CORONAVIRUS VACCINES AND METHODS OF USE

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Sep. 22, 2021, is named 50401_751_501_SL.txt and is 5,119,813 bytes in size.

BACKGROUND

Newly emerging acute respiratory virus infections caused by novel coronavirus is a significant public health concern. Importantly, there are no vaccines or specific antivirals at the time of an outbreak, specifically, for example the MERS-CoV of 2015, or 2019 SARS CoV-2 infections. The 2019 SARS CoV-2 infection outbreak in December of 2019 claimed more than 2000 lives in less than 2 months from the first reported case. Accordingly, novel and easily scalable therapeutics are necessary to combat a disease caused by such a viral infection.

SUMMARY

Patients who are immunocompromised because of autoimmunity, organ transplant or immunosuppressive treatment have reduced ability to produce antibody responses to vaccinations (Rousseau et al., A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study. Ann Oncol. 2012 February; 23(2):450-7). Seropositivity after vaccination is decreased in immunocompromised patients (Haidar et al., Immunogenicity of COVID-19 Vaccination in Immunocompromised Patients: An Observational, Prospective Cohort Study Interim Analysis. medRxiv 2021.06.28.21259576). While immunocompromised patients were excluded from the original clinical trials testing current SARS-CoV-2 vaccines targeting spike protein, follow-up analysis of immunocompromised patients have shown reduced capacity for patients to mount broad and durable anti-spike antibody responses, particularly in older patient cohorts (Boyarsky, et al., Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA. 2021; 325(17):1784-1786; Rincon-Arevalo, et al., Impaired antigen-specific memory B cell and plasma cell responses including lack of specific IgG upon SARS-CoV-2 BNT162b2 vaccination among Kidney Transplant and Dialysis patients. medRxiv 2021.04.15.21255550). Thus, induction of T cell responses to other SARS-CoV-2 viral proteins may be beneficial to enhance both cellular and humoral immunity. Thus, there is a need for a SARS-CoV-2 vaccine that specifically targets T cell responses. Patients undergoing anti-CD20 treatment were shown to be able to develop functional T cells with vaccination (Apostolidis et al., Altered cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. medRxiv 2021.06.23.21259389), indicating that patients with impaired B cells may still develop SARS-COV 2-specific T cells in response to vaccination.

Provided herein is a SARS-CoV-2 immunogenic composition (e.g., a vaccine) that specifically targets T cell responses, including CD4+ T cell responses and/or CD8+ T cell responses, and/or leverages long term persistence of T cell immunity. In some embodiments, a SARS-CoV-2 vaccine provided herein can specifically target one or more T cell responses to a polypeptide antigen of SARS-CoV-2, including, e.g., nucleocapsid, membrane protein and/or envelope protein of SARS-CoV-2. SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be useful for eliciting one or more T cell responses to SARS-CoV-2 in all patients. Protection from COVID19 has been observed in patients deficient in humoral immunity when T cell responses were present (Bange, et al., CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer. Nat Med 27, 1280-1289 (2021)) and the longevity of T cell responses from related infections from the original SARS-CoV epidemic (Le Bert et al., SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457-462 (2020)). In some embodiments, the present disclosure, among other things, provides a particular insight that SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be particularly useful for eliciting one or more T cell responses to SARS-CoV-2 in patients that have been immunocompromised in their humoral immunity, such as, for example, in some embodiments through cancer (e.g., B cell lymphoma), treatment with rituximab, methotrexate or other immunosuppressive treatment targeting the humoral immune response, or patients undergoing organ transplant. In some embodiments, T cell responses induced by SARS-CoV-2 immunogenic compositions (e.g., a vaccines) described herein can protect patients from severe COVID-19 and provide long lasting protection through T cell immunity to the SARS-CoV-2 immunogenic composition (e.g., a vaccine) provided herein. Additionally or alternatively, in some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to overcome SARS-CoV-2 variants that could reduce efficacy of other vaccines, such as those that do not target T cell responses (Davis et al., Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination. medRxiv 2021.06.23.21259327. (2021); Tada et al., Comparison of Neutralizing Antibody Titers Elicited by mRNA and Adenoviral Vector Vaccine against SARS-CoV-2 Variants. bioRxiv 2021.07.19.452771). In some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to complement and/or enhance other immunogenic compositions (e.g., a vaccines), such as those that do not target T cell responses. For example, in some embodiments, SARS-CoV-2 immunogenic compositions (e.g., a vaccines) provided herein can be used to enhance B cell responses through increased CD4+ T cell activation.

