCCGTGCCTGGGGCCCGAGGCCC

GTGCCCGGGCCCTGGCCCGCGGAGCCGGCCCGGCG

AACTCGGTC

Accordingly, preferably the HSV ICP34.5 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 7, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 8, as follows:

[SEQ ID No: 8]

AUGGCCCGCCGCCGCCGCCAUCGCGGCCCCCGCCG

CCCCCGGCCGCCCGGGCCCACGGGCGCCGUCCCAA

CCGCACAGUCCCAGGUAACCUCCACGCCCAACUCG

GAACCCGCGGUCAGGAGCGCGCCCGCGGCCGCCCC

GCCGCCGCCCCCCGCCGGUGGGCCCCCGCCUUCUU

GUUCGCUGCUGCUGCGCCAGUGGCUCCACGUUCCC

GAGUCCGCGUCCGACGACGACGAUGACGACGACUG

GCCGGACAGCCCCCCGCCCGAGCCGGCGCCAGAGG

CCCGGCCCACCGCCGCCGCCCCCCGGCCCCGGCCC

CCACCGCCCGGCGUGGGCCCGGGGGGCGGGGCUGA

CCCCUCCCACCCCCCCUCGCGCCCCUUCCGCCUUC

CGCCGCGCCUCGCCCUCCGCCUGCGCGUCACCGCG

GAGCACCUGGCGCGCCUGCGCCUGCGACGCGCGGG

CGGGGAGGGGGCGCCGGAGCCCCCCGCGACCCCCG

CGACCCCCGCGACCCCCGCGACCCCCGCGACCCCC

GCGCGGGUGCGCUUCUCGCCCCACGUCCGGGUGCG

CCACCUGGUGGUCUGGGCCUCGGCCGCCCGCCUGG

CGCGCCGCGGCUCGUGGGCCCGCGAGCGGGCCGAC

CGGGCUCGGUUCCGGCGCCGGGUGGCGGAGGCCGA

GGCGGUCAUCGGGCCGUGCCUGGGGCCCGAGGCCC

GUGCCCGGGCCCUGGCCCGCGGAGCCGGCCCGGCG

AACUCGGUC

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 8, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 6 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 9, as follows:

[SEQ ID No: 9]

ATGGCCAGAAGAAGGCGGCACAGAGGACCCAGAAG

GCCTAGACCTCCTGGACCAACAGGTGCCGTTCCTA

CCGCTCAGAGCCAAGTGACCAGCACACCCAATTCT

GAACCTGCCGICAGAAGCGCCCCTGCTGCTGCTCC

TCCACCTCCACCAGCTGGCGGACCTCCACCTTCTT

GTTCTCTGCTGCTGAGACAGIGGCTGCACGTGCCA

GAGTCCGCCTCCGACGATGATGACGATGACGACTG

GCCTGACAGCCCTCCTCCAGAACCTGCTCCTGAAG

CCAGACCTACAGCCGCTGCTCCTAGACCTAGACCA

CCACCTCCAGGTGTTGGACCTGGTGGCGGAGCTGA

TCCTTCTCACCCTCCTAGCAGACCCTTCCGGCTTC

CTCCTAGACTGGCCCTGAGACTGAGAGTGACAGCC

GAACACCTGGCCAGACTGAGACTTCGTAGAGCAGG

CGGAGAAGGCGCTCCTGAACCTCCTGCTACACCAG

CCACACCAGCTACTCCCGCAACTCCTGCCACTCCT

GCTAGAGTGCGGTTTAGCCCTCACGTCCGCGTCAG

ACATCIGGTCGTTTGGGCCTCTGCTGCCCGGCTTG

CTAGAAGAGGATCTTGGGCCAGAGAGAGAGCCGAC

GGGCTAGAGCACTTGCTAGAGGIGCCGGACCTGCC

AACAGCGTGTGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 9, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 9 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 10, as follows:

[SEQ ID No: 10]

AUGGCCAGAAGAAGGCGGCACAGAGGACCCAGAAG

GCCUAGACCUCCUGGACCAACAGGUGCCGUUCCUA

CCGCUCAGAGCCAAGUGACCAGCACACCCAAUUCU

GAACCUGCCGUCAGAAGCGCCCCUGCUGCUGCUCC

UCCACCUCCACCAGCUGGCGGACCUCCACCUUCUU

GUUCUCUGCUGCUGAGACAGUGGCUGCACGUGCCA

GAGUCCGCCUCCGACGAUGAUGACGAUGACGACUG

GCCUGACAGCCCUCCUCCAGAACCUGCUCCUGAAG

CCAGACCUACAGCCGCUGCUCCUAGACCUAGACCA

CCACCUCCAGGUGUUGGACCUGGUGGCGGAGCUGA

UCCUUCUCACCCUCCUAGCAGACCCUUCCGGCUUC

CUCCUAGACUGGCCCUGAGACUGAGAGUGACAGCC

GAACACCUGGCCAGACUGAGACUUCGUAGAGCAGG

CGGAGAAGGCGCUCCUGAACCUCCUGCUACACCAG

CCACACCAGCUACUCCCGCAACUCCUGCCACUCCU

GCUAGAGUGCGGUUUAGCCCUCACGUCCGCGUCAG

ACAUCUGGUCGUUUGGGCCUCUGCUGCCCGGCUUG

CUAGAAGAGGAUCUUGGGCCAGAGAGAGAGCCGAC

CGGGCUAGAUUUCGGAGAAGAGUGGCCGAAGCCGA

GGCCGUGAUUGGACCUUGUCUUGGCCCUGAAGCUC

GGGCUAGAGCACUUGCUAGAGGUGCCGGACCUGCC

AACAGCGUGUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 10, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be HCV E2 (hepatitis C virus E2; NS1 Protein from polyprotein ADC54662.1; Accession Number—Genomic RNA Translation ADC54662.1; UniProtKB—D3W8R2 (D3W8R2_9HEPC)), or an orthologue thereof. One action of HCV E2 is to inhibit PKR. Taylor D R, Shi S T, Romano P R, Barber G N, Lai M M C (1999). Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science, 285, 107-110. doi: 10.1126/science.285.5424.107 One embodiment of the HCV E2 polypeptide sequence is represented herein as SEQ ID No:11, as follows:

[SEQ ID No: 11]

METHVTGGSAGHTVSGFVSLLAPGAKONVQLINTN

GSWHLNSTALNCNDSLNTGWLAGLFYHHKFNSSGC

PERLASCRPLTDFDQGWGPISYANGSGPDQRPYCW

HYPPKPCGIVPAKSVCGPVYCFTPSPVVVGTTDRS

GAPTYSWGENDTDVFVLNNTRPPLGNWFGCTWMNS

TGFTKVCGAPPCVIGGAGNNTLHCPTDCFRKHPDA

TYSRCGSGPWITPRCLVDYPYRLWHYPCTINYTIF

KIRMYVGGVEHRLEAACNWTRGERCDLEDRDRSEL

SPLLLTTTQWQVLPCSFTTLPALSTGLIHLHQNIV

DVQYLYGVGSSIASWAIKWEYVVLLFLLLADARVC

SCLWMMLLISQAEA

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 11, or a variant or fragment thereof.

In one embodiment, the HCV E2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 12, as follows:

[SEQ ID No: 12]

ATGGAAACCCACGTCACCGGGGGAAGTGCCGGCCA

CACTGIGTCTGGATTTGTTAGCCTCCTCGCACCAG

GCGCCAAGCAGAACGTCCAGCTGATCAACACCAAC

GGCAGTTGGCACCTCAATAGCACGGCCCTGAACTG

CAATGATAGCCTTAACACCGGCTGGTTAGCAGGGC

TTTTCTATCACCACAAGTTCAACTCTTCAGGCTGT

ACGGAAGCGGCCCCGACCAGCGCCCCTACTGCTGG

CACTACCCCCCTAAACCTTGCGGTGTTGTGCCCGC

GAAGAGTGTGIGTGGTCCGGTATATTGCTTCACTC

CCAGCCCCGTGGTGGTGGGAACGACCGACAGGTCG

GGCGCGCCTACCIACAGCIGGGGTGAAAATGATAC

GGACGTCTTCGTCCTTAACAATACCAGGCCACCGC

TGGGCAATTGGTTCGGTTGTACCTGGATGAACTCA

ACTGGATTCACCAAAGTGTGCGGAGCGCCTCCCTG

TGTCATCGGAGGGGCGGGCAACAACACCCTGCACT

GCCCCACTGATTGCTTCCGCAAGCATCCGGACGCC

ACATACTCTCGGTGCGGCTCCGGTCCCTGGATCAC

ACCCAGGTGCCTGGTCGACTACCCGTATAGGCTTT

GGCATTATCCTTGTACCATCAACTACACCATATTT

AAAATCAGGATGTACGTGGGAGGGGTCGAGCACAG

GCTGGAAGCTGCTTGCAACTGGACGCGGGGCGAAC

GTTGCGATCTGGAAGACAGGGACAGGTCCGAGCTC

AGCCCGTTACTGCTGACCACTACACAGTGGCAGGT

CCTCCCGTGTTCCTTCACAACCCTGCCAGCCTTGT

CCACCGGCCTCATCCACCTCCACCAGAACATTGTG

GACGTGCAGTACTTGTACGGGGTGGGGTCAAGCAT

CGCGTCCTGGGCCATTAAGTGGGAGTACGTCGTTC

TCCTGTTCCTTCTGCTTGCAGACGCGCGCGTCTGC

TCCTGCTTGTGGATGATGCTACTCATATCCCAAGC

GGAGGCG

Accordingly, preferably the HCV E2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 12, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 13, as follows:

[SEQ ID No: 13]

AUGGAAACCCACGUCACCGGGGGAAGUGCCGGCCA

CACUGUGUCUGGAUUUGUUAGCCUCCUCGCACCAG

GCGCCAAGCAGAACGUCCAGCUGAUCAACACCAAC

GGCAGUUGGCACCUCAAUAGCACGGCCCUGAACUG

CAAUGAUAGCCUUAACACCGGCUGGUUAGCAGGGC

UUUUCUAUCACCACAAGUUCAACUCUUCAGGCUGU

CCUGAGAGGCUAGCCAGCUGCCGACCCCUUACCGA

UUUUGACCAGGGCUGGGGCCCUAUCAGUUAUGCCA

ACGGAAGCGGCCCCGACCAGCGCCCCUACUGCUGG

CACUACCCCCCUAAACCUUGCGGUGUUGUGCCCGC

GAAGAGUGUGUGUGGUCCGGUAUAUUGCUUCACUC

CCAGCCCCGUGGUGGUGGGAACGACCGACAGGUCG

GGCGCGCCUACCUACAGCUGGGGUGAAAAUGAUAC

GGACGUCUUCGUCCUUAACAAUACCAGGCCACCGC

UGGGCAAUUGGUUCGGUUGUACCUGGAUGAACUCA

ACUGGAUUCACCAAAGUGUGCGGAGCGCCUCCCUG

UGUCAUCGGAGGGGCGGGCAACAACACCCUGCACU

GCCCCACUGAUUGCUUCCGCAAGCAUCCGGACGCC

ACAUACUCUCGGUGCGGCUCCGGUCCCUGGAUCAC

ACCCAGGUGCCUGGUCGACUACCCGUAUAGGCUUU

GGCAUUAUCCUUGUACCAUCAACUACACCAUAUUU

AAAAUCAGGAUGUACGUGGGAGGGGUCGAGCACAG

GCUGGAAGCUGCUUGCAACUGGACGCGGGGCGAAC

GUUGCGAUCUGGAAGACAGGGACAGGUCCGAGCUC

AGCCCGUUACUGCUGACCACUACACAGUGGCAGGU

CCUCCCGUGUUCCUUCACAACCCUGCCAGCCUUGU

CCACCGGCCUCAUCCACCUCCACCAGAACAUUGUG

GACGUGCAGUACUUGUACGGGGUGGGGUCAAGCAU

CGCGUCCUGGGCCAUUAAGUGGGAGUACGUCGUUC

UCCUGUUCCUUCUGCUUGCAGACGCGCGCGUCUGC

UCCUGCUUGUGGAUGAUGCUACUCAUAUCCCAAGC

GGAGGCG

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 13, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 11 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 14, as follows:

[SEQ ID No: 14]

ATGGAAACCCACGTGACAGGCGGATCTGCCGGCCA

TACAGTGTCCGGCTTTGTGTCTCTTCIGGCCCCTG

GCGCCAAGCAGAATGTGCAGCTGATCAACACCAAC

GGCAGCTGGCACCTGAACAGCACAGCCCTGAACTG

CAACGACAGCCTGAATACCGGATGGCTGGCCGGCC

TGTTCTACCACCACAAGTTCAATAGCAGCGGCTGC

CCCGAGAGACIGGCCTCTTGTAGACCTCTGACCGA

CTTCGATCAAGGCTGGGGCCCTATCAGCTACGCCA

ATGGCTCTGGACCTGACCAGAGGCCTTACTGCTGG

CACTACCCTCCAAAGCCTTGCGGAATCGTGCCTGC

CAAGTCTGTGTGTGGCCCCGTGTACTGCTTCACCC

CATCTCCAGTGGTCGTGGGCACCACCGATAGATCT

GGCGCCCCAACATATAGCIGGGGCGAGAACGACAC

CGACGTGTTCGTGCTGAACAACACCCGGCCTCCAC

TCGGAAATTGGTTCGGCTGCACCTGGATGAACTCC

ACCGGCTTCACAAAAGTGIGCGGAGCCCCTCCTTG

TGTGATTGGCGGAGCCGGAAACAATACCCTGCACT

GCCCTACCGACTGCTTCAGAAAGCACCCCGACGCC

ACCTACAGCAGATGTGGATCTGGCCCTTGGATCAC

CCCTAGATGCCTGGTGGACTACCCCTACCGGCTGT

GGCACTATCCCTGCACCATCAACTACACCATCTTC

AAGATCCGTATGTACGTCGGCGGCGTGGAACACAG

ACTGGAAGCCGCCTGTAACTGGACCAGGGGCGAGA

GATGCGACCTGGAAGATAGAGACAGAAGCGAGCTG

AGCCCTCTGCTGCTGACCACCACACAGTGGCAGGT

CCTGCCTTGCAGCTTCACCACACTGCCTGCTCTGA

GCACCGGCCTGATTCATCTGCACCAGAACATCGTG

GACGTGCAGTACCTGTACGGCGTGGGAAGCTCTAT

TGCCAGCTGGGCCATCAAGTGGGAGTACGTGGIGC

TGCTGTTCCTGCTGCIGGCCGATGCCAGAGIGTGT

AGCTGCCTGTGGATGATGCTGCTGATCTCTCAGGC

CGAGGCCTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 14, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 14 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 15, as follows:

[SEQ ID No: 15]

AUGGAAACCCACGUGACAGGCGGAUCUGCCGGCCA

UACAGUGUCCGGCUUUGUGUCUCUUCUGGCCCCUG

GCGCCAAGCAGAAUGUGCAGCUGAUCAACACCAAC

GGCAGCUGGCACCUGAACAGCACAGCCCUGAACUG

CAACGACAGCCUGAAUACCGGAUGGCUGGCCGGCC

UGUUCUACCACCACAAGUUCAAUAGCAGCGGCUGC

CCCGAGAGACUGGCCUCUUGUAGACCUCUGACCGA

CUUCGAUCAAGGCUGGGGCCCUAUCAGCUACGCCA

AUGGCUCUGGACCUGACCAGAGGCCUUACUGCUGG

CACUACCCUCCAAAGCCUUGCGGAAUCGUGCCUGC

CAAGUCUGUGUGUGGCCCCGUGUACUGCUUCACCC

CAUCUCCAGUGGUCGUGGGCACCACCGAUAGAUCU

GGCGCCCCAACAUAUAGCUGGGGCGAGAACGACAC

CGACGUGUUCGUGCUGAACAACACCCGGCCUCCAC

UCGGAAAUUGGUUCGGCUGCACCUGGAUGAACUCC

ACCGGCUUCACAAAAGUGUGCGGAGCCCCUCCUUG

UGUGAUUGGCGGAGCCGGAAACAAUACCCUGCACU

GCCCUACCGACUGCUUCAGAAAGCACCCCGACGCC

ACCUACAGCAGAUGUGGAUCUGGCCCUUGGAUCAC

CCCUAGAUGCCUGGUGGACUACCCCUACCGGCUGU

GGCACUAUCCCUGCACCAUCAACUACACCAUCUUC

AAGAUCCGUAUGUACGUCGGCGGCGUGGAACACAG

ACUGGAAGCCGCCUGUAACUGGACCAGGGGCGAGA

GAUGCGACCUGGAAGAUAGAGACAGAAGCGAGCUG

AGCCCUCUGCUGCUGACCACCACACAGUGGCAGGU

CCUGCCUUGCAGCUUCACCACACUGCCUGCUCUGA

GCACCGGCCUGAUUCAUCUGCACCAGAACAUCGUG

GACGUGCAGUACCUGUACGGCGUGGGAAGCUCUAU

UGCCAGCUGGGCCAUCAAGUGGGAGUACGUGGUGC

UGCUGUUCCUGCUGCUGGCCGAUGCCAGAGUGUGU

AGCUGCCUGUGGAUGAUGCUGCUGAUCUCUCAGGC

CGAGGCCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 15, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be HCV NS5a (hepatitis C virus NS5a; isolate H—Genomic RNA translation: AAA45534.1; UniProtKB—P27958 (POLG_HCV77)), or an orthologue thereof. One embodiment of the HCV NS5a polypeptide sequence is represented herein as SEQ ID No:16, as follows:

[SEQ ID No: 16]

MSGSWLRDIWDWICEVLSDFKTWLKAKLMPQLPGI

PFVSCQRGYRGVWRGDGIMHTRCHCGAEITGHVKN

GTMRIVGPRTCKNMWSGTFFINAYTTGPCTPLPAP

NYKFALWRVSAEEYVEIRRVGDFHYVSGMTTDNLK

CPCQIPSPEFFTELDGVRLHRFAPPCKPLLREEVS

FRVGLHEYPVGSQLPCEPEPDVAVLTSMLTDPSHI

TAEAAGRRLARGSPPSMASSSASQLSAPSLKATCT

ANHDSPDAELIEANLLWRQEMGGNITRVESENKVV

ILDSFDPLVAEEDEREVSVPAEILRKSRRFAPALP

VWARPDYNPLLVETWKKPDYEPPVVHGCPLPPPRS

PPVPPPRKKRTVVLTESTLPTALAELATKSFGSSS

TSGITGDNTTTSSEPAPSGCPPDSDVESYSSMPPL

EGEPGDPDLSDGSWSTVSSGADTEDVVCC

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 16, or a variant or fragment thereof.

In one embodiment, the HCV NS5a polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 17, as follows:

[SEQ ID No: 17]

ATGTCCGGTTCCTGGCTAAGGGACATCTGGGACTG

GATATGCGAGGTGCTGAGCGACTTTAAGACCTGGC

TGAAAGCCAAGCTCATGCCACAACTGCCTGGGATT

CCCTTTGTGTCCTGCCAGCGCGGGTATAGGGGGGT

CTGGCGAGGAGACGGCATTATGCACACTCGCTGCC

ACTGTGGAGCTGAGATCACTGGACATGTCAAAAAC

GGGACGATGAGGATCGTCGGTCCTAGGACCTGCAA

GAACATGTGGAGTGGGACGTTCTTCATTAATGCCT

ACACCACGGGCCCCTGTACTCCCCTTCCTGCGCCG

AACTATAAGTTCGCGCTGTGGAGGGIGTCTGCAGA

GGAATACGTGGAGATAAGGCGGGTGGGGGACTTCC

ACTACGTATCGGGCATGACTACTGACAATCTCAAA

TGCCCGTGCCAGATCCCATCGCCCGAATTTTTCAC

AGAATTGGACGGGGTGCGCCTACATAGGTTTGCGC

CCCCTTGCAAGCCCTTGCTGCGGGAGGAGGTATCA

TTCAGAGTAGGACTCCACGAGTACCCGGTGGGGTC

GCAATTACCTTGCGAGCCCGAACCGGACGTAGCCG

TGTTGACGTCCATGCTCACTGATCCCTCCCATATA

ACAGCAGAGGCGGCCGGGAGAAGGTTGGCGAGAGG

GTCACCCCCTTCTATGGCCAGCTCCTCGGCTAGCC

AGCTGTCCGCTCCATCTCTCAAGGCAACTTGCACC

GCCAACCATGACTCCCCTGACGCCGAGCTCATAGA

GGCTAACCTCCTGTGGAGGCAGGAGATGGGCGGCA

ACATCACCAGGGTTGAGTCAGAGAACAAAGTGGTG

ATTCTGGACTCCTTCGATCCGCTTGTGGCAGAGGA

GGATGAGCGGGAGGTCTCCGTACCCGCAGAAATTC

TGCGGAAGTCTCGGAGATTCGCCCCAGCCCTGCCC

GTCTGGGCGCGGCCGGACTACAACCCCCTGCTAGT

AGAGACGTGGAAAAAGCCTGACTACGAACCACCTG

IGGTCCATGGCTGCCCGCTACCACCTCCACGGTCC

CCTCCTGTGCCTCCGCCTCGGAAAAAGCGTACGGT

GGTCCTCACCGAATCAACCCTACCTACTGCCTTGG

CCGAGCTTGCCACCAAAAGTTTTGGCAGCTCCTCA

ACTTCCGGCATTACGGGCGACAATACGACAACATC

CTCTGAGCCCGCCCCTTCIGGCTGCCCCCCCGACT

CCGACGTTGAGTCCTATTCTTCCATGCCCCCCCTG

GAGGGGGAGCCIGGGGATCCGGATCTCAGCGACGG

GTCATGGTCGACGGTCAGTAGTGGGGCCGACACGG

AAGATGTCGTGTGCTGC

Accordingly, preferably the HCV NS5a polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 17, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 18, as follows:

[SEQ ID No: 18]

AUGUCCGGUUCCUGGCUAAGGGACAUCUGGGACUGGAUAUGCGAGGUGCU

GAGCGACUUUAAGACCUGGCUGAAAGCCAAGCUCAUGCCACAACUGCCUG

GGAUUCCCUUUGUGUCCUGCCAGCGCGGGUAUAGGGGGGUCUGGCGAGGA

GACGGCAUUAUGCACACUCGCUGCCACUGUGGAGCUGAGAUCACUGGACA

UGUCAAAAACGGGACGAUGAGGAUCGUCGGUCCUAGGACCUGCAAGAACA

UGUGGAGUGGGACGUUCUUCAUUAAUGCCUACACCACGGGCCCCUGUACU

CCCCUUCCUGCGCCGAACUAUAAGUUCGCGCUGUGGAGGGUGUCUGCAGA

GGAAUACGUGGAGAUAAGGCGGGUGGGGGACUUCCACUACGUAUCGGGCA

UGACUACUGACAAUCUCAAAUGCCCGUGCCAGAUCCCAUCGCCCGAAUUU

UUCACAGAAUUGGACGGGGUGCGCCUACAUAGGUUUGCGCCCCCUUGCAA

GCCCUUGCUGCGGGAGGAGGUAUCAUUCAGAGUAGGACUCCACGAGUACC

CGGUGGGGUCGCAAUUACCUUGCGAGCCCGAACCGGACGUAGCCGUGUUG

ACGUCCAUGCUCACUGAUCCCUCCCAUAUAACAGCAGAGGCGGCCGGGAG

AAGGUUGGCGAGAGGGUCACCCCCUUCUAUGGCCAGCUCCUCGGCUAGCC

AGCUGUCCGCUCCAUCUCUCAAGGCAACUUGCACCGCCAACCAUGACUCC

CCUGACGCCGAGCUCAUAGAGGCUAACCUCCUGUGGAGGCAGGAGAUGGG

CGGCAACAUCACCAGGGUUGAGUCAGAGAACAAAGUGGUGAUUCUGGACU

CCUUCGAUCCGCUUGUGGCAGAGGAGGAUGAGCGGGAGGUCUCCGUACCC

GCAGAAAUUCUGCGGAAGUCUCGGAGAUUCGCCCCAGCCCUGCCCGUCUG

GGCGCGGCCGGACUACAACCCCCUGCUAGUAGAGACGUGGAAAAAGCCUG

ACUACGAACCACCUGUGGUCCAUGGCUGCCCGCUACCACCUCCACGGUCC

CCUCCUGUGCCUCCGCCUCGGAAAAAGCGUACGGUGGUCCUCACCGAAUC

AACCCUACCUACUGCCUUGGCCGAGCUUGCCACCAAAAGUUUUGGCAGCU

CCUCAACUUCCGGCAUUACGGGCGACAAUACGACAACAUCCUCUGAGCCC

GCCCCUUCUGGCUGCCCCCCCGACUCCGACGUUGAGUCCUAUUCUUCCAU

GCCCCCCCUGGAGGGGGAGCCUGGGGAUCCGGAUCUCAGCGACGGGUCAU

GGUCGACGGUCAGUAGUGGGGCCGACACGGAAGAUGUCGUGUGCUGC

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 18, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 16 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 19, as follows:

[SEQ ID No: 19]

ATGTCTGGCAGCTGGCTGAGAGACATCTGGGACTGGATTTGCGAGGTGCT

GAGCGACTTCAAGACCTGGCTGAAGGCCAAGCTGATGCCTCAGCTGCCTG

GCATCCCTTTCGTGTCCTGTCAGAGGGGCTATAGAGGCGTTTGGAGAGGC

GACGGCATCATGCACACCAGATGTCACTGTGGCGCCGAGATCACAGGCCA

CGTGAAGAACGGCACCATGAGAATCGTGGGCCCCAGAACCTGCAAGAATA

TGTGGAGCGGCACCTTCTTCATCAACGCCTACACCACCGGACCTTGCACA

CCTCTGCCTGCTCCTAACTACAAGTTCGCCCTGTGGCGGGTGTCCGCCGA

GGAATACGTGGAAATCAGAAGAGTGGGCGACTTCCACTACGTGTCCGGCA

TGACCACCGACAACCTGAAGTGCCCCTGTCAGATCCCATCTCCTGAGTTC

TTCACCGAGCTGGATGGCGTGCGGCTGCACAGATTTGCCCCTCCATGTAA

ACCCCTGCTGAGAGAAGAGGTGTCCTTTAGAGTGGGCCTGCACGAGTACC

CTGTGGGTTCTCAGCTCCCTTGCGAGCCTGAACCTGATGTGGCCGTGCTG

ACCTCCATGCTGACAGACCCTTCTCACATCACAGCCGAGGCCGCTGGAAG

AAGGCTGGCTAGAGGATCTCCTCCTAGCATGGCCTCTAGCAGCGCCTCTC

AACTGTCTGCCCCAAGCCTGAAAGCCACCTGTACCGCCAATCACGACAGC

CCTGATGCCGAGCTGATCGAGGCTAACCTGCTGTGGCGGCAAGAGATGGG

CGGCAACATCACCAGAGTGGAAAGCGAGAACAAGGTGGTCATCCTGGATA

GCTTCGACCCTCTGGTGGCCGAAGAGGACGAGAGGGAAGTGTCTGTGCCT

GCCGAGATCCTGAGAAAGAGCAGAAGATTCGCCCCTGCTCTGCCCGTGTG

GGCCAGACCTGATTACAATCCCCTGCTGGTGGAAACATGGAAGAAGCCCG

ACTACGAGCCTCCTGTGGTGCACGGATGTCCACTGCCTCCACCTAGATCT

CCACCTGTGCCACCTCCACGGAAGAAAAGAACCGTGGTGCTGACCGAGAG

CACCCTGCCTACAGCTCTGGCTGAGCTGGCCACAAAGAGCTTTGGCAGCA

GCAGCACCTCTGGCATCACCGGCGATAATACCACCACCAGCTCTGAGCCT

GCTCCAAGCGGATGTCCTCCTGACTCCGACGTGGAAAGCTACAGCAGCAT

GCCTCCTCTGGAAGGCGAACCCGGCGATCCTGATCTGTCTGATGGCTCTT

GGAGCACCGTGTCCTCTGGCGCCGATACAGAGGATGTCGTGTGCTGCTGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 19, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 19 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 20, as follows:

[SEQ ID No: 20]

AUGUCUGGCAGCUGGCUGAGAGACAUCUGGGACUGGAUUUGCGAGGUGCU

GAGCGACUUCAAGACCUGGCUGAAGGCCAAGCUGAUGCCUCAGCUGCCUG

GCAUCCCUUUCGUGUCCUGUCAGAGGGGCUAUAGAGGCGUUUGGAGAGGC

GACGGCAUCAUGCACACCAGAUGUCACUGUGGCGCCGAGAUCACAGGCCA

CGUGAAGAACGGCACCAUGAGAAUCGUGGGCCCCAGAACCUGCAAGAAUA

UGUGGAGCGGCACCUUCUUCAUCAACGCCUACACCACCGGACCUUGCACA

CCUCUGCCUGCUCCUAACUACAAGUUCGCCCUGUGGCGGGUGUCCGCCGA

GGAAUACGUGGAAAUCAGAAGAGUGGGCGACUUCCACUACGUGUCCGGCA

UGACCACCGACAACCUGAAGUGCCCCUGUCAGAUCCCAUCUCCUGAGUUC

UUCACCGAGCUGGAUGGCGUGCGGCUGCACAGAUUUGCCCCUCCAUGUAA

ACCCCUGCUGAGAGAAGAGGUGUCCUUUAGAGUGGGCCUGCACGAGUACC

CUGUGGGUUCUCAGCUCCCUUGCGAGCCUGAACCUGAUGUGGCCGUGCUG

ACCUCCAUGCUGACAGACCCUUCUCACAUCACAGCCGAGGCCGCUGGAAG

AAGGCUGGCUAGAGGAUCUCCUCCUAGCAUGGCCUCUAGCAGCGCCUCUC

AACUGUCUGCCCCAAGCCUGAAAGCCACCUGUACCGCCAAUCACGACAGC

CCUGAUGCCGAGCUGAUCGAGGCUAACCUGCUGUGGCGGCAAGAGAUGGG

CGGCAACAUCACCAGAGUGGAAAGCGAGAACAAGGUGGUCAUCCUGGAUA

GCUUCGACCCUCUGGUGGCCGAAGAGGACGAGAGGGAAGUGUCUGUGCCU

GCCGAGAUCCUGAGAAAGAGCAGAAGAUUCGCCCCUGCUCUGCCCGUGUG

GGCCAGACCUGAUUACAAUCCCCUGCUGGUGGAAACAUGGAAGAAGCCCG

ACUACGAGCCUCCUGUGGUGCACGGAUGUCCACUGCCUCCACCUAGAUCU

CCACCUGUGCCACCUCCACGGAAGAAAAGAACCGUGGUGCUGACCGAGAG

CACCCUGCCUACAGCUCUGGCUGAGCUGGCCACAAAGAGCUUUGGCAGCA

GCAGCACCUCUGGCAUCACCGGCGAUAAUACCACCACCAGCUCUGAGCCU

GCUCCAAGCGGAUGUCCUCCUGACUCCGACGUGGAAAGCUACAGCAGCAU

GCCUCCUCUGGAAGGCGAACCCGGCGAUCCUGAUCUGUCUGAUGGCUCUU

GGAGCACCGUGUCCUCUGGCGCCGAUACAGAGGAUGUCGUGUGCUGCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 20, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be VACV E3L (vaccinia virus E3L; AEY72868.1; Accession Number—Genomic DNA Translation: AEY72868.1; UniProtKB—H2DSW3 (H2DSW3_9POXV)), or an orthologue thereof. VACV E3L would inhibit innate sensing systems through inhibition of PKR and IRF3 and 7 Perdiuero B, Esteban M (2009) The interferon system and vaccinia virus evasion mechanisms. J Interferon Cytokine Res, 29, 9, 581-198.

One embodiment of the VACV E3L polypeptide sequence is represented herein as SEQ ID No:21, as follows:

[SEQ ID No: 21]

MSKIYIDERSDAEIVCAAIKNIGIEGATAAQLTRQLNMEKREVNKALYDL

QRSAMVYSSDDIPPRWFMTTEADKPDADAMADVIIDDVSREKSMREDHKS

FDDVIPAKKIIDWKDANPVTIINEYCQITKRDWSFRIESVGPSNSPTFYA

CVDIDGRVFDKADGKSKRDAKNNAAKLAVDKLLGYVIIRF

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 21, or a variant or fragment thereof.

In one embodiment, the VACV E3L polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 22, as follows:

[SEQ ID No: 22]

ATGTCTAAGATCTATATCGACGAGCGTTCTGACGCAGAGATTGTGTGTGC

GGCTATTAAAAACATTGGAATCGAAGGAGCTACTGCTGCACAACTAACTA

GACAACTTAATATGGAGAAGCGAGAAGTTAATAAAGCTCTGTACGATCTT

CAACGTAGTGCTATGGTGTACAGCTCCGACGATATTCCTCCTCGTTGGTT

TATGACAACGGAGGCGGATAAGCCGGATGCTGATGCTATGGCTGACGTCA

TAATAGATGATGTATCCCGCGAAAAATCAATGAGAGAGGATCATAAGTCT

TTTGATGATGTTATTCCGGCTAAAAAAATTATTGATTGGAAAGATGCTAA

CCCTGTCACCATTATTAATGAGTACTGCCAAATAACTAAGAGAGATTGGT

CTTTTCGTATTGAATCAGTTGGGCCTAGTAACTCTCCTACATTTTATGCC

TGTGTAGATATCGACGGAAGAGTATTCGATAAGGCCGATGGAAAATCTAA

ACGAGATGCTAAAAATAATGCAGCTAAATTGGCTGTAGATAAACTTCTTG

GGTACGTCATCATTAGATTC

Accordingly, preferably the VACV E3L polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 22, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 23, as follows:

[SEQ ID No: 23]

AUGUCUAAGAUCUAUAUCGACGAGCGUUCUGACGCAGAGAUUGUGUGUGC

GGCUAUUAAAAACAUUGGAAUCGAAGGAGCUACUGCUGCACAACUAACUA

GACAACUUAAUAUGGAGAAGCGAGAAGUUAAUAAAGCUCUGUACGAUCUU

CAACGUAGUGCUAUGGUGUACAGCUCCGACGAUAUUCCUCCUCGUUGGUU

UAUGACAACGGAGGCGGAUAAGCCGGAUGCUGAUGCUAUGGCUGACGUCA

UAAUAGAUGAUGUAUCCCGCGAAAAAUCAAUGAGAGAGGAUCAUAAGUCU

UUUGAUGAUGUUAUUCCGGCUAAAAAAAUUAUUGAUUGGAAAGAUGCUAA

CCCUGUCACCAUUAUUAAUGAGUACUGCCAAAUAACUAAGAGAGAUUGGU

CUUUUCGUAUUGAAUCAGUUGGGCCUAGUAACUCUCCUACAUUUUAUGCC

UGUGUAGAUAUCGACGGAAGAGUAUUCGAUAAGGCCGAUGGAAAAUCUAA

ACGAGAUGCUAAAAAUAAUGCAGCUAAAUUGGCUGUAGAUAAACUUCUUG

GGUACGUCAUCAUUAGAUUC

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 23, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 21 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 24, as follows:

[SEQ ID No: 24]

ATGAGCAAGATCTACATCGACGAGCGGAGCGACGCCGAGATTGTGTGTGC

CGCCATCAAGAACATCGGCATCGAAGGCGCTACAGCCGCTCAGCTGACCA

GACAGCTGAACATGGAAAAGCGGGAAGTGAACAAGGCCCTGTACGACCTG

CAGAGAAGCGCCATGGTGTACAGCAGCGACGACATCCCTCCTCGGTGGTT

TATGACCACAGAGGCCGACAAGCCCGACGCCGATGCTATGGCCGATGTGA

TCATCGACGACGTGTCCCGCGAGAAGTCCATGAGAGAGGACCACAAGAGC

TTCGATGACGTGATCCCCGCCAAGAAGATCATCGATTGGAAGGACGCCAA

TCCTGTGACCATCATCAACGAGTACTGCCAGATCACCAAGCGCGACTGGT

CCTTCAGAATCGAGAGCGTGGGCCCCAGCAACAGCCCTACCTTTTATGCC

TGCGTGGACATCGACGGCCGGGTGTTCGATAAGGCCGATGGCAAGAGCAA

GCGGGACGCCAAAAACAACGCCGCCAAACTGGCCGTGGATAAGCTGCTGG

GCTACGTGATCATCCGGTTCTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 24, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 24 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 25, as follows:

[SEQ ID No: 25]

AUGAGCAAGAUCUACAUCGACGAGCGGAGCGACGCCGAGAUUGUGUGUGC

CGCCAUCAAGAACAUCGGCAUCGAAGGCGCUACAGCCGCUCAGCUGACCA

GACAGCUGAACAUGGAAAAGCGGGAAGUGAACAAGGCCCUGUACGACCUG

CAGAGAAGCGCCAUGGUGUACAGCAGCGACGACAUCCCUCCUCGGUGGUU

UAUGACCACAGAGGCCGACAAGCCCGACGCCGAUGCUAUGGCCGAUGUGA

UCAUCGACGACGUGUCCCGCGAGAAGUCCAUGAGAGAGGACCACAAGAGC

UUCGAUGACGUGAUCCCCGCCAAGAAGAUCAUCGAUUGGAAGGACGCCAA

UCCUGUGACCAUCAUCAACGAGUACUGCCAGAUCACCAAGCGCGACUGGU

CCUUCAGAAUCGAGAGCGUGGGCCCCAGCAACAGCCCUACCUUUUAUGCC

UGCGUGGACAUCGACGGCCGGGUGUUCGAUAAGGCCGAUGGCAAGAGCAA

GCGGGACGCCAAAAACAACGCCGCCAAACUGGCCGUGGAUAAGCUGCUGG

GCUACGUGAUCAUCCGGUUCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 25, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be VACV K3L (vaccinia virus K3L; P20639.1; Accession Number—Genomic DNA Translation: AAA48009.1; UniProtKB—P20639 (K3_VACCC)), or an orthologue thereof. VACV K3L inhibits PKR. Perdiuero B, Esteban M (2009) The interferon system and vaccinia virus evasion mechanisms. J Interferon Cytokine Res, 29, 9, 581-198. One embodiment of the VACV K3L polypeptide sequence is represented herein as SEQ ID No:26, as follows:

[SEQ ID No: 26]

MLAFCYSLPNAGDVIKGRVYEKDYALYIYLFDYPHSEAILAESVKMHMDR

YVEYRDKLVGKTVKVKVIRVDYTKGYIDVNYKRMCRHQ

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 26, or a variant or fragment thereof.

In one embodiment, the VACV K3L polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 27, as follows:

[SEQ ID No: 27]

ATGCTTGCATTTTGTTATTCGTTGCCCAATGCGGGCGATGTAATAAAGGG

CAGAGTATACGAGAAGGATTATGCTCTATACATTTATCTTTTTGACTATC

CTCACTCTGAAGCTATCTTGGCAGAGAGTGTTAAGATGCATATGGATAGA

TATGTTGAATATAGGGATAAACTGGTAGGGAAAACTGTAAAAGTTAAAGT

GATTAGAGTTGATTATACAAAAGGATATATAGATGTCAATTACAAAAGGA

TGTGTAGACATCAA

Accordingly, preferably the VACV K3L polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 27, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 28, as follows:

[SEQ ID No: 28]

AUGCUUGCAUUUUGUUAUUCGUUGCCCAAUGCGGGCGAUGUAAUAAAGGG

CAGAGUAUACGAGAAGGAUUAUGCUCUAUACAUUUAUCUUUUUGACUAUC

CUCACUCUGAAGCUAUCUUGGCAGAGAGUGUUAAGAUGCAUAUGGAUAGA

UAUGUUGAAUAUAGGGAUAAACUGGUAGGGAAAACUGUAAAAGUUAAAGU

GAUUAGAGUUGAUUAUACAAAAGGAUAUAUAGAUGUCAAUUACAAAAGGA

UGUGUAGACAUCAA

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 28, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 26 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 29, as follows:

[SEQ ID No: 29]

ATGCTGGCCTTCTGCTACAGCCTGCCTAATGCCGGCGACGTGATCAAGGG

CAGAGTGTACGAGAAGGACTACGCCCTGTACATCTACCTGTTCGACTACC

CTCACAGCGAGGCCATCCTGGCCGAGTCTGTGAAGATGCACATGGACAGA

TACGTGGAATACCGGGACAAGCTCGTGGGCAAGACCGTGAAAGTGAAAGT

CATCAGAGTGGACTACACCAAGGGCTACATCGACGTGAACTACAAGCGGA

TGTGCAGGCACCAGTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 29, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 29 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 30, as follows:

[SEQ ID No: 30]

AUGCUGGCCUUCUGCUACAGCCUGCCUAAUGCCGGCGACGUGAUCAAGGG

CAGAGUGUACGAGAAGGACUACGCCCUGUACAUCUACCUGUUCGACUACC

CUCACAGCGAGGCCAUCCUGGCCGAGUCUGUGAAGAUGCACAUGGACAGA

UACGUGGAAUACCGGGACAAGCUCGUGGGCAAGACCGUGAAAGUGAAAGU

CAUCAGAGUGGACUACACCAAGGGCUACAUCGACGUGAACUACAAGCGGA

UGUGCAGGCACCAGUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 30, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be Vaccinia C6 (VACV C6—vaccinia virus C6; Accession Number—Genomic DNA Translation: AAA69602.1; UniProtKB—P17362 (C6_VACCW)), or an orthologue thereof. This protein is believed to prevent the establishment of a cellular antiviral state by blocking virus-induced phosphorylation and activation of interferon regulatory factors 3/IRF3 and 7/IRF7, transcription factors critical for the induction of interferons alpha and beta. This blockage may be produced through the inhibition of host TBK1, by binding host TBK1 adapter proteins TBKBP1 and AZI2, thereby producing a strong inhibition of the phosphorylation and activation of IRF3 and IRF7. It may also act as an inhibitor of the cellular response to type I IFN by interacting with host STAT2. Mechanistically, it may further exert its inhibitory effect after host ISGF3 complex (composed of STAT1. STAT2 and IRF9) binding to the interferon stimulated response element (Smith G L. Vaccinia Virus Protein C6: A Multifunctional Interferon Antagonist. Adv Exp Med Biol. 2018; 1052:1-7. doi: 10.1007/978-981-10-7572-8_1. PMID: 29785476.). One embodiment of the Vaccinia C6 polypeptide sequence is represented herein as SEQ ID No:31, as follows:

[SEQ ID No: 31]

MNAYNKADSFSLESDSIKDVIHDYICWLSMTDEMRPSIGNVFKAMETFKI

DAVRYYDGNIYELAKDINAMSFDGFIRSLQTIASKKDKLTVYGTMGLLSI

VVDINKGCDISNIKFAAGIIILMEYIFDDTDMSHLKVALYRRIQRRDDVD

R

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 31, or a variant or fragment thereof.

In one embodiment, the Vaccinia C6 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 32, as follows:

[SEQ ID No: 32]

ATGAATGCGTATAATAAAGCCGATTCGTTTTCTTTAGAGTCTGATTCTAT

CAAAGATGTTATACACGATTATATTTGTTGGCTCAGTATGACTGATGAAA

TGAGACCATCTATCGGAAACGTCTTTAAAGCGATGGAAACGTTTAAGATA

GACGCGGTTAGATATTACGATGGTAACATATATGAATTAGCTAAAGATAT

AAATGCGATGTCGTTTGACGGTTTTATAAGATCTCTACAAACTATCGCTT

CAAAGAAAGATAAACTCACTGTTTATGGAACCATGGGACTGCTGTCTATT

GTCGTAGATATTAACAAAGGTTGTGATATATCCAATATCAAGTTCGCTGC

CGGAATAATCATTTTAATGGAGTATATTTTTGATGACACGGATATGTCTC

ATCTTAAAGTAGCACTCTATCGTAGAATACAGAGACGTGATGATGTAGAT

AGA

Accordingly, preferably the Vaccinia C6 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 32, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 33, as follows:

[SEQ ID No: 33]

AUGAAUGCGUAUAAUAAAGCCGAUUCGUUUUCUUUAGAGUCUGAUUCUAU

CAAAGAUGUUAUACACGAUUAUAUUUGUUGGCUCAGUAUGACUGAUGAAA

UGAGACCAUCUAUCGGAAACGUCUUUAAAGCGAUGGAAACGUUUAAGAUA

GACGCGGUUAGAUAUUACGAUGGUAACAUAUAUGAAUUAGCUAAAGAUAU

AAAUGCGAUGUCGUUUGACGGUUUUAUAAGAUCUCUACAAACUAUCGCUU

CAAAGAAAGAUAAACUCACUGUUUAUGGAACCAUGGGACUGCUGUCUAUU

GUCGUAGAUAUUAACAAAGGUUGUGAUAUAUCCAAUAUCAAGUUCGCUGC

CGGAAUAAUCAUUUUAAUGGAGUAUAUUUUUGAUGACACGGAUAUGUCUC

AUCUUAAAGUAGCACUCUAUCGUAGAAUACAGAGACGUGAUGAUGUAGAU

AGA

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 33, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 31 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 34, as follows:

[SEQ ID No: 34]

ATGAACGCCTACAACAAGGCCGACAGCTTCAGCCTGGAAAGCGACAGCAT

CAAGGACGTGATCCACGACTACATCTGCTGGCTGAGCATGACCGACGAGA

TGAGGCCCAGCATCGGCAACGTGTTCAAGGCCATGGAAACCTTCAAGATC

GACGCCGTGCGGTACTACGACGGCAACATCTATGAGCTGGCCAAGGACAT

CAACGCCATGAGCTTCGACGGCTTCATCAGAAGCCTGCAGACAATCGCCA

GCAAGAAAGACAAGCTGACCGTGTACGGCACCATGGGCCTGCTGTCTATC

GTGGTGGATATCAACAAGGGCTGCGACATCAGCAACATCAAGTTCGCCGC

TGGCATCATCATCCTGATGGAGTACATCTTCGACGACACCGACATGAGCC

ACCTGAAGGTGGCCCTGTACAGAAGAATCCAGCGGAGGGACGACGTGGAC

AGATGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 34, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 34 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 35, as follows:

[SEQ ID No: 35]

AUGAACGCCUACAACAAGGCCGACAGCUUCAGCCUGGAAAGCGACAGCAU

CAAGGACGUGAUCCACGACUACAUCUGCUGGCUGAGCAUGACCGACGAGA

UGAGGCCCAGCAUCGGCAACGUGUUCAAGGCCAUGGAAACCUUCAAGAUC

GACGCCGUGCGGUACUACGACGGCAACAUCUAUGAGCUGGCCAAGGACAU

CAACGCCAUGAGCUUCGACGGCUUCAUCAGAAGCCUGCAGACAAUCGCCA

GCAAGAAAGACAAGCUGACCGUGUACGGCACCAUGGGCCUGCUGUCUAUC

GUGGUGGAUAUCAACAAGGGCUGCGACAUCAGCAACAUCAAGUUCGCCGC

UGGCAUCAUCAUCCUGAUGGAGUACAUCUUCGACGACACCGACAUGAGCC

ACCUGAAGGUGGCCCUGUACAGAAGAAUCCAGCGGAGGGACGACGUGGAC

AGAUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 35, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be MERS ORF8b (Middle East Respiratory Syndrome virus ORF8b; Accession Number—GenBank: ANF29170.1; UniProtKB—A0A1W5LGP6 (A0A1W5LGP6_MERS)), or an orthologue thereof. MERS ORF8b is believed to be an antagonist of MDA5-mediated NF-κB activation and IRF3 activation. (Lee J-Y, Bae S, Myoung J (2019) Middle East Respiratory Syndrome Coronavirus-Encoded Accessory Proteins Impair MDA5- and TBK1-Mediated Activation of NF-κB. J Microbiol Biotechnol, 29, 8,1316-1323 doi: 10.4014/jmb.1908.08004. Wong, L-yR, Ye Z W, Lui P-Y, Zheng X, Yuan S, Zhu L, Fung S-Y et al. (2020) Middle East respiratory syndrome coronavirus ORF8b accessory protein suppresses type I IFN expression by impeding HSP70-dependent activation of IRF3 kinase IKK€. J Immunol, 205, 6, 1564-1579).

One embodiment of the MERS ORF8b polypeptide sequence is represented herein as SEQ ID No:36, as follows:

[SEQ ID No: 36]

MPIPPLRKMLGIGGDRTEKLIPGMELSNWLPGGTSTTLELDPKQHSHSGL

LRMASFGSMKMAPLMLLQLLGRGTLTMIQLLLHNSRPVLSFLKTSTLRGL

EAIVNHLQEPLAQAETLPDLVHKVQDQETLPAALLQVHLESEQ

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 36, or a variant or fragment thereof.

In one embodiment, the MERS ORF8b polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 37, as follows:

[SEQ ID No: 37]

ATGCCAATTCCACCCCTGCGCAAAATGCTGGGTATTGGCGGAGACAGGAC

AGAAAAATTAATACCGGGAATTCCGGGCTGTTAAGGATGGCATCGTTTGG

GTCCATGAAGATGGCGCCACTGATGCTCCTTCAACTTTTGGGACGCGGAA

CCCTAACAATGATTCAGCTATTGTTACACAATTCGCGCCCGGTACTAAGC

TTCCTAAAAACTTCCACATTGAGGGGACTGGAGGCAATAGTCAATCATCT

TCAAGAGCCTCTAGCGCAAGCAGAAACTCTTCCAGATCTAGTTCACAAGG

TTCAAGATCAGGAAACTCTACCCGCGGCACTTCTCCAGGTCCATCTGGAA

TCGGAGCAG

Accordingly, preferably the MERS ORF8b polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 37, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 38, as follows:

[SEQ ID No: 38]

AUGCCAAUUCCACCCCUGCGCAAAAUGCUGGGUAUUGGCGGAGACAGGAC

AGAAAAAUUAAUACCGGGAAUGGAAUUAAGCAACUGGCUCCCAGGUGGUA

CUUCUACUACACUGGAACUGGACCCGAAGCAGCACUCCCAUUCCGGGCUG

UUAAGGAUGGCAUCGUUUGGGUCCAUGAAGAUGGCGCCACUGAUGCUCCU

UCAACUUUUGGGACGCGGAACCCUAACAAUGAUUCAGCUAUUGUUACACA

AUUCGCGCCCGGUACUAAGCUUCCUAAAAACUUCCACAUUGAGGGGACUG

GAGGCAAUAGUCAAUCAUCUUCAAGAGCCUCUAGCGCAAGCAGAAACUCU

UCCAGAUCUAGUUCACAAGGUUCAAGAUCAGGAAACUCUACCCGCGGCAC

UUCUCCAGGUCCAUCUGGAAUCGGAGCAG

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 38, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 36 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 39, as follows:

[SEQ ID No: 39]

ATGCCCATTCCTCCACTGAGAAAGATGCTCGGCATCGGCGGCGACAGAAC

CGAGAAGCTGATCCCTGGCATGGAACTGAGCAACTGGCTGCCTGGCGGCA

CCAGCACAACACTGGAACTGGATCCTAAGCAGCACAGCCACAGCGGCCTG

CTGAGAATGGCCAGCTTTGGCAGCATGAAGATGGCCCCTCTGATGCTGCT

GCAGCTGCTCGGAAGAGGCACCCTGACAATGATCCAGCTGCTGCTCCACA

ACAGCAGACCCGTGCTGAGCTTCCTGAAAACCAGCACACTGAGAGGCCTG

GAAGCCATCGTGAACCATCTGCAAGAGCCCCTGGCTCAGGCCGAGACACT

GCCTGATCTGGTGCACAAGGIGCAGGACCAAGAAACCCTGCCTGCCGCTC

TGCTGCAGGTCCACCTGGAATCTGAGCAGTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 39, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 39 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 40, as follows:

[SEQ ID No: 40]

AUGCCCAUUCCUCCACUGAGAAAGAUGCUCGGCAUCGGCGGCGACAGAAC

CGAGAAGCUGAUCCCUGGCAUGGAACUGAGCAACUGGCUGCCUGGCGGCA

CCAGCACAACACUGGAACUGGAUCCUAAGCAGCACAGCCACAGCGGCCUG

CUGAGAAUGGCCAGCUUUGGCAGCAUGAAGAUGGCCCCUCUGAUGCUGCU

GCAGCUGCUCGGAAGAGGCACCCUGACAAUGAUCCAGCUGCUGCUCCACA

ACAGCAGACCCGUGCUGAGCUUCCUGAAAACCAGCACACUGAGAGGCCUG

GAAGCCAUCGUGAACCAUCUGCAAGAGCCCCUGGCUCAGGCCGAGACACU

GCCUGAUCUGGUGCACAAGGUGCAGGACCAAGAAACCCUGCCUGCCGCUC

UGCUGCAGGUCCACCUGGAAUCUGAGCAGUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 40, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be KSHV ORF52 (Kaposi's sarcoma-associated herpesvirus ORF52; Accession Number—Genomic DNA Translation: ACY00451.1; UniProtKB—F5HBL8 (F5HBL8_HHV8)), or an orthologue thereof. ORF52 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is believed to directly inhibit cGAS enzymatic activity and thus prevent generation of the signalling molecule cGAMP by binding to both cGAS and DNA. (Wu J-J, Li W, Shao Y, Avey D et al. (2015) Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host Microbe. 18, 3, 333-344. doi: 10.1016/j.chom.2015.07.015.).

One embodiment of the KSHV ORF52 polypeptide sequence is represented herein as SEQ ID No:41, as follows:

[SEQ ID No: 41]

MAAPRGRPKKDLTMEDLTAKISQLTVENRELRKALGSTADPRDRPLTATE

KEAQLTATVGALSAAAAKKIEARVRTIFSKVVTQKQVDDALKGLSLRIDV

CMSDGGTAKPPPGANNRRRRGASTTRAGVDD

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 41, or a variant or fragment thereof.

In one embodiment, the KSHV ORF52 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 42, as follows:

[SEQ ID No: 42]

ATGGCCGCGCCCAGGGGCAGACCCAAAAAGGACCTTACGATGGAAGACCT

AACCGCAAAGATAAGCCAATTGACTGTGGAGAATCGGGAGCTTCGGAAAG

CACTGGGATCCACTGCCGATCCGAGAGATCGGCCTCTGACGGCCACCGAG

AAGGAAGCGCAGCTTACCGCTACTGTGGGTGCACTGAGTGCGGCGGCCGC

TAAGAAAATCGAAGCCAGGGTCAGGACAATATTCAGCAAGGTTGTAACAC

AAAAGCAAGTGGACGATGCCCTGAAGGGACTTTCGCTTAGAATCGACGTC

TGCATGTCAGACGGGGGCACCGCTAAACCGCCTCCTGGTGCCAATAACAG

GCGACGAAGAGGAGCCTCGACAACACGGGCGGGGGTTGATGAC

Accordingly, preferably the KSHV ORF52 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 42, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 43, as follows:

[SEQ ID No: 43]

AUGGCCGCGCCCAGGGGCAGACCCAAAAAGGACCUUACGAUGGAAGACCU

AACCGCAAAGAUAAGCCAAUUGACUGUGGAGAAUCGGGAGCUUCGGAAAG

CACUGGGAUCCACUGCCGAUCCGAGAGAUCGGCCUCUGACGGCCACCGAG

AAGGAAGCGCAGCUUACCGCUACUGUGGGUGCACUGAGUGCGGCGGCCGC

UAAGAAAAUCGAAGCCAGGGUCAGGACAAUAUUCAGCAAGGUUGUAACAC

AAAAGCAAGUGGACGAUGCCCUGAAGGGACUUUCGCUUAGAAUCGACGUC

UGCAUGUCAGACGGGGGCACCGCUAAACCGCCUCCUGGUGCCAAUAACAG

GCGACGAAGAGGAGCCUCGACAACACGGGCGGGGGUUGAUGAC

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 43, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 41 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 44, as follows:

[SEQ ID No: 44]

ATGGCTGCTCCTAGAGGCAGACCCAAGAAAGACCTGACCATGGAAGATCT

GACCGCCAAGATCAGCCAGCTGACCGTGGAAAACAGAGAGCTGAGAAAGG

CCCTGGGCAGCACCGCCGATCCTAGAGATAGACCTCTGACAGCCACCGAG

AAAGAGGCCCAGCTGACAGCTACAGTGGGAGCCCTTTCTGCCGCCGCTGC

CAAGAAAATTGAAGCCAGAGTGCGGACCATCTTCAGCAAGGTGGTCACCC

AGAAACAGGTGGACGATGCCCTGAAGGGCCTGAGCCTGAGAATCGACGTG

TGTATGTCTGACGGCGGCACCGCCAAACCTCCACCTGGCGCTAACAACAG

AAGAAGAAGAGGCGCCAGCACCACCAGAGCTGGCGTGGACGATTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 44, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 44 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 45, as follows:

[SEQ ID No: 45]

AUGGCUGCUCCUAGAGGCAGACCCAAGAAAGACCUGACCAUGGAAGAUCU

GACCGCCAAGAUCAGCCAGCUGACCGUGGAAAACAGAGAGCUGAGAAAGG

CCCUGGGCAGCACCGCCGAUCCUAGAGAUAGACCUCUGACAGCCACCGAG

AAAGAGGCCCAGCUGACAGCUACAGUGGGAGCCCUUUCUGCCGCCGCUGC

CAAGAAAAUUGAAGCCAGAGUGCGGACCAUCUUCAGCAAGGUGGUCACCC

AGAAACAGGUGGACGAUGCCCUGAAGGGCCUGAGCCUGAGAAUCGACGUG

UGUAUGUCUGACGGCGGCACCGCCAAACCUCCACCUGGCGCUAACAACAG

AAGAAGAAGAGGCGCCAGCACCACCAGAGCUGGCGUGGACGAUUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 45, or a fragment or variant thereof.

In one embodiment, the at least one IIP may be Ebola VP35 (EBOV VP35; NP_066244.1; Accession Number—NCBI Reference Sequence: NC_002549.1; UniProtKB—Q05127 (VP35_EBOZM)), or an orthologue thereof. Ebola virus VP35 protein is thought to (amongst other effects on innate signalling cascades) bind to the cellular protein PACT, a cellular dsRNA binding protein required for activation of RIG-I, inhibit IRF3 and IRF7 activity (Luthra P, Raman P, Mire C E, Weisand C, Isuda Y et al. (2013) Mutual antagonism between Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe., 14(1):74-84. doi: 10.1016/j.chom.2013.06.010. Hartman A L, Bird B H, Towner J S, Anoniadou Z-A, Zaki S R, Nichol S T (2008) Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of Ebola virus. J Virol. 82, 6, 2699-2704. Audet J, Kobinger G P (2015). Immune evasion in ebolavirus infections. Viral Immunol., 28, 1, 10-18.).

One embodiment of the Ebola VP35 polypeptide sequence is represented herein as SEQ ID No:46, as follows:

[SEQ ID No: 46]

MTTRTKGRGHTAATTQNDRMPGPELSGWISEQLMTGRIPVSDIFCDIENN

PGLCYASQMQQTKPNPKTRNSQTQTDPICNHSFEEVVQTLASLATVVQQQ

TIASESLEQRITSLENGLKPVYDMAKTISSLNRVCAEMVAKYDLLVMTTG

RATATAAATEAYWAEHGQPPPGPSLYEESAIRGKIESRDETVPQSVREAF

NNLNSTTSLTEENFGKPDISAKDLRNIMYDHLPGFGTAFHQLVQVICKLG

KDSNSLDIIHAEFQASLAEGDSPQCALIQITKRVPIFQDAAPPVIHIRSR

GDIPRACQKSLRPVPPSPKIDRGWVCVFQLQDGKTLGLKI

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 46, or a variant or fragment thereof.

In one embodiment, the Ebola VP35 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 47, as follows:

[SEQ ID No: 47]

ATGACAACTAGAACAAAGGGCAGGGGCCATACTGCGGCCACGACTCAAAA

CGACAGAATGCCAGGCCCTGAGCTTTCGGGCTGGATCTCTGAGCAGCTAA

TGACCGGAAGAATTCCTGTAAGCGACATCTTCTGTGATATTGAGAACAAT

CCAGGATTATGCTACGCATCCCAAATGCAACAAACGAAGCCAAACCCGAA

GACGCGCAACAGTCAAACCCAAACGGACCCAATTTGCAATCATAGTTTTG

AGGAGGTAGTACAAACATTGGCTTCATTGGCTACTGTTGTGCAACAACAA

ACCATCGCATCAGAATCATTAGAACAACGCATTACGAGTCTTGAGAATGG

TCTAAAGCCAGTTTATGATATGGCAAAAACAATCTCCTCATTGAACAGGG

TTTGTGCTGAGATGGTTGCAAAATATGATCTTCTGGTGATGACAACCGGT

CGGGCAACAGCAACCGCTGCGGCAACTGAGGCTTATTGGGCCGAACATGG

TCAACCACCACCTGGACCATCACTTTATGAAGAAAGTGCGATTCGGGGTA

AGATTGAATCGAGGAAAATTTTGGGAAACCTGACATTTCGGCAAAGGATT

TGAGAAACATTATGTATGATCACTTGCCTGGTTTTGGAACTGCTTTCCAC

CAATTAGTACAAGTGATTTGTAAATTGGGAAAAGATAGCAACTCATTGGA

CATCATTCATGCTGAGTTCCAGGCCAGCCTGGCTGAAGGAGACTCTCCTC

AATGTGCCCTAATTCAAATTACAAAAAGAGTTCCAATCTTCCAAGATGCT

GCTCCACCTGTCATCCACATCCGCTCTCGAGGTGACATTCCCCGAGCTTG

CCAGAAAAGCTTGCGTCCAGTCCCACCATCGCCCAAGATTGATCGAGGTT

GGGTATGTGTTTTTCAGCTTCAAGATGGTAAAACACTTGGACTCAAAATT

Accordingly, preferably the Ebola VP35 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 47, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 48, as follows:

[SEQ ID No: 48]

AUGACAACUAGAACAAAGGGCAGGGGCCAUACUGCGGCCACGACUCAAAA

CGACAGAAUGCCAGGCCCUGAGCUUUCGGGCUGGAUCUCUGAGCAGCUAA

UGACCGGAAGAAUUCCUGUAAGCGACAUCUUCUGUGAUAUUGAGAACAAU

CCAGGAUUAUGCUACGCAUCCCAAAUGCAACAAACGAAGCCAAACCCGAA

GACGCGCAACAGUCAAACCCAAACGGACCCAAUUUGCAAUCAUAGUUUUG

AGGAGGUAGUACAAACAUUGGCUUCAUUGGCUACUGUUGUGCAACAACAA

ACCAUCGCAUCAGAAUCAUUAGAACAACGCAUUACGAGUCUUGAGAAUGG

UCUAAAGCCAGUUUAUGAUAUGGCAAAAACAAUCUCCUCAUUGAACAGGG

UUUGUGCUGAGAUGGUUGCAAAAUAUGAUCUUCUGGUGAUGACAACCGGU

CGGGCAACAGCAACCGCUGCGGCAACUGAGGCUUAUUGGGCCGAACAUGG

UCAACCACCACCUGGACCAUCACUUUAUGAAGAAAGUGCGAUUCGGGGUA

AGAUUGAAUCUAGAGAUGAGACCGUCCCUCAAAGUGUUAGGGAGGCAUUC

AACAAUCUAAACAGUACCACUUCACUAACUGAGGAAAAUUUUGGGAAACC

UGACAUUUCGGCAAAGGAUUUGAGAAACAUUAUGUAUGAUCACUUGCCUG

GUUUUGGAACUGCUUUCCACCAAUUAGUACAAGUGAUUUGUAAAUUGGGA

AAAGAUAGCAACUCAUUGGACAUCAUUCAUGCUGAGUUCCAGGCCAGCCU

GGCUGAAGGAGACUCUCCUCAAUGUGCCCUAAUUCAAAUUACAAAAAGAG

UUCCAAUCUUCCAAGAUGCUGCUCCACCUGUCAUCCACAUCCGCUCUCGA

GGUGACAUUCCCCGAGCUUGCCAGAAAAGCUUGCGUCCAGUCCCACCAUC

GCCCAAGAUUGAUCGAGGUUGGGUAUGUGUUUUUCAGCUUCAAGAUGGUA

AAACACUUGGACUCAAAAUU

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 48, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 46 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 49, as follows:

[SEQ ID No: 49]

ATGACCACCAGGACCAAAGGCAGAGGACACACCGCCGCCACCACACAGAA

CGACAGAATGCCTGGACCTGAGCTGAGCGGCTGGATCTCTGAGCAGCTGA

TGACAGGCAGAATCCCCGTGTCCGACATCTTCTGCGACATCGAGAACAAC

CCCGGCCTGTGTTACGCCAGCCAGATGCAGCAGACCAAGCCTAATCCTAA

GACACGGAACAGCCAGACACAGACAGACCCCATCTGCAACCACAGCTTCG

AGGAAGTGGTGCAGACACTGGCCAGCCTGGCCTGAAGCCTGTGTACGACA

TGGCCAAGACCATCAGCTCCCTGAACAGAGTGTGCGCCGAGATGGTGGCC

AAATACGACCTGCTCGTGATGACCACCGGCAGAGCCACAGCTACAGCCGC

TGCCACAGAAGCCTATTGGGCCGAACATGGACAGCCTCCACCTGGACCTA

GCCTGTACGAGGAATCTGCCATCCGGGGCAAGATCGAGAGCAGGGATGAG

ACAGTGCCCCAGTCTGTGCGCGAGGCCTTCAACAACCTGAACAGCACCAC

AAGCCTGACCGAGGAAAACTTCGGCAAGCCCGACATCAGCGCCAAGGACC

TGCGGAACATTATGTACGACCATCTGCCTGGCTTCGGCACCGCCTTCCAT

CAGCTGGTGCAAGTGATCTGCAAGCTGGGCAAAGACAGCAACAGCCTGGA

CATCATCCACGCCGAGTTTCAGGCCTCTCTGGCCGAAGGCGATTCTCCTC

AGTGTGCCCTGATCCAGATCACCAAGCGGGTGCCCATCTTCCAGGATGCT

GCCCCTCCTGTGATCCACATCAGAAGCAGAGGCGACATCCCCAGAGCCTG

CCAGAAATCTCTCAGACCCGTGCCTCCATCTCCTAAGATCGACAGAGGCT

GGGTCTGCGTGTTCCAGCTGCAAGATGGCAAGACCCTGGGCCTGAAGATC

TGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 49, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 49 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 50, as follows:

[SEQ ID No: 50]

AUGACCACCAGGACCAAAGGCAGAGGACACACCGCCGCCACCACACAGAA

CGACAGAAUGCCUGGACCUGAGCUGAGCGGCUGGAUCUCUGAGCAGCUGA

UGACAGGCAGAAUCCCCGUGUCCGACAUCUUCUGCGACAUCGAGAACAAC

CCCGGCCUGUGUUACGCCAGCCAGAUGCAGCAGACCAAGCCUAAUCCUAA

GACACGGAACAGCCAGACACAGACAGACCCCAUCUGCAACCACAGCUUCG

AGGAAGUGGUGCAGACACUGGCCAGCCUGGCUACAGUUGUGCAGCAGCAG

ACAAUCGCCAGCGAGAGCCUGGAACAGAGAAUCACCAGCCUGGAAAACGG

CCUGAAGCCUGUGUACGACAUGGCCAAGACCAUCAGCUCCCUGAACAGAG

UGUGCGCCGAGAUGGUGGCCAAAUACGACCUGCUCGUGAUGACCACCGGC

AGAGCCACAGCUACAGCCGCUGCCACAGAAGCCUAUUGGGCCGAACAUGG

ACAGCCUCCACCUGGACCUAGCCUGUACGAGGAAUCUGCCAUCCGGGGCA

AGAUCGAGAGCAGGGAUGAGACAGUGCCCCAGUCUGUGCGCGAGGCCUUC

AACAACCUGAACAGCACCACAAGCCUGACCGAGGAAAACUUCGGCAAGCC

CGACAUCAGCGCCAAGGACCUGCGGAACAUUAUGUACGACCAUCUGCCUG

GCUUCGGCACCGCCUUCCAUCAGCUGGUGCAAGUGAUCUGCAAGCUGGGC

AAAGACAGCAACAGCCUGGACAUCAUCCACGCCGAGUUUCAGGCCUCUCU

GGCCGAAGGCGAUUCUCCUCAGUGUGCCCUGAUCCAGAUCACCAAGCGGG

UGCCCAUCUUCCAGGAUGCUGCCCCUCCUGUGAUCCACAUCAGAAGCAGA

GGCGACAUCCCCAGAGCCUGCCAGAAAUCUCUCAGACCCGUGCCUCCAUC

UCCUAAGAUCGACAGAGGCUGGGUCUGCGUGUUCCAGCUGCAAGAUGGCA

AGACCCUGGGCCUGAAGAUCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 50, or a fragment or variant thereof.

In another embodiment, the at least one IIP may be derived from SARS-CoV-2 ORF3b (Accession Number—NCBI Reference Sequence: NC_045512.2) or an orthologue thereof. One embodiment of the wild type of SARS-CoV-2 ORF3b polypeptide sequence from which the at least one IIP may be derived is represented herein as SEQ ID No:51. The asterisks represent stop codons in the wild-type sequence, one or more of which may be mutated in the derived IIP. SEQ ID No:51 is as follows:

[SEQ ID No: 51]

MMPTIFFAGILIVTTIVYLTIV*LLQLSLLQVMAQQVLFLNMTTRLVVIL

KNGNLE*KTVLYYTVTSLQTITSCTQLN*VQTLVLNMLPSSSTIKLLMSL

KNMSKFTQSTVHPELLIQ*WNQFMMNRRRLLACLCKHKLMSTNLCTHSFR

KRQVR*

In one embodiment, the at least one IIP may be an ORF3b*57 variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof. One embodiment of the SARS-CoV-2 ORF3b*57 variant polypeptide sequence is represented herein as SEQ ID No:52, as follows:

[SEQ ID No: 52]

MMPTIFFAGILIVTTIVYLTIVQLLQLSLLQVMAQQVLFLNMTTRLVVIL

KNGNLE

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 52, or a variant or fragment thereof.

In one embodiment, the SARS-CoV-2 ORF3b*57 variant polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 53, as follows:

[SEQ ID No: 53]

ATGATGCCAACTATTTTCTTTGCTGGCATACTAATTGTTACGACTATTGT

ATACCTTACAATAGTGCAACTTCTTCAATTGTCATTACTTCAGGTGATGG

CACAACAAGTCCTATTTCTGAACATGACTACCAGATTGGTGGTTATACTG

AAAAATGGGAATCTGGAG

Accordingly, preferably the SARS-CoV-2 ORF3b*57 variant polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 53, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 54, as follows:

[SEQ ID No: 54]

AUGAUGCCAACUAUUUUCUUUGCUGGCAUACUAAUUGUUACGACUAUUGU

AUACCUUACAAUAGUGCAACUUCUUCAAUUGUCAUUACUUCAGGUGAUGG

CACAACAAGUCCUAUUUCUGAACAUGACUACCAGAUUGGUGGUUAUACUG

AAAAAUGGGAAUCUGGAG

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 54, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 52 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 55, as follows:

[SEQ ID No: 55]

ATGATGCCGACCATCTTCTTCGCCGGCATCCTGATCGTGACCACCATCGT

GTACCTGACCATCGTGCAGCTGCTGCAGCTCAGCCTGCTGCAAGTGATGG

CTCAGCAGGTCCTGTTCCTGAATATGACCACCAGACTGGTCGTGATCCTG

AAGAACGGCAACCTGGAATGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 55, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA is sequence of SEQ ID No: 55 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 56, as follows:

[SEQ ID No: 56]

AUGAUGCCGACCAUCUUCUUCGCCGGCAUCCUGAUCGUGACCACCAUCGU

GUACCUGACCAUCGUGCAGCUGCUGCAGCUCAGCCUGCUGCAAGUGAUGG

CUCAGCAGGUCCUGUUCCUGAAUAUGACCACCAGACUGGUCGUGAUCCUG

AAGAACGGCAACCUGGAAUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 56, or a fragment or variant thereof.

In another embodiment, the at least one IIP may be an ORF3b*79 variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof. One embodiment of the SARS-CoV-2 ORF3b*79 variant polypeptide sequence is represented herein as SEQ ID No:57, as follows:

[SEQ ID No: 57]

MMPTIFFAGILIVTTIVYLTIVQLLQLSLLQVMAQQVLFLNMTTRLVVIL

KNGNLELKTVLYYTVTSLQTITSCTQLN

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 57, or a variant or fragment thereof.

In one embodiment, the SARS-CoV-2 ORF3b*79 variant polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 58, as follows:

[SEQ ID No: 58]

ATGATGCCAACTATTTTCTTTGCTGGCATACTAATTGTTACGACTATTGT

ATACCTTACAATAGTGCAACTTCTTCAATTGTCATTACTTCAGGTGATGG

CACAACAAGTCCTATTTCTGAACATGACTACCAGATTGGTGGTTATACTG

AAAAATGGGAATCTGGAGTTAAAGACTGTGTTGTATTACACAGTTACTTC

ACTTCAGACTATTACCAGCTGTACTCAACTCAAT

Accordingly, preferably the SARS-CoV-2 ORF3b*79 variant polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 58, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 59, as follows:

[SEQ ID No: 59]

AUGAUGCCAACUAUUUUCUUUGCUGGCAUACUAAUUGUUACGACUAUUGU

AUACCUUACAAUAGUGCAACUUCUUCAAUUGUCAUUACUUCAGGUGAUGG

CACAACAAGUCCUAUUUCUGAACAUGACUACCAGAUUGGUGGUUAUACUG

AAAAAUGGGAAUCUGGAGUUAAAGACUGUGUUGUAUUACACAGUUACUUC

ACUUCAGACUAUUACCAGCUGUACUCAACUCAAU

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 59, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 57 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 60, as follows:

[SEQ ID No: 60]

ATGATGCCGACCATCTTCTTCGCCGGCATCCTGATCGTGACCACCATCGT

GTACCTGACCATCGTGCAGCTGCTGCAGCTCAGCCTGCTGCAAGTGATGG

CTCAGCAGGTCCTGTTCCTGAATATGACCACCAGACTGGTCGTGATCCTG

AAGAACGGCAACCTGGAACTGAAAACCGTGCTGTACTACACCGTGACCAG

CCTGCAGACCATCACCAGCTGCACCCAGCTGAACTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 60, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 60 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 61, as follows:

[SEQ ID No: 61]

AUGAUGCCGACCAUCUUCUUCGCCGGCAUCCUGAUCGUGACCACCAUCGU

GUACCUGACCAUCGUGCAGCUGCUGCAGCUCAGCCUGCUGCAAGUGAUGG

CUCAGCAGGUCCUGUUCCUGAAUAUGACCACCAGACUGGUCGUGAUCCUG

AAGAACGGCAACCUGGAACUGAAAACCGUGCUGUACUACACCGUGACCAG

CCUGCAGACCAUCACCAGCUGCACCCAGCUGAACUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 61, or a fragment or variant thereof.

In yet another embodiment, the at least one IIP may be an ORF3b*57 Ecuador variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof. One embodiment of the SARS-CoV-2 ORF3b*57 Ecuador variant polypeptide sequence is represented herein as SEQ ID No:62, as follows:

[SEQ ID No: 62]

MMPTIFFAGILIVTTIVYLTIVQMLQLSLLQVMAQQVLFLNMTTRLVVIL

KNGNLE

Therefore, preferably the RNA construct of the first aspect comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 62, or a variant or fragment thereof.

In one embodiment, the SARS-CoV-2 ORF3b*57 Ecuador variant polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 63, as follows:

[SEQ ID No: 63]

ATGATGCCAACTATTTTCTTTGCTGGCATACTAATTGTTACGACTATTGT

ATACCTTACAATAGTGCAAATGCTTCAATTGTCATTACTTCAGGTGATGG

CACAACAAGTCCTATTTCTGAACATGACTACCAGATTGGTGGTTATACTG

AAAAATGGGAATCTGGAGTAA

Accordingly, preferably the SARS-CoV-2 ORF3b*57 Ecuador variant polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 63, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 64, as follows:

[SEQ ID No: 64]

AUGAUGCCAACUAUUUUCUUUGCUGGCAUACUAAUUGUUACGACUAUUGU

AUACCUUACAAUAGUGCAAAUGCUUCAAUUGUCAUUACUUCAGGUGAUGG

CACAACAAGUCCUAUUUCUGAACAUGACUACCAGAUUGGUGGUUAUACUG

AAAAAUGGGAAUCUGGAGUAA

Furthermore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 64, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 62 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 65, as follows:

[SEQ ID No: 65]

ATGATGCCGACCATCTTCTTCGCCGGCATCCTGATCGTGACCACCATCGT

GTACCTGACCATCGTGCAGATGCTGCAGCTGAGCCTGCTGCAAGTGATGG

CCCAGCAGGTCCTGTTCCTGAATATGACCACCAGACTGGTCGTGATCCTG

AAGAACGGCAACCTGGAATGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 65, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 65 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 66, as follows:

[SEQ ID No: 66]

AUGAUGCCGACCAUCUUCUUCGCCGGCAUCCUGAUCGUGACCACCAUCGU

GUACCUGACCAUCGUGCAGAUGCUGCAGCUGAGCCUGCUGCAAGUGAUGG

CCCAGCAGGUCCUGUUCCUGAAUAUGACCACCAGACUGGUCGUGAUCCUG

AAGAACGGCAACCUGGAAUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 66, or a fragment or variant thereof.

In other embodiments, the at least one IIP may be a viral inhibitory protein which blocks or inhibits the activity of MDA-5, and selected from a group consisting of:

- (i) a Paromyxoviridae V protein; optionally SV5B, PIV2, Mumps, SeV, Measles, or NiV;
- (ii) Encephalomyocarditis virus 2C;
- (iii) Birnavirus VP3; and
- (iv) Porcine delta coronavirus NS6.

In other embodiments, the at least one IIP may be an Arenavirus Z protein selected from a group consisting of: LASV; DANV; LCMV; LUJV; CHPV; MACV; GTOV; JUNV; and SABV. These IIPs are believed to interact with the RLR, RIG-I and MDA-5 and inhibit interaction with mitochondrial antiviral signaling (MAVS).

In other embodiments, the at least one IIP may be a 3C protease protein selected from a group consisting of: Cosackieviruses CV-A16 or CV-A6; EV D-68 or 71; and Poliovirus HEV-C. These IIPs are believed to inhibit MDA interaction with MAVS.

In other embodiments, the at least one IIP may be a 2A protease protein selected from a group consisting of: Poliovirus HEV-C; CVB3; and EV71. These IIPs are believed to inhibit the RLR pathway by cleavage of MDA-5 and MAVS.

In other embodiments, the at least one IIP may be a protein degrading or acting on RIG-I and selected from a group consisting of: hMPV G; CVB3 3C protease; Polio Virus 3Cpro; Hepatitis C NS3/4A; DENV NS3; EV71 3Cpro; FMDV Lpro and 3Cpro; Toscana Virus NSS; Influenza A/PR/8/34 NS1; and MERS ORF8b. These IIPs are preferred in the embodiment in which the RNA construct comprises saRNA or mRNA.

In other embodiments, the at least one IIP may be a protein acting on PACT selected from a group consisting of: SARS CoV N protein; and MHV N.

In other embodiments, the at least one IIP may be a protein acting against LGP2 (which enhances MDA2 signalling), including, for example, FMDV Lpro, 3Cpro and 2B.

In other embodiments, the at least one IIP may be a protein that impacts activity of TRAF3, including, for example, MERS CoV M.

In other embodiments, the at least one IIP may be a protein which acts on MAVS selected from a group consisting of: Influenza virus A PB1-F2; Hepatitis A ABC; Hepatitis B X; Hepatitis C NS3/4A; SARS-CoV NSP15; SARS CoV ORF9 (96); Coxsackievirus B3 2Apro and 3Cpro; Rhinovirus 2Apro and 3Cpro; Rotavirus VP3; GB Virus B NS3/4A; EV71 2Apro; HAV 3Cpro; Human metapneumovirus M2-2; and Enterovirus EV71 2A.

In other embodiments, the at least one IIP may be a protein that blocks IRF-3 activity selected from a group consisting of: HCV and NSP1B; Ebola vNS3; HPV16 E6; Hepatitis E methyltransferase; PRV Npro; HSV1 Us3; HSV2 Us1; CSFV Npro; BDV Npro; Bovine RV NS1 and NS2; Hepatitis B virus Orf3; PBoV NP1; Hepatitis E ORF3; and MERS ORF8b.

In other embodiments, the at least one IIP may be a protein that inhibits IRF7 activity selected from a group consisting of: Rotavirus NSP1; KSHV ORF45; EBV BZLF-1; Ebola VP35; and Enterovirus 71 and 68 3CPro.

In other embodiments, the at least one IIP may be a protein that impacts NF-kβ activity selected from a group consisting of: Polio 3C; FMDV Lpro; MERS CoV ORF4b (246aa); MuHV ORF73; Torque Teno virus ORF2; EBV EBNA1; and SV5 and hPIV2 Vproteins.

In other embodiments, the at least one IIP may be a protein that impacts TBK-1 or IKKε activities and selected from a group consisting of: BDV P; HPV E6 and HPV E7; Arenavirus NP1; HCV NS3 protein; DENV1 NS4A; DENV1, 2 and 4 NS2A and NS2B; WNV NS4A; Ebola VP35; Rabies Virus PP; PEDV N protein; and HSV1 ICP27 and VP24.

In other embodiments, the at least one IIP may be a protein that impacts on the activity of NEMO, such as for example, murine CTMV M45.

The following viral IIPs are believed to block or inhibit activation of MDA-5.

The V protein binds to the helicase domain of MDA-5 and blocks its activation by inhibiting dsRNA binding and consequent self-association. (Childs K S, Andresjeva J, Randall R E & Goobourn S (2009) Mechanism of MDA-5 inhibition by paramyxovirus V proteins. J Virol 83, 3, 1465-1473) In one embodiment, the at least one IIP is SV5B, or an orthologue thereof. One embodiment of the polypeptide sequence of Simian Virus (PIV5 Non-structural protein V) is represented herein as SEQ ID No: 95, as follows:

[SEQ ID No: 95]

MDPTDLSFSPDEINKLIETGLNTVEYFTSQQVTGTSSLGKNTIPPGVTGL

LTNAAEAKIQESTNHQKGSVGGGAKPKKPRPKIAIVPADDKTVPGKPIPN

PLLGLDSTPSTQTVLDLSGKTLPSGSYKGVKLAKFGKENLMTRFIEEPRE

NPIATSSPIDFKRGRDIGGFHRREYSIGWVGDEVKVTEWCNPSCSPITAA

ARRFECTCHQCPVTCSECERDT

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 95, or a variant or fragment thereof.

In one embodiment, the SV5B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 96, as follows:

[SEQ ID No: 96]

ATGGATCCCACTGATCTGAGCTTCTCCCCAGATGAGATCAATAAGCTCAT

AGAGACAGGCCTGAATACTGTAGAGTATTTTACTTCCCAACAAGTCACAG

GAACATCCTCTCTTGGAAAGAATACAATACCACCAGGGGTCACAGGACTA

CTAACCAATGCTGCAGAGGCAAAGATCCAAGAGTCAACTAACCATCAGAA

GGGCTCAGTTGGTGGGGGTGCAAAACCAAAGAAACCGCGACCAAAAATTG

CCATTGTGCCAGCAGATGACAAAACAGTGCCCGGAAAGCCGATCCCAAAC

CCTCTATTAGGTCTGGACTCCACCCCGAGCACCCAAACTGTGCTTGATCT

AAGTGGGAAAACATTACCATCAGGATCCTATAAGGGGGTTAAGCTTGCGA

AATTTGGAAAAGAAAATCTGATGACACGGTTCATCGAGGAACCCAGAGAG

AATCCTATCGCAACCAGTTCCCCCATCGATTTTAAGAGGGGCAGGGATAC

CGGCGGGTTCCATAGAAGGGAGTACTCAATCGGATGGGTGGGAGATGAAG

TCAAGGTCACTGAGTGGTGCAATCCATCCTGTTCTCCAATCACCGCTGCA

GCAAGGCGATTTGAATGCACTTGTCACCAGTGTCCAGTCACTTGCTCTGA

ATGTGAACGAGATACT

Accordingly, preferably the SV5B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 96, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SV5B polypeptide is provided herein as SEQ ID No: 97, as follows:

[SEQ ID No: 97]

ATGGACCCTACCGACCTGAGCTTCAGCCCCGACGAGATCAACAAGCTGAT

CGAGACAGGCCTGAACACCGTGGAATACTTCACCAGCCAGCAAGTGACCG

GCACAAGCAGCCTGGGCAAGAACACAATTCCTCCAGGCGTGACCGGCCTG

CTGACAAATGCTGCCGAGGCCAAGATCCAAGAGAGCACCAACCACCAGAA

GGGCTCTGTTGGAGGCGGAGCCAAGCCTAAGAAGCCCAGACCTAAGATCG

CCATCGTGCCCGCCGACGATAAGACAGTGCCTGGCAAGCCCATTCCTAAT

CCTCTGCTGGGCCTCGACAGCACCCCTAGCACACAGACAGTGCTGGATCT

GAGCGGCAAGACACTGCCTAGCGGCAGCTATAAGGGCGTGAAGCTGGCCA

AGTTCGGCAAAGAAAACCTGATGACCCGGTTCATCGAGGAACCCAGAGAG

AACCCTATCGCCACCAGCTCTCCCATCGACTTCAAGAGAGGCAGAGACAC

CGGCGGCTTCCACAGAAGAGAGTACAGCATTGGCTGGGTCGGAGATGAAG

TGAAAGTGACCGAGTGGTGCAACCCCAGCTGCAGCCCTATTACAGCCGCC

GCTAGAAGATTCGAGTGCACCTGTCACCAGTGTCCTGTGACCTGTAGCGA

GTGCGAGAGAGACACA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 97, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA

[SEQ ID No: 98]

AUGGACCCUACCGACCUGAGCUUCAGCCCCGACGAGAUCAACAAGCUGAU

CGAGACAGGCCUGAACACCGUGGAAUACUUCACCAGCCAGCAAGUGACCG

GCACAAGCAGCCUGGGCAAGAACACAAUUCCUCCAGGCGUGACCGGCCUG

CUGACAAAUGCUGCCGAGGCCAAGAUCCAAGAGAGCACCAACCACCAGAA

GGGCUCUGUUGGAGGCGGAGCCAAGCCUAAGAAGCCCAGACCUAAGAUCG

CCAUCGUGCCCGCCGACGAUAAGACAGUGCCUGGCAAGCCCAUUCCUAAU

CCUCUGCUGGGCCUCGACAGCACCCCUAGCACACAGACAGUGCUGGAUCU

GAGCGGCAAGACACUGCCUAGCGGCAGCUAUAAGGGCGUGAAGCUGGCCA

AGUUCGGCAAAGAAAACCUGAUGACCCGGUUCAUCGAGGAACCCAGAGAG

AACCCUAUCGCCACCAGCUCUCCCAUCGACUUCAAGAGAGGCAGAGACAC

CGGCGGCUUCCACAGAAGAGAGUACAGCAUUGGCUGGGUCGGAGAUGAAG

UGAAAGUGACCGAGUGGUGCAACCCCAGCUGCAGCCCUAUUACAGCCGCC

GCUAGAAGAUUCGAGUGCACCUGUCACCAGUGUCCUGUGACCUGUAGCGA

GUGCGAGAGAGACACA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 98, or a fragment or variant thereof.

In one embodiment, the at least one IIP is PIV2 Non-structural protein V (P19847), or an orthologue thereof. One embodiment of the polypeptide sequence of PIV2 is represented herein as SEQ ID No: 99, as follows:

[SEQ ID No: 99]

MAEEPTYTTEQVDELIHAGLGTVDFFLSRPIDAQSSLGKGSIPPGVTAVL

TSAAEAKSKPVAAGPVKPRRKKVISNTTPYTIADNIPPEKLPINTPIPNP

LLPLARPHGKMTDIDIVTGNITEGSYKGVELAKLGKQTLLTRFTSNEPVS

SAGSAQDPNFKRGGANRERARGNHRREWSIAWVGDQVKVFEWCNPRCAPV

TASARKFTCTCGSCPSICGECEGDH

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 99, or a variant or fragment thereof.

In one embodiment, the PIV2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 100, as follows:

[SEQ ID No: 100]

ATGGCCGAGGAACCAACATACACCACTGAGCAAGTTGATGAATTAATCCA

TGCTGGACTGGGAACAGTAGATTTCTTCCTATCTAGACCCATAGATGCTC

AGTCTTCTTTAGGCAAAGGCAGCATCCCACCAGGTGTCACAGCTGTTCTA

ACTAGTGCAGCGGAGGCAAAATCCAAACCAGTTGCTGCTGGTCCAGTTAA

ACCCAGGCGGAAGAAAGTGATCAGCAATACTACTCCATACACTATTGCAG

ACAATATTCCACCTGAGAAGCTACCGATCAACACTCCAATACCCAATCCA

TTACTTCCACTGGCACGCCCTCACGGAAAGATGACAGACATTGACATTGT

CACTGGGAACATTACAGAAGGATCGTACAAAGGTGTGGAGCTTGCTAAAT

TAGGGAAGCAGACACTACTCACAAGGTTCACCTCGAATGAGCCAGTCTCC

TCAGCTGGATCCGCCCAAGACCCCAACTTTAAGAGGGGGGGAGCTAATAG

AGAAAGAGCAAGAGGCAACCATAGGAGAGAATGGAGTATTGCATGGGTCG

GAGATCAGGTCAAAGTCTTCGAGTGGTGTAATCCCAGGTGTGCCCCAGTC

ACGGCCTCAGCTCGCAAGTTCACCTGCACATGCGGATCCTGCCCCAGCAT

CTGCGGAGAATGTGAAGGAGATCAT

Accordingly, preferably the PIV2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 100, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the PIV2 polypeptide is provided herein as SEQ ID No: 101, as follows:

[SEQ ID No: 101]

ATGGCCGAGGAACCTACCTACACCACCGAACAGGTGGACGAGCTGATTCA

CGCCGGACTGGGAACCGTGGACTTCTTTCTGTCCCGGCCTATCGATGCCC

AGAGCAGCCTCGGCAAGGGATCTATTCCTCCTGGCGTGACAGCCGTGCTG

ACATCTGCCGCCGAGGCCAAGTCTAAACCTGTGGCTGCTGGACCCGTGAA

GCCCAGACGGAAGAAAGTGATCAGCAACACCACACCTTACACGATCGCCG

ACAACATCCCTCCTGAGAAGCTGCCCATCAACACCCCTATTCCTAATCCT

CTGCTGCCCCTGGCCAGACCTCACGGCAAGATGACCGACATCGATATCGT

GACCGGCAACATCACCGAGGGCAGCTACAAAGGCGTGGAACTGGCCAAGC

TGGGCAAGCAGACACTGCTGACCAGATTCACCAGCAACGAGCCTGTGTCT

AGCGCCGGCTCTGCCCAGGATCCTAACTTCAAAAGAGGCGGAGCCAACAG

AGAGAGAGCCAGAGGCAACCATCGGAGAGAGTGGTCTATTGCCTGGGTCG

GAGATCAAGTGAAGGTGTTCGAGTGGTGCAACCCCAGATGTGCCCCTGTG

ACAGCCAGCGCCAGAAAGTTCACCTGTACCTGCGGCAGCTGTCCCAGCAT

TTGCGGAGAGTGTGAAGGCGACCAT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 101, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 101 is provided herein as SEQ ID No: 102, as follows:

[SEQ ID No: 102]

AUGGCCGAGGAACCUACCUACACCACCGAACAGGUGGACGAGCUGAUUCA

CGCCGGACUGGGAACCGUGGACUUCUUUCUGUCCCGGCCUAUCGAUGCCC

AGAGCAGCCUCGGCAAGGGAUCUAUUCCUCCUGGCGUGACAGCCGUGCUG

ACAUCUGCCGCCGAGGCCAAGUCUAAACCUGUGGCUGCUGGACCCGUGAA

GCCCAGACGGAAGAAAGUGAUCAGCAACACCACACCUUACACGAUCGCCG

ACAACAUCCCUCCUGAGAAGCUGCCCAUCAACACCCCUAUUCCUAAUCCU

CUGCUGCCCCUGGCCAGACCUCACGGCAAGAUGACCGACAUCGAUAUCGU

GACCGGCAACAUCACCGAGGGCAGCUACAAAGGCGUGGAACUGGCCAAGC

UGGGCAAGCAGACACUGCUGACCAGAUUCACCAGCAACGAGCCUGUGUCU

AGCGCCGGCUCUGCCCAGGAUCCUAACUUCAAAAGAGGCGGAGCCAACAG

AGAGAGAGCCAGAGGCAACCAUCGGAGAGAGUGGUCUAUUGCCUGGGUCG

GAGAUCAAGUGAAGGUGUUCGAGUGGUGCAACCCCAGAUGUGCCCCUGUG

ACAGCCAGCGCCAGAAAGUUCACCUGUACCUGCGGCAGCUGUCCCAGCAU

UUGCGGAGAGUGUGAAGGCGACCAU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 102, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Mumps Non-structural protein V (P30928), or an orthologue thereof. One embodiment of the polypeptide sequence of Mumps V protein is represented herein as SEQ ID No: 103, as follows:

[SEQ ID No: 103]

MDQFIKQDETGDLIETGMNVANHFLSAPIQGTNSLSKATIIPGVAPVLIG

NPEQKNIQYPTTSHQGSKSKGRGSGARPIIVSSSEGGTGGTQVPEPLFAQ

TGOGGIVTTVYQDPTIQPTGSYRSVELAKIGKERMINRFVEKPRTSTPVT

EFKRGAGSGCSRPDNPRGGHRREWSLSWVQGEVRVFEWCNPICSPITAAA

RFHSCKCGNCPAKCDQCERDYGPP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 103, or a variant or fragment thereof.

In one embodiment, the Mumps V polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 104, as follows:

[SEQ ID No: 104]

ATGGACCAATTTATAAAACAAGATGAGACTGGTGATTTAATTGAGACAGG

AATGAACGTTGCAAATCATTTCCTATCCGCCCCCATTCAGGGAACCAACT

CGTTGAGCAAGGCCACAATCATCCCTGGCGTTGCACCAGTACTCATTGGC

AATCCAGAGCAAAAGAACATTCAGTACCCCACCACATCACATCAGGGATC

CAAGTCAAAGGGCAGAGGCTCAGGGGCCAGGCCCATCATAGTCTCATCCT

CCGAAGGAGGCACTGGAGGGACTCAGGTTCCTGAGCCCCTTTTCGCACAA

ACAGGACAAGGTGGCATTGTCACCACCGTTTATCAGGATCCAACTATCCA

ACCAACAGGTTCATATCGAAGTGTGGAATTGGCTAAGATAGGAAAAGAGA

GAATGATTAATCGATTTGTTGAAAAACCAAGAACCTCAACGCCGGTAACA

GAATTTAAGAGGGGGGCCGGGAGCGGCTGCTCAAGGCCAGACAATCCAAG

AGGAGGGCATAGACGGGAATGGAGCCTCAGCTGGGTCCAAGGAGAGGTCC

GGGTCTTTGAGTGGTGCAACCCCATATGCTCACCTATCACTGCCGCAGCA

AGATTCCACTCCTGCAAATGTGGGAATTGCCCCGCAAAGTGCGATCAGTG

CGAACGAGATTATGGACCTCCT

Accordingly, preferably the Mumps V polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 104, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Mumps V polypeptide is provided herein as SEQ ID No: 105, as follows:

[SEQ ID No: 105]

ATGGACCAGTTCATCAAGCAGGACGAGACAGGCGACCTGATCGAAACCGG

CATGAACGTGGCCAACCACTTCCTGTCTGCCCCTATCCAGGGCACCAACA

GCCTGAGCAAGGCCACAATTATCCCTGGCGTGGCCCCTGTGCTGATCGGC

AATCCTGAGCAGAAGAACATTCAGTACCCCACCACCAGCCACCAGGGCAG

CAAGTCTAAAGGCAGAGGCTCTGGCGCTCGGCCCATCATCGTTTCTAGTA

GCGAAGGCGGCACCGGCGGAACACAGGTTCCAGAACCTCTGTTTGCCCAG

ACAGGCCAAGGCGGCATCGTGACCACAGTGTACCAGGATCCTACCATCCA

GCCTACCGGCAGCTACAGAAGCGTGGAACTGGCCAAGATCGGCAAAGAAC

GGATGATCAACCGCTTCGTGGAAAAGCCCAGAACCAGCACACCCGTGACC

GAGTTCAAAAGAGGCGCCGGAAGCGGCTGCAGCAGACCCGATAATCCTAG

AGGCGGCCATCGGAGAGAGTGGTCCCTGTCTTGGGTTCAGGGCGAAGTGC

GGGTGTTCGAGTGGTGCAATCCTATCTGCAGCCCCATCACAGCCGCCGCT

AGATTCCACAGCTGCAAGTGCGGAAACTGCCCCGCCAAGTGTGACCAGTG

CGAGAGAGATTACGGCCCTCCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 105, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 105 is provided herein as SEQ ID No: 106, as follows:

[SEQ ID No: 106]

AUGGACCAGUUCAUCAAGCAGGACGAGACAGGCGACCUGAUCGAAACCGGCAUGAACGUGGCCAACCACUUCCUGUCU

GCCCCUAUCCAGGGCACCAACAGCCUGAGCAAGGCCACAAUUAUCCCUGGCGUGGCCCCUGUGCUGAUCGGCAAUCCU

GAGCAGAAGAACAUUCAGUACCCCACCACCAGCCACCAGGGCAGCAAGUCUAAAGGCAGAGGCUCUGGCGCUCGGCCC

AUCAUCGUUUCUAGUAGCGAAGGCGGCACCGGCGGAACACAGGUUCCAGAACCUCUGUUUGCCCAGACAGGCCAAGGC

GGCAUCGUGACCACAGUGUACCAGGAUCCUACCAUCCAGCCUACCGGCAGCUACAGAAGCGUGGAACUGGCCAAGAUC

GGCAAAGAACGGAUGAUCAACCGCUUCGUGGAAAAGCCCAGAACCAGCACACCCGUGACCGAGUUCAAAAGAGGCGCC

GGAAGCGGCUGCAGCAGACCCGAUAAUCCUAGAGGCGGCCAUCGGAGAGAGUGGUCCCUGUCUUGGGUUCAGGGCGAA

GUGCGGGUGUUCGAGUGGUGCAAUCCUAUCUGCAGCCCCAUCACAGCCGCCGCUAGAUUCCACAGCUGCAAGUGCGGA

AACUGCCCCGCCAAGUGUGACCAGUGCGAGAGAGAUUACGGCCCUCCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 106, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Sendai Virus Protein V (strain Fushimi) (P69284), or an orthologue thereof. One embodiment of the polypeptide sequence of Sendai Virus Protein V (SeV V protein) is represented herein as SEQ ID No: 107, as follows:

[SEQ ID No: 107]

MDQDAFILKEDSEVEREAPGGRESLSDVIGFLDAVLSSEPTDIGGDRSWLHNTINTPQGPGSAHRAKSEGEGEVSTPS

TQDNRSGEESRVSGRTSKPEAEAHAGNLDKQNIHRAFGGRTGTNSVSQDLGDGGDSGILENPPNERGYPRSGIEDENR

EMAAHPDKRGEDQAEGLPEEVRGGTSLPDEGEGGASNNGRSMEPGSSHSARVTGVLVIPSPELEEAVLRRNKRRPTNS

GSKPLTPATVPGTRSPPLNRYNSTGSPPGKPPSTQDEHINSGDTPAVRVKDRKPPIGTRSVSDCPANGRPIHPGLETD

STKKGHRREHITYERDGYIVDESWCNPVCSRIRVIPRRELCVCKTCPKVCKLCRDDIQCMRPDPFCREIFRS

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 107, or a variant or fragment thereof.

In one embodiment, the SeV V polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 108, as follows:

[SEQ ID No: 108]

ATGGATCAAGATGCCTTCATTCTTAAAGAAGATTCTGAAGTTGAGAGGGAGGCGCCAGGAGGAAGAGAGTCGCTCTCG

GATGTTATCGGATTCCTCGATGCTGTCCTGTCGAGTGAACCAACTGACATCGGAGGGGACAGAAGCTGGCTCCACAAC

ACCATCAACACTCCCCAAGGACCAGGCTCTGCCCATAGAGCCAAAAGTGAGGGCGAAGGAGAAGTCTCAACACCGTCG

ACCCAAGATAATCGATCAGGTGAGGAGAGTAGAGTCTCTGGGAGAACAAGCAAGCCAGAGGCAGAAGCACATGCTGGA

AACCTTGATAAACAAAATATACACCGGGCCTTTGGGGGAAGAACTGGTACAAACTCTGTATCTCAGGATCTGGGCGAT

GGAGGAGACTCCGGAATCCTTGAAAATCCCCCAAATGAGAGAGGATATCCGAGATCAGGTATTGAAGATGAAAACAGA

GAGATGGCTGCGCACCCTGATAAGAGGGGAGAAGACCAAGCTGAAGGACTTCCAGAAGAGGTACGAGGAGGTACATCC

CTACCTGATGAAGGAGAAGGTGGAGCAAGTAATAATGGAAGAAGCATGGAGCCTGGCAGCTCACATAGTGCAAGAGTA

ACTGGGGTCCTGGTGATTCCTAGCCCCGAACTCGAAGAGGCTGTGCTACGGAGGAACAAAAGAAGACCTACCAACAGT

GGGTCCAAACCTCTTACTCCAGCAACCGTGCCTGGCACCCGGTCCCCACCGCTGAATCGTTACAACAGCACAGGGTCA

CCACCAGGAAAACCCCCATCTACACAGGATGAGCACATCAACTCTGGGGACACCCCCGCCGTCAGGGTCAAAGACCGG

AAACCACCAATAGGGACCCGCTCTGTCTCAGATTGTCCAGCCAACGGCCGCCCAATCCACCCGGGTCTAGAGACCGAC

TCAACAAAAAAGGGgCATAGGAGAGAACACATCATCTATGAAAGAGATGGCTACATTGTTGACGAGTCTTGGTGTAAT

CCAGTCTGCTCAAGAATTCGAGTCATCCCGAGACGCGAGTTATGTGTTTGCAAGACGTGCCCTAAAGTCTGCAAACTA

TGCAGAGATGACATTCAATGTATGCGGCCTGATCCTTTCTGCCGAGAAATCTTCCGCTCG

Accordingly, preferably the SeV V polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 108, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SeV V polypeptide is provided herein as SEQ ID No: 109, as follows:

[SEQ ID No: 109]

ATGGACCAGGACGCCTTCATCCTGAAAGAGGACAGCGAGGTCGAGAGAGAAGCCCCTGGCGGAAGAGAAAGCCTGTCC

GATGTGATCGGCTTCCTGGATGCCGTGCTGAGCAGCGAGCCTACAGATATCGGCGGCGATAGAAGCTGGCTGCACAAC

ACCATCAACACCCCTCAAGGCCCTGGCTCTGCCCACAGAGCTAAGTCTGAAGGCGAGGGCGAAGTGTCTACCCCTAGC

ACACAGGACAACAGAAGCGGCGAGGAATCCAGAGTGTCCGGCAGAACAAGCAAGCCTGAGGCCGAAGCTCACGCCGGC

AATCTGGACAAGCAGAACATCCACAGAGCCTTCGGCGGCAGAACCGGCACAAATAGCGTGTCACAGGACCTCGGAGAT

GGCGGCGATTCTGGCATCCTGGAAAACCCTCCAAACGAGCGGGGCTACCCTAGAAGCGGAATCGAGGACGAGAACAGA

GAGATGGCCGCTCATCCCGACAAGAGAGGCGAAGATCAGGCCGAGGGACTGCCTGAAGAAGTGCGCGGAGGAACAAGC

CTGCCTGACGAAGGCGAAGGCGGAGCCTCTAACAACGGCAGATCTATGGAACCCGGCAGCAGCCATAGCGCCAGAGTT

ACAGGCGTGCTGGTCATCCCATCTCCAGAGCTGGAAGAGGCTGTGCTGAGGCGGAACAAGAGAAGGCCTACCAACAGC

GGCAGCAAGCCTCTGACACCAGCTACAGTGCCTGGCACAAGAAGCCCTCCACTGAACCGGTACAACAGCACAGGCTCT

CCACCTGGCAAGCCTCCATCCACACAGGATGAGCACATCAACTCCGGCGATACCCCTGCCGTCAGAGTGAAGGACAGA

AAGCCTCCTATCGGCACCAGAAGCGTGTCCGACTGTCCTGCCAATGGCAGACCTATTCACCCCGGCCTGGAAACCGAC

AGCACCAAGAAGGGACACAGACGGGAACACATCATCTACGAGCGCGACGGCTACATCGTGGACGAGAGCTGGTGCAAC

CCTGTGTGCAGCCGGATCAGAGTGATCCCTCGGAGAGAACTGTGCGTGTGCAAGACATGCCCCAAAGTGTGCAAGCTG

TGCCGGGACGACATCCAGTGTATGCGGCCCGATCCTTTCTGCAGAGAGATCTTCAGAAGC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 109, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 109 is provided herein as SEQ ID No: 110, as follows:

[SEQ ID No: 110]

AUGGACCAGGACGCCUUCAUCCUGAAAGAGGACAGCGAGGUCGAGAGAGAAGCCCCUGGCGGAAGAGAAAGCCUGUCC

GAUGUGAUCGGCUUCCUGGAUGCCGUGCUGAGCAGCGAGCCUACAGAUAUCGGCGGCGAUAGAAGCUGGCUGCACAAC

ACCAUCAACACCCCUCAAGGCCCUGGCUCUGCCCACAGAGCUAAGUCUGAAGGCGAGGGCGAAGUGUCUACCCCUAGC

ACACAGGACAACAGAAGCGGCGAGGAAUCCAGAGUGUCCGGCAGAACAAGCAAGCCUGAGGCCGAAGCUCACGCCGGC

AAUCUGGACAAGCAGAACAUCCACAGAGCCUUCGGCGGCAGAACCGGCACAAAUAGCGUGUCACAGGACCUCGGAGAU

GGCGGCGAUUCUGGCAUCCUGGAAAACCCUCCAAACGAGCGGGGCUACCCUAGAAGCGGAAUCGAGGACGAGAACAGA

GAGAUGGCCGCUCAUCCCGACAAGAGAGGCGAAGAUCAGGCCGAGGGACUGCCUGAAGAAGUGCGCGGAGGAACAAGC

CUGCCUGACGAAGGCGAAGGCGGAGCCUCUAACAACGGCAGAUCUAUGGAACCCGGCAGCAGCCAUAGCGCCAGAGUU

ACAGGCGUGCUGGUCAUCCCAUCUCCAGAGCUGGAAGAGGCUGUGCUGAGGCGGAACAAGAGAAGGCCUACCAACAGC

GGCAGCAAGCCUCUGACACCAGCUACAGUGCCUGGCACAAGAAGCCCUCCACUGAACCGGUACAACAGCACAGGCUCU

CCACCUGGCAAGCCUCCAUCCACACAGGAUGAGCACAUCAACUCCGGCGAUACCCCUGCCGUCAGAGUGAAGGACAGA

AAGCCUCCUAUCGGCACCAGAAGCGUGUCCGACUGUCCUGCCAAUGGCAGACCUAUUCACCCCGGCCUGGAAACCGAC

AGCACCAAGAAGGGACACAGACGGGAACACAUCAUCUACGAGCGCGACGGCUACAUCGUGGACGAGAGCUGGUGCAAC

CCUGUGUGCAGCCGGAUCAGAGUGAUCCCUCGGAGAGAACUGUGCGUGUGCAAGACAUGCCCCAAAGUGUGCAAGCUG

UGCCGGGACGACAUCCAGUGUAUGCGGCCCGAUCCUUUCUGCAGAGAGAUCUUCAGAAGC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 110, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Measles Non-structural protein V (strain Ichinose-B95a) (POC774), or an orthologue thereof. One embodiment of the polypeptide sequence of Measles V protein is represented herein as SEQ ID No: 111, as follows:

[SEQ ID No: 111]

MAEEQARHVKNGLECIRALKAEPIGSLAVEEAMAAWSEISDNPGQDRATCKEEEAGSSGLSKPCLSAIGSTEGGAPRI

RGQGSGESDDDAETLGIPSRNLQASSTGLQCYHVYDHSGEAVKGIQDADSIMVQSGLDGDSTLSGGDDESENSDVDIG

EPDTEGYAITDRGSAPISMGFRASDVETAEGGEIHELLKLQSRGNNFPKLGKTLNVPPPPNPSRASTSETPIKKGHRR

EIGLIWNGDRVFIDRWCNPMCSKVTLGTIRARCTCGECPRVCEQCRTDTGVDTRIWYHNLPEIPE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 111, or a variant or fragment thereof.