Coronaviruses are single positive stranded RNA viruses that have emerged occasionally from zoonotic sources to infect human populations. Most of the infections in humans cause mild respiratory symptoms, though some recent coronavirus infections in the last decade have resulted in severe morbidity and mortality. These include the severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and the currently ongoing pandemic of SARS-CoV-2. Infection with these viruses can lead to acute respiratory distress resulting in a high mortality rate. SARS-CoV originated in 2002 in South China and its global spread led to 8096 cases and 774 deaths. The first case of MERS-CoV emerged in 2012 in Saudi Arabia and since then a total of 2494 cases and 858 associated deaths have been reported. 2019 SARS CoV-2 emerged in Wuhan, China at the end of December 2019 and by Mar. 8, 2020 had resulted in 118,096 cases including 4262 deaths globally. The rapid spread of 2019 SARS-CoV-2 resulted in the World Health Organization declaring a global pandemic of international concern.

All three coronaviruses SARS-CoV, MERS-CoV and the recently emergent SARS CoV-2 belong to the genus beta coronaviridae. SARS CoV-2 has a genome size of 30 kilobases that encodes for at least four (4) structural (spike [S], envelope [E], membrane [M], and nucleocapsid [N]) and at least fifteen (15) non-structural (NSP 1-15) proteins. S protein facilitates viral entry into target cells and entry depends on binding of the spike protein to a cellular receptor ACE2 for both SARS-CoV and SARS-CoV-2. Both viruses share a 76% amino acid identity across the genome.

The field of the present invention relates to immunotherapeutic peptides, nucleic acids encoding the peptides, peptide binding agents, and their use, for example, in the immunotherapy of a viral disease. In one aspect, the invention provides viral epitopes expressed in virus infected cells, useful alone or in combination with other anti-viral, or immunomodulatory agents to treat viral infection. The present invention is useful in immunotherapy for a coronavirus infection.

Provided herein is a composition comprising: (i) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (ii) a polynucleotide encoding a polypeptide, wherein the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to an epitope sequence of the polypeptide in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to an epitope sequence of the polypeptide; and a pharmaceutically acceptable excipient.

In some embodiments, the sequence comprising an epitope sequence from ORF1ab is C-terminal to the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

In some embodiments, the sequence comprising an epitope sequence from ORF1ab is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is N-terminal to the sequence comprising an epitope sequence from membrane glycoprotein (M).

In some embodiments, the polypeptide comprises (a) 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more epitope sequences from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

In some embodiments, the epitope sequence from ORF1ab is an epitope sequence from a non-structural protein (NSP).

In some embodiments, the non-structural protein (NSP) is selected from the group consisting of NSP1, NSP2, NSP3, NSP4 and combinations thereof.

In some embodiments, the polypeptide comprises a sequence comprising an epitope sequence from NSP1, a sequence comprising an epitope sequence from NSP2, a sequence comprising an epitope sequence from NSP3 and a sequence comprising an epitope sequence from NSP4.

In some embodiments, the epitope sequence from ORF1ab is selected from the group consisting of YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK and any combination thereof.

In some embodiments, the epitope sequence from nucleocapsid glycoprotein (N) is LLLDRLNQL.

In some embodiments, the epitope sequence from membrane phosphoprotein (M) is VATSRTLSY.

In some embodiments, the polypeptide comprises an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL and an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

In some embodiments, the polypeptide comprises (a) each of the following epitope sequences from ORF1ab: YLFDESGEFKL, YLFDESGEF, FGDDTVIEV, QLMCQPILL, TTDPSFLGRY, PTDNYITTY, PSFLGRY, AEAELAKNV, KTIQPRVEK; (b) an epitope sequence from nucleocapsid glycoprotein (N) that is LLLDRLNQL; and (c) an epitope sequence from membrane phosphoprotein (M) that is VATSRTLSY.

In some embodiments, the sequence comprising an epitope sequence from ORF1ab is selected from the group consisting of the following sequences or fragments thereof: MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEYYIFFASFY Y; MVTNNTFTLKVPHVGEIPVAYRKVLLKTIQPRVEKYLFDESGEFKLSEVGPEHSLAEY; APKEIIFLEGETLFGDDTVIEVAIILASFSAST; APKEIIFLEGETLFGDDTVIEV; HTTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWN L; TTDPSFLGRYMSALFADDLNQLTGYHTDFSSEIIGYQLMCQPILLAEAELAKNVSLILGTVSWNL; LLSAGIFGAITDVFYKENSYKVPTDNYITTY; and combinations thereof.

In some embodiments, the sequence comprising an epitope sequence from membrane glycoprotein (M) is selected from the group consisting of the following sequences or fragments thereof: ADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLACFVL AAVYRINWITGGIAIAMACLVGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRPL LESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSYYKLGASQRVAGDSGFAAYSR YRIGNYKLNTDHSSSSDNIALLVQ; FAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLVGLMWLSYFIASFR LF; LGRCDIKDLPKEITVATSRTLSYYKLGASQRVA; KLLEQWNLVIGF; NRNRFLYIIKLIFLWLLWPVTLACFVLAAVY; SELVIGAVILRGHLRIAGHHLGR; VATSRTLSYYKLGASQRV; GLMWLSYF; and combinations thereof.

In some embodiments, the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N) is selected from the group consisting of the following sequences or fragments thereof: KDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGT TLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQL ESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELI RQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKH IDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA; RMAGNGGDAALALLLLDRLNQLESKMSGKGQQQ; YKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYK TFP; SPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKA YNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWL TYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDK and combinations thereof.

In some embodiments, the polypeptide comprises one or more linker sequences.

In some embodiments, the one or more linker sequences are selected from the group consisting of GGSGGGGSGG, GGSLGGGGSG.

In some embodiments, the one or more linker sequences comprise cleavage sequences.

In some embodiments, the one or more cleavage sequences are selected from the group consisting of FRAC, KRCF, KKRY, ARMA, RRSG, MRAC, KMCG, ARCA, KKQG, YRSY, SFMN, FKAA, KRNG, YNSF, KKNG, RRRG, KRYS, and ARYA.

In some embodiments, the polypeptide comprises a transmembrane domain sequence.

In some embodiments, the transmembrane domain sequence is C-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

In some embodiments, the transmembrane domain sequence is EQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL HYT.

In some embodiments, the polypeptide comprises an SEC sequence.

In some embodiments, the SEC sequence is N-terminal to the sequence comprising an epitope sequence from ORF1ab, the sequence comprising an epitope sequence from membrane glycoprotein (M) and the sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N).

In some embodiments, the SEC sequence is MFVFLVLLPLVSSQCVNLT.

In some embodiments, the composition comprises the polynucleotide encoding the polypeptide.

In some embodiments, the polynucleotide is an mRNA.

In some embodiments, the polynucleotide comprises a codon optimized sequence for expression in a human.

In some embodiments, the polynucleotide comprises a dEarI-hAg sequence.

In some embodiments, the dEarI-hAg sequence is ATTCTTCTGGTCCCCACAGACTCAGAGAGAACCC, optionally wherein each T is a U.

In some embodiments, the polynucleotide comprises a Kozak sequence.