In one embodiment, the Measles V polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 112, as follows:

[SEQ ID No: 112]

ATGGCAGAAGAGCAGGCACGCCATGTCAAAAACGGACTGGAATGCATCCGGGCTCTCAAGGCCGAGCCCATCGGCTCA

CTGGCCGTCGAGGAAGCCATGGCAGCATGGTCAGAAATATCAGACAACCCAGGACAGGACCGAGCCACCTGCAAGGAA

GAGGAGGCAGGCAGTTCGGGTCTCAGCAAACCATGCCTCTCAGCAATTGGATCAACTGAAGGCGGTGCACCTCGCATC

CGCGGTCAGGGATCTGGAGAAAGCGATGACGACGCTGAAACTTTGGGAATCCCCTCAAGAAATCTCCAGGCATCAAGC

ACTGGGTTACAGTGTTATCATGTTTATGATCACAGCGGTGAAGCGGTTAAGGGAATCCAAGATGCTGACTCTATCATG

GTTCAATCAGGCCTTGATGGTGATAGCACCCTCTCAGGAGGAGACGATGAATCTGAAAACAGCGATGTGGATATTGGC

GAACCTGATACCGAGGGATATGCTATCACTGACCGGGGATCTGCTCCCATCTCTATGGGGTTCAGGGCTTCTGATGTT

GAAACTGCAGAAGGAGGGGAGATCCACGAGCTCCTGAAACTCCAATCCAGAGGCAACAACTTTCCGAAGCTTGGGAAA

ACTCTCAATGTTCCTCCGCCCCCGAACCCCAGTAGGGCCAGCACTTCCGAGACACCCATTAAAAAGGGgCACAGACGC

GAGATTGGCCTCATTTGGAACGGAGATCGCGTCTTTATTGACAGGTGGTGCAACCCAATGTGCTCGAAAGTCACCCTC

GGAACCATCAGGGCCAGGTGCACCTGCGGGGAATGTCCCCGAGIGTGTGAGCAATGCCGCACTGATACAGGAGTGGAC

ACCCGAATCTGGTACCACAATCTCCCCGAGATCCCAGAA

Accordingly, preferably the Measles V polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 112, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Measles V polypeptide is provided herein as SEQ ID No: 113, as follows:

[SEQ ID No: 113]

ATGGCCGAAGAACAGGCCAGACACGTGAAGAACGGCCTGGAATGCATCAGAGCCCTGAAGGCCGAGCCTATCGGATCT

CTGGCTGTGGAAGAAGCCATGGCCGCTTGGAGCGAGATCAGCGATAATCCCGGCCAGGACCGGGCCACCTGTAAAGAA

GAAGAGGCCGGATCTAGCGGCCTGAGCAAGCCTTGTCTGTCTGCCATCGGCTCTACAGAAGGCGGCGCTCCTAGAATC

AGAGGCCAAGGATCTGGCGAGAGCGACGACGATGCTGAGACACTGGGCATCCCCAGCAGAAATCTGCAGGCCAGCTCT

ACCGGCCTGCAGTGCTATCACGTGTACGATCACTCTGGCGAGGCCGTGAAGGGAATCCAGGATGCCGATAGCATCATG

GTGCAGAGCGGCCTGGATGGCGACTCTACACTTAGCGGCGGAGATGACGAGAGCGAGAACTCCGATGTGGACATCGGC

GAGCCTGATACAGAGGGCTACGCCATCACAGACAGAGGCAGCGCCCCTATCAGCATGGGCTTTAGAGCCAGCGACGTG

GAAACAGCCGAAGGCGGAGAGATTCACGAGCTGCTGAAGCTGCAGAGCCGGGGCAACAACTTTCCCAAGCTGGGCAAG

ACCCTGAACGTGCCACCTCCTCCAAATCCTAGCAGAGCCAGCACCAGCGAGACACCCATCAAGAAGGGCCACAGAAGA

GAGATCGGCCTGATCTGGAACGGCGACCGGGTGTTCATCGACAGATGGTGCAACCCCATGTGCAGCAAAGTGACCCTG

GGCACCATCCGGGCCAGATGTACATGCGGAGAGTGCCCTAGAGTGTGCGAGCAGTGCAGAACCGATACCGGCGTGGAC

ACCCGGATCTGGTATCACAACCTGCCTGAGATCCCCGAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 113, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 113 is provided herein as SEQ ID No: 114, as follows:

[SEQ ID No: 114]

AUGGCCGAAGAACAGGCCAGACACGUGAAGAACGGCCUGGAAUGCAUCAGAGCCCUGAAGGCCGAGCCUAUCGGAUCU

CUGGCUGUGGAAGAAGCCAUGGCCGCUUGGAGCGAGAUCAGCGAUAAUCCCGGCCAGGACCGGGCCACCUGUAAAGAA

GAAGAGGCCGGAUCUAGCGGCCUGAGCAAGCCUUGUCUGUCUGCCAUCGGCUCUACAGAAGGCGGCGCUCCUAGAAUC

AGAGGCCAAGGAUCUGGCGAGAGCGACGACGAUGCUGAGACACUGGGCAUCCCCAGCAGAAAUCUGCAGGCCAGCUCU

ACCGGCCUGCAGUGCUAUCACGUGUACGAUCACUCUGGCGAGGCCGUGAAGGGAAUCCAGGAUGCCGAUAGCAUCAUG

GUGCAGAGCGGCCUGGAUGGCGACUCUACACUUAGCGGCGGAGAUGACGAGAGCGAGAACUCCGAUGUGGACAUCGGC

GAGCCUGAUACAGAGGGCUACGCCAUCACAGACAGAGGCAGCGCCCCUAUCAGCAUGGGCUUUAGAGCCAGCGACGUG

GAAACAGCCGAAGGCGGAGAGAUUCACGAGCUGCUGAAGCUGCAGAGCCGGGGCAACAACUUUCCCAAGCUGGGCAAG

ACCCUGAACGUGCCACCUCCUCCAAAUCCUAGCAGAGCCAGCACCAGCGAGACACCCAUCAAGAAGGGCCACAGAAGA

GAGAUCGGCCUGAUCUGGAACGGCGACCGGGUGUUCAUCGACAGAUGGUGCAACCCCAUGUGCAGCAAAGUGACCCUG

GGCACCAUCCGGGCCAGAUGUACAUGCGGAGAGUGCCCUAGAGUGUGCGAGCAGUGCAGAACCGAUACCGGCGUGGAC

ACCCGGAUCUGGUAUCACAACCUGCCUGAGAUCCCCGAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 114, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Nipah virus Non-structural protein V (NiV V protein) (Q997F2; V_NIPAV), or an orthologue thereof. One embodiment of the polypeptide sequence of NiV V protein is represented herein as SEQ ID No: 115, as follows:

[SEQ ID No: 115]

MDKLELVNDGLNIIDFIQKNQKEIQKTYGRSSIQQPSIKDQTKAWEDFLQCTSGESEQVEGGMSKDDGDVERRNLEDL

SSTSPTDGTIGKRVSNTRDWAEGSDDIQLDPVVTDVVYHDHGGECTGYGFTSSPERGWSDYTSGANNGNVCLVSDAKM

LSYAPEIAVSKEDRETDLVHLENKLSTTGLNPTAVPFTLRNLSDPAKDSPVIAEHYYGLGVKEQNVGPQTSRNVNLDS

IKLYTSDDEEADQLEFEDEFAGSSSEVIVGISPEDEEPSSVGGKPNESIGRTIEGQSIRDNLQAKDNKSTDVPGAGPK

DSAVKEEPPQKRLPMLAEEFECSGSEDPIIRELLKENSLINCQQGKDAQPPYHWSIERSISPDKTEIVNGAVQTADRQ

RPGTPMPKSRGIPIKKGHRREISICWDGKRAWVEEWCNPACSRITPLPRRQECQCGECPTECFHCG

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 115, or a variant or fragment thereof.

In one embodiment, the NiV V polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 116, as follows:

[SEQ ID No: 116]

ATGGATAAATTGGAACTAGTCAATGATGGCCTCAATATTATTGACTTTATTCAGAAGAACCAAAAAGAAATACAGAAG

ACATACGGACGATCAAGTATTCAACAACCCAGCATCAAAGATCAAACAAAAGCCTGGGAAGATTTTCTGCAGTGCACC

AGTGGAGAATCTGAACAAGTTGAGGGGGGAATGTCTAAGGATGATGGAGATGTTGAAAGAAGAAACTTGGAGGATCTA

TCCAGTACTTCTCCCACAGATGGAACTATTGGAAAGAGAGTGTCGAACACCCGTGACTGGGCAGAAGGTTCAGATGAC

ATACAACTGGACCCAGTGGTTACAGACGTTGTATACCATGATCATGGAGGAGAATGTACCGGATATGGATTTACTTCA

AGCCCTGAGAGAGGGTGGAGTGATTACACATCAGGAGCAAACAATGGGAATGTATGTCTTGTATCTGATGCAAAGATG

CTGTCCTATGCTCCCGAAATTGCAGTTTCTAAAGAAGATCGGGAAACTGATCTAGTTCATCTTGAGAATAAACTATCT

ACTACAGGACTGAATCCCACAGCAGTACCGTTCACTCTGAGAAACCTGTCTGATCCTGCAAAAGACTCTCCTGTGATT

GCTGAACACTACTACGGACTAGGAGTTAAAGAGCAAAACGTTGGCCCTCAGACTAGCAGAAATGTCAATTTGGACAGC

ATCAAATTGTACACATCAGATGACGAAGAGGCAGATCAGCTTGAATTCGAAGATGAGTTTGCAGGAAGCTCAAGTGAA

GTGATAGTCGGCATTTCTCCTGAAGATGAAGAGCCTTCAAGTGTTGGCGGAAAACCCAATGAATCCATTGGACGTACA

ATCGAAGGCCAATCAATCCGAGACAACCTTCAAGCCAAGGACAACAAATCAACAGATGTACCAGGAGCAGGACCGAAA

GATTCAGCAGTGAAGGAAGAACCACCCCAGAAGAGGCTACCTATGTTAGCTGAAGAATTTGAGTGCTCTGGATCGGAA

GACCCAATCATTCGGGAGCTGCTGAAGGAGAACTCACTCATAAATTGTCAGCAAGGGAAAGATGCTCAGCCTCCATAT

CATTGGAGCATCGAGAGGTCAATAAGCCCGGATAAAACTGAGATCGTCAACGGTGCTGTGCAAACTGCTGACAGGCAA

AGACCAGGAACTCCGATGCCAAAGTCCCGAGGTATTCCCATTAAAAAGGGGCACAGACGCGAAATATCCATCTGCTGG

GACGGAAAACGTGCCTGGGTCGAAGAGTGGTGCAACCCGGCATGTTCGAGGATCACCCCCCTACCAAGAAGGCAAGAG

TGTCAATGCGGAGAATGTCCAACTGAATGCTTCCACTGCGGT

Accordingly, preferably the NiV V polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 116, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the NiV V polypeptide is provided herein as SEQ ID No: 117, as follows:

[SEQ ID No: 117]

ATGGACAAGCTGGAACTGGTCAACGACGGCCTGAACATCATCGACTTCATCCAGAAGAACCAGAAAGAGATCCAGAAA

ACCTACGGCCGGTCCAGCATCCAGCAGCCTAGCATCAAGGATCAGACCAAGGCCTGGGAAGATTTCCTGCAGTGTACC

AGCGGCGAGAGCGAACAGGTTGAAGGCGGCATGAGCAAGGACGACGGCGACGTGGAAAGACGGAACCTGGAAGATCTG

AGCAGCACAAGCCCTACCGATGGCACCATCGGCAAGCGGGTGTCCAACACAAGAGATTGGGCCGAGGGCAGCGACGAC

ATTCAGCTGGATCCTGTGGTCACCGATGTGGTGTACCACGATCACGGCGGCGAGTGTACAGGCTACGGCTTTACAAGC

AGCCCCGAGAGAGGCTGGAGCGATTATACAAGCGGCGCCAACAACGGCAACGTGTGCCTGGTGTCTGACGCCAAGATG

CTGAGCTACGCCCCTGAGATCGCCGTGTCCAAAGAGGACAGAGAAACCGACCTGGTGCACCTGGAAAACAAGCTGAGC

ACCACCGGACTGAACCCTACCGCCGTGCCTTTCACACTGAGAAACCTGAGCGACCCCGCCAAGGACTCTCCTGTGATT

GCCGAGCACTACTACGGCCTGGGCGTGAAAGAACAGAACGTGGGCCCTCAGACCAGCCGGAACGTGAACCTGGATTCC

ATCAAGCTGTACACCTCCGACGACGAGGAAGCCGACCAGCTGGAATTCGAGGATGAGTTTGCCGGCAGCAGCAGCGAA

GTGATTGTGGGCATCAGCCCTGAGGACGAGGAACCTAGCTCTGTTGGCGGCAAGCCCAATGAGAGCATCGGCAGAACA

ATCGAGGGCCAGAGCATCCGGGATAACCTGCAGGCCAAGGACAACAAGAGCACCGATGTTCCAGGCGCTGGCCCTAAG

GATAGCGCCGTGAAAGAGGAACCACCTCAGAAACGGCTGCCCATGCTGGCCGAGGAATTTGAGTGTAGCGGCAGCGAG

GACCCCATCATCAGAGAGCTGCTGAAAGAGAACAGCCTGATCAACTGCCAGCAGGGCAAAGACGCCCAGCCTCCTTAC

CACTGGTCCATCGAGAGATCTATCAGCCCCGACAAGACCGAGATCGTGAATGGCGCTGTGCAGACCGCCGATAGACAG

AGGCCTGGAACTCCCATGCCTAAGAGCAGAGGCATCCCCATCAAGAAGGGCCACAGAAGAGAGATCAGCATCTGCTGG

GACGGCAAGCGCGCCTGGGTTGAAGAGTGGTGTAATCCCGCCTGCAGCCGGATCACACCTCTGCCTAGAAGGCAAGAG

TGCCAGTGTGGCGAGTGTCCCACCGAGTGTTTTCACTGTGGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 117, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 117 is provided herein as SEQ ID No: 118, as follows:

[SEQ ID No: 118]

AUGGACAAGCUGGAACUGGUCAACGACGGCCUGAACAUCAUCGACUUCAUCCAGAAGAACCAGAAAGAGAUCCAGAAA

ACCUACGGCCGGUCCAGCAUCCAGCAGCCUAGCAUCAAGGAUCAGACCAAGGCCUGGGAAGAUUUCCUGCAGUGUACC

AGCGGCGAGAGCGAACAGGUUGAAGGCGGCAUGAGCAAGGACGACGGCGACGUGGAAAGACGGAACCUGGAAGAUCUG

AGCAGCACAAGCCCUACCGAUGGCACCAUCGGCAAGCGGGUGUCCAACACAAGAGAUUGGGCCGAGGGCAGCGACGAC

AUUCAGCUGGAUCCUGUGGUCACCGAUGUGGUGUACCACGAUCACGGCGGCGAGUGUACAGGCUACGGCUUUACAAGC

AGCCCCGAGAGAGGCUGGAGCGAUUAUACAAGCGGCGCCAACAACGGCAACGUGUGCCUGGUGUCUGACGCCAAGAUG

CUGAGCUACGCCCCUGAGAUCGCCGUGUCCAAAGAGGACAGAGAAACCGACCUGGUGCACCUGGAAAACAAGCUGAGC

ACCACCGGACUGAACCCUACCGCCGUGCCUUUCACACUGAGAAACCUGAGCGACCCCGCCAAGGACUCUCCUGUGAUU

GCCGAGCACUACUACGGCCUGGGCGUGAAAGAACAGAACGUGGGCCCUCAGACCAGCCGGAACGUGAACCUGGAUUCC

AUCAAGCUGUACACCUCCGACGACGAGGAAGCCGACCAGCUGGAAUUCGAGGAUGAGUUUGCCGGCAGCAGCAGCGAA

GUGAUUGUGGGCAUCAGCCCUGAGGACGAGGAACCUAGCUCUGUUGGCGGCAAGCCCAAUGAGAGCAUCGGCAGAACA

AUCGAGGGCCAGAGCAUCCGGGAUAACCUGCAGGCCAAGGACAACAAGAGCACCGAUGUUCCAGGCGCUGGCCCUAAG

GAUAGCGCCGUGAAAGAGGAACCACCUCAGAAACGGCUGCCCAUGCUGGCCGAGGAAUUUGAGUGUAGCGGCAGCGAG

GACCCCAUCAUCAGAGAGCUGCUGAAAGAGAACAGCCUGAUCAACUGCCAGCAGGGCAAAGACGCCCAGCCUCCUUAC

CACUGGUCCAUCGAGAGAUCUAUCAGCCCCGACAAGACCGAGAUCGUGAAUGGCGCUGUGCAGACCGCCGAUAGACAG

AGGCCUGGAACUCCCAUGCCUAAGAGCAGAGGCAUCCCCAUCAAGAAGGGCCACAGAAGAGAGAUCAGCAUCUGCUGG

GACGGCAAGCGCGCCUGGGUUGAAGAGUGGUGUAAUCCCGCCUGCAGCCGGAUCACACCUCUGCCUAGAAGGCAAGAG

UGCCAGUGUGGCGAGUGUCCCACCGAGUGUUUUCACUGUGGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 118, or a fragment or variant thereof.

In one embodiment, the at least one IIP is POLG_EMCV (Encephalomyocarditis virus 2C) genome polyprotein (Li L, Fan H, Song Z, Liu X, Bai J, Jiang P (2019) Encephalomyocarditis virus 2C protein antagonizes interferon-B signaling pathway through interaction with MDA5 Antiviral Res, 161, 70-84), or an orthologue thereof. One embodiment of the polypeptide sequence of EMCV is represented herein as SEQ ID No: 119, as follows:

[SEQ ID No: 119]

LKARDINDIFAILKNGEWLVKLILAIRDWIKAWIASEEKFVTMTDLVPGILEKQRDLNDPSKYKEAKEWLDNARQACL

KSGNVHIANLCKVVAPAPSKSRPEPVVVCLRGKSGQGKSFLANVLAQAISTHFTGRIDSVWYCPPDPDHFDGYNQQTV

VVMDDLGQNPDGKDFKYFAQMVSTTGFIPPMASLEDKGKPFNSKVIIATTNLYSGFTPRTMVCPDALNRRFHFDIDVS

AKDGYKINSKLDIIKALEDTHANPVAMFQYDCALLNGMAVEMKRMQQDMFKPQPPLQNVYQLVQEVIDRVELHEKVSS

HPIFKQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 119, or a variant or fragment thereof.

In one embodiment, the EMCV polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 120, as follows:

[SEQ ID No: 120]

CTCAAAGCACGTGACATCAACGACATCTTCGCCATTCTCAAGAACGGCGAGTGGCTGGTCAAACTGATCCTTGCCATC

CGCGACTGGATTAAGGCTTGGATCGCCTCAGAAGAGAAGTTTGTCACCATGACAGACTTGGTGCCTGGCATCCTTGAA

AAGCAGCGGGACCTGAACGACCCGAGCAAGTACAAGGAAGCCAAGGAGTGGCTCGACAACGCGCGCCAAGCGTGTTTG

AAGAGCGGGAACGTCCACATTGCCAACCTGTGCAAAGTGGTCGCACCAGCACCCAGCAAGTCGAGGCCCGAACCCGTG

GTTGTTTGCCTCCGCGGCAAATCTGGCCAGGGCAAGAGCTTCCTTGCAAACGTGCTTGCACAGGCAATTTCCACCCAC

TTCACCGGCAGAATCGACTCAGTGTGGTACTGCCCACCTGACCCTGACCACTTCGACGGTTACAACCAGCAAACCGTT

GTTGTGATGGATGATTTGGGCCAGAACCCTGACGGCAAGGACTTCAAATACTTTGCCCAAATGGTCTCGACCACAGGG

TTTATCCCGCCCATGGCATCACTCGAGGACAAAGGTAAACCTTTCAACAGCAAAGTCATCATCGCGACCACCAACTTG

TACTCGGGCTTCACCCCGAGGACCATGGTATGTCCCGACGCACTGAACCGGAGGTTTCACTTTGACATCGATGTGAGT

GCTAAGGATGGGTACAAAATTAACAGCAAATTGGACATTATCAAAGCACTCGAAGACACCCACGCCAACCCAGTGGCA

ATGTTTCAATACGACTGIGCCCTTCTCAACGGCATGGCCGTTGAAATGAAGAGAATGCAACAAGACATGTTCAAGCCT

CAACCACCCCTCCAGAATGTGTACCAGCTTGTTCAGGAGGTGATCGATCGGGTCGAGCTCCACGAGAAAGTGTCGAGT

CACCCGATCTTCAAGCAG

Accordingly, preferably the EMCV polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 120, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EMCV polypeptide is provided herein as SEQ ID No: 121, as follows:

[SEQ ID No: 121]

CTGAAGGCCAGAGACATCAACGACATCTTCGCCATCCTGAAGAACGGCGAGTGGCTGGTCAAGCTGATCCTGGCCATC

AGAGACTGGATCAAGGCCTGGATCGCCAGCGAAGAGAAGTTCGTGACCATGACCGATCTGGTGCCCGGCATCCTGGAA

AAGCAGAGGGACCTGAACGACCCCAGCAAGTACAAAGAGGCCAAAGAATGGCTGGACAACGCCAGACAGGCCTGCCTG

AAGTCCGGCAATGTGCATATCGCCAACCTGTGCAAGGTGGTGGCCCCTGCTCCTAGCAAGTCTAGACCTGAGCCTGTG

GTCGTGTGCCTGAGAGGCAAATCTGGCCAGGGCAAGAGCTTCCTGGCCAATGTTCTGGCCCAGGCCATCAGCACCCAC

TTCACCGGAAGAATCGACAGCGTGTGGTACTGCCCTCCTGATCCTGACCACTTCGACGGCTACAACCAGCAGACCGTG

GTGGTCATGGACGACCTGGGACAGAACCCCGACGGCAAGGACTTCAAGTACTTCGCCCAGATGGTGTCCACCACCGGC

TTCATTCCTCCAATGGCCAGCCTGGAAGATAAGGGCAAGCCCTTCAACAGCAAAGTGATCATTGCCACCACCAACCTG

TACAGCGGCTTCACCCCTAGAACCATGGTCTGCCCCGACGCTCTGAACAGACGGTTCCACTTTGACATCGACGTGTCC

GCCAAGGATGGCTACAAGATCAACTCCAAGCTGGACATCATCAAGGCCCTCGAGGACACCCACGCCAATCCTGTGGCC

ATGTTCCAGTACGATTGCGCCCTGCTGAATGGCATGGCCGTGGAAATGAAGCGGATGCAGCAGGACATGTTCAAGCCC

CAGCCTCCACTGCAGAACGTGTACCAGCTCGTGCAAGAAGTGATCGACCGGGTCGAGCTGCACGAGAAGGTGTCCTCT

CATCCCATCTTCAAGCAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 121, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 121 is provided herein as SEQ ID No: 122, as follows:

[SEQ ID No: 122]

CUGAAGGCCAGAGACAUCAACGACAUCUUCGCCAUCCUGAAGAACGGCGAGUGGCUGGUCAAGCUGAUCCUGGCCAUC

AGAGACUGGAUCAAGGCCUGGAUCGCCAGCGAAGAGAAGUUCGUGACCAUGACCGAUCUGGUGCCCGGCAUCCUGGAA

AAGCAGAGGGACCUGAACGACCCCAGCAAGUACAAAGAGGCCAAAGAAUGGCUGGACAACGCCAGACAGGCCUGCCUG

AAGUCCGGCAAUGUGCAUAUCGCCAACCUGUGCAAGGUGGUGGCCCCUGCUCCUAGCAAGUCUAGACCUGAGCCUGUG

GUCGUGUGCCUGAGAGGCAAAUCUGGCCAGGGCAAGAGCUUCCUGGCCAAUGUUCUGGCCCAGGCCAUCAGCACCCAC

UUCACCGGAAGAAUCGACAGCGUGUGGUACUGCCCUCCUGAUCCUGACCACUUCGACGGCUACAACCAGCAGACCGUG

GUGGUCAUGGACGACCUGGGACAGAACCCCGACGGCAAGGACUUCAAGUACUUCGCCCAGAUGGUGUCCACCACCGGC

UUCAUUCCUCCAAUGGCCAGCCUGGAAGAUAAGGGCAAGCCCUUCAACAGCAAAGUGAUCAUUGCCACCACCAACCUG

UACAGCGGCUUCACCCCUAGAACCAUGGUCUGCCCCGACGCUCUGAACAGACGGUUCCACUUUGACAUCGACGUGUCC

GCCAAGGAUGGCUACAAGAUCAACUCCAAGCUGGACAUCAUCAAGGCCCUCGAGGACACCCACGCCAAUCCUGUGGCC

AUGUUCCAGUACGAUUGCGCCCUGCUGAAUGGCAUGGCCGUGGAAAUGAAGCGGAUGCAGCAGGACAUGUUCAAGCCC

CAGCCUCCACUGCAGAACGUGUACCAGCUCGUGCAAGAAGUGAUCGACCGGGUCGAGCUGCACGAGAAGGUGUCCUCU

CAUCCCAUCUUCAAGCAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 122, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Birnavirus VP3 (Avian infectious bursal disease virus (IBDV) (Gumboro disease virus) Capsid Protein VP3), or an orthologue thereof (Ye C, Jia L, Sun Y, Hu B, Wang L, Xingmeng L, Zu J (2014) Inhibition of antiviral innate immunity by birnavirus VP3 protein via blockage of viral double-stranded RNA binding to the host cytoplasmic RNA detector MDA5. J Virol. 88, 18, 11154-11156). One embodiment of the polypeptide sequence of Birnavirus VP3 is represented herein as SEQ ID No: 123, as follows:

[SEQ ID No: 123]

ASEFKETPELESAVRAMEAAANVDPLFQSALSVFMWLEENGIVTDMANFALDSPNAHRMRNFLANAPQAGS

KSQRAKYGTAGYGVEARGPTPEEAQREKDTRISKKMETMGIYFATPEWVALNGHRGPSPGQLKYWQNTREIPDPNEDY

LDYVHAEKSRLASEEQILRAATSIYGAPGQAEPPQAFIDEVAKVYEINHGRGPNQEQMKDLLLTAMEMKHRNPRRALP

KPKPKPNAPTQRPPGRLGRWIRTVSDEDLE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 123, or a variant or fragment thereof.

In one embodiment, the Birnavirus VP3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 124, as follows:

[SEQ ID No: 124]

GCATCAGAGTTCAAAGAGACCCCCGAACTCGAGAGTGCCGTCAGAGCAATGGAAGCAGCAGCCAACGTGGACCCACTA

TTCCAATCTGCACTCAGTGTGTTCATGTGGCTGGAAGAGAATGGGATTGTGACTGACATGGCCAACTTCGCACTCAGC

GACCCGAACGCCCATCGGATGCGAAATTTTCTTGCAAACGCACCACAAGCAGGCAGCAAGTCGCAAAGGGCCAAGTAC

GGGACAGCAGGCTACGGAGTGGAGGCTCGGGGCCCCACACCAGAGGAAGCACAGAGGGAAAAAGACACACGGATCTCA

AAGAAGATGGAGACCATGGGCATCTACTTTGCAACACCAGAATGGGTAGCACTCAATGGGCACCGAGGGCCAAGCCCC

GGCCAGCTAAAGTACTGGCAGAACACACGAGAAATACCGGACCCAAACGAGGACTATCTAGACTACGTGCATGCAGAG

AAGAGCCGGTTGGCATCAGAAGAACAAATCCTAAGGGCAGCTACGTCGATCTACGGGGCTCCAGGACAGGCAGAGCCA

CCCCAAGCTTTCATAGACGAAGTTGCCAAAGTCTATGAAATCAACCATGGACGTGGCCCAAACCAAGAACAGATGAAA

GATCTGCTCTTGACTGCGATGGAGATGAAGCATCGCAATCCCAGGCGGGCTCTACCAAAGCCCAAGCCAAAACCCAAT

GCTCCAACACAGAGACCCCCTGGTCGGCTGGGCCGCTGGATCAGGACCGTCTCTGATGAGGACCTTGAG

Accordingly, preferably the Birnavirus VP3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 124, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Birnavirus VP3 polypeptide is provided herein as SEQ ID No: 125, as follows:

[SEQ ID No: 125]

GCCAGCGAGTTCAAAGAGACACCCGAGCTGGAAAGCGCCGTCAGAGCTATGGAAGCCGCCGCTAATGTGGACCCTCTG

TTTCAGTCTGCCCTGAGCGTGTTCATGTGGCTGGAAGAGAACGGCATCGTGACCGACATGGCCAACTTCGCCCTGTCT

GACCCCAACGCTCACCGGATGAGAAACTTTCTGGCCAACGCTCCTCAGGCCGGCAGCAAGTCTCAGAGAGCCAAATAC

GGCACAGCCGGCTACGGCGTGGAAGCCAGAGGACCTACACCTGAGGAAGCCCAGAGAGAGAAGGACACCCGGATCAGC

AAGAAAATGGAAACCATGGGCATCTACTTCGCCACACCTGAGTGGGTCGCCCTGAATGGACACAGAGGACCATCTCCA

GGCCAGCTGAAGTACTGGCAGAACACCAGAGAGATCCCCGATCCTAACGAGGACTACCTGGACTACGTGCACGCCGAG

AAAAGCAGACTGGCCAGCGAGGAACAGATCCTGAGAGCCGCCACATCCATCTATGGCGCTCCAGGACAAGCCGAACCT

CCACAGGCCTTTATCGACGAGGTGGCCAAGGTGTACGAGATCAACCACGGCAGAGGCCCCAATCAAGAGCAGATGAAG

GACCTGCTGCTGACCGCCATGGAAATGAAGCACAGAAACCCCAGACGGGCCCTGCCTAAGCCAAAGCCTAAACCTAAC

GCTCCCACACAGCGGCCTCCAGGCAGACTCGGAAGATGGATCAGAACCGTGTCCGACGAGGACCTGGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 125, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 125 is provided herein as SEQ ID No: 126, as follows:

[SEQ ID No: 126]

GCCAGCGAGUUCAAAGAGACACCCGAGCUGGAAAGCGCCGUCAGAGCUAUGGAAGCCGCCGCUAAUGUGGACCCUCUG

UUUCAGUCUGCCCUGAGCGUGUUCAUGUGGCUGGAAGAGAACGGCAUCGUGACCGACAUGGCCAACUUCGCCCUGUCU

GACCCCAACGCUCACCGGAUGAGAAACUUUCUGGCCAACGCUCCUCAGGCCGGCAGCAAGUCUCAGAGAGCCAAAUAC

GGCACAGCCGGCUACGGCGUGGAAGCCAGAGGACCUACACCUGAGGAAGCCCAGAGAGAGAAGGACACCCGGAUCAGC

AAGAAAAUGGAAACCAUGGGCAUCUACUUCGCCACACCUGAGUGGGUCGCCCUGAAUGGACACAGAGGACCAUCUCCA

GGCCAGCUGAAGUACUGGCAGAACACCAGAGAGAUCCCCGAUCCUAACGAGGACUACCUGGACUACGUGCACGCCGAG

AAAAGCAGACUGGCCAGCGAGGAACAGAUCCUGAGAGCCGCCACAUCCAUCUAUGGCGCUCCAGGACAAGCCGAACCU

CCACAGGCCUUUAUCGACGAGGUGGCCAAGGUGUACGAGAUCAACCACGGCAGAGGCCCCAAUCAAGAGCAGAUGAAG

GACCUGCUGCUGACCGCCAUGGAAAUGAAGCACAGAAACCCCAGACGGGCCCUGCCUAAGCCAAAGCCUAAACCUAAC

GCUCCCACACAGCGGCCUCCAGGCAGACUCGGAAGAUGGAUCAGAACCGUGUCCGACGAGGACCUGGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 126, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Porcine delta coronavirus NS6 protein (A0A0K2D1N4), or an orthologue thereof. Fang P, Fang L, Ren J, Hong Y, Liu X, Zhao Y, Wang D, Peng G, Xiai S (2018) Porcine deltacoronavirus accessory protein NS6 antagonises interferon beta production by interfering with the binding of RIG-I/MDA-5 to double stranded RNA. J Virol., 92, 15, e00712-18. One embodiment of the polypeptide sequence of Porcine delta coronavirus NS6 is represented herein as SEQ ID No: 127, as follows:

[SEQ ID No: 127]

MCNCHLQLRDLYRLCNKLHIRRDDVPELIDPLVKTRCFAYSLVVLANAPIAFSILPRKILINGEPLLLEYGSIYGKD

FIIRPSLQVILEDELN

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 127, or a variant or fragment thereof.

In one embodiment, the Porcine delta coronavirus NS6 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 128, as follows:

[SEQ ID No: 128]

ATGTGCAACTGCCATCTGCAGCTGCGAGATTTATATAGATTGTGCAATAAGCTGCACATCAGAAGAGACGATGTTCCT

GAGCTTATTGACCCTCTCGTTAAAACTCGCTGTTTTGCTTACAGTCTCGTGGTTCTTGCTAATGCTAATCCAATTGCA

TTTAGCATACTACCTCGGAAAATTCTTATCAATGGTGAGCCTTTACTGCTTGAATATGGTAGCATATATGGTAAAGAC

TTTATCATTAGACCATCGCTCCAAGTCATTCTTGAAGATGAATTAAAT

Accordingly, preferably the Porcine delta coronavirus NS6 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 128, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Porcine delta coronavirus NS6 polypeptide is provided herein as SEQ ID No: 129, as follows:

[SEQ ID No: 129]

ATGTGCAACTGCCATCTGCAGCTGCGGGACCTGTACCGGCTGTGTAACAAGCTGCACATCAGACGGGACGACGTGCCC

GAGCTGATCGATCCTCTGGTCAAGACCAGATGCTTCGCCTACAGCCTGGTGGTGCTGGCCAACGCCAATCCTATCGCC

TTCAGCATCCTGCCTCGGAAGATCCTGATCAACGGCGAGCCTCTGCTGCTGGAATACGGCAGCATCTACGGCAAGGAC

TTCATCATCAGACCCAGCCTGCAAGTGATCCTGGAAGATGAGCTGAACTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 129, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 129 is provided herein as SEQ ID No: 130, as follows:

[SEQ ID No: 130]

AUGUGCAACUGCCAUCUGCAGCUGCGGGACCUGUACCGGCUGUGUAACAAGCUGCACAUCAGACGGGACGACGUGCCC

GAGCUGAUCGAUCCUCUGGUCAAGACCAGAUGCUUCGCCUACAGCCUGGUGGUGCUGGCCAACGCCAAUCCUAUCGCC

UUCAGCAUCCUGCCUCGGAAGAUCCUGAUCAACGGCGAGCCUCUGCUGCUGGAAUACGGCAGCAUCUACGGCAAGGAC

UUCAUCAUCAGACCCAGCCUGCAAGUGAUCCUGGAAGAUGAGCUGAACUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 130, or a fragment or variant thereof.

In one embodiment, the at least one IIP is LASV Z protein (073557|RING finger protein Z Lassa virus (strain Mouse/Sierra Leone/Josiah/1976), or an orthologue thereof (Xing J, Ly H, Liang Y J (2015) The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production. J Virol., 89, 5, 2944-2955. One embodiment of the polypeptide sequence of LASV Z is represented herein as SEQ ID No: 131, as follows:

[SEQ ID No: 131]

MGNKQAKAPESKDSPRASLIPDATHLGPQFCKSCWFENKGLVECNNHYLCLNCLTLLLSVSNRCPICKMPLPTKLRPS

AAPTAPPTGAADSIRPPPYSP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 131, or a variant or fragment thereof.

In one embodiment, the LASV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 132, as follows:

[SEQ ID No: 132]

ATGGGAAACAAGCAAGCCAAAGCCCCAGAATCAAAAGACAGTCCGAGAGCCAGCCTGATCCCAGATGCCACACATCTA

GGGCCACAGTTCTGTAAGAGCTGCTGGTTCGAAAACAAGGGCCTGGTTGAGTGCAACAACCACTATCTGTGTCTCAAC

TGCCTCACCTTACTTCTAAGTGTCAGCAACAGGTGTCCCATTTGCAAGATGCCTCTCCCCACAAAACTGAGACCATCA

GCCGCTCCAACAGCACCTCCAACCGGAGCAGCGGACAGCATCAGACCCCCACCCTACAGTCCC

Accordingly, preferably the LASV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 132, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the LASV Z polypeptide is provided herein as SEQ ID No: 133, as follows:

[SEQ ID No: 133]

ATGGGCAACAAGCAGGCCAAGGCTCCCGAGAGCAAGGATAGCCCTAGAGCCTCTCTGATCCCCGACGCCACACATCTG

GGACCCCAGTTCTGCAAGAGCTGTTGGTTCGAGAACAAAGGCCTGGTGGAATGCAACAACCACTACCTGTGCCTGAAC

TGTCTGACCCTGCTGCTGAGCGTGTCCAACAGATGCCCCATCTGCAAGATGCCCCTGCCTACCAAGCTGAGGCCTTCT

GCTGCTCCTACAGCTCCTCCAACAGGCGCCGCTGATAGCATCAGACCTCCACCTTATAGCCCC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 133, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 133 is provided herein as SEQ ID No: 134, as follows:

[SEQ ID No: 134]

AUGGGCAACAAGCAGGCCAAGGCUCCCGAGAGCAAGGAUAGCCCUAGAGCCUCUCUGAUCCCCGACGCCACACAUCUG

GGACCCCAGUUCUGCAAGAGCUGUUGGUUCGAGAACAAAGGCCUGGUGGAAUGCAACAACCACUACCUGUGCCUGAAC

UGUCUGACCCUGCUGCUGAGCGUGUCCAACAGAUGCCCCAUCUGCAAGAUGCCCCUGCCUACCAAGCUGAGGCCUUCU

GCUGCUCCUACAGCUCCUCCAACAGGCGCCGCUGAUAGCAUCAGACCUCCACCUUAUAGCCCC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 134, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DANV Z protein (B1NX60; RING finger protein Z Dandenong virus), or an orthologue thereof. One embodiment of the polypeptide sequence of DANV Z is represented herein as SEQ ID No: 135, as follows:

[SEQ ID No: 135]

MGQAKSKETKLSKKEDRAEVLPDATYLGPLNCKSCWQRFDSLVRCHDHYLCRQCLNLLLTVSDRCPLCKHPLPTKLRV

STAPSSPPPYEE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 135, or a variant or fragment thereof.

In one embodiment, the DANV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 136, as follows:

[SEQ ID No: 136]

ATGGGTCAAGCAAAATCCAAAGAAACAAAGCTCTCCAAGAAAGAGGACAGAGCAGAGGTTCTACCTGACGCAACCTAT

CTTGGTCCTCTGAACTGCAAATCATGCTGGCAAAGGTTCGACAGTTTGGTTAGGTGCCATGACCACTACCTATGCAGG

CAATGTCTGAACCTTTTGTTGACAGTCTCAGACAGATGCCCTCTCTGCAAACACCCTCTACCGACCAAGCTGAGGGTG

TCGACAGCCCCCAGCTCACCTCCCCCCTACGAGGAG

Accordingly, preferably the DANV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 136, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DANV Z polypeptide is provided herein as SEQ ID No: 137, as follows:

[SEQ ID No: 137]

ATGGGCCAAGCCAAGAGCAAAGAGACAAAGCTGAGCAAGAAAGAGGACCGCGCCGAGGTTCTGCCCGATGCCACATAT

CTGGGCCCTCTGAACTGCAAGAGCTGCTGGCAGAGATTCGACAGCCTCGTGCGGTGCCACGATCACTACCTGTGCAGA

CAGTGCCTGAACCTGCTGCTGACCGTGTCCGATAGATGCCCTCTGTGCAAGCACCCTCTGCCTACCAAGCTGAGAGTG

TCCACCGCTCCTAGCAGCCCTCCACCTTATGAGGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 137, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 137 is provided herein as SEQ ID No: 138, as follows:

[SEQ ID No: 138]

AUGGGCCAAGCCAAGAGCAAAGAGACAAAGCUGAGCAAGAAAGAGGACCGCGCCGAGGUUCUGCCCGAUGCCACAUAU

CUGGGCCCUCUGAACUGCAAGAGCUGCUGGCAGAGAUUCGACAGCCUCGUGCGGUGCCACGAUCACUACCUGUGCAGA

CAGUGCCUGAACCUGCUGCUGACCGUGUCCGAUAGAUGCCCUCUGUGCAAGCACCCUCUGCCUACCAAGCUGAGAGUG

UCCACCGCUCCUAGCAGCCCUCCACCUUAUGAGGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 138, or a fragment or variant thereof.

In one embodiment, the at least one IIP is LCMV Z protein (P18541; RING finger protein Z Lymphocytic choriomeningitis virus (strain Armstong), or an orthologue thereof. One embodiment of the polypeptide sequence of LCMV Z protein is represented herein as SEQ ID No: 139, as follows:

[SEQ ID No: 139]

MGQGKSREEKGINSTNRAEILPDTTYLGPLSCKSCWQKFDSLVRCHDHYLCRHCLNLLLSVSDRCPLCKYPLPTRLKI

STAPSSPPPYEE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 139, or a variant or fragment thereof.

In one embodiment, the LCMV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 140, as follows:

[SEQ ID No: 140]

ATGGGTCAAGGCAAGTCCAGAGAGGAGAAAGGCACCAATAGTACAAACAGGGCCGAAATCCTACCAGATACCACCTAT

CTTGGCCCTTTAAGCTGCAAATCTTGCTGGCAGAAATTTGACAGCTTGGTAAGATGCCATGACCACTACCTTTGCAGG

CACTGTTTAAACCTTCTGCTGTCAGTATCCGACAGGTGTCCTCTTTGTAAATATCCATTACCAACCAGATTGAAGATA

TCAACAGCCCCAAGCTCTCCACCTCCCTACGAAGAG

Accordingly, preferably the LCMV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 140, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the LCMV Z polypeptide is provided herein as SEQ ID No: 141, as follows:

[SEQ ID No: 141]

ATGGGCCAGGGCAAGTCCAGAGAGGAAAAGGGCACCAACTCCACCAACCGGGCCGAGATCCTGCCTGACACCACATAT

CTGGGCCCTCTGAGCTGCAAGAGCTGCTGGCAGAAATTCGACAGCCTCGTGCGGTGCCACGACCACTACCTGTGTAGA

CACTGCCTGAACCTGCTGCTGAGCGTGTCCGATAGATGCCCTCTGTGCAAGTACCCTCTGCCTACCAGACTGAAGATC

AGCACAGCCCCTAGCAGCCCTCCACCTTACGAAGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 141, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 141 is provided herein as SEQ ID No: 142, as follows:

[SEQ ID No: 142]

AUGGGCCAGGGCAAGUCCAGAGAGGAAAAGGGCACCAACUCCACCAACCGGGCCGAGAUCCUGCCUGACACCACAUAU

CUGGGCCCUCUGAGCUGCAAGAGCUGCUGGCAGAAAUUCGACAGCCUCGUGCGGUGCCACGACCACUACCUGUGUAGA

CACUGCCUGAACCUGCUGCUGAGCGUGUCCGAUAGAUGCCCUCUGUGCAAGUACCCUCUGCCUACCAGACUGAAGAUC

AGCACAGCCCCUAGCAGCCCUCCACCUUACGAAGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 142, or a fragment or variant thereof.

In one embodiment, the at least one IIP is LUJV Z protein (C5ILC3; Multifunctional matrix-like protein Z Lujp mammarenavirus), or an orthologue thereof. One embodiment of the polypeptide sequence of LUJV Z protein is represented herein as SEQ ID No: 143, as follows:

[SEQ ID No: 143]

MGQRHSSGSGQPNPKPSDSDHEARRSELHSDASHLGPLNCKSCWKSKKALVKCYDHYLCLNCLSLLMGITPRCPFCYR

ELPKNLDLAEAPSAPPL

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 143, or a variant or fragment thereof.

In one embodiment, the LUJV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 144, as follows:

[SEQ ID No: 144]

ATGGGTCAGAGACATTCCTCTGGCTCCGGCCAACCCAACCCCAAGCCGAGTGACAGCGATCATGAAGCGAGAAGGTCA

GAGCTTCACTCGGACGCCTCCCATCTCGGACCTCTGAACTGCAAATCTTGCTGGAAGTCAAAGAAGGCACTGGTGAAG

TGCTATGATCACTACCTCTGTCTAAACTGCTTAAGCCTTCTAATGGGCATCACCCCAAGATGTCCCTTCTGTTACAGA

GAGCTACCCAAAAATCTGGACCTTGCAGAGGCACCAAGCGCACCACCCCTC

Accordingly, preferably the LUJV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 144, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the LUJV Z polypeptide is provided herein as SEQ ID No: 145, as follows:

[SEQ ID No: 145]

ATGGGCCAGAGACACAGCTCTGGAAGCGGCCAGCCTAATCCTAAGCCTAGCGACAGCGATCACGAGGCCAGAAGAAGC

GAGCTGCACTCCGATGCCTCTCACCTGGGACCTCTGAACTGCAAGAGCTGCTGGAAGTCCAAGAAAGCCCTGGTCAAG

TGCTACGACCACTACCTGTGCCTGAACTGCCTGAGCCTGCTGATGGGCATTACCCCTAGATGCCCCTTCTGCTACAGA

GAGCTGCCCAAGAACCTGGACCTGGCCGAAGCTCCTTCTGCTCCTCCTCTG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 145, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 145 is provided herein as SEQ ID No: 146, as follows:

[SEQ ID No: 146]

AUGGGCCAGAGACACAGCUCUGGAAGCGGCCAGCCUAAUCCUAAGCCUAGCGACAGCGAUCACGAGGCCAGAAGAAGC

GAGCUGCACUCCGAUGCCUCUCACCUGGGACCUCUGAACUGCAAGAGCUGCUGGAAGUCCAAGAAAGCCCUGGUCAAG

UGCUACGACCACUACCUGUGCCUGAACUGCCUGAGCCUGCUGAUGGGCAUUACCCCUAGAUGCCCCUUCUGCUACAGA

GAGCUGCCCAAGAACCUGGACCUGGCCGAAGCUCCUUCUGCUCCUCCUCUG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 146, or a fragment or variant thereof.

In one embodiment, the at least one IIP is CHPV Z protein (B2C4J2; RING finger protein Z Chapare mammarenavirus (isolate Human/Bolivia/810419/2003), or an orthologue thereof. One embodiment of the polypeptide sequence of CHPV Z protein is represented herein as SEQ ID No: 147, as follows:

[SEQ ID No: 147]

MGNTKTKDRQYQSNSSQPTNTSAPVLLRRQAEPSLYGRHNCRCCWFADTNLVNCSNHYLCLKCLNTMLRRSNLCDICG

EELPTTIIVPVEPSAPLPGQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 147, or a variant or fragment thereof.

In one embodiment, the CHPV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 148, as follows:

[SEQ ID No: 148]

ATGGGTAACACCAAAACAAAGGACAGACAGTATCAATCGAACTCAAGCCAACCCACAAACACATCTGCACCAGTTCTG

CTGAGAAGGCAGGCAGAACCAAGTCTGTATGGGAGACACAACTGCAGATGCTGTTGGTTTGCAGACACAAACCTAGTC

AATTGTTCCAACCACTACCTTTGCCTTAAATGTCTGAACACAATGTTAAGAAGATCCAATCTCTGTGACATATGCGGT

GAAGAACTTCCCACAACAATCATTGTTCCAGTGGAACCATCAGCACCACTGCCCGGACAA

Accordingly, preferably the CHPV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 148, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CHPV Z polypeptide is provided herein as SEQ ID No: 149, as follows:

[SEQ ID No: 149]

ATGGGCAACACCAAGACCAAGGACCGGCAGTACCAGAGCAACAGCAGCCAGCCTACCAACACATCTGCCCCTGTGCTG

CTGAGAAGGCAGGCCGAGCCTTCTCTGTACGGCAGACACAACTGCCGGTGCTGTTGGTTCGCCGACACCAACCTGGTC

AACTGCAGCAACCACTACCTGTGCCTGAAGTGTCTGAACACCATGCTGCGGCGGAGCAACCTGTGCGATATCTGTGGC

GAGGAACTGCCCACCACCATCATCGTGCCTGTGGAACCTTCTGCTCCTCTGCCTGGACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 149, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 149 is provided herein as SEQ ID No: 150, as follows:

[SEQ ID No: 150]

AUGGGCAACACCAAGACCAAGGACCGGCAGUACCAGAGCAACAGCAGCCAGCCUACCAACACAUCUGCCCCUGUGCUG

CUGAGAAGGCAGGCCGAGCCUUCUCUGUACGGCAGACACAACUGCCGGUGCUGUUGGUUCGCCGACACCAACCUGGUC

AACUGCAGCAACCACUACCUGUGCCUGAAGUGUCUGAACACCAUGCUGCGGCGGAGCAACCUGUGCGAUAUCUGUGGC

GAGGAACUGCCCACCACCAUCAUCGUGCCUGUGGAACCUUCUGCUCCUCUGCCUGGACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 150, or a fragment or variant thereof.

In one embodiment, the at least one IIP is MACV Z protein (Q6IUF9; RING finger protein Z Machupo virus), or an orthologue thereof. One embodiment of the polypeptide sequence of MACV Z protein is represented herein as SEQ ID No: 151, as follows:

[SEQ ID No: 151]

MGNCNKPPKRPPNTQTSAAQPSAEFRRTALPSLYGRYNCKCCWFADTNLITCNDHYLCLRCHQTMLRNSELCHICWKP

LPTSITVPVEPSAPPP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 151, or a variant or fragment thereof.

In one embodiment, the MACV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 152, as follows:

[SEQ ID No: 152]

ATGGGCAACTGTAACAAGCCTCCCAAGAGGCCTCCCAACACACAAACATCAGCCGCCCAGCCCTCAGCAGAGTTCAGG

AGAACAGCCCTACCCAGTCTCTATGGTCGCTACAACTGCAAATGTTGTTGGTTTGCCGACACAAACTTGATTACATGT

AACGACCACTACTTGTGTCTGAGATGTCATCAAACAATGCTCAGGAATTCTGAACTCTGTCACATATGCTGGAAACCA

CTACCGACATCCATCACAGTCCCCGTGGAGCCAAGCGCCCCCCCACCA

Accordingly, preferably the MACV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 152, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the MACV Z polypeptide is provided herein as SEQ ID No: 153, as follows:

[SEQ ID No: 153]

ATGGGCAACTGCAACAAGCCTCCTAAGCGGCCTCCTAACACACAGACATCTGCCGCTCAGCCTAGCGCCGAGTTCAGA

AGAACAGCCCTGCCTAGCCTGTACGGCCGGTACAACTGCAAGTGCTGTTGGTTCGCCGACACCAACCTGATCACCTGT

AACGACCACTACCTGTGCCTGCGGTGCCACCAGACCATGCTGAGAAATAGCGAGCTGTGCCACATCTGCTGGAAGCCC

CTGCCTACCAGCATCACCGTGCCTGTGGAACCTTCTGCTCCTCCTCCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 153, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 153 is provided herein as SEQ ID No: 154, as follows:

[SEQ ID No: 154]

AUGGGCAACUGCAACAAGCCUCCUAAGCGGCCUCCUAACACACAGACAUCUGCCGCUCAGCCUAGCGCCGAGUUCAGA

AGAACAGCCCUGCCUAGCCUGUACGGCCGGUACAACUGCAAGUGCUGUUGGUUCGCCGACACCAACCUGAUCACCUGU

AACGACCACUACCUGUGCCUGCGGUGCCACCAGACCAUGCUGAGAAAUAGCGAGCUGUGCCACAUCUGCUGGAAGCCC

CUGCCUACCAGCAUCACCGUGCCUGUGGAACCUUCUGCUCCUCCUCCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 154, or a fragment or variant thereof.

In one embodiment, the at least one IIP is GTOV Z protein (Q6UY71; RING finger protein Z Guanarito mammarenavirus (isolate Human/Venezuela/NH-95551/1990), or an orthologue thereof. One embodiment of the polypeptide sequence of GTOV Z protein is represented herein as SEQ ID No: 155, as follows:

[SEQ ID No: 155]

MGNSKSKSNPSSSSESQKGAPTVTEFRRTAIHSLYGRYNCKCCWFADKNLIKCSDHYLCLRCLNVMLKNSDLCNICWE

QLPTCITVPEEPSAPPE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 155, or a variant or fragment thereof.

In one embodiment, the GTOV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 156, as follows:

[SEQ ID No: 156]

ATGGGCAATTCAAAATCTAAATCCAACCCATCCAGTTCCTCAGAGTCTCAAAAAGGGGCACCAACAGTCACAGAATTT

AGGAGGACTGCCATTCACAGTCTCTATGGGAGGTACAACTGCAAGTGTTGCTGGTTTGCTGACAAGAATCTGATTAAA

TGCTCTGATCATTACCTCTGCTTGAGGTGTTTAAATGTCATGCTGAAAAACTCTGATCTTTGCAACATTTGTTGGGAG

CAGCTGCCCACATGCATCACAGTTCCGGAGGAGCCAAGCGCTCCACCGGAA

Accordingly, preferably the GTOV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 156, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the GTOV Z polypeptide is provided herein as SEQ ID No: 157, as follows:

[SEQ ID No: 157]

ATGGGCAACAGCAAGTCCAAGAGCAACCCCAGCAGCAGCTCCGAGTCTCAGAAAGGCGCTCCTACCGTGACCGAGTTC

AGAAGAACAGCCATCCACAGCCTGTACGGCCGGTACAACTGCAAGTGCTGTTGGTTCGCCGACAAGAACCTGATCAAG

TGCAGCGACCACTACCTGTGCCTGCGGTGCCTGAACGTGATGCTGAAGAACTCCGACCTGTGCAACATCTGCTGGGAG

CAGCTGCCTACCTGCATCACCGTGCCTGAGGAACCTTCTGCTCCTCCTGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 157, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 157 is provided herein as SEQ ID No: 158, as follows:

[SEQ ID No: 158]

AUGGGCAACAGCAAGUCCAAGAGCAACCCCAGCAGCAGCUCCGAGUCUCAGAAAGGCGCUCCUACCGUGACCGAGUUC

AGAAGAACAGCCAUCCACAGCCUGUACGGCCGGUACAACUGCAAGUGCUGUUGGUUCGCCGACAAGAACCUGAUCAAG

UGCAGCGACCACUACCUGUGCCUGCGGUGCCUGAACGUGAUGCUGAAGAACUCCGACCUGUGCAACAUCUGCUGGGAG

CAGCUGCCUACCUGCAUCACCGUGCCUGAGGAACCUUCUGCUCCUCCUGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 158, or a fragment or variant thereof.

In one embodiment, the at least one IIP is JUNV Z protein (Q6IVU5; RING finger protein Z OS=Junin mammarenavirus), or an orthologue thereof. One embodiment of the polypeptide sequence of JUNV Z is represented herein as SEQ ID No: 159, as follows:

[SEQ ID No: 159]

MGNCNGASKSNQPDSSRVTQPAAEFRRVAHSSLYGRYNCKCCWFADTNLITCNDHYLCLRCHQVMLRNSDLCNICWKP

LPTTITVPVEPTAPPP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 159, or a variant or fragment thereof.

In one embodiment, the JUNV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 160, as follows:

[SEQ ID No: 160]

ATGGGCAACTGCAACGGGGCATCCAAGTCAAACCAGCCAGACTCTTCAAGGGTCACACAGCCAGCCGCAGAATTCAGG

AGGGTGGCTCACAGCAGTCTATATGGTAGATACAACTGCAAGTGCTGCTGGTTTGCTGACACCAATCTGATAACCTGC

AATGATCACTACCTTTGTTTAAGGTGCCATCAGGTTATGTTAAGGAATTCGGACCTCTGCAATATCTGTTGGAAGCCC

CTACCTACCACAATCACAGTGCCGGTGGAGCCAACAGCACCACCACCA

Accordingly, preferably the JUNV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 160, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the JUNV Z polypeptide is provided herein as SEQ ID No: 161, as follows:

[SEQ ID No: 161]

ATGGGCAATTGCAACGGCGCCAGCAAGAGCAACCAGCCTGATAGCAGCAGAGTGACACAGCCTGCCGCCGAGTTTAGA

AGAGTGGCCCACAGCAGCCTGTACGGCCGGTACAATTGCAAGTGCTGTTGGTTCGCCGACACCAACCTGATCACCTGT

AACGACCACTACCTGTGCCTGCGGTGCCACCAAGTGATGCTGAGAAACAGCGACCTGTGCAACATCTGCTGGAAGCCC

CTGCCTACCACCATCACCGTGCCTGTGGAACCTACAGCTCCTCCTCCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 161, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 161 is provided herein as SEQ ID No: 162, as follows:

[SEQ ID No: 162]

AUGGGCAAUUGCAACGGCGCCAGCAAGAGCAACCAGCCUGAUAGCAGCAGAGUGACACAGCCUGCCGCCGAGUUUAGA

AGAGUGGCCCACAGCAGCCUGUACGGCCGGUACAAUUGCAAGUGCUGUUGGUUCGCCGACACCAACCUGAUCACCUGU

AACGACCACUACCUGUGCCUGCGGUGCCACCAAGUGAUGCUGAGAAACAGCGACCUGUGCAACAUCUGCUGGAAGCCC

CUGCCUACCACCAUCACCGUGCCUGUGGAACCUACAGCUCCUCCUCCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 162, or a fragment or variant thereof.

In one embodiment, the at least one IIP is SABV Z protein (Q6UY62; RING finger protein Z Sabia mammarenavirus (isolate Human/Brasil/SPH114202/1990)), or an orthologue thereof. One embodiment of the polypeptide sequence of SABV Z protein is represented herein as SEQ ID No: 163, as follows:

[SEQ ID No: 163]

MGNSKSKSKLSANQYEQQTVNSTKQVAILKRQAEPSLYGRHNCRCCWFANTNLIKCSDHYICLKCLNIMLGKSSFCDI

CGEELPTSIVVPIEPSAPPPED

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 163, or a variant or fragment thereof.

In one embodiment, the SABV Z polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 164, as follows:

[SEQ ID No: 164]

ATGGGTAACTCCAAGTCAAAATCAAAGCTGTCTGCTAACCAGTATGAACAGCAAACAGTCAATAGCACCAAACAGGTA

GCCATTTTAAAGAGACAGGCTGAACCTAGTCTGTATGGAAGACACAACTGCAGGTGCTGCTGGTTCGCCAATACAAAT

CTAATAAAATGTTCCGACCATTATATTTGTCTAAAATGTTTGAACATAATGTTGGGGAAGTCTTCTTTTTGTGACATT

TGTGGTGAAGAGCTCCCCACATCCATTGTGGTGCCCATCGAACCAAGTGCTCCACCTCCAGAAGAC

Accordingly, preferably the SABV Z polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 164, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SABV Z polypeptide is provided herein as SEQ ID No: 165, as follows:

[SEQ ID No: 165]

ATGGGCAACAGCAAGAGCAAGTCCAAGCTGAGCGCCAACCAGTACGAGCAGCAGACCGTGAACAGCACCAAACAGGTG

GCCATCCTGAAGAGACAGGCCGAGCCTAGCCTGTACGGCAGACACAACTGCCGGTGTTGTTGGTTCGCCAACACCAAC

CTGATCAAGTGCAGCGACCACTACATCTGCCTGAAGTGCCTGAACATCATGCTGGGCAAGAGCAGCTTCTGCGACATC

TGCGGAGAGGAACTGCCCACCTCTATCGTGGTGCCTATCGAGCCTTCTGCTCCTCCACCTGAGGAT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 165, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 165 is provided herein as SEQ ID No: 166, as follows:

[SEQ ID No: 166]

AUGGGCAACAGCAAGAGCAAGUCCAAGCUGAGCGCCAACCAGUACGAGCAGCAGACCGUGAACAGCACCAAACAGGUG

GCCAUCCUGAAGAGACAGGCCGAGCCUAGCCUGUACGGCAGACACAACUGCCGGUGUUGUUGGUUCGCCAACACCAAC

CUGAUCAAGUGCAGCGACCACUACAUCUGCCUGAAGUGCCUGAACAUCAUGCUGGGCAAGAGCAGCUUCUGCGACAUC

UGCGGAGAGGAACUGCCCACCUCUAUCGUGGUGCCUAUCGAGCCUUCUGCUCCUCCACCUGAGGAU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 166, or a fragment or variant thereof.

In other embodiments, the at least one IIP may be a 3C protease protein.

In one embodiment, the at least one IIP is CV-A16 3C protease (Q9QF31; Coxsackievirus A16 (strain Tainan/5079/98 Protease 3C), or an orthologue thereof (Rui Y, Su Jm Wang H, Chang J, Wang S, Zhenf W, Cai Y, Gordy J T, Markham R, Kong W, Zhang W, Yu X-F. (2017) Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68. J Virol 91, 13, e00546-17). One embodiment of the polypeptide sequence of CV-A16 3C protease is represented herein as SEQ ID No: 167, as follows:

[SEQ ID No: 167]

GPSLDFALSLLRRNIRQVQTDQGHFTMLGVRDRLAILPRHSQPGKTIWVEHKLINVLDAVELVDEQGVNLELTLVTLD

TNEKFRDVTKFIPETITGASDATLVINTEHMPSMFVPVGDVVQYGFLNLSGKPTHRTMMYNFPTKAGQCGGVVTSVGK

IIGIHIGGNGRQGFCAGLKRGYFASEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 167, or a variant or fragment thereof.

In one embodiment, the CV-A16 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 168, as follows:

[SEQ ID No: 168]

GGACCGAGCTTAGACTTTGCCTTATCCCTCCTAAGGCGCAACATTAGACAGGTGCAAACCGACCAAGGACACTTCACT

ATGTTAGGGGTGCGAGATCGCCTAGCCATTTTGCCACGCCACTCGCAACCAGGAAAAACTATCTGGGTGGAGCACAAG

TTAATTAATGTGCTGGATGCTGTCGAATTAGTGGATGAGCAAGGTGTAAACTTGGAACTCACACTAGTAACCTTAGAC

ACCAACGAAAAGTTTAGGGATGTTACCAAGTTTATTCCAGAGACGATCACCGGGGCAAGCGACGCAACCTTGGTCATC

AACACTGAGCACATGCCCTCAATGTTCGTTCCAGTGGGTGATGTTGTACAATATGGATTTCTGAATCTCAGCGGTAAG

CCCACACACCGAACCATGATGTACAATTTCCCCACAAAGGCAGGACAGTGTGGAGGGGTGGTCACCTCAGTCGGTAAG

ATCATAGGAATTCACATTGGTGGGAATGGACGCCAGGGTTTCTGCGCTGGACTGAAGAGAGGCTATTTTGCCAGTGAA

CAG

Accordingly, preferably the CV-A16 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 168, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CV-A16 3C protease polypeptide is provided herein as SEQ ID No: 169, as follows:

[SEQ ID No: 169]

GGCCCTTCTCTGGATTTTGCCCTGAGCCTGCTGCGGCGGAACATCAGACAGGTGCAGACAGATCAGGGCCACTTCACC

ATGCTGGGCGTCAGAGACAGACTGGCCATCCTGCCTAGACACAGCCAGCCTGGCAAGACCATCTGGGTCGAGCACAAG

CTGATCAACGTGCTGGACGCCGTGGAACTGGTGGATGAACAGGGCGTGAACCTGGAACTGACCCTGGTCACCCTGGAC

ACCAACGAGAAGTTCCGGGACGTGACCAAGTTCATCCCCGAGACAATCACCGGCGCCTCCGATGCCACACTGGTCATC

AATACCGAGCACATGCCCTCCATGTTCGTGCCTGTGGGAGATGTGGTGCAGTACGGCTTCCTGAACCTGAGCGGCAAG

CCCACACACCGGACCATGATGTACAACTTCCCTACCAAGGCCGGCCAGTGCGGCGGAGTGGTTACATCTGTGGGCAAG

ATCATCGGCATCCACATCGGCGGCAATGGCAGACAGGGATTTTGTGCCGGCCTGAAGAGAGGCTACTTCGCCTCTGAA

CAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 169, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 169 is provided herein as SEQ ID No: 170, as follows:

[SEQ ID No: 170]

GGCCCUUCUCUGGAUUUUGCCCUGAGCCUGCUGCGGCGGAACAUCAGACAGGUGCAGACAGAUCAGGGCCACUUCACC

AUGCUGGGCGUCAGAGACAGACUGGCCAUCCUGCCUAGACACAGCCAGCCUGGCAAGACCAUCUGGGUCGAGCACAAG

CUGAUCAACGUGCUGGACGCCGUGGAACUGGUGGAUGAACAGGGCGUGAACCUGGAACUGACCCUGGUCACCCUGGAC

ACCAACGAGAAGUUCCGGGACGUGACCAAGUUCAUCCCCGAGACAAUCACCGGCGCCUCCGAUGCCACACUGGUCAUC

AAUACCGAGCACAUGCCCUCCAUGUUCGUGCCUGUGGGAGAUGUGGUGCAGUACGGCUUCCUGAACCUGAGCGGCAAG

CCCACACACCGGACCAUGAUGUACAACUUCCCUACCAAGGCCGGCCAGUGCGGCGGAGUGGUUACAUCUGUGGGCAAG

AUCAUCGGCAUCCACAUCGGCGGCAAUGGCAGACAGGGAUUUUGUGCCGGCCUGAAGAGAGGCUACUUCGCCUCUGAA

CAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 170, or a fragment or variant thereof.

In one embodiment, the at least one IIP is CV-A6 3C protease (L7P6C4; Genome polyprotein Coxsackievirus A6 Protease 3C), or an orthologue thereof. One embodiment of the polypeptide sequence of CV-A6 3C protease is represented herein as SEQ ID No: 171, as follows:

[SEQ ID No: 171]

GPSLDFALSLLRRNIRQVQTDQGHFTMLGVRDRLAVLPRHSQPGKTIWVEHKLVNVVDAVELVDEQGVNLELTLITLD

TNEKFRDITKFIPENISAASDATLVINTEHMPSMFVPVGDVVQYGFLNLSGKPTHRTMMYNFPTKAGQCGGVVTSVGK

VIGIHIGGNGRQGFCAGLKRSYF

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 171, or a variant or fragment thereof.

In one embodiment, the CV-A6 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 172, as follows:

[SEQ ID No: 172]

GGACCTAGCCTTGATTTTGCCCTATCCCTACTGAGAAGGAACATCAGACAAGTTCAAACGGACCAAGGGCACTTCACC

ATGCTAGGAGTCAGAGATCGCTTGGCCGTCCTCCCACGACACTCACAACCCGGAAAAACTATCTGGGTAGAGCACAAG

CTAGTGAATGTTGTGGATGCTGTCGAACTAGTGGATGAGCAGGGGGTCAACTTAGAGCTGACTTTAATCACCCTCGAC

ACTAATGAGAAGTTTAGAGACATCACCAAATTTATTCCAGAGAATATCAGCGCTGCCAGCGATGCCACTCTAGTGATT

AATACAGAGCACATGCCTTCTATGTTTGTGCCAGTAGGTGATGTTGTTCAGTATGGTTTCCTGAATCTTAGTGGGAAA

CCAACCCACCGCACTATGATGTATAACTTCCCTACCAAGGCAGGACAGTGTGGAGGGGTAGTCACATCAGTTGGAAAG

GTCATTGGTATCCACATAGGAGGCAATGGCAGGCAAGGTTTCTGTGCAGGGCTCAAGAGAAGCTACTTT

Accordingly, preferably the CV-A6 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 172, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CV-A6 3C protease polypeptide is provided herein as SEQ ID No: 173, as follows:

[SEQ ID No: 173]

GGCCCTTCTCTGGATTTTGCCCTGAGCCTGCTGCGGCGGAACATCAGACAGGTGCAGACAGATCAGGGCCACTTCACC

ATGCTGGGCGTCAGAGATAGACTGGCCGTGCTGCCTAGACACAGCCAGCCTGGAAAGACCATCTGGGTCGAGCACAAG

CTGGTCAACGTGGTGGATGCCGTGGAACTGGTGGATGAGCAGGGCGTGAACCTGGAACTGACCCTGATCACCCTGGAC

ACCAACGAGAAGTTCCGGGACATCACCAAGTTCATCCCCGAGAACATCAGCGCCGCCTCCGATGCCACACTGGTCATC

AATACCGAGCACATGCCCTCCATGTTCGTGCCTGTGGGAGATGTGGTGCAGTACGGCTTCCTGAACCTGAGCGGCAAG

CCCACACACCGGACCATGATGTACAACTTCCCTACCAAGGCCGGCCAGTGCGGCGGAGTGGTTACATCTGTGGGCAAA

GTGATCGGAATCCACATCGGCGGCAATGGCAGACAGGGCTTTTGTGCCGGCCTGAAGAGAAGCTACTTC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 173, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 173 is provided herein as SEQ ID No: 174, as follows:

[SEQ ID No: 174]

GGCCCUUCUCUGGAUUUUGCCCUGAGCCUGCUGCGGCGGAACAUCAGACAGGUGCAGACAGAUCAGGGCCACUUCACC

AUGCUGGGCGUCAGAGAUAGACUGGCCGUGCUGCCUAGACACAGCCAGCCUGGAAAGACCAUCUGGGUCGAGCACAAG

CUGGUCAACGUGGUGGAUGCCGUGGAACUGGUGGAUGAGCAGGGCGUGAACCUGGAACUGACCCUGAUCACCCUGGAC

ACCAACGAGAAGUUCCGGGACAUCACCAAGUUCAUCCCCGAGAACAUCAGCGCCGCCUCCGAUGCCACACUGGUCAUC

AAUACCGAGCACAUGCCCUCCAUGUUCGUGCCUGUGGGAGAUGUGGUGCAGUACGGCUUCCUGAACCUGAGCGGCAAG

CCCACACACCGGACCAUGAUGUACAACUUCCCUACCAAGGCCGGCCAGUGCGGCGGAGUGGUUACAUCUGUGGGCAAA

GUGAUCGGAAUCCACAUCGGCGGCAAUGGCAGACAGGGCUUUUGUGCCGGCCUGAAGAGAAGCUACUUC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 174, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EV D-68 3C protease (Q68T42; Genome polyprotein Human enterovirus D68; IRF7 cleavage), or an orthologue thereof (Xiang Z, Liu L, Lei X, Zhou Z, He B, Wang J (2015) 3C protease of enterovirus D68 inhibits cellular defense mediated interferon regulatory factor. J Virol., 90, 3, 1613-2161. doi: 10.1128/JVI.02395-15. Print 2016 Feb. 1). One embodiment of the polypeptide sequence of EV D-68 3C protease is represented herein as SEQ ID No: 175, as follows:

[SEQ ID No: 175]

GPGFDFAQAIMKKNTVIARTEKGEFTMLGVYDRVAVIPTHASVGEIIYINDVETRVLDACALRDLTDTNLEITIVKLD

RNQKFRDIRHFLPRCEDDYNDAVLSVHTSKFPNMYIPVGQVTNYGFLNLGGTPTHRILMYNFPTRAGQCGGVVTTTGK

VIGIHVGGNGAQGFAAMLLHSYFTDTQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 175, or a variant or fragment thereof.

In one embodiment, the EV D-68 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 176, as follows:

[SEQ ID No: 176]

GGACCAGGATTTGATTTTGCGCAAGCCATAATGAAGAAAAATACTGTTATTGCTAGAACTGAAAAAGGCGAGTTCACA

ATGCTTGGTGTGTATGATAGAGTGGCAGTCATTCCAACACATGCATCTGTTGGAGAAATCATTTACATCAACGATGTA

GAAACCAGAGTTCTAGATGCATGTGCACTTAGAGACTTGACAGACACAAACCTAGAAATAACTATAGTCAAATTGGAT

CGCAATCAAAAATTTAGAGACATCAGACACTTTTTACCCAGATGTGAGGATGATTACAATGATGCTGTGCTTAGTGTA

CATACATCAAAATTCCCTAACATGTACATTCCAGTTGGACAAGTCACTAACTACGGCTTCTTGAACCTGGGCGGCACA

CCAACACATCGGATTTTAATGTATAATTTTCCAACAAGAGCTGGTCAGTGTGGTGGTGTGGTGACAACCACAGGTAAA

GTGATAGGAATACACGTGGGCGGGAATGGAGCTCAGGGATTCGCAGCAATGTTGCTCCACTCTTACTTTACTGATACA

CAA

Accordingly, preferably the EV D-68 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 176, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EV D-68 3C protease polypeptide is provided herein as SEQ ID No: 177, as follows:

[SEQ ID No: 177]

GGCCCTGGCTTTGATTTTGCCCAGGCCATCATGAAGAAAAACACCGTGATCGCCCGGACCGAGAAGGGCGAGTTTACA

ATGCTGGGCGTGTACGACAGAGTGGCCGTGATTCCTACACACGCCTCTGTGGGCGAGATCATCTACATCAACGACGTG

GAAACCAGAGTGCTGGACGCCTGCGCTCTGAGAGATCTGACCGACACCAACCTGGAAATCACCATCGTGAAGCTGGAC

CGGAACCAGAAGTTCCGGGACATCCGGCACTTTCTGCCCAGATGCGAGGACGACTACAACGACGCTGTGCTGAGCGTG

CACACCAGCAAGTTCCCCAACATGTACATCCCCGTGGGCCAAGTGACCAACTACGGCTTCCTGAATCTCGGCGGCACC

CCTACACACCGGATCCTGATGTACAACTTCCCCACCAGAGCCGGCCAGTGTGGCGGAGTGGTTACCACAACAGGCAAA

GTGATCGGCATCCACGTCGGCGGAAATGGCGCTCAGGGATTTGCTGCCATGCTGCTGCACAGCTACTTCACCGACACA

CAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 177, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 177 is provided herein as SEQ ID No: 178, as follows:

[SEQ ID No: 178]

GGCCCUGGCUUUGAUUUUGCCCAGGCCAUCAUGAAGAAAAACACCGUGAUCGCCCGGACCGAGAAGGGCGAGUUUACA

AUGCUGGGCGUGUACGACAGAGUGGCCGUGAUUCCUACACACGCCUCUGUGGGCGAGAUCAUCUACAUCAACGACGUG

GAAACCAGAGUGCUGGACGCCUGCGCUCUGAGAGAUCUGACCGACACCAACCUGGAAAUCACCAUCGUGAAGCUGGAC

CGGAACCAGAAGUUCCGGGACAUCCGGCACUUUCUGCCCAGAUGCGAGGACGACUACAACGACGCUGUGCUGAGCGUG

CACACCAGCAAGUUCCCCAACAUGUACAUCCCCGUGGGCCAAGUGACCAACUACGGCUUCCUGAAUCUCGGCGGCACC

CCUACACACCGGAUCCUGAUGUACAACUUCCCCACCAGAGCCGGCCAGUGUGGCGGAGUGGUUACCACAACAGGCAAA

GUGAUCGGCAUCCACGUCGGCGGAAAUGGCGCUCAGGGAUUUGCUGCCAUGCUGCUGCACAGCUACUUCACCGACACA

CAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 178, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EVD-71 3C protease (Q0JRV3; Genome polyprotein Human enterovirus 71 Protease 3C), or an orthologue thereof. One embodiment of the polypeptide sequence of EVD-71 3C protease protein is represented herein as SEQ ID No: 179, as follows:

[SEQ ID No: 179]

GPSLDFALSLLRRNIRQVQTDQGHFTMLGVRDHLAVLPRHSQPGKTIWVEHKLVKIVDAVELVDEQGVNLELTLVTLD

TNEKFRDITRFIPETISPASDATLVINTEHMPSMFVPVGDVVQYGFLNLSGKPTHRTMMYNFPTKAGQCGGAVTAVGK

VIGIHIGGNGRQGFCAALKRGYF

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 179, or a variant or fragment thereof.

In one embodiment, the EVD-71 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 180, as follows:

[SEQ ID No: 180]

GGGCCGAGCTTGGACTTCGCCCTATCTCTACTTAGGAGGAACATTAGGCAGGTCCAAACCGACCAGGGCCACTTTACA

ATGTTAGGAGTGCGAGACCACTTGGCTGTGCTCCCCAGACACTCCCAACCAGGAAAGACCATCTGGGTTGAACACAAA

TTAGTGAAGATCGTAGACGCTGTGGAGCTAGTAGATGAACAAGGGGTTAACCTAGAGCTCACACTGGTAACGCTTGAC

ACCAACGAAAAATTTAGAGACATCACAAGATTCATACCAGAAACAATTAGTCCTGCTAGTGATGCCACTTTAGTTATA

AATACTGAACATATGCCCAGTATGTTTGTGCCAGTTGGAGATGTGGTCCAGTATGGATTTTTGAACCTTAGTGGTAAG

CCCACTCACAGGACTATGATGTACAATTTCCCAACAAAAGCAGGACAGTGTGGTGGTGCTGTGACTGCCGTAGGTAAA

GTGATTGGGATTCACATTGGTGGCAACGGTAGACAAGGTTTCTGCGCTGCCCTGAAGAGGGGTTACTTT

Accordingly, preferably the EVD-71 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 180, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EVD-71 3C protease polypeptide is provided herein as SEQ ID No: 181, as follows:

[SEQ ID No: 181]

GGCCCTTCTCTGGATTTTGCCCTGAGCCTGCTGCGGCGGAACATCAGACAGGTGCAGACAGATCAGGGCCACTTCACC

ATGCTGGGCGTCAGAGATCATCTGGCCGTGCTGCCTAGACACAGCCAGCCTGGAAAGACCATCTGGGTCGAGCACAAG

CTGGTCAAGATCGTGGACGCCGTGGAACTGGTGGATGAGCAGGGCGTTAACCTGGAACTGACCCTGGTCACCCTGGAC

ACCAACGAGAAGTTCCGGGACATCACCCGGTTCATCCCCGAGACAATTAGCCCTGCCTCCGACGCCACACTGGTCATC

AATACCGAGCACATGCCCTCCATGTTCGTGCCTGTGGGAGATGTGGTGCAGTACGGCTTCCTGAACCTGAGCGGCAAG

CCCACACACCGGACCATGATGTACAACTTCCCTACCAAGGCCGGCCAGTGCGGCGGAGCTGTTACAGCTGTGGGAAAA

GTGATCGGCATCCACATCGGCGGCAATGGCAGACAGGGATTCTGTGCCGCTCTGAAGAGAGGCTACTTC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 181, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 181 is provided herein as SEQ ID No: 182, as follows:

[SEQ ID No: 182]

GGCCCUUCUCUGGAUUUUGCCCUGAGCCUGCUGCGGCGGAACAUCAGACAGGUGCAGACAGAUCAGGGCCACUUCACC

AUGCUGGGCGUCAGAGAUCAUCUGGCCGUGCUGCCUAGACACAGCCAGCCUGGAAAGACCAUCUGGGUCGAGCACAAG

CUGGUCAAGAUCGUGGACGCCGUGGAACUGGUGGAUGAGCAGGGCGUUAACCUGGAACUGACCCUGGUCACCCUGGAC

ACCAACGAGAAGUUCCGGGACAUCACCCGGUUCAUCCCCGAGACAAUUAGCCCUGCCUCCGACGCCACACUGGUCAUC

AAUACCGAGCACAUGCCCUCCAUGUUCGUGCCUGUGGGAGAUGUGGUGCAGUACGGCUUCCUGAACCUGAGCGGCAAG

CCCACACACCGGACCAUGAUGUACAACUUCCCUACCAAGGCCGGCCAGUGCGGCGGAGCUGUUACAGCUGUGGGAAAA

GUGAUCGGCAUCCACAUCGGCGGCAAUGGCAGACAGGGAUUCUGUGCCGCUCUGAAGAGAGGCUACUUC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 182, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Polio virus HEV-C 3C protease (P03300; Genome polyprotein Poliovirus type 1 (strain Mahoney) Human Enterovirus), or an orthologue thereof. Lei X, Xiao X, Wang J (2016) Innate Immunity Evasion by Enteroviruses: Insights into Virus-Host Interaction. Viruses 8, 22; doi:10.3390/v8010022. One embodiment of the polypeptide sequence of Polio virus HEV-C 3C protease is represented herein as SEQ ID No: 183, as follows:

[SEQ ID No: 183]

GPGFDYAVAMAKRNIVTATTSKGEFTMLGVHDNVAILPTHASPGESIVIDGKEVEILDAKALEDQAGTNLEITIITLK

RNEKFRDIRPHIPTQITETNDGVLIVNTSKYPNMYVPVGAVTEQGYLNLGGRQTARTLMYNFPTRAGQCGGVITCTGK

VIGMHVGGNGSHGFAAALKRSYFTQSQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 183, or a variant or fragment thereof.

In one embodiment, the Polio virus HEV-C 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 184, as follows:

[SEQ ID No: 184]

GGACCAGGGTTCGATTACGCAGTGGCTATGGCTAAAAGAAACATTGTTACAGCAACTACTAGCAAGGGAGAGTTCACT

ATGTTAGGAGTCCACGACAACGTGGCTATTTTACCAACCCACGCTTCACCTGGTGAAAGCATTGTGATCGATGGCAAA

GAAGTGGAGATCTTGGATGCCAAAGCGCTCGAAGATCAAGCAGGAACCAATCTTGAAATCACTATAATCACTCTAAAG

AGAAATGAAAAGTTCAGAGACATTAGACCACATATACCTACTCAAATCACTGAGACAAATGATGGAGTCTTGATCGTG

AACACTAGCAAGTACCCCAATATGTATGTTCCTGTCGGTGCTGTGACTGAACAGGGATATCTAAATCTCGGTGGGCGC

CAAACTGCTCGTACTCTAATGTACAACTTTCCAACCAGAGCAGGACAGTGTGGTGGAGTCATCACATGTACTGGGAAA

GTCATCGGGATGCATGTTGGTGGGAACGGTTCACACGGGTTTGCAGCGGCCCTGAAGCGATCATACTTCACTCAGAGT

CAA

Accordingly, preferably the Polio virus HEV-C 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 184, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Polio virus HEV-C 3C protease polypeptide is provided herein as SEQ ID No: 185, as follows:

[SEQ ID No: 185]

GGCCCTGGCTTTGATTATGCCGTGGCCATGGCTAAGCGGAACATCGTGACAGCCACCACCAGCAAGGGCGAGTTTACA

ATGCTGGGCGTGCACGACAACGTGGCCATCCTGCCTACACATGCTAGCCCTGGCGAGAGCATCGTGATCGACGGCAAA

GAGGTGGAAATCCTGGACGCCAAGGCTCTGGAAGATCAGGCCGGCACCAACCTGGAAATCACCATCATCACCCTGAAG

CGGAACGAGAAGTTCCGGGACATCAGACCTCACATCCCCACACAGATCACCGAGACAAACGACGGCGTGCTGATCGTG

AATACCAGCAAGTACCCCAATATGTACGTGCCCGTGGGCGCCGTGACAGAGCAGGGATATCTGAATCTCGGCGGCAGA

CAGACCGCCAGAACACTGATGTACAACTTCCCCACCAGAGCCGGCCAGTGCGGCGGAGTGATTACATGTACCGGCAAA

GTGATCGGCATGCACGTCGGCGGCAATGGCTCTCACGGATTTGCTGCCGCTCTGAAGAGAAGCTACTTCACCCAGAGC

CAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 185, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 185 is provided herein as SEQ ID No: 186, as follows:

[SEQ ID No: 186]

GGCCCUGGCUUUGAUUAUGCCGUGGCCAUGGCUAAGCGGAACAUCGUGACAGCCACCACCAGCAAGGGCGAGUUUACA

AUGCUGGGCGUGCACGACAACGUGGCCAUCCUGCCUACACAUGCUAGCCCUGGCGAGAGCAUCGUGAUCGACGGCAAA

GAGGUGGAAAUCCUGGACGCCAAGGCUCUGGAAGAUCAGGCCGGCACCAACCUGGAAAUCACCAUCAUCACCCUGAAG

CGGAACGAGAAGUUCCGGGACAUCAGACCUCACAUCCCCACACAGAUCACCGAGACAAACGACGGCGUGCUGAUCGUG

AAUACCAGCAAGUACCCCAAUAUGUACGUGCCCGUGGGCGCCGUGACAGAGCAGGGAUAUCUGAAUCUCGGCGGCAGA

CAGACCGCCAGAACACUGAUGUACAACUUCCCCACCAGAGCCGGCCAGUGCGGCGGAGUGAUUACAUGUACCGGCAAA

GUGAUCGGCAUGCACGUCGGCGGCAAUGGCUCUCACGGAUUUGCUGCCGCUCUGAAGAGAAGCUACUUCACCCAGAGC

CAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 186, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Poliovirus HEV-C 2A protease (P03300; Genome polyprotein Poliovirus type 1 (strain Mahoney) Human Enterovirus), or an orthologue thereof. Feng Q, Langeris M A, Lork M, Nguyen M, Hato S V, Lanke K, Endad L, Bhoopathi P, Fisher P B, Lloyd R E, van Kuppeveld F J M (2014) Enterovirus 2Apro targets MDA5 and MAVS in infected cells. J Virol., 88, 6, 3369-3377. One embodiment of the polypeptide sequence of Poliovirus HEV-C 2A protease is represented herein as SEQ ID No: 187, as follows:

[SEQ ID No: 187]

GFGHQNKAVYTAGYKICNYHLATQDDLQNAVNVMWSRDLLVTESRAQGTDSIARCNCNAGVYYCESRRKYYPVSFVGP

TFQYMEANNYYPARYQSHMLIGHGFASPGDCGGILRCHHGVIGIITAGGEGLVAFSDIRDLYAYEEEAMEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 187, or a variant or fragment thereof.

In one embodiment, the Poliovirus HEV-C 2A protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 188, as follows:

[SEQ ID No: 188]

GGATTCGGACACCAAAACAAAGCGGTGTACACTGCAGGTTACAAAATTTGCAACTACCACTTGGCCACTCAGGATGAT

TTGCAAAACGCAGTGAACGTCATGTGGAGTAGAGACCTCTTAGTCACAGAATCAAGAGCCCAGGGCACCGATTCAATC

GCAAGGTGCAATTGCAACGCAGGGGTGTACTACTGCGAGTCTAGAAGGAAATACTACCCAGTATCCTTCGTTGGCCCA

ACGTTCCAGTACATGGAGGCTAATAACTATTACCCAGCTAGGTACCAGTCCCATATGCTCATTGGCCATGGATTCGCA

TCTCCAGGGGATTGTGGTGGCATACTCAGATGTCACCACGGGGTGATAGGGATCATTACTGCTGGTGGCGAAGGGTTG

GTTGCATTTTCAGACATTAGAGACTTGTATGCCTACGAAGAAGAAGCCATGGAACAA

Accordingly, preferably the Poliovirus HEV-C 2A protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 188, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Poliovirus HEV-C 2A protease polypeptide is provided herein as SEQ ID No: 189, as follows:

[SEQ ID No: 189]

GGCTTTGGCCACCAGAACAAGGCCGTGTACACAGCCGGCTACAAGATCTGCAACTACCACCTGGCCACACAGGACGAC

CTGCAGAACGCCGTGAATGTGATGTGGTCCAGGGACCTGCTGGTCACCGAATCTAGAGCCCAGGGCACCGACTCTATC

GCCAGATGCAACTGTAATGCCGGCGTGTACTACTGCGAGAGCCGGCGGAAGTACTACCCCGTGTCTTTTGTGGGCCCC

ACCTTCCAGTACATGGAAGCCAACAACTACTACCCTGCCAGATACCAGAGCCACATGCTGATCGGCCACGGCTTTGCT

AGCCCTGGCGATTGTGGCGGCATCCTGAGATGTCACCATGGCGTGATCGGCATCATCACCGCTGGCGGAGAAGGACTG

GTGGCCTTCAGCGACATCAGAGATCTGTACGCCTACGAAGAGGAAGCCATGGAACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 189, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 189 is provided herein as SEQ ID No: 190, as follows:

[SEQ ID No: 190]

GGCUUUGGCCACCAGAACAAGGCCGUGUACACAGCCGGCUACAAGAUCUGCAACUACCACCUGGCCACACAGGACGAC

CUGCAGAACGCCGUGAAUGUGAUGUGGUCCAGGGACCUGCUGGUCACCGAAUCUAGAGCCCAGGGCACCGACUCUAUC

GCCAGAUGCAACUGUAAUGCCGGCGUGUACUACUGCGAGAGCCGGCGGAAGUACUACCCCGUGUCUUUUGUGGGCCCC

ACCUUCCAGUACAUGGAAGCCAACAACUACUACCCUGCCAGAUACCAGAGCCACAUGCUGAUCGGCCACGGCUUUGCU

AGCCCUGGCGAUUGUGGCGGCAUCCUGAGAUGUCACCAUGGCGUGAUCGGCAUCAUCACCGCUGGCGGAGAAGGACUG

GUGGCCUUCAGCGACAUCAGAGAUCUGUACGCCUACGAAGAGGAAGCCAUGGAACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 190, or a fragment or variant thereof.

In one embodiment, the at least one IIP is CVB3 2A protease (P03313; Genome polyprotein Coxsackievirus B3 (strain Nancy)), or an orthologue thereof. One embodiment of the polypeptide sequence of CVB3 2A protease is represented herein as SEQ ID No: 191, as follows:

[SEQ ID No: 191]

GAFGQQSGAVYVGNYRVVNRHLATSADWQNCVWESYNRDLLVSTTTAHGCDIIARCQCTTGVYFCASKNKHYPISFEG

PGLVEVQESEYYPRRYQSHVLLAAGFSEPGDCGGILRCEHGVIGIVTMGGEGVVGFADIRDLLWLEDDAMEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 191, or a variant or fragment thereof.

In one embodiment, the CVB3 2A protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 192, as follows:

[SEQ ID No: 192]

GGCGCATTTGGACAACAATCAGGGGCAGTGTATGTGGGGAACTACAGGGTGGTAAATAGACATCTAGCTACCAGTGCT

GACTGGCAAAACTGTGTGTGGGAAAGTTACAACAGAGACCTCTTAGTGAGCACGACCACAGCACATGGATGTGATATT

ATAGCCAGATGICAGTGCACAACGGGAGTGTACTTTTGTGCGTCCAAAAACAAGCACTACCCAATTTCGTTTGAAGGA

CCAGGTCTAGTAGAGGTCCAAGAGAGTGAATACTACCCCAGGAGATACCAATCCCATGTGCTTTTAGCAGCTGGATTT

TCCGAACCAGGIGACTGIGGCGGTATCCTAAGGIGTGAGCATGGTGTCATTGGCATTGTGACCATGGGGGGTGAAGGC

GTGGTCGGCTTTGCAGACATCCGTGATCTCCTGTGGCTGGAAGATGATGCAATGGAACAG

Accordingly, preferably the CVB3 2A protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 192, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CVB3 2A protease polypeptide is provided herein as SEQ ID No: 193, as follows:

[SEQ ID No: 193]

GGAGCTTTTGGACAGCAGTCTGGCGCCGTGTACGTGGGCAATTACCGGGTCGTGAATAGACACCTGGCCACCTCTGCC

GACTGGCAGAATTGTGTGTGGGAGAGCTACAACCGGGACCTGCTGGTGTCTACCACAACAGCCCACGGCTGCGACATC

ATTGCCAGATGCCAGTGTACAACCGGCGTGTACTTCTGCGCCAGCAAGAACAAGCACTACCCCATCAGCTTCGAAGGC

CCTGGCCTGGTGGAAGTGCAAGAGAGCGAGTACTACCCTCGGAGATACCAGAGCCACGTGCTGCTGGCCGCTGGCTTT

TCTGAACCTGGCGATTGTGGCGGCATCCTGAGATGTGAACACGGCGTGATCGGCATCGTGACCATGGGCGGAGAAGGC

GTTGTGGGCTTCGCCGACATTAGAGATCTGCTGTGGCTGGAAGATGACGCCATGGAACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 193, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 193 is provided herein as SEQ ID No: 194, as follows:

[SEQ ID No: 194]

GGAGCUUUUGGACAGCAGUCUGGCGCCGUGUACGUGGGCAAUUACCGGGUCGUGAAUAGACACCUGGCCACCUCUGCC

GACUGGCAGAAUUGUGUGUGGGAGAGCUACAACCGGGACCUGCUGGUGUCUACCACAACAGCCCACGGCUGCGACAUC

AUUGCCAGAUGCCAGUGUACAACCGGCGUGUACUUCUGCGCCAGCAAGAACAAGCACUACCCCAUCAGCUUCGAAGGC

CCUGGCCUGGUGGAAGUGCAAGAGAGCGAGUACUACCCUCGGAGAUACCAGAGCCACGUGCUGCUGGCCGCUGGCUUU

UCUGAACCUGGCGAUUGUGGCGGCAUCCUGAGAUGUGAACACGGCGUGAUCGGCAUCGUGACCAUGGGCGGAGAAGGC

GUUGUGGGCUUCGCCGACAUUAGAGAUCUGCUGUGGCUGGAAGAUGACGCCAUGGAACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 194, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EV71 2A protease (B9VUU3; Genome polyprotein Human enterovirus 71), or an orthologue thereof. One embodiment of the polypeptide sequence of EV71 2A protease is represented herein as SEQ ID No: 195, as follows:

[SEQ ID No: 195]

GKFGQQSGAIYVGNFRVVNRHLATHNDWANLVWEDSSRDLLVSSTTAQGCDTIARCNCQTGVYYCNSRRKHYPVSFSK

PSLIYVEASEYYPARYQSHLMLAQGHSEPGDCGGILRCQHGVVGIVSTGGNGLVGFADVRDLLWLDEEAMEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 195, or a variant or fragment thereof.

In one embodiment, the EV71 2A protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 196, as follows:

[SEQ ID No: 196]

GGAAAATTTGGGCAACAGTCTGGGGCCATTTATGTGGGTAACTTTAGAGT

GGTCAACCGTCATCTTGCCACTCACAATGATTGGGCAAATCTTGTTTGGG

AAGACAGCTCTCGCGACTTACTCGTGTCATCCACCACCGCCCAAGGTTGT

GACACGATTGCCCGCTGCAATTGCCAGACAGGGGTGTACTACTGTAACTC

GAGGAGAAAACACTACCCAGTCAGTTTTTCAAAACCCAGTCTGATCTATG

TAGAGGCTAGCGAGTATTACCCAGCCAGGTACCAGTCACATCTTATGCTC

GCACAGGGCCACTCAGAGCCTGGTGATTGCGGTGGTATCCTTAGATGCCA

ACATGGCGTCGTCGGTATAGTGTCAACTGGTGGTAACGGGCTCGTTGGCT

TTGCAGACGTCAGGGACCTCTTGTGGTTAGATGAAGAAGCTATGGAGCAG

Accordingly, preferably the EV71 2A protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 196, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EV71 2A protease polypeptide is provided herein as SEQ ID No: 197, as follows:

[SEQ ID No: 197]

GGCAAGTTTGGACAGCAGAGCGGCGCCATCTACGTGGGCAATTTCCGGGT

CGTGAACCGGCACCTGGCCACACATAACGACTGGGCCAATCTCGTGTGGG

AAGATAGCAGCAGGGACCTGCTGGTGTCCAGCACAACAGCCCAGGGCTGC

GATACAATCGCCAGATGCAATTGCCAGACCGGCGTGTACTACTGCAACAG

CAGACGGAAGCACTACCCCGTGTCCTTCAGCAAGCCCAGCCTGATCTATG

TGGAAGCCAGCGAGTACTACCCCGCCAGATACCAGTCTCACCTGATGCTG

GCCCAGGGCCATTCTGAGCCAGGCGATTGTGGCGGAATCCTGAGATGCCA

GCATGGCGTCGTGGGCATTGTGTCTACCGGCGGAAATGGCCTCGTGGGAT

TTGCCGATGTTCGCGACCTGCTGTGGCTGGACGAAGAGGCTATGGAACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 197, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 197 is provided herein as SEQ ID No: 198, as follows:

[SEQ ID No: 198]

GGCAAGUUUGGACAGCAGAGCGGCGCCAUCUACGUGGGCAAUUUCCGGGU

CGUGAACCGGCACCUGGCCACACAUAACGACUGGGCCAAUCUCGUGUGGG

AAGAUAGCAGCAGGGACCUGCUGGUGUCCAGCACAACAGCCCAGGGCUGC

GAUACAAUCGCCAGAUGCAAUUGCCAGACCGGCGUGUACUACUGCAACAG

CAGACGGAAGCACUACCCCGUGUCCUUCAGCAAGCCCAGCCUGAUCUAUG

UGGAAGCCAGCGAGUACUACCCCGCCAGAUACCAGUCUCACCUGAUGCUG

GCCCAGGGCCAUUCUGAGCCAGGCGAUUGUGGCGGAAUCCUGAGAUGCCA

GCAUGGCGUCGUGGGCAUUGUGUCUACCGGCGGAAAUGGCCUCGUGGGAU

UUGCCGAUGUUCGCGACCUGCUGUGGCUGGACGAAGAGGCUAUGGAACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 198, or a fragment or variant thereof.

In one embodiment, the at least one IIP is hMPV G protein (Q6WB94; Major surface glycoprotein G Human metapneumovirus (strain CAN97-83)), or an orthologue thereof. Bao X, Liu T, Shan Y, Li K, Garofolo R P, Casola A (2008) Human Metapneumovirus Glycoprotein G Inhibits Innate Immune Responses. PLOS Pathogens, 4, 5, e1000077. One embodiment of the polypeptide sequence of hMPV G protein is represented herein as SEQ ID No: 199, as follows:

[SEQ ID No: 199]

MEVKVENIRAIDMLKARVKNRVARSKCFKNASLILIGITTLSIALNIYLI

INYTIQKTSSESEHHTSSPPTESNKEASTISTDNPDINPNSQHPTQQSTE

NPTLNPAASVSPSETEPASTPDTTNRLSSVDRSTAQPSESRTKTKPTVHT

RNNPSTASSTQSPPRATTKAIRRATTFRMSSTGKRPTTTSVQSDSSTTTQ

NHEETGSANPQASVSTMQN

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 199, or a variant or fragment thereof.

In one embodiment, the hMPV G polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 200, as follows:

[SEQ ID No: 200]

ATGGAGGTGAAAGTAGAGAACATTCGAGCAATAGACATGCTCAAAGCAAG

AGTGAAAAATCGTGTGGCACGTAGCAAATGCTTTAAAAATGCTTCTTTAA

TCCTCATAGGAATAACTACACTGAGTATAGCTCTCAATATCTATCTGATC

ATAAACTACACAATACAAAAAACCTCATCTGAATCAGAACACCACACCAG

CTCACCACCCACAGAATCCAACAAGGAAGCTTCAACAATCTCCACAGACA

ACCCAGACATCAATCCAAACTCACAGCATCCAACTCAACAGTCCACAGAA

AACCCCACACTCAACCCCGCAGCATCAGTGAGCCCATCAGAAACAGAACC

AGCATCAACACCAGACACAACAAACCGCCTGTCCTCCGTAGACAGGTCCA

CAGCACAACCAAGTGAAAGCAGAACAAAGACAAAACCGACAGTCCACACA

AGAAACAACCCAAGCACAGCTTCCAGTACACAATCCCCACCACGGGCAAC

AACGAAGGCAATCCGCAGAGCCACCACTTTCCGCATGAGCAGCACAGGAA

AAAGACCAACCACAACATCAGTCCAGTCCGACAGCAGCACCACAACCCAA

AATCATGAAGAAACAGGTTCAGCGAACCCACAGGCATCTGTAAGCACAAT

GCAAAAC

Accordingly, preferably the hMPV G polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 200, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the hMPV G polypeptide is provided herein as SEQ ID No: 201, as follows:

[SEQ ID No: 201]

ATGGAAGTGAAGGTCGAGAACATCCGGGCCATCGACATGCTGAAGGCCAG

AGTGAAGAACAGAGTGGCCCGGTCCAAGTGCTTCAAGAACGCCAGCCTGA

TCCTGATCGGCATCACCACACTGTCTATCGCCCTGAACATCTACCTGATC

ATCAACTACACCATCCAGAAAACCAGCAGCGAGAGCGAGCACCACACAAG

CTCTCCACCTACCGAGAGCAACAAAGAGGCCAGCACCATCAGCACCGACA

ATCCCGACATCAACCCCAACTCTCAGCACCCCACACAGCAGTCCACCGAG

AATCCCACACTGAACCCTGCCGCCTCTGTGTCCCCATCTGAGACAGAACC

TGCCAGCACACCCGACACCACCAACAGACTGTCTAGCGTGGACAGAAGCA

CAGCCCAGCCTAGCGAGAGCCGGACCAAGACAAAACCTACCGTGCACACC

CGGAACAACCCTAGCACAGCCAGCTCTACACAGAGCCCTCCAAGAGCCAC

CACCAAGGCCATTAGAAGGGCCACCACCTTCCGGATGAGCAGCACCGGCA

AAAGACCTACCACCACCAGCGTGCAGAGCGACAGCAGCACAACCACACAG

AACCACGAGGAAACCGGCAGCGCCAATCCTCAGGCTAGCGTGTCCACCAT

GCAGAAC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 201, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 201 is provided herein as SEQ ID No: 202, as follows:

[SEQ ID No: 202]

AUGGAAGUGAAGGUCGAGAACAUCCGGGCCAUCGACAUGCUGAAGGCCAG

AGUGAAGAACAGAGUGGCCCGGUCCAAGUGCUUCAAGAACGCCAGCCUGA

UCCUGAUCGGCAUCACCACACUGUCUAUCGCCCUGAACAUCUACCUGAUC

AUCAACUACACCAUCCAGAAAACCAGCAGCGAGAGCGAGCACCACACAAG

CUCUCCACCUACCGAGAGCAACAAAGAGGCCAGCACCAUCAGCACCGACA

AUCCCGACAUCAACCCCAACUCUCAGCACCCCACACAGCAGUCCACCGAG

AAUCCCACACUGAACCCUGCCGCCUCUGUGUCCCCAUCUGAGACAGAACC

UGCCAGCACACCCGACACCACCAACAGACUGUCUAGCGUGGACAGAAGCA

CAGCCCAGCCUAGCGAGAGCCGGACCAAGACAAAACCUACCGUGCACACC

CGGAACAACCCUAGCACAGCCAGCUCUACACAGAGCCCUCCAAGAGCCAC

CACCAAGGCCAUUAGAAGGGCCACCACCUUCCGGAUGAGCAGCACCGGCA

AAAGACCUACCACCACCAGCGUGCAGAGCGACAGCAGCACAACCACACAG

AACCACGAGGAAACCGGCAGCGCCAAUCCUCAGGCUAGCGUGUCCACCAU

GCAGAAC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 202, or a fragment or variant thereof.