In some embodiments, the a Kozak sequences is GCCACC.

In some embodiments, the polynucleotide comprises an F element sequence.

In some embodiments, the F element sequence is a 3 UTR of amino-terminal enhancer of split (AES).

In some embodiments, the F element sequence is CTGGTACTGCATGCACGCAATGCTAGCTGCCCCTTTCCCGTCCTGGGTACCCCGAGTCTCCC CCGACCTCGGGTCCCAGGTATGCTCCCACCTCCACCTGCCCCACTCACCACCTCTGCTAGTTC CAGACACCTCC, optionally wherein each T is a U.

In some embodiments, the polynucleotide comprises an I element sequence.

In some embodiments, the I element sequence is a 3′ UTR of mitochondrially encoded 12S rRNA (mtRNR1).

In some embodiments, the I element sequence is CAAGCACGCAGCAATGCAGCTCAAAACGCTTAGCCTAGCCACACCCCCACGGGAAACAGCA GTGATTAACCTTTAGCAATAAACGAAAGTTTAACTAAGCTATACTAACCCCAGGGTTGGTCA ATTTCGTGCCAGCCACACC, optionally wherein each T is a U.

In some embodiments, the polynucleotide comprises a poly A sequence.

In some embodiments, the poly A sequence is AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGCATATGACTAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA, optionally wherein each T is a U.

In some embodiments, each of the epitope sequences from the ORF1ab, the membrane glycoprotein, and the nucleocapsid phosphoprotein are from 2019 SARS-CoV-2.

In some embodiments, one or more or each epitope elicits a T cell response.

In some embodiments, one or more or each epitope has been observed by mass spectrometry as being presented by an HLA molecule.

In some embodiments, the composition comprises (i) a polypeptide with at least 70%, 80%, 90% or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C8p1, RS C8p2 and RS C8p2full; (ii) a polynucleotide encoding a polypeptide with at least 70%, 80%, 90% or 100% sequence identity to a sequence selected from the group consisting of RS C1p1full, RS C2p1full, RS C3p1full, RS C4p1full, RS C5p1, RS C5p2, RS C5p2full, RS C6p1, RS C6p2, RS C6p2full, RS C7p1, RS C7p2, RS C7p2full, RS C8p1, RS C8p2 and RS C8p2full; or (iii) a polynucleotide with at least 70%, 80%, 90% or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS C6n1, RS C7n1, RS C8n1, RS C5n2, RS C6n2, RS C7n2, RS C8n2, RS C5n2full, RS C6n2full, RS C7n2full and RS C8n2full.

Provided herein is a pharmaceutical composition comprising a composition disclosed herein.

Provided herein is a pharmaceutical composition comprising: a polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and/or Table 16; (ii) a polynucleotide encoding the polypeptide comprising an epitope sequence of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and/or Table 16; (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to the epitope sequence in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to the epitope sequence; and a pharmaceutically acceptable excipient.

In some embodiments, the epitope sequence comprises one or more or each of the following: SAPPAQYEL, AVASKILGL, EYADVFHLY, DEFTPFDVV, VRIQPGQTF, SFRLFARTR, KFLPFQQF, VVQEGVLTA, RLDKVEAEV, FGADPIHSL, NYNYLYRLF, KYIKWPWYI, KWPWYIWLGF, LPFNDGVYF, QPTESIVRF, IPFAMQMAY, YLQPRTFLL and RLQSLQTYV.

In some embodiments, the epitope sequence is from an orf1ab protein.

In some embodiments, the epitope sequence is from an orf1a protein

In some embodiments, the epitope sequence is from a surface glycoprotein (S) or a shifted reading frame thereof.

In some embodiments, the epitope sequence is from a nucleocapsid phosphoprotein (N).

In some embodiments, the epitope sequence is from an ORF3a protein.

In some embodiments, the epitope sequence is from a membrane glycoprotein (M).

In some embodiments, the epitope sequence is from an ORF7a protein.

In some embodiments, the epitope sequence is from an ORF8 protein.

In some embodiments, the epitope sequence is from an envelope protein (E).

In some embodiments, the epitope sequence is from an ORF6 protein.

In some embodiments, the epitope sequence is from an ORF7b protein.

In some embodiments, the epitope sequence is from an ORF10 protein.

In some embodiments, the epitope sequence is from an ORF9b protein.

Provided herein is a pharmaceutical composition comprising: a polypeptide having an amino acid sequence with at least 70%, 80%, 90% or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15; or a recombinant polynucleotide encoding a polypeptide having an amino acid sequence with at least 70%, 80%, 90% or 100% sequence identity to a sequence of any one of the sequences depicted in column 2 of Table 11, column 2 of Table 12 or column 3 of Table 15.

In some embodiments, the pharmaceutical composition comprises a polynucleotide with at least 70%, 80%, 90% or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: RS C1n1, RS C2n1, RS C3n1, RS C4n1, RS C5n1, RS C6n1, RS C7n1, RS C8n1, RS C5n2, RS C6n2, RS C7n2, RS C8n2, RS C5n2full, RS C6n2full, RS C7n2full and RS C8n2full.

In some embodiments, the polynucleotide is an mRNA.

In some embodiments, the pharmaceutical composition further comprises one or more lipid components.

In some embodiments, the one or more lipids comprise a lipid nanoparticle (LNP).

In some embodiments, the LNP encapsulates the recombinant polynucleotide construct.

In some embodiments, the polypeptide is synthetic.

In some embodiments, the polypeptide is recombinant.

In some embodiments, the polypeptide is from 8-1000 amino acids in length.

In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 1000 nM or less.

In some embodiments, the epitope sequence binds to or is predicted to bind to an HLA class I or class II molecule with a KD of 500 nM or less.

In some embodiments, the epitope sequence comprises a sequence of a viral protein expressed by a virus-infected cell of a subject.

In some embodiments, the virus is 2019 SARS-CoV-2.

In some embodiments, the virus is a coronavirus.

In some embodiments, the virus is 2019 SARS-CoV-2.

In some embodiments, an HLA molecule expressed by the subject is unknown at the time of administration.

In some embodiments, the ability of the virus to avoid escape of recognition by an immune system of the subject is less compared to the ability of the virus to avoid escape of recognition by an immune system of a subject administered a pharmaceutical composition containing an epitope from a single protein or epitopes from fewer proteins than in a pharmaceutical composition disclosed herein.

In some embodiments, the subject expresses an HLA molecule encoded by an HLA allele of any one of Table 1A, Table 1B, Table 1C, Table 2Ai, Table 2Aii, Table 2B and Table 16 and the epitope sequence is an HLA allele-matched epitope sequence.

Provided herein is a method of treating or preventing a 2019 SARS-CoV-2 infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.

In some embodiments, the pharmaceutical composition is administered in addition to one or more therapeutics for the 2019 SARS-CoV-2 viral infection in the subject.

In some embodiments, the pharmaceutical composition is administered in combination with (a) a polypeptide having an amino acid sequence of a 2019 SARS-CoV-2 spike protein or fragment thereof; (b) a recombinant polynucleotide encoding a 2019 SARS-CoV-2 spike protein or fragment thereof; or a 2019 SARS-CoV-2 spike protein pharmaceutical composition comprising (a) or (b).

In some embodiments, the 2019 SARS-CoV-2 spike protein or fragment thereof is a SARS-CoV-2 spike protein or a fragment thereof.

In some embodiments, the pharmaceutical composition is administered 1-10 weeks after a first administration of the 2019 SARS-CoV-2 spike protein pharmaceutical composition.

In some embodiments, the pharmaceutical composition is administered 1-6 weeks, 1-6 months or 1-2 years or later after a first administration of the 2019 SARS-CoV-2 spike protein pharmaceutical composition.