The following viral IIPs are believed to cause cleavage of RIG-I.

In one embodiment, the at least one IIP is CVB3 3C protease (P03313; Genome polyprotein Coxsackievirus B3 (strain Nancy)), or an orthologue thereof. Xiao H, Li J, Yang X, Li Z, Wang Y, Rui Y, Liu R, Zhang W (2021) Ectopic Expression of TRIM25 Restores RIG-I Expression and IFN Production Reduced by Multiple Enteroviruses 3Cpro. Virol Sin: 1-12.doi: 10.1007/s12250-021-00410-x. One embodiment of the polypeptide sequence of CVB3 3C protease is represented herein as SEQ ID No: 203, as follows:

[SEQ ID No: 203]

GPAFEFAVAMMKRNSSTVKTEYGEFTMLGIYDRWAVLPRHAKPGPTILMN

DQEVGVLDAKELVDKDGTNLELTLLKLNRNEKFRDIRGFLAKEEVEVNEA

VLAINTSKFPNMYIPVGQVTEYGFLNLGGTPTKRMLMYNFPTRAGQCGGV

LMSTGKVLGIHVGGNGHQGFSAALLKHYFNDEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 203, or a variant or fragment thereof.

In one embodiment, the CVB3 3C protease polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 204, as follows:

[SEQ ID No: 204]

GGCCCTGCCTTTGAGTTCGCCGTCGCAATGATGAAAAGGAACTCAAGCAC

GGTGAAAACTGAATATGGCGAGTTTACCATGCTGGGCATCTATGACAGGT

GGGCCGTTTTGCCACGCCACGCCAAACCTGGGCCAACCATCTTGATGAAT

GATCAAGAGGTTGGTGTGCTAGATGCCAAGGAGCTAGTAGACAAGGACGG

CACCAACTTAGAACTGACACTACTCAAATTGAACCGGAATGAGAAGTTCA

GAGACATCAGAGGCTTCTTAGCCAAGGAGGAAGTGGAGGTTAATGAGGCA

GTGCTAGCAATTAACACCAGCAAGTTTCCCAACATGTACATTCCAGTAGG

ACAGGTCACAGAATACGGCTTCCTAAACCTAGGTGGCACACCCACCAAGA

GAATGCTTATGTACAACTTCCCCACAAGAGCAGGCCAGTGTGGTGGAGTG

CTCATGTCCACCGGCAAGGTACTGGGTATCCATGTTGGTGGAAATGGCCA

TCAGGGCTTCTCAGCAGCACTCCTCAAACACTACTTCAATGATGAGCAA

Accordingly, preferably the CVB3 3C protease polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 204, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CVB3 3C protease polypeptide is provided herein as SEQ ID No: 205, as follows:

[SEQ ID No: 205]

GGACCTGCCTTTGAATTCGCCGTGGCCATGATGAAGCGGAACAGCAGCAC

CGTGAAAACCGAGTACGGCGAGTTCACCATGCTGGGCATCTACGACAGAT

GGGCCGTGCTGCCTAGACACGCCAAACCTGGACCTACCATCCTGATGAAC

GACCAAGAAGTGGGCGTTCTGGACGCCAAAGAACTGGTGGACAAGGACGG

CACCAACCTGGAACTGACCCTGCTGAAGCTGAACCGGAACGAGAAGTTCC

GGGATATCAGAGGCTTCCTGGCCAAAGAAGAGGTGGAAGTCAACGAAGCC

GTGCTGGCCATCAACACCAGCAAGTTCCCCAACATGTACATCCCCGTGGG

CCAAGTGACAGAGTACGGCTTCCTGAATCTCGGCGGCACCCCTACCAAGC

GGATGCTGATGTACAACTTCCCCACCAGAGCCGGCCAGTGTGGCGGAGTT

CTTATGTCTACCGGCAAGGTGCTGGGAATCCACGTTGGCGGAAATGGCCA

CCAGGGCTTTTCTGCCGCTCTGCTGAAACACTACTTCAACGACGAGCAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 205, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 205 is provided herein as SEQ ID No: 206, as follows:

[SEQ ID No: 206]

GGACCUGCCUUUGAAUUCGCCGUGGCCAUGAUGAAGCGGAACAGCAGCAC

CGUGAAAACCGAGUACGGCGAGUUCACCAUGCUGGGCAUCUACGACAGAU

GGGCCGUGCUGCCUAGACACGCCAAACCUGGACCUACCAUCCUGAUGAAC

GACCAAGAAGUGGGCGUUCUGGACGCCAAAGAACUGGUGGACAAGGACGG

CACCAACCUGGAACUGACCCUGCUGAAGCUGAACCGGAACGAGAAGUUCC

GGGAUAUCAGAGGCUUCCUGGCCAAAGAAGAGGUGGAAGUCAACGAAGCC

GUGCUGGCCAUCAACACCAGCAAGUUCCCCAACAUGUACAUCCCCGUGGG

CCAAGUGACAGAGUACGGCUUCCUGAAUCUCGGCGGCACCCCUACCAAGC

GGAUGCUGAUGUACAACUUCCCCACCAGAGCCGGCCAGUGUGGCGGAGUU

CUUAUGUCUACCGGCAAGGUGCUGGGAAUCCACGUUGGCGGAAAUGGCCA

CCAGGGCUUUUCUGCCGCUCUGCUGAAACACUACUUCAACGACGAGCAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 206, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Hepatitis C NS3/4A (039929; Genome polyprotein Hepatitis C virus genotype 4a (isolate ED43)), or an orthologue thereof. One embodiment of the polypeptide sequence of Hepatitis C NS3/4A is represented herein as SEQ ID No: 207, as follows:

[SEQ ID No: 207]

APITAYAQQTRGLFSTIVTSLTGRDTNENCGEVQVLSTATQSFLGTAVNG

VMWTVYHGAGAKTISGPKGPVNQMYTNVDQDLVGWPAPPGVRSLAPCTCG

SADLYLVTRHADVIPVRRRGDTRGALLSPRPISILKGSSGGPLLCPMGHR

AGIFRAAVCTRGVAKAVDFVPVESLETTMRSPVFTDNSTPPAVPQTYQVA

HLHAPTGSGKSTKVPAAHAAQGYKVLVLNPSVAATLGFGVYMSKAYGIDP

NIRSGVRTITTGAPITYSTYGKFLADGGCSGGAYDIIICDECYSTDSTTI

LGIGTVLDQAETAGVRLTVLATATPPGSVTTPHSNIEEVALPTTGEIPFY

GKAIPLELIKGGRHLIFCHSKKKCDELARQLTSLGLNAVAYYRGLDVSVI

PTSGDVVVCATDALMTGFTGDFDSVIDCNTSVIQTVDFSLDPTFSIEITT

VPQDAVSRSQRRGRTGRGRLGTYRYVTPGERPSGMFDTAELCECYDAGCA

WYELTPAETTTRLKAYFDTPGLPVCQDHLEFWESVFTGLTHIDGHFLSQT

KQSGENFPYLVAYQATVSAKVWLAPPSWDTMWKCLIRLKPTLHGPTPLLY

RLGSVQNEVVLTHPITKYIMACMSADLEVVT

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 207, or a variant or fragment thereof.

In one embodiment, the Hepatitis C NS3/4A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 208, as follows:

[SEQ ID No: 208]

GCCCCCATCACAGCATACGCaCAGCAGACCCGCGGCTTGTTCAGCACCAT

CGTAACGAGCCTCACTGGCAGGGACACCAATGAGAATTGTGGCGAAGTGC

AGGTCTTATCCACCGCTACGCAGTCCTTCCTGGGTACTGCGGTTAACGGC

GTGATGTGGACCGTCTACCACGGGGCGGGTGCCAAGACCATCAGCGGCCC

GAAGGGACCTGTCAATCAAATGTACACTAATGTTGACCAAGACTTGGTGG

GGTGGCCAGCACCCCCCGGAGTCAGATCTCTTGCTCCGTGCACCTGCGGC

TCGGCAGACTTGTATCTAGTCACCAGGCACGCGGATGTAATACCCGTGCG

CAGGAGAGGAGACACCAGAGGAGCTCTCTTGAGCCCTAGACCAATATCCA

TTCTTAAGGGATCTTCCGGAGGTCCGCTGCTGTGCCCCATGGGACACCGC

GCCGGCATATTCCGTGCGGCGGTGTGTACTCGGGGGGTAGCCAAGGCGGT

AGACTTCGTCCCGGTTGAATCTCTTGAGACTACCATGAGATCACCAGTGT

TCACTGACAACTCAACACCCCCAGCAGTGCCCCAGACCTACCAGGTCGCG

CACCTACACGCACCAACAGGAAGTGGCAAGAGCACTAAGGTCCCGGCGGC

GCATGCTGCCCAAGGCTATAAAGTGCTAGTGCTCAATCCTTCGGTTGCGG

CCACACTGGGTTTTGGGGTATACATGTCCAAGGCATATGGCATCGACCCG

AACATCCGGTCGGGAGTCAGGACCATCACCACGGGTGCGCCAATCACGTA

CTCAACGTATGGTAAGTTCCTGGCTGATGGAGGTTGCAGCGGAGGGGCAT

ACGACATAATCATCTGTGACGAGTGCTATTCCACTGACTCCACAACGATC

CTTGGCATAGGCACAGTCCTGGACCAAGCGGAGACCGCTGGAGTGCGCCT

CACCGTGCTCGCGACTGCTACTCCGCCAGGGTCAGTGACTACACCTCATT

CCAACATAGAGGAGGTCGCCCTGCCAACAACGGGGGAAATACCCTTTTAC

GGCAAGGCGATCCCTCTGGAGCTGATCAAGGGGGGCAGACATCTCATCTT

CTGCCATTCAAAGAAAAAGTGCGATGAACTGGCCAGACAACTGACATCTC

TTGGTCTGAATGCCGTAGCCTACTACAGAGGCTTAGACGTTTCGGTGATT

CCCACGTCTGGGGACGTCGTGGTATGCGCCACGGACGCCCTCATGACGGG

TTTCACCGGCGACTTTGACTCAGTGATAGACTGCAATACATCTGTGATAC

AGACTGTTGACTTCAGCTTGGACCCCACCTTCTCCATAGAGATTACAACC

GTTCCCCAGGACGCGGTATCCCGCAGCCAGCGGAGAGGCCGCACTGGTAG

GGGGAGGTTGGGCACATACCGGTATGTCACCCCGGGAGAGAGACCATCAG

GCATGTTTGACACTGCAGAGCTTTGCGAGTGCTACGATGCCGGGTGCGCC

TGGTACGAGCTGACACCTGCTGAAACCACAACAAGGCTGAAAGCTTACTT

CGACACACCAGGCCTTCCTGTGTGCCAAGACCATCTGGAATTCTGGGAGA

GCGTCTTTACAGGGTTAACCCACATAGACGGTCATTTCCTATCCCAGACC

AAGCAATCGGGTGAGAATTTCCCGTATCTTGTTGCTTACCAAGCGACGGT

GTCGGCCAAGGTCTGGCTCGCTCCACCAAGCTGGGACACCATGTGGAAGT

GCCTAATTCGCCTTAAGCCCACCCTGCACGGGCCCACGCCCCTCCTCTAC

AGACTGGGGTCTGTGCAGAATGAAGTGGTGCTCACCCATCCCATCACCAA

ATACATCATGGCTTGCATGTCAGCTGATCTCGAGGTAGTGACA

Accordingly, preferably the Hepatitis C NS3/4A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 208, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Hepatitis C NS3/4A polypeptide is provided herein as SEQ ID No: 209, as follows:

[SEQ ID No: 209]

GCCCCTATCACAGCCTACGCTCAGCAGACCAGAGGCCTGTTCAGCACCAT

CGTGACAAGCCTGACCGGCAGAGACACCAACGAGAATTGTGGCGAGGTGC

AGGTCCTGTCTACAGCTACCCAGAGCTTTCTGGGCACCGCCGTGAATGGC

GTGATGTGGACAGTGTATCATGGCGCTGGCGCCAAGACAATCTCTGGCCC

TAAGGGCCCCGTGAACCAGATGTACACCAACGTGGACCAGGACCTCGTTG

GCTGGCCTGCTCCTCCTGGTGTTAGAAGCCTGGCTCCTTGTACATGCGGC

AGCGCCGATCTGTACCTGGTCACAAGACACGCCGACGTGATCCCCGTCAG

AAGAAGAGGCGATACAAGAGGCGCCCTGCTGAGCCCTAGACCTATCTCTA

TCCTGAAGGGCAGCTCTGGCGGCCCTCTGCTTTGTCCTATGGGACACAGA

GCCGGCATCTTCAGAGCCGCCGTGTGTACTAGAGGCGTGGCCAAGGCTGT

GGACTTCGTGCCTGTGGAAAGCCTGGAAACCACCATGAGAAGCCCCGTGT

TCACCGACAACAGCACCCCTCCAGCTGTGCCTCAGACATACCAGGTGGCC

CATCTGCATGCCCCTACAGGCTCTGGCAAGAGCACAAAAGTGCCTGCCGC

TCATGCTGCCCAGGGCTATAAGGTGCTGGTGCTCAATCCTAGCGTGGCCG

CCACACTCGGCTTTGGCGTGTACATGTCTAAGGCCTACGGCATCGACCCC

AACATCAGATCTGGCGTGCGGACCATCACAACAGGCGCCCCAATCACCTA

CTCTACCTACGGCAAGTTCCTGGCCGATGGCGGATGTTCTGGCGGAGCCT

ACGACATCATCATCTGCGACGAGTGCTACAGCACCGACAGCACCACAATC

CTCGGCATCGGCACAGTGCTGGATCAGGCTGAAACAGCCGGCGTCAGACT

GACTGTGCTGGCCACAGCTACACCTCCAGGCAGCGTGACAACCCCTCACA

GCAACATCGAGGAAGTGGCCCTGCCTACAACCGGCGAGATCCCATTCTAT

GGCAAGGCCATTCCTCTCGAGCTGATCAAAGGCGGCAGACACCTGATCTT

TTGCCACAGCAAGAAGAAGTGCGACGAGCTGGCCAGACAGCTGACATCCC

TGGGACTGAATGCCGTGGCCTACTACAGAGGACTGGACGTGTCCGTGATT

CCCACATCTGGCGACGTGGTCGTGTGTGCCACAGATGCCCTGATGACCGG

CTTCACCGGCGACTTCGATAGCGTGATCGACTGCAACACCAGCGTGATCC

AGACCGTGGACTTCTCTCTGGACCCCACCTTCAGCATCGAGATCACCACC

GTTCCTCAGGACGCCGTGTCTCGGTCACAGAGAAGAGGCAGAACAGGCAG

AGGCCGGCTGGGCACATACAGATATGTGACACCCGGCGAAAGACCCAGCG

GCATGTTTGATACAGCCGAGCTGTGCGAGTGTTACGACGCCGGATGTGCT

TGGTACGAGCTGACACCAGCCGAGACAACCACCAGACTGAAGGCCTACTT

CGACACCCCTGGCCTGCCTGTGTGTCAGGACCACCTGGAATTTTGGGAGA

GCGTGTTCACAGGACTGACCCACATCGACGGCCACTTTCTGAGCCAGACC

AAGCAGAGCGGCGAGAACTTCCCTTACCTGGTGGCCTATCAGGCTACCGT

GTCCGCCAAAGTTTGGCTGGCTCCTCCTAGCTGGGACACCATGTGGAAGT

GCCTGATCCGGCTGAAGCCTACACTGCACGGACCTACACCTCTGCTGTAC

AGACTGGGCAGCGTGCAGAATGAGGTGGTGCTGACCCATCCTATCACCAA

GTACATCATGGCCTGCATGAGCGCCGACCTGGAAGTGGTTACA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 209, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 209 is provided herein as SEQ ID No: 210, as follows:

[SEQ ID No: 210]

GCCCCUAUCACAGCCUACGCUCAGCAGACCAGAGGCCUGUUCAGCACCAU

CGUGACAAGCCUGACCGGCAGAGACACCAACGAGAAUUGUGGCGAGGUGC

AGGUCCUGUCUACAGCUACCCAGAGCUUUCUGGGCACCGCCGUGAAUGGC

GUGAUGUGGACAGUGUAUCAUGGCGCUGGCGCCAAGACAAUCUCUGGCCC

UAAGGGCCCCGUGAACCAGAUGUACACCAACGUGGACCAGGACCUCGUUG

GCUGGCCUGCUCCUCCUGGUGUUAGAAGCCUGGCUCCUUGUACAUGCGGC

AGCGCCGAUCUGUACCUGGUCACAAGACACGCCGACGUGAUCCCCGUCAG

AAGAAGAGGCGAUACAAGAGGCGCCCUGCUGAGCCCUAGACCUAUCUCUA

UCCUGAAGGGCAGCUCUGGCGGCCCUCUGCUUUGUCCUAUGGGACACAGA

GCCGGCAUCUUCAGAGCCGCCGUGUGUACUAGAGGCGUGGCCAAGGCUGU

GGACUUCGUGCCUGUGGAAAGCCUGGAAACCACCAUGAGAAGCCCCGUGU

UCACCGACAACAGCACCCCUCCAGCUGUGCCUCAGACAUACCAGGUGGCC

CAUCUGCAUGCCCCUACAGGCUCUGGCAAGAGCACAAAAGUGCCUGCCGC

UCAUGCUGCCCAGGGCUAUAAGGUGCUGGUGCUCAAUCCUAGCGUGGCCG

CCACACUCGGCUUUGGCGUGUACAUGUCUAAGGCCUACGGCAUCGACCCC

AACAUCAGAUCUGGCGUGCGGACCAUCACAACAGGCGCCCCAAUCACCUA

CUCUACCUACGGCAAGUUCCUGGCCGAUGGCGGAUGUUCUGGCGGAGCCU

ACGACAUCAUCAUCUGCGACGAGUGCUACAGCACCGACAGCACCACAAUC

CUCGGCAUCGGCACAGUGCUGGAUCAGGCUGAAACAGCCGGCGUCAGACU

GACUGUGCUGGCCACAGCUACACCUCCAGGCAGCGUGACAACCCCUCACA

GCAACAUCGAGGAAGUGGCCCUGCCUACAACCGGCGAGAUCCCAUUCUAU

GGCAAGGCCAUUCCUCUCGAGCUGAUCAAAGGCGGCAGACACCUGAUCUU

UUGCCACAGCAAGAAGAAGUGCGACGAGCUGGCCAGACAGCUGACAUCCC

UGGGACUGAAUGCCGUGGCCUACUACAGAGGACUGGACGUGUCCGUGAUU

CCCACAUCUGGCGACGUGGUCGUGUGUGCCACAGAUGCCCUGAUGACCGG

CUUCACCGGCGACUUCGAUAGCGUGAUCGACUGCAACACCAGCGUGAUCC

AGACCGUGGACUUCUCUCUGGACCCCACCUUCAGCAUCGAGAUCACCACC

GUUCCUCAGGACGCCGUGUCUCGGUCACAGAGAAGAGGCAGAACAGGCAG

AGGCCGGCUGGGCACAUACAGAUAUGUGACACCCGGCGAAAGACCCAGCG

GCAUGUUUGAUACAGCCGAGCUGUGCGAGUGUUACGACGCCGGAUGUGCU

UGGUACGAGCUGACACCAGCCGAGACAACCACCAGACUGAAGGCCUACUU

CGACACCCCUGGCCUGCCUGUGUGUCAGGACCACCUGGAAUUUUGGGAGA

GCGUGUUCACAGGACUGACCCACAUCGACGGCCACUUUCUGAGCCAGACC

AAGCAGAGCGGCGAGAACUUCCCUUACCUGGUGGCCUAUCAGGCUACCGU

GUCCGCCAAAGUUUGGCUGGCUCCUCCUAGCUGGGACACCAUGUGGAAGU

GCCUGAUCCGGCUGAAGCCUACACUGCACGGACCUACACCUCUGCUGUAC

AGACUGGGCAGCGUGCAGAAUGAGGUGGUGCUGACCCAUCCUAUCACCAA

GUACAUCAUGGCCUGCAUGAGCGCCGACCUGGAAGUGGUUACA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 210, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV NS3 protein (P17763; Genome polyprotein Dengue virus type 1 (strain Nauru/West Pac/1974)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV NS3 protein is represented herein as SEQ ID No: 211, as follows:

[SEQ ID No: 211]

SGVLWDTPSPPEVERAVLDDGIYRILQRGLLGRSQVGVGVFQEGVFHTMWHVTRGAVLMYQGKRLEPSWASVKKDLIS

YGGGWRFQGSWNAGEEVQVIAVEPGKNPKNVQTAPGTFKTPEGEVGAIALDFKPGTSGSPIVNREGKIVGLYGNGVVT

TSGTYVSAIAQAKASQEGPLPEIEDEVFRKRNLTIMDLHPGSGKTRRYLPAIVREAIRRNVRTLVLAPTRVVASEMAE

ALKGMPIRYQTTAVKSEHTGKEIVDLMCHATFTMRLLSPVRVPNYNMIIMDEAHFTDPASIAARGYISTRVGMGEAAA

IFMTATPPGSVEAFPQSNAVIQDEERDIPERSWNSGYDWITDFPGKTVWFVPSIKSGNDIANCLRKNGKRVVQLSRKT

FDTEYQKTKNNDWDYVVTTDISEMGANFRADRVIDPRRCLKPVILKDGPERVILAGPMPVTVASAAQRRGRIGRNQNK

EGDQYIYMGQPLNNDEDHAHWTEAKMLLDNINTPEGIIPALFEPEREKSAAIDGEYRLRGEARKTFVELMRRGDLPVW

LSYKVASEGFQYSDRRWCFDGERNNQVLEENMDVEIWTKEGERKKLRPRWLDARTYSDPLALREFKEFAAGRR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 211, or a variant or fragment thereof.

In one embodiment, the DENV NS3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 212, as follows:

[SEQ ID No: 212]

TCAGGAGTGCTATGGGACACACCCAGCCCTCCAGAAGTGGAAAGAGCAGTCCTTGATGATGGCATTTATAGAATTCTC

CAAAGAGGATTGTTGGGCAGGTCTCAAGTAGGAGTAGGAGTTTTTCAAGAAGGCGTGTTCCACACAATGTGGCACGTC

ACCAGGGGAGCTGTCCTCATGTACCAAGGGAAGAGACTGGAACCAAGTTGGGCCAGTGTCAAAAAAGACTTGATCTCA

TATGGAGGAGGTTGGAGGTTTCAAGGATCCTGGAACGCGGGAGAAGAAGTGCAGGTGATTGCTGTTGAACCGGGGAAG

AACCCCAAAAATGTACAGACAGCGCCGGGTACCTTCAAGACCCCTGAAGGCGAAGTTGGAGCCATAGCTCTAGACTTT

AAACCCGGCACATCTGGATCTCCTATCGTGAACAGAGAGGGAAAAATAGTAGGTCTTTATGGAAATGGAGTGGTGACA

ACAAGTGGTACCTACGTCAGCGCCATAGCTCAAGCTAAAGCATCACAAGAAGGGCCTCTACCAGAGATTGAGGACGAG

GTGTTTAGGAAAAGAAACTTAACAATAATGGACCTACATCCAGGATCGGGGAAAACAAGAAGATATCTTCCAGCCATA

GTCCGTGAGGCCATAAGAAGGAACGTGCGCACGCTAGTCTTAGCTCCCACAAGAGTTGTCGCTTCTGAAATGGCAGAG

GCGCTCAAGGGAATGCCAATAAGGTATCAGACAACAGCAGTGAAGAGTGAACACACAGGAAAAGAGATAGTTGACCTT

ATGTGTCACGCCACTTTCACTATGCGTCTCCTGTCTCCTGTGAGAGTTCCCAATTATAATATGATTATCATGGATGAA

GCACATTTTACCGATCCAGCCAGCATAGCAGCCAGAGGGTATATCTCAACCCGAGTGGGTATGGGTGAAGCAGCTGCG

ATTTTCATGACAGCCACTCCCCCCGGATCGGTGGAGGCCTTTCCACAGAGCAATGCAGTTATCCAAGATGAGGAAAGA

GACATTCCTGAAAGATCATGGAACTCAGGCTATGACTGGATCACTGATTTCCCAGGTAAAACAGTCTGGTTTGTTCCA

AGCATCAAATCAGGAAATGACATTGCCAACTGTTTAAGAAAGAATGGGAAACGGGTGGTCCAATTGAGCAGAAAAACT

TTTGACACTGAGTACCAGAAAACAAAAAATAACGACTGGGACTATGTTGTCACAACAGACATATCCGAAATGGGAGCA

AACTTCCGAGCCGACAGGGTAATAGACCCGAGGCGGTGCCTGAAACCGGTAATACTAAAAGATGGCCCAGAGCGTGTC

ATTCTAGCCGGACCGATGCCAGTTGACTGTGGCTAGCGCCGCCCAGAGGAGAGGAAGAATTGGAAGGAACCAAAATAAG

GAAGGCGATCAGTATATTTACATGGGACAGCCTCTAAACAATGATGAGGACCACGCCCATTGGACAGAAGCAAAAATG

CTCCTTGACAACATAAACACACCAGAAGGGATTATCCCAGCCCTCTTTGAGCCGGAGAGAGAAAAGAGTGCAGCAATA

GACGGGGAATACAGACTACGGGGTGAAGCGAGGAAAACGTTCGTGGAGCTCATGAGAAGAGGAGATCTACCTGTCTGG

CTATCCTACAAAGTTGCCTCAGAAGGCTTCCAGTACTCCGACAGAAGGTGGTGCTTTGATGGGGAAAGGAACAACCAG

GTGTTGGAGGAGAACATGGACGTGGAGATCTGGACAAAAGAAGGAGAAAGAAAGAAACTACGACCCCGCTGGCTGGAT

GCCAGAACATACTCTGACCCACTGGCTCTGCGCGAATTCAAAGAGTTCGCAGCAGGAAGAAGA

Accordingly, preferably the DENV NS3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 212, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV NS3 polypeptide is provided herein as SEQ ID No: 213, as follows:

[SEQ ID No: 213]

TCTGGCGTGCTGTGGGATACACCTTCTCCACCAGAGGTGGAAAGAGCCGTGCTGGACGACGGCATCTACCGGATTCTG

CAGAGAGGACTGCTGGGCAGATCTCAAGTTGGCGTGGGCGTGTTCCAAGAAGGGGTGTTCCACACCATGTGGCACGTG

ACAAGAGGCGCCGTGCTGATGTACCAGGGCAAGAGACTGGAACCTAGCTGGGCCAGCGTGAAGAAGGACCTGATCTCT

TACGGCGGAGGCTGGCGGTTTCAAGGCTCTTGGAATGCCGGCGAAGAGGTGCAAGTGATCGCCGTGGAACCCGGCAAG

AACCCCAAGAACGTTCAGACAGCCCCTGGCACCTTCAAGACCCCTGAAGGCGAAGTGGGAGCTATCGCCCTGGATTTC

AAGCCTGGCACAAGCGGCAGCCCCATCGTGAACAGAGAAGGCAAGATCGTGGGCCTGTACGGCAATGGCGTGGTCACC

ACATCTGGCACCTACGTGTCAGCCATTGCTCAGGCCAAGGCCTCTCAAGAGGGACCCCTGCCTGAGATCGAGGACGAG

GTGTTCCGGAAGCGGAACCTGACCATCATGGATCTGCACCCTGGCAGCGGCAAGACCAGAAGATATCTGCCCGCCATT

GTGCGCGAGGCCATCCGAAGAAATGTGCGGACACTGGTGCTGGCCCCTACAAGAGTGGTGGCCTCTGAAATGGCCGAG

GCTCTGAAGGGCATGCCTATCAGATACCAGACCACCGCCGTGAAGTCTGAGCACACCGGCAAAGAAATCGTGGACCTG

ATGTGCCACGCCACCTTCACCATGAGACTGCTGAGCCCTGTGCGGGTGCCCAACTACAACATGATCATCATGGACGAG

GCCCACTTCACAGACCCCGCCTCTATTGCCGCCAGAGGCTACATCTCTACCAGAGTCGGCATGGGAGAAGCCGCCGCT

ATCTTCATGACAGCCACACCTCCAGGCAGCGTGGAAGCCTTTCCTCAGTCCAATGCCGTGATCCAGGACGAAGAGAGA

GACATCCCCGAGCGGAGCTGGAACAGCGGCTACGACTGGATCACCGACTTTCCAGGCAAGACCGTTTGGTTCGTGCCC

AGCATCAAGAGCGGCAACGATATCGCCAACTGCCTGCGGAAGAACGGCAAGAGAGTGGTGCAGCTGAGCAGAAAGACC

TTCGACACCGAGTACCAAAAGACCAAGAACAACGACTGGGACTACGTCGTGACCACCGACATCTCTGAGATGGGCGCC

AACTTCAGGGCCGACAGAGTGATCGACCCTCGGAGATGTCTGAAGCCCGTGATCCTGAAGGACGGCCCTGAGAGAGTG

ATTCTGGCCGGACCTATGCCTGTGACAGTGGCTTCTGCCGCTCAGAGAAGAGGCCGGATCGGCCGGAATCAGAACAAA

GAGGGCGACCAGTACATCTACATGGGCCAGCCTCTGAACAACGATGAGGATCACGCCCACTGGACCGAGGCCAAGATG

CTGCTGGACAACATCAACACCCCTGAGGGCATCATCCCCGCTCTGTTCGAGCCCGAGAGAGAGAAGTCTGCCGCAATC

GACGGCGAGTACAGACTGAGAGGCGAGGCCAGAAAGACATTTGTGGAACTGATGCGGAGAGGCGACCTGCCTGTGTGG

CTGAGTTACAAGGTGGCCAGCGAGGGCTTCCAGTACAGCGATAGAAGATGGTGCTTCGATGGCGAGCGGAACAACCAG

GTGCTGGAAGAGAACATGGACGTGGAAATCTGGACCAAAGAAGGCGAGCGCAAGAAACTGCGGCCCAGATGGCTGGAT

GCCCGGACATATTCTGACCCTCTGGCTCTGCGCGAGTTCAAAGAGTTTGCCGCCGGAAGAAGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 213, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 213 is provided herein as SEQ ID No: 214, as follows:

[SEQ ID No: 214]

UCUGGCGUGCUGUGGGAUACACCUUCUCCACCAGAGGUGGAAAGAGCCGUGCUGGACGACGGCAUCUACCGGAUUCUG

CAGAGAGGACUGCUGGGCAGAUCUCAAGUUGGCGUGGGCGUGUUCCAAGAAGGGGUGUUCCACACCAUGUGGCACGUG

ACAAGAGGCGCCGUGCUGAUGUACCAGGGCAAGAGACUGGAACCUAGCUGGGCCAGCGUGAAGAAGGACCUGAUCUCU

UACGGCGGAGGCUGGCGGUUUCAAGGCUCUUGGAAUGCCGGCGAAGAGGUGCAAGUGAUCGCCGUGGAACCCGGCAAG

AACCCCAAGAACGUUCAGACAGCCCCUGGCACCUUCAAGACCCCUGAAGGCGAAGUGGGAGCUAUCGCCCUGGAUUUC

AAGCCUGGCACAAGCGGCAGCCCCAUCGUGAACAGAGAAGGCAAGAUCGUGGGCCUGUACGGCAAUGGCGUGGUCACC

ACAUCUGGCACCUACGUGUCAGCCAUUGCUCAGGCCAAGGCCUCUCAAGAGGGACCCCUGCCUGAGAUCGAGGACGAG

GUGUUCCGGAAGCGGAACCUGACCAUCAUGGAUCUGCACCCUGGCAGCGGCAAGACCAGAAGAUAUCUGCCCGCCAUU

GUGCGCGAGGCCAUCCGAAGAAAUGUGCGGACACUGGUGCUGGCCCCUACAAGAGUGGUGGCCUCUGAAAUGGCCGAG

GCUCUGAAGGGCAUGCCUAUCAGAUACCAGACCACCGCCGUGAAGUCUGAGCACACCGGCAAAGAAAUCGUGGACCUG

AUGUGCCACGCCACCUUCACCAUGAGACUGCUGAGCCCUGUGCGGGUGCCCAACUACAACAUGAUCAUCAUGGACGAG

GCCCACUUCACAGACCCCGCCUCUAUUGCCGCCAGAGGCUACAUCUCUACCAGAGUCGGCAUGGGAGAAGCCGCCGCU

AUCUUCAUGACAGCCACACCUCCAGGCAGCGUGGAAGCCUUUCCUCAGUCCAAUGCCGUGAUCCAGGACGAAGAGAGA

GACAUCCCCGAGCGGAGCUGGAACAGCGGCUACGACUGGAUCACCGACUUUCCAGGCAAGACCGUUUGGUUCGUGCCC

AGCAUCAAGAGCGGCAACGAUAUCGCCAACUGCCUGCGGAAGAACGGCAAGAGAGUGGUGCAGCUGAGCAGAAAGACC

UUCGACACCGAGUACCAAAAGACCAAGAACAACGACUGGGACUACGUCGUGACCACCGACAUCUCUGAGAUGGGCGCC

AACUUCAGGGCCGACAGAGUGAUCGACCCUCGGAGAUGUCUGAAGCCCGUGAUCCUGAAGGACGGCCCUGAGAGAGUG

AUUCUGGCCGGACCUAUGCCUGUGACAGUGGCUUCUGCCGCUCAGAGAAGAGGCCGGAUCGGCCGGAAUCAGAACAAA

GAGGGCGACCAGUACAUCUACAUGGGCCAGCCUCUGAACAACGAUGAGGAUCACGCCCACUGGACCGAGGCCAAGAUG

CUGCUGGACAACAUCAACACCCCUGAGGGCAUCAUCCCCGCUCUGUUCGAGCCCGAGAGAGAGAAGUCUGCCGCAAUC

GACGGCGAGUACAGACUGAGAGGCGAGGCCAGAAAGACAUUUGUGGAACUGAUGCGGAGAGGCGACCUGCCUGUGUGG

CUGAGUUACAAGGUGGCCAGCGAGGGCUUCCAGUACAGCGAUAGAAGAUGGUGCUUCGAUGGCGAGCGGAACAACCAG

GUGCUGGAAGAGAACAUGGACGUGGAAAUCUGGACCAAAGAAGGCGAGCGCAAGAAACUGCGGCCCAGAUGGCUGGAU

GCCCGGACAUAUUCUGACCCUCUGGCUCUGCGCGAGUUCAAAGAGUUUGCCGCCGGAAGAAGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 214, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EV71 3Cpro (B9VUU3; Genome polyprotein Human enterovirus 71), or an orthologue thereof. Lei X, Xiao X, Xue Q, Jin Q, He B, Wang J J. (2013) Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol, 87, 3, 1690-1698. doi: 10.1128/JVI.01855-12. Epub 2012 Nov. 21.). This IIP is believed to cleave IRF7. One embodiment of the polypeptide sequence of EV71 3Cpro is represented herein as SEQ ID No: 215, as follows:

[SEQ ID No: 215]

GPSLDFALSLLRRNVRQVQTDQGHFTMLGVRDRLAVLPRHSQPGKTIWIEHKLVNVLDAVELVDEQGVNLELTLITLD

TNEKFRDITKFIPENISTASDATLVINTEHMPSMFVPVGDVVQYGFLNLSGKPTHRTMMYNFPTKAGQCGGVVTSVGK

VIGIHIGGNGRQGFCAGLKRSYFASEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 215, or a variant or fragment thereof.

In one embodiment, the EV71 3Cpro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 216, as follows:

[SEQ ID No: 216]

GGCCCGAGCCTTGATTTTGCTCTCTCCCTACTGAGGAGGAACGTCAGGCAAGTCCAAACAGACCAGGGGCATTTCACC

ATGTTGGGTGTTAGGGATCGCTTAGCAGTCCTCCCACGCCACTCACAACCCGGCAAAACTATTTGGATTGAGCACAAA

CTCGTGAACGTCCTTGATGCAGTTGAATTGGTGGATGAGCAAGGAGTCAACCTGGAATTAACCCTCATCACTCTTGAT

ACCAACGAGAAGTTTAGGGATATCACCAAATTCATCCCGGAAAATATTAGCACTGCTAGTGATGCCACCCTAGTGATC

AACACGGAGCACATGCCCTCGATGTTTGTCCCGGTGGGTGACGTTGTGCAGTATGGTTTCCTGAATCTCAGTGGTAAG

CCTACTCATCGCACCATGATGTACAACTTTCCTACTAAGGCAGGGCAATGTGGAGGGGTGGTGACATCAGTTGGAAAA

GTCATCGGTATACACATAGGTGGCAACGGTAGACAAGGATTTTGTGCAGGTCTTAAGAGAAGCTACTTTGCCAGCGAG

CAA

Accordingly, preferably the EV71 3Cpro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 216, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EV71 3Cpro polypeptide is provided herein as SEQ ID No: 217, as follows:

[SEQ ID No: 217]

GGCCCTTCTCTGGATTTTGCCCTGAGCCTGCTGCGGAGAAATGTGCGCCAGGTGCAGACAGATCAGGGCCACTTTACA

ATGCTGGGCGTCAGAGACAGACTGGCCGTGCTGCCTAGACACTCTCAGCCTGGCAAGACCATCTGGATCGAGCACAAG

CTGGTCAACGTGCTGGACGCCGTGGAACTGGTTGATGAGCAGGGCGTGAACCTGGAACTGACCCTGATCACCCTGGAC

ACCAACGAGAAGTTCCGGGACATCACCAAGTTCATCCCCGAGAACATCAGCACCGCCAGCGACGCCACACTGGTCATC

AATACCGAGCACATGCCCAGCATGTTCGTGCCTGTGGGAGATGTGGTGCAGTACGGCTTCCTGAACCTGAGCGGCAAG

CCCACACACCGGACCATGATGTACAACTTCCCTACCAAGGCCGGCCAGTGCGGCGGAGTGGTTACATCTGTGGGCAAA

GTGATCGGCATCCACATCGGCGGCAATGGCAGACAGGGATTTTGTGCCGGCCTGAAGAGAAGCTACTTCGCCTCTGAA

CAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 217, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 217 is provided herein as SEQ ID No: 218, as follows:

[SEQ ID No: 218]

GGCCCUUCUCUGGAUUUUGCCCUGAGCCUGCUGCGGAGAAAUGUGCGCCAGGUGCAGACAGAUCAGGGCCACUUUACA

AUGCUGGGCGUCAGAGACAGACUGGCCGUGCUGCCUAGACACUCUCAGCCUGGCAAGACCAUCUGGAUCGAGCACAAG

CUGGUCAACGUGCUGGACGCCGUGGAACUGGUUGAUGAGCAGGGCGUGAACCUGGAACUGACCCUGAUCACCCUGGAC

ACCAACGAGAAGUUCCGGGACAUCACCAAGUUCAUCCCCGAGAACAUCAGCACCGCCAGCGACGCCACACUGGUCAUC

AAUACCGAGCACAUGCCCAGCAUGUUCGUGCCUGUGGGAGAUGUGGUGCAGUACGGCUUCCUGAACCUGAGCGGCAAG

CCCACACACCGGACCAUGAUGUACAACUUCCCUACCAAGGCCGGCCAGUGCGGCGGAGUGGUUACAUCUGUGGGCAAA

GUGAUCGGCAUCCACAUCGGCGGCAAUGGCAGACAGGGAUUUUGUGCCGGCCUGAAGAGAAGCUACUUCGCCUCUGAA

CAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 218, or a fragment or variant thereof.

In one embodiment, the at least one IIP is FMDV Lpro (P03307; Leader Protease Genome polyprotein foot-and-mouth disease virus (isolate-/Germany/A5Westerwald/1951 serotype A)), or an orthologue thereof. One embodiment of the polypeptide sequence of FMDV Lpro is represented herein as SEQ ID No: 219, as follows:

[SEQ ID No: 219]

MHTTDCFIALVHAIREIRALFLPRTTGKMELTLHNGEKKTFYSRPNNHDNCWLNTILQLFRYVDEPFFDWVYNSPENL

TLEAINQLEELTGLELHEGGPPALVIWNIKHLLHTGIGTASRPSEVCMVDGTDMCLADFHAGIFLKGQEHAVFACVTS

NGWYAIDDEEFYPWTPDPSDVLVFVPYDQEPLNGDWKAMVQRKLK

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 219, or a variant or fragment thereof.

In one embodiment, the FMDV Lpro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 220, as follows:

[SEQ ID No: 220]

ATGCATACAACTGACTGTTTTATCGCTTTGGTGCACGCTATCAGAGAGATCAGAGCACTTTTTCTACCACGAACCACA

GGAAAGATGGAACTCACCCTGCACAACGGCGAGAAAAAGACTTTTTACTCTAGACCCAACAACCACGACAACTGCTGG

TTGAACACCATCCTTCAGTTGTTCAGGTATGTCGATGAACCCTTCTTCGACTGGGTCTACAACTCGCCCGAGAACCTC

ACGCTTGAAGCCATCAACCAATTGGAGGAACTCACAGGACTTGAGTTGCACGAGGGCGGACCGCCTGCCCTTGTGATC

TGGAACATCAAACACTTGCTCCACACCGGCATCGGCACCGCCTCACGACCCAGTGAGGTGTGTATGGTGGACGGCACG

GACATGTGTCTTGCTGACTTCCACGCAGGCATTTTCCTGAAGGGACAGGAACACGCAGTCTTTGCGTGTGTCACCTCC

AACGGGTGGTACGCGATTGACGACGAGGAATTTTACCCCTGGACGCCTGACCCGTCAGACGTCCTGGTGTTTGTCCCG

TACGATCAAGAACCACTCAACGGGGACTGGAAAGCGATGGTTCAGAGGAAGCTTAAG

Accordingly, preferably the FMDV Lpro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 220, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the FMDV Lpro polypeptide is provided herein as SEQ ID No: 221, as follows:

[SEQ ID No: 221]

ATGCACACCACCGACTGCTTTATCGCCCTGGTGCACGCCATCAGAGAGATCAGAGCCCTGTTCCTGCCTCGGACCACC

GGCAAGATGGAACTGACACTGCACAACGGCGAGAAGAAAACCTTCTACAGCAGACCCAACAACCACGACAACTGCTGG

CTGAACACCATCCTGCAGCTGTTCAGATACGTGGACGAGCCCTTCTTCGACTGGGTGTACAACAGCCCCGAGAATCTG

ACCCTGGAAGCCATCAACCAGCTGGAAGAACTGACCGGCCTGGAACTGCATGAAGGCGGACCTCCAGCTCTGGTCATC

TGGAACATCAAACATCTGCTGCACACCGGCATCGGCACCGCCTCTAGACCATCTGAAGTGTGCATGGTGGACGGCACC

GATATGTGCCTGGCCGATTTTCACGCCGGCATCTTTCTGAAGGGCCAAGAGCATGCCGTGTTCGCCTGCGTGACAAGC

AATGGATGGTACGCCATCGACGACGAGGAATTCTACCCCTGGACACCCGATCCTAGCGACGTGCTGGTGTTCGTGCCC

TACGATCAAGAGCCCCTGAACGGCGATTGGAAGGCCATGGTGCAGCGGAAGCTGAAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 221, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 221 is provided herein as SEQ ID No: 222, as follows:

[SEQ ID No: 222]

AUGCACACCACCGACUGCUUUAUCGCCCUGGUGCACGCCAUCAGAGAGAUCAGAGCCCUGUUCCUGCCUCGGACCACC

GGCAAGAUGGAACUGACACUGCACAACGGCGAGAAGAAAACCUUCUACAGCAGACCCAACAACCACGACAACUGCUGG

CUGAACACCAUCCUGCAGCUGUUCAGAUACGUGGACGAGCCCUUCUUCGACUGGGUGUACAACAGCCCCGAGAAUCUG

ACCCUGGAAGCCAUCAACCAGCUGGAAGAACUGACCGGCCUGGAACUGCAUGAAGGCGGACCUCCAGCUCUGGUCAUC

UGGAACAUCAAACAUCUGCUGCACACCGGCAUCGGCACCGCCUCUAGACCAUCUGAAGUGUGCAUGGUGGACGGCACC

GAUAUGUGCCUGGCCGAUUUUCACGCCGGCAUCUUUCUGAAGGGCCAAGAGCAUGCCGUGUUCGCCUGCGUGACAAGC

AAUGGAUGGUACGCCAUCGACGACGAGGAAUUCUACCCCUGGACACCCGAUCCUAGCGACGUGCUGGUGUUCGUGCCC

UACGAUCAAGAGCCCCUGAACGGCGAUUGGAAGGCCAUGGUGCAGCGGAAGCUGAAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 222, or a fragment or variant thereof.

In one embodiment, the at least one IIP is FMDV 3Cpro (P03307; Protease 3C Genome polyprotein foot-and-mouth disease virus (isolate-/Germany/A5Westerwald/1951 serotype A), or an orthologue thereof. Ekanayaka P, Shin S H, Weeratunga P, Lee H, Kim T-H, Chathuranga K, Subasinghe A, Park J-H, Lee J-S (2021) Foot and mouth disease virus 3C protease antagonises interferon signaling and C142T substitution attenuates the FMD virus. Front Microbiol., 21, 737031. doi: 10.3389/fmicb.2021.737031

One embodiment of the polypeptide sequence of FMDV 3Cpro is represented herein as SEQ ID No: 223, as follows:

[SEQ ID No: 223]

SGAPPTDLQKMVMGNTKPVELILDGKTVAICCATGVFGTAYLVPRHLFAEKYDKIMLDGRAMTDSDYRVFEFEIKVKG

QDMLSDAALMVLHRGNRVRDITKHFRDTARMKKGTPVVGVINNADVGRLIFSGEALTYKDIVVCMDGDTMPGLFAYRA

ATKAGYCGGAVLAKDGADTFIVGTHSAGGNGVGYCSCVSRSMLLKMKAHIDPEPHHE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 223, or a variant or fragment thereof.

In one embodiment, the FMDV 3Cpro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 224, as follows:

[SEQ ID No: 224]

AGTGGTGCCCCCCCGACCGACTTGCAAAAGATGGTCATGGGCAACACAAAGCCTGTTGAGCTCATCCTCGACGGGAAG

ACAGTAGCCATCTGCTGTGCTACTGGAGTGTTTGGCACTGCCTACCTCGTGCCTCGTCATCTTTTCGCTGAGAAGTAT

GACAAGATCATGTTGGACGGCAGAGCCATGACAGACAGTGACTACAGAGTGTTTGAGTTCGAGATCAAAGTAAAAGGA

CAGGACATGCTCTCAGACGCCGCACTCATGGTGCTCCACCGTGGGAACCGCGTGAGAGACATCACGAAGCACTTTCGT

GACACAGCAAGAATGAAGAAAGGCACCCCCGTTGTCGGCGTGATCAACAATGCCGATGTCGGGAGACTGATTTTCTCT

GGCGAAGCCCTTACCTACAAAGACATTGTAGTGTGCATGGACGGAGACACCATGCCCGGGCTTTTTGCCTACAGAGCC

GCCACTAAGGCAGGCTACTGCGGGGGAGCCGTTCTCGCTAAGGACGGGGCTGACACTTTCATCGTTGGCACTCACTCT

GCAGGAGGTAATGGAGTTGGATACTGCTCATGCGTTTCCAGGTCCATGCTTCTCAAGATGAAGGCACACATTGACCCT

GAGCCGCACCACGAG

Accordingly, preferably the FMDV 3Cpro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 224, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the FMDV 3Cpro polypeptide is provided herein as SEQ ID No: 225, as follows:

[SEQ ID No: 225]

TCTGGTGCCCCTCCTACCGACCTGCAGAAAATGGTCATGGGCAACACCAAGCCTGTGGAACTGATCCTGGACGGCAAG

ACCGTGGCCATCTGTTGTGCAACAGGCGTGTTCGGCACCGCCTACCTGGTTCCTAGACACCTGTTCGCCGAGAAGTAC

GACAAGATCATGCTGGATGGCAGAGCCATGACCGACAGCGACTACCGGGTGTTCGAGTTCGAGATCAAAGTGAAAGGC

CAGGACATGCTGAGCGACGCCGCTCTGATGGTTCTGCACAGAGGCAACAGAGTGCGGGACATCACCAAGCACTTCCGG

GACACCGCCAGAATGAAGAAAGGCACACCTGTCGTGGGCGTGATCAACAACGCTGACGTGGGCAGACTGATCTTCTCT

GGCGAGGCCCTGACCTACAAGGACATCGTCGTGTGCATGGACGGCGACACAATGCCTGGCCTGTTTGCCTATAGAGCC

GCCACAAAGGCCGGCTACTGTGGCGGAGCTGTGCTGGCTAAAGATGGCGCCGATACCTTCATCGTGGGCACACATTCT

GCCGGCGGAAATGGCGTGGGCTACTGCTCTTGTGTGTCCAGATCCATGCTGCTGAAGATGAAGGCCCACATCGACCCC

GAGCCTCACCATGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 225, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 225 is provided herein as SEQ ID No: 226, as follows:

[SEQ ID No: 226]

UCUGGUGCCCCUCCUACCGACCUGCAGAAAAUGGUCAUGGGCAACACCAAGCCUGUGGAACUGAUCCUGGACGGCAAG

ACCGUGGCCAUCUGUUGUGCAACAGGCGUGUUCGGCACCGCCUACCUGGUUCCUAGACACCUGUUCGCCGAGAAGUAC

GACAAGAUCAUGCUGGAUGGCAGAGCCAUGACCGACAGCGACUACCGGGUGUUCGAGUUCGAGAUCAAAGUGAAAGGC

CAGGACAUGCUGAGCGACGCCGCUCUGAUGGUUCUGCACAGAGGCAACAGAGUGCGGGACAUCACCAAGCACUUCCGG

GACACCGCCAGAAUGAAGAAAGGCACACCUGUCGUGGGCGUGAUCAACAACGCUGACGUGGGCAGACUGAUCUUCUCU

GGCGAGGCCCUGACCUACAAGGACAUCGUCGUGUGCAUGGACGGCGACACAAUGCCUGGCCUGUUUGCCUAUAGAGCC

GCCACAAAGGCCGGCUACUGUGGCGGAGCUGUGCUGGCUAAAGAUGGCGCCGAUACCUUCAUCGUGGGCACACAUUCU

GCCGGCGGAAAUGGCGUGGGCUACUGCUCUUGUGUGUCCAGAUCCAUGCUGCUGAAGAUGAAGGCCCACAUCGACCCC

GAGCCUCACCAUGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 226, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Toscana Virus NSS protein (RIG 1 degradation) (P21699; Non-structural protein NS-S Toscana virus), or an orthologue thereof. One embodiment of the polypeptide sequence of Toscana Virus NSS protein is represented herein as SEQ ID No: 227, as follows:

[SEQ ID No: 227]

MQSRAVILKYRSGSGHKRSLPRFYIDCDLDTFDFEKDCSLIENEFPIYINNYKVVYKSKPTLSHFLIEKEFPAVLGPG

MISAVRTRLYEPTMRELYQESIHQLKRSNKKYLLSALRWPTGIPTLEFTDYYFEELLFLSEFDPGSIQRYLKLLVKAS

GLYNSTNEEQIVEIHRRVLIEGKKHGLTAFDLPGNDILGDICVVQAARVTRLVAKTFSKMTRDTHLMIYFSISPVELV

LSKLDKKGDKRAKAKGLMSMSAARSYDYFMRTDLGFRETALSTFWAKDWPTPQETILSDKRCLKEDMRVTKWLPSPPH

YPPL

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 227, or a variant or fragment thereof.

In one embodiment, the Toscana Virus NSS polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 228, as follows:

[SEQ ID No: 228]

ATGCAATCCAGAGCTGTCATCTTGAAGTATAGATCTGGTTCAGGCCACAAGAGGTCTTTGCCCAGGTTCTACATAGAC

TGTGATTTGGACACCTTTGATTTTGAGAAGGATTGCTCTCTGATTGAGAATGAGTTCCCCATTTACATAAACAATTAT

AAGGTGGTCTATAAGTCAAAGCCAACTCTCTCACATTTCCTCATTGAGAAGGAGTTTCCTGCTGTGCTGGGGCCTGGT

ATGATCAGTGCAGTTCGAACCAGACTTTACGAGCCAACTATGAGAGAGCTCTACCAGGAATCGATTCACCAACTAAAG

AGGAGCAACAAGAAATACCTTTTGTCTGCTCTCAGGTGGCCCACAGGGATTCCTACTCTAGAGTTTATAGACTATTAC

TTCGAGGAGCTCCTGTTCTTGTCAGAGTTTGACCCGGGGTCTATCCAGAGATACCTGAAATTACTGGTTAAGGCCTCT

GGGCTTTACAACTCCACTAATGAGGAGCAGATAGTGGAGATTCACAGACGAGTGCTCATAGAAGGCAAAAAGCACGGA

TTGACTGCTTTTGATCTCCCAGGAAATGACATCCTTGGAGACATCTGTGTGGTCCAAGCAGCACGGGTGACAAGACTG

GTTGCTAAGACATTCTCTAAGATGACCAGAGACACCCATCTGATGATATACTTCTCGATAAGCCCAGTTGAGTTGGTT

TTGAGTAAACTTGATAAGAAAGGGGACAAGAGGGCTAAAGCAAAAGGGTTGATGTCTATGAGTGCCGCTAGGTCTTAT

GACTATTTTATGAGAACTGACTTGGGATTCAGAGAGACTGCTCTTTCCACCTTTTGGGCTAAGGACTGGCCTACCCCA

CAAGAGACCATTCTATCTGACAAACGATGCCTTAAAGAAGACATGAGAGTGACAAAGTGGCTGCCTAGTCCCCCCCAC

TACCCACCCTTA

Accordingly, preferably the Toscana Virus NSS polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 228, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Toscana Virus NSS polypeptide is provided herein as SEQ ID No: 229, as follows:

[SEQ ID No: 229]

ATGCAGAGCAGAGCCGTGATCCTGAAGTACAGAAGCGGCAGCGGCCACAAGAGAAGCCTGCCTAGATTCTACATCGAC

TGCGACCTGGACACCTTCGACTTCGAGAAGGACTGCAGCCTGATCGAGAACGAGTTCCCCATCTACATCAACAACTAC

AAGGTGGTGTACAAGAGCAAGCCAACTCTGAGCCACTTCCTCATCGAGAAAGAATTCCCTGCCGTGCTCGGCCCTGGC

ATGATCTCTGCCGTTAGAACCAGACTGTACGAGCCCACCATGAGAGAGCTGTACCAAGAGAGCATCCACCAGCTGAAG

CGGAGCAACAAGAAGTACCTGCTGAGCGCCCTGAGATGGCCCACAGGCATTCCCACACTGGAATTCATCGACTACTAC

TTCGAGGAACTGCTGTTCCTGAGCGAGTTCGACCCTGGCAGCATCCAGAGATACCTGAAGCTGCTGGTCAAGGCCAGC

GGCCTGTACAACAGCACCAACGAGGAACAGATCGTGGAAATCCACCGGCGGGTGCTGATCGAGGGAAAGAAGCACGGA

CTGACCGCCTTCGACCTGCCTGGCAATGATATCCTGGGCGACATCTGCGTGGTGCAGGCCGCTAGAGTGACAAGACTG

GTGGCCAAGACCTTCAGCAAGATGACCAGAGACACCCACCTGATGATCTACTTCAGCATCAGCCCCGTGGAACTGGTG

CTGAGCAAGCTGGACAAGAAGGGCGACAAGAGAGCCAAGGCCAAGGGCCTGATGAGCATGTCTGCCGCCAGATCCTAC

GACTACTTCATGAGAACCGACCTGGGCTTCAGAGAGACAGCCCTGAGCACCTTCTGGGCCAAAGACTGGCCCACACCT

CAAGAGACAATCCTGTCCGACAAGCGGTGCCTGAAAGAAGATATGCGGGTCACCAAGTGGCTGCCCTCTCCACCTCAT

TACCCTCCACTT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 229, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 229 is provided herein as SEQ ID No: 230, as follows:

[SEQ ID No: 230]

AUGCAGAGCAGAGCCGUGAUCCUGAAGUACAGAAGCGGCAGCGGCCACAAGAGAAGCCUGCCUAGAUUCUACAUCGAC

UGCGACCUGGACACCUUCGACUUCGAGAAGGACUGCAGCCUGAUCGAGAACGAGUUCCCCAUCUACAUCAACAACUAC

AAGGUGGUGUACAAGAGCAAGCCAACUCUGAGCCACUUCCUCAUCGAGAAAGAAUUCCCUGCCGUGCUCGGCCCUGGC

AUGAUCUCUGCCGUUAGAACCAGACUGUACGAGCCCACCAUGAGAGAGCUGUACCAAGAGAGCAUCCACCAGCUGAAG

CGGAGCAACAAGAAGUACCUGCUGAGCGCCCUGAGAUGGCCCACAGGCAUUCCCACACUGGAAUUCAUCGACUACUAC

UUCGAGGAACUGCUGUUCCUGAGCGAGUUCGACCCUGGCAGCAUCCAGAGAUACCUGAAGCUGCUGGUCAAGGCCAGC

GGCCUGUACAACAGCACCAACGAGGAACAGAUCGUGGAAAUCCACCGGCGGGUGCUGAUCGAGGGAAAGAAGCACGGA

CUGACCGCCUUCGACCUGCCUGGCAAUGAUAUCCUGGGCGACAUCUGCGUGGUGCAGGCCGCUAGAGUGACAAGACUG

GUGGCCAAGACCUUCAGCAAGAUGACCAGAGACACCCACCUGAUGAUCUACUUCAGCAUCAGCCCCGUGGAACUGGUG

CUGAGCAAGCUGGACAAGAAGGGCGACAAGAGAGCCAAGGCCAAGGGCCUGAUGAGCAUGUCUGCCGCCAGAUCCUAC

GACUACUUCAUGAGAACCGACCUGGGCUUCAGAGAGACAGCCCUGAGCACCUUCUGGGCCAAAGACUGGCCCACACCU

CAAGAGACAAUCCUGUCCGACAAGCGGUGCCUGAAAGAAGAUAUGCGGGUCACCAAGUGGCUGCCCUCUCCACCUCAU

UACCCUCCACUU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 230, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Non-structural protein 1 Influenza A virus (strain A/Puerto Rico/8/1934 H1N1) (P03496; Influenza A/PR/8/34 NS1), or an orthologue thereof. One embodiment of the polypeptide sequence of Influenza A virus Non-structural protein 1 is represented herein as SEQ ID No: 231, as follows:

[SEQ ID No: 231]

MDPNTVSSFQVDCFLWHVRKRVADQELGDAPFLDRLRRDQKSLRGRGSTLGLDIETATRAGKQIVERILKEESDEALK

MTMASVPASRYLTDMTLEEMSREWSMLIPKQKVAGPLCIRMDQAIMDKNIILKANFSVIFDRLETLILLRAFTEEGAI

VGEISPLPSLPGHTAEDVKNAVGVLIGGLEWNDNTVRVSETLQRFAWRSSNENGRPPLTPKQKREMAGTIRSEV

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 231, or a variant or fragment thereof.

In one embodiment, the Non-structural protein 1 Influenza A virus polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 232, as follows:

[SEQ ID No: 232]

ATGGATCCAAACACTGTGTCAAGCTTTCAGGTAGATTGCTTTCTTTGGCATGTCCGCAAACGAGTTGCAGACCAAGAA

CTAGGTGATGCCCCATTCCTTGATCGGCTTCGCCGAGATCAGAAATCCCTAAGAGGAAGGGGCAGCACTCTTGGTCTG

GACATCGAGACAGCCACACGTGCTGGAAAGCAGATAGTGGAGCGGATTCTGAAAGAAGAATCCGATGAGGCACTTAAA

ATGACCATGGCCTCTGTACCTGCGTCGCGTTACCTAACCGACATGACTCTTGAGGAAATGTCAAGGGAATGGTCCATG

CTCATACCCAAGCAGAAAGTGGCAGGCCCTCTTTGTATCAGAATGGACCAGGCGATCATGGATAAAAACATCATACTG

AAAGCGAACTTCAGTGTGATTTTTGACCGGCTGGAGACTCTAATATTGCTAAGGGCTTTCACCGAAGAGGGAGCAATT

GTTGGCGAAATTTCACCATTGCCTTCTCTTCCAGGACATACTGCTGAGGATGTCAAAAATGCAGTTGGAGTCCTCATC

GGAGGACTTGAATGGAATGATAACACAGTTCGAGTCTCTGAAACTCTACAGAGATTCGCTTGGAGAAGCAGTAATGAG

AATGGGAGACCTCCACTCACTCCAAAACAGAAACGAGAAATGGCGGGAACAATTAGGTCAGAAGTTTGA

Accordingly, preferably the Non-structural protein 1 Influenza A virus polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 232, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Non-structural protein 1 Influenza A virus polypeptide is provided herein as SEQ ID No: 233, as follows:

[SEQ ID No: 233]

ATGGACCCCAATACCGTCAGCAGCTTCCAGGTGGACTGCTTCCTGTGGCACGTGCGGAAAAGAGTGGCCGATCAAGAA

CTGGGCGACGCCCCATTCCTGGACAGACTGAGAAGAGATCAGAAGTCCCTGAGAGGCAGAGGCAGCACACTGGGCCTC

GACATTGAGACAGCCACAAGAGCCGGCAAGCAGATCGTGGAACGGATCCTGAAAGAGGAAAGCGACGAGGCCCTGAAG

ATGACCATGGCCTCTGTGCCTGCCAGCAGATACCTGACCGACATGACCCTGGAAGAGATGAGCCGCGAGTGGTCCATG

CTGATCCCCAAGCAGAAAGTGGCCGGACCTCTGTGCATCAGAATGGATCAGGCCATCATGGACAAGAACATCATCCTG

AAGGCCAACTTCAGCGTGATCTTCGACCGGCTGGAAACCCTGATCCTGCTGAGAGCCTTTACCGAAGAGGGCGCCATC

GTGGGAGAGATCAGTCCTCTGCCTTCTCTGCCTGGACACACCGCCGAGGATGTGAAGAATGCTGTGGGCGTGCTGATC

GGCGGCCTGGAATGGAACGATAACACCGTCAGAGTGTCCGAGACACTGCAGAGATTTGCCTGGCGGAGCAGCAACGAG

AACGGCAGACCTCCTCTGACACCTAAGCAGAAAAGAGAGATGGCCGGCACCATCCGCAGCGAAGTGTAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 233, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 233 is provided herein as SEQ ID No: 234, as follows:

[SEQ ID No: 234]

AUGGACCCCAAUACCGUCAGCAGCUUCCAGGUGGACUGCUUCCUGUGGCACGUGCGGAAAAGAGUGGCCGAUCAAGAA

CUGGGCGACGCCCCAUUCCUGGACAGACUGAGAAGAGAUCAGAAGUCCCUGAGAGGCAGAGGCAGCACACUGGGCCUC

GACAUUGAGACAGCCACAAGAGCCGGCAAGCAGAUCGUGGAACGGAUCCUGAAAGAGGAAAGCGACGAGGCCCUGAAG

AUGACCAUGGCCUCUGUGCCUGCCAGCAGAUACCUGACCGACAUGACCCUGGAAGAGAUGAGCCGCGAGUGGUCCAUG

CUGAUCCCCAAGCAGAAAGUGGCCGGACCUCUGUGCAUCAGAAUGGAUCAGGCCAUCAUGGACAAGAACAUCAUCCUG

AAGGCCAACUUCAGCGUGAUCUUCGACCGGCUGGAAACCCUGAUCCUGCUGAGAGCCUUUACCGAAGAGGGCGCCAUC

GUGGGAGAGAUCAGUCCUCUGCCUUCUCUGCCUGGACACACCGCCGAGGAUGUGAAGAAUGCUGUGGGCGUGCUGAUC

GGCGGCCUGGAAUGGAACGAUAACACCGUCAGAGUGUCCGAGACACUGCAGAGAUUUGCCUGGCGGAGCAGCAACGAG

AACGGCAGACCUCCUCUGACACCUAAGCAGAAAAGAGAGAUGGCCGGCACCAUCCGCAGCGAAGUGUAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 234, or a fragment or variant thereof.

In one embodiment, the at least one IIP is SARS CoV N protein (P59595; Nucleoprotein Severe acute respiratory syndrome coronavirus), or an orthologue thereof. One embodiment of the polypeptide sequence of SARS CoV N protein is represented herein as SEQ ID No: 235, as follows:

[SEQ ID No: 235]

MSDNGPQSNQRSAPRITFGGPTDSTDNNQNGGRNGARPKQRRPQGLPNNTASWFTALTQHGKEELRFPRGQGVPINTN

SGPDDQIGYYRRATRRVRGGDGKMKELSPRWYFYYLGTGPEASLPYGANKEGIVWVATEGALNTPKDHIGTRNPNNNA

ATVLOLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRGNSRNSTPGSSRGNSPARMASGGGETALALLLLDRLNQLESK

VSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKQYNVTQAFGRRGPEQTQGNFGDQDLIRQGTDYKHWPQIAQFAPSA

SAFFGMSRIGMEVTPSGTWLTYHGAIKLDDKDPQFKDNVILLNKHIDAYKTFPPTEPKKDKKKKTDEAQPLPQRQKKQ

PTVTLLPAADMDDFSRQLQNSMSGASADSTQA

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 235, or a variant or fragment thereof.

In one embodiment, the SARS CoV N polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 236, as follows:

[SEQ ID No: 236]

ATGTCTGATAATGGACCCCAATCAAACCAACGTAGTGCCCCCCGCATTACATTTGGTGGACCCACAGATTCAACTGAC

AATAACCAGAATGGAGGACGCAATGGGGCAAGGCCAAAACAGCGCCGACCCCAAGGTTTACCCAATAATACTGCGTCT

TGGTTCACAGCTCTCACTCAGCATGGCAAGGAGGAACTTAGATTCCCTCGAGGCCAGGGCGTTCCAATCAACACCAAT

AGTGGTCCAGATGACCAAATTGGCTACTACCGAAGAGCTACCCGACGAGTTCGTGGTGGTGACGGCAAAATGAAAGAG

ATCGTATGGGTTGCAACTGAGGGAGCCTTGAATACACCCAAAGACCACATTGGCACCCGCAATCCTAATAACAATGCT

GCCACCGTGCTACAACTTCCTCAAGGAACAACATTGCCAAAAGGCTTCTACGCAGAGGGAAGCAGAGGCGGCAGTCAA

GCCTCTTCTCGCTCCTCATCACGTAGTCGCGGTAATTCAAGAAATTCAACTCCTGGCAGCAGTAGGGGAAATTCTCCT

GCTCGAATGGCTAGCGGAGGTGGTGAAACTGCCCTCGCGCTATTGCTGCTAGACAGATTGAACCAGCTTGAGAGCAAA

GTTTCTGGTAAAGGCCAACAACAACAAGGCCAAACTGTCACTAAGAAATCTGCTGCTGAGGCATCTAAAAAGCCTCGC

CAAAAACGTACTGCCACAAAACAGTACAACGTCACTCAAGCATTTGGGAGACGTGGTCCAGAACAAACCCAAGGAAAT

TTCGGGGACCAAGACCTAATCAGACAAGGAACTGATTACAAACATTGGCCGCAAATTGCACAATTTGCTCCAAGTGCC

TCTGCATTCTTTGGAATGTCACGCATTGGCATGGAAGTCACACCTTCGGGAACATGGCTGACTTATCATGGAGCCATT

AAATTGGATGACAAAGATCCACAATTCAAAGACAACGTCATACTGCTGAACAAGCACATTGACGCATACAAAACATTC

CCACCAACAGAGCCTAAAAAGGACAAAAAGAAAAAGACTGATGAAGCTCAGCCTTTGCCGCAGAGACAAAAGAAGCAG

CCCACTGTGACTCTTCTTCCTGCGGCTGACATGGATGATTTCTCCAGACAACTTCAAAATTCCATGAGTGGAGCTTCT

GCTGATTCAACTCAGGCA

Accordingly, preferably the SARS CoV N polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 236, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SARS CoV N polypeptide is provided herein as SEQ ID No: 237, as follows:

[SEQ ID No: 237]

ATGAGCGACAATGGCCCTCAGAGCAACCAGAGAAGCGCCCCTAGAATCACCTTTGGCGGCCCTACCGACAGCACCGAC

AACAACCAGAACGGCGGCAGAAATGGCGCCAGACCTAAGCAGAGAAGGCCTCAGGGCCTGCCTAACAATACCGCCAGC

TGGTTCACAGCCCTGACACAGCACGGCAAAGAGGAACTGAGATTCCCCAGAGGACAGGGCGTGCCCATCAACACAAAT

AGCGGCCCTGACGACCAGATCGGCTACTACAGACGGGCCACCAGAAGAGTTAGAGGCGGCGACGGCAAGATGAAGGAA

CTGTCCCCTCGGTGGTACTTCTACTACCTCGGCACAGGACCCGAAGCCAGCCTTCCTTATGGCGCCAACAAAGAGGGC

ATCGTCTGGGTTGCAACAGAAGGCGCCCTGAACACCCCTAAGGACCACATCGGCACCAGAAATCCCAACAACAACGCC

GCCACAGTGCTGCAGTTGCCACAGGGAACAACACTGCCCAAGGGCTTCTACGCCGAGGGATCTAGAGGCGGATCTCAG

GCCAGCAGCAGAAGCAGCTCTAGAAGCAGAGGCAACAGCCGGAATAGCACCCCTGGCAGCTCCAGAGGCAATTCCCCT

GCCAGAATGGCTTCTGGCGGCGGAGAAACAGCTCTGGCACTGCTGCTGCTCGACCGGCTGAATCAGCTGGAATCTAAG

GTGTCCGGCAAGGGCCAGCAACAGCAGGGACAGACCGTGACCAAGAAGTCTGCCGCTGAGGCCAGCAAGAAGCCCAGA

CAGAAGAGAACCGCCACCAAGCAGTACAACGTGACCCAGGCCTTTGGCAGAAGAGGCCCAGAACAGACCCAGGGCAAT

TTCGGCGACCAGGACCTGATCAGACAGGGCACCGATTACAAGCACTGGCCCCAGATCGCCCAGTTTGCCCCTTCTGCC

TCTGCCTTTTTCGGCATGAGCCGGATCGGCATGGAAGTGACACCTAGCGGCACCTGGCTGACATATCACGGCGCCATC

AAGCTGGACGACAAGGACCCTCAGTTCAAGGACAACGTGATCCTGCTGAACAAGCACATCGACGCCTACAAGACATTC

CCTCCAACCGAGCCTAAGAAGGACAAGAAGAAGAAAACCGACGAGGCCCAGCCTCTGCCACAGAGACAGAAAAAGCAG

CCCACCGTGACACTGCTGCCTGCCGCCGATATGGACGACTTCTCTAGACAGCTGCAGAACAGCATGAGCGGCGCCAGC

GCTGATTCTACACAAGCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 237, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 237 is provided herein as SEQ ID No: 238, as follows:

[SEQ ID No: 238]

AUGAGCGACAAUGGCCCUCAGAGCAACCAGAGAAGCGCCCCUAGAAUCACCUUUGGCGGCCCUACCGACAGCACCGAC

AACAACCAGAACGGCGGCAGAAAUGGCGCCAGACCUAAGCAGAGAAGGCCUCAGGGCCUGCCUAACAAUACCGCCAGC

UGGUUCACAGCCCUGACACAGCACGGCAAAGAGGAACUGAGAUUCCCCAGAGGACAGGGCGUGCCCAUCAACACAAAU

AGCGGCCCUGACGACCAGAUCGGCUACUACAGACGGGCCACCAGAAGAGUUAGAGGCGGCGACGGCAAGAUGAAGGAA

CUGUCCCCUCGGUGGUACUUCUACUACCUCGGCACAGGACCCGAAGCCAGCCUUCCUUAUGGCGCCAACAAAGAGGGC

AUCGUCUGGGUUGCAACAGAAGGCGCCCUGAACACCCCUAAGGACCACAUCGGCACCAGAAAUCCCAACAACAACGCC

GCCACAGUGCUGCAGUUGCCACAGGGAACAACACUGCCCAAGGGCUUCUACGCCGAGGGAUCUAGAGGCGGAUCUCAG

GCCAGCAGCAGAAGCAGCUCUAGAAGCAGAGGCAACAGCCGGAAUAGCACCCCUGGCAGCUCCAGAGGCAAUUCCCCU

GCCAGAAUGGCUUCUGGCGGCGGAGAAACAGCUCUGGCACUGCUGCUGCUCGACCGGCUGAAUCAGCUGGAAUCUAAG

GUGUCCGGCAAGGGCCAGCAACAGCAGGGACAGACCGUGACCAAGAAGUCUGCCGCUGAGGCCAGCAAGAAGCCCAGA

CAGAAGAGAACCGCCACCAAGCAGUACAACGUGACCCAGGCCUUUGGCAGAAGAGGCCCAGAACAGACCCAGGGCAAU

UUCGGCGACCAGGACCUGAUCAGACAGGGCACCGAUUACAAGCACUGGCCCCAGAUCGCCCAGUUUGCCCCUUCUGCC

UCUGCCUUUUUCGGCAUGAGCCGGAUCGGCAUGGAAGUGACACCUAGCGGCACCUGGCUGACAUAUCACGGCGCCAUC

AAGCUGGACGACAAGGACCCUCAGUUCAAGGACAACGUGAUCCUGCUGAACAAGCACAUCGACGCCUACAAGACAUUC

CCUCCAACCGAGCCUAAGAAGGACAAGAAGAAGAAAACCGACGAGGCCCAGCCUCUGCCACAGAGACAGAAAAAGCAG

CCCACCGUGACACUGCUGCCUGCCGCCGAUAUGGACGACUUCUCUAGACAGCUGCAGAACAGCAUGAGCGGCGCCAGC

GCUGAUUCUACACAAGCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 238, or a fragment or variant thereof.

In one embodiment, the at least one IIP is MHV N protein (P03416; Nucleoprotein Murine coronavirus (strain A59)), or an orthologue thereof. One embodiment of the polypeptide sequence of MHV N protein is represented herein as SEQ ID No: 239, as so follows:

[SEQ ID No: 239]

MSFVPGQENAGGRSSSVNRAGNGILKKTTWADQTERGPNNQNRGRRNQPKQTATTQPNSGSVVPHYSWFSGITQFQKG

KEFQFAEGQGVPIANGIPASEQKGYWYRHNRRSFKTPDGQQKQLLPRWYFYYLGTGPHAGASYGDSIEGVFWVANSQA

DTNTRSDIVERDPSSHEAIPTRFAPGTVLPQGFYVEGSGRSAPASRSGSRSQSRGPNNRARSSSNQRQPASTVKPDMA

EEIAALVLAKLGKDAGQPKQVTKQSAKEVROKILNKPRQKRTPNKQCPVQQCFGKRGPNQNFGGSEMLKLGTSDPQFP

ILAELAPTVGAFFFGSKLELVKKNSGGADEPTKDVYELQYSGAVRFDSTLPGFETIMKVLNENLNAYQKDGGADVVSP

KPQRKGRRQAQEKKDEVDNVSVAKPKSSVQRNVSRELTPEDRSLLAQILDDGVVPDGLEDDSNV

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 239, or a variant or fragment thereof.

In one embodiment, the MHV N polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 240, as follows:

[SEQ ID No: 240]

ATGTCTTTTGTTCCTGGGCAAGAAAATGCCGGTGGCAGAAGCTCCTCTGTAAACCGCGCTGGTAATGGAATCCTCAAG

AAGACCACTTGGGCTGACCAAACCGAGCGTGGACCAAATAATCAAAATAGAGGCAGAAGGAATCAGCCAAAGCAGACT

GCAACTACTCAACCCAACTCCGGGAGTGTGGTTCCCCATTACTCCTGGTTTTCTGGCATTACCCAGTTCCAAAAGGGA

AAGGAGTTTCAGTTTGCAGAAGGACAAGGAGTGCCTATTGCCAATGGAATCCCCGCTTCAGAGCAAAAGGGATATTGG

TATAGACACAACCGCCGTTCTTTTAAAACACCTGATGGGCAGCAGAAGCAATTACTGCCCAGATGGTATTTTTACTAT

CTTGGCACAGGGCCCCATGCTGGAGCCAGTTATGGAGACAGCATTGAAGGTGTCTTCTGGGTTGCAAACAGCCAAGCG

GACACCAATACCCGCTCTGATATTGTCGAAAGGGACCCAAGCAGTCATGAGGCTATTCCTACTAGGTTTGCGCCCGGC

ACGGTATTGCCTCAGGGCTTTTATGTTGAAGGCTCTGGAAGGTCTGCACCTGCTAGCCGATCTGGTTCGCGGTCACAA

TCCCGTGGGCCAAATAATCGCGCTAGAAGCAGTTCCAACCAGCGCCAGCCTGCCTCTACTGTAAAACCTGATATGGCC

GAAGAAATTGCTGCTCTTGTTTTGGCTAAGCTCGGTAAAGATGCCGGCCAGCCCAAGCAAGTAACGAAGCAAAGTGCC

AAAGAAGTCAGGCAGAAAATTTTAAACAAGCCTCGCCAAAAGAGGACTCCAAACAAGCAGTGCCCAGTGCAGCAGTGT

TTTGGAAAGAGAGGCCCCAATCAGAATTTTGGAGGCTCTGAAATGTTAAAACTTGGAACTAGTGATCCACAGTTCCCC

ATTCTTGCAGAGTTGGCTCCAACAGTTGGTGCCTTCTTCTTTGGATCTAAATTAGAATTGGTCAAAAAGAATTCTGGT

GGTGCTGATGAACCCACCAAAGATGTGTATGAGCTGCAATATTCAGGTGCAGTTAGATTTGATAGTACTCTACCTGGT

TTTGAGACTATCATGAAAGTGTTGAATGAGAATTTGAATGCCTACCAGAAGGATGGTGGTGCAGATGTGGTGAGCCCA

AAGCCCCAAAGAAAAGGGCGTAGACAGGCTCAGGAAAAGAAAGATGAAGTAGATAATGTAAGCGTTGCAAAGCCCAAA

AGCTCTGTGCAGCGAAATGTAAGTAGAGAATTAACCCCAGAGGATAGAAGTCTGTTGGCTCAGATCCTTGATGATGGC

GTAGTGCCAGATGGGTTAGAAGATGACTCTAATGTG

Accordingly, preferably the MHV N polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 240, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the MHV N polypeptide is provided herein as SEQ ID No: 241, as follows:

ATGAGCTTCGTGCCCGGCCAAGAAAATGCCGGCGGAAGATCTAGCAGCGTGAACAGAGCCGGCAACGGCATCCTGAAG

AAAACCACCTGGGCCGACCAGACCGAGAGAGGCCCCAACAACCAGAACCGGGGCAGAAGAAACCAGCCTAAGCAGACC

GCCACCACACAGCCTAATAGCGGCTCTGTGGTGCCCCACTACAGCTGGTTTAGCGGCATCACCCAGTTCCAGAAGGGC

AAAGAGTTCCAGTTCGCCGAAGGACAGGGCGTGCCAATCGCCAATGGAATCCCTGCCTCTGAGCAGAAAGGCTACTGG

TACAGACACAACCGGCGGAGCTTCAAGACCCCTGATGGACAGCAGAAACAGCTGCTGCCCAGATGGTACTTCTACTAC

CTCGGCACAGGACCTCACGCAGGCGCCTCTTATGGCGATTCTATCGAGGGCGTGTTCTGGGTCGCCAACAGCCAGGCC

GATACCAACACCAGATCCGACATCGTGGAACGGGACCCTAGCAGCCACGAGGCCATTCCTACAAGATTTGCCCCTGGC

ACCGTGCTGCCTCAGGGCTTTTATGTGGAAGGCAGCGGAAGAAGCGCCCCTGCCAGTAGATCTGGCAGCAGATCTCAG

AGCAGGGGCCCTAACAACAGAGCCAGAAGCAGCAGCAACCAGAGACAGCCTGCCAGCACCGTGAAGCCCGATATGGCC

GAAGAAATCGCCGCTCTGGTGCTGGCCAAGCTGGGAAAAGATGCCGGCCAGCCAAAGCAAGTGACCAAGCAGAGCGCC

AAAGAAGTGCGGCAGAAGATCCTGAACAAGCCCCGGCAGAAGCGGACCCCTAACAAGCAGTGTCCTGTGCAGCAGTGC

TTCGGCAAGAGGGGCCCCAATCAGAATTTTGGCGGCAGCGAGATGCTGAAGCTGGGCACAAGCGATCCTCAGTTCCCT

ATCCTGGCCGAGCTGGCTCCTACAGTGGGCGCATTTTTCTTTGGCTCCAAACTCGAGCTGGTCAAGAAGAACAGCGGC

GGAGCCGATGAGCCCACCAAGGATGTGTACGAGCTGCAGTACTCTGGCGCCGTCAGATTCGATAGCACCCTGCCTGGC

TTCGAGACAATCATGAAGGTGCTGAACGAGAACCTGAACGCCTACCAGAAGGATGGCGGCGCTGACGTGGTGTCTCCT

AAGCCTCAGAGAAAAGGCAGACGGCAGGCCCAAGAGAAGAAAGACGAGGTGGACAACGTGTCCGTGGCCAAGCCTAAG

[SEQ ID No: 241]

AGCAGCGTGCAGAGAAACGTGTCCAGAGAGCTGACCCCAGAGGACAGATCTCTGCTGGCTCAGATCCTGGACGATGGC

GTGGTGCCAGATGGCCTGGAAGATGACAGCAACGTG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 241, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 241 is provided herein as SEQ ID No: 242, as follows:

[SEQ ID No: 242]

AUGAGCUUCGUGCCCGGCCAAGAAAAUGCCGGCGGAAGAUCUAGCAGCGUGAACAGAGCCGGCAACGGCAUCCUGAAG

AAAACCACCUGGGCCGACCAGACCGAGAGAGGCCCCAACAACCAGAACCGGGGCAGAAGAAACCAGCCUAAGCAGACC

GCCACCACACAGCCUAAUAGCGGCUCUGUGGUGCCCCACUACAGCUGGUUUAGCGGCAUCACCCAGUUCCAGAAGGGC

AAAGAGUUCCAGUUCGCCGAAGGACAGGGCGUGCCAAUCGCCAAUGGAAUCCCUGCCUCUGAGCAGAAAGGCUACUGG

UACAGACACAACCGGCGGAGCUUCAAGACCCCUGAUGGACAGCAGAAACAGCUGCUGCCCAGAUGGUACUUCUACUAC

CUCGGCACAGGACCUCACGCAGGCGCCUCUUAUGGCGAUUCUAUCGAGGGCGUGUUCUGGGUCGCCAACAGCCAGGCC

GAUACCAACACCAGAUCCGACAUCGUGGAACGGGACCCUAGCAGCCACGAGGCCAUUCCUACAAGAUUUGCCCCUGGC

ACCGUGCUGCCUCAGGGCUUUUAUGUGGAAGGCAGCGGAAGAAGCGCCCCUGCCAGUAGAUCUGGCAGCAGAUCUCAG

AGCAGGGGCCCUAACAACAGAGCCAGAAGCAGCAGCAACCAGAGACAGCCUGCCAGCACCGUGAAGCCCGAUAUGGCC

GAAGAAAUCGCCGCUCUGGUGCUGGCCAAGCUGGGAAAAGAUGCCGGCCAGCCAAAGCAAGUGACCAAGCAGAGCGCC

AAAGAAGUGCGGCAGAAGAUCCUGAACAAGCCCCGGCAGAAGCGGACCCCUAACAAGCAGUGUCCUGUGCAGCAGUGC

UUCGGCAAGAGGGGCCCCAAUCAGAAUUUUGGCGGCAGCGAGAUGCUGAAGCUGGGCACAAGCGAUCCUCAGUUCCCU

AUCCUGGCCGAGCUGGCUCCUACAGUGGGCGCAUUUUUCUUUGGCUCCAAACUCGAGCUGGUCAAGAAGAACAGCGGC

GGAGCCGAUGAGCCCACCAAGGAUGUGUACGAGCUGCAGUACUCUGGCGCCGUCAGAUUCGAUAGCACCCUGCCUGGC

UUCGAGACAAUCAUGAAGGUGCUGAACGAGAACCUGAACGCCUACCAGAAGGAUGGCGGCGCUGACGUGGUGUCUCCU

AAGCCUCAGAGAAAAGGCAGACGGCAGGCCCAAGAGAAGAAAGACGAGGUGGACAACGUGUCCGUGGCCAAGCCUAAG

AGCAGCGUGCAGAGAAACGUGUCCAGAGAGCUGACCCCAGAGGACAGAUCUCUGCUGGCUCAGAUCCUGGACGAUGGC

GUGGUGCCAGAUGGCCUGGAAGAUGACAGCAACGUG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 242, or a fragment or variant thereof.

In one embodiment, the at least one IIP is FMDV 2B protein (P03307; Protease 3C Genome polyprotein foot-and-mouth disease virus (isolate-/Germany/A5Westerwald/1951 serotype A), or an orthologue thereof. One embodiment of the polypeptide sequence of FMDV 2B protein is represented herein as SEQ ID No: 243, as follows:

[SEQ ID No: 243]

PFFFSDVRSNFSKLVETINQMQEDMSTKHGPDFNRLVSAFEELAAGVKAIRTGLDEAKPWYKLIKLLSRLSCMAAVAA

RSKDPVLVAIMLADTGLEILDSTFVVKKISDSLSSLFHVPAPVFSFGAPILLAGLVKVASSFFRSTPEDLERAEKQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 243, or a variant or fragment thereof.

In one embodiment, the FMDV 2B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 244, as follows:

[SEQ ID No: 244]

CCCTTCTTCTTCTCTGACGTTAGGTCAAACTTTTCTAAGCTGGTGGAAACCATCAACCAGATGCAGGAAGACATGTCA

ACAAAACACGGGCCCGACTTTAACCGGTTGGTGTCCGCCTTTGAGGAACTGGCCGCTGGAGTAAAAGCCATCAGGACC

GGCCTCGACGAGGCCAAACCCTGGTACAAGCTTATCAAACTCCTAAGCCGCCTGTCGTGCATGGCCGCTGTGGCAGCA

CGGTCCAAGGACCCAGTCCTTGTGGCCATCATGCTGGCCGACACCGGTCTCGAGATTCTGGACAGCACTTTCGTCGTG

AAGAAGATCTCCGACTCGCTCTCCAGTCTCTTCCACGTGCCGGCCCCCGTCTTCAGTTTCGGAGCCCCGATTCTGCTA

GCCGGGCTGGTCAAGGTCGCCTCGAGTTTCTTCCGGTCCACGCCCGAAGACCTTGAGAGAGCAGAGAAACAG

Accordingly, preferably the FMDV 2B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 244, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the FMDV 2B polypeptide is provided herein as SEQ ID No: 245, as follows:

[SEQ ID No: 245]

CCGTTCTTCTTTAGCGACGTGCGGAGCAACTTCAGCAAGCTGGTGGAAACCATCAACCAGATGCAAGAGGACATGAGC

ACCAAGCACGGCCCCGACTTCAACAGACTGGTGTCCGCCTTTGAGGAACTGGCCGCTGGCGTGAAGGCCATCAGAACA

GGACTGGATGAGGCCAAGCCTTGGTACAAGCTGATCAAGCTGCTGAGCCGGCTGAGCTGTATGGCTGCTGTGGCCGCC

AGATCCAAGGATCCTGTGCTGGTGGCCATCATGCTGGCCGATACAGGCCTGGAAATCCTGGACAGCACCTTCGTGGTC

AAGAAGATCAGCGACAGCCTGAGCAGCCTGTTCCACGTGCCAGCTCCAGTGTTCTCTTTTGGCGCCCCTATTCTGCTG

GCCGGCCTGGTCAAAGTGGCCAGCAGCTTCTTTAGAAGCACCCCTGAGGACCTGGAACGGGCCGAAAAACAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 245, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 245 is provided herein as SEQ ID No: 246, as follows:

[SEQ ID No: 246]

CCGUUCUUCUUUAGCGACGUGCGGAGCAACUUCAGCAAGCUGGUGGAAACCAUCAACCAGAUGCAAGAGGACAUGAGC

ACCAAGCACGGCCCCGACUUCAACAGACUGGUGUCCGCCUUUGAGGAACUGGCCGCUGGCGUGAAGGCCAUCAGAACA

GGACUGGAUGAGGCCAAGCCUUGGUACAAGCUGAUCAAGCUGCUGAGCCGGCUGAGCUGUAUGGCUGCUGUGGCCGCC

AGAUCCAAGGAUCCUGUGCUGGUGGCCAUCAUGCUGGCCGAUACAGGCCUGGAAAUCCUGGACAGCACCUUCGUGGUC

AAGAAGAUCAGCGACAGCCUGAGCAGCCUGUUCCACGUGCCAGCUCCAGUGUUCUCUUUUGGCGCCCCUAUUCUGCUG

GCCGGCCUGGUCAAAGUGGCCAGCAGCUUCUUUAGAAGCACCCCUGAGGACCUGGAACGGGCCGAAAAACAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 246, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Influenza virus A PB1-F2 (B4URE5; Protein PB1-F2 Influenza A virus (strain A/Russia:St.Petersburg/8/2006 H1N1), or an orthologue thereof. One embodiment of the polypeptide sequence of Influenza virus A PB1-F2 is represented herein as SEQ ID No: 247, as follows:

[SEQ ID No: 247]

MGQEQDTPWILSTGHISTQKREDGQQTPKLEHRNSTRLMGHFQKTMNQVVMPKQIVYWRRWLSLRNPILVFLKTRVLK

RWRLFSKHE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 247, or a variant or fragment thereof.

In one embodiment, the Influenza virus A PB1-F2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 248, as follows:

[SEQ ID No: 248]

ATGGGACAGGAACAGGATACACCATGGATACTGTCAACAGGACACATCAGTACTCAGAAAAGGGAAGATGGACAACAA

ACACCGAAACTGGAGCACCGCAACTCAACCCGATTGATGGGCCACTTCCAGAAGACAATGAACCAAGTGGTTATGCCC

AAACAGATTGTGTATTGGAGGCGATGGCTTTCCTTGAGGAATCCCATCCTGGTATTTTTGAAAACTCGTGTATTGAAA

CGATGGAGGTTGTTCAGCAAACACGAG

Accordingly, preferably the Influenza virus A PB1-F2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 248, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Influenza virus A PB1-F2 polypeptide is provided herein as SEQ ID No: 249, as follows:

[SEQ ID No: 249]

ATGGGCCAAGAGCAGGACACACCTTGGATCCTGAGCACCGGCCACATCAGCACCCAGAAGAGAGAGGACGGACAGCAG

ACCCCTAAGCTGGAACACCGGAACAGCACCAGACTGATGGGCCACTTCCAGAAAACCATGAACCAGGTGGTCATGCCC

AAGCAGATCGTGTACTGGCGGAGATGGCTGAGCCTGCGGAATCCTATCCTGGTGTTCCTGAAAACCCGGGTGCTGAAG

AGATGGCGGCTGTTCTCTAAGCACGAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 249, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 249 is provided herein as SEQ ID No: 250, as follows:

[SEQ ID No: 250]

AUGGGCCAAGAGCAGGACACACCUUGGAUCCUGAGCACCGGCCACAUCAGCACCCAGAAGAGAGAGGACGGACAGCAG

ACCCCUAAGCUGGAACACCGGAACAGCACCAGACUGAUGGGCCACUUCCAGAAAACCAUGAACCAGGUGGUCAUGCCC

AAGCAGAUCGUGUACUGGCGGAGAUGGCUGAGCCUGCGGAAUCCUAUCCUGGUGUUCCUGAAAACCCGGGUGCUGAAG

AGAUGGCGGCUGUUCUCUAAGCACGAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 250, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Hepatitis A Protein 3ABC (Q05794; Genome polyprotein Human hepatitis A virus genotype IA (isolate HAS-15)), or an orthologue thereof. One embodiment of the polypeptide sequence of Hepatitis A Protein 3ABC is represented herein as SEQ ID No: 251, as follows:

[SEQ ID No: 251]

GISDDDSAVAEFFQSFPSGEPSNSKLSSFFQSVTNHKWVAVGAAVGILGLLVGGWFVYKHFSRKEEEPIPAEGVYHGV

TKPKQVIKLDADPVESQSTLEIAGLVRKNLVQFGVGEKNGCVRWVMNALGVKDDWLLVPSHAYKFEKDYEMMEFYFNR

GGTYYSISAGNVVIQSLDVGFQDVVLMKVPTIPKFRDITQHFIKKGDVPRALNRLATLVTTVNGTPMLISEGPLKMEE

KATYVHKKNDGTTVDLTVDQAWRGKGEGLPGMCGGALVSSNQSIQNAILGIHVAGGNSILVAKLITQEMFQNIDKKIE

SQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 251, or a variant or fragment thereof.

In one embodiment, the Hepatitis A Protein 3ABC polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 252, as follows:

[SEQ ID No: 252]

GGAATTTCAGATGATGACAGTGCAGTAGCTGAGTTTTTCCAGTCTTTTCCATCTGGTGAACCATCAAATTCCAAGTTA

TCTAGTTTTTTCCAATCTGTCACTAATCACAAGTGGGTTGCTGTGGGAGCTGCAGTTGGTATTCTTGGATTGCTAGTG

GGAGGATGGTTTGTGTATAAGCATTTTTCCCGCAAAGAGGAAGAACCAATTCCAGCTGAAGGGGTTTATCATGGAGTG

ACTAAGCCCAAACAAGTGATTAAATTGGATGCAGATCCAGTAGAGTCCCAGTCAACTCTAGAAATAGCAGGATTAGTT

AGGAAAAATTTGGTTCAGTTTGGAGTTGGTGAGAAAAATGGATGTGTGAGATGGGTCATGAATGCCTTAGGAGTGAAG

GATGATTGGTTGTTAGTACCTTCTCATGCTTATAAATTTGAAAAGGATTATGAAATGATGGAGTTTTATTTCAATAGA

GGTGGAACTTACTATTCAATTTCAGCTGGTAATGTTGTTATTCAATCTTTAGATGTGGGATTCCAAGATGTTGTTCTA

ATGAAGGTTCCTACAATTCCCAAGTTTAGAGATATTACTCAACATTTTATTAAGAAAGGAGATGTGCCTAGAGCCTTG

AATCGCTTGGCAACATTAGTGACAACCGTTAATGGAACTCCTATGTTAATTTCTGAGGGACCTTTAAAAATGGAAGAA

AAAGCCACTTATGTTCATAAGAAGAACGATGGTACTACGGTTGATTTGACTGTAGATCAGGCATGGAGAGGAAAAGGT

GAAGGTCTTCCTGGAATGTGTGGTGGGGCCCTAGTGTCATCAAATCAGTCCATACAAAATGCAATTTTGGGTATTCAT

GTTGCTGGAGGAAATTCAATTCTTGTGGCAAAGTTGATTACTCAAGAAATGTTTCAAAACATTGATAAGAAAATTGAA

AGTCAG

Accordingly, preferably the Hepatitis A Protein 3ABC polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 252, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Hepatitis A Protein 3ABC polypeptide is provided herein as SEQ ID No: 253, as follows:

[SEQ ID No: 253]

GGCATCAGCGACGATGATTCTGCCGTGGCCGAGTTCTTCCAGAGCTTTCCTAGCGGCGAGCCCAGCAACAGCAAGCTG

AGCAGCTTCTTCCAGTCCGTGACCAACCACAAATGGGTCGCCGTGGGAGCCGCTGTGGGAATTCTGGGACTTCTCGTT

GGCGGATGGTTCGTGTACAAGCACTTCAGCCGGAAAGAGGAAGAACCCATTCCTGCCGAGGGCGTGTACCACGGCGTG

ACCAAACCTAAGCAAGTGATCAAGCTGGACGCCGATCCTGTGGAAAGCCAGAGCACACTGGAAATCGCCGGACTCGTG

CGGAAGAACCTGGTGCAGTTTGGCGTGGGCGAGAAGAACGGCTGTGTCAGATGGGTCATGAACGCCCTGGGCGTGAAG

GACGATTGGCTGCTGGTTCCTAGCCACGCCTACAAGTTCGAGAAGGACTACGAGATGATGGAATTCTACTTCAACAGA

GGCGGCACCTACTACAGCATCAGCGCCGGCAATGTGGTCATCCAGTCTCTGGATGTGGGCTTCCAGGACGTGGTGCTG

ATGAAGGTGCCAACAATCCCCAAGTTCCGGGACATCACCCAGCACTTCATCAAGAAAGGCGACGTGCCCAGGGCTCTG

AACAGACTGGCTACCCTGGTCACCACCGTGAACGGCACACCCATGCTGATCTCTGAGGGCCCACTGAAGATGGAAGAG

AAGGCCACCTACGTGCACAAGAAGAACGACGGCACCACAGTGGACCTGACCGTGGATCAAGCTTGGAGAGGCAAAGGC

GAGGGCCTGCCTGGAATGTGTGGCGGAGCACTGGTGTCCAGCAACCAGAGCATCCAGAATGCCATCCTGGGCATCCAT

GTGGCTGGCGGCAATTCTATCCTGGTGGCCAAGCTGATCACCCAAGAGATGTTCCAGAACATCGACAAGAAGATCGAG

AGCCAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 253, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 253 is provided herein as SEQ ID No: 254, as follows:

[SEQ ID No: 254]

GGCAUCAGCGACGAUGAUUCUGCCGUGGCCGAGUUCUUCCAGAGCUUUCCUAGCGGCGAGCCCAGCAACAGCAAGCUG

AGCAGCUUCUUCCAGUCCGUGACCAACCACAAAUGGGUCGCCGUGGGAGCCGCUGUGGGAAUUCUGGGACUUCUCGUU

GGCGGAUGGUUCGUGUACAAGCACUUCAGCCGGAAAGAGGAAGAACCCAUUCCUGCCGAGGGCGUGUACCACGGCGUG

ACCAAACCUAAGCAAGUGAUCAAGCUGGACGCCGAUCCUGUGGAAAGCCAGAGCACACUGGAAAUCGCCGGACUCGUG

CGGAAGAACCUGGUGCAGUUUGGCGUGGGCGAGAAGAACGGCUGUGUCAGAUGGGUCAUGAACGCCCUGGGCGUGAAG

GACGAUUGGCUGCUGGUUCCUAGCCACGCCUACAAGUUCGAGAAGGACUACGAGAUGAUGGAAUUCUACUUCAACAGA

GGCGGCACCUACUACAGCAUCAGCGCCGGCAAUGUGGUCAUCCAGUCUCUGGAUGUGGGCUUCCAGGACGUGGUGCUG

AUGAAGGUGCCAACAAUCCCCAAGUUCCGGGACAUCACCCAGCACUUCAUCAAGAAAGGCGACGUGCCCAGGGCUCUG

AACAGACUGGCUACCCUGGUCACCACCGUGAACGGCACACCCAUGCUGAUCUCUGAGGGCCCACUGAAGAUGGAAGAG

AAGGCCACCUACGUGCACAAGAAGAACGACGGCACCACAGUGGACCUGACCGUGGAUCAAGCUUGGAGAGGCAAAGGC

GAGGGCCUGCCUGGAAUGUGUGGCGGAGCACUGGUGUCCAGCAACCAGAGCAUCCAGAAUGCCAUCCUGGGCAUCCAU

GUGGCUGGCGGCAAUUCUAUCCUGGUGGCCAAGCUGAUCACCCAAGAGAUGUUCCAGAACAUCGACAAGAAGAUCGAG

AGCCAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 254, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Hepatitis B X protein (P03165; Protein X Hepatitis B virus genotype D), or an orthologue thereof. One embodiment of the polypeptide sequence of Hepatitis B X protein is represented herein as SEQ ID No: 255, as follows:

[SEQ ID No: 255]

MAARLCCQLDPARDVLCLRPVGAESRGRPFSGSLGTLSSPSPSAVSTDHG

AHLSLRGLPVCAFSSAGPCALRFTSARRMETTVKAQPFLPKVLHKRTLGL

SVMSTTDLEAYFKDCLFKDWEELGEEIRLKVFVLGGCRHKLVCAPAPCNF

FTSA

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 255, or a variant or fragment thereof.

In one embodiment, the Hepatitis B X polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 256, as follows:

[SEQ ID No: 256]

ATGGCTGCTAGGCTGTGCTGCCAACTGGATCCTGCGCGGGACGTCCTTTG

TTTACGTCCCGTCGGCGCTGAATCCCGCGGACGACCCTTCTCGGGGTCGC

TTGGGACTCTCTCGTCCCCTTCTCCGTCTGCCGTTTCGACCGACCACGGG

GCGCACCTCTCTTTACGCGGACTCCCCGTCTGTGCCTTCTCATCTGCCGG

ACCGTGTGCACTTCGCTTCACCTCTGCACGTCGCATGGAGACCACCGTGA

AAGCCCAACCATTCTTGCCCAAGGTCTTACATAAGAGGACTCTTGGACTC

TCTGTAATGTCAACGACCGACCTTGAGGCATACTTCAAAGACTGTTTGTT

TAAAGACTGGGAGGAGTTGGGGGAGGAGATTAGATTAAAGGTCTTTGTAT

TAGGAGGCTGTAGGCATAAATTGGTCTGCGCACCAGCACCATGCAACTTT

TTCACCTCTGCC

Accordingly, preferably the Hepatitis B X polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 256, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Hepatitis B X polypeptide is provided herein as SEQ ID No: 257, as follows:

[SEQ ID No: 257]

ATGGCCGCCAGACTGTGCTGTCAACTGGACCCTGCTAGGGACGTGCTGTG

TCTCAGACCTGTGGGAGCCGAGTCTAGAGGCAGACCTTTTTCTGGCTCTC

TGGGCACCCTGAGCAGCCCATCTCCATCTGCCGTGTCTACAGATCACGGC

GCCCACCTGTCTCTGAGAGGACTGCCTGTGTGTGCCTTTAGCAGCGCCGG

ACCTTGCGCTCTGAGATTCACATCTGCCAGACGGATGGAAACCACCGTGA

AGGCCCAGCCTTTCCTGCCTAAGGTGCTGCACAAGAGAACCCTGGGCCTG

AGCGTGATGAGCACCACAGATCTGGAAGCCTACTTCAAGGATTGCCTGTT

CAAGGACTGGGAAGAACTGGGCGAAGAGATCCGGCTGAAGGTGTTCGTGC

TCGGCGGATGCAGACACAAGCTCGTGTGTGCTCCCGCTCCTTGCAACTTC

TTTACCAGCGCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 257, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 257 is provided herein as SEQ ID No: 258, as follows:

[SEQ ID No: 258]

AUGGCCGCCAGACUGUGCUGUCAACUGGACCCUGCUAGGGACGUGCUGUG

UCUCAGACCUGUGGGAGCCGAGUCUAGAGGCAGACCUUUUUCUGGCUCUC

UGGGCACCCUGAGCAGCCCAUCUCCAUCUGCCGUGUCUACAGAUCACGGC

GCCCACCUGUCUCUGAGAGGACUGCCUGUGUGUGCCUUUAGCAGCGCCGG

ACCUUGCGCUCUGAGAUUCACAUCUGCCAGACGGAUGGAAACCACCGUGA

AGGCCCAGCCUUUCCUGCCUAAGGUGCUGCACAAGAGAACCCUGGGCCUG

AGCGUGAUGAGCACCACAGAUCUGGAAGCCUACUUCAAGGAUUGCCUGUU

CAAGGACUGGGAAGAACUGGGCGAAGAGAUCCGGCUGAAGGUGUUCGUGC

UCGGCGGAUGCAGACACAAGCUCGUGUGUGCUCCCGCUCCUUGCAACUUC

UUUACCAGCGCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 258, or a fragment or variant thereof.

In one embodiment, the at least one IIP is SARS-CoV NSP15 (P0C6X7; Replicase polyprotein Severe acute respiratory syndrome coronavirus), or an orthologue thereof. One embodiment of the polypeptide sequence of SARS-CoV NSP15 is represented herein as SEQ ID No: 259, as follows:

[SEQ ID No: 259]

SLENVAYNVVNKGHFDGHAGEAPVSIINNAVYTKVDGIDVEIFENKTTLP

VNVAFELWAKRNIKPVPEIKILNNLGVDIAANTVIWDYKREAPAHVSTIG

VCTMTDIAKKPTESACSSLTVLFDGRVEGQVDLFRNARNGVLITEGSVKG

LTPSKGPAQASVNGVTLIGESVKTQFNYFKKVDGIIQQLPETYFTQSRDL

EDFKPRSQMETDFLELAMDEFIQRYKLEGYAFEHIVYGDFSHGQLGGLHL

MIGLAKRSQDSPLKLEDFIPMDSTVKNYFITDAQTGSSKCVCSVIDLLLD

DFVEIIKSQDLSVISKVVKVTIDYAEISFMLWCKDGHVETFYPKLQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 259, or a variant or fragment thereof.

In one embodiment, the SARS-CoV NSP15 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 260, as follows:

[SEQ ID No: 260]

AGTTTAGAAAATGTGGCTTATAATGTTGTTAATAAAGGACACTTTGATGG

ACACGCCGGCGAAGCACCTGTTTCCATCATTAATAATGCTGTTTACACAA

AGGTAGATGGTATTGATGTGGAGATCTTTGAAAATAAGACAACACTTCCT

GTTAATGTTGCATTTGAGCTTTGGGCTAAGCGTAACATTAAACCAGTGCC

AGAGATTAAGATACTCAATAATTTGGGTGTTGATATCGCTGCTAATACTG

TAATCTGGGACTACAAAAGAGAAGCCCCAGCACATGTATCTACAATAGGT

GTCTGCACAATGACTGACATTGCCAAGAAACCTACTGAGAGTGCTTGTTC

TTCACTTACTGTCTTGTTTGATGGTAGAGTGGAAGGACAGGTAGACCTTT

TTAGAAACGCCCGTAATGGTGTTTTAATAACAGAAGGTTCAGTCAAAGGT

CTAACACCTTCAAAGGGACCAGCACAAGCTAGCGTCAATGGAGTCACATT

AATTGGAGAATCAGTAAAAACACAGTTTAACTACTTTAAGAAAGTAGACG

GCATTATTCAACAGTTGCCTGAAACCTACTTTACTCAGAGCAGAGACTTA

GAGGATTTTAAGCCCAGATCACAAATGGAAACTGACTTTCTCGAGCTCGC

TATGGATGAATTCATACAGCGATATAAGCTCGAGGGCTATGCCTTCGAAC

ACATCGTTTATGGAGATTTCAGTCATGGACAACTTGGCGGTCTTCATTTA

ATGATAGGCTTAGCCAAGCGCTCACAAGATTCACCACTTAAATTAGAGGA

TTTTATCCCTATGGACAGCACAGTGAAAAATTACTTCATAACAGATGCGC

AAACAGGTTCATCAAAATGTGTGTGTTCTGTGATTGATCTTTTACTTGAT

GACTTTGTCGAGATAATAAAGTCACAAGATTTGTCAGTGATTTCAAAAGT

GGTCAAGGTTACAATTGACTATGCTGAAATTTCATTCATGCTTTGGTGTA

AGGATGGACATGTTGAAACCTTCTACCCAAAACTACAA

Accordingly, preferably the SARS-CoV NSP15 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 260, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SARS-CoV NSP15 polypeptide is provided herein as SEQ ID No: 261, as follows:

[SEQ ID No: 261]

AGCCTGGAAAACGTGGCCTACAACGTGGTCAACAAGGGCCACTTTGATGG

CCACGCTGGCGAAGCCCCTGTGTCCATCATTAACAACGCCGTGTACACCA

AGGTGGACGGCATCGACGTGGAAATCTTCGAGAACAAGACCACACTGCCC

GTGAATGTGGCCTTCGAGCTGTGGGCCAAGCGGAACATTAAGCCCGTGCC

TGAGATCAAGATCCTGAACAACCTGGGCGTCGACATTGCCGCCAACACCG

TGATCTGGGACTACAAGAGAGAAGCCCCAGCTCACGTGTCCACCATCGGC

GTGTGTACCATGACCGATATCGCCAAGAAGCCCACCGAGAGCGCCTGTAG

CTCTCTGACCGTGCTGTTCGACGGCAGAGTGGAAGGCCAGGTGGACCTGT

TCAGAAACGCCAGAAACGGCGTGCTGATCACCGAGGGCTCTGTGAAGGGA

CTGACCCCTTCTAAGGGACCTGCTCAGGCCTCTGTGAATGGCGTGACACT

GATCGGCGAGAGCGTGAAAACCCAGTTCAACTACTTCAAGAAGGTCGACG

GGATCATCCAGCAGCTGCCCGAGACATACTTCACCCAGAGCCGCGACCTG

GAAGATTTCAAGCCTCGGAGCCAGATGGAAACCGACTTCCTGGAACTGGC

CATGGACGAGTTCATCCAGCGGTACAAGCTGGAAGGCTACGCCTTTGAGC

ACATCGTGTACGGCGATTTCAGCCACGGACAGCTCGGAGGACTGCACCTG

ATGATTGGCCTGGCCAAGAGAAGCCAGGACAGCCCTCTGAAGCTCGAGGA

CTTCATCCCCATGGACAGCACCGTGAAGAATTACTTCATCACAGACGCCC

AGACCGGCAGCTCTAAGTGCGTGTGTAGCGTGATCGACCTGCTGCTGGAC

GACTTTGTGGAAATCATCAAGAGCCAGGACCTGAGCGTGATCTCCAAGGT

GGTCAAAGTGACCATCGACTACGCCGAGATCAGCTTCATGCTGTGGTGCA

AGGACGGCCACGTGGAAACATTCTACCCCAAGCTGCAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 261, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 261 is provided herein as SEQ ID No: 262, as follows:

[SEQ ID No: 262]

AGCCUGGAAAACGUGGCCUACAACGUGGUCAACAAGGGCCACUUUGAUGG

CCACGCUGGCGAAGCCCCUGUGUCCAUCAUUAACAACGCCGUGUACACCA

AGGUGGACGGCAUCGACGUGGAAAUCUUCGAGAACAAGACCACACUGCCC

GUGAAUGUGGCCUUCGAGCUGUGGGCCAAGCGGAACAUUAAGCCCGUGCC

UGAGAUCAAGAUCCUGAACAACCUGGGCGUCGACAUUGCCGCCAACACCG

UGAUCUGGGACUACAAGAGAGAAGCCCCAGCUCACGUGUCCACCAUCGGC

GUGUGUACCAUGACCGAUAUCGCCAAGAAGCCCACCGAGAGCGCCUGUAG

CUCUCUGACCGUGCUGUUCGACGGCAGAGUGGAAGGCCAGGUGGACCUGU

UCAGAAACGCCAGAAACGGCGUGCUGAUCACCGAGGGCUCUGUGAAGGGA

CUGACCCCUUCUAAGGGACCUGCUCAGGCCUCUGUGAAUGGCGUGACACU

GAUCGGCGAGAGCGUGAAAACCCAGUUCAACUACUUCAAGAAGGUCGACG

GGAUCAUCCAGCAGCUGCCCGAGACAUACUUCACCCAGAGCCGCGACCUG

GAAGAUUUCAAGCCUCGGAGCCAGAUGGAAACCGACUUCCUGGAACUGGC

CAUGGACGAGUUCAUCCAGCGGUACAAGCUGGAAGGCUACGCCUUUGAGC

ACAUCGUGUACGGCGAUUUCAGCCACGGACAGCUCGGAGGACUGCACCUG

AUGAUUGGCCUGGCCAAGAGAAGCCAGGACAGCCCUCUGAAGCUCGAGGA

CUUCAUCCCCAUGGACAGCACCGUGAAGAAUUACUUCAUCACAGACGCCC

AGACCGGCAGCUCUAAGUGCGUGUGUAGCGUGAUCGACCUGCUGCUGGAC

GACUUUGUGGAAAUCAUCAAGAGCCAGGACCUGAGCGUGAUCUCCAAGGU

GGUCAAAGUGACCAUCGACUACGCCGAGAUCAGCUUCAUGCUGUGGUGCA

AGGACGGCCACGUGGAAACAUUCUACCCCAAGCUGCAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 262, or a fragment or variant thereof.

In one embodiment, the at least one IIP is SARS CoV Orf9b (P59636; SARS ORF9b protein Severe acute respiratory syndrome coronavirus), or an orthologue thereof. One embodiment of the polypeptide sequence of SARS CoV Orf9b is represented herein as SEQ ID No: 263, as follows:

[SEQ ID No: 263]

MDPNQTNVVPPALHLVDPQIQLTITRMEDAMGQGQNSADPKVYPIILRLG

SQLSLSMARRNLDSLEARAFQSTPIVVQMTKLATTEELPDEFVVVTAK

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 263, or a variant or fragment thereof.

In one embodiment, the SARS CoV Orf9b polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 264, as follows:

[SEQ ID No: 264]

ATGGACCCCAATCAAACCAACGTAGTGCCCCCCGCATTACATTTGGTGGA

CCCACAGATTCAACTGACAATAACCAGAATGGAGGACGCAATGGGGCAAG

GCCAAAACAGCGCCGACCCCAAGGTTTACCCAATAATACTGCGTCTTGGT

TCACAGCTCTCACTCAGCATGGCAAGGAGGAACTTAGATTCCCTCGAGGC

CAGGGCGTTCCAATCAACACCAATAGTGGTCCAGATGACCAAATTGGCTA

CTACCGAAGAGCTACCCGACGAGTTCGTGGTGGTGACGGCAAAA

Accordingly, preferably the SARS CoV Orf9b polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 264, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the SARS CoV Orf9b polypeptide is provided herein as SEQ ID No: 265, as follows:

[SEQ ID No: 265]

ATGGACCCCAACCAGACCAATGTGGTGCCTCCTGCTCTGCACCTGGTGGA

CCCTCAGATCCAGCTGACCATCACCAGAATGGAAGATGCCATGGGCCAGG

GCCAGAACAGCGCCGATCCTAAGGTGTACCCCATCATCCTGAGACTGGGC

AGCCAGCTGAGCCTGAGCATGGCCAGAAGAAACCTGGACAGCCTGGAAGC

CAGAGCCTTCCAGAGCACACCTATCGTGGTGCAGATGACCAAGCTGGCCA

CCACCGAGGAACTGCCCGATGAGTTTGTGGTGGTCACCGCCAAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 265, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 265 is provided herein as SEQ ID No: 266, as follows:

[SEQ ID No: 266]

AUGGACCCCAACCAGACCAAUGUGGUGCCUCCUGCUCUGCACCUGGUGGA

CCCUCAGAUCCAGCUGACCAUCACCAGAAUGGAAGAUGCCAUGGGCCAGG

GCCAGAACAGCGCCGAUCCUAAGGUGUACCCCAUCAUCCUGAGACUGGGC

AGCCAGCUGAGCCUGAGCAUGGCCAGAAGAAACCUGGACAGCCUGGAAGC

CAGAGCCUUCCAGAGCACACCUAUCGUGGUGCAGAUGACCAAGCUGGCCA

CCACCGAGGAACUGCCCGAUGAGUUUGUGGUGGUCACCGCCAAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 266, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Rhinovirus 2Apro (P23008; Genome polyprotein Human rhinovirus 1A), or an orthologue thereof. One embodiment of the polypeptide sequence of Rhinovirus 2Apro is represented herein as SEQ ID No: 267, as follows:

[SEQ ID No: 267]

GPSDLYVHVGNLIYRNLHLFNSEMHDSILISYSSDLITYRTNTIGDDYIP

NCNCTEATYYCRHKNRYYPIKVTPHDWYEIQESEYYPKHIQYNLLIGEGP

CEPGDCGGKLLCRHGVIGIITAGGEGHVAFIDLRQFHCAEEQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 267, or a variant or fragment thereof.

In one embodiment, the Rhinovirus 2Apro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 268, as follows:

[SEQ ID No: 268]

GGGCCCAGTGATCTATATGTGCATGTAGGTAACTTAATATATAGAAACTT

ACATCTGTTCAATTCTGAAATGCATGATTCAATTTTGATTTCATACTCTT

CTGATTTAATCATATACCGCACAAACACTATAGGTGATGATTATATTCCC

AATTGTAACTGCACTGAGGCTACTTATTATTGTAGACACAAAAATAGGTA

TTACCCAATAAAAGTTACTCCACATGATTGGTATGAAATACAAGAGAGTG

AATATTACCCCAAACACATCCAATACAACCTATTAATTGGTGAAGGACCA

TGTGAACCTGGTGATTGTGGTGGAAAACTTCTTTGTAGACATGGTGTCAT

TGGCATAATCACAGCAGGTGGTGAAGGTCATGTAGCATTTATAGATCTTA

GACAATTTCACTGTGCTGAGGAACAA

Accordingly, preferably the Rhinovirus 2Apro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 268, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Rhinovirus 2Apro polypeptide is provided herein as SEQ ID No: 269, as follows:

[SEQ ID No: 269]

GGCCCTAGCGATCTGTATGTGCACGTGGGCAACCTGATCTACCGGAACCT

GCACCTGTTCAACAGCGAGATGCACGACAGCATCCTGATCAGCTACAGCA

GCGACCTGATCATCTATCGGACCAACACCATCGGCGACGACTACATCCCC

AACTGCAACTGTACCGAGGCCACCTACTACTGCCGGCACAAGAACCGGTA

CTACCCCATCAAAGTGACCCCTCACGATTGGTACGAGATCCAAGAGAGCG

AGTACTACCCTAAGCACATCCAGTACAACCTGCTGATCGGCGAGGGACCT

TGCGAGCCTGGCGATTGTGGTGGAAAGCTGCTGTGTAGACACGGCGTGAT

CGGCATCATTACAGCCGGCGGAGAAGGACACGTGGCCTTTATCGACCTGC

GGCAGTTTCACTGCGCCGAGGAACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 269, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 269 is provided herein as SEQ ID No: 270, as follows:

[SEQ ID No: 270]

GGCCCUAGCGAUCUGUAUGUGCACGUGGGCAACCUGAUCUACCGGAACCU

GCACCUGUUCAACAGCGAGAUGCACGACAGCAUCCUGAUCAGCUACAGCA

GCGACCUGAUCAUCUAUCGGACCAACACCAUCGGCGACGACUACAUCCCC

AACUGCAACUGUACCGAGGCCACCUACUACUGCCGGCACAAGAACCGGUA

CUACCCCAUCAAAGUGACCCCUCACGAUUGGUACGAGAUCCAAGAGAGCG

AGUACUACCCUAAGCACAUCCAGUACAACCUGCUGAUCGGCGAGGGACCU

UGCGAGCCUGGCGAUUGUGGUGGAAAGCUGCUGUGUAGACACGGCGUGAU

CGGCAUCAUUACAGCCGGCGGAGAAGGACACGUGGCCUUUAUCGACCUGC

GGCAGUUUCACUGCGCCGAGGAACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 270, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Rhinovirus 3Cpro (P23008; Genome polyprotein Human rhinovirus 1A), or an orthologue thereof. One embodiment of the polypeptide sequence of Rhinovirus 3Cpro is represented herein as SEQ ID No: 271, as follows:

[SEQ ID No: 271]

GPEEEFGRSILKNNTCVITTGNGKFTGLGIHDRILIIPTHADPGREVQVN

GVHTKVLDSYDLYNRDGVKLEITVIQLDRNEKFRDIRKYIPETEDDYPEC

NLALSANQDEPTIIKVGDVVSYGNILLSGNQTARMLKYNYPTKSGYCGGV

LYKIGQILGIHVGGNGRDGFSAMLLRSYFTDTQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 271, or a variant or fragment thereof.

In one embodiment, the Rhinovirus 3Cpro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 272, as follows:

[SEQ ID No: 272]

GGTCCAGAAGAAGAATTTGGAAGGTCAATTCTCAAAAACAATACTTGTGT

GATTACTACAGGTAATGGAAAATTTACAGGTCTTGGTATACATGACAGAA

TTCTAATCATCCCAACACATGCTGATCCAGGTAGAGAGGTCCAAGTTAAT

GGTGTCCACACTAAGGTTCTAGACTCATATGATCTTTATAATAGAGATGG

AGTTAAACTTGAAATAACGGTCATACAATTAGATAGAAATGAAAAATTTA

GGGACATTAGAAAGTATATACCTGAAACAGAAGACGATTATCCAGAATGC

AATTTGGCACTTTCAGCTAATCAAGATGAACCAACTATAATTAAAGTAGG

AGATGTAGTGTCCTATGGCAATATTTTGCTTAGTGGAAATCAAACAGCCA

GAATGCTTAAATATAATTACCCCACAAAATCAGGGTATTGTGGAGGGGTA

CTATATAAAATTGGTCAAATTCTAGGTATTCATGTGGGTGGAAATGGAAG

GGATGGTTTTTCAGCTATGTTACTTAGATCATACTTTACAGATACTCAG

Accordingly, preferably the Rhinovirus 3Cpro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 272, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Rhinovirus 3Cpro polypeptide is provided herein as SEQ ID No: 273, as follows:

[SEQ ID No: 273]

GGACCTGAGGAAGAGTTCGGCAGATCCATCCTGAAGAACAATACCTGCGT

GATCACCACCGGCAACGGCAAGTTTACAGGCCTGGGCATCCACGACCGGA

TCCTGATCATTCCCACACACGCCGATCCTGGCCGGGAAGTGCAAGTGAAT

GGCGTGCACACCAAGGTGCTGGACAGCTACGACCTGTACAACCGCGACGG

CGTGAAGCTGGAAATCACCGTGATTCAGCTGGACCGGAACGAGAAGTTCC

GGGACATCCGGAAGTACATCCCCGAGACAGAGGACGACTACCCCGAGTGT

AATCTGGCCCTGAGCGCCAACCAGGACGAGCCCACAATTATCAAAGTGGG

CGACGTGGTGTCCTACGGCAACATCCTGCTGTCCGGCAATCAGACCGCCA

GAATGCTGAAGTACAACTACCCCACCAAGAGCGGCTACTGTGGCGGCGTG

CTGTATAAGATCGGCCAGATCCTGGGAATTCACGTCGGCGGCAATGGCAG

AGATGGCTTCTCTGCTATGCTGCTGCGGAGCTACTTCACCGACACACAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 273, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 273 is provided herein as SEQ ID No: 274, as follows:

[SEQ ID No: 274]

GGACCUGAGGAAGAGUUCGGCAGAUCCAUCCUGAAGAACAAUACCUGCGU

GAUCACCACCGGCAACGGCAAGUUUACAGGCCUGGGCAUCCACGACCGGA

UCCUGAUCAUUCCCACACACGCCGAUCCUGGCCGGGAAGUGCAAGUGAAU

GGCGUGCACACCAAGGUGCUGGACAGCUACGACCUGUACAACCGCGACGG

CGUGAAGCUGGAAAUCACCGUGAUUCAGCUGGACCGGAACGAGAAGUUCC

GGGACAUCCGGAAGUACAUCCCCGAGACAGAGGACGACUACCCCGAGUGU

AAUCUGGCCCUGAGCGCCAACCAGGACGAGCCCACAAUUAUCAAAGUGGG

CGACGUGGUGUCCUACGGCAACAUCCUGCUGUCCGGCAAUCAGACCGCCA

GAAUGCUGAAGUACAACUACCCCACCAAGAGCGGCUACUGUGGCGGCGUG

CUGUAUAAGAUCGGCCAGAUCCUGGGAAUUCACGUCGGCGGCAAUGGCAG

AGAUGGCUUCUCUGCUAUGCUGCUGCGGAGCUACUUCACCGACACACAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 274, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Rotavirus VP3 (A2T3S5; Protein VP3 Rotavirus A (isolate RVA/Monkey/South Africa/SA11-H96/1958/G3P5B[2])), or an orthologue thereof. One embodiment of the polypeptide sequence of Rotavirus VP3 is represented herein as SEQ ID No: 275, as follows:

[SEQ ID No: 275]

MKVLALRHSVAQVYADTQVYVHDDTKDSYENAFLISNLTTHNILYLNYSI

KTLEILNKSGIAAIALQSLEELFTLIRCNFTYDYELDIIYLHDYSYYTNN

EIRTDQHWITKTNIEEYLLPGWKLTYVGYNGSETRGHYNFSFKCQNAATD

DDLIIEYIYSEALDFQNFMLKKIKERMTTSLPIARLSNRVFRDKLFPSLL

KEHKNVVNVGPRNESMFTFLNYPTIKQFSNGAYLVKDTIKLKQERWLGKR

ISQFDIGQYKNMLNVLTAIYYYYNLYKSKPIIYMIGSAPSYWIYDVRHYS

DFFFETWDPLDTPYSSIHHKELFFINDVKKLKDNSILYIDIRTDRGNADW

KKWRKTVEEQTINNLDIAYEYLRTGKAKVCCVKMTAMDLELPISAKLLHH

PTTEIRSEFYLLLDTWDLTNIRRFIPKGVLYSFINNIITENVFIQQPFKV

KVLNDSYIVALYALSNDFNNRSEVIKLINNQKQSLITVRINNTFKDEPKV

GFKNIYDWTFLPTDFDTKEAIITSYDGCLGLFGLSISLASKPTGNNHLFI

LSGTDKYYKLDQFANHTSISRRSHQIRFSESATSYSGYIFRDLSNNNFNL

IGTNIENSVSGHVYNALIYYRYNYSFDLKRWIYLHSIDKVDIEGGKYYEL

APIELIYACRSAKEFATLQDDLTVLRYSNEIENYINTVYSITYADDPNYF

IGIQFRNIPYKYDVKIPHLTFGVLHISDNMVPDVIDILKIMKNELFKMDI

TTSYTYMLSDGIYVANVSGVLSTYFKIYNVFYKNQITFGQSRMFIPHITL

SFNNMRTVRIETTKLQIKSTYLRKIKGDTVFDMVE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 275, or a variant or fragment thereof.

In one embodiment, the Rotavirus VP3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 276, as follows:

[SEQ ID No: 276]

ATGAAAGTACTAGCTTTAAGACACAGTGTGGCTCAAGTGTATGCAGACAC

TCAAGTCTACGTTCATGATGATACAAAAGATAGTTATGAAAACGCTTTTT

TAATCTCTAATCTTACGACCCATAATATTTTATACTTAAATTATAGCATT

AAAACATTAGAAATATTAAATAAGTCAGGAATAGCTGCAATTGCTTTACA

ATCACTTGAAGAATTATTCACATTAATAAGGTGTAATTTCACTTATGATT

ATGAACTTGATATAATATATTTACATGATTATTCATATTATACCAATAAT

GAAATTAGAACAGACCAACATTGGATAACAAAAACAAATATTGAAGAATA

TTTACTACCTGGATGGAAATTAACATATGTTGGTTATAATGGAAGTGAAA

CTAGAGGACATTATAACTTTTCATTTAAATGTCAAAACGCTGCAACAGAT

GATGATCTAATAATTGAATACATTTATTCAGAAGCGTTGGACTTCCAAAA

TTTTATGTTAAAAAAGATAAAGGAAAGAATGACTACATCGTTGCCTATAG

CTAGATTATCTAACAGAGTATTTAGGGATAAGTTATTCCCATCATTATTG

AAAGAACATAAGAATGTAGTGAACGTTGGTCCGCGTAATGAATCTATGTT

TACATTTTTAAATTATCCAACTATAAAACAATTTTCAAATGGTGCGTATT

TAGTAAAAGATACTATAAAATTAAAACAAGAACGATGGTTAGGTAAAAGG

ATATCTCAGTTTGATATTGGTCAGTATAAAAATATGCTGAATGTTCTTAC

AGCAATTTATTATTACTATAATTTATATAAAAGTAAACCAATTATATATA

TGATCGGATCTGCTCCATCTTATTGGATATATGACGTTAGGCATTATTCC

GATTTTTTCTTTGAAACTTGGGATCCATTGGACACACCATATTCATCAAT

CCATCACAAAGAATTATTTTTTATAAATGATGTGAAGAAACTGAAGGATA

ACTCAATATTGTATATTGATATAAGAACCGATAGGGGCAATGCTGATTGG

AAAAAATGGAGAAAGACAGTAGAAGAACAAACTATTAATAATTTGGACAT

AGCTTATGAATATTTACGAACGGGTAAAGCGAAGGTGTGTTGTGTTAAGA

TGACAGCTATGGATTTGGAACTGCCAATTTCAGCTAAATTACTGCACCAC

CCAACTACGGAAATAAGATCAGAATTTTATTTATTACTAGATACTTGGGA

TTTAACTAACATTAGGAGGTTCATTCCTAAAGGCGTGTTATATTCATTTA

TAAACAATATAATAACTGAAAATGTGTTTATTCAACAACCATTTAAAGTA

AAAGTACTGAATGATAGTTATATTGTAGCGTTATATGCATTATCAAATGA

TTTTAATAATAGATCAGAAGTAATTAAATTAATTAATAATCAGAAACAAT

CTCTAATAACTGTTAGAATAAATAATACGTTTAAGGATGAACCAAAAGTT

GGGTTCAAAAATATCTATGATTGGACCTTTCTTCCAACCGACTTTGATAC

CAAAGAAGCTATAATTACTTCATACGACGGTTGTTTAGGACTCTTTGGTT

TGTCTATATCGTTAGCATCAAAACCAACAGGGAATAATCATTTATTCATT

TTAAGTGGTACAGATAAGTATTATAAATTGGATCAATTTGCTAATCACAC

CAGTATATCGAGAAGATCACACCAAATTAGGTTTTCGGAATCTGCTACTT

CATATTCAGGTTATATATTTAGAGATTTGTCCAATAATAATTTTAATCTA

ATTGGTACTAATATAGAGAATTCAGTATCAGGTCATGTATATAATGCTTT

AATTTATTATAGATATAATTATTCATTTGATCTTAAACGCTGGATTTATT

TACATTCTATAGATAAAGTTGATATAGAAGGAGGAAAGTATTATGAACTC

GCACCAATAGAATTAATTTATGCATGTAGATCAGCAAAAGAATTTGCTAC

ATTGCAGGATGACTTAACTGTATTGAGATATTCAAACGAAATAGAGAATT

ATATTAATACAGTATATAGTATAACATACGCTGATGATCCGAATTACTTT

ATCGGAATACAATTTAGAAATATACCATATAAATATGATGTTAAAATACC

GCATTTAACCTTCGGAGTATTACATATTTCTGATAACATGGTGCCAGACG

TGATTGACATACTAAAGATAATGAAGAATGAATTATTTAAAATGGATATT

ACGACCAGTTATACATATATGTTATCAGATGGAATCTACGTAGCAAATGT

TAGTGGAGTATTATCTACATACTTTAAAATCTATAACGTATTTTATAAAA

ATCAAATAACTTTTGGCCAATCCAGAATGTTTATTCCGCACATAACATTA

AGCTTCAATAACATGAGAATGGTTGAG

Accordingly, preferably the Rotavirus VP3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 276, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Rotavirus VP3 polypeptide is provided herein as SEQ ID No: 277, as follows:

[SEQ ID No: 277]

ATGAAGGTGCTGGCCCTGAGACATTCTGTGGCCCAGGTGTACGCCGACAC

ACAGGTCTACGTGCACGACGACACCAAGGACAGCTACGAGAACGCCTTCC

TGATCAGCAACCTGACCACACACAACATCCTGTACCTGAACTACAGCATC

AAGACCCTCGAGATCCTGAACAAGAGCGGAATCGCCGCTATCGCCCTGCA

GAGCCTGGAAGAACTGTTCACCCTGATCCGGTGCAACTTCACCTACGACT

ACGAGCTGGACATCATCTACCTGCACGATTACAGCTACTACACCAACAAC

GAGATCCGGACCGACCAGCACTGGATCACCAAGACCAACATCGAGGAATA

CCTGCTGCCTGGCTGGAAGCTGACCTACGTGGGCTACAATGGCAGCGAGA

CACGGGGCCACTACAACTTCAGCTTCAAGTGCCAGAACGCCGCCACCGAC

GACGACCTGATCATCGAGTACATCTACAGCGAGGCCCTGGACTTCCAGAA

CTTCATGCTGAAGAAAATCAAAGAACGGATGACCACCAGCCTGCCTATCG

CCAGACTGAGCAACCGGGTGTTCCGGGACAAGCTGTTTCCCAGCCTGCTG

AAAGAACACAAGAACGTGGTCAACGTGGGCCCCAGAAACGAGAGCATGTT

CACCTTTCTGAACTACCCCACCATCAAGCAGTTCAGCAACGGCGCCTACC

TGGTCAAGGACACAATCAAGCTGAAGCAAGAGAGATGGCTGGGCAAGAGA

ATCAGCCAGTTCGACATCGGCCAGTACAAGAACATGCTGAACGTGCTGAC

CGCCATCTACTACTACTATAACCTGTACAAGAGCAAGCCGATCATCTACA

TGATTGGCAGCGCCCCTAGCTACTGGATCTACGACGTGCGGCACTACAGC

GACTTTTTCTTCGAAACCTGGGATCCCCTGGACACCCCTTACAGCAGCAT

CCACCACAAAGAGCTGTTCTTCATCAACGACGTGAAGAAGCTCAAGGACA

ACAGCATCCTCTACATCGACATCAGAACCGACCGGGGCAACGCCGACTGG

AAGAAATGGCGGAAAACCGTGGAAGAACAGACCATCAACAACCTGGATAT

CGCCTACGAGTACCTGCGGACCGGCAAGGCCAAAGTGTGCTGCGTGAAGA

TGACAGCCATGGACCTGGAACTGCCCATCAGCGCCAAACTGCTGCACCAT

CCTACCACCGAGATCAGAAGCGAGTTCTATCTGCTGCTGGACACCTGGGA

CCTGACCAATATCAGACGGTTCATCCCCAAGGGCGTGCTGTACTCCTTTA

TCAACAACATCATCACCGAGAACGTGTTCATCCAGCAGCCGTTCAAAGTG

AAAGTGCTGAACGACAGCTACATCGTGGCCCTGTACGCCCTGAGCAACGA

CTTCAACAATCGGAGCGAAGTGATCAAACTGATCAACAATCAGAAGCAGT

CCCTGATCACCGTGCGCATCAACAATACCTTCAAGGACGAGCCCAAAGTG

GGCTTCAAGAATATCTACGACTGGACCTTCCTGCCTACCGACTTCGACAC

CAAAGAGGCCATCATCACAAGCTACGACGGCTGCCTGGGCCTGTTTGGCC

TGTCTATTAGCCTGGCCAGCAAGCCCACCGGCAACAACCACCTGTTTATC

CTGAGCGGCACCGACAAGTACTACAAGCTGGATCAGTTCGCCAACCACAC

CAGCATCAGCAGAAGAAGCCACCAGATCCGGTTCAGCGAGAGCGCCACAA

GCTATAGCGGCTACATCTTCCGGGACCTGTCCAACAACAACTTCAACCTG

ATCGGCACGAACATCGAGAACAGCGTGTCCGGCCACGTGTACAACGCCCT

GATCTACTACCGGTACAACTACTCCTTCGACCTGAAGCGGTGGATCTATC

TGCACAGCATCGACAAGGTGGACATCGAAGGCGGCAAGTACTATGAGCTG

GCCCCTATCGAGCTGATCTACGCCTGCAGAAGCGCCAAAGAGTTCGCCAC

ACTGCAGGACGATCTGACCGTGCTGAGATACAGCAATGAGATCGAGAACT

ACATCAACACCGTGTACTCCATCACCTACGCCGACGATCCCAACTACTTC

ATCGGAATCCAGTTCCGCAACATCCCCTATAAGTACGACGTCAAGATCCC

TCACCTGACCTTCGGCGTGCTGCACATCAGCGACAACATGGTGCCCGACG

TGATCGACATCCTGAAGATCATGAAGAATGAGCTGTTCAAGATGGACATC

ACCACCAGCTACACCTACATGCTGAGCGACGGCATCTACGTGGCCAATGT

GTCTGGCGTGCTGAGCACCTACTTCAAGATCTACAACGTGTTCTACAAGA

ACCAGATCACCTTCGGCCAGAGCCGGATGTTCATCCCTCACATCACCCTG

AGCTTTAACAACATGCGGACCGTGCGGATCGAAACCACCAAGCTGCAGAT

CAAGAGCATCTACCTCCGGAAGATCAAGGGCGACACCGTGTTCGACATGG

TGGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 277, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 277 is provided herein as SEQ ID No: 278, as follows:

[SEQ ID No: 278]

AUGAAGGUGCUGGCCCUGAGACAUUCUGUGGCCCAGGUGUACGCCGACAC

ACAGGUCUACGUGCACGACGACACCAAGGACAGCUACGAGAACGCCUUCC

UGAUCAGCAACCUGACCACACACAACAUCCUGUACCUGAACUACAGCAUC

AAGACCCUCGAGAUCCUGAACAAGAGCGGAAUCGCCGCUAUCGCCCUGCA

GAGCCUGGAAGAACUGUUCACCCUGAUCCGGUGCAACUUCACCUACGACU

ACGAGCUGGACAUCAUCUACCUGCACGAUUACAGCUACUACACCAACAAC

GAGAUCCGGACCGACCAGCACUGGAUCACCAAGACCAACAUCGAGGAAUA

CCUGCUGCCUGGCUGGAAGCUGACCUACGUGGGCUACAAUGGCAGCGAGA

CACGGGGCCACUACAACUUCAGCUUCAAGUGCCAGAACGCCGCCACCGAC

GACGACCUGAUCAUCGAGUACAUCUACAGCGAGGCCCUGGACUUCCAGAA

CUUCAUGCUGAAGAAAAUCAAAGAACGGAUGACCACCAGCCUGCCUAUCG

CCAGACUGAGCAACCGGGUGUUCCGGGACAAGCUGUUUCCCAGCCUGCUG

AAAGAACACAAGAACGUGGUCAACGUGGGCCCCAGAAACGAGAGCAUGUU

CACCUUUCUGAACUACCCCACCAUCAAGCAGUUCAGCAACGGCGCCUACC

UGGUCAAGGACACAAUCAAGCUGAAGCAAGAGAGAUGGCUGGGCAAGAGA

AUCAGCCAGUUCGACAUCGGCCAGUACAAGAACAUGCUGAACGUGCUGAC

CGCCAUCUACUACUACUAUAACCUGUACAAGAGCAAGCCGAUCAUCUACA

UGAUUGGCAGCGCCCCUAGCUACUGGAUCUACGACGUGCGGCACUACAGC

GACUUUUUCUUCGAAACCUGGGAUCCCCUGGACACCCCUUACAGCAGCAU

CCACCACAAAGAGCUGUUCUUCAUCAACGACGUGAAGAAGCUCAAGGACA

ACAGCAUCCUCUACAUCGACAUCAGAACCGACCGGGGCAACGCCGACUGG

AAGAAAUGGCGGAAAACCGUGGAAGAACAGACCAUCAACAACCUGGAUAU

CGCCUACGAGUACCUGCGGACCGGCAAGGCCAAAGUGUGCUGCGUGAAGA

UGACAGCCAUGGACCUGGAACUGCCCAUCAGCGCCAAACUGCUGCACCAU

CCUACCACCGAGAUCAGAAGCGAGUUCUAUCUGCUGCUGGACACCUGGGA

CCUGACCAAUAUCAGACGGUUCAUCCCCAAGGGCGUGCUGUACUCCUUUA

UCAACAACAUCAUCACCGAGAACGUGUUCAUCCAGCAGCCGUUCAAAGUG

AAAGUGCUGAACGACAGCUACAUCGUGGCCCUGUACGCCCUGAGCAACGA

CUUCAACAAUCGGAGCGAAGUGAUCAAACUGAUCAACAAUCAGAAGCAGU

CCCUGAUCACCGUGCGCAUCAACAAUACCUUCAAGGACGAGCCCAAAGUG

GGCUUCAAGAAUAUCUACGACUGGACCUUCCUGCCUACCGACUUCGACAC

CAAAGAGGCCAUCAUCACAAGCUACGACGGCUGCCUGGGCCUGUUUGGCC

UGUCUAUUAGCCUGGCCAGCAAGCCCACCGGCAACAACCACCUGUUUAUC

CUGAGCGGCACCGACAAGUACUACAAGCUGGAUCAGUUCGCCAACCACAC

CAGCAUCAGCAGAAGAAGCCACCAGAUCCGGUUCAGCGAGAGCGCCACAA

GCUAUAGCGGCUACAUCUUCCGGGACCUGUCCAACAACAACUUCAACCUG

AUCGGCACGAACAUCGAGAACAGCGUGUCCGGCCACGUGUACAACGCCCU

GAUCUACUACCGGUACAACUACUCCUUCGACCUGAAGCGGUGGAUCUAUC

UGCACAGCAUCGACAAGGUGGACAUCGAAGGCGGCAAGUACUAUGAGCUG

GCCCCUAUCGAGCUGAUCUACGCCUGCAGAAGCGCCAAAGAGUUCGCCAC

ACUGCAGGACGAUCUGACCGUGCUGAGAUACAGCAAUGAGAUCGAGAACU

ACAUCAACACCGUGUACUCCAUCACCUACGCCGACGAUCCCAACUACUUC

AUCGGAAUCCAGUUCCGCAACAUCCCCUAUAAGUACGACGUCAAGAUCCC

UCACCUGACCUUCGGCGUGCUGCACAUCAGCGACAACAUGGUGCCCGACG

UGAUCGACAUCCUGAAGAUCAUGAAGAAUGAGCUGUUCAAGAUGGACAUC

ACCACCAGCUACACCUACAUGCUGAGCGACGGCAUCUACGUGGCCAAUGU

GUCUGGCGUGCUGAGCACCUACUUCAAGAUCUACAACGUGUUCUACAAGA

ACCAGAUCACCUUCGGCCAGAGCCGGAUGUUCAUCCCUCACAUCACCCUG

AGCUUUAACAACAUGCGGACCGUGCGGAUCGAAACCACCAAGCUGCAGAU

CAAGAGCAUCUACCUCCGGAAGAUCAAGGGCGACACCGUGUUCGACAUGG

UGGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 278, or a fragment or variant thereof.

In one embodiment, the at least one IIP is GB Virus B NS3/4A (Q69422; Genome polyprotein Hepatitis GB virus B), or an orthologue thereof. One embodiment of the polypeptide sequence of GB Virus B NS3/4A is represented herein as SEQ ID No: 279, as follows:

[SEQ ID No: 279]

APFTLQCLSERGTLSAMAVVMTGIDPRTWTGTIFRLGSLATSYMGFVCDN

VLYTAHHGSKGRRLAHPTGSIHPITVDAANDQDIYQPPCGAGSLTRCSCG

ETKGYLVTRLGSLVEVNKSDDPYWCVCGALPMAVAKGSSGAPILCSSGHV

IGMFTAARNSGGSVSQIRVRPLVCAGYHPQYTAHATLDTKPTVPNEYSVQ

ILIAPTGSGKSTKLPLSYMQEKYEVLVLNPSVATTASMPKYMHATYGVNP

NCYFNGKCTNTGASLTYSTYGMYLTGACSRNYDVIICDECHATDATTVLG

IGKVLTEAPSKNVRLVVLATATPPGVIPTPHANITEIQLTDEGTIPFHGK

KIKEENLKKGRHLIFEATKKHCDELANELARKGITAVSYYRGCDISKIPE

GDCVVVATDALCTGYTGDFDSVYDCSLMVEGTCHVDLDPTFTMGVRVCGV

SAIVKGQRRGRTGRGRAGIYYYVDGSCTPSGMVPECNIVEAFDAAKAWYG

LSSTEAQTILDTYRTQPGLPAIGANLDEWADLFSMVNPEPSFVNTAKRTA

DNYVLLTAAQLQLCHQYGYAAPNDAPRWQGARLGKKPCGVLWRLDGADAC

PGPEPSEVTRYQMCFTEVNTSGTAALAVGVGVAMAYLAIDTFGATCVRRC

WSITSVPTGATVAPVVDEEEIVEEC

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 279, or a variant or fragment thereof.

In one embodiment, the GB Virus B NS3/4A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 280, as follows:

[SEQ ID No: 280]

GCACCTTTTACGCTGCAGTGTCTCTCTGAACGTGGCACGCTGTCAGCGAT

GGCAGTGGTCATGACTGGTATAGACCCCCGAACTTGGACTGGAACTATCT

TCAGATTAGGATCTCTGGCCACTAGCTACATGGGATTTGTTTGTGACAAC

GTGTTGTATACTGCTCACCATGGCAGCAAGGGGCGCCGGTTGGCTCATCC

CACAGGCTCCATACACCCAATAACCGTTGACGCGGCTAATGACCAGGACA

TCTATCAACCACCATGTGGAGCTGGGTCCCTTACTCGGTGCTCTTGCGGG

GAGACCAAGGGGTATCTGGTAACACGACTGGGGTCATTGGTTGAGGTCAA

CAAATCCGATGACCCTTATTGGTGTGTGTGCGGGGCCCTTCCCATGGCTG

TTGCCAAGGGTTCTTCAGGTGCCCCGATTCTGTGCTCCTCCGGGCATGTT

ATTGGGATGTTCACCGCTGCTAGAAATTCTGGCGGTTCAGTCAGCCAGAT

TAGGGTTAGGCCGTTGGTGTGTGCTGGATACCATCCCCAGTACACAGCAC

ATGCCACTCTTGATACAAAACCTACTGTGCCTAACGAGTATTCAGTGCAA

ATTTTAATTGCCCCCACTGGCAGCGGCAAGTCAACCAAATTACCACTTTC

TTACATGCAGGAGAAGTATGAGGTCTTGGTCCTAAATCCCAGTGTGGCTA

CAACAGCATCAATGCCAAAGTACATGCACGCGACGTACGGCGTGAATCCA

AATTGCTATTTTAATGGCAAATGTACCAACACAGGGGCTTCACTTACGTA

CAGCACATATGGCATGTACCTGACCGGAGCATGTTCCCGGAACTATGACG

TCATCATTTGTGACGAATGCCATGCTACCGATGCAACCACCGTGTTGGGC

ATTGGAAAGGTTCTAACCGAAGCTCCATCCAAAAATGTTAGGCTAGTGGT

TCTTGCCACGGCTACCCCCCCTGGAGTAATCCCTACACCACATGCCAACA

TAACTGAGATTCAATTAACCGATGAAGGCACTATCCCCTTTCATGGAAAA

AAGATTAAGGAGGAAAATCTGAAGAAAGGGAGACACCTTATCTTTGAGGC

TACCAAAAAACACTGTGATGAGCTTGCTAACGAGTTAGCTCGAAAGGGAA

TAACAGCTGTCTCTTACTATAGGGGATGTGACATCTCAAAAATCCCTGAG

GGCGACTGTGTAGTAGTTGCCACTGATGCCTTGTGTACAGGGTACACTGG

TGACTTTGATTCCGTGTATGACTGCAGCCTCATGGTAGAAGGCACATGCC

ATGTTGACCTTGACCCTACTTTCACCATGGGTGTTCGTGTGTGCGGGGTC

TCAGCAATAGTTAAAGGCCAGCGTAGGGGCCGCACAGGCCGTGGGAGAGC

TGGCATATACTACTATGTAGACGGGAGTTGTACCCCTTCGGGTATGGTTC

CTGAATGCAACATTGTTGAAGCCTTCGACGCAGCCAAGGCATGGTATGGT

TTGTCATCAACAGAAGCTCAAACTATTCTGGACACCTATCGCACCCAACC

TGGGTTACCTGCGATAGGAGCAAATTTGGACGAGTGGGCTGATCTCTTTT

CTATGGTCAACCCCGAACCTTCATTTGTCAATACTGCAAAAAGAACTGCT

GACAATTATGTTTTGTTGACTGCAGCCCAACTACAACTGTGTCATCAGTA

TGGCTATGCTGCTCCCAATGACGCACCACGGTGGCAGGGAGCCCGGCTTG

GGAAAAAACCTTGTGGGGTTCTGTGGCGCTTGGACGGCGCTGACGCCTGT

CCTGGCCCAGAGCCCAGCGAGGTGACCAGATACCAAATGTGCTTCACTGA

AGTCAATACTTCTGGGACAGCCGCACTCGCTGTTGGCGTTGGAGTGGCTA

TGGCTTATCTAGCCATTGACACTTTTGGCGCCACTTGTGTGCGGCGTTGC

TGGTCTATTACATCAGTCCCTACCGGTGCTACTGTCGCCCCAGTGGTTGA

CGAAGAAGAAATCGTGGAGGAGTGT

Accordingly, preferably the GB Virus B NS3/4A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 280, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the GB Virus B NS3/4A polypeptide is provided herein as SEQ ID No: 281, as follows:

[SEQ ID No: 281]

GCCCCTTTCACACTGCAATGCCTGAGCGAGAGAGGCACCCTGTCTGCCAT

GGCCGTGGTTATGACAGGCATCGACCCTAGAACCTGGACCGGCACCATCT

TCAGACTGGGAAGCCTGGCCACAAGCTACATGGGCTTCGTGTGCGACAAC

GTGCTGTACACAGCCCACCACGGCAGCAAAGGCAGAAGGCTGGCTCACCC

TACAGGCAGCATTCACCCCATCACAGTGGACGCCGCCAACGACCAGGATA

TCTACCAACCTCCTTGCGGCGCTGGCAGCCTGACCAGATGTTCTTGTGGC

GAGACAAAGGGCTACCTGGTCACCAGGCTGGGATCCCTGGTGGAAGTGAA

CAAGAGCGACGACCCCTATTGGTGCGTGTGTGGCGCACTGCCTATGGCTG

TGGCCAAAGGATCTTCTGGCGCCCCTATCCTGTGTAGCTCTGGCCACGTG

ATCGGCATGTTTACCGCCGCCAGAAATAGCGGCGGCAGCGTGTCACAGAT

TAGAGTGCGGCCTCTTGTGTGCGCCGGCTATCACCCTCAGTATACAGCCC

ACGCCACACTGGACACCAAGCCTACCGTGCCTAACGAGTACAGCGTGCAG

ATCCTGATCGCCCCAACAGGCAGCGGCAAGAGCACAAAACTGCCCCTGAG

CTACATGCAAGAGAAGTACGAGGTGCTGGTGCTGAACCCTAGCGTGGCCA

CAACAGCCAGCATGCCCAAGTACATGCACGCCACCTATGGCGTGAACCCC

AACTGCTACTTCAACGGCAAGTGCACCAATACCGGCGCCAGCCTGACATA

CAGCACCTACGGCATGTATCTGACCGGCGCCTGCAGCAGAAACTACGACG

TGATCATCTGCGACGAGTGCCACGCCACCGATGCCACAACTGTGCTCGGA

ATCGGCAAGGTGCTGACAGAGGCCCCTAGCAAGAATGTGCGACTGGTGGT

GCTGGCCACTGCTACACCACCTGGCGTTATCCCTACACCTCACGCCAACA

TCACCGAGATCCAGCTGACCGACGAGGGCACAATCCCATTCCACGGCAAG

AAGATCAAAGAGGAAAACCTGAAGAAGGGCCGCCACCTGATCTTCGAGGC

CACCAAGAAACACTGTGACGAGCTGGCCAACGAACTGGCCAGAAAGGGCA

TCACCGCCGTGTCCTACTACAGAGGCTGCGACATCAGCAAGATCCCCGAG

GGCGATTGTGTGGTGGTGGCTACAGATGCCCTGTGTACCGGCTACACCGG

CGACTTCGATAGCGTGTACGACTGCAGCCTGATGGTGGAAGGCACCTGTC

ATGTGGATCTGGACCCCACCTTTACCATGGGCGTCAGAGTGTGCGGAGTG

TCCGCCATCGTGAAGGGCCAGAGAAGAGGCAGAACTGGCAGAGGCAGAGC

CGGCATCTACTACTATGTGGACGGCAGCTGTACCCCTAGCGGCATGGTGC

CTGAGTGCAACATCGTGGAAGCCTTCGATGCCGCCAAGGCTTGGTACGGC

CTGTCTAGCACAGAGGCTCAGACCATCCTGGACACCTACAGAACCCAGCC

AGGACTGCCTGCCATCGGCGCCAATCTTGATGAATGGGCCGACCTGTTCA

GCATGGTCAACCCCGAGCCTAGCTTCGTGAACACCGCCAAGAGAACCGCC

GACAACTACGTGCTGCTGACAGCCGCTCAGCTCCAGCTGTGTCACCAGTA

CGGATACGCCGCTCCTAACGACGCCCCTAGATGGCAAGGCGCTAGACTGG

GCAAGAAACCATGTGGCGTTCTGTGGCGACTGGATGGCGCTGATGCTTGT

CCTGGACCTGAGCCTAGCGAAGTGACCAGATACCAGATGTGCTTCACCGA

AGTGAATACCAGCGGCACAGCTGCCCTGGCCGTTGGTGTTGGAGTGGCCA

TGGCTTACCTGGCCATCGATACCTTTGGCGCCACATGCGTGCGGAGATGC

TGGTCTATCACCAGCGTTCCAACAGGCGCTACAGTGGCCCCTGTGGTGGA

TGAGGAAGAGATTGTGGAAGAGTGC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 281, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 281 is provided herein as SEQ ID No: 282, as follows:

[SEQ ID No: 282]

GCCCCUUUCACACUGCAAUGCCUGAGCGAGAGAGGCACCCUGUCUGCCAU

GGCCGUGGUUAUGACAGGCAUCGACCCUAGAACCUGGACCGGCACCAUCU

UCAGACUGGGAAGCCUGGCCACAAGCUACAUGGGCUUCGUGUGCGACAAC

GUGCUGUACACAGCCCACCACGGCAGCAAAGGCAGAAGGCUGGCUCACCC

UACAGGCAGCAUUCACCCCAUCACAGUGGACGCCGCCAACGACCAGGAUA

UCUACCAACCUCCUUGCGGCGCUGGCAGCCUGACCAGAUGUUCUUGUGGC

GAGACAAAGGGCUACCUGGUCACCAGGCUGGGAUCCCUGGUGGAAGUGAA

CAAGAGCGACGACCCCUAUUGGUGCGUGUGUGGCGCACUGCCUAUGGCUG

UGGCCAAAGGAUCUUCUGGCGCCCCUAUCCUGUGUAGCUCUGGCCACGUG

AUCGGCAUGUUUACCGCCGCCAGAAAUAGCGGCGGCAGCGUGUCACAGAU

UAGAGUGCGGCCUCUUGUGUGCGCCGGCUAUCACCCUCAGUAUACAGCCC

ACGCCACACUGGACACCAAGCCUACCGUGCCUAACGAGUACAGCGUGCAG

AUCCUGAUCGCCCCAACAGGCAGCGGCAAGAGCACAAAACUGCCCCUGAG

CUACAUGCAAGAGAAGUACGAGGUGCUGGUGCUGAACCCUAGCGUGGCCA

CAACAGCCAGCAUGCCCAAGUACAUGCACGCCACCUAUGGCGUGAACCCC

AACUGCUACUUCAACGGCAAGUGCACCAAUACCGGCGCCAGCCUGACAUA

CAGCACCUACGGCAUGUAUCUGACCGGCGCCUGCAGCAGAAACUACGACG

UGAUCAUCUGCGACGAGUGCCACGCCACCGAUGCCACAACUGUGCUCGGA

AUCGGCAAGGUGCUGACAGAGGCCCCUAGCAAGAAUGUGCGACUGGUGGU

GCUGGCCACUGCUACACCACCUGGCGUUAUCCCUACACCUCACGCCAACA

UCACCGAGAUCCAGCUGACCGACGAGGGCACAAUCCCAUUCCACGGCAAG

AAGAUCAAAGAGGAAAACCUGAAGAAGGGCCGCCACCUGAUCUUCGAGGC

CACCAAGAAACACUGUGACGAGCUGGCCAACGAACUGGCCAGAAAGGGCA

UCACCGCCGUGUCCUACUACAGAGGCUGCGACAUCAGCAAGAUCCCCGAG

GGCGAUUGUGUGGUGGUGGCUACAGAUGCCCUGUGUACCGGCUACACCGG

CGACUUCGAUAGCGUGUACGACUGCAGCCUGAUGGUGGAAGGCACCUGUC

AUGUGGAUCUGGACCCCACCUUUACCAUGGGCGUCAGAGUGUGCGGAGUG

UCCGCCAUCGUGAAGGGCCAGAGAAGAGGCAGAACUGGCAGAGGCAGAGC

CGGCAUCUACUACUAUGUGGACGGCAGCUGUACCCCUAGCGGCAUGGUGC

CUGAGUGCAACAUCGUGGAAGCCUUCGAUGCCGCCAAGGCUUGGUACGGC

CUGUCUAGCACAGAGGCUCAGACCAUCCUGGACACCUACAGAACCCAGCC

AGGACUGCCUGCCAUCGGCGCCAAUCUUGAUGAAUGGGCCGACCUGUUCA

GCAUGGUCAACCCCGAGCCUAGCUUCGUGAACACCGCCAAGAGAACCGCC

GACAACUACGUGCUGCUGACAGCCGCUCAGCUCCAGCUGUGUCACCAGUA

CGGAUACGCCGCUCCUAACGACGCCCCUAGAUGGCAAGGCGCUAGACUGG

GCAAGAAACCAUGUGGCGUUCUGUGGCGACUGGAUGGCGCUGAUGCUUGU

CCUGGACCUGAGCCUAGCGAAGUGACCAGAUACCAGAUGUGCUUCACCGA

AGUGAAUACCAGCGGCACAGCUGCCCUGGCCGUUGGUGUUGGAGUGGCCA

UGGCUUACCUGGCCAUCGAUACCUUUGGCGCCACAUGCGUGCGGAGAUGC

UGGUCUAUCACCAGCGUUCCAACAGGCGCUACAGUGGCCCCUGUGGUGGA

UGAGGAAGAGAUUGUGGAAGAGUGC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 282, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HAV 3Cpro (P08617; Genome polyprotein Human hepatitis A virus genotype IB (isolate HM175)), or an orthologue thereof. One embodiment of the polypeptide sequence of HAV 3Cpro is represented herein as SEQ ID No: 283, as follows:

[SEQ ID No: 283]

STLEIAGLVRKNLVQFGVGEKNGCVRWVMNALGVKDDWLLVPSHAYKFEK

DYEMMEFYFNRGGTYYSISAGNVVIQSLDVGFQDVVLMKVPTIPKFRDIT

QHFIKKGDVPRALNRLATLVTTVNGTPMLISEGPLKMEEKATYVHKKNDG

TTVDLTVDQAWRGKGEGLPGMCGGALVSSNQSIQNAILGIHVAGGNSILV

AKLVTQEMFQNIDKKIESQ

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 283, or a variant or fragment thereof.

In one embodiment, the HAV 3Cpro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 284, as follows:

[SEQ ID No: 284]

TCAACTTTGGAAATAGCAGGACTGGTTAGGAAGAACTTGGTTCAGTTTGG

AGTTGGAGAGAAGAATGGATGTGTGAGATGGGTTATGAATGCCTTGGGAG

TGAAAGATGATTGGCTGCTTGTGCCTTCCCATGCTTATAAATTTGAGAAA

GATTATGAAATGATGGAGTTTTATTTTAATAGAGGTGGAACTTACTATTC

AATTTCAGCTGGTAATGTTGTTATTCAATCTTTGGATGTGGGATTCCAGG

ATGTTGTTCTGATGAAGGTTCCTACAATTCCTAAGTTTAGAGATATTACT

CAGCATTTTATTAAGAAAGGGGATGTGCCTAGAGCTTTGAATCGCCTGGC

AACATTAGTGACAACTGTAAATGGAACCCCTATGTTAATTTCTGAGGGCC

CACTAAAGATGGAAGAGAAAGCTACTTATGTTCATAAGAAAAATGATGGT

ACAACAGTTGATTTAACTGTGGATCAGGCATGGAGAGGAAAAGGCGAAGG

TCTTCCTGGAATGTGTGGTGGGGCCTTGGTTTCATCGAATCAATCTATAC

AGAATGCAATCTTGGGCATCCATGTTGCTGGAGGAAATTCAATTCTTGTT

GCAAAATTGGTTACTCAAGAAATGTTCCAAAATATTGATAAGAAAATTGA

AAGTCAG

Accordingly, preferably the HAV 3Cpro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 284, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HAV 3Cpro polypeptide is provided herein as SEQ ID No: 285, as follows:

[SEQ ID No: 285]

AGCACACTGGAAATCGCCGGACTCGTGCGGAAGAACCTGGTGCAGTTTGGCGTGGGCGAGAAGAACGGCTGTGTCAGA

TGGGTCATGAACGCCCTGGGCGTGAAGGACGATTGGCTGCTGGTTCCTAGCCACGCCTACAAGTTCGAGAAGGACTAC

GAGATGATGGAATTCTACTTCAACAGAGGCGGCACCTACTACAGCATCAGCGCCGGCAATGTGGTCATCCAGTCTCTG

GATGTGGGCTTCCAGGACGTGGTGCTGATGAAGGTGCCAACAATCCCCAAGTTCCGGGACATCACCCAGCACTTCATC

AAGAAAGGCGACGTGCCCAGGGCTCTGAACAGACTGGCTACCCTGGTCACCACCGTGAACGGCACACCCATGCTGATC

TCTGAGGGCCCACTGAAGATGGAAGAGAAGGCCACCTACGTGCACAAGAAGAACGACGGCACCACAGTGGACCTGACC

GTGGATCAAGCTTGGAGAGGCAAAGGCGAGGGCCTGCCTGGAATGTGTGGCGGAGCACTGGTGTCCAGCAACCAGAGC

ATCCAGAATGCCATCCTGGGCATCCATGTGGCTGGCGGCAATTCTATCCTGGTGGCCAAGCTGGTCACCCAAGAGATG

TTCCAGAACATCGACAAGAAGATCGAGAGCCAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 285, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 285 is provided herein as SEQ ID No: 286, as follows:

[SEQ ID No: 286]

AGCACACUGGAAAUCGCCGGACUCGUGCGGAAGAACCUGGUGCAGUUUGGCGUGGGCGAGAAGAACGGCUGUGUCAGA

UGGGUCAUGAACGCCCUGGGCGUGAAGGACGAUUGGCUGCUGGUUCCUAGCCACGCCUACAAGUUCGAGAAGGACUAC

GAGAUGAUGGAAUUCUACUUCAACAGAGGCGGCACCUACUACAGCAUCAGCGCCGGCAAUGUGGUCAUCCAGUCUCUG

GAUGUGGGCUUCCAGGACGUGGUGCUGAUGAAGGUGCCAACAAUCCCCAAGUUCCGGGACAUCACCCAGCACUUCAUC

AAGAAAGGCGACGUGCCCAGGGCUCUGAACAGACUGGCUACCCUGGUCACCACCGUGAACGGCACACCCAUGCUGAUC

UCUGAGGGCCCACUGAAGAUGGAAGAGAAGGCCACCUACGUGCACAAGAAGAACGACGGCACCACAGUGGACCUGACC

GUGGAUCAAGCUUGGAGAGGCAAAGGCGAGGGCCUGCCUGGAAUGUGUGGCGGAGCACUGGUGUCCAGCAACCAGAGC

AUCCAGAAUGCCAUCCUGGGCAUCCAUGUGGCUGGCGGCAAUUCUAUCCUGGUGGCCAAGCUGGUCACCCAAGAGAUG

UUCCAGAACAUCGACAAGAAGAUCGAGAGCCAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 286, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Human metapneumovirus M2-2 (Q6WB96; Protein M2-2 Human metapneumovirus (strain CAN97-83)), or an orthologue thereof. One embodiment of the polypeptide sequence of Human metapneumovirus M2-2 is represented herein as SEQ ID No: 287, as follows:

[SEQ ID No: 287]

MTLHMPCKTVKALIKCSEHGPVFITIEVDEMIWTQKELKEALSDGIVKS

HTNIYNCYLENIEITYVKAYLS

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 287, or a variant or fragment thereof.

In one embodiment, the Human metapneumovirus M2-2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 288, as follows:

[SEQ ID No: 288]

ATGACTCTTCATATGCCCTGCAAGACAGTGAAAGCATTAATCAAGTGCAGTGAGCATGGTCCTGTTTTCATTACTATA

GAGGTTGATGAAATGATATGGACTCAAAAAGAATTAAAAGAAGCTTTGTCCGATGGGATAGTGAAGTCTCACACCAAC

ATTTACAATTGTTATTTAGAAAACATAGAAATTATATATGTCAAGGCTTACTTAAGT

Accordingly, preferably the Human metapneumovirus M2-2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 288, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Human metapneumovirus M2-2 polypeptide is provided herein as SEQ ID No: 289, as follows:

[SEQ ID No: 289]

ATGACCCTGCACATGCCCTGCAAGACAGTGAAGGCCCTGATCAAGTGTAGCGAGCACGGCCCCGTGTTCATCACCATT

GAGGTGGACGAGATGATCTGGACCCAGAAAGAGCTGAAAGAGGCCCTGAGCGACGGCATCGTGAAGTCCCACACCAAC

ATCTACAACTGCTACCTCGAGAACATCGAGATCATCTACGTGAAGGCCTACCTGAGC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 289, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 289 is provided herein as SEQ ID No: 290, as follows:

[SEQ ID No: 290]

AUGACCCUGCACAUGCCCUGCAAGACAGUGAAGGCCCUGAUCAAGUGUAGCGAGCACGGCCCCGUGUUCAUCACCAUU

GAGGUGGACGAGAUGAUCUGGACCCAGAAAGAGCUGAAAGAGGCCCUGAGCGACGGCAUCGUGAAGUCCCACACCAAC

AUCUACAACUGCUACCUCGAGAACAUCGAGAUCAUCUACGUGAAGGCCUACCUGAGC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 290, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Hepatitis E methyltransferase (Q9WC28; Non-structural polyprotein pORF1 Methyltransferase Hepatitis E virus genotype 1), or an orthologue thereof. One embodiment of the polypeptide sequence of Hepatitis E methyltransferase is represented herein as SEQ ID No: 291, as follows:

[SEQ ID No: 291]

EVFWNQPIQRVIHNELELYCRARSGRCLEIGAHPRSINDNPNVVHRCFLRPVGRDVQRWYTAPTRGPAANCRRSALRG

LPAADRTYCFDGFSGCSCPAETGIALYSLHDMSPSDVAEAMFRHGMTRLYAALHLPPEVLLPPGTYRTASYLLIHDGR

RVVVTYEGDTSAGYNHDVSNLRSWI

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 291, or a variant or fragment thereof.

In one embodiment, the Hepatitis E methyltransferase polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 292, as follows:

[SEQ ID No: 292]

GAGGTTTTCTGGAATCAACCCATCCAGCGTGTCATTCATAACGAGCTGGAGCTTTACTGCCGCGCTCGCTCCGGCCGC

TGTCTTGAAATTGGCGCCCATCCCCGCTCAATAAATGATAATCCTAATGTGGTCCACCGCTGCTTCCTCCGCCCTGTT

GGGCGTGATGTTCAGCGCTGGTATACTGCTCCCACTCGCGGGCCGGCTGCTAATTGCCGCCGTTCCGCGTTGCGTGGG

CTTCCCGCTGCTGACCGCACATACTGCTTCGACGGGTTTTCTGGCTGTAGCTGCCCCGCCGAGACGGGTATCGCCCTT

TACTCCCTCCATGATATGTCACCATCTGATGTTGCCGAGGCCATGTTCCGCCATGGTATGACGCGGCTTTATGCTGCC

CTCCATCTTCCGCCTGAGGTCTTGCTGCCCCCTGGCACATATCGCACCGCATCGTATTTGCTGATTCATGACGGCAGG

CGCGTTGTGGTGACGTATGAGGGTGATACTAGTGCTGGTTACAACCACGATGTCTCCAACTTGCGCTCCTGGATT

Accordingly, preferably the Hepatitis E methyltransferase polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 292, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Hepatitis E methyltransferase polypeptide is provided herein as SEQ ID No: 293, as follows:

[SEQ ID No: 293]

GAGGTGTTCTGGAACCAGCCTATCCAGAGAGTGATCCACAACGAGCTGGAACTGTACTGCAGAGCCAGATCCGGCCGG

TGTCTGGAAATTGGAGCCCATCCTCGGAGCATCAACGACAACCCCAACGTGGTGCACAGATGCTTTCTGAGGCCCGTG

GGCAGAGATGTGCAGCGGTGGTATACAGCCCCTACAAGAGGACCTGCCGCCAACTGTAGAAGAAGCGCCCTGAGAGGA

CTGCCTGCCGCCGATAGAACCTACTGCTTCGATGGCTTCAGCGGCTGCAGCTGTCCTGCCGAAACTGGAATCGCCCTG

TACAGCCTGCACGACATGAGCCCATCTGATGTGGCCGAGGCCATGTTCAGACACGGCATGACCAGACTGTACGCCGCT

CTGCATCTGCCTCCAGAAGTTCTGCTGCCTCCTGGCACCTACAGAACCGCCAGCTATCTGCTGATCCACGATGGGAGA

AGAGTGGTGGTCACCTACGAGGGCGATACAAGCGCCGGCTACAACCACGACGTGTCCAACCTGAGAAGCTGGATC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 293, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 293 is provided herein as SEQ ID No: 294, as follows:

[SEQ ID No: 294]

GAGGUGUUCUGGAACCAGCCUAUCCAGAGAGUGAUCCACAACGAGCUGGAACUGUACUGCAGAGCCAGAUCCGGCCGG

UGUCUGGAAAUUGGAGCCCAUCCUCGGAGCAUCAACGACAACCCCAACGUGGUGCACAGAUGCUUUCUGAGGCCCGUG

GGCAGAGAUGUGCAGCGGUGGUAUACAGCCCCUACAAGAGGACCUGCCGCCAACUGUAGAAGAAGCGCCCUGAGAGGA

CUGCCUGCCGCCGAUAGAACCUACUGCUUCGAUGGCUUCAGCGGCUGCAGCUGUCCUGCCGAAACUGGAAUCGCCCUG

UACAGCCUGCACGACAUGAGCCCAUCUGAUGUGGCCGAGGCCAUGUUCAGACACGGCAUGACCAGACUGUACGCCGCU

CUGCAUCUGCCUCCAGAAGUUCUGCUGCCUCCUGGCACCUACAGAACCGCCAGCUAUCUGCUGAUCCACGAUGGGAGA

AGAGUGGUGGUCACCUACGAGGGCGAUACAAGCGCCGGCUACAACCACGACGUGUCCAACCUGAGAAGCUGGAUC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 294, or a fragment or variant thereof.

In one embodiment, the at least one IIP is PRRV Npro (P24381; Serine/threonine-protein kinase US3 homolog Suid herpesvirus 2 (strain NIA-3) Pseudorabies Virus), or an orthologue thereof. One embodiment of the polypeptide sequence of PRRV Npro is represented herein as SEQ ID No: 295, as follows:

[SEQ ID No: 295]

MLAMWRWVTKRSRLRRGHAHLGGNKGVRGICSLYLAGLSRGLSRVHAQRSHAATMADAGIPDEILYSDISDDEIIIDG

DGDGDSSGDEDDDDGGLTRQAASRIATDLGFEVLQPLQSGSEGRVFVARRPGEADTVVLKVGQKPSTLMEGMLLKRLA

HDNVMSLKQMLARGPVTCLVLPHFRCDLYSYLTMRDGPLDMRDAGRVIRSVLRGLAYLHGMRIMHRDVKAENIFLEDV

DTVCLGDLGAARCNVAAPNFYGLAGTIETNAPEVLARDRYDTKVDVWGAGVVLFETLAYPKTIAGGDEPAINGEMHLI

DLIRALGVHPEEFPPDTRLRSEFVRYAGTHRQPYTQYARVARLGLPETGAFLIYKMLTFDPVRRPSADEILNFGMWTV

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 295, or a variant or fragment thereof.

In one embodiment, the PRRV Npro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 296, as follows:

[SEQ ID No: 296]

ATGCTGGCGATGTGGAGATGGGTCACCAAGAGGTCGCGGCTCCGCCGAGGCCACGCCCATCTTGGGGGAAATAAAGGA

GTCCGGGGAATTTGTTCCTTATACCTTGCCGGGCTCAGCAGGGGGTTGTCGCGCGTCCACGCCCAGCGCTCGCACGCA

GCAACAATGGCCGACGCCGGAATCCCCGACGAGATCCTGTACTCGGACATCAGCGACGACGAGATCATCATCGACGGC

GACGGCGACGGCGACAGCAGCGGGGACGAGGACGACGATGACGGGGGGCTGACGCGGCAGGCCGCGTCGCGCATCGCC

ACGGACCTGGGCTTCGAGGTGCTGCAGCCCCTGCAGTCGGGCTCGGAGGGCCGCGTCTTCGTGGCCCGCCGGCCCGGC

GAGGCGGACACGGTGGTGCTGAAGGTGGGCCAGAAGCCCTCGACGCTGATGGAGGGCATGCTGCTGAAGCGCCTGGCC

CACGATAACGTCATGAGCCTGAAGCAGATGCTCGCCCGGGGCCCGGTGACGTGCCTGGTCCTGCCGCACTTTCGGTGC

GATCTGTACAGCTACCTGACCATGCGGGACGGGCCGCTGGACATGCGCGACGCCGGGCGCGTGATCCGGTCCGTGCTC

CGCGGGCTCGCCTACCTGCACGGGATGCGCATCATGCACCGCGACGTCAAGGCGGAGAACATCTTCCTCGAGGACGTG

GACACGGTGTGCCTGGGGGACCTCGGGGCCGCGCGCTGCAACGTGGCGGCGCCCAACTTTTACGGGCTCGCCGGGACC

ATCGAGACCAACGCCCCCGAGGTGCTCGCGCGCGACCGCTACGACACCAAGGTCGACGTCTGGGGCGCGGGGGTGGTG

CTCTTCGAGACGCTGGCCTACCCCAAGACGATCGCCGGCGGGGACGAGCCCGCGATCAACGGGGAGATGCACCTGATC

GACCTCATCCGCGCCCTCGGGGTGCACCCCGAGGAGTTCCCGCCCGACACGCGCCTCCGGAGCGAGTTCGTCCGGTAC

GCCGGGACCCACCGCCAGCCGTACACGCAGTACGCGCGCGTGGCTCGCCTCGGGCTGCCCGAGACGGGGGCTTTCCTG

ATTTACAAGATGTTGACGTTTGATCCCGTCCGCCGCCCTTCCGCTGATGAGATACTCAACTTTGGAATGTGGACCGTA

Accordingly, preferably the PRRV Npro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 296, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the PRRV Npro polypeptide is provided herein as SEQ ID No: 297, as follows:

[SEQ ID No: 297]

ATGCTGGCCATGTGGCGCTGGGTCACCAAGAGAAGCAGACTGAGAAGAGGACACGCCCACCTCGGCGGAAACAAGGGC

GTTAGAGGCATCTGCAGCCTGTATCTGGCCGGCCTGTCTAGAGGACTGAGCAGAGTGCATGCCCAGAGATCTCACGCC

GCCACAATGGCCGATGCTGGCATCCCTGATGAGATCCTGTACAGCGACATCAGCGACGACGAGATCATCATCGATGGC

GACGGCGACGGGGATAGCAGCGGAGATGAGGATGACGATGATGGCGGCCTGACAAGACAGGCTGCCAGCAGAATTGCC

ACCGACCTGGGATTTGAGGTGCTGCAGCCTCTGCAGTCTGGCTCTGAGGGCAGAGTGTTCGTGGCTAGAAGGCCTGGC

GAAGCCGATACCGTGGTGCTGAAAGTGGGCCAGAAACCTAGCACACTGATGGAAGGCATGCTGCTGAAGAGACTGGCC

CACGACAACGTGATGAGCCTGAAGCAGATGCTGGCTAGAGGCCCTGTGACCTGTCTGGTGCTGCCTCACTTCAGATGC

GACCTGTACTCCTACCTGACCATGAGAGATGGCCCTCTGGATATGCGCGACGCCGGCAGAGTGATCAGATCTGTGCTG

AGAGGCCTGGCCTACCTGCACGGCATGAGAATCATGCACAGGGACGTGAAGGCCGAGAACATCTTTCTGGAAGATGTG

GACACCGTGTGCCTGGGCGATCTGGGAGCCGCTAGATGTAATGTGGCCGCTCCTAACTTCTACGGCCTGGCCGGAACC

ATCGAGACAAATGCCCCTGAAGTGCTGGCCCGGGACAGATACGATACCAAGGTGGACGTTTGGGGAGCCGGCGTGGTC

CTGTTTGAGACACTGGCTTACCCCAAGACAATCGCTGGCGGCGACGAGCCTGCTATCAATGGCGAGATGCACCTGATC

GACCTGATCAGAGCCCTGGGCGTGCACCCTGAGGAATTCCCTCCAGACACACGGCTGCGGAGCGAGTTCGTTAGATAC

GCCGGAACACACAGACAGCCCTACACACAGTATGCCAGAGTGGCCAGACTGGGCCTGCCTGAAACAGGCGCCTTCCTG

ATCTACAAGATGCTGACCTTCGATCCCGTGCGGAGGCCTTCTGCCGATGAGATTCTGAACTTCGGCATGTGGACCGTG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 297, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 297 is provided herein as SEQ ID No: 298, as follows:

[SEQ ID No: 298]

AUGCUGGCCAUGUGGCGCUGGGUCACCAAGAGAAGCAGACUGAGAAGAGGACACGCCCACCUCGGCGGAAACAAGGGC

GUUAGAGGCAUCUGCAGCCUGUAUCUGGCCGGCCUGUCUAGAGGACUGAGCAGAGUGCAUGCCCAGAGAUCUCACGCC

GCCACAAUGGCCGAUGCUGGCAUCCCUGAUGAGAUCCUGUACAGCGACAUCAGCGACGACGAGAUCAUCAUCGAUGGC

GACGGCGACGGGGAUAGCAGCGGAGAUGAGGAUGACGAUGAUGGCGGCCUGACAAGACAGGCUGCCAGCAGAAUUGCC

ACCGACCUGGGAUUUGAGGUGCUGCAGCCUCUGCAGUCUGGCUCUGAGGGCAGAGUGUUCGUGGCUAGAAGGCCUGGC

GAAGCCGAUACCGUGGUGCUGAAAGUGGGCCAGAAACCUAGCACACUGAUGGAAGGCAUGCUGCUGAAGAGACUGGCC

CACGACAACGUGAUGAGCCUGAAGCAGAUGCUGGCUAGAGGCCCUGUGACCUGUCUGGUGCUGCCUCACUUCAGAUGC

GACCUGUACUCCUACCUGACCAUGAGAGAUGGCCCUCUGGAUAUGCGCGACGCCGGCAGAGUGAUCAGAUCUGUGCUG

AGAGGCCUGGCCUACCUGCACGGCAUGAGAAUCAUGCACAGGGACGUGAAGGCCGAGAACAUCUUUCUGGAAGAUGUG

GACACCGUGUGCCUGGGCGAUCUGGGAGCCGCUAGAUGUAAUGUGGCCGCUCCUAACUUCUACGGCCUGGCCGGAACC

AUCGAGACAAAUGCCCCUGAAGUGCUGGCCCGGGACAGAUACGAUACCAAGGUGGACGUUUGGGGAGCCGGCGUGGUC

CUGUUUGAGACACUGGCUUACCCCAAGACAAUCGCUGGCGGCGACGAGCCUGCUAUCAAUGGCGAGAUGCACCUGAUC

GACCUGAUCAGAGCCCUGGGCGUGCACCCUGAGGAAUUCCCUCCAGACACACGGCUGCGGAGCGAGUUCGUUAGAUAC

GCCGGAACACACAGACAGCCCUACACACAGUAUGCCAGAGUGGCCAGACUGGGCCUGCCUGAAACAGGCGCCUUCCUG

AUCUACAAGAUGCUGACCUUCGAUCCCGUGCGGAGGCCUUCUGCCGAUGAGAUUCUGAACUUCGGCAUGUGGACCGUG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 298, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HSV1 US3 (P04413; Serine/threonine-protein kinase US3 Human herpesvirus 1 (strain 17)), or an orthologue thereof. One embodiment of the polypeptide sequence of HSV1 US3 is represented herein as SEQ ID No: 299, as follows:

[SEQ ID No: 299]

MACRKFCRVYGGQGRRKEEAVPPETKPSRVFPHGPFYTPAEDACLDSPPPETPKPSHTTPPSEAERLCHLQEILAQMY

GNQDYPIEDDPSADAADDVDEDAPDDVAYPEEYAEELFLPGDATGPLIGANDHIPPPCGASPPGIRRRSRDEIGATGF

TAEELDAMDREAARAISRGGKPPSTMAKLVTGMGFTIHGALTPGSEGCVFDSSHPDYPQRVIVKAGWYTSTSHEARLL

RRLDHPAILPLLDLHVVSGVTCLVLPKYQADLYTYLSRRLNPLGRPQIAAVSROLLSAVDYIHRQGIIHRDIKTENIF

INTPEDICLGDFGAACFVQGSRSSPFPYGIAGTIDTNAPEVLAGDPYTTTVDIWSAGLVIFETAVHNASLFSAPRGPK

RGPCDSQITRIIRQAQVHVDEFSPHPESRLTSRYRSRAAGNNRPPYTRPAWTRYYKMDIDVEYLVCKALTFDGALRPS

AAELLCLPLFQQK

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 299, or a variant or fragment thereof.

In one embodiment, the HSV1 US3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 300, as follows:

[SEQ ID No: 300]

ATGGCCTGTCGTAAGTTTTGTCGCGTTTACGGGGGACAGGGCAGGAGGAAGGAGGAGGCCGTCCCGCCGGAGACAAAG

CCGTCCCGGGTGTTTCCTCATGGCCCCTTTTATACCCCAGCCGAGGACGCGTGCCTGGACTCCCCGCCCCCGGAGACC

CCCAAACCTTCCCACACCACACCACCCAGCGAGGCCGAGCGCCTGTGTCATCTGCAGGAGATCCTTGCCCAGATGTAC

GGAAACCAGGACTACCCCATAGAGGACGACCCCAGCGCGGATGCCGCGGACGATGTCGACGAGGACGCCCCGGACGAC

GTGGCCTATCCGGAGGAATACGCAGAGGAGCTTTTTCTGCCCGGGGACGCGACCGGTCCCCTTATCGGGGCCAACGAC

CACATCCCTCCCCCGTGTGGCGCATCTCCCCCCGGTATACGACGACGCAGCCGGGATGAGATTGGGGCCACGGGATTT

ACCGCGGAAGAGCTGGACGCCATGGACAGGGAGGCGGCTCGAGCCATCAGCCGCGGCGGCAAGCCCCCCTCGACCATG

GCCAAGCTGGTGACTGGCATGGGCTTTACGATCCACGGAGCGCTCACCCCAGGATCGGAGGGGTGTGTCTTTGACAGC

AGCCATCCAGATTACCCCCAACGGGTAATCGTGAAGGCGGGGTGGTACACGAGCACGAGCCACGAGGCGCGACTGCTG

AGGCGACTGGACCACCCGGCGATCCTGCCCCTCCTGGACCTGCATGTCGTCTCCGGGGTCACGTGTCTGGTCCTCCCC

AAGTACCAGGCCGACCTGTATACCTATCTGAGTAGGCGCCTGAACCCACTGGGACGCCCGCAGATCGCAGCGGTCTCC

CGGCAGCTCCTAAGCGCCGTTGACTACATTCACCGCCAGGGCATTATCCACCGCGACATTAAGACCGAAAATATTTTT

ATTAACACCCCCGAGGACATTTGCCTGGGGGACTTTGGCGCCGCGTGCTTCGTGCAGGGTTCCCGATCAAGCCCCTTC

CCCTACGGAATCGCCGGAACCATCGACACCAACGCCCCCGAGGTCCTGGCCGGGGATCCGTATACCACGACCGTCGAC

ATTTGGAGCGCCGGTCTGGTGATCTTCGAGACTGCCGTCCACAACGCGTCCTTGTTCTCGGCCCCCCGCGGCCCCAAA

AGGGGCCCGTGCGACAGTCAGATCACCCGCATCATCCGACAGGCCCAGGTCCACGTTGACGAGTTTTCCCCGCATCCA

GAATCGCGCCTCACCTCGCGCTACCGCTCCCGCGCGGCCGGGAACAATCGCCCGCCGTACACCCGACCGGCCTGGACC

CGCTACTACAAGATGGACATAGACGTCGAATATCTGGTTTGCAAAGCCCTCACCTTCGACGGCGCGCTTCGCCCCAGC

GCCGCAGAGCTGCTTTGTTTGCCGCTGTTTCAACAGAAA

Accordingly, preferably the HSV1 US3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 300, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HSV1 US3 polypeptide is provided herein as SEQ ID No: 301, as follows:

[SEQ ID No: 301]

ATGGCCTGCCGGAAGTTCTGTAGAGTGTACGGCGGACAGGGGCGCAGAAAAGAGGAAGCCGTTCCTCCTGAGACAAAG

CCCAGCAGAGTGTTCCCTCACGGCCCCTTTTACACCCCTGCCGAAGATGCCTGTCTGGACAGCCCTCCTCCAGAAACA

CCTAAGCCTAGCCACACCACACCTCCAAGCGAGGCCGAAAGACTGTGCCATCTGCAAGAGATTCTGGCCCAGATGTAC

GGCAACCAGGACTACCCCATCGAGGACGATCCATCTGCCGATGCCGCCGACGATGTGGATGAAGATGCCCCTGATGAC

GTGGCCTATCCTGAGGAATACGCCGAGGAACTGTTCCTGCCTGGCGACGCTACAGGACCTCTGATCGGAGCCAACGAT

CACATCCCTCCACCTTGTGGCGCTAGCCCTCCTGGCATCAGAAGAAGAAGCAGGGACGAGATCGGCGCCACCGGCTTT

ACAGCCGAAGAACTGGACGCCATGGACAGAGAAGCCGCCAGAGCCATTTCTAGAGGCGGCAAGCCTCCTAGCACCATG

GCCAAACTGGTTACCGGCATGGGCTTCACCATTCACGGCGCTCTGACACCTGGCTCTGAGGGCTGTGTGTTCGACAGC

TCTCACCCCGACTATCCCCAGCGCGTGATCGTGAAAGCCGGCTGGTACACAAGCACAAGCCACGAGGCCAGACTGCTG

CGGAGACTGGATCATCCTGCCATCCTGCCTCTGCTGGATCTGCATGTGGTGTCCGGCGTGACATGTCTGGTGCTGCCT

AAGTACCAGGCCGACCTGTACACCTACCTGAGCAGAAGGCTGAACCCTCTGGGCAGACCTCAGATTGCCGCTGTGTCA

AGACAGCTGCTGAGCGCTGTGGACTACATCCACAGACAGGGCATCATCCACCGGGACATCAAGACCGAGAATATCTTC

ATCAACACGCCCGAGGACATCTGCCTGGGCGATTTTGGCGCCGCTTGCTTCGTGCAAGGCAGCAGAAGCAGCCCCTTT

CCTTATGGAATCGCCGGCACCATCGACACAAACGCCCCTGAAGTTCTGGCCGGCGATCCTTACACCACCACCGTGGAT

ATTTGGAGCGCCGGACTGGTCATCTTCGAGACAGCCGTGCATAACGCCAGCCTGTTCTCTGCCCCTAGAGGCCCTAAA

AGAGGCCCCTGCGATAGCCAGATCACCCGGATCATTAGACAGGCCCAGGTGCACGTGGACGAGTTCTCTCCACATCCT

GAGAGCCGGCTGACCAGCCGGTACAGATCTAGAGCCGCCGGAAACAACCGGCCTCCATACACAAGACCTGCCTGGACA

CGGTACTACAAGATGGACATCGACGTGGAATACCTCGTGTGCAAGGCCCTGACCTTCGATGGCGCCCTTAGACCTTCT

GCCGCCGAACTGCTTTGCCTGCCACTGTTCCAGCAGAAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 301, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 301 is provided herein as SEQ ID No: 302, as follows:

[SEQ ID No: 302]

AUGGCCUGCCGGAAGUUCUGUAGAGUGUACGGCGGACAGGGGCGCAGAAAAGAGGAAGCCGUUCCUCCUGAGACAAAG

CCCAGCAGAGUGUUCCCUCACGGCCCCUUUUACACCCCUGCCGAAGAUGCCUGUCUGGACAGCCCUCCUCCAGAAACA

CCUAAGCCUAGCCACACCACACCUCCAAGCGAGGCCGAAAGACUGUGCCAUCUGCAAGAGAUUCUGGCCCAGAUGUAC

GGCAACCAGGACUACCCCAUCGAGGACGAUCCAUCUGCCGAUGCCGCCGACGAUGUGGAUGAAGAUGCCCCUGAUGAC

GUGGCCUAUCCUGAGGAAUACGCCGAGGAACUGUUCCUGCCUGGCGACGCUACAGGACCUCUGAUCGGAGCCAACGAU

CACAUCCCUCCACCUUGUGGCGCUAGCCCUCCUGGCAUCAGAAGAAGAAGCAGGGACGAGAUCGGCGCCACCGGCUUU

ACAGCCGAAGAACUGGACGCCAUGGACAGAGAAGCCGCCAGAGCCAUUUCUAGAGGCGGCAAGCCUCCUAGCACCAUG

GCCAAACUGGUUACCGGCAUGGGCUUCACCAUUCACGGCGCUCUGACACCUGGCUCUGAGGGCUGUGUGUUCGACAGC

UCUCACCCCGACUAUCCCCAGCGCGUGAUCGUGAAAGCCGGCUGGUACACAAGCACAAGCCACGAGGCCAGACUGCUG

CGGAGACUGGAUCAUCCUGCCAUCCUGCCUCUGCUGGAUCUGCAUGUGGUGUCCGGCGUGACAUGUCUGGUGCUGCCU

AAGUACCAGGCCGACCUGUACACCUACCUGAGCAGAAGGCUGAACCCUCUGGGCAGACCUCAGAUUGCCGCUGUGUCA

AGACAGCUGCUGAGCGCUGUGGACUACAUCCACAGACAGGGCAUCAUCCACCGGGACAUCAAGACCGAGAAUAUCUUC

AUCAACACGCCCGAGGACAUCUGCCUGGGCGAUUUUGGCGCCGCUUGCUUCGUGCAAGGCAGCAGAAGCAGCCCCUUU

CCUUAUGGAAUCGCCGGCACCAUCGACACAAACGCCCCUGAAGUUCUGGCCGGCGAUCCUUACACCACCACCGUGGAU

AUUUGGAGCGCCGGACUGGUCAUCUUCGAGACAGCCGUGCAUAACGCCAGCCUGUUCUCUGCCCCUAGAGGCCCUAAA

AGAGGCCCCUGCGAUAGCCAGAUCACCCGGAUCAUUAGACAGGCCCAGGUGCACGUGGACGAGUUCUCUCCACAUCCU

GAGAGCCGGCUGACCAGCCGGUACAGAUCUAGAGCCGCCGGAAACAACCGGCCUCCAUACACAAGACCUGCCUGGACA

CGGUACUACAAGAUGGACAUCGACGUGGAAUACCUCGUGUGCAAGGCCCUGACCUUCGAUGGCGCCCUUAGACCUUCU

GCCGCCGAACUGCUUUGCCUGCCACUGUUCCAGCAGAAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 302, or a fragment or variant thereof.

In one embodiment, the at least one HP is HSV2 US1 (A0A290Y3Z3; A0A290Y3Z3 HHV2 US1 Human herpesvirus 2), or an orthologue thereof. One embodiment of the polypeptide sequence of HSV2 US1 is represented herein as SEQ ID No: 303, as follows:

[SEQ ID No: 303]

MADIPPDPPALNTTPVNHAPPSPPPGSRKRRRPVLPSSSESEGKPDTESESSSTESSEDEAGDLRGGRRRSPRELGGR

YFLDLSAESTTGTESEGTGPSDDDDDDASDGWLVDTPPRKSKRPRINLRLTSSPDRRAGVVFPEVWRNDRPIRAAQPQ

APAQSSGDRAAAPRRSARQAQMRSGAAWTLDLHYIRQCVNQLFRILRAAPNPPGSANRLRHLVRDCYLMGYCRTRLGP

RTWGRLLQISGGTWDVRLRNAIREVEARFEPAAEPVCELPCLNARRYGPECDVGNLETNGGSTSDDEISDATDSDDTL

ASHSDTEGGPSPAGRENPESASGGAIAARLECEFGTFDWTSEEGSQPWLSAVVADTSSAERSGLPAPGACRATEAPER

EDGCRKMRFPAACPYPCGHTFLRP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 303, or a variant or fragment thereof.

In one embodiment, the HSV2 US1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 304, as follows:

[SEQ ID No: 304]

ATGGCAGACATCCCCCCGGACCCGCCCGCGCTCAACACGACGCCTGTGAATCATGCTCCCCCATCCCCGCCCCCGGGT

TCACGGAAGCGCAGACGCCCCGTCCTCCCCAGCTCGTCGGAATCTGAGGGTAAGCCCGACACAGAATCGGAATCCTCC

TCGACCGAGTCGTCCGAGGATGAGGCGGGAGACCTACGCGGCGGGCGCCGTCGCTCCCCGCGGGAGCTCGGGGGGAGG

TATTTTTTGGATCTGTCGGCAGAATCGACCACGGGGACGGAATCGGAGGGAACGGGGCCGTCGGACGACGATGATGAT

GATGCGTCAGACGGCTGGTTGGTTGACACCCCCCCCCGTAAATCCAAGCGACCCCGAATCAACCTGCGATTAACGAGC

TCCCCCGACCGGCGCGCGGGTGTGGTTTTCCCCGAGGTGTGGAGAAACGACAGACCTATCCGCGCGGCGCAACCCCAG

GCCCCGGCCCAGTCTTCCGGGGATCGCGCAGCCGCACCGCGGCGCTCTGCTCGCCAGGCCCAGATGCGGAGCGGAGCC

GCCTGGACGCTTGATCTGCATTACATACGCCAGTGCGTCAACCAGCTCTTTCGGATCCTGCGTGCCGCCCCGAACCCG

CCCGGCAGCGCCAACCGCCTGCGCCACCTGGTGCGAGACTGCTACCTCATGGGCTACTGCCGGACCCGCCTGGGGCCG

CGCACGTGGGGCCGCCTGCTGCAGATCTCGGGCGGAACCTGGGACGTGCGCCTGCGAAACGCAATCCGGGAGGTCGAG

GCGCGTTTTGAACCCGCCGCCGAGCCCGTGTGCGAGCTGCCCTGTCTGAACGCCAGGCGTTACGGCCCCGAGTGTGAT

GTTGGCAATCTCGAGACCAACGGCGGCTCGACGAGCGATGATGAGATATCGGATGCGACGGACTCGGACGATACCCTC

GCGTCCCATTCCGACACGGAGGGGGGGCCCTCCCCGGCCGGCCGGGAGAACCCGGAATCCGCGTCCGGCGGGGCTATC

GCGGCTCGGCTGGAGTGTGAGTTTGGGACGTTTGACTGGACGTCCGAGGAGGGCTCCCAGCCCTGGCTGTCCGCGGTG

GTCGCCGATACCAGCTCCGCCGAACGCTCTGGCCTACCCGCCCCGGGCGCGTGTCGCGCAACGGAAGCCCCAGAACGC

GAGGACGGGTGCCGAAAAATGCGCTTCCCCGCCGCCTGCCCCTATCCCTGCGGCCACACATTTCTCCGGCCA

Accordingly, preferably the HSV2 US1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 304, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HSV2 US1 polypeptide is provided herein as SEQ ID No: 305, as follows:

[SEQ ID No: 305]

ATGGCCGACATTCCTCCTGATCCTCCAGCTCTGAACACCACACCTGTGAATCACGCCCCTCCATCTCCACCACCTGGC

AGCAGAAAGAGAAGAAGGCCTGTCCTGCCTAGCAGCAGCGAGTCTGAGGGCAAGCCTGATACAGAGAGCGAGAGCAGC

AGCACAGAGAGCAGCGAGGACGAAGCTGGCGATCTTAGAGGCGGCAGAAGAAGAAGCCCCAGAGAACTCGGCGGCAGA

TACTTCCTGGATCTGAGCGCCGAGAGCACCACCGGCACTGAATCTGAAGGCACAGGCCCCAGCGACGACGATGACGAT

GATGCCTCTGATGGCTGGCTGGTGGACACCCCTCCTAGAAAGTCCAAGCGGCCCAGAATCAACCTGCGGCTGACAAGC

TCTCCTGATCGCAGAGCTGGCGTGGTGTTCCCCGAAGTGTGGCGGAACGACAGACCTATCAGAGCCGCTCAGCCTCAG

GCTCCTGCTCAGTCTAGCGGAGATAGAGCTGCCGCTCCTAGAAGATCTGCCAGACAGGCCCAGATGAGAAGCGGAGCT

GCTTGGACACTGGACCTGCACTACATCCGGCAGTGCGTGAACCAGCTGTTCCGGATCCTTCGGGCTGCCCCTAATCCA

CCTGGCTCCGCCAATAGACTGAGACACCTTGTGCGGGACTGCTACCTGATGGGCTACTGCAGAACAAGACTGGGCCCC

AGAACATGGGGCAGACTGCTGCAAATCTCTGGCGGCACATGGGACGTGCGGCTGAGAAACGCCATTAGAGAGGTGGAA

GCCAGATTCGAGCCAGCCGCTGAGCCTGTGTGTGAACTGCCTTGTCTGAACGCTCGGAGATACGGCCCCGAGTGTGAT

GTGGGCAACCTGGAAACAAATGGCGGCAGCACCTCCGACGACGAGATCTCTGATGCCACCGACAGCGACGATACACTG

GCCAGCCACAGCGATACAGAAGGCGGACCATCTCCTGCCGGAAGAGAGAATCCTGAGTCTGCCTCTGGCGGAGCTATC

GCCGCAAGACTGGAATGCGAGTTCGGCACCTTCGACTGGACAAGCGAGGAAGGCTCTCAGCCTTGGCTGTCTGCTGTG

GTGGCCGATACCTCTAGCGCCGAAAGATCTGGACTTCCTGCTCCTGGCGCCTGCAGAGCTACAGAAGCTCCTGAAAGA

GAGGACGGCTGCAGAAAGATGCGGTTCCCTGCCGCCTGTCCTTATCCTTGCGGCCACACATTTCTGCGGCCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 305, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 305 is provided herein as SEQ ID No: 306, as follows:

[SEQ ID No: 306]

AUGGCCGACAUUCCUCCUGAUCCUCCAGCUCUGAACACCACACCUGUGAAUCACGCCCCUCCAUCUCCACCACCUGGC

AGCAGAAAGAGAAGAAGGCCUGUCCUGCCUAGCAGCAGCGAGUCUGAGGGCAAGCCUGAUACAGAGAGCGAGAGCAGC

AGCACAGAGAGCAGCGAGGACGAAGCUGGCGAUCUUAGAGGCGGCAGAAGAAGAAGCCCCAGAGAACUCGGCGGCAGA

UACUUCCUGGAUCUGAGCGCCGAGAGCACCACCGGCACUGAAUCUGAAGGCACAGGCCCCAGCGACGACGAUGACGAU

GAUGCCUCUGAUGGCUGGCUGGUGGACACCCCUCCUAGAAAGUCCAAGCGGCCCAGAAUCAACCUGCGGCUGACAAGC

UCUCCUGAUCGCAGAGCUGGCGUGGUGUUCCCCGAAGUGUGGCGGAACGACAGACCUAUCAGAGCCGCUCAGCCUCAG

GCUCCUGCUCAGUCUAGCGGAGAUAGAGCUGCCGCUCCUAGAAGAUCUGCCAGACAGGCCCAGAUGAGAAGCGGAGCU

GCUUGGACACUGGACCUGCACUACAUCCGGCAGUGCGUGAACCAGCUGUUCCGGAUCCUUCGGGCUGCCCCUAAUCCA

CCUGGCUCCGCCAAUAGACUGAGACACCUUGUGCGGGACUGCUACCUGAUGGGCUACUGCAGAACAAGACUGGGCCCC

AGAACAUGGGGCAGACUGCUGCAAAUCUCUGGCGGCACAUGGGACGUGCGGCUGAGAAACGCCAUUAGAGAGGUGGAA

GCCAGAUUCGAGCCAGCCGCUGAGCCUGUGUGUGAACUGCCUUGUCUGAACGCUCGGAGAUACGGCCCCGAGUGUGAU

GUGGGCAACCUGGAAACAAAUGGCGGCAGCACCUCCGACGACGAGAUCUCUGAUGCCACCGACAGCGACGAUACACUG

GCCAGCCACAGCGAUACAGAAGGCGGACCAUCUCCUGCCGGAAGAGAGAAUCCUGAGUCUGCCUCUGGCGGAGCUAUC

GCCGCAAGACUGGAAUGCGAGUUCGGCACCUUCGACUGGACAAGCGAGGAAGGCUCUCAGCCUUGGCUGUCUGCUGUG

GUGGCCGAUACCUCUAGCGCCGAAAGAUCUGGACUUCCUGCUCCUGGCGCCUGCAGAGCUACAGAAGCUCCUGAAAGA

GAGGACGGCUGCAGAAAGAUGCGGUUCCCUGCCGCCUGUCCUUAUCCUUGCGGCCACACAUUUCUGCGGCCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 306, or a fragment or variant thereof.

In one embodiment, the at least one IIP is CSFV NPro (P19712; Genome polyprotein Classical swine fever virus (strain Alfort)), or an orthologue thereof. One embodiment of the polypeptide sequence of CSFV NPro is represented herein as SEQ ID No: 307, as follows:

[SEQ ID No: 307]

MELNHFELLYKTSKQKPVGVEEPVYDTAGRPLFGNPSEVHPQSTLKLPHDRGRGDIRTTLRDLPRKGDCRSGNHLGPV

SGIYIKPGPVYYQDYTGPVYHRAPLEFFDEAQFCEVTKRIGRVTGSDGKLYHIYVCVDGCILLKLAKRGTPRTLKWIR

NFTNCPLWVTSC

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 307, or a variant or fragment thereof.

In one embodiment, the CSFV NPro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 308, as follows:

[SEQ ID No: 308]

ATGGAGTTGAATCATTTTGAATTATTATACAAAACAAGCAAACAAAAACCAGTGGGAGTGGAGGAACCGGTGTATGAC

ACCGCGGGGAGACCACTATTTGGGAACCCAAGTGAGGTACACCCACAATCAACGCTGAAGCTGCCACACGACAGGGGG

AGAGGAGATATCAGAACAACACTGAGGGACCTACCCAGGAAAGGTGACTGTAGGAGTGGCAACCATCTAGGCCCGGTT

AGTGGGATATACATAAAGCCCGGCCCTGTCTACTATCAGGACTACACGGGCCCAGTCTATCACAGAGCTCCTTTAGAG

TTCTTTGATGAGGCCCAGTTCTGCGAGGTGACTAAGAGAATAGGCAGGGTCACGGGTAGTGATGGTAAGCTTTACCAC

ATATATGTGTGCGTCGATGGTTGCATACTGCTGAAATTAGCCAAAAGGGGCACACCCAGAACCCTAAAGTGGATTAGG

AACTTCACCAACTGTCCATTATGGGTAACCAGTTGC

Accordingly, preferably the CSFV NPro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 308, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the CSFV NPro polypeptide is provided herein as SEQ ID No: 309, as follows:

[SEQ ID No: 309]

ATGGAACTGAACCACTTCGAGCTGCTGTACAAGACCAGCAAGCAGAAACCCGTGGGCGTCGAGGAACCCGTGTATGAT

ACAGCTGGCAGACCCCTGTTCGGCAACCCCTCTGAAGTGCACCCTCAGAGCACACTGAAGCTGCCCCACGATAGAGGC

AGAGGCGACATCAGAACCACACTGCGGGACCTGCCTAGAAAGGGCGATTGCAGAAGCGGCAATCATCTGGGCCCTGTG

TCCGGCATCTACATCAAGCCTGGACCAGTGTACTACCAGGACTACACAGGCCCCGTGTACCACAGAGCCCCTCTGGAA

TTCTTCGACGAGGCCCAGTTCTGCGAAGTGACCAAGAGAATCGGCAGAGTGACCGGCTCCGACGGCAAGCTGTACCAC

ATCTACGTGTGCGTGGACGGCTGCATCCTGCTGAAGCTGGCCAAGAGAGGCACCCCTAGAACACTGAAGTGGATCCGG

AACTTCACCAACTGTCCTCTGTGGGTCACCAGCTGC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 309, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 309 is provided herein as SEQ ID No: 310, as follows:

[SEQ ID No: 310]

AUGGAACUGAACCACUUCGAGCUGCUGUACAAGACCAGCAAGCAGAAACCCGUGGGCGUCGAGGAACCCGUGUAUGAU

ACAGCUGGCAGACCCCUGUUCGGCAACCCCUCUGAAGUGCACCCUCAGAGCACACUGAAGCUGCCCCACGAUAGAGGC

AGAGGCGACAUCAGAACCACACUGCGGGACCUGCCUAGAAAGGGCGAUUGCAGAAGCGGCAAUCAUCUGGGCCCUGUG

UCCGGCAUCUACAUCAAGCCUGGACCAGUGUACUACCAGGACUACACAGGCCCCGUGUACCACAGAGCCCCUCUGGAA

UUCUUCGACGAGGCCCAGUUCUGCGAAGUGACCAAGAGAAUCGGCAGAGUGACCGGCUCCGACGGCAAGCUGUACCAC

AUCUACGUGUGCGUGGACGGCUGCAUCCUGCUGAAGCUGGCCAAGAGAGGCACCCCUAGAACACUGAAGUGGAUCCGG

AACUUCACCAACUGUCCUCUGUGGGUCACCAGCUGC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 310, or a fragment or variant thereof.

In one embodiment, the at least one IIP is BDV Npro (A0A290YXI0; Autoprotease p20 Border disease virus), or an orthologue thereof. One embodiment of the polypeptide sequence of BDV Npro is represented herein as SEQ ID No: 311, as follows:

[SEQ ID No: 311]

MELNKFELLYKTSKQRPVGAVEPVYDSAGNPLYGERTTVHPQATLKLPHHRGVAEVITTLKDLPRKGDCRSGNHRGPV

SGIYIKPGPVIYQDYKRPVYHRAPLEQFTKVQICEATKRVGRVTGSDGKLYHLYVCMDGCILLKLASRTVNAVLKWTH

NTLDCPLWVTSC

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 311, or a variant or fragment thereof.

In one embodiment, the BDV Npro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 312, as follows:

[SEQ ID No: 312]

ATGGAGTTGAATAAGTTTGAACTTTTATACAAAACAAGTAAACAAAGACCAGTAGGGGCTGTTGAACCAGTTTATGAC

TCAGCGGGTAACCCCCTATATGGTGAAAGAACAACAGTACACCCGCAAGCCACTCTGAAACTACCACATCACAGGGGA

GTAGCCGAGGTGATAACAACCCTGAAGGATTTGCCCAGGAAAGGAGACTGCAGGAGTGGAAACCATCGAGGCCCAGTG

AGTGGTATATACATCAAGCCAGGTCCAGTCATATACCAGGATTACAAGAGACCGGTGTACCACAGGGCTCCTCTGGAG

CAGTTCACGAAGGTACAAATCTGTGAGGCTACGAAAAGGGTGGGGAGAGTCACTGGCAGCGATGGCAAATTGTACCAC

CTATACGTTTGCATGGATGGTTGCATATTGCTGAAACTGGCAAGCAGGACCGTGAATGCAGTGCTAAAATGGACACAT

AACACTCTGGACTGTCCACTTTGGGTTACAAGCTGC

Accordingly, preferably the BDV Npro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 312, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the BDV Npro polypeptide is provided herein as SEQ ID No: 313, as follows:

[SEQ ID No: 313]

ATGGAACTGAACAAGTTCGAGCTGCTGTACAAGACCAGCAAGCAGAGGCCTGTGGGAGCCGTGGAACCTGTGTATGAT

AGCGCCGGCAATCCCCTGTACGGCGAGAGAACAACAGTGCACCCTCAGGCCACACTGAAGCTGCCTCATCATAGAGGC

GTGGCCGAAGTGATCACAACCCTGAAGGACCTGCCTCGGAAGGGCGATTGCAGAAGCGGCAATCACAGAGGCCCTGTG

TCCGGCATCTACATCAAGCCCGGACCTGTGATCTACCAGGACTACAAGCGGCCCGTGTACCACAGAGCACCCCTGGAA

CAGTTCACCAAGGTGCAGATTTGCGAGGCCACCAAGCGCGTGGGAAGAGTGACAGGCTCTGACGGCAAGCTGTACCAC

CTGTACGTGTGCATGGACGGCTGCATCCTGCTGAAACTGGCCAGCAGAACCGTGAACGCCGTGCTGAAGTGGACCCAC

AACACCCTGGATTGCCCTCTGTGGGTCACCAGCTGT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 313, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 313 is provided herein as SEQ ID No: 314, as follows:

[SEQ ID No: 314]

AUGGAACUGAACAAGUUCGAGCUGCUGUACAAGACCAGCAAGCAGAGGCCUGUGGGAGCCGUGGAACCUGUGUAUGAU

AGCGCCGGCAAUCCCCUGUACGGCGAGAGAACAACAGUGCACCCUCAGGCCACACUGAAGCUGCCUCAUCAUAGAGGC

GUGGCCGAAGUGAUCACAACCCUGAAGGACCUGCCUCGGAAGGGCGAUUGCAGAAGCGGCAAUCACAGAGGCCCUGUG

UCCGGCAUCUACAUCAAGCCCGGACCUGUGAUCUACCAGGACUACAAGCGGCCCGUGUACCACAGAGCACCCCUGGAA

CAGUUCACCAAGGUGCAGAUUUGCGAGGCCACCAAGCGCGUGGGAAGAGUGACAGGCUCUGACGGCAAGCUGUACCAC

CUGUACGUGUGCAUGGACGGCUGCAUCCUGCUGAAACUGGCCAGCAGAACCGUGAACGCCGUGCUGAAGUGGACCCAC

AACACCCUGGAUUGCCCUCUGUGGGUCACCAGCUGU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 314, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Bovine RV NS1 (Q8JZ13; Non-structural protein 1 Bovine Rotavirus A), or an orthologue thereof. One embodiment of the polypeptide sequence of Bovine RV NS1 is represented herein as SEQ ID No: 315, as follows:

[SEQ ID No: 315]

MATFKDACYHYKKLNKLNSLVLKLGANDEWRPAPVTKYKGWCLDCCQYTN

LTYCRGCALYHVCQWCSQYNRCFLDEEPHLLRMRTFKDVVTKEDIEGLLT

MYETLFPINEKLVNKFINSVKQRKCRNEYLLEWYNHLLMPITLQALTINL

EDNVYYMFGYYDCMEHENQTPFQFVNLLEKYDKLLLDDRNFHRMSHLPVI

LQQEYALRYFSKSRFLSKGKKRLSRSDFSDNLMEDRHSPTSLMQVVRNCI

SIHIDDCEWNKACTLIVDARNYISIMNSSYTEHYSVSQRCKLFTKYKFGI

VSKLVKPNYIFSSHESCALNVHNCKWCQINNHYKVWEDFRLRKIYNNVMD

FIRALVKSNVNVGHCSSQESVYKYVPDLFLICKTEKWSEAVEMLFNYLEP

VNVNGTEYVLLDYEVNWEVRGLVMQNMDGKVPRILNMNDTKKILSAMIFD

WFDTRYMRETPMTTSTTNQLRTLNKRNELIDEYDLELSDVE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 315, or a variant or fragment thereof.

In one embodiment, the Bovine RV NS1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 316, as follows:

[SEQ ID No: 316]

ATGGCGACTTTTAAGGACGCTTGTTATCATTATAAAAAGTTGAATAAATT

AAATAGTTTAGTGCTCAAACTAGGAGCAAATGATGAATGGAGGCCAGCAC

CAGTGACAAAATATAAAGGATGGTGTTTAGATTGTTGTCAATATACAAAT

TTGACATATTGCAGAGGGTGCGCTCTATACCATGTATGTCAGTGGTGCAG

TCAGTATAACAGGTGTTTCTTAGATGAAGAACCCCATTTGCTGAGAATGC

GAACATTTAAAGATGTAGTAACAAAAGAAGATATAGAAGGACTGCTAACC

ATGTATGAAACGTTGTTTCCAATAAATGAAAAGTTAGTGAATAAATTCAT

AAACTCTGTGAAGCAGCGTAAGTGTAGGAATGAGTATTTGTTAGAATGGT

ATAACCACTTACTAATGCCAATAACATTGCAAGCATTGACTATAAATCTT

GAGGATAATGTATATTATATGTTTGGATACTATGATTGCATGGAGCATGA

AAACCAAACACCATTCCAATTTGTTAACCTACTAGAAAAATATGATAAAT

TGCTACTAGATGATAGAAATTTCCATAGAATGTCACACTTACCAGTAATA

TTGCAACAAGAGTATGCGTTGAGATATTTTTCAAAATCAAGATTTTTAAG

TAAAGGGAAGAAAAGATTGAGTAGGAGTGATTTCTCAGATAATCTTATGG

AAGATAGACATAGTCCAACATCATTAATGCAAGTGGTACGTAACTGCATC

AGTATACACATAGATGATTGTGAATGGAATAAAGCGTGTACGCTTATAGT

TGATGCTAGAAATTATATTAGTATTATGAATTCATCGTATACTGAGCATT

ACAGTGTGTCACAAAGATGTAAACTGTTCACTAAGTATAAATTTGGGATT

GTATCAAAATTGGTGAAACCGAATTACATTTTTTCTAGCCATGAATCATG

CGCATTAAACGTACACAATTGTAAATGGTGTCAGATCAATAACCATTACA

AAGTGTGGGAAGATTTTAGACTTAGGAAAATATACAATAATGTAATGGAT

TTTATCAGGGCACTTGTGAAATCGAATGTAAACGTTGGACATTGTTCATC

ACAGGAATCAGTGTATAAGTATGTACCGGATTTATTTTTAATTTGTAAAA

CGGAAAAATGGAGCGAAGCTGTCGAAATGTTATTTAATTATCTAGAACCA

GTGAACGTAAATGGAACGGAGTATGTATTATTAGACTATGAAGTGAACTG

GGAAGTGAGGGGACTAGTCATGCAAAACATGGACGGGAAAGTACCAAGAA

TTTTGAATATGAATGATACAAAGAAGATACTGAGTGCAATGATATTTGAC

TGGTTTGACACAAGATATATGAGAGAAACACCAATGACGACGTCAACAAC

AAACCAACTTCGAACACTGAACAAAAGGAATGAGCTCATAGATGAGTACG

ATTTAGAACTTTCAGATGTTGAA

Accordingly, preferably the Bovine RV NS1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 316, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Bovine RV NS1 polypeptide is provided herein as SEQ ID No: 317, as follows:

[SEQ ID No: 317]

ATGGCCACCTTCAAGGACGCCTGCTACCACTACAAGAAGCTGAACAAGCT

GAATAGCCTGGTGCTGAAGCTGGGCGCCAATGATGAATGGCGACCTGCTC

CTGTGACCAAGTACAAAGGCTGGTGCCTGGACTGCTGCCAGTACACCAAT

CTGACCTACTGCAGAGGCTGCGCCCTGTACCACGTCTGTCAGTGGTGCAG

CCAGTACAACCGGTGCTTCCTGGACGAGGAACCCCATCTGCTGCGGATGC

GGACCTTTAAGGACGTGGTCACCAAAGAGGACATCGAGGGCCTGCTGACT

ATGTACGAGACACTGTTCCCCATCAACGAGAAGCTGGTCAACAAGTTCAT

CAACAGCGTGAAGCAGCGGAAGTGCCGGAACGAGTACCTGCTGGAATGGT

ACAATCATCTGCTGATGCCCATCACACTGCAGGCCCTGACCATCAACCTG

GAAGATAACGTGTACTACATGTTCGGCTACTACGACTGCATGGAACACGA

GAATCAGACCCCTTTCCAGTTCGTGAACCTGCTCGAGAAGTACGACAAGC

TGCTGCTGGACGACCGGAACTTCCACCGGATGTCTCATCTGCCCGTGATC

CTGCAGCAAGAGTACGCCCTGCGGTACTTCAGCAAGAGCCGGTTTCTGAG

CAAGGGCAAGAAGCGGCTGAGCAGAAGCGACTTCAGCGACAACCTGATGG

AAGATCGGCACAGCCCCACCAGCCTGATGCAGGTCGTCAGAAACTGCATC

AGCATCCACATCGACGACTGTGAATGGAACAAGGCCTGCACACTGATCGT

GGACGCCCGCAACTACATCTCCATCATGAACAGCAGCTACACCGAGCACT

ACAGCGTGTCCCAGCGGTGCAAGCTGTTCACAAAGTACAAGTTCGGCATC

GTGTCCAAGCTCGTGAAGCCCAATTACATCTTCAGCAGCCACGAGAGCTG

TGCCCTGAACGTGCACAACTGCAAGTGGTGCCAGATCAACAATCACTACA

AAGTGTGGGAAGATTTCCGGCTGCGGAAGATCTACAACAACGTGATGGAC

TTCATCCGCGCTCTGGTCAAGAGCAACGTGAACGTGGGCCACTGCAGCAG

CCAAGAGTCCGTGTACAAATACGTGCCCGACCTGTTCCTGATCTGCAAGA

CCGAGAAGTGGAGCGAGGCCGTGGAAATGCTGTTCAACTACCTGGAACCT

GTGAACGTCAACGGCACCGAGTACGTCCTGCTGGACTACGAAGTGAACTG

GGAAGTGCGGGGCCTCGTGATGCAGAACATGGATGGCAAGGTGCCCCGGA

TCCTGAACATGAACGACACCAAGAAAATCCTGAGCGCCATGATCTTCGAT

TGGTTCGACACCCGGTACATGCGCGAGACACCTATGACCACCAGCACCAC

CAACCAGCTGCGGACCCTGAACAAGAGAAACGAGCTGATCGACGAGTACG

ACCTGGAACTGAGCGACGTGGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 317, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 317 is provided herein as SEQ ID No: 318, as follows:

[SEQ ID No: 318]

AUGGCCACCUUCAAGGACGCCUGCUACCACUACAAGAAGCUGAACAAGCU

GAAUAGCCUGGUGCUGAAGCUGGGCGCCAAUGAUGAAUGGCGACCUGCUC

CUGUGACCAAGUACAAAGGCUGGUGCCUGGACUGCUGCCAGUACACCAAU

CUGACCUACUGCAGAGGCUGCGCCCUGUACCACGUCUGUCAGUGGUGCAG

CCAGUACAACCGGUGCUUCCUGGACGAGGAACCCCAUCUGCUGCGGAUGC

GGACCUUUAAGGACGUGGUCACCAAAGAGGACAUCGAGGGCCUGCUGACU

AUGUACGAGACACUGUUCCCCAUCAACGAGAAGCUGGUCAACAAGUUCAU

CAACAGCGUGAAGCAGCGGAAGUGCCGGAACGAGUACCUGCUGGAAUGGU

ACAAUCAUCUGCUGAUGCCCAUCACACUGCAGGCCCUGACCAUCAACCUG

GAAGAUAACGUGUACUACAUGUUCGGCUACUACGACUGCAUGGAACACGA

GAAUCAGACCCCUUUCCAGUUCGUGAACCUGCUCGAGAAGUACGACAAGC

UGCUGCUGGACGACCGGAACUUCCACCGGAUGUCUCAUCUGCCCGUGAUC

CUGCAGCAAGAGUACGCCCUGCGGUACUUCAGCAAGAGCCGGUUUCUGAG

CAAGGGCAAGAAGCGGCUGAGCAGAAGCGACUUCAGCGACAACCUGAUGG

AAGAUCGGCACAGCCCCACCAGCCUGAUGCAGGUCGUCAGAAACUGCAUC

AGCAUCCACAUCGACGACUGUGAAUGGAACAAGGCCUGCACACUGAUCGU

GGACGCCCGCAACUACAUCUCCAUCAUGAACAGCAGCUACACCGAGCACU

ACAGCGUGUCCCAGCGGUGCAAGCUGUUCACAAAGUACAAGUUCGGCAUC

GUGUCCAAGCUCGUGAAGCCCAAUUACAUCUUCAGCAGCCACGAGAGCUG

UGCCCUGAACGUGCACAACUGCAAGUGGUGCCAGAUCAACAAUCACUACA

AAGUGUGGGAAGAUUUCCGGCUGCGGAAGAUCUACAACAACGUGAUGGAC

UUCAUCCGCGCUCUGGUCAAGAGCAACGUGAACGUGGGCCACUGCAGCAG

CCAAGAGUCCGUGUACAAAUACGUGCCCGACCUGUUCCUGAUCUGCAAGA

CCGAGAAGUGGAGCGAGGCCGUGGAAAUGCUGUUCAACUACCUGGAACCU

GUGAACGUCAACGGCACCGAGUACGUCCUGCUGGACUACGAAGUGAACUG

GGAAGUGCGGGGCCUCGUGAUGCAGAACAUGGAUGGCAAGGUGCCCCGGA

UCCUGAACAUGAACGACACCAAGAAAAUCCUGAGCGCCAUGAUCUUCGAU

UGGUUCGACACCCGGUACAUGCGCGAGACACCUAUGACCACCAGCACCAC

CAACCAGCUGCGGACCCUGAACAAGAGAAACGAGCUGAUCGACGAGUACG

ACCUGGAACUGAGCGACGUGGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 318, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Bovine RV NS2 (Q86505; Non-structural protein 2 Bovine Rotavirus A), or an orthologue thereof. One embodiment of the polypeptide sequence of Bovine RV NS2 is represented herein as SEQ ID No: 319, as follows:

[SEQ ID No: 319]

MAELACFCYPHLESDTYRFIPFNSLAIKCMLTAKVDKKDQDKFYNSIIYG

IAPPPQFKKRYNTNDNSRGMNYETPMFNKVAVLICEALNSIKVTQSDVAS

VLSKVISVRHLENLVLRRENHQDVLFHSKELLLRSVLIAIGHSKEIETTA

TAEGGEVVFQNAAFTMWKLTYLEHRLMPILDQNFIEYKITVNEDKPISES

HVRELIAELRWQYNKFAVITHGKGHYRVVKYSSVANHADRVYATFKSNNK

NGNVIEFNLLDQRIIWQNWYAFTSSMKQGNTLEICKKLLFQKMKRESNPF

KGLSTDRKMDEVSQIGI

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 319, or a variant or fragment thereof.

In one embodiment, the Bovine RV NS2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 320, as follows:

[SEQ ID No: 320]

ATGGCTGAGCTAGCTTGCTTTTGTTATCCCCATTTGGAGAGCGATACGTA

TAGATTCATTCCATTTAACAGTTTAGCTATAAAATGTATGTTGACAGCAA

AAGTGGACAAAAAAGATCAGGATAAGTTTTACAATTCAATAATTTATGGC

ATTGCACCACCGCCACAGTTCAAAAAACGTTATAACACAAATGATAATTC

GAGAGGAATGAATTATGAAACTCCAATGTTTAATAAAGTGGCGGTATTAA

TTTGTGAAGCGTTGAATTCAATTAAAGTTACTCAATCTGATGTTGCGAGT

GTACTTTCAAAAGTAATTTCTGTAAGACATTTAGAGAATTTGGTACTGAG

AAGAGAGAACCATCAGGACGTGCTTTTCCATTCAAAAGAGTTGTTGCTGA

GATCAGTACTAATAGCTATTGGTCACTCAAAAGAAATTGAAACAACTGCC

ACTGCTGAAGGAGGGGAAGTAGTTTTTCAAAATGCAGCTTTTACAATGTG

GAAACTGACATACCTGGAGCATAGACTAATGCCAATTTTGGATCAAAATT

TTATCGAATATAAAATAACAGTGAATGAAGATAAACCAATTTCAGAATCA

CATGTAAGAGAACTCATTGCTGAATTGCGGTGGCAATACAACAAATTTGC

AGTAATTACACATGGTAAAGGTCACTACAGAGTTGTAAAATATTCATCAG

TTGCGAATCATGCAGATAGAGTTTACGCTACTTTCAAGAGCAATAATAAG

AATGGGAATGTGATAGAGTTTAATCTACTTGATCAAAGAATAATATGGCA

GAACTGGTATGCGTTTACATCCTCAATGAAACAAGGCAACACTCTTGAAA

TATGCAAGAAACTACTGTTCCAAAAGATGAAGCGAGAAAGTAATCCGTTT

AAGGGACTGTCAACTGATAGAAAGATGGATGAGGTCTCTCAAATAGGAAT

T

Accordingly, preferably the Bovine RV NS2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 320, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Bovine RV NS2 polypeptide is provided herein as SEQ ID No: 321, as follows:

[SEQ ID No: 321]

ATGGCCGAGCTGGCCTGCTTTTGTTACCCTCACCTGGAAAGCGATACCTA

CCGGTTCATCCCCTTCAACAGCCTGGCCATCAAGTGCATGCTGACCGCCA

AGGTGGACAAGAAGGACCAGGACAAGTTCTACAACAGCATCATCTACGGA

ATCGCCCCTCCACCTCAGTTCAAGAAGCGGTACAACACCAACGACAACAG

CCGGGGCATGAACTACGAGACACCCATGTTCAACAAGGTGGCCGTGCTGA

TCTGCGAGGCCCTGAACTCCATCAAAGTGACCCAGTCCGATGTGGCCAGC

GTGCTGAGCAAAGTGATCTCTGTGCGGCACCTCGAGAACCTGGTGCTGCG

GAGAGAAAACCACCAGGACGTGCTGTTCCACAGCAAAGAGCTGCTGCTGA

GATCTGTGCTGATCGCCATCGGCCACTCCAAAGAGATCGAGACAACCGCC

ACAGCCGAAGGCGGAGAGGTGGTGTTTCAGAATGCCGCCTTCACCATGTG

GAAGCTGACCTACCTGGAACACCGGCTGATGCCCATCCTGGACCAGAACT

TCATCGAGTACAAGATCACCGTGAACGAGGACAAGCCCATCAGCGAGTCT

CACGTGCGGGAACTGATTGCCGAGCTGCGGTGGCAGTACAACAAGTTCGC

CGTGATCACACACGGCAAGGGCCACTACAGAGTGGTCAAGTACAGCAGCG

TGGCCAACCACGCCGATAGAGTGTACGCCACCTTCAAGAGCAACAACAAG

AACGGCAACGTGATCGAGTTCAACCTGCTGGACCAGCGGATCATCTGGCA

GAATTGGTACGCCTTTACCAGCAGCATGAAGCAGGGCAACACCCTGGAAA

TCTGCAAGAAGCTCCTGTTCCAGAAGATGAAGAGAGAGAGCAACCCCTTC

AAGGGCCTGAGCACCGACCGGAAGATGGATGAGGTGTCCCAGATCGGCAT

C

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 321, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 321 is provided herein as SEQ ID No: 322, as follows:

[SEQ ID No: 322]

AUGGCCGAGCUGGCCUGCUUUUGUUACCCUCACCUGGAAAGCGAUACCUA

CCGGUUCAUCCCCUUCAACAGCCUGGCCAUCAAGUGCAUGCUGACCGCCA

AGGUGGACAAGAAGGACCAGGACAAGUUCUACAACAGCAUCAUCUACGGA

AUCGCCCCUCCACCUCAGUUCAAGAAGCGGUACAACACCAACGACAACAG

CCGGGGCAUGAACUACGAGACACCCAUGUUCAACAAGGUGGCCGUGCUGA

UCUGCGAGGCCCUGAACUCCAUCAAAGUGACCCAGUCCGAUGUGGCCAGC

GUGCUGAGCAAAGUGAUCUCUGUGCGGCACCUCGAGAACCUGGUGCUGCG

GAGAGAAAACCACCAGGACGUGCUGUUCCACAGCAAAGAGCUGCUGCUGA

GAUCUGUGCUGAUCGCCAUCGGCCACUCCAAAGAGAUCGAGACAACCGCC

ACAGCCGAAGGCGGAGAGGUGGUGUUUCAGAAUGCCGCCUUCACCAUGUG

GAAGCUGACCUACCUGGAACACCGGCUGAUGCCCAUCCUGGACCAGAACU

UCAUCGAGUACAAGAUCACCGUGAACGAGGACAAGCCCAUCAGCGAGUCU

CACGUGCGGGAACUGAUUGCCGAGCUGCGGUGGCAGUACAACAAGUUCGC

CGUGAUCACACACGGCAAGGGCCACUACAGAGUGGUCAAGUACAGCAGCG

UGGCCAACCACGCCGAUAGAGUGUACGCCACCUUCAAGAGCAACAACAAG

AACGGCAACGUGAUCGAGUUCAACCUGCUGGACCAGCGGAUCAUCUGGCA

GAAUUGGUACGCCUUUACCAGCAGCAUGAAGCAGGGCAACACCCUGGAAA

UCUGCAAGAAGCUCCUGUUCCAGAAGAUGAAGAGAGAGAGCAACCCCUUC

AAGGGCCUGAGCACCGACCGGAAGAUGGAUGAGGUGUCCCAGAUCGGCAU

C

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 322, or a fragment or variant thereof.

In one embodiment, the at least one IIP is PBoV NP1 (D7RF52; Non-structural protein NP-1 Porcine bocavirus 1), or an orthologue thereof. One embodiment of the polypeptide sequence of PBoV NP1 is represented herein as SEQ ID No: 323, as follows:

[SEQ ID No: 323]

MSSARSDTDTGRRGKRSRSRSRSRDRDQAPGLPPKKRDYRRRSGERGSES

SPDRSTRGSPSCSTASRTSRVTSATWRRPNDSRDGGKIWGNKNKKNKTNP

YEVFSQHMARFKPDKSYCGFYWHSCRMARKGTDYIFTEGMRDFQKRCKDN

KCEWKDVREIMFGLKKVLDQGYRNMMYHFRHTQCEKCNYWDEVYKMHLAN

VSPSETEPQELTDEEILAAAMEVDGTHE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 323, or a variant or fragment thereof.

In one embodiment, the PBoV NP1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 324, as follows:

[SEQ ID No: 324]

ATGAGCTCAGCGAGATCCGACACAGACACAGGCAGGAGAGGGAAGCGGTC

GAGGAGCCGGTCGAGGAGCCGCGACCGGGACCAAGCACCGGGGCTGCCTC

CGAAAAAAAGGGACTATCGCCGTCGGAGTGGGGAGAGAGGCTCGGAGTCC

TCACCAGATCGCTCGACGAGGGGGAGCCCATCGTGCTCCACTGCTTCGAG

AACATCCCGAGTGACTTCAGCGACATGGAGGAGACCGAATGACTCTCGGG

ACGGGGGGAAAATATGGGGAAATAAAAATAAAAAGAATAAAACAAACCCT

TACGAGGTATTCAGCCAGCACATGGCCAGGTTCAAGCCAGATAAAAGCTA

TTGTGGCTTCTACTGGCACAGCTGCCGGATGGCTCGTAAGGGCACAGATT

ATATCTTTACCGAGGGAATGAGGGATTTCCAAAAACGCTGTAAAGACAAT

AAATGTGAGTGGAAAGATGTCAGGGAGATCATGTTCGGCCTCAAAAAGGT

CTTAGATCAGGGATATAGAAATATGATGTATCACTTTAGACATACCCAGT

GTGAGAAATGTAACTACTGGGATGAAGTGTATAAAATGCACCTGGCTAAC

GTGTCTCCTTCTGAAACAGAACCGCAGGAACTGACAGACGAGGAGATATT

AGCCGCGGCCATGGAGGTCGATGGCACCCACGAA

Accordingly, preferably the PBoV NP1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 324, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the PBoV NP1 polypeptide is provided herein as SEQ ID No: 325, as follows:

[SEQ ID No: 325]

ATGAGCAGCGCCAGAAGCGATACCGACACAGGCAGACGGGGCAAGAGAAG

CAGAAGCCGGTCCAGAAGCAGAGACAGAGATCAGGCTCCTGGCCTGCCTC

CTAAGAAGCGGGACTACAGAAGAAGATCCGGCGAGAGAGGCAGCGAGAGC

AGCCCTGATAGAAGCACAAGAGGCAGCCCTAGCTGTAGCACCGCCAGCAG

AACAAGCAGAGTGACCTCTGCCACTTGGCGGAGGCCCAACGATTCTAGAG

ATGGCGGCAAGATCTGGGGCAACAAGAACAAGAAGAACAAAACGAACCCC

TACGAGGTGTTCAGCCAGCACATGGCCAGATTCAAGCCCGACAAGAGCTA

CTGCGGCTTCTACTGGCACAGCTGCCGGATGGCCAGAAAGGGCACCGACT

ACATCTTCACCGAGGGCATGAGAGACTTCCAGAAGCGGTGCAAGGACAAC

AAGTGCGAGTGGAAGGACGTGCGCGAGATCATGTTCGGCCTGAAGAAGGT

GCTGGACCAGGGCTACAGAAACATGATGTACCACTTCCGGCACACCCAGT

GCGAGAAGTGCAACTACTGGGACGAAGTGTACAAGATGCACCTGGCCAAC

GTGTCCCCATCCGAGACAGAGCCTCAAGAGCTGACCGACGAGGAAATTCT

GGCCGCTGCCATGGAAGTGGATGGCACACATGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 325, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 325 is provided herein as SEQ ID No: 326, as follows:

[SEQ ID No: 326]

AUGAGCAGCGCCAGAAGCGAUACCGACACAGGCAGACGGGGCAAGAGAAG

CAGAAGCCGGUCCAGAAGCAGAGACAGAGAUCAGGCUCCUGGCCUGCCUC

CUAAGAAGCGGGACUACAGAAGAAGAUCCGGCGAGAGAGGCAGCGAGAGC

AGCCCUGAUAGAAGCACAAGAGGCAGCCCUAGCUGUAGCACCGCCAGCAG

AACAAGCAGAGUGACCUCUGCCACUUGGCGGAGGCCCAACGAUUCUAGAG

AUGGCGGCAAGAUCUGGGGCAACAAGAACAAGAAGAACAAAACGAACCCC

UACGAGGUGUUCAGCCAGCACAUGGCCAGAUUCAAGCCCGACAAGAGCUA

CUGCGGCUUCUACUGGCACAGCUGCCGGAUGGCCAGAAAGGGCACCGACU

ACAUCUUCACCGAGGGCAUGAGAGACUUCCAGAAGCGGUGCAAGGACAAC

AAGUGCGAGUGGAAGGACGUGCGCGAGAUCAUGUUCGGCCUGAAGAAGGU

GCUGGACCAGGGCUACAGAAACAUGAUGUACCACUUCCGGCACACCCAGU

GCGAGAAGUGCAACUACUGGGACGAAGUGUACAAGAUGCACCUGGCCAAC

GUGUCCCCAUCCGAGACAGAGCCUCAAGAGCUGACCGACGAGGAAAUUCU

GGCCGCUGCCAUGGAAGUGGAUGGCACACAUGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 326, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Hepatitis E Orf3 (P69616; Protein ORF3 Hepatitis E virus genotype 1), or an orthologue thereof. One embodiment of the polypeptide sequence of Hepatitis E Orf3 is represented herein as SEQ ID No: 327, as follows:

[SEQ ID No: 327]

MGSRPCALGLFCCCSSCFCLCCPRHRPVSRLAAVVGGAAAVPAVVSGVTG

LILSPSQSPIFIQPTPSPPMSPLRPGLDLVFANPPDHSAPLGVTRPSAPP

LPHVVDLPQLGPRR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 327, or a variant or fragment thereof.

In one embodiment, the Hepatitis E Orf3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 328, as follows:

[SEQ ID No: 328]

ATGGGTTCGCGACCATGCGCCCTCGGCCTATTTTGTTGCTGCTCCTCATG

TTTTTGCCTATGCTGCCCGCGCCACCGCCCGGTCAGCCGTCTGGCCGCCG

TCGTGGGCGGCGCAGCGGCGGTTCCGGCGGTGGTTTCTGGGGTGACCGGG

TTGATTCTCAGCCCTTCGCAATCCCCTATATTCATCCAACCAACCCCTTC

GCCCCCGATGTCACCGCTGCGGCCGGGGCTGGACCTCGTGTTCGCCAACC

CGCCCGACCACTCGGCTCCGCTTGGCGTGACCAGGCCCAGCGCCCCGCCG

TTGCCTCACGTCGTAGACCTACCACAGCTGGGGCCGCGCCGC

Accordingly, preferably the Hepatitis E Orf3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 328, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Hepatitis E Orf3 polypeptide is provided herein as SEQ ID No: 329, as follows:

[SEQ ID No: 329]

ATGGGCAGCAGACCTTGTGCTCTGGGCCTGTTCTGCTGCTGCAGCTCCTG

CTTCTGCCTGTGCTGCCCTAGACACAGACCCGTGTCTAGACTGGCCGCTG

TTGTTGGCGGAGCTGCTGCTGTTCCAGCTGTGGTGTCTGGCGTGACAGGC

CTGATTCTGAGCCCTTCTCAGAGCCCCATCTTCATCCAGCCTACACCTAG

TCCTCCAATGAGCCCTCTGAGGCCTGGACTGGATCTGGTGTTCGCCAATC

CTCCTGATCACTCTGCCCCTCTGGGCGTGACAAGACCTTCTGCTCCTCCT

CTGCCACACGTGGTGGATCTGCCTCAACTGGGCCCTAGAAGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 329, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 329 is provided herein as SEQ ID No: 330, as follows:

[SEQ ID No: 330]

AUGGGCAGCAGACCUUGUGCUCUGGGCCUGUUCUGCUGCUGCAGCUCCUG

CUUCUGCCUGUGCUGCCCUAGACACAGACCCGUGUCUAGACUGGCCGCUG

UUGUUGGCGGAGCUGCUGCUGUUCCAGCUGUGGUGUCUGGCGUGACAGGC

CUGAUUCUGAGCCCUUCUCAGAGCCCCAUCUUCAUCCAGCCUACACCUAG

UCCUCCAAUGAGCCCUCUGAGGCCUGGACUGGAUCUGGUGUUCGCCAAUC

CUCCUGAUCACUCUGCCCCUCUGGGCGUGACAAGACCUUCUGCUCCUCCU

CUGCCACACGUGGUGGAUCUGCCUCAACUGGGCCCUAGAAGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 330, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Rotavirus NSP1 (Q99FX5; Non-structural protein 1 Rotavirus A (strain RVA/SA11-4F/G3P6[1])), or an orthologue thereof. Barro M, Patton J T (2007) Rotavirus NSP1 inhibits expression of type 1 interferon by antagonising the function of interferon regulatory factors IRF3, IRF5 and IRF7. J Virol, 81, 9, 4473-4481. This IIP is believed to induce degradation of IRF7. One embodiment of the polypeptide sequence of Rotavirus NSP1 is represented herein as SEQ ID No: 331, as follows:

[SEQ ID No: 331]

MATFKDACFHYRRLTALNRRLCNIGANSICMPVPDAKIKGWCLECCQIAD

LTHCYGCSLPHVCKWCVQNRRCFLDNEPHLLKLRTVKHPITKDKLQCIID

LYNIIFPINDKVIRKFERMIKQRKCRNQYKIEWYNHLLLPITLNAAAFKF

DENNLYYVFGLYEKSVSDIYAPYRIVNFINEFDKLLLDDINFTRMSNLPI

ELRNHYAKKYFQLSRLPSSKLKQIYFSDFTKETVIFNTYTKTPGRSIYRN

VTEFNWRDELELYSDLKNDKNKLIAAMMTSKYTRFYAHDNNFGRLKMTIF

ELGHHCQPNYVASNHPGNASDIQYCKWCNIKYFLSKIDWRIRDMYNLLME

FIKDCYKSNVNVGHCSSVENIYPLIKRLIWSLFTNHMDQTIEEVFNHMSP

VSVEGTNVIMLILGLNISLYNEIKRTLNVDSIPMVLNLNEFSSIVKSISS

KWYNVDELDKLPMSIKSTEELIEMKNSGTLTEEFELLISNSEDDNE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 331, or a variant or fragment thereof.

In one embodiment, the Rotavirus NSP1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 332, as follows:

[SEQ ID No: 332]

ATGGCTACTTTTAAAGATGCATGCTTTCATTATCGTAGATTAACTGCTTT

AAATCGGAGATTATGCAACATTGGTGCAAATTCTATTTGCATGCCAGTTC

CTGATGCGAAGATTAAGGGGTGGTGTTTAGAATGTTGTCAAATAGCTGAT

TTAACCCATTGTTATGGTTGCTCATTGCCGCATGTTTGCAAATGGTGTGT

TCAGAACAGAAGATGCTTCCTTGACAATGAACCTCATTTGCTTAAGCTTA

GAACTGTGAAACATCCAATTACCAAAGACAAATTACAGTGTATCATAGAC

TTGTACAATATAATATTTCCAATTAATGATAAAGTAATTAGAAAATTTGA

AAGAATGATAAAGCAAAGAAAATGTAGGAATCAATATAAAATTGAATGGT

ATAATCATTTGCTGCTCCCAATTACATTAAATGCTGCTGCATTTAAGTTT

GATGAAAATAATCTTTATTATGTTTTTGGGTTATATGAGAAATCAGTCAG

TGATATATATGCTCCATATAGAATTGTTAACTTTATAAATGAATTTGATA

AATTATTGCTTGATGATATTAACTTTACAAGAATGTCCAATCTACCAATA

GAGTTGAGAAACCATTATGCAAAGAAATACTTCCAATTATCAAGACTGCC

ATCATCAAAACTAAAGCAAATTTACTTTTCAGATTTTACTAAAGAAACTG

TGATTTTTAATACTTATACAAAAACGCCAGGAAGATCAATATACAGAAAT

GTAACTGAATTTAATTGGAGAGATGAATTGGAGCTTTATTCTGATTTAAA

AAATGATAAGAATAAATTAATTGCTGCAATGATGACGAGTAAGTATACTC

GGTTCTATGCTCATGATAATAATTTTGGAAGGTTGAAAATGACAATATTT

GAGTTGGGACATCATTGTCAGCCTAACTACGTGGCATCTAATCACCCAGG

CAATGCTTCCGATATCCAGTACTGTAAATGGTGTAATATAAAATATTTTC

TTAGTAAAATTGATTGGCGGATTCGTGATATGTATAATTTATTGATGGAA

TTTATTAAGGATTGTTATAAAAGTAATGTTAACGTTGGACATTGTAGTTC

TGTTGAAAACATATATCCTTTAATTAAAAGATTAATTTGGAGTTTGTTTA

CTAATCACATGGATCAAACAATTGAAGAAGTGTTTAATCACATGTCGCCA

GTGTCAGTTGAAGGTACGAATGTCATCATGTTGATTCTTGGATTGAATAT

TAGTTTGTATAATGAAATTAAGCGCACTTTGAATGTAGATAGCATACCAA

TGGTACTTAATTTAAATGAATTCAGTGAGGAACTGATTGAAATGAAGAAT

TCTGGAACTTTAACTGAAGAATTTGAGCTACTGATCTCCAACTCAGAAGA

TGACAATGAG

Accordingly, preferably the Rotavirus NSP1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 332, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Rotavirus NSP1 polypeptide is provided herein as SEQ ID No: 333, as follows:

[SEQ ID No: 333]

ATGGCCACCTTCAAGGACGCCTGCTTCCACTACAGACGGCTGACAGCCCT

GAATCGGCGGCTGTGTAATATCGGCGCCAACAGCATCTGCATGCCCGTGC

CTGACGCCAAGATCAAAGGCTGGTGCCTGGAATGCTGCCAGATCGCCGAT

CTCACCCACTGCTACGGCTGTTCTCTGCCCCATGTGTGCAAGTGGTGCGT

GCAGAACAGACGGTGCTTCCTGGACAACGAGCCCCATCTGCTGAAGCTGA

GAACCGTGAAGCACCCCATCACCAAGGACAAGCTGCAGTGCATCATCGAC

CTGTACAACATCATCTTCCCCATCAACGACAAAGTGATCCGGAAGTTCGA

GCGGATGATCAAGCAGCGGAAGTGCCGGAACCAGTACAAGATCGAGTGGT

ACAATCATCTGCTGCTGCCCATCACACTGAACGCCGCTGCCTTCAAGTTC

GACGAGAACAACCTGTACTACGTGTTCGGCCTGTACGAGAAGTCCGTGTC

CGACATCTACGCCCCTTACCGGATCGTGAACTTCATCAACGAGTTCGATA

AGCTGCTGCTGGACGACATCAACTTCACCCGGATGAGCAACCTGCCTATC

GAGCTGAGAAACCACTACGCCAAGAAGTACTTTCAGCTGAGCAGACTGCC

CAGCAGCAAGCTGAAGCAGATCTACTTCTCCGACTTCACCAAAGAAACCG

TGATCTTCAACACCTACACCAAGACACCCGGCAGATCCATCTACCGGAAC

GTGACCGAGTTCAACTGGCGGGACGAGCTGGAACTGTACAGCGACCTGAA

GAACGACAAGAACAAGCTGATCGCCGCCATGATGACCAGCAAGTACACCC

GGTTCTACGCCCACGACAACAATTTCGGCCGGCTGAAGATGACCATCTTC

GAGCTGGGCCACCACTGCCAGCCTAATTACGTGGCCTGGCGGATCCGGGA

CATGTACAACCTGCTGATGGAATTCATCAAGGACTGCTACAAGAGCAACG

TGAACGTGGGCCACTGCAGCAGCGTCGAGAACATCTACCCTCTGATCAAG

CGGCTGATCTGGTCCCTGTTCACCAACCACATGGACCAGACCATCGAAGA

GGTGTTCAATCACATGAGCCCCGTGTCCGTGGAAGGCACCAACGTGATCA

TGCTGATCCTGGGCCTGAACATCAGCCTGTACAATGAGATCAAGCGCACC

CTGAACGTGGACAGCATCCCCATGGTGCTGAACCTGAACGAGTTCAGCAG

CATCGTGAAGTCCATCTCCAGCAAGTGGTATAACGTGGACGAACTGGACA

AACTGCCCATGAGCATCAAGTCCACCGAGGAACTGATCGAGATGAAGAAC

AGCGGCACCCTGACCGAGGAATTCGAGCTGCTGATCTCCAACAGCGAGGA

CGACAACGAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 333, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 333 is provided herein as SEQ ID No: 334, as follows:

[SEQ ID No: 334]

AUGGCCACCUUCAAGGACGCCUGCUUCCACUACAGACGGCUGACAGCCCU

GAAUCGGCGGCUGUGUAAUAUCGGCGCCAACAGCAUCUGCAUGCCCGUGC

CUGACGCCAAGAUCAAAGGCUGGUGCCUGGAAUGCUGCCAGAUCGCCGAU

CUCACCCACUGCUACGGCUGUUCUCUGCCCCAUGUGUGCAAGUGGUGCGU

GCAGAACAGACGGUGCUUCCUGGACAACGAGCCCCAUCUGCUGAAGCUGA

GAACCGUGAAGCACCCCAUCACCAAGGACAAGCUGCAGUGCAUCAUCGAC

CUGUACAACAUCAUCUUCCCCAUCAACGACAAAGUGAUCCGGAAGUUCGA

GCGGAUGAUCAAGCAGCGGAAGUGCCGGAACCAGUACAAGAUCGAGUGGU

ACAAUCAUCUGCUGCUGCCCAUCACACUGAACGCCGCUGCCUUCAAGUUC

GACGAGAACAACCUGUACUACGUGUUCGGCCUGUACGAGAAGUCCGUGUC

CGACAUCUACGCCCCUUACCGGAUCGUGAACUUCAUCAACGAGUUCGAUA

AGCUGCUGCUGGACGACAUCAACUUCACCCGGAUGAGCAACCUGCCUAUC

GAGCUGAGAAACCACUACGCCAAGAAGUACUUUCAGCUGAGCAGACUGCC

CAGCAGCAAGCUGAAGCAGAUCUACUUCUCCGACUUCACCAAAGAAACCG

UGAUCUUCAACACCUACACCAAGACACCCGGCAGAUCCAUCUACCGGAAC

GUGACCGAGUUCAACUGGCGGGACGAGCUGGAACUGUACAGCGACCUGAA

GAACGACAAGAACAAGCUGAUCGCCGCCAUGAUGACCAGCAAGUACACCC

GGUUCUACGCCCACGACAACAAUUUCGGCCGGCUGAAGAUGACCAUCUUC

GAGCUGGGCCACCACUGCCAGCCUAAUUACGUGGCCUCUAAUCACCCCGG

CAACGCCAGCGAUAUCCAGUACUGCAAAUGGUGCAAUAUCAAGUACUUCC

UGAGCAAGAUCGACUGGCGGAUCCGGGACAUGUACAACCUGCUGAUGGAA

UUCAUCAAGGACUGCUACAAGAGCAACGUGAACGUGGGCCACUGCAGCAG

CGUCGAGAACAUCUACCCUCUGAUCAAGCGGCUGAUCUGGUCCCUGUUCA

CCAACCACAUGGACCAGACCAUCGAAGAGGUGUUCAAUCACAUGAGCCCC

GUGUCCGUGGAAGGCACCAACGUGAUCAUGCUGAUCCUGGGCCUGAACAU

CAGCCUGUACAAUGAGAUCAAGCGCACCCUGAACGUGGACAGCAUCCCCA

UGGUGCUGAACCUGAACGAGUUCAGCAGCAUCGUGAAGUCCAUCUCCAGC

AAGUGGUAUAACGUGGACGAACUGGACAAACUGCCCAUGAGCAUCAAGUC

CACCGAGGAACUGAUCGAGAUGAAGAACAGCGGCACCCUGACCGAGGAAU

UCGAGCUGCUGAUCUCCAACAGCGAGGACGACAACGAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 334, or a fragment or variant thereof.

In one embodiment, the at least one IIP is KSHV ORF45 (Q77UV9; HHV8 ORF 45 Human herpesvirus 8 OX), or an orthologue thereof. One embodiment of the polypeptide sequence of KSHV ORF45 is represented herein as SEQ ID No: 335, as follows:

[SEQ ID No: 335]

MAMFVRTSSSTHDEERMLPIEGAPRRRPPVKFIFPPPPLSSLPGFGRPRG

YAGPTVIDMSAPDDVFAEDTPSPPATPLDLQISPDQSSGESEYDEDEEDE

DEEENDDVQEEDEPEGYPADFFQPLSHLRPRPLARRAHTPKPVAVVAGRV

RSSTDTAESEASMGWVSQDDGFSPAGLSPSDDEGVAILEPMAAYTGTGAY

GLSPASRNSVPGTQSSPYSDPDEGPSWRPLRAAPTAIVDLTSDSDSDDSS

NSPDVNNEAAFTDARHFSHQPPSSEEDGEDQGEVLSQRIGLMDVGQKRKR

QSTASSGSEDVVRCQRQPNLSRKAVASVIIISSGSDTDEEPSSAVSVIVS

PSSTKGHLPTQSPSTSAHSISSGSTTTAGSRCSDPTRILASTPPLCGNGA

YNWPWLD

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 335, or a variant or fragment thereof.

In one embodiment, the KSHV ORF45 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 336, as follows:

[SEQ ID No: 336]

CGACCCCCCGTGAAGTTCATATTCCCACCTCCACCTCTTTCATCACTTCC

AGGATTTGGCAGGCCGCGCGGCTATGCTGGACCCACGGTGATAGATATGT

CTGCCCCAGACGACGTCTTCGCCGAGGACACGCCATCGCCGCCAGCAACC

CCTCTGGATCTACAGATATCCCCGGATCAGTCGAGCGGCGAATCTGAATA

TGACGAGGATGAGGAAGATGAAGATGAAGAAGAAAATGACGATGTTCAGG

AGGAAGACGAGCCAGAGGGGTACCCTGCAGACTTTTTTCAACCTTTATCT

CACTTGCGCCCGAGGCCTCTGGCCAGACGGGCCCATACGCCCAAACCGGT

AGCAGTGGTAGCGGGCCGCGTGCGCAGTTCAACGGACACGGCGGAGTCCG

AGGCGTCCATGGGATGGGTTAGTCAGGATGACGGATTTTCCCCTGCTGGG

CTCTCACCTTCAGACGACGAGGGGGTTGCTATCCTGGAACCGATGGCGGC

ATACACTGGGACCGGGGCATACGGACTTTCACCTGCTTCCAGAAATAGTG

TACCTGGAACACAAAGTTCACCATACAGCGACCCTGATGAAGGGCCCTCG

TGGCGCCCCCTGCGCGCCGCACCCACCGCGATCGTCGACCTGACATCGGA

CTCTGATAGCGATGACAGTTCCAACTCTCCGGACGTGAACAATGAGGCCG

CGTTTACCGACGCGCGCCATTTTTCCCACCAGCCACCCTCGTCCGAGGAG

GACGGAGAAGACCAAGGGGAAGTATTGAGTCAGAGAATCGGGCTCATGGA

CGTGGGCCAGAAGCGCAAAAGGCAGTCTACCGCCTCCTCIGGTAGCGAGG

ATGTGGTGCGCTGCCAGAGACAACCAAACTTAAGCCGCAAAGCAGTGGCG

TCTGTGATAATTATATCCTCGGGGAGTGACACAGACGAGGAGCCCTCGTC

CGCCGTGAGCGTGATCGTGTCTCCGTCGAGCACAAAGGGTCACCTCCCAA

CCCAATCTCCCAGTACTTCCGCCCACTCGATTTCATCAGGAAGCACAACT

ACCGCGGGGTCCAGGTGCAGCGACCCAACCCGCATCCTGGCCTCCACGCC

ACCCCTGTGTGGAAACGGTGCATATAACTGGCCGTGGCTGGAC

Accordingly, preferably the KSHV ORF45 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 336, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the KSHV ORF45 polypeptide is provided herein as SEQ ID No: 337, as follows:

[SEQ ID No: 337]

ATGGCCATGTTTGTGCGGACCAGCAGCAGCACCCACGACGAGGAAAGAAT

GCTGCCTATCGAGGGCGCTCCTCGGAGAAGGCCTCCTGTGAAGTTCATCT

TCCCACCTCCACCACTGAGCAGCCTGCCTGGATTTGGCAGACCTAGAGGC

TACGCCGGACCTACCGTGATCGATATGAGCGCCCCTGACGATGTGTTCGC

CGAGGATACACCTTCTCCACCAGCCACACCTCTGGACCTGCAGATCAGCC

CTGATCAGTCTAGCGGCGAGAGCGAGTACGATGAGGACGAAGAGGACGAG

GATGAGGAAGAGAACGACGACGTCCAAGAGGAAGATGAGCCCGAGGGCTA

CCCCGCCGATTTCTTTCAGCCTCTGTCTCACCTGAGGCCTGCCGAGTCCG

AAGCCAGCATGGGATGGGTGTCACAGGACGATGGATTCAGCCCTGCCGGA

CTGAGCCCTTCCGATGATGAAGGCGTGGCCATCCTGGAACCTATGGCCGC

CTATACTGGCACAGGCGCCTATGGACTGTCTCCCGCCAGCAGAAATAGCG

TGCCAGGCACACAGAGCAGCCCCTACTCTGATCCTGATGAGGGCCCATCT

TGGAGGCCCCTTAGAGCTGCTCCTACCGCCATCGTGGATCTGACCAGCGA

CAGCGATAGCGACGACAGCAGCAATAGCCCCGACGTGAACAATGAGGCCG

CCTTCACAGACGCCCGGCACTTTTCTCATCAGCCTCCAAGCAGCGAAGAG

GATGGCGAGGATCAGGGCGAAGTGCTGTCTCAGAGAATCGGCCTGATGGA

CGTGGGCCAGAAGCGGAAGAGACAGAGCACAGCCAGCAGCGGCTCTGAGG

ATGTCGTCAGATGCCAGAGACAGCCCAACCTGAGCAGAAAGGCCGTGGCC

AGCGTGATCATCATCAGCTCTGGCAGCGACACCGATGAGGAACCTAGCTC

TGCCGTGTCCGTGATCGTGTCTCCTAGCAGCACCAAGGGCCATCTGCCTA

CACAGAGCCCTAGCACAAGCGCCCACTCTATCTCTAGCGGCAGCACAACA

ACAGCCGGCAGCAGATGCAGCGACCCCACAAGAATTCTGGCCAGCACACC

TCCTCTGTGCGGCAACGGCGCTTACAATTGGCCTTGGCTGGAT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 337, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 337 is provided herein as SEQ ID No: 338, as follows:

[SEQ ID No: 338]

AUGGCCAUGUUUGUGCGGACCAGCAGCAGCACCCACGACGAGGAAAGAAU

GCUGCCUAUCGAGGGCGCUCCUCGGAGAAGGCCUCCUGUGAAGUUCAUCU

UCCCACCUCCACCACUGAGCAGCCUGCCUGGAUUUGGCAGACCUAGAGGC

UACGCCGGACCUACCGUGAUCGAUAUGAGCGCCCCUGACGAUGUGUUCGC

CGAGGAUACACCUUCUCCACCAGCCACACCUCUGGACCUGCAGAUCAGCC

CUGAUCAGUCUAGCGGCGAGAGCGAGUACGAUGAGGACGAAGAGGACGAG

GAUGAGGAAGAGAACGACGACGUCCAAGAGGAAGAUGAGCCCGAGGGCUA

CCCCGCCGAUUUCUUUCAGCCUCUGUCUCACCUGAGGCCUCGGCCUCUUG

CUAGAAGGGCCCACACACCUAAACCUGUGGCUGUGGUGGCCGGAAGAGUG

CGGUCUAGCACAGAUACAGCCGAGUCCGAAGCCAGCAUGGGAUGGGUGUC

ACAGGACGAUGGAUUCAGCCCUGCCGGACUGAGCCCUUCCGAUGAUGAAG

GCGUGGCCAUCCUGGAACCUAUGGCCGCCUAUACUGGCACAGGCGCCUAU

GGACUGUCUCCCGCCAGCAGAAAUAGCGUGCCAGGCACACAGAGCAGCCC

CUACUCUGAUCCUGAUGAGGGCCCAUCUUGGAGGCCCCUUAGAGCUGCUC

CUACCGCCAUCGUGGAUCUGACCAGCGACAGCGAUAGCGACGACAGCAGC

AAUAGCCCCGACGUGAACAAUGAGGCCGCCUUCACAGACGCCCGGCACUU

UUCUCAUCAGCCUCCAAGCAGCGAAGAGGAUGGCGAGGAUCAGGGCGAAG

UGCUGUCUCAGAGAAUCGGCCUGAUGGACGUGGGCCAGAAGCGGAAGAGA

CAGAGCACAGCCAGCAGCGGCUCUGAGGAUGUCGUCAGAUGCCAGAGACA

GCCCAACCUGAGCAGAAAGGCCGUGGCCAGCGUGAUCAUCAUCAGCUCUG

GCAGCGACACCGAUGAGGAACCUAGCUCUGCCGUGUCCGUGAUCGUGUCU

CCUAGCAGCACCAAGGGCCAUCUGCCUACACAGAGCCCUAGCACAAGCGC

CCACUCUAUCUCUAGCGGCAGCACAACAACAGCCGGCAGCAGAUGCAGCG

ACCCCACAAGAAUUCUGGCCAGCACACCUCCUCUGUGCGGCAACGGCGCU

UACAAUUGGCCUUGGCUGGAU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 338, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EBV BZLF-1 (P03206; Trans-activator protein BZLF1 Epstein-Barr virus (strain B95-8)), or an orthologue thereof. Hahn A M, Huye L E, Ning S, Webster-Cyriaque J M Pagano J S (2005) Interferon Regulatory Factor 7 Is Negatively Regulated by the Epstein-Barr Virus Immediate-Early Gene, J Virol, 79, 15, 10040-10052 doi:10.1128/JVI.790.15.10040-10052.2005. One embodiment of the polypeptide sequence of EBV BZLF-1 is represented herein as SEQ ID No: 339, as follows:

[SEQ ID No: 339]

MMDPNSTSEDVKFTPDPYQVPFVQAFDQATRVYQDLGGPSQAPLPCVLWP

VLPEPLPQGQLTAYHVSTAPTGSWFSAPQPAPENAYQAYAAPQLFPVSDI

TQNQQTNQAGGEAPQPGDNSTVQTAAAVVFACPGANQGQQLADIGVPQPA

PVAAPARRTRKPQQPESLEECDSELEIKRYKNRVASRKCRAKFKQLLQHY

REVAAAKSSENDRLRLLLKQMCPSLDVDSIIPRTPDVLHEDLLNF

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 339, or a variant or fragment thereof.

In one embodiment, the EBV BZLF-1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 340, as follows:

[SEQ ID No: 340]

ATGATGGACCCAAACTCGACTTCTGAAGATGTAAAATTTACACCTGACCC

ATACCAGGTGCCTTTTGTACAAGCTTTTGACCAAGCTACCAGAGTCTATC

AGGACCTGGGAGGGCCATCGCAAGCTCCTTTGCCTTGTGTGCTGTGGCCG

GTGCTGCCAGAGCCTCTGCCACAAGGCCAGCTAACTGCCTATCATGTTTC

AACCGCTCCGACTGGGTCGTGGTTTTCTGCCCCTCAGCCTGCTCCTGAGA

ATGCTTATCAAGCTTATGCAGCACCTCAGCTGTTCCCAGTCTCCGACATA

ACCCAGAATCAACAGACTAACCAAGCCGGGGGAGAAGCACCTCAACCTGG

AGACAATTCTACTGTTCAAACAGCAGCAGCAGTGGTGTTTGCTTGCCCCG

GGGCTAACCAAGGACAACAGCTAGCAGACATTGGTGTTCCACAGCCTGCA

CCAGTGGCTGCCCCGGCACGACGCACACGGAAACCACAACAGCCAGAATC

GCTGGAGGAATGCGATTCTGAACTAGAAATAAAGCGATACAAGAATCGGG

TGGCTTCCAGAAAATGCCGGGCCAAGTTTAAGCAACTGCTGCAGCACTAC

CGTGAGGTCGCTGCTGCCAAATCATCTGAAAATGACAGGCTGCGCCTCCT

GTTGAAGCAGATGTGCCCAAGCCTGGATGTTGACTCCATTATCCCCCGGA

CACCAGATGTTTTACACGAGGATCTCTTAAATTTC

Accordingly, preferably the EBV BZLF-1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 340, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EBV BZLF-1 polypeptide is provided herein as SEQ ID No: 341, as follows:

[SEQ ID No: 341]

ATGATGGACCCCAACAGCACCAGCGAGGACGTGAAGTTCACCCCTGATCC

TTACCAGGTGCCATTCGTGCAGGCCTTCCCTGAACCTCTGCCTCAGGGAC

AGCTGACAGCCTACCATGTGTCTACAGCCCCTACCGGCAGCTGGTTTTCT

GCTCCTCAACCTGCTCCTGAGAACGCCTACCAGGCCTATGCTGCCCCTCA

GCTGTTTCCCGTGTCCGACATCACCCAGAACCAGCAGACAAATCAGGCTG

GCGGAGAAGCTCCTCAGCCTGGCGATAATAGCACCGTGCAGACAGCTGCC

GCCGTGGTGTTTGCTTGTCCTGGCGCTAATCAGGGCCAGCAGCTGGCTGA

TATTGGCGTGCCACAACCAGCTCCAGTGGCCGCTCCTGCCAGAAGAACAA

GAAAGCCTCAGCAGCCCGAGAGCCTGGAAGAGTGCGATAGCGAGCTGGAA

ATCAAGCGGTACAAGAACAGAGTGGCCAGCCGGAAGTGCCGGGCCAAGTT

TAAACAGCTGCTCCAGCACTACAGAGAGGTGGCCGCTGCCAAGAGCAGCG

AGAACGATAGACTGCGGCTGCTGCTGAAGCAGATGTGCCCTAGCCTGGAC

GTGGACAGCATCATCCCCAGAACACCCGATGTGCTGCACGAGGACCTGCT

GAACTTT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 341, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 341 is provided herein as SEQ ID No: 342, as follows:

[SEQ ID No: 342]

AUGAUGGACCCCAACAGCACCAGCGAGGACGUGAAGUUCACCCCUGAUCC

UUACCAGGUGCCAUUCGUGCAGGCCUUCGAUCAGGCCACCAGAGUGUACC

AGGAUCUCGGCGGACCUUCUCAGGCUCCUCUGCCUUGUGUUCUGUGGCCU

GUGCUGCCUGAACCUCUGCCUCAGGGACAGCUGACAGCCUACCAUGUGUC

UACAGCCCCUACCGGCAGCUGGUUUUCUGCUCCUCAACCUGCUCCUGAGA

ACGCCUACCAGGCCUAUGCUGCCCCUCAGCUGUUUCCCGUGUCCGACAUC

ACCCAGAACCAGCAGACAAAUCAGGCUGGCGGAGAAGCUCCUCAGCCUGG

CGAUAAUAGCACCGUGCAGACAGCUGCCGCCGUGGUGUUUGCUUGUCCUG

GCGCUAAUCAGGGCCAGCAGCUGGCUGAUAUUGGCGUGCCACAACCAGCU

CCAGUGGCCGCUCCUGCCAGAAGAACAAGAAAGCCUCAGCAGCCCGAGAG

CCUGGAAGAGUGCGAUAGCGAGCUGGAAAUCAAGCGGUACAAGAACAGAG

UGGCCAGCCGGAAGUGCCGGGCCAAGUUUAAACAGCUGCUCCAGCACUAC

AGAGAGGUGGCCGCUGCCAAGAGCAGCGAGAACGAUAGACUGCGGCUGCU

GCUGAAGCAGAUGUGCCCUAGCCUGGACGUGGACAGCAUCAUCCCCAGAA

CACCCGAUGUGCUGCACGAGGACCUGCUGAACUUU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 342, or a fragment or variant thereof.

In one embodiment, the at least one IIP is MuHV Orf73 (041974; MHV68 ORF73 protein Murine herpesvirus 4), or an orthologue thereof. One embodiment of the polypeptide sequence of MuHV Orf73 is represented herein as SEQ ID No: 343, as follows:

[SEQ ID No: 343]

MPTSPPTTRNTTSGKTRSGCKRRCFNKPAAMPPKRRRAPKRPAPPPPPGC

QGDEESSQGTQTPNPPSPPVPPSSPTLPSSPVPPSSPVHEPPSPSPPPAP

PSPDVDVEGLDVGETDDPGPPPPKRYSRYQKPHNPSDPLPKKYQGMRRHL

QVTAPRLFDPEGHPPTHFKSAVMFSSTHPYTLNKLHKCIQSKHVLSTPVS

CLPLVPGTTQQCVTYYLLSFVEDKKQAKKLKRVVLAYCEKYHSSVEGTIV

KAKPYFPLPEPPTEPPTDPEQPSTSTQASGTQHGPTASLDAGAEQGATGS

PGSSPGQQGQGSQT

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 343, or a variant or fragment thereof.

In one embodiment, the MuHV Orf73 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 344, as follows:

[SEQ ID No: 344]

ATGCCCACATCCCCACCGACTACACGCAACACAACCTCAGGCAAAACCAG

ATCAGGGTGCAAACGTAGGTGCTTCAACAAACCAGCAGCCATGCCTCCTA

AAAGACGCCGCGCTCCAAAAAGACCAGCCCCTCCTCCACCACCGGGATGC

CAAGGTGATGAGGAGTCCAGCCAGGGAACTCAAACGCCAAACCCCCCATC

ACCACCAGTGCCCCCTTCATCACCAACACTTCCCTCATCCCCCGTCCCTC

CTTCATCACCAGTACATGAGCCACCATCTCCTTCCCCCCCACCAGCCCCA

CCATCACCAGATGTTGATGTTGAAGGTTTAGATGTAGGAGAGACAGACGA

TCCCGGTCCCCCTCCACCAAAAAGATACTCCAGGTATCAAAAACCGCATA

ATCCATCTGATCCATTGCCTAAAAAATATCAGGGAATGCGAAGACACCTG

CAGGTGACAGCACCCAGGTTATTTGATCCCGAGGGTCACCCCCCAACACA

TTTTAAGTCAGCTGTTATGTTTAGTAGCACACATCCCTACACTTTGAATA

AACTTCACAAGTGTATCCAAAGCAAACATGTACTCTCAACACCAGTTAGC

TGTTTACCCTTGGTACCAGGCACAACACAACAGTGTGTAACATACTATTT

ACTTTCATTTGTTGAAGACAAGAAACAGGCCAAAAAACTAAAAAGGGTTG

TCTTGGCCTACTGTGAAAAATACCACAGCAGCGTAGAAGGTACTATAGTC

AAGGCAAAGCCTTATTTTCCCTTACCAGAGCCCCCTACAGAGCCCCCTAC

AGACCCCGAGCAGCCATCCACAAGTACACAAGCTTCTGGCACACAACATG

GTCCCACAGCATCTCTGGATGCCGGTGCAGAGCAAGGTGCCACAGGATCA

CCTGGATCTAGTCCAGGACAACAGGGACAAGGGTCTCAGACA

Accordingly, preferably the MuHV Orf73 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 344, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the MuHV Orf73 polypeptide is provided herein as SEQ ID No: 345, as follows:

[SEQ ID No: 345]

ATGCCTACAAGCCCTCCTACCACCAGAAACACCACCAGCGGCAAGACAAGAAGCGGCTGCAAGCGGCGGTGCTTCAAC

AAACCTGCTGCCATGCCTCCTAAGCGGCGGAGAGCACCTAAAAGACCTGCTCCTCCTCCACCTCCTGGTTGCCAAGGC

GACGAGGAATCTTCTCAGGGCACCCAGACACCTAATCCTCCATCTCCACCTGTGCCTCCAAGCAGCCCTACACTGCCA

TCTTCTCCAGTGCCACCTAGCAGCCCAGTGCACGAACCACCTAGTCCAAGTCCTCCACCAGCTCCACCTTCTCCAGAC

GTGGACGTGGAAGGACTGGATGTGGGCGAGACAGACGATCCTGGACCTCCACCACCTAAGCGGTACAGCAGATACCAG

AAGCCTCACAACCCCAGCGATCCTCTGCCTAAGAAATACCAGGGCATGCGCCGGCATCTGCAAGTGACAGCCCCTAGA

CTGTTCGACCCTGAGGGACACCCTCCTACACACTTCAAGAGCGCCGTGATGTTCAGCAGCACACACCCCTACACTCTG

AACAAGCTGCACAAGTGCATCCAGAGCAAACACGTGCTGAGCACCCCTGTGTCCTGTCTGCCTCTGGTGCCTGGAACC

ACACAGCAGTGCGTGACCTACTACCTGCTGAGCTTCGTGGAAGATAAGAAGCAGGCCAAGAAACTGAAGAGAGTGGTG

CTGGCCTACTGCGAGAAGTACCACAGCAGCGTGGAAGGCACCATCGTGAAGGCCAAGCCTTACTTCCCACTGCCTGAG

CCTCCAACCGAGCCACCTACAGATCCTGAGCAGCCTAGCACAAGCACACAGGCCTCTGGAACACAGCACGGACCTACA

GCTAGTCTGGATGCTGGTGCTGAACAGGGCGCCACAGGATCACCTGGAAGTAGCCCTGGACAGCAAGGCCAGGGATCT

CAGACA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 345, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 345 is provided herein as SEQ ID No: 346, as follows:

[SEQ ID No: 346]

AUGCCUACAAGCCCUCCUACCACCAGAAACACCACCAGCGGCAAGACAAGAAGCGGCUGCAAGCGGCGGUGCUUCAAC

AAACCUGCUGCCAUGCCUCCUAAGCGGCGGAGAGCACCUAAAAGACCUGCUCCUCCUCCACCUCCUGGUUGCCAAGGC

GACGAGGAAUCUUCUCAGGGCACCCAGACACCUAAUCCUCCAUCUCCACCUGUGCCUCCAAGCAGCCCUACACUGCCA

UCUUCUCCAGUGCCACCUAGCAGCCCAGUGCACGAACCACCUAGUCCAAGUCCUCCACCAGCUCCACCUUCUCCAGAC

GUGGACGUGGAAGGACUGGAUGUGGGCGAGACAGACGAUCCUGGACCUCCACCACCUAAGCGGUACAGCAGAUACCAG

AAGCCUCACAACCCCAGCGAUCCUCUGCCUAAGAAAUACCAGGGCAUGCGCCGGCAUCUGCAAGUGACAGCCCCUAGA

CUGUUCGACCCUGAGGGACACCCUCCUACACACUUCAAGAGCGCCGUGAUGUUCAGCAGCACACACCCCUACACUCUG

AACAAGCUGCACAAGUGCAUCCAGAGCAAACACGUGCUGAGCACCCCUGUGUCCUGUCUGCCUCUGGUGCCUGGAACC

ACACAGCAGUGCGUGACCUACUACCUGCUGAGCUUCGUGGAAGAUAAGAAGCAGGCCAAGAAACUGAAGAGAGUGGUG

CUGGCCUACUGCGAGAAGUACCACAGCAGCGUGGAAGGCACCAUCGUGAAGGCCAAGCCUUACUUCCCACUGCCUGAG

CCUCCAACCGAGCCACCUACAGAUCCUGAGCAGCCUAGCACAAGCACACAGGCCUCUGGAACACAGCACGGACCUACA

GCUAGUCUGGAUGCUGGUGCUGAACAGGGCGCCACAGGAUCACCUGGAAGUAGCCCUGGACAGCAAGGCCAGGGAUCU

CAGACA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 346, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Torque Teno virus Orf2 (A7XCD9; ORF2 protein Torque teno virus (isolate Human/Finland/Hel32/2002)), or an orthologue thereof. Zheng H, Ye L, Fang X, Li B, Wang Y, Xiang X, Kong L, Wang W et al. (2007) Torque teno virus (SANBAN isolate) ORF2 protein suppresses NF-kB pathways via interaction with IkappaB kinases. J Virol, 81, 21, 11917-11924. It is believed that this IIP suppresses canonical and non-canonical Nf-KB pathways. One embodiment of the polypeptide sequence of Torque Teno virus Orf2 is represented herein as SEQ ID No: 347, as follows:

[SEQ ID No: 347]

MWQPPTQNGTQLERHWFESVWRSHAAFCSCGDCIGHLQHLATNLGRPPAPQPPRDQHPPHIRGLPALPAPPSNRNSWP

GTGGDAAGGEAGGSRGAGDGGDGELADEDLLDAIALAAE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 347, or a variant or fragment thereof.

In one embodiment, the Torque Teno virus Orf2 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 348, as follows:

[SEQ ID No: 348]

ATGTGGCAGCCACCTACCCAGAATGGAACCCAACTCGAACGGCACTGGTTCGAGTCCGTTTGGCGTTCGCATGCTGCC

TTTTGTAGCTGTGGCGACTGTATTGGCCATCTTCAGCATCTGGCTACTAACCTGGGTCGACCACCTGCTCCACAACCG

CCGCGAGACCAACACCCACCGCACATAAGAGGGCTCCCGGCACTCCCGGCACCTCCCAGTAACAGAAACTCATGGCCT

GGTACTGGTGGAGACGCCGCCGGAGGAGAGGCTGGTGGAAGCCGAGGCGCAGGAGATGGAGGAGACGGAGAGCTCGCA

GACGAGGACCTGCTAGACGCCATCGCGCTCGCCGCAGAG

Accordingly, preferably the Torque Teno virus Orf2 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 348, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Torque Teno virus Orf2 polypeptide is provided herein as SEQ ID No: 349, as follows:

[SEQ ID No: 349]

ATGTGGCAGCCTCCTACACAGAATGGCACCCAGCTGGAACGGCATTGGTTCGAGAGCGTTTGGAGAAGCCACGCCGCT

TTCTGCAGCTGCGGAGATTGCATCGGACATCTGCAGCACCTGGCCACCAATCTGGGTAGACCTCCAGCTCCTCAGCCT

CCTCGAGATCAGCACCCTCCTCACATCAGAGGACTGCCTGCACTTCCTGCTCCTCCAAGCAACAGAAACAGCTGGCCT

GGCACAGGCGGAGATGCTGCTGGCGGAGAAGCTGGTGGATCTAGAGGTGCCGGCGACGGTGGCGACGGCGAACTTGCT

GATGAAGATCTGCTGGACGCTATCGCCCTGGCCGCTGAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 349, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 349 is provided herein as SEQ ID No: 350, as follows:

[SEQ ID No: 350]

AUGUGGCAGCCUCCUACACAGAAUGGCACCCAGCUGGAACGGCAUUGGUUCGAGAGCGUUUGGAGAAGCCACGCCGCU

UUCUGCAGCUGCGGAGAUUGCAUCGGACAUCUGCAGCACCUGGCCACCAAUCUGGGUAGACCUCCAGCUCCUCAGCCU

CCUCGAGAUCAGCACCCUCCUCACAUCAGAGGACUGCCUGCACUUCCUGCUCCUCCAAGCAACAGAAACAGCUGGCCU

GGCACAGGCGGAGAUGCUGCUGGCGGAGAAGCUGGUGGAUCUAGAGGUGCCGGCGACGGUGGCGACGGCGAACUUGCU

GAUGAAGAUCUGCUGGACGCUAUCGCCCUGGCCGCUGAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 350, or a fragment or variant thereof.

In one embodiment, the at least one IIP is EBV EBNA1 (P03211; Epstein-Barr nuclear antigen 1 Epstein-Barr virus (strain B95-8)), or an orthologue thereof. One embodiment of the polypeptide sequence of EBV EBNA1 is represented herein as SEQ ID No: 351, as follows:

[SEQ ID No: 351]

MSDEGPGTGPGNGLGEKGDTSGPEGSGGSGPQRRGGDNHGRGRGRGRGRGGGRPGAPGGSGSGPRHRDGVRRPQKRPS

CIGCKGTHGGTGAGAGAGGAGAGGAGAGGGAGAGGGAGGAGGAGGAGAGGGAGAGGGAGGAGGAGAGGGAGAGGGAGG

AGAGGGAGGAGGAGAGGGAGAGGGAGGAGAGGGAGGAGGAGAGGGAGAGGAGGAGGAGAGGAGAGGGAGGAGGAGAGG

AGAGGAGAGGAGAGGAGGAGAGGAGGAGAGGAGGAGAGGGAGGAGAGGGAGGAGAGGAGGAGAGGAGGAGAGGAGGAG

AGGGAGAGGAGAGGGGRGRGGSGGRGRGGSGGRGRGGSGGRRGRGRERARGGSRERARGRGRGRGEKRPRSPSSQSSS

SGSPPRRPPPGRRPFFHPVGEADYFEYHQEGGPDGEPDVPPGAIEQGPADDPGEGPSTGPRGQGDGGRRKKGGWFGKH

RGQGGSNPKFENIAEGLRALLARSHVERTTDEGTWVAGVFVYGGSKTSLYNLRRGTALAIPQCRLTPLSRLPFGMAPG

PGPQPGPLRESIVCYFMVFLQTHIFAEVLKDAIKDLVMTKPAPTCNIRVTVCSFDDGVDLPPWFPPMVEGAAAEGDDG

DDGDEGGDGDEGEEGQE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 351, or a variant or fragment thereof.

In one embodiment, the EBV EBNA1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 352, as follows:

[SEQ ID No: 352]

ATGTCTGACGAGGGGCCAGGTACAGGACCTGGAAATGGCCTAGGAGAGAAGGGAGACACATCTGGACCAGAAGGCTCC

GGCGGCAGTGGACCTCAAAGAAGAGGGGGTGATAACCATGGACGAGGACGGGGAAGAGGACGAGGACGAGGAGGCGGA

AGACCAGGAGCCCCGGGCGGCTCAGGATCAGGGCCAAGACATAGAGATGGTGTCCGGAGACCCCAAAAACGTCCAAGT

TGCATTGGCTGCAAAGGGACCCACGGTGGAACAGGAGCAGGAGCAGGAGCGGGAGGGGCAGGAGCAGGAGGGGCAGGA

GCAGGAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCA

GGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGGG

GCAGGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGA

GGGGCAGGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGCAGGAGGGGCAGGA

GGGGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGG

GCAGGAGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGGG

GCAGGAGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGAGGGGCAGGAGGG

GCAGGAGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGGGGCAGGAGCAGGAGGGGCAGGAGGGGCAGGA

GCAGGAGGAGGGGCAGGAGCAGGAGGGGCAGGAGCAGGAGGTGGAGGCCGGGGTCGAGGAGGCAGTGGAGGCCGGGGT

CGAGGAGGTAGTGGAGGCCGGGGTCGAGGAGGTAGTGGAGGCCGCCGGGGTAGAGGACGTGAAAGAGCCAGGGGGGGA

AGTCGTGAAAGAGCCAGGGGGAGAGGTCGTGGACGTGGAGAAAAGAGGCCCAGGAGTCCCAGTAGTCAGTCATCATCA

TCCGGGTCTCCACCGCGCAGGCCCCCTCCAGGTAGAAGGCCATTTTTCCACCCTGTAGGGGAAGCCGATTATTTTGAA

TACCACCAAGAAGGTGGCCCAGATGGTGAGCCTGACGTGCCCCCGGGAGCGATAGAGCAGGGCCCCGCAGATGACCCA

GGAGAAGGCCCAAGCACTGGACCCCGGGGTCAGGGTGATGGAGGCAGGCGCAAAAAAGGAGGGTGGTTTGGAAAGCAT

CGTGGTCAAGGAGGTTCCAACCCGAAATTTGAGAACATTGCAGAAGGTTTAAGAGCTCTCCTGGCTAGGAGTCACGTA

GAAAGGACTACCGACGAAGGAACTTGGGTCGCCGGTGTGTTCGTATATGGAGGTAGTAAGACCTCCCTTTACAACCTA

AGGCGAGGAACTGCCCTTGCTATTCCACAATGTCGTCTTACACCATTGAGTCGTCTCCCCTTTGGAATGGCCCCTGGA

CCCGGCCCACAACCTGGCCCGCTAAGGGAGTCCATTGTCTGTTATTTCATGGTCTTTTTACAAACTCATATATTTGCT

GAGGTTTTGAAGGATGCGATTAAGGACCTTGTTATGACAAAGCCCGCTCCTACCTGCAATATCAGGGTGACTGTGTGC

AGCTTTGACGATGGAGTAGATTTGCCTCCCTGGTTTCCACCTATGGTGGAAGGGGCTGCCGCGGAGGGTGATGACGGA

GATGACGGAGATGAAGGAGGTGATGGAGATGAGGGTGAGGAAGGGCAGGAGTGA

Accordingly, preferably the EBV EBNA1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 352, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the EBV EBNA1 polypeptide is provided herein as SEQ ID No: 353, as follows:

[SEQ ID No: 353]

ATGTCCGATGAAGGCCCTGGAACAGGCCCTGGCAATGGACTGGGAGAGAAGGGCGATACAAGCGGCCCTGAAGGTTCT

GGCGGATCTGGCCCTCAAAGAAGAGGCGGCGATAATCACGGCAGAGGACGCGGAAGAGGTAGAGGCAGAGGCGGAGGT

AGACCTGGTGCTCCTGGTGGTTCTGGCTCTGGCCCTAGACATAGAGATGGCGTCAGACGGCCTCAGAAGAGGCCTTCT

TGTATCGGCTGCAAGGGCACACATGGCGGAACAGGTGCTGGTGCTGGCGCAGGCGGAGCAGGCGCTGGTGGTGCAGGC

GCTGGCGGCGGTGCCGGTGCAGGCGGCGGAGCTGGTGGCGCTGGCGGTGCTGGCGGAGCTGGTGCAGGCGGAGGTGCC

GGCGCTGGTGGCGGAGCAGGCGGAGCTGGCGGAGCCGGCGCTGGCGGTGGCGCTGGTGCCGGCGGAGGCGCAGGCGGC

GCTGGTGCTGGTGGTGGTGCTGGCGGCGCAGGCGGTGCAGGCGCAGGCGGAGGCGCTGGCGCTGGCGGTGGTGCAGGC

GGTGCTGGCGCTGGCGGCGGTGCTGGCGGAGCCGGTGGTGCTGGTGCTGGTGGCGGAGCTGGCGCTGGCGGAGCTGGC

GGTGCAGGCGGCGCAGGCGCTGGTGGCGCTGGCGCAGGCGGTGGCGCTGGCGGAGCAGGCGGAGCTGGCGCTGGCGGC

GCAGGCGCAGGCGGAGCCGGTGCTGGCGGAGCTGGTGCTGGTGGTGCAGGCGGAGCTGGTGCCGGTGGCGCTGGTGGT

GCCGGTGCCGGTGGTGCCGGCGGAGCCGGCGCAGGCGGCGGTGCAGGCGGAGCAGGCGCAGGCGGCGGAGCTGGTGGT

GCCGGCGCAGGCGGCGCTGGTGGTGCTGGTGCCGGCGGAGCTGGTGGCGCAGGCGCTGGCGGTGCAGGCGGTGCCGGT

GCCGGTGGTGGTGCAGGCGCAGGCGGTGCTGGTGCCGGCGGTGGCGGAAGAGGAAGAGGTGGTAGCGGAGGCCGAGGA

CGAGGCGGAAGTGGTGGTCGTGGTAGAGGCGGCAGCGGAGGAAGAAGAGGACGGGGTAGAGAACGAGCTAGAGGCGGA

TCTAGAGAGAGAGCCCGAGGCAGAGGAAGAGGCCGCGGAGAGAAAAGACCTAGAAGCCCTAGCAGCCAGAGCAGCTCT

AGCGGATCTCCACCTAGAAGGCCACCTCCAGGCAGACGGCCATTCTTTCACCCTGTGGGCGAAGCCGACTACTTCGAG

TACCACCAAGAAGGCGGACCTGACGGCGAACCTGATGTTCCTCCTGGCGCCATTGAACAGGGCCCAGCTGATGATCCT

GGCGAGGGACCTTCTACAGGCCCTAGAGGACAAGGCGACGGCGGCAGACGAAAGAAAGGCGGATGGTTCGGCAAGCAC

AGAGGCCAAGGTGGCAGCAACCCCAAGTTCGAGAATATCGCCGAGGGCCTGAGAGCCCTGCTGGCCAGATCTCACGTG

GAAAGAACCACCGACGAAGGCACATGGGTGGCAGGCGTGTTCGTTTACGGCGGCTCTAAGACCAGCCTGTACAACCTG

AGAAGAGGCACAGCCCTGGCCATTCCTCAGTGCAGACTGACCCCTCTGAGCAGACTGCCTTTTGGCATGGCTCCTGGA

CCTGGACCTCAACCTGGACCACTGAGAGAATCCATCGTGTGCTACTTCATGGTGTTTCTGCAGACCCACATCTTCGCC

GAGGTGCTGAAGGACGCCATCAAGGACCTGGTCATGACAAAGCCCGCTCCTACCTGCAACATCAGAGTGACCGTGTGC

AGCTTCGACGACGGCGTTGACCTGCCTCCTTGGTTTCCTCCAATGGTGGAAGGCGCTGCTGCCGAAGGCGACGATGGC

GACGACGGCGACGAAGGTGGCGACGGCGACGAGGGCGAAGAAGGACAAGAGTAA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 353, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 353 is provided herein as SEQ ID No: 354, as follows:

[SEQ ID No: 354]

AUGUCCGAUGAAGGCCCUGGAACAGGCCCUGGCAAUGGACUGGGAGAGAAGGGCGAUACAAGCGGCCCUGAAGGUUCU

GGCGGAUCUGGCCCUCAAAGAAGAGGCGGCGAUAAUCACGGCAGAGGACGCGGAAGAGGUAGAGGCAGAGGCGGAGGU

AGACCUGGUGCUCCUGGUGGUUCUGGCUCUGGCCCUAGACAUAGAGAUGGCGUCAGACGGCCUCAGAAGAGGCCUUCU

UGUAUCGGCUGCAAGGGCACACAUGGCGGAACAGGUGCUGGUGCUGGCGCAGGCGGAGCAGGCGCUGGUGGUGCAGGC

GCUGGCGGCGGUGCCGGUGCAGGCGGCGGAGCUGGUGGCGCUGGCGGUGCUGGCGGAGCUGGUGCAGGCGGAGGUGCC

GGCGCUGGUGGCGGAGCAGGCGGAGCUGGCGGAGCCGGCGCUGGCGGUGGCGCUGGUGCCGGCGGAGGCGCAGGCGGC

GCUGGUGCUGGUGGUGGUGCUGGCGGCGCAGGCGGUGCAGGCGCAGGCGGAGGCGCUGGCGCUGGCGGUGGUGCAGGC

GGUGCUGGCGCUGGCGGCGGUGCUGGCGGAGCCGGUGGUGCUGGUGCUGGUGGCGGAGCUGGCGCUGGCGGAGCUGGC

GGUGCAGGCGGCGCAGGCGCUGGUGGCGCUGGCGCAGGCGGUGGCGCUGGCGGAGCAGGCGGAGCUGGCGCUGGCGGC

GCAGGCGCAGGCGGAGCCGGUGCUGGCGGAGCUGGUGCUGGUGGUGCAGGCGGAGCUGGUGCCGGUGGCGCUGGUGGU

GCCGGUGCCGGUGGUGCCGGCGGAGCCGGCGCAGGCGGCGGUGCAGGCGGAGCAGGCGCAGGCGGCGGAGCUGGUGGU

GCCGGCGCAGGCGGCGCUGGUGGUGCUGGUGCCGGCGGAGCUGGUGGCGCAGGCGCUGGCGGUGCAGGCGGUGCCGGU

GCCGGUGGUGGUGCAGGCGCAGGCGGUGCUGGUGCCGGCGGUGGCGGAAGAGGAAGAGGUGGUAGCGGAGGCCGAGGA

CGAGGCGGAAGUGGUGGUCGUGGUAGAGGCGGCAGCGGAGGAAGAAGAGGACGGGGUAGAGAACGAGCUAGAGGCGGA

UCUAGAGAGAGAGCCCGAGGCAGAGGAAGAGGCCGCGGAGAGAAAAGACCUAGAAGCCCUAGCAGCCAGAGCAGCUCU

AGCGGAUCUCCACCUAGAAGGCCACCUCCAGGCAGACGGCCAUUCUUUCACCCUGUGGGCGAAGCCGACUACUUCGAG

UACCACCAAGAAGGCGGACCUGACGGCGAACCUGAUGUUCCUCCUGGCGCCAUUGAACAGGGCCCAGCUGAUGAUCCU

GGCGAGGGACCUUCUACAGGCCCUAGAGGACAAGGCGACGGCGGCAGACGAAAGAAAGGCGGAUGGUUCGGCAAGCAC

AGAGGCCAAGGUGGCAGCAACCCCAAGUUCGAGAAUAUCGCCGAGGGCCUGAGAGCCCUGCUGGCCAGAUCUCACGUG

GAAAGAACCACCGACGAAGGCACAUGGGUGGCAGGCGUGUUCGUUUACGGCGGCUCUAAGACCAGCCUGUACAACCUG

AGAAGAGGCACAGCCCUGGCCAUUCCUCAGUGCAGACUGACCCCUCUGAGCAGACUGCCUUUUGGCAUGGCUCCUGGA

CCUGGACCUCAACCUGGACCACUGAGAGAAUCCAUCGUGUGCUACUUCAUGGUGUUUCUGCAGACCCACAUCUUCGCC

GAGGUGCUGAAGGACGCCAUCAAGGACCUGGUCAUGACAAAGCCCGCUCCUACCUGCAACAUCAGAGUGACCGUGUGC

AGCUUCGACGACGGCGUUGACCUGCCUCCUUGGUUUCCUCCAAUGGUGGAAGGCGCUGCUGCCGAAGGCGACGAUGGC

GACGACGGCGACGAAGGUGGCGACGGCGACGAGGGCGAAGAAGGACAAGAGUAA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ 50 ID No: 354, or a fragment or variant thereof.

In one embodiment, the at least one IIP is BDV P protein (POC799; Phosphoprotein Borna disease virus (strain V)), or an orthologue thereof. It is believed that this IIP acts as a decoy protein for phosphorylation by TBK, thus effecting reduction in TBK activity and activation of IRF3 and 7. One embodiment of the polypeptide sequence of BDV P protein is represented herein as SEQ ID No: 355, as follows:

[SEQ ID No: 355]

MATRPSSLVDSLEDEEDPQTLRRERPGSPRPRKVPRNALTQPVDQLLKDLRKNPSMISDPDQRTGREQLSNDELIKKL

VTELAENSMIEAEEVRGTLGDISARIEAGFESLSALQVETIQTAQRCDHSDSIRILGENIKILDRSMKTMMETMKLMM

EKVDLLYASTAVGTSAPMLPSHPAPPRIYPQLPSAPTTDEWDIIP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 355, or a variant or fragment thereof.

In one embodiment, the BDV P polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 356, as follows:

[SEQ ID No: 356]

ATGGCAACGCGACCATCGAGTCTGGTCGACTCCCTGGAGGACGAAGAAGATCCCCAGACACTACGACGGGAACGACCG

GGGTCACCAAGACCACGGAAGGTCCCAAGGAATGCATTGACCCAACCAGTAGACCAGCTCCTGAAGGACCTCAGGAAG

AACCCCTCCATGATCTCAGACCCAGACCAGCGAACCGGAAGGGAGCAGCTGTCGAATGATGAGCTAATCAAGAAGTTA

GTGACGGAGCTGGCCGAGAATAGCATGATCGAGGCTGAGGAGGTGCGGGGCACTCTTGGAGACATCTCGGCTCGTATC

GAGGCAGGGTTTGAGTCCCTGTCCGCCCTCCAAGTGGAAACCATCCAGACAGCTCAGCGGTGCGATCACTCCGACAGC

ATCAGGATCCTCGGCGAGAACATCAAGATACTAGATCGCTCCATGAAGACAATGATGGAGACAATGAAGCTCATGATG

GAGAAGGTGGATCTCCTCTACGCATCAACCGCCGTTGGGACCTCTGCACCCATGTTGCCCTCCCATCCTGCACCTCCG

CGCATTTATCCCCAGCTCCCAAGTGCCCCGACAACGGATGAATGGGACATCATACCA

Accordingly, preferably the BDV P polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 356, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the BDV P polypeptide is provided herein as SEQ ID No: 357, as follows:

[SEQ ID No: 357]

ATGGCCACAAGACCTAGCAGCCTGGTGGACAGCCTGGAAGATGAGGAAGATCCCCAGACACTGCGGAGAGAGAGGCCT

GGATCTCCCAGACCTAGAAAGGTGCCCAGAAACGCCCTGACACAGCCCGTTGATCAGCTGCTGAAGGACCTGAGAAAG

AACCCCAGCATGATCAGCGACCCCGACCAGAGAACCGGAAGAGAGCAGCTGTCTAACGACGAGCTGATTAAGAAGCTG

GTCACCGAGCTGGCCGAGAACTCCATGATTGAGGCCGAAGAAGTGCGGGGCACCCTGGGCGATATCTCTGCCAGAATC

GAGGCCGGCTTTGAGTCTCTGAGCGCCCTGCAGGTTGAGACAATCCAGACAGCCCAGAGATGCGACCACAGCGACAGC

ATCAGAATCCTGGGCGAGAACATCAAGATCCTGGATCGGAGCATGAAGACCATGATGGAAACCATGAAGCTGATGATG

GAAAAGGTGGACCTGCTGTACGCCAGCACAGCCGTGGGAACATCTGCTCCCATGCTGCCTTCTCACCCCGCTCCTCCA

AGAATCTACCCTCAGCTGCCTAGCGCTCCCACCACCGATGAGTGGGATATCATCCCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 357, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 357 is provided herein as SEQ ID No: 358, as follows:

[SEQ ID No: 358]

AUGGCCACAAGACCUAGCAGCCUGGUGGACAGCCUGGAAGAUGAGGAAGAUCCCCAGACACUGCGGAGAGAGAGGCCU

GGAUCUCCCAGACCUAGAAAGGUGCCCAGAAACGCCCUGACACAGCCCGUUGAUCAGCUGCUGAAGGACCUGAGAAAG

AACCCCAGCAUGAUCAGCGACCCCGACCAGAGAACCGGAAGAGAGCAGCUGUCUAACGACGAGCUGAUUAAGAAGCUG

GUCACCGAGCUGGCCGAGAACUCCAUGAUUGAGGCCGAAGAAGUGCGGGGCACCCUGGGCGAUAUCUCUGCCAGAAUC

GAGGCCGGCUUUGAGUCUCUGAGCGCCCUGCAGGUUGAGACAAUCCAGACAGCCCAGAGAUGCGACCACAGCGACAGC

AUCAGAAUCCUGGGCGAGAACAUCAAGAUCCUGGAUCGGAGCAUGAAGACCAUGAUGGAAACCAUGAAGCUGAUGAUG

GAAAAGGUGGACCUGCUGUACGCCAGCACAGCCGUGGGAACAUCUGCUCCCAUGCUGCCUUCUCACCCCGCUCCUCCA

AGAAUCUACCCUCAGCUGCCUAGCGCUCCCACCACCGAUGAGUGGGAUAUCAUCCCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 358, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HPV E7 (P03129; Protein E7 Human papillomavirus type 16), or an orthologue thereof. One embodiment of the polypeptide sequence of HPV E7 is represented herein as SEQ ID No: 359, as follows:

[SEQ ID No: 359]

MHGDTPTLHEYMLDLQPETTDLYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFCCKCDSTLRLCVQSTHVDIRT

LEDLLMGTLGIVCPICSQKP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 359, or a variant or fragment thereof.

In one embodiment, the HPV E7 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 360, as follows:

[SEQ ID No: 360]

ATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACAACTGATCTCTACTGTTATGAG

CAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAGAACCGGACAGAGCCCATTAC

AATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCACACACGTAGACATTCGTACT

TTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCA

Accordingly, preferably the HPV E7 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 360, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HPV E7 polypeptide is provided herein as SEQ ID No: 361, as follows:

[SEQ ID No: 361]

ATGCACGGCGATACCCCTACACTGCACGAGTACATGCTGGACCTGCAGCCTGAGACAACCGACCTGTACTGCTACGAG

CAGCTGAACGACAGCAGCGAGGAAGAGGACGAGATTGACGGACCTGCCGGACAGGCCGAACCTGATAGAGCCCACTAC

AATATCGTGACCTTCTGCTGCAAGTGCGACAGCACCCTGAGACTGTGTGTGCAGAGCACCCACGTGGACATCAGAACC

CTGGAAGATCTGCTGATGGGCACCCTGGGCATCGTGTGCCCTATCTGTTCTCAGAAGCCC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 361, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 361 is provided herein as SEQ ID No: 362, as follows:

[SEQ ID No: 362]

AUGCACGGCGAUACCCCUACACUGCACGAGUACAUGCUGGACCUGCAGCCUGAGACAACCGACCUGUACUGCUACGAG

CAGCUGAACGACAGCAGCGAGGAAGAGGACGAGAUUGACGGACCUGCCGGACAGGCCGAACCUGAUAGAGCCCACUAC

AAUAUCGUGACCUUCUGCUGCAAGUGCGACAGCACCCUGAGACUGUGUGUGCAGAGCACCCACGUGGACAUCAGAACC

CUGGAAGAUCUGCUGAUGGGCACCCUGGGCAUCGUGUGCCCUAUCUGUUCUCAGAAGCCC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 362, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Arenavirus NP1 protein (A0A2H4RDN2; Nucleoprotein Arenavirus sp.), or an orthologue thereof. One embodiment of the polypeptide sequence of Arenavirus NP1 protein is represented herein as SEQ ID No: 363, as follows:

[SEQ ID No: 363]

MSNSKEVKSFLWTQALRRELSPYCTSVKLQVIKDAQSLLHSLDFSEVSNVQRLMRKDKRDDGDLKRLRDLNQAVNNLV

ELKSQQQKNVLSVGQLSSDDLLVLAADIDRLKAKITRTERPQSNGVYMGNLTAQQLEQRKKLLELVGMTRPNLRAGSD

GVVRVWDVKNPDLLNNQFGTMPSLTIACMTKQGQSDINDVVQALTDLGLIYTAKYPNSSDLDQLVKTHPVLGIIDTEK

SAINVSGYNFSLSAAVKAGACMLDGGNMLETIKVTPQNIDPILKKTLAVKKSVGMFVSDTPGDRNPYENLLYKICLSG

NGWPYIASRTSILGRAWDNTVVDLGSSNPITKPLNQQARDKVPGLQQTVGLTYSQIMCLKDIMTGMDPTSKTWIDIEG

RAEDPVEIAIYQPAGGQYIHFYREPTDAKQFKQDSKYSHGIDIVDLFRVQPGLTSAVIESLPKGMVLICQGSEDIRKL

LDSQGRRDIKLIDVMMSKIDARKFENEVWDDLKTLCNMHTGVVHEKKKRGGKQEITPHCALLDCIMYEAATQGSYKTP

KLTPLLPTDLVFRAGAPKVTL

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 363, or a variant or fragment thereof.

In one embodiment, the Arenavirus NP1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 364, as follows:

[SEQ ID No: 364]

ATGAGCAACTCCAAGGAGGTGAAGTCCTTTCTTTGGACTCAAGCCCTTAGGAGGGAATTATCACCATACTGCACAAGT

GTCAAACTTCAAGTTATCAAGGATGCTCAGAGTCTCCTTCACAGCTTGGATTTCTCAGAAGTGAGTAATGTACAACGC

TTGATGAGGAAGGACAAAAGGGATGACGGTGACTTGAAGAGGCTGAGAGATTTAAATCAGGCAGTCAACAATCTTGTT

GAACTAAAATCTCAACAGCAGAAAAATGTCTTAAGTGTGGGGCAGCTGTCATCTGATGACCTTTTAGTCCTCGCTGCT

GACATTGACAGGCTGAAAGCAAAGATAACCAGGACAGAGAGGCCCCAATCTAATGGGGTCTACATGGGGAACCTCACA

GCTCAGCAACTTGAACAACGAAAGAAGCTCCTAGAGTTGGTGGGGATGACCAGACCAAACTTAAGAGCTGGTTCTGAT

GGTGTTGTCAGGGTGTGGGACGTGAAGAATCCTGATCTCTTGAATAACCAATTTGGCACAATGCCCAGTCTAACGATT

GCCTGCATGACAAAACAAGGACAATCAGACATAAATGATGTTGTTCAGGCATTAACTGACTTGGGGCTAATTTATACA

GCTAAGTACCCAAATTCATCAGATCTTGATCAACTTGTCAAAACCCATCCAGTTTTGGGCATCATAGACACAGAAAAA

TCTGCCATCAATGTTTCAGGTTACAACTTCAGCCTGTCAGCTGCAGTTAAGGCAGGTGCATGTATGCTAGATGGGGGT

AACATGCTCGAGACCATAAAGGTAACACCTCAGAATATTGATCCAATTCTGAAGAAGACTCTGGCAGTTAAAAAGTCT

GTTGGCATGTTTGTCTCAGACACACCAGGTGACAGAAACCCATATGAAAACTTACTATACAAGATCTGCCTCTCAGGC

AGTAACCCAATCACAAAGCCCCTCAATCAGCAAGCTAGAGACAAAGTTCCTGGTTTGCAGCAAACAGTTGGACTCACA

TACTCACAAATCATGTGTCTCAAAGACATAATGACCGGTATGGACCCGACAAGTAAGACTTGGATTGACATTGAGGGC

AGGGCTGAGGACCCAGTGGAGATTGCCATCTACCAGCCAGCTGGTGGGCAATATATTCATTTCTACAGAGAACCAACA

GATGCCAAGCAATTTAAGCAGGATTCTAAGTACTCACATGGCATTGACATTGTTGACCTGTTTAGGGTGCAACCAGGC

CTTACAAGTGCTGTGATAGAGAGTCTACCGAAAGGGATGGTCTTAACTTGTCAGGGATCTGAGGACATAAGAAAGCTG

TTAGATAGTCAGGGGCGCCGAGACATCAAGTTAATTGATGTGATGATGAGCAAGATTGATGCACGGAAGTTTGAAAAT

GAGGTCTGGGATGATCTTAAAACACTGTGCAACATGCACACTGGGGTGGTCCATGAGAAGAAGAAGAGAGGTGGTAAA

CAAGAAATAACACCTCACTGTGCACTTCTAGACTGCATTATGTATGAGGCAGCCACCCAGGGGTCATACAAGACCCCC

AAATTAACACCTCTGCTACCAACTGACTTGGTGTTTAGAGCAGGAGCACCCAAAGTCACTCTG

Accordingly, preferably the Arenavirus NP1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 364, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Arenavirus NP1 polypeptide is provided herein as SEQ ID No: 365, as follows:

[SEQ ID No: 365]

ATGAGCAACAGCAAAGAAGTCAAGAGCTTCCTCTGGACACAGGCCCTGAGAAGAGAGCTGAGCCCTTACTGCACCAGC

GTGAAGCTGCAAGTGATCAAGGACGCCCAGAGCCTGCTGCACAGCCTGGATTTTTCCGAGGTGTCCAACGTGCAGCGG

CTGATGCGGAAGGACAAGAGAGATGACGGCGACCTGAAGCGGCTGAGGGATCTGAATCAGGCCGTGAACAACCTGGTG

GAACTGAAGTCCCAGCAGCAGAAAAACGTGCTGAGCGTGGGCCAGCTGAGCAGCGACGATCTGCTTGTTCTGGCCGCC

GACATCGACAGACTGAAGGCCAAGATCACCAGAACCGAGCGGCCTCAGAGCAACGGCGTGTACATGGGAAATCTGACA

GCCCAGCAGCTGGAACAGCGGAAGAAACTGCTGGAACTCGTGGGCATGACCCGGCCTAATCTGAGAGCTGGCTCTGAT

GGCGTCGTCAGAGTGTGGGACGTGAAGAACCCCGACCTGCTGAACAACCAGTTCGGCACCATGCCTAGCCTGACAATC

GCCTGCATGACCAAGCAGGGCCAGAGCGACATCAACGATGTGGTGCAGGCACTGACCGACCTGGGCCTGATCTACACC

GCCAAGTATCCCAACAGCAGCGACCTGGATCAGCTGGTCAAGACACACCCTGTGCTGGGCATCATCGACACCGAGAAG

TCCGCCATCAACGTGTCCGGCTACAACTTCTCTCTGTCTGCCGCCGTGAAAGCCGGCGCTTGTATGCTGGATGGCGGC

AACATGCTGGAAACCATCAAAGTGACCCCTCAGAACATCGACCCCATCCTGAAGAAAACCCTGGCCGTGAAGAAAAGC

GTGGGGATGTTCGTGTCTGACACCCCTGGCGACAGAAACCCCTACGAGAACCTGCTGTACAAGATCTGCCTGAGCGGC

AACGGCTGGCCCTATATCGCCAGCAGAACCAGCATTCTGGGCAGAGCCTGGGACAACACCGTGGTGGATCTGGGCAGC

AGCAACCCCATCACCAAGCCTCTGAACCAGCAGGCCAGAGATAAGGTGCCAGGCCTGCAGCAGACAGTGGGCCTGACA

TACAGCCAGATCATGTGCCTGAAGGACATCATGACCGGCATGGACCCCACCAGCAAGACATGGATCGACATCGAGGGC

AGAGCTGAGGACCCTGTGGAAATCGCCATCTACCAACCTGCCGGCGGACAGTACATCCACTTCTACAGAGAGCCCACC

GACGCCAAGCAGTTCAAGCAGGACAGCAAGTACAGCCACGGCATCGATATCGTGGACCTGTTCAGAGTGCAGCCCGGA

CTGACATCTGCCGTGATCGAGTCTCTGCCCAAAGGCATGGTCCTGACCTGTCAGGGCAGCGAGGACATCAGAAAGCTG

CTCGACAGCCAGGGCAGAAGAGACATCAAGCTGATCGACGTGATGATGAGCAAGATCGACGCCCGGAAGTTCGAGAAC

GAAGTGTGGGATGACCTGAAAACCCTCTGCAACATGCACACCGGCGTGGTGCACGAGAAGAAGAAGAGAGGCGGCAAG

CAAGAGATCACCCCTCACTGTGCTCTGCTGGACTGCATTATGTACGAGGCCGCCACACAGGGCAGCTACAAGACCCCT

AAACTGACCCCTCTGCTGCCTACCGATCTGGTGTTTAGAGCCGGCGCACCCAAAGTGACACTG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 365, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 365 is provided herein as SEQ ID No: 366, as follows:

[SEQ ID No: 366]

AUGAGCAACAGCAAAGAAGUCAAGAGCUUCCUCUGGACACAGGCCCUGAGAAGAGAGCUGAGCCCUUACUGCACCAGC

GUGAAGCUGCAAGUGAUCAAGGACGCCCAGAGCCUGCUGCACAGCCUGGAUUUUUCCGAGGUGUCCAACGUGCAGCGG

CUGAUGCGGAAGGACAAGAGAGAUGACGGCGACCUGAAGCGGCUGAGGGAUCUGAAUCAGGCCGUGAACAACCUGGUG

GAACUGAAGUCCCAGCAGCAGAAAAACGUGCUGAGCGUGGGCCAGCUGAGCAGCGACGAUCUGCUUGUUCUGGCCGCC

GACAUCGACAGACUGAAGGCCAAGAUCACCAGAACCGAGCGGCCUCAGAGCAACGGCGUGUACAUGGGAAAUCUGACA

GCCCAGCAGCUGGAACAGCGGAAGAAACUGCUGGAACUCGUGGGCAUGACCCGGCCUAAUCUGAGAGCUGGCUCUGAU

GGCGUCGUCAGAGUGUGGGACGUGAAGAACCCCGACCUGCUGAACAACCAGUUCGGCACCAUGCCUAGCCUGACAAUC

GCCUGCAUGACCAAGCAGGGCCAGAGCGACAUCAACGAUGUGGUGCAGGCACUGACCGACCUGGGCCUGAUCUACACC

GCCAAGUAUCCCAACAGCAGCGACCUGGAUCAGCUGGUCAAGACACACCCUGUGCUGGGCAUCAUCGACACCGAGAAG

UCCGCCAUCAACGUGUCCGGCUACAACUUCUCUCUGUCUGCCGCCGUGAAAGCCGGCGCUUGUAUGCUGGAUGGCGGC

AACAUGCUGGAAACCAUCAAAGUGACCCCUCAGAACAUCGACCCCAUCCUGAAGAAAACCCUGGCCGUGAAGAAAAGC

GUGGGGAUGUUCGUGUCUGACACCCCUGGCGACAGAAACCCCUACGAGAACCUGCUGUACAAGAUCUGCCUGAGCGGC

AACGGCUGGCCCUAUAUCGCCAGCAGAACCAGCAUUCUGGGCAGAGCCUGGGACAACACCGUGGUGGAUCUGGGCAGC

AGCAACCCCAUCACCAAGCCUCUGAACCAGCAGGCCAGAGAUAAGGUGCCAGGCCUGCAGCAGACAGUGGGCCUGACA

UACAGCCAGAUCAUGUGCCUGAAGGACAUCAUGACCGGCAUGGACCCCACCAGCAAGACAUGGAUCGACAUCGAGGGC

AGAGCUGAGGACCCUGUGGAAAUCGCCAUCUACCAACCUGCCGGCGGACAGUACAUCCACUUCUACAGAGAGCCCACC

GACGCCAAGCAGUUCAAGCAGGACAGCAAGUACAGCCACGGCAUCGAUAUCGUGGACCUGUUCAGAGUGCAGCCCGGA

CUGACAUCUGCCGUGAUCGAGUCUCUGCCCAAAGGCAUGGUCCUGACCUGUCAGGGCAGCGAGGACAUCAGAAAGCUG

CUCGACAGCCAGGGCAGAAGAGACAUCAAGCUGAUCGACGUGAUGAUGAGCAAGAUCGACGCCCGGAAGUUCGAGAAC

GAAGUGUGGGAUGACCUGAAAACCCUCUGCAACAUGCACACCGGCGUGGUGCACGAGAAGAAGAAGAGAGGCGGCAAG

CAAGAGAUCACCCCUCACUGUGCUCUGCUGGACUGCAUUAUGUACGAGGCCGCCACACAGGGCAGCUACAAGACCCCU

AAACUGACCCCUCUGCUGCCUACCGAUCUGGUGUUUAGAGCCGGCGCACCCAAAGUGACACUG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 366, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HCV NS3 protein (P27958; Genome polyprotein Hepatitis C virus genotype 1a (isolate H77)), or an orthologue thereof. One embodiment of the polypeptide sequence of HCV NS3 protein is represented herein as SEQ ID No: 367, as follows:

[SEQ ID No: 367]

APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTATQTFLATCINGVCWTVYHGAGTRTIASPKGPVIQTYTNV

DQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPLLCPTGHAVGLFRA

AVCTRGVAKAVDFIPVENLETTMRSPVFTDNSSPPAVPQSFQVAHLHAPTGSGKSTKVPAAYAAKGYKVLVLNPSVAA

TLGFGAYMSKAHGVDPNIRTGVRTITTGSPITYSTYGKFLADAGCSGGAYDIIICDECHSTDATSISGIGTVLDQAET

AGARLVVLATATPPGSVTVSHPNIEEVALSTTGEIPFYGKAIPLEVIKGGRHLIFCHSKKKCDELAAKLVALGINAVA

YYRGLDVSVIPTSGDVVVVSTDALMTGFTGDFDSVIDCNTCVTQTVDFSLDPTFTIETTTLPQDAVSRTQRRGRTGRG

KPGIYRFVAPGERPSGMFDSSVLCECYDAGCAWYELTPAETTVRLRAYMNTPGLPVCQDHLGFWEGVFTGLTHIDAHF

LSQTKQSGENFPYLVAYQATVCARAQAPPPSWDQMRKCLIRLKPTLHGPTPLLYRLGAVQNEVTLTHPITKYIMTCMS

ADLEVVT

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 367, or a variant or fragment thereof.

In one embodiment, the HCV NS3 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 368, as follows:

[SEQ ID No: 368]

GCGCCCATCACGGCGTACGCCCAGCAGACGAGAGGCCTCCTAGGGTGTATAATCACCAGCCTGACTGGCCGGGACAAA

AACCAAGTGGAGGGTGAGGTCCAGATCGTGTCAACTGCTACCCAGACCTTCCTGGCAACGTGCATCAATGGGGTATGC

TGGACTGTCTACCACGGGGCCGGAACGAGGACCATCGCATCACCCAAGGGTCCTGTCATCCAGACGTATACCAATGTG

GATCAAGACCTCGTGGGCTGGCCCGCTCCTCAAGGTTCCCGCTCATTGACACCCTGCACCTGCGGCTCCTCGGACCTT

TACCTGGTCACGAGGCACGCCGATGTCATTCCCGTGCGCCGGCGAGGTGATAGCAGGGGTAGCCTGCTTTCGCCCCGG

CCCATTTCCTACTTGAAAGGCTCCTCGGGGGGTCCGCTGTTGTGCCCCACGGGACACGCCGTGGGCCTATTCAGGGCC

GCGGTGTGCACCCGTGGAGTGGCTAAGGCGGTGGACTTTATCCCTGTGGAGAACCTAGAGACAACCATGAGATCCCCG

GTGTTCACGGACAACTCCTCTCCACCAGCAGTGCCCCAGAGCTTCCAGGTGGCCCACCTGCATGCTCCCACCGGCAGC

GGTAAGAGCACCAAGGTCCCGGCTGCGTACGCAGCCAAGGGCTACAAGGTGTTGGTGCTCAACCCCTCTGTTGCTGCA

ACACTGGGCTTTGGTGCTTACATGTCCAAGGCCCATGGGGTTGATCCTAATATCAGGACCGGGGTGAGAACAATTACC

ACTGGCAGCCCCATCACGTACTCCACCTACGGCAAGTTCCTTGCCGACGCCGGGTGCTCAGGAGGTGCTTATGACATA

ATAATTTGTGACGAGTGCCACTCCACGGATGCCACATCCATCTCGGGCATCGGCACTGTCCTTGACCAAGCAGAGACT

GCGGGGGCGAGACTGGTTGTGCTCGCCACTGCTACCCCTCCGGGCTCCGTCACTGTGTCCCATCCTAACATCGAGGAG

GTTGCTCTGTCCACCACCGGAGAGATCCCCTTTTACGGCAAGGCTATCCCCCTCGAGGTGATCAAGGGGGGAAGACAT

CTCATCTTCTGCCACTCAAAGAAGAAGTGCGACGAGCTCGCCGCGAAGCTGGTCGCATTGGGCATCAATGCCGTGGCC

TACTACCGCGGTCTTGACGTGTCTGTCATCCCGACCAGCGGCGATGTTGTCGTCGTGTCGACCGATGCTCTCATGACT

GGCTTTACCGGCGACTTCGACTCTGTGATAGACTGCAACACGTGTGTCACTCAGACAGTCGATTTTAGCCTTGACCCT

ACCTTTACCATTGAGACAACCACGCTCCCCCAGGATGCTGTCTCCAGGACTCAACGCCGGGGCAGGACTGGCAGGGGG

AAGCCAGGCATCTATAGATTTGTGGCACCGGGGGAGCGCCCCTCCGGCATGTTCGACTCGTCCGTCCTCTGTGAGTGC

TATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCCGAGACTACAGTTAGGCTACGAGCGTACATGAACACCCCG

GGGCTTCCCGTGTGCCAGGACCATCTTGGATTTTGGGAGGGCGTCTTTACGGGCCTCACTCATATAGATGCCCACTTT

CTATCCCAGACAAAGCAGAGTGGGGAGAACTTTCCTTACCTGGTAGCGTACCAAGCCACCGTGTGCGCTAGGGCTCAA

GCCCCTCCCCCATCGTGGGACCAGATGCGGAAGTGTTTGATCCGCCTTAAACCCACCCTCCATGGGCCAACACCCCTG

CTATACAGACTGGGCGCTGTTCAGAATGAAGTCACCCTGACGCACCCAATCACCAAATACATCATGACATGCATGTCG

GCCGACCTGGAGGTCGTCACG

Accordingly, preferably the HCV NS3 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 368, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HCV NS3 polypeptide is provided herein as SEQ ID No: 369, as follows:

[SEQ ID No: 369]

GCCCCTATCACAGCCTACGCTCAGCAGACAAGAGGCCTGCTGGGCTGCATCATCACAAGCCTGACCGGCAGAGACAAG

AACCAGGTGGAAGGCGAGGTGCAGATCGTGTCTACAGCTACCCAGACCTTCCTGGCCACCTGTATCAATGGCGTGTGC

TGGACCGTGTATCACGGCGCTGGCACCAGAACAATCGCCTCTCCAAAGGGCCCTGTGATCCAGACCTACACCAACGTG

GACCAGGATCTCGTTGGCTGGCCTGCTCCTCAGGGCAGCAGATCTCTGACCCCTTGTACATGCGGCAGCAGCGACCTG

TACCTGGTCACAAGACACGCCGACGTGATCCCCGTCAGAAGAAGAGGCGATAGCAGAGGCAGCCTGCTGAGCCCTAGA

CCTATCAGCTACCTGAAGGGCAGCTCTGGCGGACCTCTGCTGTGTCCAACAGGACATGCCGTGGGCCTGTTTAGAGCC

GCCGTGTGTACAAGAGGCGTGGCCAAAGCCGTGGACTTCATCCCCGTGGAAAACCTGGAAACCACCATGCGGAGCCCC

GTGTTCACCGACAATTCTAGCCCTCCAGCCGTGCCTCAGAGCTTCCAAGTGGCTCATCTGCATGCCCCTACAGGCAGC

GGCAAGAGCACAAAAGTGCCTGCCGCCTATGCCGCCAAGGGCTATAAGGTGCTGGTGCTGAATCCCAGCGTGGCCGCC

ACACTTGGCTTTGGCGCCTATATGTCTAAAGCCCACGGCGTGGACCCCAACATCAGAACCGGCGTGCGGACAATCACA

ACAGGCAGCCCTATCACCTACTCTACCTACGGCAAGTTCCTGGCCGATGCCGGATGTTCTGGCGGAGCCTACGACATC

ATCATCTGCGACGAGTGCCACAGCACCGACGCCACATCTATCTCTGGCATCGGCACCGTGCTGGATCAGGCCGAAACA

GCTGGTGCTAGACTGGTGGTGCTGGCCACAGCTACACCTCCAGGCTCTGTGACAGTGTCTCACCCCAATATCGAGGAA

GTGGCCCTGTCTACAACCGGCGAGATCCCATTCTATGGCAAGGCCATTCCTCTGGAAGTGATCAAAGGCGGCAGACAC

CTGATCTTTTGCCACTCCAAGAAGAAGTGCGACGAGCTGGCCGCCAAACTGGTGGCCCTTGGAATCAATGCCGTGGCC

TACTACAGAGGACTGGACGTGTCCGTGATTCCCACATCTGGCGACGTGGTGGTGGTGTCCACTGATGCCCTGATGACC

GGCTTCACCGGCGACTTCGATAGCGTGATCGACTGCAATACCTGCGTGACCCAGACCGTGGATTTCTCTCTGGACCCC

ACCTTCACCATCGAGACAACCACACTGCCTCAGGACGCCGTGTCTCGGACACAGAGAAGAGGCAGAACCGGAAGAGGC

AAGCCCGGCATCTACAGATTTGTGGCCCCTGGCGAAAGACCCAGCGGCATGTTTGATAGCAGCGTGCTGTGCGAGTGC

TACGATGCTGGCTGTGCTTGGTACGAGCTGACCCCTGCCGAGACTACCGTTAGACTGCGGGCCTACATGAACACCCCT

GGCCTGCCTGTGTGTCAGGACCACCTCGGATTTTGGGAGGGCGTGTTCACAGGACTGACCCACATCGACGCCCACTTT

CTGAGCCAGACAAAGCAGAGCGGCGAGAACTTCCCTTACCTGGTGGCTTACCAGGCCACCGTGTGTGCTAGAGCACAA

GCCCCTCCACCTAGCTGGGACCAGATGAGGAAGTGCCTGATCCGGCTGAAGCCTACACTGCACGGACCAACACCACTG

CTGTATAGACTGGGCGCCGTGCAGAACGAAGTGACCCTGACACATCCCATCACCAAGTACATCATGACCTGCATGAGC

GCCGACCTGGAAGTGGTCACA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 369, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 369 is provided herein as SEQ ID No: 370, as follows:

[SEQ ID No: 370]

GCCCCUAUCACAGCCUACGCUCAGCAGACAAGAGGCCUGCUGGGCUGCAUCAUCACAAGCCUGACCGGCAGAGACAAG

AACCAGGUGGAAGGCGAGGUGCAGAUCGUGUCUACAGCUACCCAGACCUUCCUGGCCACCUGUAUCAAUGGCGUGUGC

UGGACCGUGUAUCACGGCGCUGGCACCAGAACAAUCGCCUCUCCAAAGGGCCCUGUGAUCCAGACCUACACCAACGUG

GACCAGGAUCUCGUUGGCUGGCCUGCUCCUCAGGGCAGCAGAUCUCUGACCCCUUGUACAUGCGGCAGCAGCGACCUG

UACCUGGUCACAAGACACGCCGACGUGAUCCCCGUCAGAAGAAGAGGCGAUAGCAGAGGCAGCCUGCUGAGCCCUAGA

CCUAUCAGCUACCUGAAGGGCAGCUCUGGCGGACCUCUGCUGUGUCCAACAGGACAUGCCGUGGGCCUGUUUAGAGCC

GCCGUGUGUACAAGAGGCGUGGCCAAAGCCGUGGACUUCAUCCCCGUGGAAAACCUGGAAACCACCAUGCGGAGCCCC

GUGUUCACCGACAAUUCUAGCCCUCCAGCCGUGCCUCAGAGCUUCCAAGUGGCUCAUCUGCAUGCCCCUACAGGCAGC

GGCAAGAGCACAAAAGUGCCUGCCGCCUAUGCCGCCAAGGGCUAUAAGGUGCUGGUGCUGAAUCCCAGCGUGGCCGCC

ACACUUGGCUUUGGCGCCUAUAUGUCUAAAGCCCACGGCGUGGACCCCAACAUCAGAACCGGCGUGCGGACAAUCACA

ACAGGCAGCCCUAUCACCUACUCUACCUACGGCAAGUUCCUGGCCGAUGCCGGAUGUUCUGGCGGAGCCUACGACAUC

AUCAUCUGCGACGAGUGCCACAGCACCGACGCCACAUCUAUCUCUGGCAUCGGCACCGUGCUGGAUCAGGCCGAAACA

GCUGGUGCUAGACUGGUGGUGCUGGCCACAGCUACACCUCCAGGCUCUGUGACAGUGUCUCACCCCAAUAUCGAGGAA

GUGGCCCUGUCUACAACCGGCGAGAUCCCAUUCUAUGGCAAGGCCAUUCCUCUGGAAGUGAUCAAAGGCGGCAGACAC

CUGAUCUUUUGCCACUCCAAGAAGAAGUGCGACGAGCUGGCCGCCAAACUGGUGGCCCUUGGAAUCAAUGCCGUGGCC

UACUACAGAGGACUGGACGUGUCCGUGAUUCCCACAUCUGGCGACGUGGUGGUGGUGUCCACUGAUGCCCUGAUGACC

GGCUUCACCGGCGACUUCGAUAGCGUGAUCGACUGCAAUACCUGCGUGACCCAGACCGUGGAUUUCUCUCUGGACCCC

ACCUUCACCAUCGAGACAACCACACUGCCUCAGGACGCCGUGUCUCGGACACAGAGAAGAGGCAGAACCGGAAGAGGC

AAGCCCGGCAUCUACAGAUUUGUGGCCCCUGGCGAAAGACCCAGCGGCAUGUUUGAUAGCAGCGUGCUGUGCGAGUGC

UACGAUGCUGGCUGUGCUUGGUACGAGCUGACCCCUGCCGAGACUACCGUUAGACUGCGGGCCUACAUGAACACCCCU

GGCCUGCCUGUGUGUCAGGACCACCUCGGAUUUUGGGAGGGCGUGUUCACAGGACUGACCCACAUCGACGCCCACUUU

CUGAGCCAGACAAAGCAGAGCGGCGAGAACUUCCCUUACCUGGUGGCUUACCAGGCCACCGUGUGUGCUAGAGCACAA

GCCCCUCCACCUAGCUGGGACCAGAUGAGGAAGUGCCUGAUCCGGCUGAAGCCUACACUGCACGGACCAACACCACUG

CUGUAUAGACUGGGCGCCGUGCAGAACGAAGUGACCCUGACACAUCCCAUCACCAAGUACAUCAUGACCUGCAUGAGC

GCCGACCUGGAAGUGGUCACA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 370, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 1 NS4A protein (P17763; Genome polyprotein Dengue virus type 1 (strain Nauru/West Pac/1974)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 1 NS4A protein is represented herein as SEQ ID No: 371, as follows:

[SEQ ID No: 371]

SVSGDLILEIGKLPQHLTQRAQNALDNLVMLHNSEQGGKAYRHAMEELPDTIETLMLLALIAVLTGGVTLFFLSGRGL

GKTSIGLLCVIASSALLWMASVEPHWIAASIILEFFLMVLLIPEPDRQR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 371, or a variant or fragment thereof.

In one embodiment, the DENV 1 NS4A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 372, as follows:

[SEQ ID No: 372]

AGCGTCTCAGGTGACCTAATATTAGAAATAGGGAAACTTCCACAACATTTAACGCAAAGGGCCCAGAACGCCTTGGAC

AATCTGGTTATGTTGCACAACTCTGAACAAGGAGGAAAAGCCTATAGACACGCCATGGAAGAACTACCAGACACCATA

GAAACGTTAATGCTCCTAGCTTTGATAGCTGTGCTGACTGGTGGAGTGACGTTGTTCTTCCTATCAGGAAGGGGTCTA

GGAAAAACATCCATTGGCCTACTCTGCGTGATTGCCTCAAGCGCACTGCTATGGATGGCCAGTGTGGAACCCCATTGG

ATAGCGGCCTCTATCATACTGGAGTTCTTTCTGATGGTGTTGCTTATTCCAGAGCCGGACAGACAGCGC

Accordingly, preferably the DENV 1 NS4A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 372, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 1 NS4A polypeptide is provided herein as SEQ ID No: 373, as follows:

[SEQ ID No: 373]

TCCGTTAGCGGCGACCTGATCCTGGAAATCGGCAAGCTGCCTCAGCACCTGACACAGAGAGCACAGAACGCCCTGGAC

AACCTGGTCATGCTGCACAACTCTGAGCAAGGCGGCAAGGCCTACAGACACGCCATGGAAGAACTGCCCGACACCATC

GAGACACTGATGCTGCTGGCCCTGATCGCTGTTCTGACAGGCGGAGTGACCCTGTTCTTCCTGTCTGGCAGAGGCCTG

GGCAAGACCTCTATCGGACTGCTGTGTGTGATCGCCAGCTCTGCCCTGCTGTGGATGGCTTCTGTGGAACCTCATTGG

ATCGCCGCCTCTATTATCCTGGAATTCTTCCTGATGGTGCTGCTGATCCCCGAGCCTGACAGACAGAGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 373, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 373 is provided herein as SEQ ID No: 374, as follows:

[SEQ ID No: 374]

UCCGUUAGCGGCGACCUGAUCCUGGAAAUCGGCAAGCUGCCUCAGCACCUGACACAGAGAGCACAGAACGCCCUGGAC

AACCUGGUCAUGCUGCACAACUCUGAGCAAGGCGGCAAGGCCUACAGACACGCCAUGGAAGAACUGCCCGACACCAUC

GAGACACUGAUGCUGCUGGCCCUGAUCGCUGUUCUGACAGGCGGAGUGACCCUGUUCUUCCUGUCUGGCAGAGGCCUG

GGCAAGACCUCUAUCGGACUGCUGUGUGUGAUCGCCAGCUCUGCCCUGCUGUGGAUGGCUUCUGUGGAACCUCAUUGG

AUCGCCGCCUCUAUUAUCCUGGAAUUCUUCCUGAUGGUGCUGCUGAUCCCCGAGCCUGACAGACAGAGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 374, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 1 NS2A (P17763; Genome polyprotein Dengue virus type 1 (strain Nauru/West Pac/1974)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 1 NS2A is represented herein as SEQ ID No: 375, as follows:

[SEQ ID No: 375]

GSGEVDSFSLGLLCISIMIEEVMRSRWSRKMLMTGTLAVFLLLTMGQLTWNDLIRLCIMVGANASDKMGMGTTYLALM

ATFRMRPMFAVGLLFRRLTSREVLLLTVGLSLVASVELPNSLEELGDGLAMGIMMLKLLTDFQSHQLWATLLSLTFVK

TTFSLHYAWKTMAMILSIVSLFPLCLSTTSQKTTWLPVLLGSLGCKPLTMFLITENKIWGRK

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 375, or a variant or fragment thereof.

In one embodiment, the DENV 1 NS2A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 376, as follows:

[SEQ ID No: 376]

GGGTCAGGAGAAGTGGACAGTTTTTCACTAGGACTGCTATGCATATCAATAATGATCGAAGAGGTAATGAGATCCAGA

TGGAGCAGAAAAATGCTGATGACTGGAACATTGGCTGTGTTCCTCCTTCTCACAATGGGACAATTGACATGGAATGAT

CTGATCAGGCTATGTATCATGGTTGGAGCCAACGCTTCAGACAAGATGGGGATGGGAACAACGTACCTAGCTTTGATG

GCCACTTTCAGAATGAGACCAATGTTCGCAGTCGGGCTACTGTTTCGCAGATTAACATCTAGAGAAGTTCTTCTTCTT

ACAGTTGGATTGAGTCTGGTGGCATCTGTAGAACTACCAAATTCCTTAGAGGAGCTAGGGGATGGACTTGCAATGGGC

ATCATGATGTTGAAATTACTGACTGATTTTCAGTCACATCAGCTATGGGCTACCTTGCTGTCTTTAACATTTGTCAAA

ACAACTTTTTCATTGCACTATGCATGGAAGACAATGGCTATGATACTGTCAATTGTATCTCTCTTCCCTTTATGCCTG

TCCACGACTTCTCAAAAAACAACATGGCTTCCGGTGTTGCTGGGATCTCTTGGATGCAAACCACTAACCATGTTTCTT

ATAACAGAAAACAAAATCTGGGGAAGGAAA

Accordingly, preferably the DENV 1 NS2A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 376, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 1 NS2A polypeptide is provided herein as SEQ ID No: 377, as follows:

[SEQ ID No: 377]

GGATCTGGCGAGGTGGACTCTTTTTCTCTGGGCCTGCTGTGCATCAGCATCATGATCGAGGAAGTGATGCGGAGCCGC

TGGTCCCGGAAAATGCTGATGACTGGAACCCTGGCCGTGTTCCTGCTGCTGACAATGGGACAGCTGACCTGGAACGAC

CTGATCCGGCTGTGTATCATGGTCGGAGCCAACGCCAGCGACAAGATGGGCATGGGCACAACCTATCTGGCCCTGATG

GCCACCTTCCGGATGAGGCCTATGTTTGCCGTGGGACTGCTGTTCAGAAGGCTGACCTCTAGAGAGGTGCTGCTGCTC

ACAGTGGGCCTGTCTCTGGTGGCTTCTGTGGAACTGCCCAACAGCCTGGAAGAACTCGGAGATGGACTGGCCATGGGC

ATTATGATGCTCAAGCTGCTGACCGACTTCCAGAGCCACCAGCTGTGGGCTACACTGCTGAGCCTGACCTTCGTGAAA

ACCACCTTCAGCCTGCACTACGCCTGGAAAACAATGGCCATGATCCTGAGCATCGTGTCTCTGTTCCCTCTGTGCCTG

AGCACCACCAGCCAGAAAACCACATGGCTGCCTGTGCTGCTGGGCTCTCTGGGCTGTAAACCCCTGACCATGTTCCTG

ATCACCGAGAACAAGATCTGGGGCAGAAAG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 377, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 377 is provided herein as SEQ ID No: 378, as follows:

[SEQ ID No: 378]

GGAUCUGGCGAGGUGGACUCUUUUUCUCUGGGCCUGCUGUGCAUCAGCAUCAUGAUCGAGGAAGUGAUGCGGAGCCGC

UGGUCCCGGAAAAUGCUGAUGACUGGAACCCUGGCCGUGUUCCUGCUGCUGACAAUGGGACAGCUGACCUGGAACGAC

CUGAUCCGGCUGUGUAUCAUGGUCGGAGCCAACGCCAGCGACAAGAUGGGCAUGGGCACAACCUAUCUGGCCCUGAUG

GCCACCUUCCGGAUGAGGCCUAUGUUUGCCGUGGGACUGCUGUUCAGAAGGCUGACCUCUAGAGAGGUGCUGCUGCUC

ACAGUGGGCCUGUCUCUGGUGGCUUCUGUGGAACUGCCCAACAGCCUGGAAGAACUCGGAGAUGGACUGGCCAUGGGC

AUUAUGAUGCUCAAGCUGCUGACCGACUUCCAGAGCCACCAGCUGUGGGCUACACUGCUGAGCCUGACCUUCGUGAAA

ACCACCUUCAGCCUGCACUACGCCUGGAAAACAAUGGCCAUGAUCCUGAGCAUCGUGUCUCUGUUCCCUCUGUGCCUG

AGCACCACCAGCCAGAAAACCACAUGGCUGCCUGUGCUGCUGGGCUCUCUGGGCUGUAAACCCCUGACCAUGUUCCUG

AUCACCGAGAACAAGAUCUGGGGCAGAAAG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 378, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 2 NS2A (P29990; Genome polyprotein Dengue virus type 2 (strain Thailand/16681/1984)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 2 NS2A is represented herein as SEQ ID No: 379, as follows:

[SEQ ID No: 379]

GHGQVDNFSLGVLGMALFLEEMLRTRVGTKHAILLVAVSFVTLIIGNMSFRDLGRVMVMVGATMTDDIGMGVTYLALL

AAFKVRPTFAAGLLLRKLTSKALMMTTIGIVLSSQSTTPETILELTDALALGMMVLKMVRNMEKYQLAVTIMAILCVP

NAVILQNAWKVSCTILAVVSVSPLFLTSSQQKTDWIPLALTIKGLNPTAIFLTTLSRISKKR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 379, or a variant or fragment thereof.

In one embodiment, the DENV 2 NS2A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 380, as follows:

[SEQ ID No: 380]

GGACATGGGCAGGTCGACAACTTTTCACTAGGAGTCTTGGGAATGGCATTGTTCCTGGAGGAAATGCTTAGGACCCGA

GTAGGAACGAAACATGCAATACTACTAGTTGCAGTTTCTTTTGTGACATTGATCATAGGGAACATGTCCTTTAGAGAC

CTGGGAAGAGTAATGGTTATGGTAGGCGCCACTATGACGGATGACATAGGTATGGGCGTGACTTATCTTGCCCTACTA

GCAGCCTTCAAAGTCAGACCAACTTTTGCAGCTGGACTACTCTTGAGAAAGCTGACCTCCAAGGCATTGATGATGACT

ACTATAGGAATTGTACTCTCCTCCCAGAGCACTACACCAGAGACCATTCTTGAGTTGACTGATGCGTTAGCCTTAGGC

ATGATGGTCCTCAAAATGGTGAGAAATATGGAAAAGTATCAATTGGCAGTGACTATCATGGCTATCTTGTGCGTCCCA

AACGCAGTGATATTACAAAACGCATGGAAAGTGAGTTGCACGATATTGGCAGTGGTGTCCGTTTCCCCACTGTTCTTA

ACATCCTCACAGCAAAAAACGGATTGGATACCATTAGCGTTGACGATCAAAGGTCTCAATCCAACAGCTATTTTTCTA

ACAACCCTCTCAAGAACCAGCAAGAAAAGG

Accordingly, preferably the DENV 2 NS2A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 380, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 2 NS2A polypeptide is provided herein as SEQ ID No: 381, as follows:

[SEQ ID No: 381]

GGACACGGACAGGTGGACAATTTTTCCCTGGGCGTGCTCGGCATGGCCCTGTTTCTGGAAGAGATGCTGAGAACCAGA

GTGGGCACCAAGCACGCCATTCTGCTGGTGGCCGTGTCCTTCGTGACACTGATCATCGGCAACATGAGCTTCCGCGAC

CTGGGCAGAGTGATGGTCATGGTCGGAGCCACCATGACCGACGATATCGGCATGGGCGTGACCTATCTGGCTCTGCTG

GCCGCTTTTAAAGTGCGGCCTACATTTGCCGCCGGACTGCTGCTGAGAAAGCTGACATCTAAGGCCCTGATGATGACC

ACCATCGGCATCGTGCTGAGCAGCCAGAGCACCACACCTGAGACAATCCTGGAACTGACCGACGCTCTGGCCCTGGGA

ATGATGGTGCTGAAGATGGTCCGAAACATGGAAAAGTACCAGCTGGCCGTGACCATCATGGCCATCCTGTGTGTGCCC

AACGCCGTGATCCTGCAGAACGCCTGGAAGGTGTCCTGTACCATCCTGGCCGTGGTGTCTGTGTCCCCTCTGTTTCTG

ACCAGCAGCCAGCAGAAAACCGACTGGATCCCACTGGCTCTGACCATCAAGGGCCTGAATCCTACCGCCATCTTCCTG

ACCACACTGAGCCGGACCAGCAAGAAGAGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 381, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 381 is provided herein as SEQ ID No: 382, as follows:

[SEQ ID No: 382]

GGACACGGACAGGUGGACAAUUUUUCCCUGGGCGUGCUCGGCAUGGCCCUGUUUCUGGAAGAGAUGCUGAGAACCAGA

GUGGGCACCAAGCACGCCAUUCUGCUGGUGGCCGUGUCCUUCGUGACACUGAUCAUCGGCAACAUGAGCUUCCGCGAC

CUGGGCAGAGUGAUGGUCAUGGUCGGAGCCACCAUGACCGACGAUAUCGGCAUGGGCGUGACCUAUCUGGCUCUGCUG

GCCGCUUUUAAAGUGCGGCCUACAUUUGCCGCCGGACUGCUGCUGAGAAAGCUGACAUCUAAGGCCCUGAUGAUGACC

ACCAUCGGCAUCGUGCUGAGCAGCCAGAGCACCACACCUGAGACAAUCCUGGAACUGACCGACGCUCUGGCCCUGGGA

AUGAUGGUGCUGAAGAUGGUCCGAAACAUGGAAAAGUACCAGCUGGCCGUGACCAUCAUGGCCAUCCUGUGUGUGCCC

AACGCCGUGAUCCUGCAGAACGCCUGGAAGGUGUCCUGUACCAUCCUGGCCGUGGUGUCUGUGUCCCCUCUGUUUCUG

ACCAGCAGCCAGCAGAAAACCGACUGGAUCCCACUGGCUCUGACCAUCAAGGGCCUGAAUCCUACCGCCAUCUUCCUG

ACCACACUGAGCCGGACCAGCAAGAAGAGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 382, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 4 NS2A (P09866; Genome polyprotein Dengue virus type 4 (strain Dominica/814669/1981)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 4 NS2A is represented herein as SEQ ID No: 383, as follows:

[SEQ ID No: 383]

GQGTSETFSMGLLCLTLFVEECLRRRVTRKHMILVVVITLCAIILGGLTWMDLLRALIMLGDTMSGRIGGQIHLAIMA

VFKMSPGYVLGVFLRKLTSRETALMVIGMAMTTVLSIPHDLMELIDGISLGLILLKIVTQFDNTQVGTLALSLTFIRS

TMPLVMAWRTIMAVLFVVTLIPLCRTSCLQKQSHWVEITALILGAQALPVYLMTLMKGASRR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 383, or a variant or fragment thereof.

In one embodiment, the DENV 4 NS2A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 384, as follows:

[SEQ ID No: 384]

GGACAGGGCACATCAGAAACTTTTTCTATGGGTCTGTTGTGCCTGACCTTGTTTGTGGAAGAATGCTTGAGGAGAAGA

TTACTACGAGCCCTCATCATGTTGGGGGACACTATGTCTGGTAGAATAGGAGGACAGATCCACCTAGCCATCATGGCA

GTGTTCAAGATGTCACCAGGATACGTGCTGGGTGTGTTTTTAAGGAAACTCACTTCAAGAGAGACAGCACTAATGGTA

ATAGGAATGGCCATGACAACGGTGCTTTCAATTCCACATGACCTTATGGAACTCATTGATGGAATATCACTGGGACTA

AGCTGTCTTCAAAAACAGTCTCATTGGGTAGAAATAACAGCACTCATCCTAGGAGCCCAAGCTCTGCCAGTGTACCTA

ATGACTCTTATGAAAGGAGCCTCAAGAAGA

Accordingly, preferably the DENV 4 NS2A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 384, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 4 NS2A polypeptide is provided herein as SEQ ID No: 385, as follows:

[SEQ ID No: 385]

GGCCAGGGAACAAGCGAGACATTTTCCATGGGCCTGCTGTGTCTGACCCTGTTCGTGGAAGAGTGCCTGCGGAGAAGA

GTGACCCGGAAGCACATGATCCTGGTGGTGGTCATCACCCTGTGCGCCATCATTCTCGGCGGCCTGACATGGATGGAT

CTGCTGAGAGCCCTGATCATGCTGGGCGATACCATGAGCGGCAGAATCGGCGGACAGATCCACCTGGCCATCATGGCC

GTGTTCAAGATGAGCCCTGGCTACGTGCTGGGCGTGTTCCTGAGAAAGCTGACCAGCAGAGAAACAGCCCTGATGGTC

ATCGGAATGGCCATGACCACCGTGCTGAGCATCCCTCACGACCTGATGGAACTGATCGACGGCATCAGCCTGGGCCTG

ATCCTGCTGAAGATCGTGACCCAGTTCGACAACACCCAAGTGGGCACACTGGCCCTGAGCCTGACCTTCATCAGATCC

ACAATGCCCCTCGTGATGGCCTGGCGGACAATTATGGCCGTGCTGTTCGTCGTGACACTGATCCCTCTGTGCAGAACC

AGCTGCCTGCAGAAACAGAGCCACTGGGTCGAGATCACCGCTCTGATTCTGGGAGCACAGGCCCTGCCTGTGTACCTG

ATGACACTTATGAAGGGCGCCAGCAGACGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 385, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 385 is provided herein as SEQ ID No: 386, as follows:

[SEQ ID No: 386]

GGCCAGGGAACAAGCGAGACAUUUUCCAUGGGCCUGCUGUGUCUGACCCUGUUCGUGGAAGAGUGCCUGCGGAGAAGA

GUGACCCGGAAGCACAUGAUCCUGGUGGUGGUCAUCACCCUGUGCGCCAUCAUUCUCGGCGGCCUGACAUGGAUGGAU

CUGCUGAGAGCCCUGAUCAUGCUGGGCGAUACCAUGAGCGGCAGAAUCGGCGGACAGAUCCACCUGGCCAUCAUGGCC

GUGUUCAAGAUGAGCCCUGGCUACGUGCUGGGCGUGUUCCUGAGAAAGCUGACCAGCAGAGAAACAGCCCUGAUGGUC

AUCGGAAUGGCCAUGACCACCGUGCUGAGCAUCCCUCACGACCUGAUGGAACUGAUCGACGGCAUCAGCCUGGGCCUG

AUCCUGCUGAAGAUCGUGACCCAGUUCGACAACACCCAAGUGGGCACACUGGCCCUGAGCCUGACCUUCAUCAGAUCC

ACAAUGCCCCUCGUGAUGGCCUGGCGGACAAUUAUGGCCGUGCUGUUCGUCGUGACACUGAUCCCUCUGUGCAGAACC

AGCUGCCUGCAGAAACAGAGCCACUGGGUCGAGAUCACCGCUCUGAUUCUGGGAGCACAGGCCCUGCCUGUGUACCUG

AUGACACUUAUGAAGGGCGCCAGCAGACGG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 386, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 1 NS2B (P17763; Genome polyprotein Dengue virus type 1 (strain Nauru/West Pac/1974)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 1 NS2B is represented herein as SEQ ID No: 387, as follows:

[SEQ ID No: 387]

SWPLNEGIMAVGIVSILLSSLLKNDVPLAGPLIAGGMLIACYVISGSSADLSLEKAAEVSWEEEAEHSGASHNILVEV

QDDGTMKIKDEERDDTLTILLKATLLAISGVYPMSIPATLFVWYFWQKKKQR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 387, or a variant or fragment thereof.

In one embodiment, the DENV 1 NS2B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 388, as follows:

[SEQ ID No: 388]

AGCTGGCCTCTCAATGAAGGAATTATGGCTGTTGGAATAGTTAGCATTCTTCTAAGTTCACTTCTCAAGAATGATGTG

CCACTAGCTGGCCCACTAATAGCTGGAGGCATGCTAATAGCATGTTATGTCATATCTGGAAGCTCGGCCGATTTATCA

CTGGAGAAAGCGGCTGAGGTCTCCTGGGAAGAAGAAGCAGAACACTCTGGTGCCTCACACAACATACTAGTGGAGGTC

CAAGATGATGGAACCATGAAGATAAAGGATGAAGAGAGAGATGACACACTCACCATTCTCCTCAAAGCAACTCTGCTA

GCAATCTCAGGGGTATACCCAATGTCAATACCGGCGACCCTCTTTGTGTGGTATTTTTGGCAGAAAAAGAAACAGAGA

Accordingly, preferably the DENV 1 NS2B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 388, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 1 NS2B polypeptide is provided herein as SEQ ID No: 389, as follows:

[SEQ ID No: 389]

AGCTGGCCTCTGAACGAGGGAATTATGGCCGTGGGCATCGTGTCCATCCTGCTGTCTAGCCTGCTGAAGAACGACGTG

CCACTGGCCGGACCTCTTATTGCTGGCGGAATGCTGATCGCCTGCTACGTGATCAGCGGCAGCTCTGCCGATCTGAGC

CTGGAAAAAGCCGCCGAGGTGTCCTGGGAAGAAGAGGCCGAACATTCTGGCGCCTCTCACAACATCCTGGTGGAAGTG

CAGGACGACGGCACCATGAAGATCAAGGACGAGGAACGGGACGACACCCTGACCATTCTGCTGAAGGCTACCCTGCTG

GCCATCAGCGGAGTGTACCCTATGAGCATCCCCGCCACTCTGTTCGTGTGGTACTTCTGGCAGAAGAAGAAGCAGCGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 389, or a fragment or variant thereof.

[SEQ ID No: 390]

AGCUGGCCUCUGAACGAGGGAAUUAUGGCCGUGGGCAUCGUGUCCAUCCUGCUGUCUAGCCUGCUGAAGAACGACGUG

CCACUGGCCGGACCUCUUAUUGCUGGCGGAAUGCUGAUCGCCUGCUACGUGAUCAGCGGCAGCUCUGCCGAUCUGAGC

CUGGAAAAAGCCGCCGAGGUGUCCUGGGAAGAAGAGGCCGAACAUUCUGGCGCCUCUCACAACAUCCUGGUGGAAGUG

CAGGACGACGGCACCAUGAAGAUCAAGGACGAGGAACGGGACGACACCCUGACCAUUCUGCUGAAGGCUACCCUGCUG

GCCAUCAGCGGAGUGUACCCUAUGAGCAUCCCCGCCACUCUGUUCGUGUGGUACUUCUGGCAGAAGAAGAAGCAGCGG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 390, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 2 NS2B (P29990; Genome polyprotein Dengue virus type 2 (strain Thailand/16681/1984)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 2 NS2B is represented herein as SEQ ID No: 391, as follows:

[SEQ ID No: 391]

SWPLNEAIMAVGMVSILASSLLKNDIPMTGPLVAGGPLTVCYVLTGRSA

DLELERAADVKWEDQAEISGSSPILSITISEDGSMSIKNEEEEQTLTIL

IRTGLLVISGLFPVSIPITAAAWYLWEVKKQR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 391, or a variant or fragment thereof.

In one embodiment, the DENV 2 NS2B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 392, as follows:

[SEQ ID No: 392]

AGCTGGCCATTAAATGAGGCTATCATGGCAGTCGGGATGGTGAGCATTTTAGCCAGTTCTCTCCTAAAAAATGATATT

CTGGAGAGAGCAGCCGATGTCAAATGGGAAGACCAGGCAGAGATATCAGGAAGCAGCCCAATCCTGTCAATAACAATA

TCAGAAGATGGTAGCATGTCGATAAAAAATGAAGAGGAAGAACAAACACTGACCATACTCATTAGAACAGGATTGCTG

GTGATCTCAGGACTTTTTCCTGTATCAATACCAATCACGGCAGCAGCATGGTACCTGTGGGAAGTGAAGAAACAACGG

Accordingly, preferably the DENV 2 NS2B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 392, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 2 NS2B polypeptide is provided herein as SEQ ID No: 393, as follows:

[SEQ ID No: 393]

AGCTGGCCTCTGAACGAGGCCATTATGGCCGTCGGCATGGTGTCTATCCTGGCCAGCAGCCTGCTGAAGAACGACATC

CCTATGACAGGCCCTCTGGTGGCTGGTGGACCTCTGACAGTGTGTTACGTGCTGACAGGCAGAAGCGCCGACCTGGAA

CTTGAAAGGGCCGCTGATGTGAAGTGGGAAGATCAGGCCGAGATCAGCGGCAGCAGCCCTATCCTGAGCATCACCATC

AGCGAGGACGGCAGCATGAGCATCAAGAACGAGGAAGAGGAACAGACCCTGACCATCCTGATCAGAACCGGCCTGCTG

GTCATCAGCGGACTGTTCCCTGTGTCAATCCCCATCACAGCCGCCGCTTGGTATCTGTGGGAAGTGAAGAAGCAGCGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 393, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 393 is provided herein as SEQ ID No: 394, as follows:

[SEQ ID No: 394]

AGCUGGCCUCUGAACGAGGCCAUUAUGGCCGUCGGCAUGGUGUCUAUCCUGGCCAGCAGCCUGCUGAAGAACGACAUC

CCUAUGACAGGCCCUCUGGUGGCUGGUGGACCUCUGACAGUGUGUUACGUGCUGACAGGCAGAAGCGCCGACCUGGAA

CUUGAAAGGGCCGCUGAUGUGAAGUGGGAAGAUCAGGCCGAGAUCAGCGGCAGCAGCCCUAUCCUGAGCAUCACCAUC

AGCGAGGACGGCAGCAUGAGCAUCAAGAACGAGGAAGAGGAACAGACCCUGACCAUCCUGAUCAGAACCGGCCUGCUG

GUCAUCAGCGGACUGUUCCCUGUGUCAAUCCCCAUCACAGCCGCCGCUUGGUAUCUGUGGGAAGUGAAGAAGCAGCGG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 394, or a fragment or variant thereof.

In one embodiment, the at least one IIP is DENV 4 NS2B (P09866; Genome polyprotein virus type 4 (strain Dominica/814669/1981)), or an orthologue thereof. One embodiment of the polypeptide sequence of DENV 4 NS2B is represented herein as SEQ ID No: 395, as follows:

[SEQ ID No: 395]

SWPLNEGIMAVGLVSLLGSALLKNDVPLAGPMVAGGLLLAAYVMSGSSA

DLSLEKAANVQWDEMADITGSSPIIEVKQDEDGSFSIRDVEETNMITLL

VKLALITVSGLYPLAIPVTMTLWYMWQVKTQR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 395, or a variant or fragment thereof.

In one embodiment, the DENV 4 NS2B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 396, as follows:

[SEQ ID No: 396]

TCTTGGCCTCTTAACGAGGGCATAATGGCTGTGGGTTTGGTTAGTCTCTTAGGAAGCGCTCTTTTAAAGAATGATGTC

CCTTTAGCTGGCCCAATGGTGGCAGGAGGCTTACTTCTGGCGGCTTACGTGATGAGTGGTAGCTCAGCAGATCTGTCA

CTAGAGAAGGCCGCCAACGTGCAGTGGGATGAAATGGCAGACATAACAGGCTCAAGCCCAATCATAGAAGTGAAGCAG

GATGAAGATGGCTCTTTCTCCATACGGGACGTCGAGGAAACCAATATGATAACCCTTTTGGTGAAACTGGCACTGATA

ACAGTGTCAGGTCTCTACCCCTTGGCAATTCCAGTCACAATGACCTTATGGTACATGTGGCAAGTGAAAACACAAAGA

Accordingly, preferably the DENV 4 NS2B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 396, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the DENV 4 NS2B polypeptide is provided herein as SEQ ID No: 397, as follows:

[SEQ ID No: 397]

AGCTGGCCTCTGAACGAGGGAATCATGGCCGTTGGCCTGGTGTCTCTGCTGGGATCTGCCCTGCTGAAGAACGATGTG

CCTCTGGCCGGACCTATGGTTGCTGGTGGACTGCTGCTGGCCGCCTATGTGATGTCTGGAAGCAGCGCCGATCTGAGC

CTGGAAAAGGCCGCTAACGTGCAGTGGGACGAGATGGCCGATATCACAGGCAGCAGCCCCATCATCGAAGTGAAGCAG

GATGAGGACGGCAGCTTCAGCATCCGCGACGTGGAAGAGACAAACATGATCACCCTGCTGGTCAAGCTGGCCCTGATC

ACCGTGTCTGGCCTGTATCCTCTGGCTATCCCCGTGACCATGACACTGTGGTACATGTGGCAAGTGAAAACCCAGCGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 397, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 397 is provided herein as SEQ ID No: 398, as follows:

[SEQ ID No: 398]

AGCUGGCCUCUGAACGAGGGAAUCAUGGCCGUUGGCCUGGUGUCUCUGCUGGGAUCUGCCCUGCUGAAGAACGAUGUG

CCUCUGGCCGGACCUAUGGUUGCUGGUGGACUGCUGCUGGCCGCCUAUGUGAUGUCUGGAAGCAGCGCCGAUCUGAGC

CUGGAAAAGGCCGCUAACGUGCAGUGGGACGAGAUGGCCGAUAUCACAGGCAGCAGCCCCAUCAUCGAAGUGAAGCAG

GAUGAGGACGGCAGCUUCAGCAUCCGCGACGUGGAAGAGACAAACAUGAUCACCCUGCUGGUCAAGCUGGCCCUGAUC

ACCGUGUCUGGCCUGUAUCCUCUGGCUAUCCCCGUGACCAUGACACUGUGGUACAUGUGGCAAGUGAAAACCCAGCGG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 398, or a fragment or variant thereof.

In one embodiment, the at least one IIP is WNV NS4A (P06935; Genome polyprotein West Nile virus NS4A), or an orthologue thereof. One embodiment of the polypeptide sequence of WNV NS4A is represented herein as SEQ ID No: 399, as follows:

[SEQ ID No: 399]

SQIGLVEVLGRMPEHFMVKTWEALDTMYVVATAEKGGRAHRMALEELPD

ALQTIVLIALLSVMSLGVFFLLMQRKGIGKIGLGGVILGAATFFCWMAE

VPGTKIAGMLLLSLLLMIVLIPEPEKQR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 399, or a variant or fragment thereof.

In one embodiment, the WNV NS4A polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 400, as follows:

[SEQ ID No: 400]

TCACAAATCGGGCTCGTTGAGGTGCTCGGGAGAATGCCTGAACACTTCATGGTGAAAACTTGGGAGGCATTGGACACG

ATGTATGTGGTGGCGACCGCTGAAAAAGGAGGCCGAGCTCACAGGATGGCTCTTGAGGAGCTACCGGACGCCCTTCAG

ACAATAGTTTTGATTGCACTATTGAGTGTGATGTCCTTAGGTGTGTTTTTTCTACTCATGCAAAGGAAGGGCATTGGT

AAGATTGGCTTGGGAGGAGTAATCTTAGGAGCTGCCACATTCTTCTGCTGGATGGCTGAAGTCCCAGGAACGAAAATA

GCAGGCATGCTCCTGCTTTCCCTGCTGCTCATGATTGTTTTGATTCCGGAGCCGGAAAAGCAGCGC

Accordingly, preferably the WNV NS4A polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 400, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the WNV NS4A polypeptide is provided herein as SEQ ID No: 401, as follows:

[SEQ ID No: 401]

TCTCAGATCGGCCTGGTGGAAGTGCTGGGCAGAATGCCTGAGCACTTCATGGTCAAGACCTGGGAAGCCCTGGACACT

ATGTACGTGGTGGCCACAGCCGAGAAAGGCGGCAGAGCACATAGAATGGCCCTGGAAGAACTGCCCGACGCTCTGCAG

ACAATCGTGCTGATTGCCCTGCTGAGCGTGATGAGCCTGGGCGTGTTCTTCCTGCTGATGCAGAGAAAAGGCATCGGC

AAGATCGGACTCGGCGGCGTTATACTGGGAGCCGCCACCTTCTTTTGCTGGATGGCTGAAGTGCCCGGCACCAAGATT

GCCGGAATGCTGCTGCTGTCCCTGCTGCTGATGATTGTGCTGATCCCCGAGCCTGAGAAGCAGAGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 401, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 401 is provided herein as SEQ ID No: 402, as follows:

[SEQ ID No: 402]

UCUCAGAUCGGCCUGGUGGAAGUGCUGGGCAGAAUGCCUGAGCACUUCAUGGUCAAGACCUGGGAAGCCCUGGACACU

AUGUACGUGGUGGCCACAGCCGAGAAAGGCGGCAGAGCACAUAGAAUGGCCCUGGAAGAACUGCCCGACGCUCUGCAG

ACAAUCGUGCUGAUUGCCCUGCUGAGCGUGAUGAGCCUGGGCGUGUUCUUCCUGCUGAUGCAGAGAAAAGGCAUCGGC

AAGAUCGGACUCGGCGGCGUUAUACUGGGAGCCGCCACCUUCUUUUGCUGGAUGGCUGAAGUGCCCGGCACCAAGAUU

GCCGGAAUGCUGCUGCUGUCCCUGCUGCUGAUGAUUGUGCUGAUCCCCGAGCCUGAGAAGCAGAGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 402, or a fragment or variant thereof.

In one embodiment, the at least one IIP is WNV NS4B (P06935; Genome polyprotein West Nile virus NS4A), or an orthologue thereof. One embodiment of the polypeptide sequence of WNV NS4B is represented herein as SEQ ID No: 403, as follows:

[SEQ ID No: 403]

NEMGWLDKTKNDIGSLLGHRPEARETTLGVESFLLDLRPATAWSLYAVTTAVLTPLLKHLITSDYINTSLTSINVQAS

ALFTLARGFPFVDVGVSALLLAVGCWGQVTLTVTVTAAALLFCHYAYMVPGWQAEAMRSAQRRTAAGIMKNVVVDGIV

ATDVPELERTTPVMQKKVGQIILILVSMAAVVVNPSVRTVREAGILTTAAAVTLWENGASSVWNATTAIGLCHIMRGG

WLSCLSIMWTLIKNMEKPGLKR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 403, or a variant or fragment thereof.

In one embodiment, the WNV NS4B polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 404, as follows:

[SEQ ID No: 404]

AATGAAATGGGCTGGCTGGACAAGACCAAGAATGACATTGGCAGCCTGTTGGGGCACAGGCCAGAAGCTAGAGAGACG

ACCCTGGGAGTTGAGAGCTTCTTACTTGATCTGCGGCCGGCCACGGCATGGTCGCTCTATGCCGTAACGACAGCCGTT

CTCACCCCTTTGCTGAAGCATCTAATCACGTCAGACTACATCAACACTTCGTTGACCTCAATAAACGTCCAAGCCAGC

GCGTTGTTCACTTTGGCCAGAGGCTTCCCTTTTGTGGACGTTGGTGTGTCAGCTCTCTTGCTGGCGGTCGGGTGCTGG

GGTCAGGTGACTCTGACTGTGACTGTGACTGCAGCTGCTCTGCTCTTTTGCCACTATGCTTACATGGTGCCAGGCTGG

CAAGCGGAAGCCATGCGATCTGCCCAGCGGCGGACAGCTGCTGGCATCATGAAAAATGTAGTGGTGGATGGGATCGTG

GCCACTGATGTACCTGAACTTGAACGAACAACTCCAGTCATGCAGAAAAAAGTTGGACAGATCATATTGATCTTGGTA

TCAATGGCCGCGGTGGTCGTCAATCCATCAGTGAGAACCGTCAGAGAGGCCGGAATTCTGACTACAGCAGCAGCAGTC

ACCCTATGGGAGAATGGTGCTAGTTCAGTGTGGAATGCAACGACAGCTATTGGCCTTTGTCACATCATGCGAGGAGGA

TGGCTCTCGTGTCTCTCCATCATGTGGACTCTCATCAAAAACATGGAGAAACCAGGCCTCAAGAGG

Accordingly, preferably the WNV NS4B polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 404, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the WNV NS4B polypeptide is provided herein as SEQ ID No: 405, as follows:

[SEQ ID No: 405]

AACGAGATGGGCTGGCTGGACAAGACCAAGAACGACATCGGAAGCCTGCTGGGCCACAGACCTGAGGCCAGAGAAACA

ACCCTGGGCGTCGAGAGCTTCCTGCTGGATCTTAGACCTGCCACCGCTTGGAGCCTGTACGCCGTTACAACAGCCGTG

CTGACCCCTCTGCTGAAGCACCTGATCACCAGCGACTACATCAACACCAGCCTGACCAGCATCAACGTGCAGGCCAGC

GCTCTGTTTACCCTGGCCAGAGGCTTCCCCTTTGTGGACGTGGGAGTTTCTGCTCTGCTGCTGGCCGTTGGCTGTTGG

GGACAAGTGACCCTGACCGTGACAGTGACTGCTGCCGCTCTGCTGTTCTGCCACTACGCCTATATGGTGCCTGGATGG

CAGGCCGAGGCCATGAGATCTGCCCAGAGAAGAACAGCCGCCGGAATCATGAAGAACGTGGTGGTGGATGGCATCGTG

GCCACCGACGTTCCAGAGCTGGAAAGAACCACACCTGTGATGCAGAAGAAAGTCGGCCAGATCATCCTGATCCTGGTG

TCCATGGCCGCCGTGGTGGTCAATCCTAGCGTGCGGACAGTTAGAGAGGCCGGCATCCTGACAACAGCTGCCGCTGTT

ACCCTGTGGGAGAATGGCGCTAGCAGCGTGTGGAATGCCACCACAGCCATCGGCCTGTGCCACATCATGAGAGGCGGC

TGGCTGAGCTGCCTGAGCATCATGTGGACCCTGATCAAGAACATGGAAAAGCCCGGCCTGAAGCGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 405, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 405 is provided herein as SEQ ID No: 406, as follows:

[SEQ ID No: 406]

AACGAGAUGGGCUGGCUGGACAAGACCAAGAACGACAUCGGAAGCCUGCUGGGCCACAGACCUGAGGCCAGAGAAACA

ACCCUGGGCGUCGAGAGCUUCCUGCUGGAUCUUAGACCUGCCACCGCUUGGAGCCUGUACGCCGUUACAACAGCCGUG

CUGACCCCUCUGCUGAAGCACCUGAUCACCAGCGACUACAUCAACACCAGCCUGACCAGCAUCAACGUGCAGGCCAGC

GCUCUGUUUACCCUGGCCAGAGGCUUCCCCUUUGUGGACGUGGGAGUUUCUGCUCUGCUGCUGGCCGUUGGCUGUUGG

GGACAAGUGACCCUGACCGUGACAGUGACUGCUGCCGCUCUGCUGUUCUGCCACUACGCCUAUAUGGUGCCUGGAUGG

CAGGCCGAGGCCAUGAGAUCUGCCCAGAGAAGAACAGCCGCCGGAAUCAUGAAGAACGUGGUGGUGGAUGGCAUCGUG

GCCACCGACGUUCCAGAGCUGGAAAGAACCACACCUGUGAUGCAGAAGAAAGUCGGCCAGAUCAUCCUGAUCCUGGUG

UCCAUGGCCGCCGUGGUGGUCAAUCCUAGCGUGCGGACAGUUAGAGAGGCCGGCAUCCUGACAACAGCUGCCGCUGUU

ACCCUGUGGGAGAAUGGCGCUAGCAGCGUGUGGAAUGCCACCACAGCCAUCGGCCUGUGCCACAUCAUGAGAGGCGGC

UGGCUGAGCUGCCUGAGCAUCAUGUGGACCCUGAUCAAGAACAUGGAAAAGCCCGGCCUGAAGCGG

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 406, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Rabies Virus PP (P69479; Phosphoprotein Rabies virus (strain ERA)), or an orthologue thereof. One embodiment of the polypeptide sequence of Rabies Virus PP is represented herein as SEQ ID No: 407, as follows:

[SEQ ID No: 407]

MSKIFVNPSAIRAGLADLEMAEETVDLINRNIEDNQAHLQGEPIEVDNLPEDMGRLHLDDGKSPNPGEMAKVGEGKYR

EDFQMDEGEDPSFLFQSYLENVGVQIVRQMRSGERFLKIWSQTVEEIISYVAVNFPNPPGKSSEDKSTQTTGRELKKE

TTPTPSQRESQSSKARMAAQTASGPPALEWSATNEKDDLSVEAEIAHQIAESFSKKYKFPSRSSGILLYNFEQLKMNL

DDIVKEAKNVPGVTRLAHDGSKLPLRCVLGWVALANSKKFQLLVESDKLSKIMQDDLNRYTSC

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 407, or a variant or fragment thereof.

In one embodiment, the Rabies Virus PP polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 408, as follows:

[SEQ ID No: 408]

ATGAGCAAGATCTTTGTCAATCCTAGTGCTATTAGAGCCGGTCTGGCCGATCTTGAGATGGCTGAAGAAACTGTTGAT

CTGATCAATAGAAATATCGAAGACAATCAGGCTCATCTCCAAGGGGAACCCATAGAAGTGGACAATCTCCCTGAGGAT

ATGGGGCGACTTCACCTGGATGATGGAAAATCGCCCAACCCTGGTGAGATGGCCAAGGTGGGAGAAGGCAAGTATCGA

GAGGACTTTCAGATGGATGAAGGAGAGGATCCTAGCTTCCTGTTCCAGTCATACCTGGAAAATGTTGGAGTCCAAATA

GTCAGACAAATGAGGTCAGGAGAGAGATTTCTCAAGATATGGTCACAGACCGTAGAAGAGATTATATCCTATGTCGCG

GTCAACTTTCCCAACCCTCCAGGAAAGTCTTCAGAGGATAAATCAACCCAGACTACTGGCCGAGAGCTCAAGAAGGAG

ACAACACCCACTCCTTCTCAGAGAGAAAGCCAATCATCGAAAGCCAGGATGGCGGCTCAAACTGCTTCTGGCCCTCCA

GCCCTTGAATGGTCGGCCACCAATGAAAAGGATGATCTATCAGTGGAGGCTGAGATCGCTCACCAGATTGCAGAAAGT

TTCTCCAAAAAATATAAGTTTCCCTCTCGATCCTCAGGGATACTCTTGTATAATTTTGAGCAATTGAAAATGAACCTT

GATGATATAGTTAAAGAGGCAAAAAATGTACCAGGTGTGACCCGTTTAGCCCATGACGGGTCCAAACTCCCCCTAAGA

TGTGTACTGGGATGGGTCGCTTTGGCCAACTCTAAGAAATTCCAGTTGTTAGTCGAATCCGACAAGCTGAGTAAAATC

ATGCAAGATGACTTGAATCGCTATACATCTTGC

Accordingly, preferably the Rabies Virus PP polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 408, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Rabies Virus PP polypeptide is provided herein as SEQ ID No: 409, as follows:

[SEQ ID No: 409]

ATGAGCAAGATCTTCGTGAACCCCAGCGCCATCAGAGCCGGACTGGCTGATCTGGAAATGGCCGAGGAAACCGTGGAC

CTGATCAACCGGAACATCGAGGACAATCAGGCCCATCTGCAGGGCGAGCCTATCGAGGTTGACAACCTGCCTGAGGAC

ATGGGCAGACTGCACCTGGATGATGGCAAGAGCCCTAATCCTGGCGAGATGGCCAAAGTCGGCGAGGGCAAGTACCGC

GAGGACTTCCAAATGGACGAGGGCGAAGATCCCAGCTTCCTGTTCCAGTCCTACCTGGAAAACGTGGGCGTGCAGATC

GTGCGGCAGATGAGAAGCGGCGAGCGGTTCCTGAAGATCTGGTCCCAGACCGTGGAAGAGATCATCAGCTACGTGGCC

GTGAACTTCCCCAATCCTCCAGGCAAGAGCAGCGAGGACAAGAGCACACAGACCACCGGCAGAGAGCTGAAGAAAGAG

ACAACCCCTACACCTAGCCAGAGAGAGAGCCAGAGCAGCAAGGCCAGAATGGCCGCTCAGACAGCTTCTGGACCTCCT

GCACTTGAGTGGAGCGCCACCAACGAGAAGGACGACCTGTCTGTGGAAGCCGAGATCGCCCACCAGATCGCCGAGAGC

TTCAGCAAGAAGTACAAGTTCCCCAGCAGAAGCAGCGGCATCCTGCTGTACAACTTCGAGCAGCTGAAGATGAACCTG

GACGACATCGTGAAAGAGGCCAAGAACGTCCCCGGCGTGACAAGACTGGCCCACGATGGATCTAAGCTGCCCCTGAGA

TGTGTGCTCGGATGGGTTGCCCTGGCCAACAGCAAGAAATTCCAGCTGCTGGTGGAAAGCGACAAGCTGTCCAAGATC

ATGCAGGACGATCTGAACCGGTACACCAGCTGC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 409, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 409 is provided herein as SEQ ID No: 410, as follows:

[SEQ ID No: 410]

AUGAGCAAGAUCUUCGUGAACCCCAGCGCCAUCAGAGCCGGACUGGCUGAUCUGGAAAUGGCCGAGGAAACCGUGGAC

CUGAUCAACCGGAACAUCGAGGACAAUCAGGCCCAUCUGCAGGGCGAGCCUAUCGAGGUUGACAACCUGCCUGAGGAC

AUGGGCAGACUGCACCUGGAUGAUGGCAAGAGCCCUAAUCCUGGCGAGAUGGCCAAAGUCGGCGAGGGCAAGUACCGC

GAGGACUUCCAAAUGGACGAGGGCGAAGAUCCCAGCUUCCUGUUCCAGUCCUACCUGGAAAACGUGGGCGUGCAGAUC

GUGCGGCAGAUGAGAAGCGGCGAGCGGUUCCUGAAGAUCUGGUCCCAGACCGUGGAAGAGAUCAUCAGCUACGUGGCC

GUGAACUUCCCCAAUCCUCCAGGCAAGAGCAGCGAGGACAAGAGCACACAGACCACCGGCAGAGAGCUGAAGAAAGAG

ACAACCCCUACACCUAGCCAGAGAGAGAGCCAGAGCAGCAAGGCCAGAAUGGCCGCUCAGACAGCUUCUGGACCUCCU

GCACUUGAGUGGAGCGCCACCAACGAGAAGGACGACCUGUCUGUGGAAGCCGAGAUCGCCCACCAGAUCGCCGAGAGC

UUCAGCAAGAAGUACAAGUUCCCCAGCAGAAGCAGCGGCAUCCUGCUGUACAACUUCGAGCAGCUGAAGAUGAACCUG

GACGACAUCGUGAAAGAGGCCAAGAACGUCCCCGGCGUGACAAGACUGGCCCACGAUGGAUCUAAGCUGCCCCUGAGA

UGUGUGCUCGGAUGGGUUGCCCUGGCCAACAGCAAGAAAUUCCAGCUGCUGGUGGAAAGCGACAAGCUGUCCAAGAUC

AUGCAGGACGAUCUGAACCGGUACACCAGCUGC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 410, or a fragment or variant thereof.

In one embodiment, the at least one IIP is PEDV N protein (Q07499; Nucleoprotein Porcine epidemic diarrhea virus (strain CV777)), or an orthologue thereof. One embodiment of the polypeptide sequence of PEDV N protein is represented herein as SEQ ID No: 411, as follows:

[SEQ ID No: 411]

MASVSFQDRGRKRVPLSLYAPLRVTNDKPLSKVLANNAVPTNKGNKDQQIGYWNEQIRWRMRRGERIEQPSNWHFYYL

GTGPHGDLRYRTRTEGVFWVAKEGAKTEPTNLGVRKASEKPIIPKFSQQLPSVVEIVEPNTPPASRANSRSRSRGNGN

NRSRSPSNNRGNNQSRGNSQNRGNNQGRGASQNRGGNNNNNNKSRNQSNNRNQSNDRGGVTSRDDLVAAVKDALKSLG

IGENPDRHKQQQKPKQEKSDNSGKNTPKKNKSRATSKERDLKDIPEWRRIPKGENSVAACFGPRGGFKNFGDAEFVEK

GVDASGYAQIASLAPNVAALLFGGNVAVRELADSYEITYNYKMTVPKSDPNVELLVSQVDAFKTGNAKLQRKKEKKNK

RETTLQQHEEAIYDDVGAPSDVTHANLEWDTAVDGGDTAVEIINEIFDTGN

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 411, or a variant or fragment thereof.

In one embodiment, the PEDV N polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 412, as follows:

[SEQ ID No: 412]

ATGGCTTCTGTCAGCTTTCAGGATCGTGGCCGCAAACGGGTGCCATTATCTCTCTATGCCCCTCTTAGGGTTACTAAT

GACAAGCCCCTTTCTAAGGTACTTGCAAACAACGCTGTACCCACTAACAAGGGGAATAAGGACCAGCAAATTGGGTAC

TGGAATGAGCAAATTCGCTGGCGCATGCGCCGTGGTGAGCGAATTGAACAACCTTCCAATTGGCATTTCTACTACCTC

GGAACAGGACCTCACGGCGACCTCCGTTATAGGACTCGTACTGAGGGTGTTTTCTGGGTTGCTAAAGAAGGCGCAAAG

ACTGAACCCACTAATTTGGGTGTCAGAAAGGCGTCTGAAAAGCCAATCATTCCAAAATTCTCTCAACAGCTCCCCAGT

GTAGTTGAGATTGTTGAACCTAACACACCTCCTGCTTCACGTGCAAATTCGCGTAGCAGGAGTCGTGGCAATGGCAAC

AATAGGTCTAGATCTCCAAGTAACAACAGAGGCAATAACCAGTCCCGTGGTAATTCACAGAATCGTGGAAATAACCAG

GGTCGTGGAGCTTCTCAGAACAGAGGAGGCAATAATAATAACAATAACAAGTCTCGTAACCAGTCCAATAACAGGAAC

CAGTCAAATGACCGTGGTGGTGTAACATCACGCGATGATCTGGTGGCTGCTGTCAAGGATGCACTTAAATCTTTGGGT

ATTGGAGAAAATCCTGACAGGCATAAGCAACAGCAGAAGCCTAAGCAGGAAAAGTCTGACAACAGCGGCAAAAATACA

CCTAAGAAGAACAAATCCAGGGCCACTTCGAAGGAACGTGACCTCAAAGACATCCCAGAGTGGAGGAGAATTCCCAAG

GGCGAAAATAGCGTAGCAGCTTGCTTCGGACCCAGAGGGGGCTTCAAAAACTTTGGAGATGCGGAATTTGTCGAAAAA

GGTGTTGATGCGTCAGGCTATGCTCAGATCGCCAGTTTAGCACCAAATGTTGCAGCATTGCTCTTTGGTGGTAATGTG

GCTGTTCGTGAGCTAGCGGACTCTTACGAGATTACATACAACTATAAAATGACTGTGCCAAAGTCAGATCCAAATGTT

GAGCTTCTTGTTTCACAGGTGGATGCATTTAAAACTGGGAATGCAAAACTCCAGAGAAAGAAGGAAAAGAAGAACAAG

CGTGAAACCACGCTGCAGCAGCATGAAGAGGCCATCTACGATGATGTGGGTGCGCCATCTGATGTGACCCATGCCAAT

CTGGAATGGGACACAGCTGTTGATGGTGGTGATACGGCCGTTGAAATTATCAACGAGATCTTCGATACAGGAAAT

Accordingly, preferably the PEDV N polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 412, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the PEDV N polypeptide is provided herein as SEQ ID No: 413, as follows:

[SEQ ID No: 413]

ATGGCCAGCGTCAGCTTTCAGGACCGGGGCAGAAAAAGAGTGCCCCTGTCTCTGTACGCCCCTCTGAGAGTGACCAAC

GACAAGCCCCTGAGCAAGGTGCTGGCCAACAATGCCGTGCCTACCAACAAGGGCAACAAGGACCAGCAGATCGGCTAC

TGGAACGAGCAGATCCGGTGGCGGATGAGAAGAGGCGAGAGAATCGAGCAGCCCAGCAACTGGCACTTCTACTACCTC

GGCACAGGCCCTCACGGCGACCTGAGATACAGAACCAGAACCGAGGGCGTGTTCTGGGTCGCCAAAGAGGGCGCCAAG

ACCGAGCCTACAAATCTCGGCGTCAGAAAGGCCAGCGAGAAGCCTATCATCCCCAAGTTCAGCCAGCAGCTGCCCAGC

GTGGTGGAAATCGTGGAACCCAATACTCCTCCTGCCAGCCGGGCCAACAGCAGAAGCAGATCTAGAGGCAACGGCAAC

AATCGGAGCAGAAGCCCCAGCAACAACCGGGGCAACAACCAGTCCAGAGGCAACAGCCAGAACCGCGGAAACAATCAA

GGCAGAGGCGCTAGCCAGAACAGAGGCGGCAACAACAACAATAACAACAAGAGCCGGAACCAGTCTAACAACCGCAAC

CAGAGCAACGATAGAGGCGGCGTGACCAGCAGGGATGATCTGGTGGCTGCCGTGAAGGATGCCCTGAAGTCTCTCGGC

ATCGGCGAGAACCCCGACAGACACAAGCAGCAGCAGAAACCCAAGCAAGAGAAGTCCGACAACAGCGGCAAGAACACC

CCTAAGAAGAACAAGAGCAGGGCCACCAGCAAAGAGCGGGACCTGAAGGATATTCCCGAGTGGCGGAGAATCCCCAAG

GGCGAGAATTCTGTGGCCGCCTGCTTTGGACCAAGAGGCGGCTTCAAGAATTTCGGCGACGCCGAGTTCGTGGAAAAA

GGCGTGGACGCCTCTGGCTATGCCCAGATTGCATCTCTGGCCCCTAATGTGGCTGCCCTGCTGTTTGGCGGAAACGTG

GCCGTTAGAGAGCTGGCCGATAGCTACGAGATCACCTACAACTACAAGATGACCGTGCCTAAGAGCGACCCCAACGTG

GAACTGCTGGTGTCTCAGGTGGACGCATTCAAGACCGGCAACGCCAAGCTGCAGCGCAAGAAAGAGAAGAAAAACAAG

CGCGAGACAACCCTGCAGCAGCACGAGGAAGCTATCTACGACGACGTGGGAGCCCCTTCCGATGTGACACACGCCAAC

CTGGAATGGGACACAGCAGTGGATGGCGGCGATACCGCCGTGGAAATCATCAACGAGATCTTCGACACCGGCAAC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 413, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 413 is provided herein as SEQ ID No: 414, as follows:

[SEQ ID No: 414]

AUGGCCAGCGUCAGCUUUCAGGACCGGGGCAGAAAAAGAGUGCCCCUGUCUCUGUACGCCCCUCUGAGAGUGACCAAC

GACAAGCCCCUGAGCAAGGUGCUGGCCAACAAUGCCGUGCCUACCAACAAGGGCAACAAGGACCAGCAGAUCGGCUAC

UGGAACGAGCAGAUCCGGUGGCGGAUGAGAAGAGGCGAGAGAAUCGAGCAGCCCAGCAACUGGCACUUCUACUACCUC

GGCACAGGCCCUCACGGCGACCUGAGAUACAGAACCAGAACCGAGGGCGUGUUCUGGGUCGCCAAAGAGGGCGCCAAG

ACCGAGCCUACAAAUCUCGGCGUCAGAAAGGCCAGCGAGAAGCCUAUCAUCCCCAAGUUCAGCCAGCAGCUGCCCAGC

GUGGUGGAAAUCGUGGAACCCAAUACUCCUCCUGCCAGCCGGGCCAACAGCAGAAGCAGAUCUAGAGGCAACGGCAAC

AAUCGGAGCAGAAGCCCCAGCAACAACCGGGGCAACAACCAGUCCAGAGGCAACAGCCAGAACCGCGGAAACAAUCAA

GGCAGAGGCGCUAGCCAGAACAGAGGCGGCAACAACAACAAUAACAACAAGAGCCGGAACCAGUCUAACAACCGCAAC

CAGAGCAACGAUAGAGGCGGCGUGACCAGCAGGGAUGAUCUGGUGGCUGCCGUGAAGGAUGCCCUGAAGUCUCUCGGC

AUCGGCGAGAACCCCGACAGACACAAGCAGCAGCAGAAACCCAAGCAAGAGAAGUCCGACAACAGCGGCAAGAACACC

CCUAAGAAGAACAAGAGCAGGGCCACCAGCAAAGAGCGGGACCUGAAGGAUAUUCCCGAGUGGCGGAGAAUCCCCAAG

GGCGAGAAUUCUGUGGCCGCCUGCUUUGGACCAAGAGGCGGCUUCAAGAAUUUCGGCGACGCCGAGUUCGUGGAAAAA

GGCGUGGACGCCUCUGGCUAUGCCCAGAUUGCAUCUCUGGCCCCUAAUGUGGCUGCCCUGCUGUUUGGCGGAAACGUG

GCCGUUAGAGAGCUGGCCGAUAGCUACGAGAUCACCUACAACUACAAGAUGACCGUGCCUAAGAGCGACCCCAACGUG

GAACUGCUGGUGUCUCAGGUGGACGCAUUCAAGACCGGCAACGCCAAGCUGCAGCGCAAGAAAGAGAAGAAAAACAAG

CGCGAGACAACCCUGCAGCAGCACGAGGAAGCUAUCUACGACGACGUGGGAGCCCCUUCCGAUGUGACACACGCCAAC

CUGGAAUGGGACACAGCAGUGGAUGGCGGCGAUACCGCCGUGGAAAUCAUCAACGAGAUCUUCGACACCGGCAAC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 414, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HSV1 ICP27 (P10238; ICP27 mRNA export factor Human herpesvirus 1 (strain 17)), or an orthologue thereof. One embodiment of the polypeptide sequence of HSV1 ICP27 is represented herein as SEQ ID No: 415, as follows:

[SEQ ID No: 415]

MATDIDMLIDLGLDLSDSDLDEDPPEPAESRRDDLESDSSGECSSSDEDMEDPHGEDGPEPILDAARPAVRPSRPEDP

GVPSTQTPRPTERQGPNDPQPAPHSVWSRLGARRPSCSPEQHGGKVARLQPPPTKAQPARGGRRGRRRGRGRGGPGAA

DGLSDPRRRAPRTNRNPGGPRPGAGWTDGPGAPHGEAWRGSEQPDPPGGQRTRGVRQAPPPLMTLAIAPPPADPRAPA

PERKAPAADTIDATTRLVLRSISERAAVDRISESFGRSAQVMHDPFGGQPFPAANSPWAPVLAGQGGPFDAETRRVSW

ETLVAHGPSLYRTFAGNPRAASTAKAMRDCVLRQENFIEALASADETLAWCKMCIHHNLPLRPQDPIIGTTAAVLDNL

ATRLRPFLQCYLKARGLCGLDELCSRRRLADIKDIASFVFVILARLANRVERGVAEIDYATLGVGVGEKMHFYLPGAC

MAGLIEILDTHRQECSSRVCELTASHIVAPPYVHGKYFYCNSLF

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 415, or a variant or fragment thereof.

In one embodiment, the HSV1 ICP27 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 416, as follows:

[SEQ ID No: 416]

ATGGCGACTGACATTGATATGCTAATTGACCTCGGCCTGGACCTCTCCGACAGCGATCTGGACGAGGACCCCCCCGAG

CCGGCGGAGAGCCGCCGCGACGACCTGGAATCGGACAGCAGCGGGGAGTGTTCCTCGTCGGACGAGGACATGGAAGAC

CCCCACGGAGAGGACGGACCGGAGCCGATACTCGACGCCGCTCGCCCGGCGGTCCGCCCGTCTCGTCCAGAAGACCCC

GGCGTACCCAGCACCCAGACGCCTCGTCCGACGGAGCGGCAGGGCCCCAACGATCCTCAACCAGCGCCCCACAGTGTG

TGGTCGCGCCTCGGGGCCCGGCGACCGTCTTGCTCCCCCGAGCAGCACGGGGGCAAGGTGGCCCGCCTCCAACCCCCA

CCGACCAAAGCCCAGCCTGCCCGCGGCGGACGCCGTGGGCGTCGCAGGGGTCGGGGTCGCGGTGGTCCCGGGGCTGCC

GATGGTTTGTCGGACCCCCGCCGGCGTGCCCCCAGAACCAATCGCAACCCTGGGGGACCCCGCCCCGGGGCGGGGTGG

ACGGACGGCCCCGGCGCCCCCCATGGCGAGGCGTGGCGCGGCAGTGAGCAGCCCGACCCACCCGGAGGCCAGCGGACA

CGGGGCGTGCGCCAAGCACCCCCCCCGCTAATGACGCTGGCGATTGCCCCCCCGCCCGCGGACCCCCGCGCCCCGGCC

CCGGAGCGAAAGGCGCCCGCCGCCGACACCATCGACGCCACCACGCGGTTGGTCCTGCGCTCCATCTCCGAGCGCGCG

GCGGTCGACCGCATCAGCGAGAGCTTTGGCCGCAGCGCACAGGTCATGCACGACCCCTTTGGGGGGCAGCCGTTTCCC

GCCGCGAATAGCCCCTGGGCCCCGGTGCTGGCGGGCCAAGGAGGGCCCTTTGACGCCGAGACCAGACGGGTCTCCTGG

GAAACCTTGGTCGCCCACGGCCCGAGCCTCTATCGCACTTTTGCCGGCAATCCTCGGGCCGCATCGACCGCCAAGGCC

ATGCGCGACTGCGTGCTGCGCCAAGAAAATTTCATCGAGGCGCTGGCCTCCGCCGACGAGACGCTGGCGTGGTGCAAG

ATGTGCATCCACCACAACCTGCCGCTGCGCCCCCAGGACCCCATTATCGGGACGACCGCGGCTGTGCTGGATAACCTC

GCCACGCGCCTGCGGCCCTTTCTCCAGTGCTACCTGAAGGCGCGAGGCCTGTGCGGCCTGGACGAACTGTGTTCGCGG

CGGCGTCTGGCGGACATTAAGGACATTGCATCCTTCGTGTTTGTCATTCTGGCCAGGCTCGCCAACCGCGTCGAGCGT

GGCGTCGCGGAGATCGACTACGCGACCCTTGGTGTCGGGGTCGGAGAGAAGATGCATTTCTACCTCCCCGGGGCCTGC

ATGGCGGGCCTGATCGAAATCCTAGACACGCACCGCCAGGAGTGTTCGAGTCGTGTCTGCGAGTTGACGGCCAGTCAC

ATCGTCGCCCCCCCGTACGTGCACGGCAAATATTTTTATTGCAACTCCCTGTTT

Accordingly, preferably the HSV1 ICP27 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 416, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HSV1 ICP27 polypeptide is provided herein as SEQ ID No: 417, as follows:

[SEQ ID No: 417]

ATGGCCACCGACATCGACATGCTGATCGACCTGGGCCTCGACCTGAGCGACTCTGACCTGGATGAAGATCCTCCTGAG

CCTGCCGAGAGCAGAAGGGACGATCTGGAAAGCGATAGCAGCGGCGAGTGTAGCAGCAGCGACGAGGACATGGAAGAT

CCCCACGGCGAGGATGGACCTGAGCCTATTCTGGATGCCGCCAGACCTGCCGTCAGACCTTCTAGACCTGAAGATCCA

GGCGTGCCCAGCACACAGACCCCTAGACCTACAGAGAGACAGGGCCCCAACGATCCTCAGCCTGCTCCTCATAGCGTG

TGGTCTAGACTGGGAGCCAGAAGGCCTAGCTGTAGCCCTGAACAGCACGGCGGAAAAGTGGCCAGACTGCAGCCTCCT

CCAACAAAGGCTCAACCTGCTAGAGGCGGCAGACGGGGCAGAAGAAGAGGTAGAGGAAGAGGTGGACCTGGCGCCGCT

GATGGACTGTCTGATCCTAGAAGAAGGGCCCCTCGGACCAACAGAAATCCTGGCGGACCTAGACCAGGCGCCGGATGG

ACAGATGGACCAGGTGCTCCACATGGCGAGGCTTGGAGAGGATCTGAGCAGCCTGATCCTCCAGGCGGCCAAAGAACA

AGAGGCGTTAGACAGGCTCCTCCTCCTCTGATGACCCTGGCTATTGCTCCTCCACCAGCCGATCCTAGAGCACCCGCT

CCAGAAAGAAAAGCCCCTGCCGCCGATACCATCGACGCCACAACAAGACTGGTGCTGCGGAGCATCTCTGAGAGGGCC

GCTGTGGATAGAATCAGCGAGAGCTTTGGGAGAAGCGCCCAAGTGATGCACGACCCTTTTGGCGGCCAGCCTTTTCCT

GCCGCCAATTCTCCTTGGGCTCCTGTGCTTGCTGGACAAGGCGGCCCTTTTGACGCCGAGACAAGAAGAGTGTCCTGG

GAGACACTGGTGGCCCACGGACCTAGCCTGTACAGAACATTCGCCGGCAATCCAAGAGCCGCCAGCACAGCCAAAGCC

ATGAGAGACTGCGTGCTGAGACAAGAGAACTTCATCGAGGCCCTGGCCAGCGCCGATGAGACACTTGCTTGGTGCAAG

ATGTGCATCCACCACAACCTGCCTCTGAGGCCACAGGACCCTATCATCGGAACAACAGCTGCCGTGCTGGATAACCTG

GCTACCAGACTGAGGCCCTTCCTGCAGTGCTACCTGAAGGCCAGAGGACTGTGTGGCCTGGATGAGCTGTGCTCCAGA

AGAAGGCTGGCTGACATCAAGGATATCGCCAGCTTCGTGTTCGTGATTCTGGCCCGGCTGGCCAACAGAGTGGAAAGA

GGCGTGGCCGAGATCGACTATGCCACACTCGGAGTTGGCGTGGGCGAGAAGATGCACTTTTATCTGCCTGGCGCCTGC

ATGGCCGGCCTGATCGAAATTCTGGACACCCACAGACAAGAGTGCAGCTCCAGAGTGTGCGAGCTGACAGCCTCTCAC

ATTGTGGCCCCTCCATACGTGCACGGCAAGTACTTCTACTGCAACAGCCTGTTC

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 417, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 417 is provided herein as SEQ ID No: 418, as follows:

[SEQ ID No: 418]

AUGGCCACCGACAUCGACAUGCUGAUCGACCUGGGCCUCGACCUGAGCGACUCUGACCUGGAUGAAGAUCCUCCUGAG

CCUGCCGAGAGCAGAAGGGACGAUCUGGAAAGCGAUAGCAGCGGCGAGUGUAGCAGCAGCGACGAGGACAUGGAAGAU

CCCCACGGCGAGGAUGGACCUGAGCCUAUUCUGGAUGCCGCCAGACCUGCCGUCAGACCUUCUAGACCUGAAGAUCCA

GGCGUGCCCAGCACACAGACCCCUAGACCUACAGAGAGACAGGGCCCCAACGAUCCUCAGCCUGCUCCUCAUAGCGUG

UGGUCUAGACUGGGAGCCAGAAGGCCUAGCUGUAGCCCUGAACAGCACGGCGGAAAAGUGGCCAGACUGCAGCCUCCU

CCAACAAAGGCUCAACCUGCUAGAGGCGGCAGACGGGGCAGAAGAAGAGGUAGAGGAAGAGGUGGACCUGGCGCCGCU

GAUGGACUGUCUGAUCCUAGAAGAAGGGCCCCUCGGACCAACAGAAAUCCUGGCGGACCUAGACCAGGCGCCGGAUGG

ACAGAUGGACCAGGUGCUCCACAUGGCGAGGCUUGGAGAGGAUCUGAGCAGCCUGAUCCUCCAGGCGGCCAAAGAACA

AGAGGCGUUAGACAGGCUCCUCCUCCUCUGAUGACCCUGGCUAUUGCUCCUCCACCAGCCGAUCCUAGAGCACCCGCU

CCAGAAAGAAAAGCCCCUGCCGCCGAUACCAUCGACGCCACAACAAGACUGGUGCUGCGGAGCAUCUCUGAGAGGGCC

GCUGUGGAUAGAAUCAGCGAGAGCUUUGGGAGAAGCGCCCAAGUGAUGCACGACCCUUUUGGCGGCCAGCCUUUUCCU

GCCGCCAAUUCUCCUUGGGCUCCUGUGCUUGCUGGACAAGGCGGCCCUUUUGACGCCGAGACAAGAAGAGUGUCCUGG

GAGACACUGGUGGCCCACGGACCUAGCCUGUACAGAACAUUCGCCGGCAAUCCAAGAGCCGCCAGCACAGCCAAAGCC

AUGAGAGACUGCGUGCUGAGACAAGAGAACUUCAUCGAGGCCCUGGCCAGCGCCGAUGAGACACUUGCUUGGUGCAAG

AUGUGCAUCCACCACAACCUGCCUCUGAGGCCACAGGACCCUAUCAUCGGAACAACAGCUGCCGUGCUGGAUAACCUG

GCUACCAGACUGAGGCCCUUCCUGCAGUGCUACCUGAAGGCCAGAGGACUGUGUGGCCUGGAUGAGCUGUGCUCCAGA

AGAAGGCUGGCUGACAUCAAGGAUAUCGCCAGCUUCGUGUUCGUGAUUCUGGCCCGGCUGGCCAACAGAGUGGAAAGA

GGCGUGGCCGAGAUCGACUAUGCCACACUCGGAGUUGGCGUGGGCGAGAAGAUGCACUUUUAUCUGCCUGGCGCCUGC

AUGGCCGGCCUGAUCGAAAUUCUGGACACCCACAGACAAGAGUGCAGCUCCAGAGUGUGCGAGCUGACAGCCUCUCAC

AUUGUGGCCCCUCCAUACGUGCACGGCAAGUACUUCUACUGCAACAGCCUGUUC

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 418, or a fragment or variant thereof.

In one embodiment, the at least one IIP is HSV1VP24 (F8RDC3; Capsid scaffolding protein VP24 cleavage product of UL26 Human herpesvirus 1), or an orthologue thereof. One embodiment of the polypeptide sequence of HSV1 VP24 is represented herein as SEQ ID No: 419, as follows:

[SEQ ID No: 419]

MAADAPGDRMEEPLPDRAVPIYVAGFLALYDSGDSGELALDPDTVRAALPPDNPLPINVDHRAGCEVGRVLAVVDDPR

GPFFVGLIACVQLERVLETAASAAIFERRGPPLSREERLLYLITNYLPSVSLATKRLGGEAHPDRTLFAHVALCAIGR

RLGTIVTYDTGLDAAIAPFRHLSPASREGARRLAAEAELALSGRTWAPGVEALTHTLLSTAVNNMMLRDRWSLVAERR

RQAGIAGHTYLQA

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 419, or a variant or fragment thereof.

In one embodiment, the HSV1VP24 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 420, as follows:

[SEQ ID No: 420]

ATGGCAGCCGATGCCCCGGGAGACAGGATGGAGGAGCCCCTGCCAGACAG

GGCCGTGCCCATTTACGTGGCTGGGTTTTTGGCCCTGTATGACAGCGGGG

ACTCGGGCGAGTTGGCATTGGATCCGGATACGGTGCGGGCGGCCCTGCCT

CCGGATAACCCACTCCCGATTAACGTGGACCACCGCGCTGGCTGCGAGGT

GGGGCGGGTGCTGGCCGTGGTCGACGACCCCCGCGGGCCGTTTTTTGTGG

GGCTGATCGCCTGCGTGCAGCTGGAGCGCGTCCTCGAGACGGCCGCCAGC

GCTGCGATTTTCGAGCGCCGCGGGCCGCCGCTCTCCCGGGAGGAGCGCCT

GTTGTACCTGATCACCAACTACCTGCCCTCGGTCTCCCTGGCCACAAAAC

GCCTGGGGGGCGAGGCGCACCCCGATCGCACGCTGTTCGCGCACGTCGCG

CTGTGCGCGATCGGGAGGCGCCTCGGCACTATCGTCACCTACGACACCGG

TCTCGACGCCGCCATCGCGCCCTTTCGCCACCTGTCGCCGGCGTCTCGCG

AGGGGGCGCGGCGACTGGCCGCCGAGGCCGAGCTCGCGCTGTCCGGACGC

ACCTGGGCGCCCGGCGTGGAGGCGCTGACCCACACGCTGCTTTCCACCGC

CGTTAACAACATGATGCTGCGGGACCGCTGGAGCCTGGTGGCCGAGCGGC

GGCGGCAGGCCGGGATTGCCGGACACACCTACCTCCAGGCG

Accordingly, preferably the HSV1 VP24 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 420, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the HSV1 VP24 polypeptide is provided herein as SEQ ID No: 421, as follows:

[SEQ ID No: 421]

ATGGCTGCTGATGCCCCTGGCGACAGAATGGAAGAACCCCTGCCTGATAG

AGCCGTGCCTATCTACGTGGCCGGATTTCTGGCCCTGTACGACTCTGGCG

ATTCTGGCGAACTGGCCCTGGATCCTGATACAGTCAGAGCCGCTCTGCCT

CCTGACAACCCTCTGCCAATCAACGTGGACCACAGAGCCGGCTGTGAAGT

GGGAAGAGTGCTGGCCGTGGTGGACGATCCTAGAGGCCCTTTCTTTGTGG

GCCTGATCGCCTGCGTGCAGCTGGAAAGAGTTCTGGAAACAGCCGCCAGC

GCCGCCATCTTCGAAAGAAGAGGACCTCCTCTGAGCCGGGAAGAGAGACT

GCTGTACCTGATCACCAACTACCTGCCTAGCGTGTCCCTGGCCACAAAGA

GACTTGGCGGAGAGGCCCATCCTGACAGAACCCTGTTTGCCCATGTGGCC

CTGTGTGCCATTGGTAGAAGGCTGGGCACCATCGTGACCTACGATACAGG

ACTGGACGCCGCTATCGCCCCATTCAGACATCTGAGCCCTGCCAGCAGAG

AAGGCGCCAGAAGGCTTGCTGCTGAAGCCGAACTGGCTCTGAGCGGCAGA

ACATGGGCTCCAGGTGTTGAAGCCCTGACACACACCCTGCTGAGCACCGC

CGTGAACAACATGATGCTGCGGGACAGATGGTCCCTGGTGGCCGAGAGAA

GAAGGCAGGCTGGAATTGCCGGCCACACATATCTGCAGGCT

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 421, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 421 is provided herein as SEQ ID No: 422, as follows:

[SEQ ID No: 422]

AUGGCUGCUGAUGCCCCUGGCGACAGAAUGGAAGAACCCCUGCCUGAUAG

AGCCGUGCCUAUCUACGUGGCCGGAUUUCUGGCCCUGUACGACUCUGGCG

AUUCUGGCGAACUGGCCCUGGAUCCUGAUACAGUCAGAGCCGCUCUGCCU

CCUGACAACCCUCUGCCAAUCAACGUGGACCACAGAGCCGGCUGUGAAGU

GGGAAGAGUGCUGGCCGUGGUGGACGAUCCUAGAGGCCCUUUCUUUGUGG

GCCUGAUCGCCUGCGUGCAGCUGGAAAGAGUUCUGGAAACAGCCGCCAGC

GCCGCCAUCUUCGAAAGAAGAGGACCUCCUCUGAGCCGGGAAGAGAGACU

GCUGUACCUGAUCACCAACUACCUGCCUAGCGUGUCCCUGGCCACAAAGA

GACUUGGCGGAGAGGCCCAUCCUGACAGAACCCUGUUUGCCCAUGUGGCC

CUGUGUGCCAUUGGUAGAAGGCUGGGCACCAUCGUGACCUACGAUACAGG

ACUGGACGCCGCUAUCGCCCCAUUCAGACAUCUGAGCCCUGCCAGCAGAG

AAGGCGCCAGAAGGCUUGCUGCUGAAGCCGAACUGGCUCUGAGCGGCAGA

ACAUGGGCUCCAGGUGUUGAAGCCCUGACACACACCCUGCUGAGCACCGC

CGUGAACAACAUGAUGCUGCGGGACAGAUGGUCCCUGGUGGCCGAGAGAA

GAAGGCAGGCUGGAAUUGCCGGCCACACAUAUCUGCAGGCU

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 422, or a fragment or variant thereof.

In one embodiment, the at least one IIP is Murine CTMV M45 (Q06A28; Ribonucleoside-diphosphate reductase large subunit-like protein Murine herpesvirus 1 (strain Smith) Murine Cytomegalovirus M45 Protein), or an orthologue thereof. Fliss P, Pechenick Jowers T et al (2012) Viral Mediated Redirection of NEMO/IKKγ to Autophagosomes Curtails the Inflammatory Cascade. PLoS Pathogens 8, 2. It is believed that M45 induces proteasome-independent degradation of NEMO. One embodiment of the polypeptide sequence of Murine CTMV M45 is represented herein as SEQ ID No: 423, as follows:

[SEQ ID No: 423]

MDRQPKVYSDPDNGFFFLDVPMPDDGQGGQQTATTAAGGAFGVGGGHSVP

YVRIMNGVSGIQIGNHNAMSIASCWSPSYTDRRRRSYPKTATNAAADRVA

AAVSAANAAVNAAAAAAAAGGGGGANLLAAAVTCANQRGCCGGNGGHSLP

PTRMPKTNATAAAAPAVAGASNAKSDNNHANATSGAGSAAATPAATTPAA

TAVENRRPSPSPSTASTAPCDEGSSPRHHRPSHVSVGTQATPSTPIPIPA

PRCSTGQQQQQPQAKKLKPAKADPLLYAATMPPPASVTTAAAAAVAPESE

SSPAASAPPAAAAMATGGDDEDQSSFSFVSDDVLGEFEDLRIAGLPVRDE

MRPPTPTMTVIPVSRPFRAGRDSGRDALFDDAVESVRCYCHGILGNSRFC

ALVNEKCSEPAKERMARIRRYAADVTRCGPLALYTAIVSSANRLIQTDPS

CDLDLAECYVETASKRNAVPLSAFYRDCDRLRDAVAAFFKTYGMVVDAMA

QRITERVGPALGRGLYSTVVMMDRCGNSFQGREETPISVFARVAAALAVE

CEVDGGVSYKILSSKPVDAAQAFDAFLSALCSFAIIPSPRVLAYAGFGGS

NPIFDAVSYRAQFYSAESTINGTLHDICDMVTNGLSVSVSAADLGGDIVA

SLHILGQQCKALRPYARFKTVLRIYFDIWSVDALKIFSFILDVGREYEGL

MAFAVNTPRIFWDRYLDSSGDKMWLMFARREAAALCGLDLKSFRNVYEKM

ERDGRSAITVSPWWAVCQLDACVARGNTAVVFPHNVKSMIPENIGRPAVC

GPGVSVVSGGFVGCTPIHELCINLENCVLEGAAVESSVDVVLGLGCRFSF

KALESLVRDAVVLGNLLIDMTVRTNAYGAGKLLTLYRDLHIGVVGFHAVM

NRLGQKFADMESYDLNQRIAEFIYYTAVRASVDLCMAGADPFPKFPKSLY

AAGRFYPDLFDDDERGPRRMTKEFLEKLREDVVKHGIRNASFITGCSADE

AANLAGTTPGFWPRRDNVFLEQTPLMMTPTKDQMLDECVRSVKIEPHRLH

EEDLSCLGENRPVELPVLNSRLRQISKESATVAVRRGRSAPFYDDSDDED

EVACSETGWTVSTDAVIKMCVDRQPFVDHAQSLPVAIGFGGSSVELARHL

RRGNALGLSVGVYKCSMPPSVNYR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 423, or a variant or fragment thereof.

In one embodiment, the Murine CTMV M45 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 424, as follows:

[SEQ ID No: 424]

ATGGATCGCCAGCCCAAAGTCTACTCCGACCCGGACAACGGATTCTTCTT

TTTGGATGTCCCCATGCCTGACGACGGGCAGGGAGGCCAGCAGACCGCCA

CCACCGCTGCCGGGGGAGCCTTCGGGGTGGGTGGGGGGCACAGCGTGCCC

TACGTCAGGATCATGAATGGAGTCTCTGGAATACAGATCGGAAACCATAA

TGCTATGAGCATCGCCTCTTGCTGGAGTCCCTCCTACACTGACCGACGCC

GCAGGAGCTACCCCAAGACCGCGACCAACGCGGCGGCAGACAGGGTCGCC

GCTGCCGTCTCCGCCGCCAATGCTGCTGTCAATGCTGCTGCCGCGGCTGC

TGCCGCCGGCGGGGGCGGCGGCGCTAACCTACTGGCTGCTGCTGTCACTT

GTGCAAATCAGCGAGGTTGCTGCGGAGGAAATGGGGGGCATTCCCTCCCT

CCCACCCGAATGCCGAAGACCAACGCTACCGCCGCGGCCGCTCCTGCCGT

CGCCGGTGCTTCCAACGCCAAGAGTGACAACAATCACGCTAACGCCACCT

CTGGTGCTGGATCCGCGGCCGCCACCCCCGCCGCCACCACCCCCGCCGCC

ACCGCCGTCGAAAACCGACGACCCAGCCCGAGCCCCTCTACAGCCTCGAC

TGCGCCCTGTGACGAGGGATCTTCTCCTCGCCACCATCGTCCTAGTCACG

TTAGTGTCGGCACTCAGGCGACTCCGTCGACTCCTATCCCGATTCCCGCT

CCCCGGTGCAGCACAGGCCAACAACAACAGCAACCTCAAGCCAAGAAGCT

TAAGCCCGCTAAAGCTGATCCCCTCCTGTACGCGGCGACGATGCCGCCTC

CCGCGAGCGTAACGACCGCCGCTGCCGCTGCCGTCGCCCCTGAATCCGAA

TCCTCACCTGCCGCTTCGGCACCACCAGCAGCAGCAGCGATGGCGACCGG

GGGAGACGACGAAGATCAGTCGTCTTTCTCGTTCGTGAGCGACGACGTCC

TCGGAGAATTCGAAGATCTGCGCATCGCCGGGCTCCCCGTCAGGGACGAG

ATGCGCCCCCCGACCCCGACGATGACGGTCATTCCCGTCAGCAGGCCCTT

CCGCGCGGGGCGCGACAGCGGGCGCGACGCCTTGTTTGACGACGCCGTCG

AGTCCGTGCGCTGCTACTGCCACGGCATCCTCGGCAACAGCCGATTCTGC

GCCCTCGTCAACGAGAAGTGCTCCGAACCCGCCAAGGAGCGCATGGCTCG

CATCCGCCGCTACGCCGCGGACGTGACGCGCTGCGGACCCCTCGCGCTCT

ACACCGCCATCGTCTCCAGCGCCAACCGTCTCATCCAGACCGACCCGTCG

TGCGACCTGGATCTCGCCGAATGTTACGTCGAGACGGCGTCCAAGAGGAA

CGCCGTCCCCCTCTCGGCCTTCTACCGCGACTGCGATCGCCTGCGGGATG

CTGTCGCCGCGTTCTTCAAGACCTACGGCATGGTGGTGGACGCCATGGCG

CAGCGCATCACGGAGCGGGTCGGGCCGGCCCTGGGTAGGGGCCTCTACTC

GACCGTCGTCATGATGGATCGCTGCGGAAACAGCTTCCAGGGACGCGAGG

AGACCCCCATCTCCGTCTTCGCCCGGGTCGCCGCGGCTCTCGCCGTCGAG

TGCGAGGTCGACGGGGGCGTCTCGTACAAGATCCTCAGCTCCAAGCCCGT

CGACGCCGCGCAGGCCTTCGACGCCTTCCTCTCCGCCCTCTGCTCCTTCG

CCATCATCCCCTCGCCGCGGGTCCTGGCCTACGCCGGGTTCGGCGGTTCC

AACCCGATCTTCGACGCCGTTTCTTACCGCGCTCAGTTCTACTCGGCCGA

GAGCACGATCAACGGCACCCTGCACGACATCTGCGACATGGTGACCAACG

GCCTCTCGGTGTCCGTCAGCGCGGCGGACCTCGGAGGCGACATCGTGGCC

TCTCTGCACATCCTCGGACAGCAGTGCAAGGCGCTGCGGCCGTACGCGCG

ATTCAAGACCGTCTTGAGGATCTACTTCGACATCTGGTCCGTCGACGCTC

TCAAGATCTTCTCTTTCATCCTCGACGTCGGGCGGGAATACGAGGGCCTG

ATGGCCTTCGCGGTCAACACGCCGAGGATCTTCTGGGATCGCTACCTAGA

CAGCTCCGGCGACAAGATGTGGCTCATGTTCGCGAGGCGGGAGGCCGCGG

CCCTGTGCGGCCTCGACCTCAAGTCCTTCCGTAACGTCTACGAGAAGATG

GAGCGTGACGGGCGCAGCGCCATCACCGTCTCGCCCTGGTGGGCCGTCTG

TCAGCTCGACGCGTGCGTGGCGCGGGGCAACACGGCCGTGGTCTTCCCTC

ACAACGTCAAGAGTATGATCCCCGAGAACATCGGGCGCCCCGCCGTGTGC

GGACCCGGCGTCTCCGTCGTCTCCGGCGGCTTCGTCGGCTGTACCCCCAT

CCACGAGCTGTGCATCAACCTGGAGAACTGCGTCCTGGAGGGCGCGGCAG

TCGAGAGCTCCGTCGACGTGGTCCTCGGTCTCGGTTGCCGCTTCAGCTTC

AAGGCCCTGGAGTCCCTGGTCCGCGACGCGGTGGTGCTGGGTAACCTGCT

CATCGACATGACCGTGCGCACCAACGCGTACGGCGCCGGCAAGCTCCTGA

CGCTCTATCGCGACCTGCACATCGGGGTCGTCGGCTTCCACGCTGTGATG

AATCGCCTCGGGCAGAAGTTCGCCGACATGGAGTCTTACGACCTCAACCA

GCGTATCGCGGAGTTTATCTACTACACCGCCGTGCGGGCCAGCGTCGACC

TGTGCATGGCGGGCGCCGATCCGTTCCCCAAGTTCCCTAAGAGCCTGTAC

GCGGCCGGCCGCTTCTACCCCGACCTCTTCGACGACGACGAGCGCGGCCC

GCGTCGCATGACCAAGGAGTTCCTCGAGAAACTACGTGAAGACGTGGTGA

AACACGGCATCAGGAACGCCTCCTTCATCACCGGCTGCTCGGCCGACGAA

GCCGCCAACCTGGCGGGCACCACTCCGGGCTTCTGGCCGCGCCGCGACAA

CGTCTTTCTCGAGCAGACGCCGCTCATGATGACCCCGACGAAGGATCAGA

TGCTCGATGAGTGCGTGCGCTCCGTCAAGATCGAGCCCCATCGCCTGCAC

GAGGAGGATCTCTCCTGTCTCGGCGAGAACCGGCCCGTCGAGCTGCCCGT

GCTCAACAGCCGCCTCAGGCAGATCTCGAAAGAGTCCGCGACGGTCGCCG

TGCGCCGCGGCCGCTCGGCGCCCTTCTACGACGACTCGGACGACGAGGAC

GAGGTGGCGTGCTCCGAGACCGGCTGGACCGTGTCGACCGACGCGGTCAT

CAAGATGTGCGTCGACAGACAGCCGTTCGTCGACCATGCGCAGTCGCTGC

CCGTCGCCATCGGCTTCGGGGGGTCTTCGGTGGAATTGGCGCGTCATCTG

AGACGAGGGAACGCTCTGGGACTGTCCGTCGGAGTATATAAATGTAGTAT

GCCCCCTTCCGTGAATTATCGC

Accordingly, preferably the Murine CTMV M45 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 424, or a variant or fragment thereof.

One embodiment of codon optimised nucleic acid (DNA) encoding the Murine CTMV M45 polypeptide is provided herein as SEQ ID No: 425, as follows:

[SEQ ID No: 425]

ATGGACAGACAGCCCAAGGTGTACAGCGACCCCGACAACGGCTTCTTCTT

CCTGGATGTGCCCATGCCTGACGATGGCCAAGGCGGACAGCAGACAGCTA

CAACAGCTGCCGGCGGAGCCTTTGGAGTTGGCGGAGGACATTCTGTGCCC

TACGTGCGGATCATGAATGGCGTGTCCGGCATCCAGATCGGCAACCACAA

CGCCATGTCTATCGCCAGCTGTTGGAGCCCCAGCTACACCGATCGGCGGA

GAAGAAGCTACCCTAAGACCGCCACAAACGCCGCTGCCGATAGAGTGGCT

GCTGCTGTGTCTGCCGCTAACGCTGCTGTGAATGCTGCTGCCGCTGCTGC

AGCCGCAGGCGGCGGAGGCGGAGCTAATCTTCTTGCAGCAGCCGTGACCT

GCGCCAACCAGAGAGGATGTTGCGGAGGAAATGGCGGCCACAGCCTGCCT

CCAACCAGAATGCCTAAGACCAATGCCACAGCCGCTGCAGCTCCAGCAGT

TGCCGGTGCCTCTAATGCCAAGAGCGACAACAACCACGCCAACGCCACAT

CTGGCGCTGGATCTGCTGCTGCTACACCAGCCGCTACAACACCAGCTGCC

ACCGCCGTTGAGAACAGAAGGCCATCTCCAAGTCCTAGCACCGCCAGCAC

AGCCCCTTGTGATGAGGGAAGCAGCCCCAGACACCACAGACCTAGCCATG

TGTCTGTGGGCACACAGGCCACACCTAGCACACCAATTCCTATTCCAGCT

CCTCGGTGCTCCACAGGCCAGCAGCAACAACAGCCTCAGGCCAAGAAGCT

GAAGCCCGCCAAAGCTGACCCTCTGCTGTATGCCGCAACCATGCCTCCTC

CAGCCTCTGTGACTACTGCCGCAGCAGCTGCAGTGGCCCCTGAGTCTGAA

TCTTCTCCTGCCGCTTCTGCCCCTCCAGCAGCCGCCGCTATGGCTACAGG

CGGAGATGATGAGGACCAGAGCAGCTTCTCCTTCGTGTCCGATGATGTGC

TGGGCGAGTTCGAGGACCTGAGAATTGCTGGACTGCCCGTGCGGGATGAG

ATGAGGCCTCCTACACCTACCATGACAGTGATCCCCGTGTCTCGGCCTTT

CAGAGCCGGCAGAGATTCTGGCAGAGATGCCCTGTTCGACGACGCCGTGG

AAAGCGTGCGGTGTTACTGTCACGGCATCCTGGGCAACAGCAGATTCTGC

GCCCTGGTCAACGAGAAGTGTAGCGAGCCTGCCAAAGAACGGATGGCCCG

GATTAGAAGATACGCCGCCGACGTGACAAGATGCGGACCTCTGGCTCTGT

ACACCGCCATTGTGTCTAGCGCCAACCGGCTGATCCAGACAGACCCTAGC

TGTGACCTGGATCTGGCCGAGTGCTACGTGGAAACCGCCTCCAAGAGAAA

CGCCGTGCCTCTGAGCGCCTTCTACAGAGACTGCGACAGACTGAGAGATG

CCGTGGCCGCCTTCTTCAAGACCTACGGCATGGTGGTGGACGCCATGGCT

CAGAGAATCACCGAGAGAGTGGGACCCGCTCTCGGCAGAGGACTGTATTC

TACCGTGGTCATGATGGACAGATGCGGCAACAGCTTCCAGGGCAGAGAAG

AGACACCCATCAGCGTGTTCGCCAGAGTGGCTGCTGCTCTGGCCGTGGAA

TGTGAAGTGGATGGCGGCGTGTCCTACAAGATCCTGAGCAGCAAGCCTGT

GGATGCCGCTCAGGCCTTCGATGCCTTTCTGAGCGCCCTGTGCAGCTTCG

CCATCATTCCATCTCCAAGAGTGCTGGCCTACGCCGGCTTTGGCGGCAGC

AATCCTATCTTTGACGCCGTGTCTTACAGGGCCCAGTTCTACAGCGCCGA

GAGCACCATCAATGGCACCCTGCACGACATCTGCGACATGGTCACAAACG

GCCTGTCCGTGTCTGTGTCTGCCGCTGATCTCGGCGGAGATATCGTGGCC

TCTCTGCACATTCTGGGCCAGCAGTGCAAAGCCCTGAGGCCTTACGCCAG

ATTCAAGACCGTGCTGCGGATCTACTTCGACATTTGGAGCGTGGACGCCC

TGAAGATCTTTAGCTTCATCCTGGACGTGGGGCGCGAGTACGAAGGACTG

ATGGCCTTTGCCGTGAATACCCCTCGGATCTTCTGGGACAGATACCTGGA

CAGCAGCGGCGACAAGATGTGGCTGATGTTTGCCAGAAGAGAAGCCGCCG

CTCTGTGCGGCCTGGATCTGAAGTCCTTCCGGAACGTGTACGAGAAGATG

GAACGCGACGGCCGCTCTGCCATCACAGTTAGTCCTTGGTGGGCCGTGTG

TCAGCTGGATGCCTGTGTGGCCAGAGGCAATACCGCCGTGGTGTTCCCTC

ACAACGTGAAGTCTATGATCCCCGAGAACATCGGCAGGCCAGCCGTGTGT

GGACCTGGCGTTAGTGTTGTGTCTGGCGGCTTCGTGGGCTGCACACCTAT

TCACGAGCTGTGCATCAACCTGGAAAACTGCGTGCTGGAAGGCGCCGCTG

TGGAATCCTCTGTGGATGTGGTGCTCGGCCTGGGCTGCAGATTCAGCTTT

AAGGCCCTGGAAAGCCTCGTGCGGGATGCTGTGGTTCTGGGCAACCTGCT

GATCGACATGACCGTGCGGACCAATGCCTATGGCGCTGGCAAACTGCTGA

CCCTGTACCGGGATCTGCACATCGGCGTTGTGGGATTCCACGCCGTGATG

AACAGACTGGGCCAGAAATTCGCCGACATGGAAAGCTACGACCTGAACCA

GCGGATCGCCGAGTTCATCTACTACACAGCCGTCAGAGCCAGCGTGGACC

TGTGTATGGCTGGCGCCGATCCATTTCCTAAGTTCCCCAAGAGCCTGTAC

GCCGCTGGCAGATTCTACCCCGACCTGTTCGACGACGATGAGAGGGGCCC

TAGACGGATGACCAAAGAGTTCCTGGAAAAGCTGAGGGAAGATGTGGTCA

AGCACGGCATCCGGAACGCCAGCTTTATCACAGGCTGTAGCGCCGACGAG

GCCGCCAATCTTGCTGGAACAACACCCGGCTTTTGGCCCAGACGGGACAA

TGTGTTTCTGGAACAGACCCCTCTGATGATGACCCCTACCAAGGACCAGA

TGCTGGACGAGTGCGTGCGGAGCGTGAAGATCGAACCTCACAGACTGCAC

GAAGAGGACCTGAGCTGCCTGGGCGAGAACAGACCTGTGGAACTGCCCGT

GCTGAACAGCAGACTGCGGCAGATCAGCAAAGAAAGCGCCACCGTGGCCG

TGCGGAGAGGAAGAAGTGCTCCATTCTACGACGACAGCGACGACGAGGAT

GAAGTGGCCTGTTCTGAGACAGGCTGGACCGTGTCTACCGATGCCGTGAT

CAAGATGTGCGTGGACAGACAGCCCTTCGTGGATCACGCTCAGTCTCTGC

CTGTGGCCATCGGCTTTGGAGGCTCTAGCGTGGAACTGGCCAGACACCTG

AGAAGAGGCAATGCCCTGGGACTGTCTGTGGGCGTGTACAAGTGTAGCAT

GCCTCCTAGCGTGAACTACCGG

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 425, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 425 is provided herein as SEQ ID No: 426, as follows:

[SEQ ID No: 426]

AUGGACAGACAGCCCAAGGUGUACAGCGACCCCGACAACGGCUUCUUCUU

CCUGGAUGUGCCCAUGCCUGACGAUGGCCAAGGCGGACAGCAGACAGCUA

CAACAGCUGCCGGCGGAGCCUUUGGAGUUGGCGGAGGACAUUCUGUGCCC

UACGUGCGGAUCAUGAAUGGCGUGUCCGGCAUCCAGAUCGGCAACCACAA

CGCCAUGUCUAUCGCCAGCUGUUGGAGCCCCAGCUACACCGAUCGGCGGA

GAAGAAGCUACCCUAAGACCGCCACAAACGCCGCUGCCGAUAGAGUGGCU

GCUGCUGUGUCUGCCGCUAACGCUGCUGUGAAUGCUGCUGCCGCUGCUGC

AGCCGCAGGCGGCGGAGGCGGAGCUAAUCUUCUUGCAGCAGCCGUGACCU

GCGCCAACCAGAGAGGAUGUUGCGGAGGAAAUGGCGGCCACAGCCUGCCU

CCAACCAGAAUGCCUAAGACCAAUGCCACAGCCGCUGCAGCUCCAGCAGU

UGCCGGUGCCUCUAAUGCCAAGAGCGACAACAACCACGCCAACGCCACAU

CUGGCGCUGGAUCUGCUGCUGCUACACCAGCCGCUACAACACCAGCUGCC

ACCGCCGUUGAGAACAGAAGGCCAUCUCCAAGUCCUAGCACCGCCAGCAC

AGCCCCUUGUGAUGAGGGAAGCAGCCCCAGACACCACAGACCUAGCCAUG

UGUCUGUGGGCACACAGGCCACACCUAGCACACCAAUUCCUAUUCCAGCU

CCUCGGUGCUCCACAGGCCAGCAGCAACAACAGCCUCAGGCCAAGAAGCU

GAAGCCCGCCAAAGCUGACCCUCUGCUGUAUGCCGCAACCAUGCCUCCUC

CAGCCUCUGUGACUACUGCCGCAGCAGCUGCAGUGGCCCCUGAGUCUGAA

UCUUCUCCUGCCGCUUCUGCCCCUCCAGCAGCCGCCGCUAUGGCUACAGG

CGGAGAUGAUGAGGACCAGAGCAGCUUCUCCUUCGUGUCCGAUGAUGUGC

UGGGCGAGUUCGAGGACCUGAGAAUUGCUGGACUGCCCGUGCGGGAUGAG

AUGAGGCCUCCUACACCUACCAUGACAGUGAUCCCCGUGUCUCGGCCUUU

CAGAGCCGGCAGAGAUUCUGGCAGAGAUGCCCUGUUCGACGACGCCGUGG

AAAGCGUGCGGUGUUACUGUCACGGCAUCCUGGGCAACAGCAGAUUCUGC

GCCCUGGUCAACGAGAAGUGUAGCGAGCCUGCCAAAGAACGGAUGGCCCG

GAUUAGAAGAUACGCCGCCGACGUGACAAGAUGCGGACCUCUGGCUCUGU

ACACCGCCAUUGUGUCUAGCGCCAACCGGCUGAUCCAGACAGACCCUAGC

UGUGACCUGGAUCUGGCCGAGUGCUACGUGGAAACCGCCUCCAAGAGAAA

CGCCGUGCCUCUGAGCGCCUUCUACAGAGACUGCGACAGACUGAGAGAUG

CCGUGGCCGCCUUCUUCAAGACCUACGGCAUGGUGGUGGACGCCAUGGCU

CAGAGAAUCACCGAGAGAGUGGGACCCGCUCUCGGCAGAGGACUGUAUUC

UACCGUGGUCAUGAUGGACAGAUGCGGCAACAGCUUCCAGGGCAGAGAAG

AGACACCCAUCAGCGUGUUCGCCAGAGUGGCUGCUGCUCUGGCCGUGGAA

UGUGAAGUGGAUGGCGGCGUGUCCUACAAGAUCCUGAGCAGCAAGCCUGU

GGAUGCCGCUCAGGCCUUCGAUGCCUUUCUGAGCGCCCUGUGCAGCUUCG

CCAUCAUUCCAUCUCCAAGAGUGCUGGCCUACGCCGGCUUUGGCGGCAGC

AAUCCUAUCUUUGACGCCGUGUCUUACAGGGCCCAGUUCUACAGCGCCGA

GAGCACCAUCAAUGGCACCCUGCACGACAUCUGCGACAUGGUCACAAACG

GCCUGUCCGUGUCUGUGUCUGCCGCUGAUCUCGGCGGAGAUAUCGUGGCC

UCUCUGCACAUUCUGGGCCAGCAGUGCAAAGCCCUGAGGCCUUACGCCAG

AUUCAAGACCGUGCUGCGGAUCUACUUCGACAUUUGGAGCGUGGACGCCC

UGAAGAUCUUUAGCUUCAUCCUGGACGUGGGGCGCGAGUACGAAGGACUG

AUGGCCUUUGCCGUGAAUACCCCUCGGAUCUUCUGGGACAGAUACCUGGA

CAGCAGCGGCGACAAGAUGUGGCUGAUGUUUGCCAGAAGAGAAGCCGCCG

CUCUGUGCGGCCUGGAUCUGAAGUCCUUCCGGAACGUGUACGAGAAGAUG

GAACGCGACGGCCGCUCUGCCAUCACAGUUAGUCCUUGGUGGGCCGUGUG

UCAGCUGGAUGCCUGUGUGGCCAGAGGCAAUACCGCCGUGGUGUUCCCUC

ACAACGUGAAGUCUAUGAUCCCCGAGAACAUCGGCAGGCCAGCCGUGUGU

GGACCUGGCGUUAGUGUUGUGUCUGGCGGCUUCGUGGGCUGCACACCUAU

UCACGAGCUGUGCAUCAACCUGGAAAACUGCGUGCUGGAAGGCGCCGCUG

UGGAAUCCUCUGUGGAUGUGGUGCUCGGCCUGGGCUGCAGAUUCAGCUUU

AAGGCCCUGGAAAGCCUCGUGCGGGAUGCUGUGGUUCUGGGCAACCUGCU

GAUCGACAUGACCGUGCGGACCAAUGCCUAUGGCGCUGGCAAACUGCUGA

CCCUGUACCGGGAUCUGCACAUCGGCGUUGUGGGAUUCCACGCCGUGAUG

AACAGACUGGGCCAGAAAUUCGCCGACAUGGAAAGCUACGACCUGAACCA

GCGGAUCGCCGAGUUCAUCUACUACACAGCCGUCAGAGCCAGCGUGGACC

UGUGUAUGGCUGGCGCCGAUCCAUUUCCUAAGUUCCCCAAGAGCCUGUAC

GCCGCUGGCAGAUUCUACCCCGACCUGUUCGACGACGAUGAGAGGGGCCC

UAGACGGAUGACCAAAGAGUUCCUGGAAAAGCUGAGGGAAGAUGUGGUCA

AGCACGGCAUCCGGAACGCCAGCUUUAUCACAGGCUGUAGCGCCGACGAG

GCCGCCAAUCUUGCUGGAACAACACCCGGCUUUUGGCCCAGACGGGACAA

UGUGUUUCUGGAACAGACCCCUCUGAUGAUGACCCCUACCAAGGACCAGA

UGCUGGACGAGUGCGUGCGGAGCGUGAAGAUCGAACCUCACAGACUGCAC

GAAGAGGACCUGAGCUGCCUGGGCGAGAACAGACCUGUGGAACUGCCCGU

GCUGAACAGCAGACUGCGGCAGAUCAGCAAAGAAAGCGCCACCGUGGCCG

UGCGGAGAGGAAGAAGUGCUCCAUUCUACGACGACAGCGACGACGAGGAU

GAAGUGGCCUGUUCUGAGACAGGCUGGACCGUGUCUACCGAUGCCGUGAU

CAAGAUGUGCGUGGACAGACAGCCCUUCGUGGAUCACGCUCAGUCUCUGC

CUGUGGCCAUCGGCUUUGGAGGCUCUAGCGUGGAACUGGCCAGACACCUG

AGAAGAGGCAAUGCCCUGGGACUGUCUGUGGGCGUGUACAAGUGUAGCAU

GCCUCCUAGCGUGAACUACCGG

In another embodiment, the inhibitor of an innate signalling pathway is Pangolin CoV-2 ORF3b*57 variant protein, (i.e. a mutated form the Pangolin CoV-2 ORF3b protein where a premature stop codon has been altered to AA glutamine (NCBI Reference Sequence: QIG55946.1; UniProtKB—A0A6M3G7Q4 (A0A6M3G7Q4_9BETC)), or an orthologue thereof (Konno Y, Kimura I, Uriu K, Fukushi M, Irie T, Koyanagi Y, Sauter D, Gifford R, USFQ-COVID19 Consortium, Nakagawa S and Sato K. 2020. SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is increased by a naturally occurring elongation variant. Cell Reports 32: Issue 12. doi.org/10.116/j.celrep.2020.108185. One embodiment of the Pangolin CoV-2 ORF3b*57 is represented herein as SEQ ID No: 427, as follows:

[SEQ ID No: 427]

MMLTTSCVGILIVTTIVFHTIVQLLQLSLPPVMAQQIPLQNMTTKLVVIL

RNGNLE

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 427, or a variant or fragment thereof.

In one embodiment, the Pangolin CoV-2 ORF3b*57 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 428, as follows:

[SEQ ID No: 428]

ATGATGCTAACTACTTCCTGTGTTGGCATACTAATTGTTACGACTATTGT

ATTCCATACAATAGTGCAACTTCTTCAATTGTCATTACCTCCGGTGATGG

CACAACAAATCCCATTACAGAACATGACTACCAAATTGGTGGTTATTTTG

AGAAATGGGAATCTGGAG

Accordingly, preferably the Pangolin CoV-2 ORF3b*57 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 428, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 429, as follows:

[SEQ ID No: 429]

AUGAUGCUAACUACUUCCUGUGUUGGCAUACUAAUUGUUACGACUAUUGU

AUUCCAUACAAUAGUGCAACUUCUUCAAUUGUCAUUACCUCCGGUGAUGG

CACAACAAAUCCCAUUACAGAACAUGACUACCAAAUUGGUGGUUAUUUUG

AGAAAUGGGAAUCUGGAG

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 429, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 442 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 430, as follows:

[SEQ ID No: 430]

ATGATGCTGACCACCAGCTGTGTGGGCATCCTGATCGTGACCACCATCGT

GTTCCACACAATCGTGCAGCTGCTGCAGCTCAGCCTGCCTCCTGTTATGG

CCCAGCAGATCCCTCTGCAGAACATGACCACAAAGCTGGTCGTGATCCTG

CGGAACGGCAACCTGGAATGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 430, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 430 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 431, as follows:

[SEQ ID No: 431]

AUGAUGCUGACCACCAGCUGUGUGGGCAUCCUGAUCGUGACCACCAUCGU

GUUCCACACAAUCGUGCAGCUGCUGCAGCUCAGCCUGCCUCCUGUUAUGG

CCCAGCAGAUCCCUCUGCAGAACAUGACCACAAAGCUGGUCGUGAUCCUG

CGGAACGGCAACCUGGAAUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 431, or a fragment or variant thereof.

In another embodiment, the inhibitor of an innate signalling pathway is Pangolin CoV-2 ORF3b*79 variant protein, (i.e. a mutated form the Pangolin CoV-2 ORF3b protein where a premature stop codon has been altered to AA glutamine (NCBI Reference Sequence: QIG55946.1; UniProtKB—A0A6M3G7Q4 (A0A6M3G7Q4_9BETC)), or an orthologue thereof (Konno Y, Kimura I, Uriu K, Fukushi M, Irie T, Koyanagi Y, Sauter D, Gifford R, USFQ-COVID19 Consortium, Nakagawa S and Sato K. 2020. SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is increased by a naturally occurring elongation variant. Cell Reports 32: Issue 12. doi.org/10.116/j.celrep.2020.108185. One embodiment of the Pangolin CoV-2 ORF3b*79 is represented herein as SEQ ID No: 432, as follows:

[SEQ ID No: 432]

MMLTTSCVGILIVTTIVFHTIVQLLQLSLPPVMAQQIPLQNMTTKLVVIL

RNGNLELKTVLYYTATSLQITTSCTQLN

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 432, or a variant or fragment thereof.

In one embodiment, the Pangolin CoV-2 ORF3b*79 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 433, as follows:

[SEQ ID No: 433]

ATGATGCTAACTACTTCCTGTGTTGGCATACTAATTGTTACGACTATTGT

ATTCCATACAATAGTGCAACTTCTTCAATTGTCATTACCTCCGGTGATGG

CACAACAAATCCCATTACAGAACATGACTACCAAATTGGTGGTTATTTTG

AGAAATGGGAATCTGGAGCTGAAGACTGTGTTGTATTACACAGCTACTTC

ACTTCAGATTACTACCAGCTGTACTCAACTCAAT

Accordingly, preferably the Pangolin CoV-2 ORF3b*79 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 433, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 434, as follows:

[SEQ ID No: 434]

AUGAUGCUAACUACUUCCUGUGUUGGCAUACUAAUUGUUACGACUAUUGU

AUUCCAUACAAUAGUGCAACUUCUUCAAUUGUCAUUACCUCCGGUGAUGG

CACAACAAAUCCCAUUACAGAACAUGACUACCAAAUUGGUGGUUAUUUUG

AGAAAUGGGAAUCUGGAGCUGAAGACUGUGUUGUAUUACACAGCUACUUC

ACUUCAGAUUACUACCAGCUGUACUCAACUCAAU

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 434, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 432 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 435, as follows:

[SEQ ID No: 435]

ATGATGCTGACCACCAGCTGTGTGGGCATCCTGATCGTGACCACCATCGTG

TTCCACACAATCGTGCAGCTGCTGCAGCTCAGCCTGCCTCCTGTTATGGCC

CAGCAGATCCCTCTGCAGAACATGACCACAAAGCTGGTCGTGATCCTGCGG

AACGGCAACCTGGAACTGAAAACCGTGCTGTACTACACCGCCACCAGCCTG

CAGATCACCACAAGCTGCACCCAGCTGAACTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 435, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 435 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 436, as follows:

[SEQ ID No: 436]

AUGAUGCUGACCACCAGCUGUGUGGGCAUCCUGAUCGUGACCACCAUCGUG

UUCCACACAAUCGUGCAGCUGCUGCAGCUCAGCCUGCCUCCUGUUAUGGCC

CAGCAGAUCCCUCUGCAGAACAUGACCACAAAGCUGGUCGUGAUCCUGCGG

AACGGCAACCUGGAACUGAAAACCGUGCUGUACUACACCGCCACCAGCCUG

CAGAUCACCACAAGCUGCACCCAGCUGAACUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 436, or a fragment or variant thereof.

In another embodiment, the inhibitor of an innate signalling pathway is MERS-ORF4a protein (NCBI Reference Sequence: AGV08457.1; UniProtKB—T2BBG6 (T2BBG6_MERS)), or an orthologue thereof. One embodiment of the MERS-ORF4a is represented herein as SEQ ID No: 437, as follows:

[SEQ ID No: 437]

MDYVSLLNQIWQKYLNSPYTTCLYIPKPTAKYTPLVGTSLHPVLWNCQLSF

AGYTESAVNSTKALAKQDAAQRIAWLLHKDGGIPDGCSLYLRHSSLFAQSE

EEESFSN

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 437, or a variant or fragment thereof.

In one embodiment, the MERS-ORF4a polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 438, as follows:

[SEQ ID No: 438]

ATGGACTACGTGTCCCTGCTGAACCAGATTTGGCAGAAGTACCTGAACAGC

CCCTACACCACCTGTCTGTACATCCCCAAGCCTACCGCCAAGTACACACCT

CTCGTGGGCACATCTCTGCACCCCGTGCTGTGGAATTGCCAGCTGAGCTTT

GCCGGCTACACCGAGTCTGCCGTGAACAGCACAAAGGCCCTGGCCAAACAG

GACGCCGCTCAGAGAATTGCCTGGCTGCTGCACAAGGATGGCGGCATCCCT

GATGGCTGTAGCCTGTACCTGAGACACAGCAGCCTGTTCGCCCAGAGCGAG

GAAGAGGAATCCTTCAGCAAC

Accordingly, preferably the MERS-ORF4a polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 438, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 439, as follows:

[SEQ ID No: 439]

AUGGACUACGUGUCCCUGCUGAACCAGAUUUGGCAGAAGUACCUGAACAGC

CCCUACACCACCUGUCUGUACAUCCCCAAGCCUACCGCCAAGUACACACCU

CUCGUGGGCACAUCUCUGCACCCCGUGCUGUGGAAUUGCCAGCUGAGCUUU

GCCGGCUACACCGAGUCUGCCGUGAACAGCACAAAGGCCCUGGCCAAACAG

GACGCCGCUCAGAGAAUUGCCUGGCUGCUGCACAAGGAUGGCGGCAUCCCU

GAUGGCUGUAGCCUGUACCUGAGACACAGCAGCCUGUUCGCCCAGAGCGAG

GAAGAGGAAUCCUUCAGCAAC

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 439, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 437 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No: 440, as follows:

[SEQ ID No: 440]

ATGGACTACGTGTCCCTGCTGAATCAGATCTGGCAGAAGTACCTGAACAGC

CCCTACACCACCTGTCTGTACATCCCCAAGCCTACCGCCAAGTACACACCT

CTCGTGGGCACATCTCTGCACCCCGTGCTGTGGAATTGCCAGCTGAGCTTT

GCCGGCTACACCGAGAGCGCCGTGAATAGCACAAAGGCCCTGGCCAAACAG

GACGCCGCTCAGAGAATTGCCTGGCTGCTGCACAAGGATGGCGGCATCCCT

GATGGCTGTAGCCTGTACCTGAGACACAGCAGCCTGTTCGCCCAGAGCGAG

GAAGAGGAATCCTTCAGCAACTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 440 or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 440 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 441, as follows:

[SEQ ID No: 441]

AUGGACUACGUGUCCCUGCUGAAUCAGAUCUGGCAGAAGUACCUGAACAGC

CCCUACACCACCUGUCUGUACAUCCCCAAGCCUACCGCCAAGUACACACCU

CUCGUGGGCACAUCUCUGCACCCCGUGCUGUGGAAUUGCCAGCUGAGCUUU

GCCGGCUACACCGAGAGCGCCGUGAAUAGCACAAAGGCCCUGGCCAAACAG

GACGCCGCUCAGAGAAUUGCCUGGCUGCUGCACAAGGAUGGCGGCAUCCCU

GAUGGCUGUAGCCUGUACCUGAGACACAGCAGCCUGUUCGCCCAGAGCGAG

GAAGAGGAAUCCUUCAGCAACUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 441, or a fragment or variant thereof.

In another embodiment, the inhibitor of an innate signalling pathway is BVDV nPro protein (NCBI Reference Sequence: AAA42854.1; UniProtKB—P19711 (POLG_BVDVN)), or an orthologue thereof. One embodiment of the BVDV nPro is represented herein as SEQ ID No:442, as follows:

[SEQ ID No: 442]

MELITNELLYKTYKQKPVGVEEPVYDQAGDPLFGERGAVHPQSTLKLPHKR

GERDVPTNLASLPKRGDCRTGNSRGPVSGIYLKPGPLFYQDYKGPVYHRAP

LELFEEGSMCETTKRIGRVTGSDGKLYHIYVCIDGCIIIKSATRSYQRVFR

WVHNRLDCPLWVTSC

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 442, or a variant or fragment thereof.

In one embodiment, the BVDV nPro polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 443, as follows:

[SEQ ID No: 443]

ATGGAGTTGATCACAAATGAACTTTTATACAAAACATACAAACAAAAACCC

GTCGGGGTGGAGGAACCTGTTTATGATCAGGCAGGTGATCCCTTATTTGGT

GAAAGGGGAGCAGTCCACCCTCAATCGACGCTAAAGCTCCCACACAAGAGA

GGGGAACGCGATGTTCCAACCAACTTGGCATCCTTACCAAAAAGAGGTGAC

TGCAGGACGGGTAATAGCAGAGGACCTGTGAGCGGGATCTACCTGAAGCCA

GGGCCACTATTTTACCAGGACTATAAAGGTCCCGTCTATCACAGGGCCCCG

CTGGAGCTCTTTGAGGAGGGATCCATGTGTGAAACGACTAAACGGATAGGG

AGAGTAACTGGAAGTGACGGAAAGCTGTACCACATTTATGTGTGTATAGAT

GGATGTATAATAATAAAAAGTGCCACGAGAAGTTACCAAAGGGTGTTCAGG

TGGGTCCATAATAGGCTTGACTGCCCTCTATGGGTCACAAGTTGC

Accordingly, preferably the BVDV nPro polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO:443, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No:444, as follows:

[SEQ ID No: 444]

AUGGAGUUGAUCACAAAUGAACUUUUAUACAAAACAUACAAACAAAAACCC

GUCGGGGUGGAGGAACCUGUUUAUGAUCAGGCAGGUGAUCCCUUAUUUGGU

GAAAGGGGAGCAGUCCACCCUCAAUCGACGCUAAAGCUCCCACACAAGAGA

GGGGAACGCGAUGUUCCAACCAACUUGGCAUCCUUACCAAAAAGAGGUGAC

UGCAGGACGGGUAAUAGCAGAGGACCUGUGAGCGGGAUCUACCUGAAGCCA

GGGCCACUAUUUUACCAGGACUAUAAAGGUCCCGUCUAUCACAGGGCCCCG

CUGGAGCUCUUUGAGGAGGGAUCCAUGUGUGAAACGACUAAACGGAUAGGG

AGAGUAACUGGAAGUGACGGAAAGCUGUACCACAUUUAUGUGUGUAUAGAU

GGAUGUAUAAUAAUAAAAAGUGCCACGAGAAGUUACCAAAGGGUGUUCAGG

UGGGUCCAUAAUAGGCUUGACUGCCCUCUAUGGGUCACAAGUUGC

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No:444, or a variant or fragment thereof.

[SEQ ID No: 445]

ATGGAACTGATCACCAACGAGCTGCTGTACAAGACCTACAAGCAGAAACCC

GTGGGCGTCGAGGAACCCGTGTATGATCAAGCTGGCGACCCTCTGTTTGGC

GAGAGAGGCGCTGTTCACCCTCAGAGCACACTGAAGCTGCCCCACAAGCGG

GGCGAAAGAGATGTGCCTACCAACCTGGCCAGCCTGCCTAAGAGAGGCGAT

TGCAGAACCGGCAATAGCAGAGGCCCTGTGTCCGGCATCTACCTGAAACCT

GGACCACTGTTCTACCAGGACTACAAGGGCCCCGTGTACCACAGAGCACCC

CTGGAACTTTTCGAAGAGGGCAGCATGTGCGAAACCACCAAGCGGATCGGA

AGAGTGACCGGCTCTGACGGCAAGCTGTACCACATCTACGTGTGCATCGAC

GGCTGCATCATCATCAAGAGCGCCACCAGATCCTACCAGCGGGTGTTCAGA

TGGGTGCACAACAGACTGGACTGCCCTCTGTGGGTCACCAGCTGCTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 445, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 445 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 446, as follows:

[SEQ ID No: 446]

AUGGAACUGAUCACCAACGAGCUGCUGUACAAGACCUACAAGCAGAAACCC

GUGGGCGUCGAGGAACCCGUGUAUGAUCAAGCUGGCGACCCUCUGUUUGGC

GAGAGAGGCGCUGUUCACCCUCAGAGCACACUGAAGCUGCCCCACAAGCGG

GGCGAAAGAGAUGUGCCUACCAACCUGGCCAGCCUGCCUAAGAGAGGCGAU

UGCAGAACCGGCAAUAGCAGAGGCCCUGUGUCCGGCAUCUACCUGAAACCU

GGACCACUGUUCUACCAGGACUACAAGGGCCCCGUGUACCACAGAGCACCC

CUGGAACUUUUCGAAGAGGGCAGCAUGUGCGAAACCACCAAGCGGAUCGGA

AGAGUGACCGGCUCUGACGGCAAGCUGUACCACAUCUACGUGUGCAUCGAC

GGCUGCAUCAUCAUCAAGAGCGCCACCAGAUCCUACCAGCGGGUGUUCAGA

UGGGUGCACAACAGACUGGACUGCCCUCUGUGGGUCACCAGCUGCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No:446, or a fragment or variant thereof.

In another embodiment, the inhibitor of an innate signalling pathway is HSV US1 protein (NCBI Reference Sequence: CAB06708.1; UniProtKB—P89474 (ICP22_HHV2H)), or an orthologue thereof. One embodiment of the HSV US1 is represented herein as SEQ ID No: 447, as follows:

[SEQ ID No: 447]

MVRDCYLMGYCRTRLGPRTWGRLLQISGGTWDVRLRNAIREVEAHFEPAAE

PVCELPCLNARRYGPECDVGNLETNGGSTSDDEISDATDSDDTLASHSDTE

GGPSPAGRENPESASGGAIAARLECEFGTFDWTSEEGSQPWLSAVVADTSS

AERSGLPAPGACRATEAPEREDGCRKMRFPAACPYPCGHTFLRP

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 447, or a variant or fragment thereof.

In one embodiment, the HSV US1 polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No:448, as follows:

[SEQ ID No: 448]

ATGGTGCGAGACTGCTACCTCATGGGCTACTGCCGGACCCGCCTGGGGCCG

CGCACGTGGGGCCGCCTGCTGCAGATCTCGGGCGGAACCTGGGACGTGCGC

CTGCGAAACGCAATCCGGGAGGTCGAGGCGCATTTTGAACCCGCCGCCGAG

CCCGTGTGCGAGCTGCCCTGTCTGAACGCCAGGCGTTACGGCCCCGAGTGT

GATGTTGGCAATCTCGAGACCAACGGCGGCTCGACGAGCGATGATGAGATA

TCGGATGCGACGGACTCGGACGATACCCTCGCGTCCCATTCCGACACGGAG

GGGGGGCCCTCCCCGGCCGGCCGGGAGAACCCGGAATCCGCGTCCGGCGGG

GCTATCGCGGCTCGGCTGGAGTGTGAGTTTGGGACGTTTGACTGGACGTCC

GAGGAGGGCTCCCAGCCCTGGCTGTCCGCGGTGGTCGCCGATACCAGCTCC

GCCGAACGCTCTGGCCTACCCGCCCCGGGCGCGTGTCGCGCAACGGAAGCC

CCAGAACGCGAGGACGGGTGCCGAAAAATGCGCTTCCCCGCCGCCTGCCCC

TATCCCTGCGGCCACACATTTCTCCGGCCA

Accordingly, preferably the HSV US1 polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO:448, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 449, as follows:

[SEQ ID No: 449]

AUGGUGCGAGACUGCUACCUCAUGGGCUACUGCCGGACCCGCCUGGGGCCG

CGCACGUGGGGCCGCCUGCUGCAGAUCUCGGGCGGAACCUGGGACGUGCGC

CUGCGAAACGCAAUCCGGGAGGUCGAGGCGCAUUUUGAACCCGCCGCCGAG

CCCGUGUGCGAGCUGCCCUGUCUGAACGCCAGGCGUUACGGCCCCGAGUGU

GAUGUUGGCAAUCUCGAGACCAACGGCGGCUCGACGAGCGAUGAUGAGAUA

UCGGAUGCGACGGACUCGGACGAUACCCUCGCGUCCCAUUCCGACACGGAG

GGGGGGCCCUCCCCGGCCGGCCGGGAGAACCCGGAAUCCGCGUCCGGCGGG

GCUAUCGCGGCUCGGCUGGAGUGUGAGUUUGGGACGUUUGACUGGACGUCC

GAGGAGGGCUCCCAGCCCUGGCUGUCCGCGGUGGUCGCCGAUACCAGCUCC

GCCGAACGCUCUGGCCUACCCGCCCCGGGCGCGUGUCGCGCAACGGAAGCC

CCAGAACGCGAGGACGGGUGCCGAAAAAUGCGCUUCCCCGCCGCCUGCCCC

UAUCCCUGCGGCCACACAUUUCUCCGGCCA

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 449, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 447 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No:450, as follows:

[SEQ ID No: 450]

ATGGTCCGAGACTGCTACCTGATGGGCTACTGCAGAACCAGACTGGGCCC

TAGAACATGGGGCAGACTGCTGCAGATCTCTGGCGGCACATGGGATGTGC

GGCTGAGAAACGCCATCAGAGAGGTGGAAGCCCACTTCGAGCCTGCCGCT

GAACCTGTGTGTGAACTGCCCTGTCTGAACGCTAGAAGATACGGCCCTGA

GTGCGACGTGGGCAACCTGGAAACAAATGGCGGCAGCACCAGCGACGACG

AGATCTCTGATGCCACCGACAGCGACGATACACTGGCCAGCCACAGCGAT

ACAGAAGGCGGACCATCTCCTGCCGGAAGAGAGAATCCTGAGTCTGCCTC

TGGCGGAGCTATCGCCGCTAGACTGGAATGCGAGTTCGGCACCTTCGACT

GGACAAGCGAGGAAGGCTCTCAGCCTTGGCTGTCTGCTGTGGTGGCCGAT

ACAAGCAGCGCCGAAAGATCTGGACTTCCTGCTCCTGGCGCCTGCAGAGC

TACAGAAGCTCCTGAAAGAGAGGACGGCTGCAGAAAGATGCGGTTCCCTG

CCGCCTGTCCTTATCCTTGCGGCCACACATTTCTGCGGCCCTGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 450, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 450 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No:451, as follows:

[SEQ ID No: 451]

AUGGUCCGAGACUGCUACCUGAUGGGCUACUGCAGAACCAGACUGGGCCC

UAGAACAUGGGGCAGACUGCUGCAGAUCUCUGGCGGCACAUGGGAUGUGC

GGCUGAGAAACGCCAUCAGAGAGGUGGAAGCCCACUUCGAGCCUGCCGCU

GAACCUGUGUGUGAACUGCCCUGUCUGAACGCUAGAAGAUACGGCCCUGA

GUGCGACGUGGGCAACCUGGAAACAAAUGGCGGCAGCACCAGCGACGACG

AGAUCUCUGAUGCCACCGACAGCGACGAUACACUGGCCAGCCACAGCGAU

ACAGAAGGCGGACCAUCUCCUGCCGGAAGAGAGAAUCCUGAGUCUGCCUC

UGGCGGAGCUAUCGCCGCUAGACUGGAAUGCGAGUUCGGCACCUUCGACU

GGACAAGCGAGGAAGGCUCUCAGCCUUGGCUGUCUGCUGUGGUGGCCGAU

ACAAGCAGCGCCGAAAGAUCUGGACUUCCUGCUCCUGGCGCCUGCAGAGC

UACAGAAGCUCCUGAAAGAGAGGACGGCUGCAGAAAGAUGCGGUUCCCUG

CCGCCUGUCCUUAUCCUUGCGGCCACACAUUUCUGCGGCCCUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No: 452 or a fragment or variant thereof.

In another embodiment, the inhibitor of an innate signalling pathway is MERS CoV M protein (NCBI Reference Sequence: AGV08396.1; UniProtKB—T2BB40 (T2BB40_MERS)), or an orthologue thereof. One embodiment of the MERS CoV M is represented herein as SEQ ID No: 452, as follows:

[SEQ ID No: 452]

MSNMTQLTEAQIIAIIKDWNFAWSLIFLLITIVLQYGYPSRSMTVYVFKM

FVLWLLWPSSMALSIFSAIYPIDLASQIISGIVAAVSAMMWISYFVQSIR

LFMRTGSWWSFNPETNCLLNVPFGGTTVVRPLVEDSTSVTAVVTNGHLKM

AGMHFGACDYDRLPNEVTVAKPNVLIALKMVKRQSYGTNSGVAIYHRYKA

GNYRSPPITADIELALLR

Therefore, preferably the RNA construct comprises a nucleotide sequence which encodes an amino acid sequence substantially as set out in SEQ ID No: 452, or a variant or fragment thereof.

In one embodiment, the MERS CoV M polypeptide is encoded by the DNA nucleotide sequence of SEQ ID No: 453, as follows:

[SEQ ID No: 453]

ATGTCTAATATGACGCAACTCACTGAGGCGCAGATTATTGCCATTATTAA

AGACTGGAACTTTGCATGGTCCCTGATCTTTCTCTTAATTACTATCGTAC

TACAGTATGGATACCCATCCCGTAGTATGACTGTCTATGTCTTTAAAATG

TTTGTTTTATGGCTCCTATGGCCATCTTCCATGGCGCTATCAATATTTAG

CGCCATTTATCCAATTGATCTAGCTTCCCAGATAATCTCTGGCATTGTAG

CAGCTGTTTCAGCTATGATGTGGATTTCCTACTTTGTGCAGAGTATCCGG

CTGTTTATGAGAACTGGATCATGGTGGTCATTCAATCCTGAGACTAATTG

CCTTTTGAACGTTCCATTTGGTGGTACAACTGTCGTACGTCCACTCGTAG

AGGACTCCACCAGTGTAACTGCTGTTGTAACCAATGGCCACCTCAAAATG

GCTGGCATGCATTTCGGTGCTTGTGACTACGACAGACTTCCTAATGAAGT

CACCGTGGCCAAACCCAATGTGCTGATTGCTTTAAAAATGGTGAAGCGGC

AAAGCTACGGAACTAATTCCGGCGTTGCCATTTACCATAGATATAAGGCA

GGTAATTACAGGAGTCCGCCTATTACGGCGGATATTGAACTTGCATTGCT

TCGA

Accordingly, preferably the MERS CoV M polypeptide is encoded by the DNA nucleotide sequence substantially as set out in SEQ ID NO: 453, or a variant or fragment thereof.

Thus, the RNA construct may comprise an RNA nucleotide sequence of SEQ ID No: 454, as follows:

[SEQ ID No: 454]

AUGUCUAAUAUGACGCAACUCACUGAGGCGCAGAUUAUUGCCAUUAUUAA

AGACUGGAACUUUGCAUGGUCCCUGAUCUUUCUCUUAAUUACUAUCGUAC

UACAGUAUGGAUACCCAUCCCGUAGUAUGACUGUCUAUGUCUUUAAAAUG

UUUGUUUUAUGGCUCCUAUGGCCAUCUUCCAUGGCGCUAUCAAUAUUUAG

CGCCAUUUAUCCAAUUGAUCUAGCUUCCCAGAUAAUCUCUGGCAUUGUAG

CAGCUGUUUCAGCUAUGAUGUGGAUUUCCUACUUUGUGCAGAGUAUCCGG

CUGUUUAUGAGAACUGGAUCAUGGUGGUCAUUCAAUCCUGAGACUAAUUG

CCUUUUGAACGUUCCAUUUGGUGGUACAACUGUCGUACGUCCACUCGUAG

AGGACUCCACCAGUGUAACUGCUGUUGUAACCAAUGGCCACCUCAAAAUG

GCUGGCAUGCAUUUCGGUGCUUGUGACUACGACAGACUUCCUAAUGAAGU

CACCGUGGCCAAACCCAAUGUGCUGAUUGCUUUAAAAAUGGUGAAGCGGC

AAAGCUACGGAACUAAUUCCGGCGUUGCCAUUUACCAUAGAUAUAAGGCA

GGUAAUUACAGGAGUCCGCCUAUUACGGCGGAUAUUGAACUUGCAUUGCU

UCGA

Therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out in SEQ ID No: 454, or a variant or fragment thereof.

The inventors then subjected the protein sequence of SEQ ID No: 452 to codon optimisation for human expression, and one embodiment of the codon optimised nucleic acid (DNA) sequence that includes that includes a start (ATG) and a stop (TGA) codon is provided herein as SEQ ID No:455, as follows:

[SEQ ID No: 455]

ATGAGCAACATGACCCAGCTGACAGAGGCCCAGATCATTGCCATCATCAA

GGACTGGAACTTCGCTTGGAGCCTGATCTTCCTGCTGATCACCATCGTGC

TGCAGTACGGCTACCCCAGCAGATCCATGACCGTGTACGTGTTCAAGATG

TTCGTCCTGTGGCTGCTGTGGCCCAGCTCTATGGCCCTGAGCATCTTCAG

CGCCATCTATCCCATCGACCTGGCCAGCCAGATCATCTCTGGAATCGTGG

CCGCCGTGTCCGCCATGATGTGGATCAGCTACTTCGTGCAGAGCATCCGG

CTGTTCATGAGAACCGGCAGCTGGTGGTCCTTCAATCCCGAGACAAACTG

CCTGCTGAACGTGCCCTTTGGCGGCACTACAGTCGTCAGACCCCTGGTGG

AAGATAGCACCTCTGTGACCGCCGTGGTCACCAATGGCCACCTGAAAATG

GCCGGCATGCACTTCGGCGCCTGCGACTATGACAGACTGCCCAACGAAGT

GACCGTGGCCAAGCCTAATGTGCTGATCGCCCTGAAGATGGTCAAGCGGC

AGAGCTACGGCACCAATTCTGGCGTGGCCATCTACCACAGATACAAGGCC

GGCAACTACAGAAGCCCTCCTATCACCGCCGACATCGAGCTGGCTCTGCT

GAGATGA

Hence, preferably the RNA construct is encoded by a DNA sequence substantially as set out in SEQ ID No: 455, or a fragment or variant thereof.

In an embodiment, the RNA sequence corresponding to the codon optimised DNA sequence of SEQ ID No: 455 that includes a start (AUG) and a stop (UGA) codon is provided herein as SEQ ID No: 456, as follows:

[SEQ ID No: 456]

AUGAGCAACAUGACCCAGCUGACAGAGGCCCAGAUCAUUGCCAUCAUCAA

GGACUGGAACUUCGCUUGGAGCCUGAUCUUCCUGCUGAUCACCAUCGUGC

UGCAGUACGGCUACCCCAGCAGAUCCAUGACCGUGUACGUGUUCAAGAUG

UUCGUCCUGUGGCUGCUGUGGCCCAGCUCUAUGGCCCUGAGCAUCUUCAG

CGCCAUCUAUCCCAUCGACCUGGCCAGCCAGAUCAUCUCUGGAAUCGUGG

CCGCCGUGUCCGCCAUGAUGUGGAUCAGCUACUUCGUGCAGAGCAUCCGG

CUGUUCAUGAGAACCGGCAGCUGGUGGUCCUUCAAUCCCGAGACAAACUG

CCUGCUGAACGUGCCCUUUGGCGGCACUACAGUCGUCAGACCCCUGGUGG

AAGAUAGCACCUCUGUGACCGCCGUGGUCACCAAUGGCCACCUGAAAAUG

GCCGGCAUGCACUUCGGCGCCUGCGACUAUGACAGACUGCCCAACGAAGU

GACCGUGGCCAAGCCUAAUGUGCUGAUCGCCCUGAAGAUGGUCAAGCGGC

AGAGCUACGGCACCAAUUCUGGCGUGGCCAUCUACCACAGAUACAAGGCC

GGCAACUACAGAAGCCCUCCUAUCACCGCCGACAUCGAGCUGGCUCUGCU

GAGAUGA

Hence, preferably the RNA construct comprises a sequence substantially as set out in SEQ ID No:456, or a fragment or variant thereof.

The at least one innate inhibitor protein (IIP) may not be selected from a group of IIPs consisting of: ORF4a (NS4a) of any coronavirus, ORF3b of any coronavirus, or the nucleocapsid proteins of mouse hepatitis virus and SARS (coronavirus); and orthologues thereof.

The at least one innate inhibitor protein (IIP) may not be selected from a group of IIPs consisting of: HSV-2 Us1; HSV-1 Us1; HSV-1Us11; ORF V20.0L; BVDV Npro; Langat NS5; Influenza NS1; PIV-5 V; SARS-CoV-2 ORF3b; and MERS-CoV ORF4a.

The RNA construct comprises a nucleotide sequence which encodes the at least one therapeutic biomolecule. This is referred to as the gene of interest (GOI) in FIG. 1.

The at least one therapeutic biomolecule may comprise a therapeutic protein. The skilled person would understand that therapeutic protein relates to any protein that has therapeutic application, preferably in human. Exemplary therapeutic biomolecules that can be encoded by the RNA molecule include proteins or peptides derived from pathogens, such as bacteria, viruses, fungi, protozoa/or parasites. The protein or peptide may be an antigen, and therefore one which may stimulate or trigger and immune response in the host. Hence, in the embodiment in which the at least one therapeutic biomolecule is an antigen, the RNA construct of the first aspect may be regarded as a vaccine.

The protein or peptide derived from a virus may be a viral antigen. The viral antigen may be derived from a virus selected from the group consisting of: Orthomyxoviruses; Paramyxoviridae viruses; Metapneumovirus and Morbilliviruses; Pneumoviruses; Paramyxoviruses; Poxviridae; Metapneumoviruses; Morbilliviruses; Picornaviruses; Enteroviruseses; Bunyaviruses; Phlebovirus; Nairovirus; Heparnaviruses; Togaviruses; Alphavirus; Arterivirus; Flaviviruses; Pestiviruses; Hepadnaviruses; Rhabdoviruses; Caliciviridae; Coronaviruses; Retroviruses; Reoviruses; Parvoviruses; Delta hepatitis virus (HDV); Hepatitis E virus (HEV); Human Herpesviruses and Papovaviruses.

The Orthomyxoviruses may be Influenza A, B and C. The Paramyxoviridae virus may be Pneumoviruses (RSV), Paramyxoviruses (PIV). The Metapneumovirus may be Morbilliviruses (e.g., measles). The Pneumovirus may be Respiratory syncytial virus (RSV), Bovine respiratory syncytial virus, Pneumonia virus of mice, or Turkey rhinotracheitis virus. The Paramyxovirus may be Parainkuenza virus types 1-4 (PIV), Mumps, Sendai viruses, Simian virus 5, Bovine parainkuenza virus, Nipahvirus, Henipavirus or Newcastle disease virus. The Poxviridae may be Variola vera, for example Variola major and Variola minor. The Metapneumovirus may be human metapneumovirus (hMPV) or avian metapneumoviruses (aMPV). The Morbillivirus may be measles. The Picornaviruses may be Enteroviruses, Rhinoviruses, Heparnavirus, Parechovirus, Cardioviruses and Aphthoviruses. The Enteroviruses may be Poliovirus types 1, 2 or 3, Coxsackie A virus types 1 to 22 and 24, Coxsackie B virus types 1 to 6, Echovirus (ECHO) virus) types 1 to 9, 11 to 27 and 29 to 34 or Enterovirus 68 to 71. The Bunyavirus may be California encephalitis virus. The Phlebovirus may be Rift Valley Fever virus. The Nairovirus may be Crimean-Congo hemorrhagic fever virus. The Heparnaviruses may be Hepatitis A virus (HAV). The Togaviruses may be Rubivirus. The Flavivirus may be Tick-borne encephalitis (TBE) virus, Dengue (types 1, 2, 3 or 4) virus, Yellow Fever virus, Japanese encephalitis virus, Kyasanur Forest Virus, West Nile encephalitis virus, St. Louis encephalitis virus, Russian spring-summer encephalitis virus or Powassan encephalitis virus. The Pestivirus may be Bovine viral diarrhea (BVDV), Classical swine fever (CSFV) or Border disease (BDV). The Hepadnavirus may be Hepatitis B virus or Hepatitis C virus. The Rhabdovirus may be Lyssavirus (Rabies virus) or Vesiculovirus (VSV). The Caliciviridae may be Norwalk virus, or Norwalk-like Viruses, such as Hawaii Virus and Snow Mountain Virus. The Coronavirus may be SARS CoV-1, SARS-CoV-2, MERS, Human respiratory coronavirus, Avian infectious bronchitis (IBV), Mouse hepatitis virus (MHV), or Porcine transmissible gastroenteritis virus (TGEV). The Retrovirus may be Oncovirus, a Lentivirus or a Spumavirus. The Reovirus may be an Orthoreo virus, a Rotavirus, an Orbivirus, or a Coltivirus. The Parvovirus may be Parvovirus B 19. The Human Herpesvirus may be Herpes Simplex Viruses (HSV), Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Human Herpesvirus 6 (HHV6), Human Herpesvirus 7 (HHV7), or Human Herpesvirus 8 (HHV8). The Papovavirus may be Papilloma viruses, Polyomaviruses, Adenoviruess or Arenaviruses.

The protein or peptide derived from bacteria may be a bacterial antigen.

The bacterial antigen may derived from a bacterium selected from the group consisting of: Neisseria meningitides, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, Bordetella pertussis, Burkholderia sp. (e.g., Burkholderia mallei, Burkholderia pseudomallei and Burkholderia cepacia), Staphylococcus aureus, Haemophilus influenzae, Clostridium tetani (Tetanus), Clostridium perfringens, Clostridium botulinums, Cornynebacterium diphtheriae (Diphtheria), Pseudomonas aeruginosa, Legionella pneumophila, Coxiella burnetii, Brucella sp. (e.g., B. abortus, B. canis, B. melitensis, B. neotomae, B. ovis, B. suis and B. pinnipediae, Francisella sp. (e.g., F. novicida, F. philomiragia and F. tularensis), Streptococcus agalactiae, Neiserria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum (Syphilis), Haemophilus ducreyi, Enterococcusfaecalis, Enterococcus faecium, Helicobacter pylori, Staphylococcus saprophyticus, Yersinia enter ocolitica, E. coli, Bacillus anthracis (anthrax), Yersinia pestis (plague), Mycobacterium tuberculosis, Rickettsia, Listeria, Chlamydia pneumoniae, Vibrio cholerae, Salmonella typhi (typhoid fever), Borrelia burgdorfer, Porphyromonas s and Klebsiella sp.

The protein or peptide derived from a fungus may be a fungal antigen.

The fungal antigen may be derived from a fungus selected from the group consisting of Dermatophytres, including: Epidermophyton koccusum, Microsporum audouini, Microsporum canis, Microsporum distortum, Microsporum equinum, Microsporum gypsum, Microsporum nanum, Trichophyton concentricum, Trichophyton equinum, Trichophyton gallinae, Trichophyton gypseum, Trichophyton megnini, Trichophyton mentagrophytes, Trichophyton quinckeanum, Trichophyton rubrum, Trichophyton schoenleini, Trichophyton tonsurans, Trichophyton verrucosum, T verrucosum var. album, var. discoides, var. ochraceum, Trichophyton violaceum, and/or Trichophyton faviforme; or from Aspergillus fumigatus, Aspergillus kavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus, Aspergillus sydowii, Aspergillus kavatus, Aspergillus glaucus, Blastoschizomyces capitatus, Candida albicans, Candida enolase, Candida tropicalis, Candida glabrata, Candida krusei, Candida parapsilosis, Candida stellatoidea, Candida kusei, Candida parakwsei, Candida lusitaniae, Candida pseudotropicalis, Candida guilliermondi, Cladosporium carrionii, Coccidioides immitis, Blastomyces dermatidis, Cryptococcus neoformans, Geotrichum clavatum, Histoplasma capsulatum, Klebsiella pneumoniae, Microsporidia, Encephalitozoon spp., Septata intestinalis and Enterocytozoon bieneusi; Brachiola spp, Microsporidium spp., Nosema spp., Pleistophora spp., Trachipleistophora spp., Vittaforma spp Paracoccidioides brasiliensis, Pneumocystis carinii, Pythiumn insidiosum, Pityrosporum ovale, Sacharomyces cerevisiae, Saccharomyces boulardii, Saccharomyces pombe, Scedosporium apiosperum, Sporothrix schenckii, Trichosporon beigelii, Toxoplasma gondii, Penicillium marneffei, Malassezia spp., Fonsecaea spp., Wangiella spp., Sporothrix spp., Basidiobolus spp., Conidiobolus spp., Rhizopus spp, Mucor spp, Absidia spp, Mortierella spp, Cunninghamella spp, Saksenaea spp., Alternaria spp, Curvularia spp, Helminthosporium spp, Fusarium spp, Aspergillus spp, Penicillium spp, Monolinia spp, Rhizoctonia spp, Paecilomyces spp, Pithomyces spp, and Cladosporium spp. The protein or peptide derived from a protozoan may be a protozoan antigen.

The protozoan antigen may be derived from a protozoan selected from the group consisting of: Entamoeba histolytica, Giardia lambli, Cryptosporidium parvum, Cyclospora cayatanensis and Toxoplasma.

The therapeutic biomolecule may be a protein or peptide derived from a plant. Preferably, the protein or peptide is a plant antigen. For example, the plant antigen may be derived from Ricinus communis.

In another embodiment, the therapeutic biomolecule may be an immunogen or an antigen. Preferably, the immunogen or an antigen is a tumour immunogen or antigen, or cancer immunogen or antigen. The tumour immunogens and antigens may be peptide-containing tumour antigens, such as a polypeptide tumour antigen or glycoprotein tumour antigens.

The tumour antigens may be (a) full length molecules associated with cancer cells, (b) homologs and modified forms of the same, including molecules with deleted, added and/or substituted portions, and (c) fragments of the same.

Suitable tumour immunogens include: class I-restricted antigens recognized by CD 8+ lymphocytes or class II-restricted antigens recognized by CD4+ lymphocytes.

The tumour antigen may be an antigen that is associated with a cancer selected from the group consisting of: a testis cancer, melanoma, lung cancer, head and neck cancer, NSCLC, breast cancer, gastrointestinal cancer, bladder cancer, colorectal cancer, pancreatic cancer, lymphoma, leukaemia, renal cancer, hepatoma, ovarian cancer, gastric cancer and prostate cancer.

The tumour antigen may be selected from:

- (a) cancer-testis antigens, such as NY-ESO-I, SSX2, SCP-1, as well as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-I, GAGE-2, MAGE-I, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12 (which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumours);
- (b) mutated antigens, for example, p53 (associated with various solid tumours, e.g., colorectal, lung, head and neck cancer), p21/Ras (associated with, e.g., melanoma, pancreatic cancer and colorectal cancer), CDK4 (associated with, e.g., melanoma), MUM-1 (associated with, e.g., melanoma), caspase-8 (associated with, e.g., head and neck cancer), CIA 0205 (associated with, e.g., bladder cancer), HLA-A2-R1701, beta catenin (associated with, e.g., melanoma), TCR (associated with, e.g., T-cell non-Hodgkins lymphoma), BCR-abl (associated with, e.g., chronic myelogenous leukemia), triosephosphate isomerase, KIA 0205, CDC-27, and LDLR-FUT;
- (c) over-expressed antigens, for example, Galectin 4 (associated with, e.g., colorectal cancer), Galectin 9 (associated with, e.g., Hodgkin's disease), proteinase 3 (associated with, e.g., chronic myelogenous leukemia), WT 1 (associated with, e.g., various leukaemias), carbonic anhydrase (associated with, e.g., renal cancer), aldolase A (associated with, e.g., lung cancer), PRAME (associated with, e.g., melanoma), HER-2/neu (associated with, e.g., breast, colon, lung and ovarian cancer), alpha-fetoprotein (associated with, e.g., hepatoma), KSA (associated with, e.g., colorectal cancer), gastrin (associated with, e.g., pancreatic and gastric cancer), telomerase catalytic protein, MUC-I (associated with, e.g., breast and ovarian cancer), G-250 (associated with, e.g., renal cell carcinoma), p53 (associated with, e.g., breast, colon cancer), and carcinoembryonic antigen (associated with, e.g., breast cancer, lung cancer, and cancers of the gastrointestinal tract such as colorectal cancer);
- (d) shared antigens, for example, melanoma-melanocyte differentiation antigens, such as MART-1/Melan A, gplOO, MClR, melanocyte-stimulating hormone receptor, tyrosinase, tyrosinase related protein-1/TRPl and tyrosinase related protein-2/TRP2 (associated with, e.g., melanoma);
- (e) prostate-associated antigens, such as PAP, PSA, PSMA, PSH-Pl, PSM-Pl, PSM-P2, associated with e.g., prostate cancer; and/or
- (f) immunoglobulin idiotypes (associated with myeloma and B cell lymphomas, for example).

The therapeutic biomolecule may be a eukaryotic protein or peptide. In one embodiment, the eukaryotic protein or peptide is a mammalian protein or peptide. The mammalian protein or peptide may be selected from the group consisting of: an enzyme; an enzyme inhibitor; a hormone; an immune system protein; a receptor; a binding protein; a transcription factor; translation factor; tumour growth suppressing protein; a structural protein; and a blood protein.

The immune system protein may be an antibody or antigen binding fragment thereof. Accordingly, the therapeutic biomolecule may be an antibody or antigen binding fragment thereof. The antigen binding fragment may comprise an individual heavy or light chain, or a fragment thereof, such as VL, VH and Fd; a monovalent fragment, such as Fv, Fab, and Fab′; a bivalent fragment, such as F(ab′)₂; a single chain Fv (scFv); one or more complementarity determining region (CDR); or a Fc fragment.

The enzyme may be selected from the group consisting of: chymosin; gastric lipase; tissue plasminogen activator; streptokinase; a cholesterol biosynthetic or degradative steriodogenic enzyme; kinases; phosphodiesterases; methylases; de-methylases; dehydrogenases; cellulases; proteases; lipases; phospholipases; aromatases; cytochromes; adenylate or guanylaste cyclases and neuramidases.

The enzyme inhibitor may be tissue inhibitor of metalloproteinase (TIMP). The hormone may be growth hormone.

The immune system protein may be selected from the group consisting of: a cytokine; a chemokine; a lymphokine; erythropoietin; an integrin; addressin; selectin; homing receptors; T cell receptors and immunoglobulins.

The cytokine may be an interleukin, for example IL-2, IL-4 and/or IL-6, colony stimulating factor (CSF), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF) or tumour necrosis factor (TNF).

The chemokine may be a macrophage inflammatory protein-2 and/or a plasminogen activator.

The lymphokine may be an interferon.

The immunoglobulin may be a natural, modified or chimeric immunoglobulin or a fragment thereof. Preferably, the immunoglobulin is a chimeric immunoglobulin having dual activity such as antibody enzyme or antibody-toxin chimera.

The hormone may be selected from the group consisting of: insulin, thyroid hormone, catecholamines, gonadotrophines, trophic hormones, prolactin, oxytocin, dopamine, bovine somatotropin, leptins; growth hormones (e.g., human growth hormone), growth factors (e.g., epidermal growth factor, nerve growth factor, insulin-like growth factor and the like).

The receptor may be a steroid hormone receptor or a peptide receptor. Preferably, the receptor is a growth factor receptor.

The binding protein may be a growth factor binding protein.

The tumour growth suppressing protein may be a protein that inhibits angiogenesis.

The structural protein may be selected from the group consisting of: collagen; fibroin; fibrinogen; elastin; tubulin; actin; and myosin.

The blood protein may be selected from the group consisting of thrombin; serum albumin; Factor VII; Factor VIII; insulin; Factor IX; Factor X; tissue plasminogen activator; protein C; von Willebrand factor; antithrombin III; glucocerebrosidase; erythropoietin granulocyte colony stimulating factor (GCSF) or modified Factor VIII; and anticoagulants.

In one preferred embodiment, the therapeutic biomolecule is a cytokine which is capable of regulating lymphoid homeostasis, preferably a cytokine which is involved in and preferably induces or enhances development, priming, expansion, differentiation and/or survival of T cells. Thus, preferably, the cytokine is an interleukin. Most preferably, IL-2, IL-7, IL-12, IL-15, or IL-21.

The therapeutic biomolecule may be protein that is capable of enhancing reprogramming of somatic cells to cells having stem cell characteristics. The protein that is capable of enhancing reprogramming of somatic cells to cells having stem cell characteristics may be selected from the group consisting of: OCT4, SOX2, NANOG, LIN28, p53, ART-4, BAGE, ss-catenin/m, Bcr-abL CAMEL, CAP-1, CASP-8, CDC27/m, CD 4/m, CEA, CLAUDIN-12, c-MYC, CT, Cyp-B, DAM, ELF2M, ETV6-AML1, G250, GAGE, GnT-V, GaplOO, HAGE, HER-2/neu, HPV-E7, HPV-E6, HAST-2, hTERT (or hTRT), LAGE, LDLR/FUT, MAGE-A, MAGE-B, MAGE-C, MART-1/Melan-A, MC1R, Myosin/m, MUC1, MUM-1, -2, -3, NA88-A, NF1, NY-ESO-1, NY-BR-1, p190 minor BCR-abL, Plac-1, Pml/RARa, PRAME, proteinase 3, PSA, PSM, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, SCGB3A2, SCP1, SCP2, SCP3, SSX, SURVIVIN, TEL/AML1, TPI/m, TRP-1, TRP-2, TRP-2/INT2, TPTE and WT, preferably WT-1.

Preferably, MAGE-A is selected from the group consisting of: MAGE-A 1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A 10, MAGE-A 11, or MAGE-A 12. Preferably, the protein that is capable of enhancing reprogramming of somatic cells to cells having stem cell characteristics is OCT4, SOX2, LF4; c-MYC; NANOG; LIN28.

The therapeutic biomolecule may be a biomolecule that is utilised for the modification of cells ex vivo for cell-therapy indications. Thus, preferably the therapeutic biomolecule may be selected from the group consisting of an immunoglobulin, a T-cell receptor and NK receptor.

The therapeutic biomolecule may be an RNA molecule that is capable of regulating expression of endogenous host genes, for example an interfering RNA, such as small RNA, siRNA or microRNA.

The sequence encoding the at least one viral innate inhibitor protein (IIP) may be disposed anywhere within the RNA construct of the first aspect, such that the sequence encoding the therapeutic biomolecule (i.e. the GOI in FIG. 1) may be disposed either 5′ or 3′ to the sequence encoding the at least one IIP.

For example, in one embodiment, the sequence encoding the therapeutic biomolecule is preferably disposed 5′ to the sequence encoding the at least one innate modulatory protein. See for example, the saRNA embodiments 2a, 3a, 4a, and the mRNA embodiments 6a and 7a shown in FIG. 1.

However, in another embodiment, the sequence encoding the therapeutic biomolecule is preferably disposed 3′ to the sequence encoding the at least one innate modulatory protein. See for example, the saRNA embodiments 2b, 3b, 4b, and the mRNA embodiments 6b and 7b shown in FIG. 1.

Preferably, the RNA construct according to the first aspect comprises at least one promotor, which may be either genomic or subgenomic. Preferably, however, the promoter is a subgenomic promoter, as is shown in FIG. 1 (embodiments 1-4b).

Preferably, therefore, saRNA constructs of the invention comprise a promoter. The skilled person would understand that the subgenomic promotor relates to a promoter that is operably linked to the sequences encoding the at least one therapeutic biomolecule and the at least one innate inhibitor protein, such that it enables the transcription of the nucleotide sequence encoding the therapeutic biomolecule and the at least one innate modulatory protein.

Preferably, the subgenomic promoter is 26S, which is provided herein as SEQ ID No: 67, as follows:

[SEQ ID No: 67]

GGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACAT

Accordingly, preferably the promoter (which is preferably a subgenomic promoter) is as substantially as set out in SEQ ID NO: 67, or a variant or fragment thereof.

In one embodiment, the same promotor is operably linked to the sequence encoding the at least therapeutic biomolecule and the sequence encoding the at least one innate modulatory protein.

The inventor's designs, wherein both the therapeutic biomolecule (i.e. GOI) and IIP are encoded by a single strand of RNA, advantageously enables the use of much smaller doses of RNA, because it ensures that the protein is being expressed in the same cell that is sensing the RNA, and can also be replicated, therefore having the additional aspect of expression and amplification of the innate modulatory component.

Thus, in one embodiment of the RNA construct, the promoter is disposed 5′ of the sequence encoding the at least one therapeutic biomolecule and the sequence encoding the at least one innate inhibitor protein, such that the promoter is operably linked to both sequences, thereby driving expression of both.

In another embodiment, however, a first promotor is operably linked to the sequence encoding the at least one therapeutic biomolecule, and a second promotor is operably linked the sequence encoding the at least one innate inhibitor protein. This is referred to as a double genomic construct. Preferably, the first and/or second promoter is genomic or subgenomic. Preferably, both promoters are subgenomic promoters, such as 26S.

The RNA construct may encode at least two, three, four or five IIPs. In embodiments in which there is more than one sequence encoding an innate modulatory protein, a single promotor may be operably linked to all sequences encoding an innate modulatory protein.

Alternatively, a promotor may be linked to each of the sequences encoding an innate modulatory protein, such that each innate modulatory protein is operably linked to a separate promoter. In this embodiment, the separate promoters may comprise the same promotor sequence or different promoter sequences. In another embodiment, different promotors are operably linked to each sequence encoding an innate modulatory protein.

The RNA construct may further comprise a linker sequence disposed between the sequence encoding the at least one therapeutic biomolecule and the sequence encoding the at least one innate modulatory protein. This linker sequence is such that it allows the production of the IIP and the production of the therapeutic molecule from the single promoter. In one embodiment, the linker sequence encodes a peptide linker that is configured to be digested or cleaved following translation, to thereby separate the at least one therapeutic biomolecule and the at least one innate modulatory protein in the host cell. As such, the linker sequence is preferably a cleavable peptide, which may form a cleavage site, for example a 2A peptide (Furler S, Paterna J-C, Weibel M and Bueler H Recombinant AAV vectors containing the foot and mouth disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons Gene Ther. 2001, vol. 8, PP: 864-873).

Preferably, the linker sequence encoding the 2A peptide sequence connects the two coding sequence together. This enables the RNA construct to overcome the size restrictions that may occur with expression in various vectors and enables expression and translation of all of the peptides encoded by the RNA construct of the first aspect to occur under control of a single promoter, as a single protein. Thus, following the translation of the single protein comprising the sequences of the IIP, the 2A peptide, and the therapeutic biomolecule, cleavage occurs in the viral 2A peptide sequence at the terminal glycine-proline link, thereby liberating two polypeptides.

The 2A spacer sequence may be any known variant, which includes those sequences referred to as E2A, F2A, P2A and T2A, as disclosed in Wang Y et al. Scientific Reports 2015, 5, i.e. suitable 2A peptides include the porcine teschovirus-1 2A (P2A)—ATNFSLLKQAGDVEENPGP (SEQ ID No: 68), Thosea asigna virus 2A (T2A)—QCTNYALLKLAGDVESNPGP (SEQ ID No: 69), equine rhinitis A virus 2A (E2A), and Foot and mouth disease virus 2A (F2A) VKQTLNFDLLKLAGDVESNPGP (SEQ ID No: 70). Preferably, the 2A peptide is Thosea asigna virus 2A (T2A).

In another embodiment, the cleavable peptide is a self-cleaving peptide. In an embodiment, the linker comprises a viral 2A peptide spacer and further comprises a furin cleavage site. Preferably, the self-cleaving peptide is a furin/2A peptide. Insertion of an upstream furin cleavage site allows the removal of 2A residues that would otherwise remain attached to the upstream protein.

The furin sequence may be disposed 3′ or 5′ of the 2A sequence. Preferably, however, the furin sequence is disposed 5′ of the 2A sequence, and preferably with a GSG spacer disposed between the furin and 2A sequence.

The skilled person would appreciate that furin is a ubiquitous calcium-dependent proprotein convertase located in the secretory pathway (mainly in the golgi and trans-golgi network) that cleaves precursor proteins at a specific recognition sequence—canonically R-X-R/K/X-R (SEQ ID No: 71), and cleaving the proprotein after the final R. Thus, in one embodiment the furin sequence is R-X-R/K/X-R. However, preferably, the furin sequence is the optimised sequence RRRRRR (SEQ ID No: 72) a GSG sequence. Preferably, the GSG spacer is disposed 3′ of the furin sequence and 5′ of the 2A sequence.

Thus, preferably, the spacer sequence is the furin/T2A, as provided by NCBI Reference Sequence: GenBank: AAC97195.1, and provided herein as SEQ ID No: 73, as follows:

[SEQ ID No: 73]

RRRRRRGSGEGRGSLLTCGDVEENPGP

Hence, preferably the spacer sequence comprises an amino acid sequence substantially as set out in SEQ ID NO: 73, or a variant or fragment thereof.

FIG. 1 shows embodiments 2a, 2b and 6a, 6b in which the GOI and IIP are linked by a nucleotide sequence which encodes the Furin-T2a cleavage site. In one embodiment, shown as either 2a or 6a in FIG. 1, the F-T2a cleavage site separates a 5′ GOI and a 3′ IIP. In one embodiment, shown as either 2b or 6b in FIG. 1, the F-T2a cleavage site separates a 3′ GOI and a 5′ IIP.

In embodiments in which the RNA construct or replicon comprises more than one sequence encoding an innate modulatory protein, the construct may comprise linker sequences disposed between each sequence encoding an innate modulatory protein, or only between some IIPs.

In one embodiment, the sequence encoding the at least one therapeutic biomolecule and the sequence encoding the at least one innate modulatory protein may be separated by a stop codon followed by an internal ribosome entry site (IRES) sequence capable of initiating translation of the downstream sequence, whichever sequence that may be (i.e. GOI or IIP as shown in embodiments 3a, 3b, 7a or 7b in FIG. 1). Therefore, preferably the IRES sequence is disposed between the sequence encoding the at least one therapeutic biomolecule and the sequence encoding at least one innate modulatory protein. Where multiple sequences encoding at least one innate modulatory protein are used, linker sequences may include combinations of known cleavage sequences and/or IRES sequences. In one embodiment, shown as either 3a or 7a in FIG. 1, the IRES site separates a 5′ GOI and a 3′ IIP. In one embodiment, shown as either 3b or 7b in FIG. 1, the IRES site separates a 3′ GOI and a 5′ IIP.

In an embodiment, the IRES is a picornavirus IRES. Oher typical IRES sequences include those such as the IRES sequence of encephalomyocarditis virus (EMCV) or vascular endothelial growth factor and type 1 collagen-inducible protein (VCIP), and would be known to those skilled in the art.

In other embodiments, the IRES may be selected from a rhinovirus IRES, a hepatitis A virus IRES, a hepatitis C virus IRES, a poliovirus IRES, an enterovirus IRES, a cardiovirus IRES, an aphthovirus IRES, flavivirus IRES, a pestivirus IRES, a cripavirus IRES, a Rhopalosiphum padi virus IRES, or any suitable IRES. In particular, the IRES may be any IRES described by the “IRESite” which provides a database of experimentally verified IRES structures (http://www.iresite.org/), or as disclosed in “New Messenger RNA Research Communications” (ISBN: 1-60021-488-6).

In a preferred embodiment, the IRES is a foot-and-mouth disease virus (FMDV) IRES, which may be as set out in SEQ ID No:74, or a fragment or variant thereof, as follows:

[SEQ ID NO: 74]

AGCAGGTTTCCCCAACTGACACAAAACGTGCAACTTGAAACTCCGCCTGG

TCTTTCCAGGTCTAGAGGGGTAACACTTTGTACTGCGTTTGGCTCCACGC

TCGATCCACTGGCGAGTGTTAGTAACAGCACTGTTGCTTCGTAGCGGAGC

ATGACGGCCGTGGGAACTCCTCCTTGGTAACAAGGACCCACGGGGCCAAA

AGCCACGCCCACACGGGCCCGTCATGTGTGCAACCCCAGCACGGCGACTT

TACTGCGAAACCCACTTTAAAGTGACATTGAAACTGGTACCCACACACTG

GTGACAGGCTAAGGATGCCCTTCAGGTACCCCGAGGTAACACGCGACACT

CGGGATCTGAGAAGGGGACTGGGGCTTCTATAAAAGCGCTCGGTTTAAAA

AGCTTCTATGCCTGAATAGGTGACCGGAGGTCGGCACCTTTCCTTTGCAA

TTACTGACCAC

In another preferred embodiment, the IRES is an encephalomyocarditis virus (EMCV) IRES. The EMCV IRES may be as set out in SEQ ID No:75, or a fragment or variant thereof, as follows:

[SEQ ID NO: 75]

CGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATA

TGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAA

CCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGC

CAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGG

AAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGG

AACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATA

AGATACACCTGCCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATT

GTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTTCATGTGTTTAG

TCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTC

CTTTGAAAAACACGATGATAATA

Therefore, preferably the IRES comprises a nucleotide sequence substantially as set out in SEQ ID No: 74 or 75, or a fragment or variant thereof.

Alternatively, instead of an IRES or a 2A linker, the linker sequence may comprise a sequence encoding a flexible linker, which allows for the expression of both the therapeutic biomolecule and IIP as a single polypeptide chain, but wherein the therapeutic biomolecule and IIP act as independent proteins. Hence, the proteins exert their effects in the same manner as if they were singly expressed.

The flexible linker sequence may be as disclosed by WO 2013/061076 A1 (Oxford Biomedica). The flexible linker sequence may be referred to herein as SEQ ID No:76, or a fragment or variant thereof, as follows:

[SEQ ID NO: 76]

GGAGGTGGCGGGTCCGGGGGCGGGGGTAGCGGTGGCGGGGGCTCC

Preferably, therefore, the flexible linker sequence comprises a nucleotide sequence substantially as set out in SEQ ID No: 76, or a fragment or variant thereof.

In one preferred embodiment, the flexible linker sequence comprises a nucleotide sequence encoding an amino acid sequence referred to herein as SEQ ID NO: 77, or a fragment or variant thereof, as set out below:

[SEQ ID NO: 77]

GGGGSGGGGSGGGGS

Preferably, therefore, the flexible linker sequence encodes an amino acid sequence substantially as set out in SEQ ID No: 77, or a fragment or variant thereof.

In yet another embodiment, the sequence encoding the at least one therapeutic biomolecule and the at least one innate inhibitor protein may be separated by a stop codon followed by a second subgenomic promotor sequence capable of initiating transcription of the downstream sequence. Examples of this embodiment are illustrated in FIG. 1, embodiments 4a and 4b.

The RNA construct (preferably when it is a saRNA construct) may encode at least one non-structural protein (NSP), disposed 5′ or 3′ of the sequence encoding the at least one therapeutic biomolecule and the at least one innate modulatory protein. Preferably, the sequence encoding the at least one NSP is disposed 5′ of the sequences encoding the therapeutic biomolecule and the at least one innate modulatory protein. Thus, preferably the sequence encoding the at least one NSP is disposed at the 5′ end of the RNA construct.

The at least one non-structural protein, which is encoded by the RNA construct, may be the RNA polymerase NSP4. The one or more non-structural protein preferably encodes a replicase. Preferably, the construct encodes NSP1, NSP2, NSP3 and NSP4. The skilled person would understand that NSP1 is the viral capping enzyme and membrane anchor of the replication complex (RC), while NSP2 is an RNA helicase and the protease responsible for the ns polyprotein processing. NSP3 interacts with several host proteins and may modulate protein poly- and mono-ADP-ribosylation, and NSP4 is the core viral RNA-dependent RNA polymerase.

In one embodiment, NSP1 is provided herein as SEQ ID No: 78, as follows:

[SEQ ID No: 78]

MEKVHVDIEEDSPFLRALQRSFPQFEVEAKQVTDNDHANARAFSHLASKLI

ETEVDPSDTILDIGSAPARRMYSKHKYHCICPMRCAEDPDRLYKYATKLKK

NCKEITDKELDKKMKELAAVMSDPDLETETMCLHDDESCRYEGQVAVYQDV

YAVDGPTSLYHQANKGVRVAYWIGFDTTPFMFKNLAGAYPSYSTNWADETV

LTARNIGLCSSDVMERSRRGMSILRKKYLKPSNNVLFSVGSTIYHEKRDLL

RSWHLPSVFHLRGKQNYTCRCETIVSCDGYVVKRIAISPGLYGKPSGYAAT

MHREGFFARWAKEYKEDQEDERPLGLRDRQLVMGCCWAFRRHKITSIYKRP

DTQTIIKVNSDFHSFVLPRIGSNTLEIGLRTRIRKMLEEHKEPSPLITAED

VQEAKCAADEAKEVREAEELRAALPPLAADVEEPTLEADVDLMLQEAGA

Accordingly, NSP1 preferably comprises an amino acid sequence as substantially as set out in SEQ ID No: 78, or a biologically active variant or fragment thereof.

In one embodiment, NSP1 is encoded by a nucleotide sequence a defined in SEQ ID No: 79, as follows:

[SEQ ID No: 79]

ATGGAGAAAGTTCACGTTGACATCGAGGAAGACAGCCCATTCCTCAGAGCT

TTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTCACTGAT

AATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATC

GAAACGGAGGTGGACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCC

GCCCGCAGAATGTATTCTAAGCACAAGTATCATTGTATCTGTCCGATGAGA

TGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAA

AACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTG

GCCGCCGTCATGAGCGACCCTGACCTGGAAACTGAGACTATGTGCCTCCAC

GACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGTTTACCAGGATGTA

TACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTT

AGAGTCGCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAAC

TTGGCTGGAGCATATCCATCATACTCTACCAACTGGGCCGACGAAACCGTG

TTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGAGCGGTCA

CGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAAT

GTTCTATTCTCTGTTGGCTCGACCATCTACCACGAGAAGAGGGACTTACTG

AGGAGCTGGCACCTGCCGTCTGTATTTCACTTACGTGGCAAGCAAAATTAC

ACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAGA

ATAGCTATCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACG

ATGCACCGCGAGGGATTCTTGTGCTGCAAAGTGACAGACACATTGAACGGG

GAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAGCTACATTGTGTGAC

CAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAA

CTGCTGGTTGGGCTCAACCAGCGTATAGTCGTCAACGGTCGCACCCAGAGA

AACACCAATACCATGAAAAATTACCTTTTGCCCGTAGTGGCCCAGGCATTT

GCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAAGGCCACTA

GGACTACGAGATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGG

CACAAGATAACATCTATTTATAAGCGCCCGGATACCCAAACCATCATCAAA

GTGAACAGCGATTTCCACTCATTCGTGCTGCCCAGGATAGGCAGTAACACA

TTGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACAAG

GAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAGCTAAGTGCGCA

GCCGATGAGGCTAAGGAGGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTA

CCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTGGAAGCCGATGTCGAC

TTGATGTTACAAGAGGCTGGGGCC

Accordingly, NSP1 is preferably encoded by a nucleotide sequence as substantially as set out in SEQ ID No: 79, or a variant or fragment thereof.

Accordingly, therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out as SEQ ID No: 80, or a variant or fragment thereof.

[SEQ ID No: 80]

AUGGAGAAAGUUCACGUUGACAUCGAGGAAGACAGCCCAUUCCUCAGAGCUUUGCAGCGGAGCUUCCCGCAGUUUGAG

GUAGAAGCCAAGCAGGUCACUGAUAAUGACCAUGCUAAUGCCAGAGCGUUUUCGCAUCUGGCUUCAAAACUGAUCGAA

ACGGAGGUGGACCCAUCCGACACGAUCCUUGACAUUGGAAGUGCGCCCGCCCGCAGAAUGUAUUCUAAGCACAAGUAU

CAUUGUAUCUGUCCGAUGAGAUGUGCGGAAGAUCCGGACAGAUUGUAUAAGUAUGCAACUAAGCUGAAGAAAAACUGU

AAGGAAAUAACUGAUAAGGAAUUGGACAAGAAAAUGAAGGAGCUGGCCGCCGUCAUGAGCGACCCUGACCUGGAAACU

GAGACUAUGUGCCUCCACGACGACGAGUCGUGUCGCUACGAAGGGCAAGUCGCUGUUUACCAGGAUGUAUACGCGGUU

GACGGACCGACAAGUCUCUAUCACCAAGCCAAUAAGGGAGUUAGAGUCGCCUACUGGAUAGGCUUUGACACCACCCCU

UUUAUGUUUAAGAACUUGGCUGGAGCAUAUCCAUCAUACUCUACCAACUGGGCCGACGAAACCGUGUUAACGGCUCGU

AACAUAGGCCUAUGCAGCUCUGACGUUAUGGAGCGGUCACGUAGAGGGAUGUCCAUUCUUAGAAAGAAGUAUUUGAAA

CCAUCCAACAAUGUUCUAUUCUCUGUUGGCUCGACCAUCUACCACGAGAAGAGGGACUUACUGAGGAGCUGGCACCUG

CCGUCUGUAUUUCACUUACGUGGCAAGCAAAAUUACACAUGUCGGUGUGAGACUAUAGUUAGUUGCGACGGGUACGUC

GUUAAAAGAAUAGCUAUCAGUCCAGGCCUGUAUGGGAAGCCUUCAGGCUAUGCUGCUACGAUGCACCGCGAGGGAUUC

UUGUGCUGCAAAGUGACAGACACAUUGAACGGGGAGAGGGUCUCUUUUCCCGUGUGCACGUAUGUGCCAGCUACAUUG

UGUGACCAAAUGACUGGCAUACUGGCAACAGAUGUCAGUGCGGACGACGCGCAAAAACUGCUGGUUGGGCUCAACCAG

CGUAUAGUCGUCAACGGUCGCACCCAGAGAAACACCAAUACCAUGAAAAAUUACCUUUUGCCCGUAGUGGCCCAGGCA

UUUGCUAGGUGGGCAAAGGAAUAUAAGGAAGAUCAAGAAGAUGAAAGGCCACUAGGACUACGAGAUAGACAGUUAGUC

AUGGGGUGUUGUUGGGCUUUUAGAAGGCACAAGAUAACAUCUAUUUAUAAGCGCCCGGAUACCCAAACCAUCAUCAAA

GUGAACAGCGAUUUCCACUCAUUCGUGCUGCCCAGGAUAGGCAGUAACACAUUGGAGAUCGGGCUGAGAACAAGAAUC

AGGAAAAUGUUAGAGGAGCACAAGGAGCCGUCACCUCUCAUUACCGCCGAGGACGUACAAGAAGCUAAGUGCGCAGCC

GAUGAGGCUAAGGAGGUGCGUGAAGCCGAGGAGUUGCGCGCAGCUCUACCACCUUUGGCAGCUGAUGUUGAGGAGCCC

ACUCUGGAAGCCGAUGUCGACUUGAUGUUACAAGAGGCUGGGGCC

In one embodiment, NSP2 is provided herein as SEQ ID No: 81, as follows:

[SEQ ID No: 81]

GSVETPRGLIKVTSYDGEDKIGSYAVLSPQAVLKSEKLSCIHPLAEQVIVITHSGRKGRYAVEPYHGKVVVPEGHAIP

VQDFQALSESATIVYNEREFVNRYLHHIATHGGALNTDEEYYKTVKPSEHDGEYLYDIDRKQCVKKELVTGLGLTGEL

VDPPFHEFAYESLRTRPAAPYQVPTIGVYGVPGSGKSGIIKSAVTKKDLVVSAKKENCAEIIRDVKKMKGLDVNARTV

DSVLLNGCKHPVETLYIDEAFACHAGTLRALIAIIRPKKAVLCGDPKQCGFFNMMCLKVHFNHEICTQVFHKSISRRC

TKSVTSVVSTLFYDKKMRTTNPKETKIVIDTTGSTKPKQDDLILTCFRGWVKQLQIDYKGNEIMTAAASQGLTRKGVY

AVRYKVNENPLYAPTSEHVNVLLTRTEDRIVWKTLAGDPWIKTLTAKYPGNFTATIEEWQAEHDAIMRHILERPDPTD

VFQNKANVCWAKALVPVLKTAGIDMTTEQWNTVDYFETDKAHSAEIVLNQLCVRFFGLDLDSGLFSAPTVPLSIRNNH

WDNSPSPNMYGLNKEVVRQLSRRYPQLPRAVATGRVYDMNTGTLRNYDPRINLVPVNRRLPHALVLHHNEHPQSDFSS

FVSKLKGRTVLVVGEKLSVPGKMVDWLSDRPEATFRARLDLGIPGDVPKYDIIFVNVRTPYKYHHYQQCEDHAIKLSM

LTKKACLHLNPGGTCVSIGYGYADRASESIIGAIARQFKFSRVCKPKSSLEETEVLFVFIGYDRKARTHNSYKLSSTL

TNIYTGSRLHEAGC

Accordingly, NSP2 preferably comprises an amino acid sequence as substantially as set out in SEQ ID No: 81, or a biologically active variant or fragment thereof.

In one embodiment, NSP2 is encoded by a nucleotide sequence a defined in SEQ ID No: 82, as follows:

[SEQ ID No: 82]

GGCTCAGTGGAGACACCTCGTGGCTTGATAAAGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTG

CTTTCTCCGCAGGCTGTACTCAAGAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGATAACA

CACTCTGGCCGAAAAGGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGACATGCAATACCC

GTCCAGGACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCGTAAACAGGTACCTGCAC

CATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTGTCAAGCCCAGCGAGCACGACGGC

GAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAGTCACTGGGCTAGGGCTCACAGGCGAGCTG

GTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAACACGACCAGCCGCTCCTTACCAAGTACCAACCATA

GGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCATCATTAAAAGCGCAGTCACCAAAAAAGATCTAGTGGTGAGC

GCCAAGAAAGAAAACTGTGCAGAAATTATAAGGGACGTCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTG

GACTCAGTGCTCTTGAATGGATGCAAACACCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGT

ACTCTCAGAGCGCTCATAGCCATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTT

AACATGATGTGCCTGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGC

ACTAAATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACTAAG

ATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAGGGTGGGTGAAG

CAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCTGACCCGTAAAGGTGTGTAT

GCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAACATGTGAACGTCCTACTGACCCGCACG

GAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGATAAAAACACTGACTGCCAAGTACCCTGGGAATTTC

ACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGATGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGAC

GTCTTCCAGAATAAGGCAAACGTGTGTTGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACC

ACTGAACAATGGAACACTGTGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGC

GTGAGGTTCTTTGGACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCAC

TGGGATAACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACCCACAA

CTGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGATCCGCGCATAAAC

CTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACACCCACAGAGTGACTTTTCTTCA

TTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGTTGTCCGTCCCAGGCAAAATGGTTGACTGG

TTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGATTTAGGCATCCCAGGTGATGTGCCCAAATATGACATA

ATATTTGTTAATGTGAGGACCCCATATAAATACCATCACTATCAGCAGTGTGAAGACCATGCCATTAAGCTTAGCATG

TTGACCAAGAAAGCTTGTCTGCATCTGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATGGTTACGCTGACAGGGCC

AGCGAAAGCATCATTGGTGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAG

ACGGAAGTTCTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGCACAATTCTTACAAGCTTTCATCAACCTTG

ACCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGT

Accordingly, preferably NSP2 is encoded by a nucleotide sequence as substantially as set out in SEQ ID No: 82, or a variant or fragment thereof.

Thus, the RNA construct may comprise SEQ ID No: 83, as follows:

[SEQ ID No: 83]

GGCUCAGUGGAGACACCUCGUGGCUUGAUAAAGGUUACCAGCUACGAUGGCGAGGACAAGAUCGGCUCUUACGCUGUG

CUUUCUCCGCAGGCUGUACUCAAGAGUGAAAAAUUAUCUUGCAUCCACCCUCUCGCUGAACAAGUCAUAGUGAUAACA

CACUCUGGCCGAAAAGGGCGUUAUGCCGUGGAACCAUACCAUGGUAAAGUAGUGGUGCCAGAGGGACAUGCAAUACCC

GUCCAGGACUUUCAAGCUCUGAGUGAAAGUGCCACCAUUGUGUACAACGAACGUGAGUUCGUAAACAGGUACCUGCAC

CAUAUUGCCACACAUGGAGGAGCGCUGAACACUGAUGAAGAAUAUUACAAAACUGUCAAGCCCAGCGAGCACGACGGC

GAAUACCUGUACGACAUCGACAGGAAACAGUGCGUCAAGAAAGAACUAGUCACUGGGCUAGGGCUCACAGGCGAGCUG

GUGGAUCCUCCCUUCCAUGAAUUCGCCUACGAGAGUCUGAGAACACGACCAGCCGCUCCUUACCAAGUACCAACCAUA

GGGGUGUAUGGCGUGCCAGGAUCAGGCAAGUCUGGCAUCAUUAAAAGCGCAGUCACCAAAAAAGAUCUAGUGGUGAGC

GCCAAGAAAGAAAACUGUGCAGAAAUUAUAAGGGACGUCAAGAAAAUGAAAGGGCUGGACGUCAAUGCCAGAACUGUG

GACUCAGUGCUCUUGAAUGGAUGCAAACACCCCGUAGAGACCCUGUAUAUUGACGAAGCUUUUGCUUGUCAUGCAGGU

ACUCUCAGAGCGCUCAUAGCCAUUAUAAGACCUAAAAAGGCAGUGCUCUGCGGGGAUCCCAAACAGUGCGGUUUUUUU

AACAUGAUGUGCCUGAAAGUGCAUUUUAACCACGAGAUUUGCACACAAGUCUUCCACAAAAGCAUCUCUCGCCGUUGC

ACUAAAUCUGUGACUUCGGUCGUCUCAACCUUGUUUUACGACAAAAAAAUGAGAACGACGAAUCCGAAAGAGACUAAG

AUUGUGAUUGACACUACCGGCAGUACCAAACCUAAGCAGGACGAUCUCAUUCUCACUUGUUUCAGAGGGUGGGUGAAG

CAGUUGCAAAUAGAUUACAAAGGCAACGAAAUAAUGACGGCAGCUGCCUCUCAAGGGCUGACCCGUAAAGGUGUGUAU

GCCGUUCGGUACAAGGUGAAUGAAAAUCCUCUGUACGCACCCACCUCAGAACAUGUGAACGUCCUACUGACCCGCACG

GAGGACCGCAUCGUGUGGAAAACACUAGCCGGCGACCCAUGGAUAAAAACACUGACUGCCAAGUACCCUGGGAAUUUC

ACUGCCACGAUAGAGGAGUGGCAAGCAGAGCAUGAUGCCAUCAUGAGGCACAUCUUGGAGAGACCGGACCCUACCGAC

GUCUUCCAGAAUAAGGCAAACGUGUGUUGGGCCAAGGCUUUAGUGCCGGUGCUGAAGACCGCUGGCAUAGACAUGACC

ACUGAACAAUGGAACACUGUGGAUUAUUUUGAAACGGACAAAGCUCACUCAGCAGAGAUAGUAUUGAACCAACUAUGC

GUGAGGUUCUUUGGACUCGAUCUGGACUCCGGUCUAUUUUCUGCACCCACUGUUCCGUUAUCCAUUAGGAAUAAUCAC

UGGGAUAACUCCCCGUCGCCUAACAUGUACGGGCUGAAUAAAGAAGUGGUCCGUCAGCUCUCUCGCAGGUACCCACAA

CUGCCUCGGGCAGUUGCCACUGGAAGAGUCUAUGACAUGAACACUGGUACACUGCGCAAUUAUGAUCCGCGCAUAAAC

CUAGUACCUGUAAACAGAAGACUGCCUCAUGCUUUAGUCCUCCACCAUAAUGAACACCCACAGAGUGACUUUUCUUCA

UUCGUCAGCAAAUUGAAGGGCAGAACUGUCCUGGUGGUCGGGGAAAAGUUGUCCGUCCCAGGCAAAAUGGUUGACUGG

UUGUCAGACCGGCCUGAGGCUACCUUCAGAGCUCGGCUGGAUUUAGGCAUCCCAGGUGAUGUGCCCAAAUAUGACAUA

AUAUUUGUUAAUGUGAGGACCCCAUAUAAAUACCAUCACUAUCAGCAGUGUGAAGACCAUGCCAUUAAGCUUAGCAUG

UUGACCAAGAAAGCUUGUCUGCAUCUGAAUCCCGGCGGAACCUGUGUCAGCAUAGGUUAUGGUUACGCUGACAGGGCC

AGCGAAAGCAUCAUUGGUGCUAUAGCGCGGCAGUUCAAGUUUUCCCGGGUAUGCAAACCGAAAUCCUCACUUGAAGAG

ACGGAAGUUCUGUUUGUAUUCAUUGGGUACGAUCGCAAGGCCCGUACGCACAAUUCUUACAAGCUUUCAUCAACCUUG

ACCAACAUUUAUACAGGUUCCAGACUCCACGAAGCCGGAUGU

Accordingly, therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out as SEQ ID No: 83, or a variant or fragment thereof.

In one embodiment, NSP3 is provided herein as SEQ ID No: 84, as follows:

[SEQ ID No: 84]

APSYHVVRGDIATATEGVIINAANSKGQPGGGVCGALYKKFPESFDLQPIEVGKARLVKGAAKHIIHAVGPNFNKVSE

VEGDKQLAEAYESIAKIVNDNNYKSVAIPLLSTGIFSGNKDRLTQSLNHLLTALDTTDADVAIYCRDKKWEMTLKEAV

ARREAVEEICISDDSSVTEPDAELVRVHPKSSLAGRKGYSTSDGKTFSYLEGTKFHQAAKDIAEINAMWPVATEANEQ

VCMYILGESMSSIRSKCPVEESEASTPPSTLPCLCIHAMTPERVQRLKASRPEQITVCSSFPLPKYRITGVQKIQCSQ

PILFSPKVPAYIHPRKYLVETPPVDETPEPSAENQSTEGTPEQPPLITEDETRTRTPEPIIIEEEEEDSISLLSDGPT

HQVLQVEADIHGPPSVSSSSWSIPHASDFDVDSLSILDTLEGASVTSGATSAETNSYFAKSMEFLARPVPAPRTVFRN

AQQQRFDAGA

Accordingly, preferably NSP3 comprises an amino acid sequence as substantially as set out in SEQ ID No: 84, or a biologically active variant or fragment thereof.

In one embodiment, NSP3 is encoded by a nucleotide sequence a defined in SEQ ID No: 85, as follows:

[SEQ ID No: 85]

GCACCCTCATATCATGTGGTGCGAGGGGATATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACAGCAAA

GGACAACCTGGCGGAGGGGTGTGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGCCGATCGAAGTA

GGAAAAGCGCGACTGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAG

GTTGAAGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCAACGATAACAATTACAAGTCAGTA

GCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGACTAACCCAATCATTGAACCATTTGCTGACA

GCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGGACAAGAAATGGGAAATGACTCTCAAGGAAGCAGTG

GCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCGACGACTCTTCAGTGACAGAACCTGATGCAGAGCTGGTGAGG

GTGCATCCGAAGAGTTCTTTGGCTGGAAGGAAGGGCTACAGCACAAGCGATGGCAAAACTTTCTCATATTTGGAAGGG

ACCAAGTTTCACCAGGCGGCCAAGGATATAGCAGAAATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAG

GTATGCATGTATATCCTCGGAGAAAGCATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACA

CCACCTAGCACGCTGCCTTGCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCA

GAACAAATTACTGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAG

CCTATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAGACGAG

ACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAACCGAGGATGAGACC

AGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGTTTGCTGTCAGATGGCCCGACC

CACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTATCTAGCTCATCCTGGTCCATTCCTCATGCA

TCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCTGGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCC

GAGACTAACTCTTACTTCGCAAAGAGTATGGAGTTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAAC

CCTCCACATCCCGCTCCGCGCACAAGAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCC

ACCCCGCCAGGCGTGAATAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCG

GCACAACAACAATGACGGTTTGATGCGGGTGCA

Accordingly, preferably NSP3 comprises an amino acid sequence as substantially as set out in SEQ ID No: 85, or a biologically active variant or fragment thereof.

Thus, the RNA construct may comprise SEQ ID No: 86, as follows:

[SEQ ID No: 86]

GCACCCUCAUAUCAUGUGGUGCGAGGGGAUAUUGCCACGGCCACCGAAGGAGUGAUUAUAAAUGCUGCUAACAGCAAA

GGACAACCUGGCGGAGGGGUGUGCGGAGCGCUGUAUAAGAAAUUCCCGGAAAGCUUCGAUUUACAGCCGAUCGAAGUA

GGAAAAGCGCGACUGGUCAAAGGUGCAGCUAAACAUAUCAUUCAUGCCGUAGGACCAAACUUCAACAAAGUUUCGGAG

GUUGAAGGUGACAAACAGUUGGCAGAGGCUUAUGAGUCCAUCGCUAAGAUUGUCAACGAUAACAAUUACAAGUCAGUA

GCGAUUCCACUGUUGUCCACCGGCAUCUUUUCCGGGAACAAAGAUCGACUAACCCAAUCAUUGAACCAUUUGCUGACA

GCUUUAGACACCACUGAUGCAGAUGUAGCCAUAUACUGCAGGGACAAGAAAUGGGAAAUGACUCUCAAGGAAGCAGUG

GCUAGGAGAGAAGCAGUGGAGGAGAUAUGCAUAUCCGACGACUCUUCAGUGACAGAACCUGAUGCAGAGCUGGUGAGG

GUGCAUCCGAAGAGUUCUUUGGCUGGAAGGAAGGGCUACAGCACAAGCGAUGGCAAAACUUUCUCAUAUUUGGAAGGG

ACCAAGUUUCACCAGGCGGCCAAGGAUAUAGCAGAAAUUAAUGCCAUGUGGCCCGUUGCAACGGAGGCCAAUGAGCAG

GUAUGCAUGUAUAUCCUCGGAGAAAGCAUGAGCAGUAUUAGGUCGAAAUGCCCCGUCGAAGAGUCGGAAGCCUCCACA

CCACCUAGCACGCUGCCUUGCUUGUGCAUCCAUGCCAUGACUCCAGAAAGAGUACAGCGCCUAAAAGCCUCACGUCCA

GAACAAAUUACUGUGUGCUCAUCCUUUCCAUUGCCGAAGUAUAGAAUCACUGGUGUGCAGAAGAUCCAAUGCUCCCAG

CCUAUAUUGUUCUCACCGAAAGUGCCUGCGUAUAUUCAUCCAAGGAAGUAUCUCGUGGAAACACCACCGGUAGACGAG

ACUCCGGAGCCAUCGGCAGAGAACCAAUCCACAGAGGGGACACCUGAACAACCACCACUUAUAACCGAGGAUGAGACC

AGGACUAGAACGCCUGAGCCGAUCAUCAUCGAAGAGGAAGAAGAGGAUAGCAUAAGUUUGCUGUCAGAUGGCCCGACC

CACCAGGUGCUGCAAGUCGAGGCAGACAUUCACGGGCCGCCCUCUGUAUCUAGCUCAUCCUGGUCCAUUCCUCAUGCA

UCCGACUUUGAUGUGGACAGUUUAUCCAUACUUGACACCCUGGAGGGAGCUAGCGUGACCAGCGGGGCAACGUCAGCC

GAGACUAACUCUUACUUCGCAAAGAGUAUGGAGUUUCUGGCGCGACCGGUGCCUGCGCCUCGAACAGUAUUCAGGAAC

CCUCCACAUCCCGCUCCGCGCACAAGAACACCGUCACUUGCACCCAGCAGGGCCUGCUCGAGAACCAGCCUAGUUUCC

ACCCCGCCAGGCGUGAAUAGGGUGAUCACUAGAGAGGAGCUCGAGGCGCUUACCCCGUCACGCACUCCUAGCAGGUCG

GUCUCGAGAACCAGCCUGGUCUCCAACCCGCCAGGCGUAAAUAGGGUGAUUACAAGAGAGGAGUUUGAGGCGUUCGUA

GCACAACAACAAUGACGGUUUGAUGCGGGUGCA

Accordingly, therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out as SEQ ID No: 86, or a variant or fragment thereof.

In one embodiment, NSP4 is provided herein as SEQ ID No: 87, as follows:

[SEQ ID No: 87]

YIFSSDTGQGHLQQKSVRQTVLSEVVLERTELEISYAPRLDQEKEELLRKKLQLNPTPANRSRYQSRKVENMKAITAR

RILQGLGHYLKAEGKVECYRTLHPVPLYSSSVNRAFSSPKVAVEACNAMLKENFPTVASYCIIPEYDAYLDMVDGASC

CLDTASFCPAKLRSFPKKHSYLEPTIRSAVPSAIQNTLQNVLAAATKRNCNVTQMRELPVLDSAAFNVECFKKYACNN

EYWETFKENPIRLTEENVVNYITKLKGPKAAALFAKTHNLNMLQDIPMDRFVMDLKRDVKVTPGTKHTEERPKVQVIQ

AADPLATAYLCGIHRELVRRLNAVLLPNIHTLFDMSAEDFDAIIAEHFQPGDCVLETDIASFDKSEDDAMALTALMIL

EDLGVDAELLTLIEAAFGEISSIHLPTKTKFKFGAMMKSGMFLTLFVNTVINIVIASRVLRERLIGSPCAAFIGDDNI

VKGVKSDKLMADRCATWLNMEVKIIDAVVGEKAPYFCGGFILCDSVTGTACRVADPLKRLFKLGKPLAADDEHDDDRR

RALHEESTRWNRVGILSELCKAVESRYETVGTSIIVMAMTTLASSVKSFSYLRGAPITLYG

Accordingly, preferably NSP4 comprises an amino acid sequence as substantially as set out in SEQ ID No: 87, or a biologically active variant or fragment thereof.

In one embodiment, NSP4 is encoded by a nucleotide sequence a defined in SEQ ID No: 88, as follows:

[SEQ ID No: 88]

TACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACAACAAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTG

TTGGAGAGGACCGAATTGGAGATTTCGTATGCCCCGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTA

CAGTTAAATCCCACACCTGCTAACAGAAGCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGA

CGTATTCTGCAAGGCCTAGGGCATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCT

TTGTATTCATCTAGTGTGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAGAG

AACTTTCCGACTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGGAGCTTCATGC

TGCTTAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCCTATTTGGAACCCACAATA

CGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAGCTGCCACAAAAAGAAATTGCAATGTC

ACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAATGTGGAATGCTTCAAGAAATATGCGTGTAATAAT

GAATATTGGGAAACGTTTAAAGAAAACCCCATCAGGCTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAAAA

GGACCAAAAGCTGCTGCTCTTTTTGCGAAGACACATAATTTGAATATGTTGCAGGACATACCAATGGACAGGTTTGTA

ATGGACTTAAAGAGAGACGTGAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGGTACAGGTGATCCAG

GCTGCCGATCCGCTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTT

CCGAACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGGGGAT

TGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCGTTAATGATTCTG

GAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAATTTCATCAATACATTTGCCC

ACTAAAACTAAATTTAAATTCGGAGCCATGATGAAATCTGGAATGTTCCTCACACTGTTTGTGAACACAGTCATTAAC

ATTGTAATCGCAAGCAGAGTGTTGAGAGAACGGCTAACCGGATCACCATGTGCAGCATTCATTGGAGATGACAATATC

GTGAAAGGAGTCAAATCGGACAAATTAATGGCAGACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGAT

GCTGTGGTGGGCGAGAAAGCGCCTTATTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGT

GTGGCAGACCCCCTAAAAAGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGA

AGGGCATTGCATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAAGG

TATGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCAGCTACCTG

AGAGGGGCCCCTATAACTCTCTACGGC

Accordingly, preferably NSP4 is encoded by a nucleotide sequence as substantially as set out in SEQ ID No: 88, or a variant or fragment thereof.

Thus, the RNA construct may comprise SEQ ID No: 89, as follows:

[SEQ ID No: 89]

UACAUCUUUUCCUCCGACACCGGUCAAGGGCAUUUACAACAAAAAUCAGUAAGGCAAACGGUGCUAUCCGAAGUGGUG

UUGGAGAGGACCGAAUUGGAGAUUUCGUAUGCCCCGCGCCUCGACCAAGAAAAAGAAGAAUUACUACGCAAGAAAUUA

CAGUUAAAUCCCACACCUGCUAACAGAAGCAGAUACCAGUCCAGGAAGGUGGAGAACAUGAAAGCCAUAACAGCUAGA

CGUAUUCUGCAAGGCCUAGGGCAUUAUUUGAAGGCAGAAGGAAAAGUGGAGUGCUACCGAACCCUGCAUCCUGUUCCU

UUGUAUUCAUCUAGUGUGAACCGUGCCUUUUCAAGCCCCAAGGUCGCAGUGGAAGCCUGUAACGCCAUGUUGAAAGAG

AACUUUCCGACUGUGGCUUCUUACUGUAUUAUUCCAGAGUACGAUGCCUAUUUGGACAUGGUUGACGGAGCUUCAUGC

UGCUUAGACACUGCCAGUUUUUGCCCUGCAAAGCUGCGCAGCUUUCCAAAGAAACACUCCUAUUUGGAACCCACAAUA

CGAUCGGCAGUGCCUUCAGCGAUCCAGAACACGCUCCAGAACGUCCUGGCAGCUGCCACAAAAAGAAAUUGCAAUGUC

ACGCAAAUGAGAGAAUUGCCCGUAUUGGAUUCGGCGGCCUUUAAUGUGGAAUGCUUCAAGAAAUAUGCGUGUAAUAAU

GAAUAUUGGGAAACGUUUAAAGAAAACCCCAUCAGGCUUACUGAAGAAAACGUGGUAAAUUACAUUACCAAAUUAAAA

GGACCAAAAGCUGCUGCUCUUUUUGCGAAGACACAUAAUUUGAAUAUGUUGCAGGACAUACCAAUGGACAGGUUUGUA

AUGGACUUAAAGAGAGACGUGAAAGUGACUCCAGGAACAAAACAUACUGAAGAACGGCCCAAGGUACAGGUGAUCCAG

GCUGCCGAUCCGCUAGCAACAGCGUAUCUGUGCGGAAUCCACCGAGAGCUGGUUAGGAGAUUAAAUGCGGUCCUGCUU

CCGAACAUUCAUACACUGUUUGAUAUGUCGGCUGAAGACUUUGACGCUAUUAUAGCCGAGCACUUCCAGCCUGGGGAU

UGUGUUCUGGAAACUGACAUCGCGUCGUUUGAUAAAAGUGAGGACGACGCCAUGGCUCUGACCGCGUUAAUGAUUCUG

GAAGACUUAGGUGUGGACGCAGAGCUGUUGACGCUGAUUGAGGCGGCUUUCGGCGAAAUUUCAUCAAUACAUUUGCCC

ACUAAAACUAAAUUUAAAUUCGGAGCCAUGAUGAAAUCUGGAAUGUUCCUCACACUGUUUGUGAACACAGUCAUUAAC

AUUGUAAUCGCAAGCAGAGUGUUGAGAGAACGGCUAACCGGAUCACCAUGUGCAGCAUUCAUUGGAGAUGACAAUAUC

GUGAAAGGAGUCAAAUCGGACAAAUUAAUGGCAGACAGGUGCGCCACCUGGUUGAAUAUGGAAGUCAAGAUUAUAGAU

GCUGUGGUGGGCGAGAAAGCGCCUUAUUUCUGUGGAGGGUUUAUUUUGUGUGACUCCGUGACCGGCACAGCGUGCCGU

GUGGCAGACCCCCUAAAAAGGCUGUUUAAGCUUGGCAAACCUCUGGCAGCAGACGAUGAACAUGAUGAUGACAGGAGA

AGGGCAUUGCAUGAAGAGUCAACACGCUGGAACCGAGUGGGUAUUCUUUCAGAGCUGUGCAAGGCAGUAGAAUCAAGG

UAUGAAACCGUAGGAACUUCCAUCAUAGUUAUGGCCAUGACUACUCUAGCUAGCAGUGUUAAAUCAUUCAGCUACCUG

AGAGGGGCCCCUAUAACUCUCUACGGC

Accordingly, therefore, preferably the RNA construct comprises an RNA nucleotide sequence substantially as set out as SEQ ID No: 89, or a variant or fragment thereof.

Preferably, together with proteins present in a host cell, the non-structural proteins encoded by the RNA construct of the invention form an enzyme complex (i.e. a replicase) that is required for genome replication and transcription of the sequences encoding the at least one therapeutic biomolecule and the at least one innate modulatory protein. For example, the one or more non-structural protein may encode a polymerase to enable the construct to amplify the nucleotide sequences encoding the at least one peptide or protein of interest (i.e. therapeutic biomolecule) and the at least one innate modulatory protein.

The host cell may be a eukaryotic or prokaryotic host cell. Preferably, the host cell is a eukaryotic host cell. More preferably, the host cell is a mammalian host cell.

The RNA construct may further comprise a promoter disposed 5′ of the at least one non-structural protein, such that the promoter is operably linked to the sequence encoding the at least one non-structural protein and enables expression of the at least one non-structural protein in a host cell.

Preferably, the RNA construct comprises a 5′ UTR conserved sequence element, which may be referred to herein as SEQ ID No: 90, as follows:

[SEQ ID No: 90]

AUGGGCGGCGCAUGAGAGAAGCCCAGACCAAUUACCUACCCAAA

Accordingly, preferably the UTR is disposed 5′ of the at least one non-structural protein and comprises a nucleotide sequence substantially as set out in SEQ ID No: 90, or a fragment or variant thereof.

Preferably, the RNA construct comprises a 3′ UTR conserved sequence element, which may be referred to herein as SEQ ID No: 91, as follows:

[SEQ ID No: 91]

AAUUGGCAAGCUGCUUACAUAGAACUCGCGGCGAUUGGCAUGCCGCCUU

AAAAUUUUUAUUUUAUUUUUCUUUUCUUUUCCGAAUCGGAUUUUGUUUU

UAAUAUUUCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Accordingly, preferably the 3′ UTR is disposed 3′ of the at least one non-structural protein and comprises a nucleotide sequence substantially as set out in SEQ ID No: 91, or a fragment or variant thereof.

Preferably, the RNA construct comprises a polyA tail. Preferably, the polyA tail is disposed at the 3′ end of the construct. The poly A tail may comprise at least 35 nt, or at least 40 nt, or at least 45 nt, or at least 50 nt, wherein each nt is an adenine. In another embodiment, the polyA tail may comprise at least 55 nt or at least 60 nt, wherein each nt is an adenine. In yet another embodiment, the polyA tail may comprise at least 60 adenines, followed by one or more non-adenine nucleotides (i.e. G, C or T, preferably guanine), and then another at least 35 nt, or at least 40 nt, or at least 45 nt, or at least 50 nt, or at least 55 nt, or at least 60 nt, wherein each nt is an adenine.

The RNA construct may further comprise a 5′ cap. In the context of the present invention, the term “5′-cap” includes a 5′-cap analog that resembles the RNA cap structure and is modified to possess the ability to stabilize RNA and/or enhance translation of RNA if attached thereto, preferably in vivo and/or in a cell.

An RNA with a 5′-cap may be achieved by in vitro transcription of a DNA template in presence of said 5′-cap, wherein said 5′-cap is co-transcriptionally incorporated into the generated RNA strand, or the RNA may be generated, for example, by in vitro transcription, and the 5′-cap may be attached to the RNA post-transcriptionally using capping enzymes, for example, capping enzymes of vaccinia virus. In capped RNA, the 3′ position of the first base of a (capped) RNA molecule is linked to the 5′ position of the subsequent base of the RNA molecule (“second base”) via a phosphodiester bond.

In one embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one therapeutic biomolecule, a linker sequence, and at least one sequence encoding an IIP. In one embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one IIP, a linker sequence, and a sequence encoding at least one therapeutic biomolecule. The linker may be F-T2a or IRES in either embodiment.

In another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a sub genomic promoter, a sequence encoding at least one therapeutic biomolecule, a linker sequence, and a sequence encoding at least one viral IIP. In another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a sub genomic promoter, a sequence encoding at least one viral IIP, a linker sequence, and a sequence encoding at least one therapeutic biomolecule. The linker may be F-T2a or IRES in either embodiment.

In yet another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a sub genomic promoter, a sequence encoding at least one therapeutic biomolecule, a linker sequence, a sequence encoding at least one viral IIP, and a polyA tail. In yet another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a sub genomic promoter, a sequence encoding at least one viral IIP, a linker sequence, a sequence encoding at least one therapeutic biomolecule, and a polyA tail. The linker may be F-T2a or IRES in either embodiment.

In another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a first sub genomic promoter, a sequence encoding at least one therapeutic biomolecule, a second sub genomic promoter, a sequence encoding at least one viral IIP, and a polyA tail. In another embodiment, the RNA construct comprises, preferably 5′ to 3′, a promoter, a sequence encoding at least one non-structural protein, a first sub genomic promoter, a sequence encoding at least one viral IIP, a second sub genomic promoter, a sequence encoding at least one therapeutic biomolecule, and a polyA tail.

Most preferably, the RNA construct comprises, 5′ to 3′, a 5′ cap, a promoter, nsP1, nsP2, nsP3, nsP4, the sub genomic promoter 26S, a sequence encoding a therapeutic biomolecule, a linker sequence, a sequence encoding the viral IIP and a polyA tail. Most preferably, the RNA construct comprises, 5′ to 3′, a 5′ cap, a promoter, nsP1, nsP2, nsP3v, nsP4, the sub genomic promoter 26S, a sequence encoding a viral IIP, a linker sequence, a sequence encoding a therapeutic biomolecule; and a polyA tail.

In one embodiment, therefore, the RNA construct may encode or comprise a GOI—furin T2A—HCV E6 (which is the first viral IIP mentioned herein, but it will be appreciated that any of the IIPs or linkers disclosed herein may be used). Hence, the RNA construct may comprise or consist of a single RNA construct comprising or consisting of SEQ ID No: 92, a GOI, and SEQ ID No: 457, in a single RNA construct. SEQ ID No: 92 and SEQ ID No: 457 are as follows:

[SEQ ID No: 92]

AUGGGCGGCGCAUGAGAGAAGCCCAGACCAAUUACCUACCCAAAAUGGAGAAAGUUCACGUUGACAUCGAGG

AAGACAGCCCAUUCCUCAGAGCUUUGCAGCGGAGCUUCCCGCAGUUUGAGGUAGAAGCCAAGCAGGUCACUG

AUAAUGACCAUGCUAAUGCCAGAGCGUUUUCGCAUCUGGCUUCAAAACUGAUCGAAACGGAGGUGGACCCAU

CCGACACGAUCCUUGACAUUGGAAGUGCGCCCGCCCGCAGAAUGUAUUCUAAGCACAAGUAUCAUUGUAUCU

GUCCGAUGAGAUGUGCGGAAGAUCCGGACAGAUUGUAUAAGUAUGCAACUAAGCUGAAGAAAAACUGUAAGG

AAAUAACUGAUAAGGAAUUGGACAAGAAAAUGAAGGAGCUGGCCGCCGUCAUGAGCGACCCUGACCUGGAAA

CUGAGACUAUGUGCCUCCACGACGACGAGUCGUGUCGCUACGAAGGGCAAGUCGCUGUUUACCAGGAUGUAU

ACGCGGUUGACGGACCGACAAGUCUCUAUCACCAAGCCAAUAAGGGAGUUAGAGUCGCCUACUGGAUAGGCU

UUGACACCACCCCUUUUAUGUUUAAGAACUUGGCUGGAGCAUAUCCAUCAUACUCUACCAACUGGGCCGACG

AAACCGUGUUAACGGCUCGUAACAUAGGCCUAUGCAGCUCUGACGUUAUGGAGCGGUCACGUAGAGGGAUGU

CCAUUCUUAGAAAGAAGUAUUUGAAACCAUCCAACAAUGUUCUAUUCUCUGUUGGCUCGACCAUCUACCACG

AGAAGAGGGACUUACUGAGGAGCUGGCACCUGCCGUCUGUAUUUCACUUACGUGGCAAGCAAAAUUACACAU

GUCGGUGUGAGACUAUAGUUAGUUGCGACGGGUACGUCGUUAAAAGAAUAGCUAUCAGUCCAGGCCUGUAUG

GGAAGCCUUCAGGCUAUGCUGCUACGAUGCACCGCGAGGGAUUCUUGUGCUGCAAAGUGACAGACACAUUGA

ACGGGGAGAGGGUCUCUUUUCCCGUGUGCACGUAUGUGCCAGCUACAUUGUGUGACCAAAUGACUGGCAUAC

UGGCAACAGAUGUCAGUGCGGACGACGCGCAAAAACUGCUGGUUGGGCUCAACCAGCGUAUAGUCGUCAACG

GUCGCACCCAGAGAAACACCAAUACCAUGAAAAAUUACCUUUUGCCCGUAGUGGCCCAGGCAUUUGCUAGGU

GGGCAAAGGAAUAUAAGGAAGAUCAAGAAGAUGAAAGGCCACUAGGACUACGAGAUAGACAGUUAGUCAUGG

GGUGUUGUUGGGCUUUUAGAAGGCACAAGAUAACAUCUAUUUAUAAGCGCCCGGAUACCCAAACCAUCAUCA

AAGUGAACAGCGAUUUCCACUCAUUCGUGCUGCCCAGGAUAGGCAGUAACACAUUGGAGAUCGGGCUGAGAA

CAAGAAUCAGGAAAAUGUUAGAGGAGCACAAGGAGCCGUCACCUCUCAUUACCGCCGAGGACGUACAAGAAG

CUAAGUGCGCAGCCGAUGAGGCUAAGGAGGUGCGUGAAGCCGAGGAGUUGCGCGCAGCUCUACCACCUUUGG

CAGCUGAUGUUGAGGAGCCCACUCUGGAAGCCGAUGUCGACUUGAUGUUACAAGAGGCUGGGGCCGGCUCAG

UGGAGACACCUCGUGGCUUGAUAAAGGUUACCAGCUACGAUGGCGAGGACAAGAUCGGCUCUUACGCUGUGC

UUUCUCCGCAGGCUGUACUCAAGAGUGAAAAAUUAUCUUGCAUCCACCCUCUCGCUGAACAAGUCAUAGUGA

UAACACACUCUGGCCGAAAAGGGCGUUAUGCCGUGGAACCAUACCAUGGUAAAGUAGUGGUGCCAGAGGGAC

AUGCAAUACCCGUCCAGGACUUUCAAGCUCUGAGUGAAAGUGCCACCAUUGUGUACAACGAACGUGAGUUCG

UAAACAGGUACCUGCACCAUAUUGCCACACAUGGAGGAGCGCUGAACACUGAUGAAGAAUAUUACAAAACUG

UCAAGCCCAGCGAGCACGACGGCGAAUACCUGUACGACAUCGACAGGAAACAGUGCGUCAAGAAAGAACUAG

UCACUGGGCUAGGGCUCACAGGCGAGCUGGUGGAUCCUCCCUUCCAUGAAUUCGCCUACGAGAGUCUGAGAA

CACGACCAGCCGCUCCUUACCAAGUACCAACCAUAGGGGUGUAUGGCGUGCCAGGAUCAGGCAAGUCUGGCA

UCAUUAAAAGCGCAGUCACCAAAAAAGAUCUAGUGGUGAGCGCCAAGAAAGAAAACUGUGCAGAAAUUAUAA

GGGACGUCAAGAAAAUGAAAGGGCUGGACGUCAAUGCCAGAACUGUGGACUCAGUGCUCUUGAAUGGAUGCA

AACACCCCGUAGAGACCCUGUAUAUUGACGAAGCUUUUGCUUGUCAUGCAGGUACUCUCAGAGCGCUCAUAG

CCAUUAUAAGACCUAAAAAGGCAGUGCUCUGCGGGGAUCCCAAACAGUGCGGUUUUUUUAACAUGAUGUGCC

UGAAAGUGCAUUUUAACCACGAGAUUUGCACACAAGUCUUCCACAAAAGCAUCUCUCGCCGUUGCACUAAAU

CUGUGACUUCGGUCGUCUCAACCUUGUUUUACGACAAAAAAAUGAGAACGACGAAUCCGAAAGAGACUAAGA

UUGUGAUUGACACUACCGGCAGUACCAAACCUAAGCAGGACGAUCUCAUUCUCACUUGUUUCAGAGGGUGGG

UGAAGCAGUUGCAAAUAGAUUACAAAGGCAACGAAAUAAUGACGGCAGCUGCCUCUCAAGGGCUGACCCGUA

AAGGUGUGUAUGCCGUUCGGUACAAGGUGAAUGAAAAUCCUCUGUACGCACCCACCUCAGAACAUGUGAACG

UCCUACUGACCCGCACGGAGGACCGCAUCGUGUGGAAAACACUAGCCGGCGACCCAUGGAUAAAAACACUGA

CUGCCAAGUACCCUGGGAAUUUCACUGCCACGAUAGAGGAGUGGCAAGCAGAGCAUGAUGCCAUCAUGAGGC

ACAUCUUGGAGAGACCGGACCCUACCGACGUCUUCCAGAAUAAGGCAAACGUGUGUUGGGCCAAGGCUUUAG

UGCCGGUGCUGAAGACCGCUGGCAUAGACAUGACCACUGAACAAUGGAACACUGUGGAUUAUUUUGAAACGG

ACAAAGCUCACUCAGCAGAGAUAGUAUUGAACCAACUAUGCGUGAGGUUCUUUGGACUCGAUCUGGACUCCG

GUCUAUUUUCUGCACCCACUGUUCCGUUAUCCAUUAGGAAUAAUCACUGGGAUAACUCCCCGUCGCCUAACA

UGUACGGGCUGAAUAAAGAAGUGGUCCGUCAGCUCUCUCGCAGGUACCCACAACUGCCUCGGGCAGUUGCCA

CUGGAAGAGUCUAUGACAUGAACACUGGUACACUGCGCAAUUAUGAUCCGCGCAUAAACCUAGUACCUGUAA

ACAGAAGACUGCCUCAUGCUUUAGUCCUCCACCAUAAUGAACACCCACAGAGUGACUUUUCUUCAUUCGUCA

GCAAAUUGAAGGGCAGAACUGUCCUGGUGGUCGGGGAAAAGUUGUCCGUCCCAGGCAAAAUGGUUGACUGGU

UGUCAGACCGGCCUGAGGCUACCUUCAGAGCUCGGCUGGAUUUAGGCAUCCCAGGUGAUGUGCCCAAAUAUG

ACAUAAUAUUUGUUAAUGUGAGGACCCCAUAUAAAUACCAUCACUAUCAGCAGUGUGAAGACCAUGCCAUUA

AGCUUAGCAUGUUGACCAAGAAAGCUUGUCUGCAUCUGAAUCCCGGCGGAACCUGUGUCAGCAUAGGUUAUG

GUUACGCUGACAGGGCCAGCGAAAGCAUCAUUGGUGCUAUAGCGCGGCAGUUCAAGUUUUCCCGGGUAUGCA

AACCGAAAUCCUCACUUGAAGAGACGGAAGUUCUGUUUGUAUUCAUUGGGUACGAUCGCAAGGCCCGUACGC

ACAAUUCUUACAAGCUUUCAUCAACCUUGACCAACAUUUAUACAGGUUCCAGACUCCACGAAGCCGGAUGUG

CACCCUCAUAUCAUGUGGUGCGAGGGGAUAUUGCCACGGCCACCGAAGGAGUGAUUAUAAAUGCUGCUAACA

GCAAAGGACAACCUGGCGGAGGGGUGUGCGGAGCGCUGUAUAAGAAAUUCCCGGAAAGCUUCGAUUUACAGC

CGAUCGAAGUAGGAAAAGCGCGACUGGUCAAAGGUGCAGCUAAACAUAUCAUUCAUGCCGUAGGACCAAACU

UCAACAAAGUUUCGGAGGUUGAAGGUGACAAACAGUUGGCAGAGGCUUAUGAGUCCAUCGCUAAGAUUGUCA

ACGAUAACAAUUACAAGUCAGUAGCGAUUCCACUGUUGUCCACCGGCAUCUUUUCCGGGAACAAAGAUCGAC

UAACCCAAUCAUUGAACCAUUUGCUGACAGCUUUAGACACCACUGAUGCAGAUGUAGCCAUAUACUGCAGGG

ACAAGAAAUGGGAAAUGACUCUCAAGGAAGCAGUGGCUAGGAGAGAAGCAGUGGAGGAGAUAUGCAUAUCCG

ACGACUCUUCAGUGACAGAACCUGAUGCAGAGCUGGUGAGGGUGCAUCCGAAGAGUUCUUUGGCUGGAAGGA

AGGGCUACAGCACAAGCGAUGGCAAAACUUUCUCAUAUUUGGAAGGGACCAAGUUUCACCAGGCGGCCAAGG

AUAUAGCAGAAAUUAAUGCCAUGUGGCCCGUUGCAACGGAGGCCAAUGAGCAGGUAUGCAUGUAUAUCCUCG

GAGAAAGCAUGAGCAGUAUUAGGUCGAAAUGCCCCGUCGAAGAGUCGGAAGCCUCCACACCACCUAGCACGC

UGCCUUGCUUGUGCAUCCAUGCCAUGACUCCAGAAAGAGUACAGCGCCUAAAAGCCUCACGUCCAGAACAAA

UUACUGUGUGCUCAUCCUUUCCAUUGCCGAAGUAUAGAAUCACUGGUGUGCAGAAGAUCCAAUGCUCCCAGC

CUAUAUUGUUCUCACCGAAAGUGCCUGCGUAUAUUCAUCCAAGGAAGUAUCUCGUGGAAACACCACCGGUAG

ACGAGACUCCGGAGCCAUCGGCAGAGAACCAAUCCACAGAGGGGACACCUGAACAACCACCACUUAUAACCG

AGGAUGAGACCAGGACUAGAACGCCUGAGCCGAUCAUCAUCGAAGAGGAAGAAGAGGAUAGCAUAAGUUUGC

UGUCAGAUGGCCCGACCCACCAGGUGCUGCAAGUCGAGGCAGACAUUCACGGGCCGCCCUCUGUAUCUAGCU

CAUCCUGGUCCAUUCCUCAUGCAUCCGACUUUGAUGUGGACAGUUUAUCCAUACUUGACACCCUGGAGGGAG

CUAGCGUGACCAGCGGGGCAACGUCAGCCGAGACUAACUCUUACUUCGCAAAGAGUAUGGAGUUUCUGGCGC

GACCGGUGCCUGCGCCUCGAACAGUAUUCAGGAACCCUCCACAUCCCGCUCCGCGCACAAGAACACCGUCAC

UUGCACCCAGCAGGGCCUGCUCGAGAACCAGCCUAGUUUCCACCCCGCCAGGCGUGAAUAGGGUGAUCACUA

GAGAGGAGCUCGAGGCGCUUACCCCGUCACGCACUCCUAGCAGGUCGGUCUCGAGAACCAGCCUGGUCUCCA

ACCCGCCAGGCGUAAAUAGGGUGAUUACAAGAGAGGAGUUUGAGGCGUUCGUAGCACAACAACAAUGACGGU

UUGAUGCGGGUGCAUACAUCUUUUCCUCCGACACCGGUCAAGGGCAUUUACAACAAAAAUCAGUAAGGCAAA

CGGUGCUAUCCGAAGUGGUGUUGGAGAGGACCGAAUUGGAGAUUUCGUAUGCCCCGCGCCUCGACCAAGAAA

AAGAAGAAUUACUACGCAAGAAAUUACAGUUAAAUCCCACACCUGCUAACAGAAGCAGAUACCAGUCCAGGA

AGGUGGAGAACAUGAAAGCCAUAACAGCUAGACGUAUUCUGCAAGGCCUAGGGCAUUAUUUGAAGGCAGAAG

GAAAAGUGGAGUGCUACCGAACCCUGCAUCCUGUUCCUUUGUAUUCAUCUAGUGUGAACCGUGCCUUUUCAA

GCCCCAAGGUCGCAGUGGAAGCCUGUAACGCCAUGUUGAAAGAGAACUUUCCGACUGUGGCUUCUUACUGUA

UUAUUCCAGAGUACGAUGCCUAUUUGGACAUGGUUGACGGAGCUUCAUGCUGCUUAGACACUGCCAGUUUUU

GCCCUGCAAAGCUGCGCAGCUUUCCAAAGAAACACUCCUAUUUGGAACCCACAAUACGAUCGGCAGUGCCUU

CAGCGAUCCAGAACACGCUCCAGAACGUCCUGGCAGCUGCCACAAAAAGAAAUUGCAAUGUCACGCAAAUGA

GAGAAUUGCCCGUAUUGGAUUCGGCGGCCUUUAAUGUGGAAUGCUUCAAGAAAUAUGCGUGUAAUAAUGAAU

AUUGGGAAACGUUUAAAGAAAACCCCAUCAGGCUUACUGAAGAAAACGUGGUAAAUUACAUUACCAAAUUAA

AAGGACCAAAAGCUGCUGCUCUUUUUGCGAAGACACAUAAUUUGAAUAUGUUGCAGGACAUACCAAUGGACA

GGUUUGUAAUGGACUUAAAGAGAGACGUGAAAGUGACUCCAGGAACAAAACAUACUGAAGAACGGCCCAAGG

UACAGGUGAUCCAGGCUGCCGAUCCGCUAGCAACAGCGUAUCUGUGCGGAAUCCACCGAGAGCUGGUUAGGA

GAUUAAAUGCGGUCCUGCUUCCGAACAUUCAUACACUGUUUGAUAUGUCGGCUGAAGACUUUGACGCUAUUA

UAGCCGAGCACUUCCAGCCUGGGGAUUGUGUUCUGGAAACUGACAUCGCGUCGUUUGAUAAAAGUGAGGACG

ACGCCAUGGCUCUGACCGCGUUAAUGAUUCUGGAAGACUUAGGUGUGGACGCAGAGCUGUUGACGCUGAUUG

AGGCGGCUUUCGGCGAAAUUUCAUCAAUACAUUUGCCCACUAAAACUAAAUUUAAAUUCGGAGCCAUGAUGA

AAUCUGGAAUGUUCCUCACACUGUUUGUGAACACAGUCAUUAACAUUGUAAUCGCAAGCAGAGUGUUGAGAG

AACGGCUAACCGGAUCACCAUGUGCAGCAUUCAUUGGAGAUGACAAUAUCGUGAAAGGAGUCAAAUCGGACA

AAUUAAUGGCAGACAGGUGCGCCACCUGGUUGAAUAUGGAAGUCAAGAUUAUAGAUGCUGUGGUGGGCGAGA

AAGCGCCUUAUUUCUGUGGAGGGUUUAUUUUGUGUGACUCCGUGACCGGCACAGCGUGCCGUGUGGCAGACC

CCCUAAAAAGGCUGUUUAAGCUUGGCAAACCUCUGGCAGCAGACGAUGAACAUGAUGAUGACAGGAGAAGGG

CAUUGCAUGAAGAGUCAACACGCUGGAACCGAGUGGGUAUUCUUUCAGAGCUGUGCAAGGCAGUAGAAUCAA

GGUAUGAAACCGUAGGAACUUCCAUCAUAGUUAUGGCCAUGACUACUCUAGCUAGCAGUGUUAAAUCAUUCA

GCUACCUGAGAGGGGCCCCUAUAACUCUCUACGGCUAACCUGAAUGGACUACGACAUAGUCUAGUCCGCCAA

GUCUAGCAUAUGGCCACC -----------------GOI-----------------

[SEQ ID No: 457]

CGGAGACGGCGCAGAAGAAGAGGAUCUGGCGAAGGCAGAGGCAGCCUGCUUACAUGUGGCGACGUGGAAGAG

AACCCCGGACCUAUGCACCAGAAACGGACCGCCAUGUUCCAGGAUCCUCAAGAGAGGCCCAGAAAGCUGCCU

CAGCUGUGUACCGAGCUGCAGACCACCAUCCACGACAUCAUCCUGGAAUGCGUGUACUGCAAGCAGCAGCUC

CUGCGGAGAGAGGUGUACGAUUUCGCCUUCCGGGACCUGUGCAUCGUGUACAGAGAUGGCAACCCCUACGCC

GUGUGCGACAAGUGCCUGAAGUUCUACAGCAAGAUCAGCGAGUACCGGCACUACUGCUACAGCCUGUACGGC

ACCACACUGGAACAGCAGUACAACAAGCCCCUGUGCGACCUGCUGAUCCGGUGCAUCAACUGCCAGAAACCU

CUGUGCCCCGAGGAAAAGCAGCGGCACCUGGACAAGAAGCAGCGGUUCCACAACAUCAGAGGCCGGUGGACC

GGCAGAUGCAUGAGCUGUUGUCGGAGCAGCAGAACCAGACGGGAAACCCAGCUGUGAGCGGCCGCGAAUUGG

CAAGCUGCUUACAUAGAACUCGCGGCGAUUGGCAUGCCGCCUUAAAAUUUUUAUUUUAUUUUUCUUUUCUUU

UCCGAAUCGGAUUUUGUUUUUAAUAUUUCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Accordingly, preferably the RNA construct comprises a nucleotide sequence substantially as set out above, comprising or consisting of SEQ ID No: 92, a GOI, and SEQ ID No: 457, or a fragment or variant thereof.

In a second aspect of the invention, there is provided a nucleic acid sequence encoding the RNA construct of the first aspect.

In one embodiment, the nucleic acid sequence may encode a GOI—furin T2A—HCV E6 (which is the first viral IIP mentioned herein, but it will be appreciated that any of the IIPs or linkers disclosed herein may be used). Thus, the nucleic acid sequence may comprise or consist of SEQ ID No: 93, a GOI, and SEQ ID No: 458. SEQ ID No: 93 and SEQ ID No: 458 are as follows:

[SEQ ID No: 93]

ATGGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAGTTCACGTTGACATCGAGG

AAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAGAAGCCAAGCAGGTCACTG

ATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCGAAACGGAGGTGGACCCAT

CCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGCACAAGTATCATTGTATCT

GTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGCTGAAGAAAAACTGTAAGG

AAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTGGCCGCCGTCATGAGCGACCCTGACCTGGAAA

CTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCGCTGTTTACCAGGATGTAT

ACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAGTCGCCTACTGGATAGGCT

TTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACTCTACCAACTGGGCCGACG

AAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGAGCGGTCACGTAGAGGGATGT

CCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCTGTTGGCTCGACCATCTACCACG

AGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACTTACGTGGCAAGCAAAATTACACAT

GTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAGAATAGCTATCAGTCCAGGCCTGTATG

GGAAGCCTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTCTTGTGCTGCAAAGTGACAGACACATTGA

ACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAGCTACATTGTGTGACCAAATGACTGGCATAC

TGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCTGGTTGGGCTCAACCAGCGTATAGTCGTCAACG

GTCGCACCCAGAGAAACACCAATACCATGAAAAATTACCTTTTGCCCGTAGTGGCCCAGGCATTTGCTAGGT

GGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAAGGCCACTAGGACTACGAGATAGACAGTTAGTCATGG

GGTGTTGTTGGGCTTTTAGAAGGCACAAGATAACATCTATTTATAAGCGCCCGGATACCCAAACCATCATCA

AAGTGAACAGCGATTTCCACTCATTCGTGCTGCCCAGGATAGGCAGTAACACATTGGAGATCGGGCTGAGAA

CAAGAATCAGGAAAATGTTAGAGGAGCACAAGGAGCCGTCACCTCTCATTACCGCCGAGGACGTACAAGAAG

CTAAGTGCGCAGCCGATGAGGCTAAGGAGGTGCGTGAAGCCGAGGAGTTGCGCGCAGCTCTACCACCTTTGG

CAGCTGATGTTGAGGAGCCCACTCTGGAAGCCGATGTCGACTTGATGTTACAAGAGGCTGGGGCCGGCTCAG

TGGAGACACCTCGTGGCTTGATAAAGGTTACCAGCTACGATGGCGAGGACAAGATCGGCTCTTACGCTGTGC

TTTCTCCGCAGGCTGTACTCAAGAGTGAAAAATTATCTTGCATCCACCCTCTCGCTGAACAAGTCATAGTGA

TAACACACTCTGGCCGAAAAGGGCGTTATGCCGTGGAACCATACCATGGTAAAGTAGTGGTGCCAGAGGGAC

ATGCAATACCCGTCCAGGACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGTACAACGAACGTGAGTTCG

TAAACAGGTACCTGCACCATATTGCCACACATGGAGGAGCGCTGAACACTGATGAAGAATATTACAAAACTG

TCAAGCCCAGCGAGCACGACGGCGAATACCTGTACGACATCGACAGGAAACAGTGCGTCAAGAAAGAACTAG

TCACTGGGCTAGGGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCGCCTACGAGAGTCTGAGAA

CACGACCAGCCGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAGGATCAGGCAAGTCTGGCA

TCATTAAAAGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAAACTGTGCAGAAATTATAA

GGGACGTCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAGTGCTCTTGAATGGATGCA

AACACCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTACTCTCAGAGCGCTCATAG

CCATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTTTTTTTAACATGATGTGCC

TGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCTCTCGCCGTTGCACTAAAT

CTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGAATCCGAAAGAGACTAAGA

TTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCACTTGTTTCAGAGGGTGGG

TGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCTCTCAAGGGCTGACCCGTA

AAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCACCTCAGAACATGTGAACG

TCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACCCATGGATAAAAACACTGA

CTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGCATGATGCCATCATGAGGC

ACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGTGTTGGGCCAAGGCTTTAG

TGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTGTGGATTATTTTGAAACGG

ACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTTTGGACTCGATCTGGACTCCG

GTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGGGATAACTCCCCGTCGCCTAACA

TGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACCCACAACTGCCTCGGGCAGTTGCCA

CTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGATCCGCGCATAAACCTAGTACCTGTAA

ACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACACCCACAGAGTGACTTTTCTTCATTCGTCA

GCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGTTGTCCGTCCCAGGCAAAATGGTTGACTGGT

TGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGATTTAGGCATCCCAGGTGATGTGCCCAAATATG

ACATAATATTTGTTAATGTGAGGACCCCATATAAATACCATCACTATCAGCAGTGTGAAGACCATGCCATTA

AGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATCTGAATCCCGGCGGAACCTGTGTCAGCATAGGTTATG

GTTACGCTGACAGGGCCAGCGAAAGCATCATTGGTGCTATAGCGCGGCAGTTCAAGTTTTCCCGGGTATGCA

AACCGAAATCCTCACTTGAAGAGACGGAAGTTCTGTTTGTATTCATTGGGTACGATCGCAAGGCCCGTACGC

ACAATTCTTACAAGCTTTCATCAACCTTGACCAACATTTATACAGGTTCCAGACTCCACGAAGCCGGATGTG

CACCCTCATATCATGTGGTGCGAGGGGATATTGCCACGGCCACCGAAGGAGTGATTATAAATGCTGCTAACA

GCAAAGGACAACCTGGCGGAGGGGTGTGCGGAGCGCTGTATAAGAAATTCCCGGAAAGCTTCGATTTACAGC

CGATCGAAGTAGGAAAAGCGCGACTGGTCAAAGGTGCAGCTAAACATATCATTCATGCCGTAGGACCAAACT

TCAACAAAGTTTCGGAGGTTGAAGGTGACAAACAGTTGGCAGAGGCTTATGAGTCCATCGCTAAGATTGTCA

ACGATAACAATTACAAGTCAGTAGCGATTCCACTGTTGTCCACCGGCATCTTTTCCGGGAACAAAGATCGAC

TAACCCAATCATTGAACCATTTGCTGACAGCTTTAGACACCACTGATGCAGATGTAGCCATATACTGCAGGG

ACAAGAAATGGGAAATGACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGGAGGAGATATGCATATCCG

ACGACTCTTCAGTGACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGAGTTCTTTGGCTGGAAGGA

AGGGCTACAGCACAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGTTTCACCAGGCGGCCAAGG

ATATAGCAGAAATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGGTATGCATGTATATCCTCG

GAGAAAGCATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCTCCACACCACCTAGCACGC

TGCCTTGCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAGCCTCACGTCCAGAACAAA

TTACTGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGAAGATCCAATGCTCCCAGC

CTATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCGTGGAAACACCACCGGTAG

ACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAACAACCACCACTTATAACCG

AGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAGAGGATAGCATAAGTTTGC

TGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGCCGCCCTCTGTATCTAGCT

CATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATACTTGACACCCTGGAGGGAG

CTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACCTCGCAAAGAGTATGGAGTTTCTGGCGC

GACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGCGCACAAGAACACCGTCAC

TTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCGTGAATAGGGTGATCACTA

GAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGAGAACCAGCCTGGTCTCCA

ACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAGCACAACAACAATGACGGT

TTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACAACAAAAATCAGTAAGGCAAA

CGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTATGCCCCGCGCCTCGACCAAGAAA

AAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTAACAGAAGCAGATACCAGTCCAGGA

AGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGGCCTAGGGCATTATTTGAAGGCAGAAG

GAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTATTCATCTAGTGTGAACCGTGCCTTTTCAA

GCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAGAGAACTTTCCGACTGTGGCTTCTTACTGTA

TTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGGAGCTTCATGCTGCTTAGACACTGCCAGTTTTT

GCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCCTATTTGGAACCCACAATACGATCGGCAGTGCCTT

CAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAGCTGCCACAAAAAGAAATTGCAATGTCACGCAAATGA

GAGAATTGCCCGTATTGGATTCGGCGGCCTTTAATGTGGAATGCTTCAAGAAATATGCGTGTAATAATGAAT

ATTGGGAAACGTTTAAAGAAAACCCCATCAGGCTTACTGAAGAAAACGTGGTAAATTACATTACCAAATTAA

AAGGACCAAAAGCTGCTGCTCTTTTTGCGAAGACACATAATTTGAATATGTTGCAGGACATACCAATGGACA

GGTTTGTAATGGACTTAAAGAGAGACGTGAAAGTGACTCCAGGAACAAAACATACTGAAGAACGGCCCAAGG

TACAGGTGATCCAGGCTGCCGATCCGCTAGCAACAGCGTATCTGTGCGGAATCCACCGAGAGCTGGTTAGGA

GATTAAATGCGGTCCTGCTTCCGAACATTCATACACTGTTTGATATGTCGGCTGAAGACTTTGACGCTATTA

TAGCCGAGCACTTCCAGCCTGGGGATTGTGTTCTGGAAACTGACATCGCGTCGTTTGATAAAAGTGAGGACG

ACGCCATGGCTCTGACCGCGTTAATGATTCTGGAAGACTTAGGTGTGGACGCAGAGCTGTTGACGCTGATTG

AGGCGGCTTTCGGCGAAATTTCATCAATACATTTGCCCACTAAAACTAAATTTAAATTCGGAGCCATGATGA

AATCTGGAATGTTCCTCACACTGTTTGTGAACACAGTCATTAACATTGTAATCGCAAGCAGAGTGTTGAGAG

AACGGCTAACCGGATCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGAAAGGAGTCAAATCGGACA

AATTAATGGCAGACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAGATGCTGTGGTGGGCGAGA

AAGCGCCTTATTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAGCGTGCCGTGTGGCAGACC

CCCTAAAAAGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATGATGATGACAGGAGAAGGG

CATTGCATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGTGCAAGGCAGTAGAATCAA

GGTATGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTAGCAGTGTTAAATCATTCA

GCTACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGACATAGTCTAGTCCGCCAA

GTCTAGCATATGGCCACC ----------------GOI-------------------

[SEQ ID No: 458]

CGGAGACGGCGCAGAAGAAGAGGATCTGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAG

AACCCCGGACCTATGCACCAGAAACGGACCGCCATGTTCCAGGATCCTCAAGAGAGGCCCAGAAAGCTGCCT

CAGCTGTGTACCGAGCTGCAGACCACCATCCACGACATCATCCTGGAATGCGTGTACTGCAAGCAGCAGCTC

CTGCGGAGAGAGGTGTACGATTTCGCCTTCCGGGACCTGTGCATCGTGTACAGAGATGGCAACCCCTACGCC

GTGTGCGACAAGTGCCTGAAGTTCTACAGCAAGATCAGCGAGTACCGGCACTACTGCTACAGCCTGTACGGC

ACCACACTGGAACAGCAGTACAACAAGCCCCTGTGCGACCTGCTGATCCGGTGCATCAACTGCCAGAAACCT

CTGTGCCCCGAGGAAAAGCAGCGGCACCTGGACAAGAAGCAGCGGTTCCACAACATCAGAGGCCGGTGGACC

GGCAGATGCATGAGCTGTTGTCGGAGCAGCAGAACCAGACGGGAAACCCAGCTGTGAGCGGCCGCGAATTGG

CAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTT

TCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Accordingly, preferably the nucleic acid sequence comprises a nucleotide sequence substantially as set out above, comprising or consisting of SEQ ID No: 93, a GOI, and SEQ ID No: 458, or a fragment or variant thereof.

In a third aspect, there is provided an expression cassette comprising a nucleic acid sequence according to the second aspect.

The nucleic acid sequences of the invention are preferably harboured in a recombinant vector, for example a recombinant vector for delivery into a host cell of interest to enable production of the RNA construct.

Accordingly, in a fourth aspect, there is provided a recombinant vector comprising the expression cassette according to the third aspect.

In one embodiment, the vector may comprise a DNA sequence which encodes or comprises an saRNA plasmid construct harbouring a GOI—furin T2A—HCV E6 (which is the first viral IIP mentioned herein, but it will be appreciated that any of the IIPs or linkers disclosed herein may be used). Therefore, the vector may comprise the nucleic acid sequence of SEQ ID No: 94, a GOI, and the nucleic acid sequence of SEQ ID No: 459, in a single vector. SEQ ID No: 94 and SEQ ID No: 459 are as follows, where “GOI” represents the position of the therapeutic biomolecule encoding sequence:

[SEQ ID No: 94]

TAATACGACTCACTATAGATGGGCGGCGCATGAGAGAAGCCCAGACCAATTACCTACCCAAAATGGAGAAAG

TTCACGTTGACATCGAGGAAGACAGCCCATTCCTCAGAGCTTTGCAGCGGAGCTTCCCGCAGTTTGAGGTAG

AAGCCAAGCAGGTCACTGATAATGACCATGCTAATGCCAGAGCGTTTTCGCATCTGGCTTCAAAACTGATCG

AAACGGAGGTGGACCCATCCGACACGATCCTTGACATTGGAAGTGCGCCCGCCCGCAGAATGTATTCTAAGC

ACAAGTATCATTGTATCTGTCCGATGAGATGTGCGGAAGATCCGGACAGATTGTATAAGTATGCAACTAAGC

TGAAGAAAAACTGTAAGGAAATAACTGATAAGGAATTGGACAAGAAAATGAAGGAGCTGGCCGCCGTCATGA

GCGACCCTGACCTGGAAACTGAGACTATGTGCCTCCACGACGACGAGTCGTGTCGCTACGAAGGGCAAGTCG

CTGTTTACCAGGATGTATACGCGGTTGACGGACCGACAAGTCTCTATCACCAAGCCAATAAGGGAGTTAGAG

TCGCCTACTGGATAGGCTTTGACACCACCCCTTTTATGTTTAAGAACTTGGCTGGAGCATATCCATCATACT

CTACCAACTGGGCCGACGAAACCGTGTTAACGGCTCGTAACATAGGCCTATGCAGCTCTGACGTTATGGAGC

GGTCACGTAGAGGGATGTCCATTCTTAGAAAGAAGTATTTGAAACCATCCAACAATGTTCTATTCTCTGTTG

GCTCGACCATCTACCACGAGAAGAGGGACTTACTGAGGAGCTGGCACCTGCCGTCTGTATTTCACTTACGTG

GCAAGCAAAATTACACATGTCGGTGTGAGACTATAGTTAGTTGCGACGGGTACGTCGTTAAAAGAATAGCTA

TCAGTCCAGGCCTGTATGGGAAGCCTTCAGGCTATGCTGCTACGATGCACCGCGAGGGATTCTTGTGCTGCA

AAGTGACAGACACATTGAACGGGGAGAGGGTCTCTTTTCCCGTGTGCACGTATGTGCCAGCTACATTGTGTG

ACCAAATGACTGGCATACTGGCAACAGATGTCAGTGCGGACGACGCGCAAAAACTGCTGGTTGGGCTCAACC

AGCGTATAGTCGTCAACGGTCGCACCCAGAGAAACACCAATACCATGAAAAATTACCTTTTGCCCGTAGTGG

CCCAGGCATTTGCTAGGTGGGCAAAGGAATATAAGGAAGATCAAGAAGATGAAAGGCCACTAGGACTACGAG

ATAGACAGTTAGTCATGGGGTGTTGTTGGGCTTTTAGAAGGCACAAGATAACATCTATTTATAAGCGCCCGG

ATACCCAAACCATCATCAAAGTGAACAGCGATTTCCACTCATTCGTGCTGCCCAGGATAGGCAGTAACACAT

TGGAGATCGGGCTGAGAACAAGAATCAGGAAAATGTTAGAGGAGCACAAGGAGCCGTCACCTCTCATTACCG

CCGAGGACGTACAAGAAGCTAAGTGCGCAGCCGATGAGGCTAAGGAGGTGCGTGAAGCCGAGGAGTTGCGCG

CAGCTCTACCACCTTTGGCAGCTGATGTTGAGGAGCCCACTCTGGAAGCCGATGTCGACTTGATGTTACAAG

AGGCTGGGGCCGGCTCAGTGGAGACACCTCGTGGCTTGATAAAGGTTACCAGCTACGATGGCGAGGACAAGA

TCGGCTCTTACGCTGTGCTTTCTCCGCAGGCTGTACTCAAGAGTGAAAAATTATCTTGCATCCACCCTCTCG

CTGAACAAGTCATAGTGATAACACACTCTGGCCGAAAAGGGCGTTATGCCGTGGAACCATACCATGGTAAAG

TAGTGGTGCCAGAGGGACATGCAATACCCGTCCAGGACTTTCAAGCTCTGAGTGAAAGTGCCACCATTGTGT

ACAACGAACGTGAGTTCGTAAACAGGTACCTGCACCATATTGCCACACATGGAGGAGCGCTGAACACTGATG

AAGAATATTACAAAACTGTCAAGCCCAGCGAGCACGACGGCGAATACCTGTACGACATCGACAGGAAACAGT

GCGTCAAGAAAGAACTAGTCACTGGGCTAGGGCTCACAGGCGAGCTGGTGGATCCTCCCTTCCATGAATTCG

CCTACGAGAGTCTGAGAACACGACCAGCCGCTCCTTACCAAGTACCAACCATAGGGGTGTATGGCGTGCCAG

GATCAGGCAAGTCTGGCATCATTAAAAGCGCAGTCACCAAAAAAGATCTAGTGGTGAGCGCCAAGAAAGAAA

ACTGTGCAGAAATTATAAGGGACGTCAAGAAAATGAAAGGGCTGGACGTCAATGCCAGAACTGTGGACTCAG

TGCTCTTGAATGGATGCAAACACCCCGTAGAGACCCTGTATATTGACGAAGCTTTTGCTTGTCATGCAGGTA

CTCTCAGAGCGCTCATAGCCATTATAAGACCTAAAAAGGCAGTGCTCTGCGGGGATCCCAAACAGTGCGGTT

TTTTTAACATGATGTGCCTGAAAGTGCATTTTAACCACGAGATTTGCACACAAGTCTTCCACAAAAGCATCT

CTCGCCGTTGCACTAAATCTGTGACTTCGGTCGTCTCAACCTTGTTTTACGACAAAAAAATGAGAACGACGA

ATCCGAAAGAGACTAAGATTGTGATTGACACTACCGGCAGTACCAAACCTAAGCAGGACGATCTCATTCTCA

CTTGTTTCAGAGGGTGGGTGAAGCAGTTGCAAATAGATTACAAAGGCAACGAAATAATGACGGCAGCTGCCT

CTCAAGGGCTGACCCGTAAAGGTGTGTATGCCGTTCGGTACAAGGTGAATGAAAATCCTCTGTACGCACCCA

CCTCAGAACATGTGAACGTCCTACTGACCCGCACGGAGGACCGCATCGTGTGGAAAACACTAGCCGGCGACC

CATGGATAAAAACACTGACTGCCAAGTACCCTGGGAATTTCACTGCCACGATAGAGGAGTGGCAAGCAGAGC

ATGATGCCATCATGAGGCACATCTTGGAGAGACCGGACCCTACCGACGTCTTCCAGAATAAGGCAAACGTGT

GTTGGGCCAAGGCTTTAGTGCCGGTGCTGAAGACCGCTGGCATAGACATGACCACTGAACAATGGAACACTG

TGGATTATTTTGAAACGGACAAAGCTCACTCAGCAGAGATAGTATTGAACCAACTATGCGTGAGGTTCTTTG

GACTCGATCTGGACTCCGGTCTATTTTCTGCACCCACTGTTCCGTTATCCATTAGGAATAATCACTGGGATA

ACTCCCCGTCGCCTAACATGTACGGGCTGAATAAAGAAGTGGTCCGTCAGCTCTCTCGCAGGTACCCACAAC

TGCCTCGGGCAGTTGCCACTGGAAGAGTCTATGACATGAACACTGGTACACTGCGCAATTATGATCCGCGCA

TAAACCTAGTACCTGTAAACAGAAGACTGCCTCATGCTTTAGTCCTCCACCATAATGAACACCCACAGAGTG

ACTTTTCTTCATTCGTCAGCAAATTGAAGGGCAGAACTGTCCTGGTGGTCGGGGAAAAGTTGTCCGTCCCAG

GCAAAATGGTTGACTGGTTGTCAGACCGGCCTGAGGCTACCTTCAGAGCTCGGCTGGATTTAGGCATCCCAG

GTGATGTGCCCAAATATGACATAATATTTGTTAATGTGAGGACCCCATATAAATACCATCACTATCAGCAGT

GTGAAGACCATGCCATTAAGCTTAGCATGTTGACCAAGAAAGCTTGTCTGCATCTGAATCCCGGCGGAACCT

GTGTCAGCATAGGTTATGGTTACGCTGACAGGGCCAGCGAAAGCATCATTGGTGCTATAGCGCGGCAGTTCA

AGTTTTCCCGGGTATGCAAACCGAAATCCTCACTTGAAGAGACGGAAGTTCTGTTTGTATTCATTGGGTACG

ATCGCAAGGCCCGTACGCACAATTCTTACAAGCTTTCATCAACCTTGACCAACATTTATACAGGTTCCAGAC

TCCACGAAGCCGGATGTGCACCCTCATATCATGTGGTGCGAGGGGATATTGCCACGGCCACCGAAGGAGTGA

TTATAAATGCTGCTAACAGCAAAGGACAACCTGGCGGAGGGGTGTGCGGAGCGCTGTATAAGAAATTCCCGG

AAAGCTTCGATTTACAGCCGATCGAAGTAGGAAAAGCGCGACTGGTCAAAGGTGCAGCTAAACATATCATTC

ATGCCGTAGGACCAAACTTCAACAAAGTTTCGGAGGTTGAAGGTGACAAACAGTTGGCAGAGGCTTATGAGT

CCATCGCTAAGATTGTCAACGATAACAATTACAAGTCAGTAGCGATTCCACTGTTGTCCACCGGCATCTTTT

CCGGGAACAAAGATCGACTAACCCAATCATTGAACCATTTGCTGACAGCTTTAGACACCACTGATGCAGATG

TAGCCATATACTGCAGGGACAAGAAATGGGAAATGACTCTCAAGGAAGCAGTGGCTAGGAGAGAAGCAGTGG

AGGAGATATGCATATCCGACGACTCTTCAGTGACAGAACCTGATGCAGAGCTGGTGAGGGTGCATCCGAAGA

GTTCTTTGGCTGGAAGGAAGGGCTACAGCACAAGCGATGGCAAAACTTTCTCATATTTGGAAGGGACCAAGT

TTCACCAGGCGGCCAAGGATATAGCAGAAATTAATGCCATGTGGCCCGTTGCAACGGAGGCCAATGAGCAGG

TATGCATGTATATCCTCGGAGAAAGCATGAGCAGTATTAGGTCGAAATGCCCCGTCGAAGAGTCGGAAGCCT

CCACACCACCTAGCACGCTGCCTTGCTTGTGCATCCATGCCATGACTCCAGAAAGAGTACAGCGCCTAAAAG

CCTCACGTCCAGAACAAATTACTGTGTGCTCATCCTTTCCATTGCCGAAGTATAGAATCACTGGTGTGCAGA

AGATCCAATGCTCCCAGCCTATATTGTTCTCACCGAAAGTGCCTGCGTATATTCATCCAAGGAAGTATCTCG

TGGAAACACCACCGGTAGACGAGACTCCGGAGCCATCGGCAGAGAACCAATCCACAGAGGGGACACCTGAAC

AACCACCACTTATAACCGAGGATGAGACCAGGACTAGAACGCCTGAGCCGATCATCATCGAAGAGGAAGAAG

AGGATAGCATAAGTTTGCTGTCAGATGGCCCGACCCACCAGGTGCTGCAAGTCGAGGCAGACATTCACGGGC

CGCCCTCTGTATCTAGCTCATCCTGGTCCATTCCTCATGCATCCGACTTTGATGTGGACAGTTTATCCATAC

TTGACACCCTGGAGGGAGCTAGCGTGACCAGCGGGGCAACGTCAGCCGAGACTAACTCTTACTTCGCAAAGA

GTATGGAGTTTCTGGCGCGACCGGTGCCTGCGCCTCGAACAGTATTCAGGAACCCTCCACATCCCGCTCCGC

GCACAAGAACACCGTCACTTGCACCCAGCAGGGCCTGCTCGAGAACCAGCCTAGTTTCCACCCCGCCAGGCG

TGAATAGGGTGATCACTAGAGAGGAGCTCGAGGCGCTTACCCCGTCACGCACTCCTAGCAGGTCGGTCTCGA

GAACCAGCCTGGTCTCCAACCCGCCAGGCGTAAATAGGGTGATTACAAGAGAGGAGTTTGAGGCGTTCGTAG

CACAACAACAATGACGGTTTGATGCGGGTGCATACATCTTTTCCTCCGACACCGGTCAAGGGCATTTACAAC

AAAAATCAGTAAGGCAAACGGTGCTATCCGAAGTGGTGTTGGAGAGGACCGAATTGGAGATTTCGTATGCCC

CGCGCCTCGACCAAGAAAAAGAAGAATTACTACGCAAGAAATTACAGTTAAATCCCACACCTGCTAACAGAA

GCAGATACCAGTCCAGGAAGGTGGAGAACATGAAAGCCATAACAGCTAGACGTATTCTGCAAGGCCTAGGGC

ATTATTTGAAGGCAGAAGGAAAAGTGGAGTGCTACCGAACCCTGCATCCTGTTCCTTTGTATTCATCTAGTG

TGAACCGTGCCTTTTCAAGCCCCAAGGTCGCAGTGGAAGCCTGTAACGCCATGTTGAAAGAGAACTTTCCGA

CTGTGGCTTCTTACTGTATTATTCCAGAGTACGATGCCTATTTGGACATGGTTGACGGAGCTTCATGCTGCT

TAGACACTGCCAGTTTTTGCCCTGCAAAGCTGCGCAGCTTTCCAAAGAAACACTCCTATTTGGAACCCACAA

TACGATCGGCAGTGCCTTCAGCGATCCAGAACACGCTCCAGAACGTCCTGGCAGCTGCCACAAAAAGAAATT

GCAATGTCACGCAAATGAGAGAATTGCCCGTATTGGATTCGGCGGCCTTTAATGTGGAATGCTTCAAGAAAT

ATGCGTGTAATAATGAATATTGGGAAACGTTTAAAGAAAACCCCATCAGGCTTACTGAAGAAAACGTGGTAA

ATTACATTACCAAATTAAAAGGACCAAAAGCTGCTGCTCTTTTTGCGAAGACACATAATTTGAATATGTTGC

AGGACATACCAATGGACAGGTTTGTAATGGACTTAAAGAGAGACGTGAAAGTGACTCCAGGAACAAAACATA

CTGAAGAACGGCCCAAGGTACAGGTGATCCAGGCTGCCGATCCGCTAGCAACAGCGTATCTGTGCGGAATCC

ACCGAGAGCTGGTTAGGAGATTAAATGCGGTCCTGCTTCCGAACATTCATACACTGTTTGATATGTCGGCTG

AAGACTTTGACGCTATTATAGCCGAGCACTTCCAGCCTGGGGATTGTGTTCTGGAAACTGACATCGCGTCGT

TTGATAAAAGTGAGGACGACGCCATGGCTCTGACCGCGTTAATGATTCTGGAAGACTTAGGTGTGGACGCAG

AGCTGTTGACGCTGATTGAGGCGGCTTTCGGCGAAATTTCATCAATACATTTGCCCACTAAAACTAAATTTA

AATTCGGAGCCATGATGAAATCTGGAATGTTCCTCACACTGTTTGTGAACACAGTCATTAACATTGTAATCG

CAAGCAGAGTGTTGAGAGAACGGCTAACCGGATCACCATGTGCAGCATTCATTGGAGATGACAATATCGTGA

AAGGAGTCAAATCGGACAAATTAATGGCAGACAGGTGCGCCACCTGGTTGAATATGGAAGTCAAGATTATAG

ATGCTGTGGTGGGCGAGAAAGCGCCTTATTTCTGTGGAGGGTTTATTTTGTGTGACTCCGTGACCGGCACAG

CGTGCCGTGTGGCAGACCCCCTAAAAAGGCTGTTTAAGCTTGGCAAACCTCTGGCAGCAGACGATGAACATG

ATGATGACAGGAGAAGGGCATTGCATGAAGAGTCAACACGCTGGAACCGAGTGGGTATTCTTTCAGAGCTGT

GCAAGGCAGTAGAATCAAGGTATGAAACCGTAGGAACTTCCATCATAGTTATGGCCATGACTACTCTAGCTA

GCAGTGTTAAATCATTCAGCTACCTGAGAGGGGCCCCTATAACTCTCTACGGCTAACCTGAATGGACTACGA

CATAGTCTAGTCCGCCAAGTCTAGCATATGGCCACC---------GOI---------

[SEQ ID No: 459]

CGGAGACGGCGCAGAAGAAGAGGATCTGGCGAAGGCAGAGGCAGCCTGCTTACATGTGGCGACGTGGAAGAG

AACCCCGGACCTATGCACCAGAAACGGACCGCCATGTTCCAGGATCCTCAAGAGAGGCCCAGAAAGCTGCCT

CAGCTGTGTACCGAGCTGCAGACCACCATCCACGACATCATCCTGGAATGCGTGTACTGCAAGCAGCAGCTC

CTGCGGAGAGAGGTGTACGATTTCGCCTTCCGGGACCTGTGCATCGTGTACAGAGATGGCAACCCCTACGCC

GTGTGCGACAAGTGCCTGAAGTTCTACAGCAAGATCAGCGAGTACCGGCACTACTGCTACAGCCTGTACGGC

ACCACACTGGAACAGCAGTACAACAAGCCCCTGTGCGACCTGCTGATCCGGTGCATCAACTGCCAGAAACCT

CTGTGCCCCGAGGAAAAGCAGCGGCACCTGGACAAGAAGCAGCGGTTCCACAACATCAGAGGCCGGTGGACC

GGCAGATGCATGAGCTGTTGTCGGAGCAGCAGAACCAGACGGGAAACCCAGCTGTGAGCGGCCGCGAATTGG

CAAGCTGCTTACATAGAACTCGCGGCGATTGGCATGCCGCCTTAAAATTTTTATTTTATTTTTCTTTTCTTT

TCCGAATCGGATTTTGTTTTTAATATTTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACGCGTCGA

GGGGAATTAATTCTTGAAGACGAAAGGGCCAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTG

TTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACCCTGATAAATGCTTCAATAATA

TTGAAAAAGGAAGAGTATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCT

TCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCACGAGTGGG

TTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGAT

GAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGAGCAACTCGGTCG

CCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCTTACGGATGGCAT

GACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAAC

GATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTG

GGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAATGGCAACAAC

GTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGGATGGAGGC

GGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGC

CGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTAT

CTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGAT

TAAGCATTGGTAACTGTCAGACCAAGTTTACTCATATATACTTTAGATTGATTTAAAACTTCATTTTTAATT

TAAAAGGATCTAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCA

CTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTG

CTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCC

GAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTAGTTAGGCCACCA

CTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGG

CGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAAC

GGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGTGAGCA

TTGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGG

AGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTG

ACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGAGCTC

Accordingly, preferably the vector comprises the nucleotide sequence substantially as set out above, comprising or consisting of SEQ ID NO: 94, a GOI, and SEQ ID No: 459, or a variant or fragment thereof.

The saRNA constructs of the invention may be made using a DNA plasmid, as a template. RNA copies may then be made by in vitro transcription using a polymerase, such as T7 polymerase, and the T7 promoter may be upstream of the saRNA. Hence, the saRNA constructs of the invention may be made using the DNA plasmid having a nucleic acid sequence substantially as set out above, comprising or consisting of SEQ ID No: 94, a GOI, and SEQ ID No: 459, or a variant or fragment thereof, as the template. Of course, it will be appreciated that other RNA polymerases could be used instead of T7 polymerase, for example the SP6 or the T3 polymerase, in which case the saRNA construct may comprise the SP6 or T3 promoter instead.

The vector of the fourth aspect encoding the RNA construct of the first aspect may for example be a plasmid, cosmid or phage and/or be a viral vector. Such recombinant vectors are highly useful in the delivery systems of the invention for transforming cells with the nucleotide sequences. The nucleotide sequences may preferably be a DNA sequence, and it is this DNA sequence which encodes the RNA sequence forming the RNA construct of the first aspect.

Recombinant vectors encoding the RNA construct of the first aspect may also include other functional elements. For example, they may further comprise a variety of other functional elements including a suitable promoter for initiating transgene expression upon introduction of the vector in a host cell. For instance, the vector is preferably capable of autonomously replicating in the nucleus of the host cell, such as a bacterial cell. In this case, elements which induce or regulate DNA replication may be required in the recombinant vector. Alternatively, the recombinant vector may be designed such that it integrates into the genome of a host cell. In this case, DNA sequences which favour targeted integration (e.g. by homologous recombination) are envisaged. Suitable promoters may include the SV40 promoter, CMV, EF1a, PGK, viral long terminal repeats, as well as inducible promoters, such as the Tetracycline inducible system, as examples. The cassette or vector may also comprise a terminator, such as the Beta globin, SV40 polyadenylation sequences or synthetic polyadenylation sequences. The recombinant vector may also comprise a promoter or regulator or enhancer to control expression of the nucleic acid as required.

The vector may also comprise DNA coding for a gene that may be used as a selectable marker in the cloning process, i.e. to enable selection of cells that have been transfected or transformed, and to enable the selection of cells harbouring vectors incorporating heterologous DNA. For example, ampicillin, neomycin, puromycin or chloramphenicol resistance is envisaged. Alternatively, the selectable marker gene may be in a different vector to be used simultaneously with the vector containing the transgene(s). The cassette or vector may also comprise DNA involved with regulating expression of the nucleotide sequence, or for targeting the expressed polypeptide to a certain part of the host cell.

Purified vector may be inserted directly into a host cell by suitable means, e.g. direct endocytotic uptake. The vector may be introduced directly into a host cell (e.g. a eukaryotic or prokaryotic cell) by transfection, infection, electroporation, microinjection, cell fusion, protoplast fusion or ballistic bombardment. Alternatively, vectors of the invention may be introduced directly into a host cell using a particle gun.

The nucleic acid molecule may (but not necessarily) be one, which becomes incorporated in the DNA of the host cell. Undifferentiated cells may be stably transformed leading to the production of genetically modified daughter cells (in which case regulation of expression in the subject may be required e.g. with specific transcription factors or gene activators). Alternatively, the delivery system may be designed to favour unstable or transient transformation of differentiated cells. When this is the case, regulation of expression may be less important because expression of the DNA molecule will stop when the transformed cells die or stop expressing the protein.

Alternatively, the delivery system may provide the nucleic acid molecule to the host cell without it being incorporated in a vector. For instance, the nucleic acid molecule may be incorporated within a liposome or virus particle. Alternatively a “naked” nucleic acid molecule may be inserted into a host cell by a suitable means e.g. direct endocytotic uptake.

In a fifth aspect, there is provided a pharmaceutical composition comprising the RNA construct of the first aspect, the nucleic acid sequence of the second aspect, the expression cassette of the third aspect or the vector of the fourth aspect, and a pharmaceutically acceptable vehicle.

In a sixth aspect, there is provided a process for making the pharmaceutical composition according to the fifth aspect, the method comprising contacting the RNA construct of the first aspect, the nucleic acid sequence of the second aspect, the expression cassette of the third aspect or the vector of the fourth aspect, with a pharmaceutically acceptable vehicle.

In a seventh aspect, there is provided a method of preparing the RNA construct of the first aspect, the method comprising:

- a) i) introducing, into a host cell, the vector of the fourth aspect; and
  - ii) culturing the host cell under conditions to result in the production of the RNA construct of the first aspect; or
- b) transcribing the RNA construct from the vector according to the fourth aspect.

The host cell of step a) may be a eukaryotic or prokaryotic host cell. Preferably, the host cell is a eukaryotic host cell. More preferably, the host cell is a mammalian host cell such as Human embryonic kidney 293 cells or Chinese hamster ovary (CHO) cells. Step (b) may be performed in vitro or in vivo, preferably in vitro.

Suitable methods of in vitro transcription are well known in the art and would be known to those skilled in the art. For example, as described in Molecular Cloning, A Laboratory Manual, 2nd edition. (1989) editor C Nolan, Cold Spring Harbor Laboratory Press.

The RNA replicon of the first aspect is particularly suitable for therapy.

While the inventors envisaged that the RNA construct of the first aspect would be generated by in vitro transcription for in vivo use in therapy, those experienced in the art will recognise that the RNA construct can be generated in vivo in a subject for therapy, by in vivo delivery of the nucleic acid according to the second aspect, the expression cassette according to the third aspect, or the vector according to the fourth aspect to a subject.

Hence, according to an eighth aspect, there is provided a RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect, for use as a medicament or in therapy.

In a ninth aspect of the invention, there is provided a RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect, for use in the prevention, amelioration or treatment of a protozoan, fungal, bacterial or viral infection.

The protozoan, fungal, bacterial or viral infection may be an infection of a protozoa, fungus, bacterium or virus as defined in the first aspect.

In a tenth aspect of the invention, there is provided an RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect, for use in the prevention, amelioration or treatment of cancer.

The cancer may be as defined in the first aspect.

In an eleventh aspect of the invention, there is provided a method for treating a protozoan, fungal, bacterial or viral infection, the method comprising administering, to a subject in need thereof, a therapeutically effective amount of the RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.

The protozoan, fungal, bacterial or viral infection to be treated may be an infection of a protozoa, fungus, bacterium or virus as defined in the first aspect.

In a twelfth aspect of the invention, there is provided a method for treating cancer, the method comprising administering, to a subject in need thereof, a therapeutically effective amount of the RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.

The cancer to be treated may be as defined in the first aspect.

The RNA construct described herein provides an effective means of vaccinating a subject (e.g. against a viral, bacterial or fungal infection) and cancer.

Accordingly, in a thirteenth aspect of the invention, there is provided a vaccine comprising the RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.

The adjuvant incorporated into a delivery formulation may be selected form the group consisting of a bacterial lipopeptide, lipoprotein and lipoteichoic acid; mycobacterial lipoglycan; yeast zymosan, porin, Lipopolysaccharide, Lipid A, monophosphoryl lipid A (MPL), Flagellin, CpG DNA, hemozoin, Tomatine, ISCOM, ISCOMATRIX™, squalene based emulsions, polymers such as PEI, Carbopol, lipid nanoparticles and bacterial toxins (CT, LT). Other examples of adjuvants incorporated into the delivery formulation may include an aluminium salt, a synthetic form of DNA, a carbohydrate, a tablet binder, an ion exchange resin, a preservative, a polymer, an emulsion and/or a lipid. Examples of adjuvants may include monosodium glutamate, sucrose, dextrose, aluminum bovine, human serum albumin, cytosine phosphoguanine, potassium phosphate, plasdone C, anhydrous lactose, cellulose, polacrilin potassium, glycerine, asparagine, citric acid, potassium phosphate magnesium sulfate, iron ammonium citrate, 2-phenoxyethanol, aluminium, beta-propiolactone, bovine extract, DOPC, EDTA, formaldehyde, thimerosal, phenol, potassium aluminum sulfate, potassium glutamate, sodium borate, sodium metabisulphite, urea, PLGA, PVA, PLA, PVP, cyclodextrin-based stabilisers, oil in water emulsion adjuvants and/or lipid-based adjuvants.

In a fourteenth aspect of the invention, there is provided an RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect, for use in stimulating an immune response in a subject.

The immune response may be stimulated against a protozoa, bacterium, virus, fungus or cancer as per the antigens defined in the first aspect.

In another aspect, there is provided a method of vaccinating a subject, the method comprising administering, or having administered, to a subject in need thereof, a therapeutically effective amount of the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.

According to a fifteenth aspect, there is provided an RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect, for use in stem cell therapy.

Stem cell therapy may relate to the reprogramming somatic cells to cells having stem cell characteristics.

Somatic cells may be reprogrammed by delivering one or more proteins that are capable of enhancing reprogramming of somatic cells to cells having stem cell characteristics as defined in the first aspect.

According to a sixteenth aspect, there is provided a method of modifying a cell ex vivo or in vitro, comprising delivering, to the cell, the RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.

Preferably, the method is performed ex vivo.

The cell may be a eukaryotic or prokaryotic cell. Preferably, the cell is a eukaryotic cell. More preferably, the cell is a mammalian host cell. Most preferably, the cell is a human cell.

Preferably, the modified cell is suitable for cell-therapy indications.

In a seventeenth aspect, there is provided a modified cell obtained from, or obtainable by, the method of the sixteenth aspect.

In an eighteenth aspect, there is provided the modified cell of the seventeenth aspect, for use in therapy, optionally cell therapy.

It will be appreciated that the RNA construct according to the first aspect, the nucleic acid according to the second aspect, the expression cassette according to the third aspect, the vector according to the fourth aspect or the pharmaceutical composition according to the fifth aspect (herein known as the active agents) may be used in a medicament, which may be used as a monotherapy (i.e. use of the active agent), for treating, ameliorating, or preventing disease or vaccination. Alternatively, the active agents according to the invention may be used as an adjunct to, or in combination with, known therapies for treating, ameliorating, or preventing disease.

The RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition of the invention may be combined in compositions having a number of different forms depending, in particular, on the manner in which the composition is to be used. Thus, for example, the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micellar solution, transdermal patch, liposome suspension, polyplex, emulsion, lipid nanoparticles (with RNA on the surface or encapsulated) or any other suitable form that may be administered to a person or animal in need of treatment or vaccination. It will be appreciated that the vehicle of medicaments according to the invention should be one which is well-tolerated by the subject to whom it is given.

The RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition of the invention may also be incorporated within a slow- or delayed-release device. Such devices may, for example, be inserted on or under the skin, and the medicament may be released over weeks or even months. The device may be located at least adjacent to the treatment site. Such devices may be particularly advantageous when long-term treatment with the RNA construct or the recombinant vector is required and which would normally require frequent administration (e.g. at least daily injection).

In a preferred embodiment, however, medicaments according to the invention may be administered to a subject by injection into the blood stream, muscle, skin or directly into a site requiring treatment. Most preferably, the medicaments, including the RNA construct, are injected into muscle. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion), or intradermal (bolus or infusion), or intramuscular (bolus or infusion).

It will be appreciated that the amount of RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition that is required is determined by its biological activity and bioavailability, which in turn depends on the mode of administration, the physiochemical properties of the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition and whether it is being used as a monotherapy or in a combined therapy. The frequency of administration will also be influenced by the half-life of the active agent within the subject being treated. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition in use, the strength of the pharmaceutical composition, the mode of administration, and the type and advancement of the viral infection. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.

Generally, a daily dose of between 0.001 μg/kg of body weight and 10 mg/kg of body weight, or between 0.1 μg/kg of body weight and 1 mg/kg of body weight, of the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition of the invention may be used for treating, ameliorating, or preventing a disease, depending upon the active agent used.

Daily doses may be given as a single administration (e.g. a single daily injection or inhalation of a nasal spray). Alternatively, the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition may require administration twice or more times during a day. As an example, the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition may be administered as two (or more depending upon the severity of the disease being treated) daily doses of between 0.07 μg and 700 mg (i.e. assuming a body weight of 70 kg). A patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3- or 4-hourly intervals thereafter. Alternatively, a slow release device may be used to provide optimal doses of the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention to a patient without the need to administer repeated doses.

Preferably, however, the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention may be given as a weekly dose, and more preferably a fortnightly dose.

Known procedures, such as those conventionally employed by the pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.), may be used to form specific formulations of the RNA construct, nucleic acid sequence, expression cassette or vector according to the invention and precise therapeutic regimes (such as daily doses of the agents and the frequency of administration).

A “subject” may be a vertebrate, mammal, or domestic animal. Hence, compositions and medicaments according to the invention may be used to treat any mammal, for example livestock (e.g. a horse), pets, or may be used in other veterinary applications. Most preferably, however, the subject is a human being.

A “therapeutically effective amount” of the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition is any amount which, when administered to a subject, is the amount of the aforementioned that is needed to ameliorate, prevent or treat any given disease.

For example, the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition of the invention may be used from about 0.0001 mg to about 800 mg, and preferably from about 0.001 mg to about 500 mg. It is preferred that the amount of the replicon, nucleic acid sequence, expression cassette, vector or pharmaceutical composition is an amount from about 0.001 mg to about 250 mg, and most preferably from about 0.01 mg to about 1 mg. Preferably, the RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention is administered at a dose of 1-200 g.

A “pharmaceutically acceptable vehicle” as referred to herein, is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions.

In one embodiment, the pharmaceutically acceptable vehicle may be a solid, and the composition may be in the form of a powder or tablet. A solid pharmaceutically acceptable vehicle may include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet-disintegrating agents. The vehicle may also be an encapsulating material. In powders, the vehicle is a finely divided solid that is in admixture with the finely divided active agents according to the invention. In tablets, the active agent (e.g. RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention) may be mixed with a vehicle having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active agents. Suitable solid vehicles include, for example calcium phosphate, magnesium stearate, tale, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. In another embodiment, the pharmaceutical vehicle may be a gel and the composition may be in the form of a cream or the like.

However, the pharmaceutical vehicle may be a liquid, and the pharmaceutical composition is in the form of a solution. Liquid vehicles are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention may be dissolved or suspended in a pharmaceutically acceptable liquid vehicle such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid vehicle can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid vehicles for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid vehicles are useful in sterile liquid form compositions for parenteral administration. The liquid vehicle for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, subcutaneous, intradermal, intrathecal, epidural, intraperitoneal, intravenous and particularly intramuscular injection. The nucleic acid sequence, or expression cassette of the invention may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.

The RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition of the invention may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like. The RNA construct, nucleic acid sequence, expression cassette, vector or pharmaceutical composition according to the invention can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.

It will be appreciated that the invention extends to any nucleic acid or peptide or variant, derivative or analogue thereof, which comprises substantially the amino acid or nucleic acid sequences of any of the sequences referred to herein, including variants or fragments thereof. The terms “substantially the amino acid/nucleotide/peptide sequence”, “variant” and “fragment”, can be a sequence that has at least 40% sequence identity with the amino acid/nucleotide/peptide sequences of any one of the sequences referred to herein, for example 40% identity with any of the sequences identified herein.

Amino acid/polynucleotide/polypeptide sequences with a sequence identity which is greater than 65%, more preferably greater than 70%, even more preferably greater than 75%, and still more preferably greater than 80% sequence identity to any of the sequences referred to are also envisaged. Preferably, the amino acid/polynucleotide/polypeptide sequence has at least 85% identity with any of the sequences referred to, more preferably at least 90% identity, even more preferably at least 92% identity, even more preferably at least 95% identity, even more preferably at least 97% identity, even more preferably at least 98% identity and, most preferably at least 99% identity with any of the sequences referred to herein.

The skilled technician will appreciate how to calculate the percentage identity between two amino acid/polynucleotide/polypeptide sequences. In order to calculate the percentage identity between two amino acid/polynucleotide/polypeptide sequences, an alignment of the two sequences must first be prepared, followed by calculation of the sequence identity value. The percentage identity for two sequences may take different values depending on:—(i) the method used to align the sequences, for example, ClustalW, BLAST, FASTA, Smith-Waterman (implemented in different programs), or structural alignment from 3D comparison; and (ii) the parameters used by the alignment method, for example, local vs global alignment, the pair-score matrix used (e.g. BLOSUM62, PAM250, Gonnet etc.), and gap-penalty, e.g. functional form and constants.

Having made the alignment, there are many different ways of calculating percentage identity between the two sequences. For example, one may divide the number of identities by: (i) the length of shortest sequence; (ii) the length of alignment; (iii) the mean length of sequence; (iv) the number of non-gap positions; or (v) the number of equivalenced positions excluding overhangs. Furthermore, it will be appreciated that percentage identity is also strongly length dependent. Therefore, the shorter a pair of sequences is, the higher the sequence identity one may expect to occur by chance.

Hence, it will be appreciated that the accurate alignment of protein or DNA sequences is a complex process. The popular multiple alignment program ClustalW (Thompson et al., 1994, Nucleic Acids Research, 22, 4673-4680; Thompson et al., 1997, Nucleic Acids Research, 24, 4876-4882) is a preferred way for generating multiple alignments of proteins or DNA in accordance with the invention. Suitable parameters for ClustalW may be as follows: For DNA alignments: Gap Open Penalty=15.0, Gap Extension Penalty=6.66, and Matrix=Identity. For protein alignments: Gap Open Penalty=10.0, Gap Extension Penalty=0.2, and Matrix=Gonnet. For DNA and Protein alignments: ENDGAP=−1, and GAPDIST=4. Those skilled in the art will be aware that it may be necessary to vary these and other parameters for optimal sequence alignment.

Preferably, calculation of percentage identities between two amino acid/polynucleotide/polypeptide sequences may then be calculated from such an alignment as (N/T)*100, where N is the number of positions at which the sequences share an identical residue, and T is the total number of positions compared including gaps and either including or excluding overhangs. Preferably, overhangs are included in the calculation. Hence, a most preferred method for calculating percentage identity between two sequences comprises (i) preparing a sequence alignment using the ClustalW program using a suitable set of parameters, for example, as set out above; and (ii) inserting the values of N and T into the following formula:—Sequence Identity=(N/T)*100.

Alternative methods for identifying similar sequences will be known to those skilled in the art. For example, a substantially similar nucleotide sequence will be encoded by a sequence which hybridizes to DNA sequences or their complements under stringent conditions. By stringent conditions, the inventors mean the nucleotide hybridises to filter-bound DNA or RNA in 3× sodium chloride/sodium citrate (SSC) at approximately 45° C. followed by at least one wash in 0.2×SSC/0.1% SDS at approximately 20-65° C. Alternatively, a substantially similar polypeptide may differ by at least 1, but less than 5, 10, 20, 50 or 100 amino acids from any of the sequences described herein.

Due to the degeneracy of the genetic code, it is clear that any nucleic acid sequence described herein could be varied or changed without substantially affecting the sequence of the protein encoded thereby, to provide a functional variant thereof. Suitable nucleotide variants are those having a sequence altered by the substitution of different codons that encode the same amino acid within the sequence, thus producing a silent (synonymous) change. Other suitable variants are those having homologous nucleotide sequences but comprising all, or portions of, sequence, which are altered by the substitution of different codons that encode an amino acid with a side chain of similar biophysical properties to the amino acid it substitutes, to produce a conservative change. For example, small non-polar, hydrophobic amino acids include glycine, alanine, leucine, isoleucine, valine, proline, and methionine. Large non-polar, hydrophobic amino acids include phenylalanine, tryptophan and tyrosine. The polar neutral amino acids include serine, threonine, cysteine, asparagine and glutamine. The positively charged (basic) amino acids include lysine, arginine and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. It will therefore be appreciated which amino acids may be replaced with an amino acid having similar biophysical properties, and the skilled technician will know the nucleotide sequences encoding these amino acids.

All of the features described herein (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:—

FIG. 1 shows a schematic of various embodiments (denoted 1-7) of the RNA construct of the invention (e.g. a saRNA replicon on the left, or a mRNA construct). The saRNA replicon (1-4) is based on an alpha virus backbone. This so-called ‘Stealthicon’ vector includes a 5′ UTR followed by nucleic acid encoding Non-structural Proteins (NSP1-4) from an alphavirus, such as VEEV, a sub-genomic promoter (SGP), a GOI (Gene of Interest), such as a viral, bacterial, fungal or mammalian protein or antigen, a viral innate inhibitor protein (IIP), a 3′ UTR and a 3′ poly A tail. The mRNA construct (5-7) includes a 5′ UTR, a GOI (Gene of Interest), such as a viral, bacterial, fungal or mammalian protein or antigen, a viral innate inhibitor protein (IIP), a 3′ UTR and a 3′ poly A tail. The order of the IIP and GOI can be varied for both saRNA and mRNA as shown in the different illustrated embodiments;

FIG. 2 illustrates the immune response in a subject vaccinated (an initial primer jab followed by a subsequent boost jab) with a messenger RNA (mRNA) vaccine;

FIG. 3 illustrates the immune response in a subject vaccinated (an initial primer jab followed by a boost jab) with a standard self-amplifying (saRNA) vaccine;

FIG. 4 illustrates the immune response in a subject vaccinated (an initial primer jab followed by a boost jab) with one embodiment of the RNA construct of the invention, for example the Stealthicon vector shown in FIG. 1;

FIG. 5 illustrates the antigen expression level in a subject vaccinated (an initial primer jab followed by a boost jab) with one embodiment of the RNA construct of the invention, i.e. the Stealthicon vector shown in FIG. 1;

FIG. 6 shows f-Luc expression in HeLa cells following transfection with VEEV replicons containing selected IIP in F-T2A configuration relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr;

FIG. 7 shows f-Luc expression in HeLa cells following transfection with VEEV replicons containing selected IIP in F-T2A configuration relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr;

FIG. 8 shows f-Luc expression in HeLa cells following transfection with selected VEEV replicons containing IP in F-T2A configuration relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr;

FIG. 9 shows f-Luc expression in HeLa cells following transfection with VEEV replicons containing IIP in a double sub-genomic promoter (DSGP) configuration relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr;

FIG. 10 shows the increase in VEGF-A expression in HeLa cells following transfection with saRNA containing the IIP HSV ICP34.5 in a F-T2A configuration compared to saRNA without IIP and relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing VEGF-A as a secreted reporter protein and assessed for protein expression in the culture media after 48 hr by ELISA;

FIG. 11 compares f-Luc expression in HeLa cells following transfection with saRNA containing f-Luc as the GOI (construct 1) and with the IIP MERS ORF4a in F-T2A configuration (constructs 2a and 2b), IRES configuration (construct 3b) and DSGP configurations (constructs 4a and 4b) shown in FIG. 1. HeLa cells were transfected with RNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr, and

FIG. 12 shows n-Luc expression f-Luc expression in HeLa cells following transfection with mRNA containing IIP in F-T2A configuration relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with RNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr.

EXAMPLES

The inventors hypothesized that cis encoding proteins from non-viral sources, such as humans and other mammals, that are known to inhibit the innate recognition of saRNA or mRNA, would dampen the innate sensing in the host cell, and enhance both the protein expression and immunogenicity of RNA vaccines. Thus, the inventors designed and tested a range of RNA constructs (saRNA and mRNA) containing viral innate immune inhibitor proteins (IIPs) and a gene of interest (GOI), and then characterized whether these constructs enhance both intracellular and secreted protein expression (encoded by the gene of interest).

Materials and Methods

Cloning of saRNA Replicon Plasmids Containing IIPs

SaRNA encoding firefly luciferase (fLuc) and replicase derived from the Venezuelan equine encephalitis virus (VEEV) were cloned into a plasmid vector, as previously described (1). Replicon plasmids containing reporter gene followed by IIP (firefly luciferase f-Luc; Uniprot: Q27758) were generated with Furin-T2A or double sub-genomic promoters. Double sub-genomic (DSG) constructs are designed to initiate transcription of separate RNA molecules encoding the fLuc and IIP and were produced by cloning into a base double sub-genomic vector using Gibson assembly and a nucleotide base overlap. Briefly, plasmid DNA was restriction digested for 2 h at 37° C. and used in a NEB Builder HiFi DNA assembly reaction with gene fragment strings synthesised by GeneArt (Regensburg, Germany) or Integrated DNA Technologies (IDT) (Iowa, USA) according to manufacturer's protocol (New England BioLabs, UK). Furin-T2A (F-T2A) constructs designed to generate a single RNA transcript from the VEEV primary sub-genomic promoter with no stop codon for fLuc translation were produced by cloning IIP with F-T2A sequence into restriction enzyme sites of the corresponding DSG plasmid vector. After incubation at 50° C. for 30 min, 2 uL of the NEB Builder HiFi assembly reaction was used to transform NEB 10-alpha bacteria and the transformants plated onto LB agar plates and incubated overnight. Colonies were selected, expanded overnight and recombinant plasmid purified using Qiagen plasmid miniprep kits (Qiagen, UK). Purified clonal plasmids were analysed using a diagnostic restriction enzyme digest and those which exhibited the correct digestion pattern were fully sequenced to confirm nucleotide identity (Eurofins, Germany).

Plasmids that had IIP followed by the reporter gene in the F-T2A or DSG form as well as constructs that utilized the ECMV IRES internal ribosomal entry sequence (which initiates protein translation from the IRES element at a site internal to a messenger RNA transcript; Bochkov and Palmenburg, Biotechniques 41(3):283-4, 2006) were generated by VectorBuilder (VectorBuilder, Germany) using standard molecular techniques.

The incorporated interferon inhibiting proteins (IIP) can be found with the following database identifiers/accession numbers: EBOV VP35 (Ebola virus VP35; NP_066244.1; Accession Number—NCBI Reference Sequence: NC_002549.1; UniProtKB—Q05127 (VP35_EBOZM); EV71-2Apro (Enterovirus 71 2A pro; Accession Numbers—GenBank KC875402.1 and AG028195.1; UniProtKB—Q66478 (POLG_HE71B); HCV E2 (hepatitis C virus E2; NS1 Protein from polyprotein AAA45534.1; Accession Number—Genomic RNA Translation AAA45534.1; UniProtKB—P27958 (384-746) (POLG_HCV77)); HCV NS5a (hepatitis C virus NS5a; isolate H—Genomic RNA translation: AAA45534.1; UniProtKB—P27958 (POLG_HCV77)); HPV E6 (Human papillomavirus E6; NP_041325.1; Accession Number—NCBI Reference Sequence: NC_001526.4; UniProtKB—P03126 (VE6_HPV16)); HSV ICP34.5 (Herpes simplex virus ICP34.5; YP_009137073.1; Accession Number—NCBI Reference Sequence: NC_001806.2; UniProtKB—P36313 (ICP34_HHV11)); KSHV ORF52 (Kaposi's sarcoma-associated herpesvirus ORF52; Accession Number—Genomic DNA Translation: ACY00451.1; UniProtKB—F5HBL8 (F5HBL8_HHV8)); MERS ORF8b (Middle East Respiratory Syndrome virus ORF8b; Accession Number—Genomic RNA Translation ANF29170.1; UniProtKB—A0A1W5LGP6 (A0A1W5LGP6_MERS)); VACV C6 Vaccinia C6 (vaccinia virus C6; Accession Number—Genomic DNA Translation: AAA69602.1; UniProtKB—P17362 (C6_VACCW)); VACV K3L (vaccinia virus K3L; Accession Number—Genomic DNA Translation: AAA48009.1; UniProtKB—P20639 (K3 VACCC)); PIV 5 V (Parainfluenza virus 5 V; ENA protein ID: AAA47882.1; GenBank Accession Number J03142.1; UniProtKB—P11207; V_PIV5)); SARS ORF3b*57 variant (Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2) ORF3b protein-mutated stop codon at AA 23; Genomic RNA Translation QTT40181.1; UniProtKB—PoDTF1 (ORF3B_SARS2)); SARS ORF3b*79 variant (Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2) ORF3b protein-mutated stop codons at AA 23 and AA 57; Genomic RNA Translation QTT40181.1; UniProtKB—PoDTF1 (ORF3B_SARS2)); SARS ORF3b*57 Ecuador variant (Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2) ORF3b protein-mutated stop codon at AA 23; Ecuador mutation at AA 24 (L24M); Genomic RNA Translation QTT40181.1; UniProtKB—PoDTF1 (ORF3B_SARS2)); Pangolin ORF3b *57 (Pangolin Coronavirus—Genomic RNA Translation: QIG55946.1; ORF3b protein-mutated stop codon at AA 23; UniProtKB—A0A6M3G7Q4 (A0A6M3G7Q4_9BETC)); Pangolin ORF3b *79 (Pangolin Coronavirus—Genomic RNA Translation: QIG55946.1; ORF3b protein-mutated stop codons at AA 23 and AA 57; UniProtKB—A0A6M3G7Q4 (A0A6M3G7Q4_9BETC)); MERS ORF4a (Middle East respiratory syndrome-related coronavirus (MERS-CoV) NS4A protein—Genomic RNA Translation: AGV08457.1; UniProtKB: T2BBG6 (T2BBG6_MERS)); BVDV nPro (Bovine viral diarrhea virus (BVDV) (Mucosal disease virus) N-terminal protease (aa 1-168)—Genomic RNA Translation: AAA42854.1; UniProtKB: P19711 (POLG_BVDVN)); HSV US1 (Human herpesvirus 2 (strain HG52) (HHV-2) (Human herpes simplex virus 2) E3 ubiquitin ligase ICP22 US1—Genomic DNA Translation: CAB06708.1; UniProtKB: P89474 (ICP22_HHV2H)); MERS CoV M (Middle East respiratory syndrome-related coronavirus (MERS-CoV) Membrane protein (M)-Genomic RNA Translation: AGV08396.1; UniProtKB: T2BB40 (T2BB40_MERS)).

(1) A. K. Blakney, P. F. McKay, R. J. Shattock, Structural Components for Amplification of Positive and Negative Strand VEEV Splitzicons. Frontiers in Molecular Biosciences 5, 71 (2018).

Cloning of Plasmids Containing IIPs for RNA Transcription

IIP were inserted into a base plasmid using restriction digestion followed by Gibson assembly with a nucleotide base overlap region and included a F-T2A sequence to allow for a single transcript expression of the n-Luc followed by an IIP. The base plasmid consisted of an mRNA encoding a luminous shrimp nanoluciferase (n-Luc) expression cassette with a T7 promoter, an alpha-globin 5′ UTR and a beta-globin 3′ UTR. Briefly, the n-Luc plasmid construct was linearized with restriction enzymes for 2 h at 37° C. and then used in a NEB Builder HiFi DNA assembly reaction essentially as described in the NEB Builder HiFi assembly protocol (New England BioLabs, UK). After incubation at 50° C. for 30 min, 2 uL of the assembly reaction was used to transform NEB 10-alpha bacteria as per protocol and the transformants plated onto LB agar plates and incubated overnight for colony growth. Colonies were selected and expanded overnight, the recombinant plasmid purified from the bacteria using Qiagen plasmid miniprep kit (Qiagen, UK) and purified clonal plasmids were analysed initially using a diagnostic restriction enzyme digest and those which exhibited the correct digestion pattern were fully sequenced to confirm nucleotide identity (Eurofins, Germany).

Plasmids that had IIP followed by the n-Luc in the F-T2A or DSG form as well as constructs that utilized the ECMV IRES internal ribosomal entry sequence (which initiates protein translation from the IRES element at a site internal to a messenger RNA transcript; Bochkov and Palmenburg, Biotechniques 41(3):283-4, 2006) for both the saRNA replicons and the plasmids used for mRNA transcription were generated by VectorBuilder (VectorBuilder, Germany) using standard molecular techniques.

In Vitro Transcription of saRNA

Plasmid DNA (pDNA) was transformed into Escherichia coli (E. coli) (New England BioLabs, UK) and cultured in 100 mL of Luria Broth (LB) with 100 μg/mL of carbenicillin (Sigma Aldrich, UK). pDNA was isolated using a Plasmid Plus MaxiPrep kit (QIAGEN, UK) and the final concentration measured on a NanoDrop One (ThermoFisher, UK). saRNA was transcribed from the pDNA template using CleanCap Reagent AG (Tebu-bio, France) to produce an RNA transcript with a naturally occurring Cap 1 structure. Briefly, the pDNA template was linearized for 3 h at 37° C., then 1 μg of the linearized pDNA template used in the standard CleanCap Transcription protocol (Tebu-bio, France) according to the manufacturer's protocol. Transcripts were purified by LiCl precipitation at −20° C. for at least 30 min, centrifuged at 20,000 g for 20 min at 4° C. to pellet the RNA, rinsed once with 70% EtOH, centrifuged again at 20,000 g for 5 min at 4° C. and resuspended in UltraPure H₂O (Ambion, UK) and stored at −80° C. until further use.

In Vitro Transcription of RNA

pDNA was transformed into E. coli (New England BioLabs, UK), cultured in 100 mL of Luria Broth (LB) with 100 μg/mL of carbenicillin (Sigma Aldrich, UK). Plasmid was purified using a Plasmid Plus MaxiPrep kit (QIAGEN, UK) and the concentration and purity measured on a NanoDrop One (ThermoFisher, UK). RNA was transcribed from the plasmid DNA template using the MEGAscript™ T7 Transcription protocol (ThermoFisher, UK) followed by a ScriptCap™ m7G Capping System post translation (Cambio, UK). Briefly, pDNA was linearized for 3 h at 37° C., and 1 μg of the linearized pDNA template used in the standard reaction protocol. After the MEGAscript™ T7 Transcription the transcripts were purified by LiCl precipitation at −20° C. for at least 30 min, then centrifuged at 20,000 g for 20 min at 4° C. to pellet the RNA, rinsed once with 70% EtOH, centrifuged again at 20,000 g for 5 min at 4° C. and resuspended in UltraPure H₂O (Ambion, UK). The transcripts were then post-transcriptionally capped using the ScriptCap™ m7G Capping System standard protocol and finally LiCl precipitated as described above. Purified and Cap 1 capped RNA was then resuspended in UltraPure H₂O (Ambion, UK) and stored at −80° C. until further use.

Measurement of IIP Activity

In order to establish the ability of saRNA containing viral IIP to increase saRNA f-luc expression relative to saRNA without IIP; the ability of mRNA containing IIP to increase mRNA n-luc expression relative to mRNA without IIP and the ability of mRNA containing IIP to increase f-luc expression from saRNA without IIP, constructs were tested in interferon competent HeLa cells and expression compared to that obtained in HEK293T/17 cells which do not have a functional antiviral signalling pathway. Both cell lines were cultured in high glucose Dulbecco's Modified Eagle's Medium (cDMEM) (Sigma-Aldrich, Merck, UK) containing 10% (v/v) fetal bovine serum (FBS), 5 mg/mL L-glutamine (Gibco, ThermoFisher, UK) and 5 mg/mL penicillin/streptomycin (Sigma-Aldrich, Merck, UK).

Assessment of IIP on saRNA Firefly Luciferase (f-Luc) Expression

HEK293T/17 cells were plated at a density of 25000 cells per well and HeLa cells at a density of 10000 cells per well into flat clear bottom 96-well plates (Corning Costar) and incubated for 24 hr. 10 uL of OptiMEM (ThermoFisher, UK) containing 0.15 μL lipofectamine MessengerMAX (ThermoFisher, UK) and 100 ng of saRNA IIP constructs or saRNA control (no IIP) was added to triplicate wells and after a further 24 hr, plates were centrifuged at 630 g for 5 min at room temperature, 50 μL of medium removed from each well and 50 μL of ONE-Glo™ Ex Reagent D-luciferin reagent (Promega, UK) added and mixed by pipetting. The total volume from each well was then transferred to a flat bottom opaque white 96-well plate (Corning Costar) and fluorescence measured on a FLUOstar OMEGA plate reader within 10 min (BMG LABTECH, UK). Background fluorescence from control wells containing no saRNA was subtracted from the signal for each well containing saRNA. Then the signal obtained for saRNA containing IIP in HeLa cells was expressed as a fold change from signal obtained with control saRNA and to that obtained in HEK293T/17 cells.

Assessment of IIP on saRNA VEGF-A Expression

HEK293T/17 or Hela cells were transfected with 100 ng saRNA containing the VEGF-A gene using the same methods as described for testing of constructs expressing f-Luc. After 48 hr the VEGF-A in the cell culture media was measured using a human VEGF-A ELISA kit (Invitrogen, UK). Briefly, assay plate wells were washed twice with 400 uL wash buffer before addition of test samples or VEGF-A standard (15.6 μg/ml to 1000 μg/ml). Plates were then incubated at room temperature for 2 hr in a microplate shaker (300 rpm; Jencons Scientific Ltd, UK) before washing six times with 400 uL wash buffer 100 uL of Biotin-conjugate detection antibody (1:100 dilution) was added to each well and plates incubated in a microplate shaker (1 hr RT, 300 rpm). After six washes with 400 uL of wash buffer, the streptavidin-HRP (1:100 dilution) second layer conjugate (100 uL) was added and after a further 1 hr incubation and six further washes, 100 uL of TMB substrate was added to each well. After incubation in the dark for 30 min at RT in the dark, 100 uL of the Stop solution was added and the absorbance of each well read at 450 nm in a VersaMax microplate spectrophotometer (Molecular Devices, UK). VEGF-A levels in the samples were determined by interpolation to the standard curve.

Assessment of IIP on RNA Nano-Luciferase (n-Luc) Expression

HEK293T/17 cells were plated at a density of 25000 cells per well and HeLa cells at a density of 10000 cells per well into flat clear bottom 96-well plates (Corning Costar) and incubated for 24 hr. 10 uL of OptiMEM (ThermoFisher, UK) containing 0.15 μL lipofectamine MessengerMAX (ThermoFisher, UK) and 100 ng of saRNA IIP constructs or saRNA control (no IIP) was added to triplicate wells and after a further 24 hr, plates were centrifuged at 630 g for 5 min at room temperature, 50 μL of medium removed from each well and 50 μL of NanoDLR™ Stop & Glo® Reagent (Promega, UK) added and mixed by pipetting. The total volume from each well was then transferred to a flat bottom opaque white 96-well plate (Corning Costar) and fluorescence measured on a FLUOstar® OMEGA plate reader within 10 min (BMG LABTECH, UK). Background fluorescence from control wells containing no RNA was subtracted from the signal for each well containing RNA. Then the signal obtained for RNA containing IIP in HeLa cells was expressed as a fold change from signal obtained with control RNA and to that obtained in HEK293T/17 cells.

Example 1—Structural Design of Viral Innate Inhibitor Protein (IIP) Constructs

Viral innate inhibitor proteins (IIPs) can be incorporated into an RNA construct of the invention, which can be a self-amplifying RNA (saRNA) or messenger RNA (mRNA), in order to reduce or ablate the innate recognition and response that may modify or reduce protein expression and translation, i.e. the protein encoded by a Gene of Interest (GOI), which can be any therapeutic biomolecule.

Various embodiments of design configurations for the RNA construct of the invention are shown in FIG. 1. SaRNA expression constructs are based on an alphavirus backbone where the non-structural proteins are maintained, but the gene of interest (GOI) is inserted downstream of a subgenomic promotor (SGP) replacing the structural genes of the virus (see Embodiment “1” in FIG. 1). The GOI can be any protein at all, and may include viral, bacterial, fungal or mammalian protein, i.e. a biotherapeutic protein. However, the inventors envisage that the RNA construct of the invention will demonstrate significant utility in the vaccine space, and so the GOI would encode a vaccine antigen, such as a viral, bacterial or fungal protein, such as a coat protein.

saRNA Constructs (Left Hand of FIG. 1)

Any IIP can be encoded within the saRNA using the following design approaches:

- Embodiment “2a” in FIG. 1 shows a saRNA construct encoding a fusion protein including a peptide cleavage motif (e.g. furin-T2a), such that the protein encoded by the GOI (e.g. the antigen of interest) and the IIP are cleaved into separate proteins on translation in the host cell;
- In Embodiment “2b” in FIG. 1, the order of the GOI and IIP have been reversed, such that the IIP is 5′ of the GOI, again with a peptide cleavage motif between the IIP and the GOI so that two separate proteins are produced in the host cell following translation of the saRNA construct;
- In Embodiment “3a”, the IIP has been inserted downstream of the GOI stop codon. The subgenomic promoter drives translation of the GOI, and expression/translation of the IIP is driven by the inclusion of an internal ribosomal entry site (IRES);
- In Embodiment “3b”, the order of the GOI and IIP has been reversed such that translation of the IIP is promoted by the subgenomic promotor and of the GOI by the IRES;
- In Embodiment “4a”, the IIP has been inserted downstream of the GOI stop codon. Translation of the GOI is promoted by the first subgenomic promoter and translation of the IIP is driven by the inclusion of a second subgenomic promotor;
- In Embodiment “4b”, the position of the IIP and GOI have been swapped around, i.e. with the IIP placed before the GOI.

mRNA Constructs (Right Hand of FIG. 1)

Referring to FIG. 1, any IIP can also be encoded within mRNA (see Embodiment “5”) using the following design approaches:

- In embodiment “6a”, the mRNA construct encodes a fusion protein including a peptide cleavage motif (e.g. F-T2a) such that the GOI and IIP are cleaved into separate proteins on translation;
- In Embodiment “6b”, the order of the GOI and IIP have been reversed such that the IIP is 5′ of the GOI;
- In Embodiment “7a”, the IIP has been inserted downstream of the GOI stop codon where translation is driven by the inclusion of an internal ribosomal entry site (IRES);
- In Embodiment “7b”, the order of the GOI and IIP has been reversed such that translation is promoted by the subgenomic promotor and the GOI by the IRES.

The inventors have tested a large number of viral IIPs in the various embodiments of RNA constructs illustrated in FIG. 1, and believe that they each have potential to modify expression and response to saRNA and RNA.

Example 2—Construction and Testing of saRNA Constructs Comprising a Viral Innate

Inhibitor Protein (IIP) The inventors designed, constructed and then tested a series of diverse viral IIPs in different replicon configurations on expression of the reporter gene, f-Luc or VEGF-A, and the results of the expression studies are shown in FIGS. 6-11.

Referring to FIG. 6, there is shown the fold increase in f-Luc expression in HeLa cells following transfection with VEEV replicons containing HPV E6, HSV ICP34.5, HCV E2, VACV E3L, MERS ORF8b or VACV K3L in an F-T2A configuration. HEK293T/17 and HeLa cells were transfected with saRNA (100 ng) containing luciferase as a reporter protein and assessed for protein expression after 24 hr. HeLa cells are known to have more intact IFN expression pathways compared to HEK293T/17 and therefore increased expression (fold increase) relative to a control (saRNA containing luciferase as reporter protein and no IIP) indicates that the IIP is increasing saRNA expression. Of these IIP, HSV ICP34.5 produced the greatest increase in f-Luc expression. Data shown are constructs providing a greater than −2-fold increase in luciferase expression in HeLa cells relative to expression in HEK293T/17 cells and are mean f SEM of data obtained in 3 independent experiments using 3 separate batches of saRNA.

Referring to FIG. 7, there is shown f-Luc expression in HeLa cells following transfection with VEEV replicons containing KHSV ORF52, EBOV VP35, SARS ORF3b* 57 variant, SARS ORF3b*79 variant, SARS ORF3b*57 Equador variant or Pangolin ORF3b* 57 in an F-T2A configuration relative to expression in HEK293T/17 cells. Details of experimental methods are provided in FIG. 6. Of these EBOV VP35 and SARS ORF3b*79 variant produced the greatest increase in f-Luc expression. Data shown are constructs providing a greater than 2-fold increase in luciferase expression in HeLa cells relative to expression in HEK293T/17 cells and are mean f SEM of data obtained in 3 independent experiments using 3 separate batches of saRNA.

Referring to FIG. 8, there is shown f-Luc expression in HeLa cells following transfection with selected VEEV replicons containing IIP in F-T2A configuration relative to expression in HEK293T/17 cells. Details of experimental methods are provided in FIG. 6. PIV V5 and MERS ORF4a produced the greatest increase inf-Luc expression. Data shown are constructs providing a greater than 2-fold increase in luciferase expression in HeLa cells relative to expression in HEK293T/17 cells and are mean f SEM of data obtained in 3 independent experiments using 3 separate batches of saRNA.

Referring to FIG. 9, there is shown f-Luc expression in HeLa cells following transfection with VEEV replicons containing IIP in a double sub-genomic promoter (DSGP) configuration relative to expression in HEK293T/17 cells. Details of experimental methods are provided in FIG. 6. HCV E2, VACV E3L and PIV 5V produced similar increases in f-Luc expression. Data shown are constructs providing a greater than 2-fold increase in luciferase expression in HeLa cells relative to expression in HEK293T/17 cells and are mean f SEM of data obtained in 3 independent experiments using 3 separate batches of saRNA.

Referring to FIG. 10, there is shown the increase in VEGF-A secretion from HeLa cells following transfection with saRNA containing the IIP HSV ICP34.5 in a F-T2A configuration compared to saRNA without IIP and relative to expression in HEK293T/17 cells. HEK293T/17 and HeLa cells were transfected with RNA (100 ng) containing VEGF-A as a reporter protein and assessed for protein expression and secretion into the culture media after 48 hr by ELISA. HeLa cells are known to have more intact IFN expression pathways compared to HEK293T/17 and therefore increased expression relative to a control (RNA containing VEGF-A as GOI and no IIP) indicates that HSV ICP34.5 increases saRNA GOI expression. Data are from one experiment and represent the mean f SEM of three replicate measurements.

Referring to FIG. 11, there is shown f-Luc expression in HeLa cells following transfection with saRNA containing f-Luc as the GOI (construct 1) and with the IIP MERS ORF4a in F-T2A configuration (constructs 2a and 2b), IRES configuration (construct 3b) and DSGP configurations (constructs 4a and 4b) shown in FIG. 1. Details of experimental methods are provided in FIG. 6. Data are mean±SEM of data obtained in 3 independent experiments using 3 separate batches of saRNA. P<0.05 repeated measures ANOVA compared to construct with no IIP.

Example 3—Construction and Testing RNA Constructs Comprising a Viral Innate Inhibitor Protein (IIP)

The inventors designed, constructed and then tested a series of diverse viral IIPs, and the results of the expression studies are shown in FIG. 12.

Referring to FIG. 12, there is shown n-Luc expression in HeLa cells following transfection with RNA containing IIP in F-T2A configuration relative to expression in HEK293T/17 cells. Details of experimental methods are provided in FIG. 6. Data shown are constructs providing a greater than 2-fold increase in luciferase expression and are mean±SEM of data obtained in 3 independent experiments using 3 separate batches of RNA.

CONCLUSIONS

The inventors believe that the constructs described herein display many advantages over those described in the prior art, including:

- i) insertion of nucleotide sequences encoding any of the innate modulatory proteins directly into the RNA construct, such as mRNA or saRNA, enabling dual protein expression of the IIP protein and the biotherapeutic molecule encoded by the gene of interest;
- ii) as opposed to delivering two different and separate strands of RNA, one encoding the gene of interest (GOI), i.e. the therapeutic biomolecule, and one encoding the IIP, a single strand is required to be delivered;
- iii) the IIP inhibits innate sensing of RNA, thus enabling higher protein expression;
- iv) when the RNA construct is a saRNA, the IIP expression itself is self-amplified by virtue of being co-expressed on the sub-genome strand with the GOI; and/or
- v) an increase in both the magnitude and duration of protein expression compared to conventional VEEV RNA replicon constructs.

Numbered Paragraphs

The following paragraphs form part of the description and not the claims

- 1. An RNA construct encoding: (i) at least one therapeutic biomolecule; and (ii) at least one viral innate inhibitor protein (IIP).
- 2. The RNA construct according to paragraph 1, wherein the construct is an mRNA, saRNA or a trans-replicon system, most preferably saRNA.
- 3. The RNA construct according to either paragraph 1 or paragraph 2, wherein the construct comprises or is derived from a positive stranded RNA virus selected from the group of genus consisting of: alphavirus; picornavirus; flavivirus; rubivirus; pestivirus; hepacivirus; calicivirus and coronavirus, preferably an alphavirus, optionally VEEV.
- 4. The RNA construct according to any preceding paragraph, wherein the at least one innate inhibitor protein (IIP) is HPV E6 or HSV ICP34.5, or an orthologue thereof.
- 5. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is HCV E2 or HCV NS5a, or an orthologue thereof.
- 6. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is VACV E3L or VACV K3L, or an orthologue thereof.
- 7. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is MERS ORF8B, or an orthologue thereof.
- 8. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is KSHV ORF52, or an orthologue thereof.
- 9. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is Ebola VP35, or an orthologue thereof.
- 10. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is Vaccinia C6, or an orthologue thereof.
- 11. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is an ORF3b*57 variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof.
- 12. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is an ORF3b*79 variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof.
- 13. The RNA construct according to any one of paragraphs 1-3, wherein the at least one innate inhibitor protein (IIP) is an ORF3b*57 Ecuador variant of the wild type of SARS-CoV-2 ORF3b, or an orthologue thereof.
- 14. The RNA construct according to any preceding paragraph, wherein the therapeutic biomolecule comprises a therapeutic protein, preferably the protein or peptide is an antigen, and more preferably a viral antigen.
- 15. A nucleic acid sequence encoding the RNA construct according to any preceding paragraph.
- 16. An expression cassette comprising a nucleic acid sequence according to paragraph 15.
- 17 A recombinant vector comprising the expression cassette according to paragraph 16.
- 18. A pharmaceutical composition comprising the RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16 or the vector according to paragraph 17, and a pharmaceutically acceptable vehicle.
- 19. A method of preparing the RNA construct according to any one of paragraphs 1 to 14, the method comprising:
  - a) i) introducing, into a host cell, the vector according to paragraph 17; and
  - ii) culturing the host cell under conditions to result in the production of the RNA construct according to any one of paragraphs 1 to 14; or
  - b) transcribing the RNA construct from the vector according to paragraph 17.
- 20. The RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16 or the vector according to paragraph 17 or the pharmaceutical composition according to paragraph 18, for use as a medicament or in therapy.
- 21. The RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16 or the vector according to paragraph 17 or the pharmaceutical composition according to paragraph 18, for use in the prevention, amelioration or treatment of a protozoan, fungal, bacterial or viral infection.
- 22. The RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16, the vector according to paragraph 17 or the pharmaceutical composition according to paragraph 18, for use in the prevention, amelioration or treatment of cancer.
- 23. A vaccine comprising the RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16, the vector according to paragraph 17 or the pharmaceutical composition according to paragraph 18.
- 24. The RNA construct according to any one of paragraphs 1 to 14, the nucleic acid sequence according to paragraph 15, the expression cassette according to paragraph 16, the vector according to paragraph 17 or the pharmaceutical composition according to paragraph 18, for use in stimulating an immune response in a subject.

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