In some embodiments, the pharmaceutical composition is administered on the same day or simultaneously with an administration of the 2019 SARS-CoV-2 spike protein pharmaceutical composition.

In some embodiments, the pharmaceutical composition is co-formulated with the polypeptide having an amino acid sequence of a 2019 SARS-CoV-2 spike protein or fragment thereof or the recombinant polynucleotide encoding a 2019 SARS-CoV-2 spike protein or fragment thereof.

In some embodiments, the pharmaceutical composition is administered before an administration of the 2019 SARS-CoV-2 spike protein pharmaceutical composition, such as 2-10 weeks before an administration of the 2019 SARS-CoV-2 spike protein pharmaceutical composition.

In some embodiments, the pharmaceutical composition is administered prophylactically.

In some embodiments, the pharmaceutical composition is administered once every 1, 2, 3, 4, 5, 6 or more weeks; or once every 1-7, 7-14, 14-21, 21-28, or 28-35 days; or once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.

Use of a composition described herein for preparing a therapeutic for treating or preventing a respiratory viral infection caused by 2019 SARS CoV-2 virus.

Use of a composition described herein or a pharmaceutical composition described herein for use as a medicament.

Provided herein is a composition or a pharmaceutical composition disclosed herein for use in the treatment or prevention of a respiratory viral infection caused by 2019 SARS CoV-2 virus.

Provided herein is a method of treating or preventing an infection by a virus or treating a respiratory disease or condition associated with an infection by a virus comprising administering to a subject in need thereof a pharmaceutical composition comprising: (i) a polypeptide comprising at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (ii) a polynucleotide encoding a polypeptide, wherein the polypeptide comprises at least two of the following (a) a sequence comprising an epitope sequence from ORF1ab, (b) a sequence comprising an epitope sequence from membrane glycoprotein (M) and (c) a sequence comprising an epitope sequence from nucleocapsid phosphoprotein (N); (iii) a T cell receptor (TCR) or a T cell comprising the TCR, wherein the TCR binds to an epitope sequence of the polypeptide in complex with a corresponding HLA class I or class II molecule; (iv) an antigen presenting cell comprising (i) or (ii); or (v) an antibody or B cell comprising the antibody, wherein the antibody binds to an epitope sequence of the polypeptide.

In some embodiments, the subject has an immunodeficiency.

In some embodiments, the subject has a B cell immunodeficiency.

In some embodiments, the subject has a reduced ability to produce an antibody response to an antigen compared to a subject without an immunodeficiency.

In some embodiments, the subject has a reduced ability to produce an antibody response to a vaccination compared to a subject without an immunodeficiency.

In some embodiments, the subject has a reduced ability to produce an anti-spike protein antibody response and/or an anti-RBD antibody response compared to a subject without an immunodeficiency.

In some embodiments, the subject can produce a T cell response or does not have a reduced ability to produce a T cell response compared to a subject without an immunodeficiency.

In some embodiments, the pharmaceutical composition is protective against a variant of 2019 SARS CoV-2.

In some embodiments, the variant of 2019 SARS CoV-2 is alpha, beta, gamma, delta, epsilon, zeta, eta, theta, iota, kappa or lambda.

In some embodiments, the subject produces a T cell response to an epitope of the polypeptide.

In some embodiments, the subject produces a T cell response to the epitope sequence from ORF1ab, the epitope sequence from membrane glycoprotein (M) and/or the epitope sequence from nucleocapsid phosphoprotein (N).

In some embodiments, the subject is an organ transplant recipient.

In some embodiments, the organ transplant recipient is a sold organ transplant recipient, a stem cell transplant recipient or a bone marrow transplant recipient.

In some embodiments, the subject received an organ transplant less than 1 year, less than 6 months or less than 3 months after the pharmaceutical composition is administered.

In some embodiments, the subject is expected to receive an organ transplant less than 1 year, less than 6 months or less than 3 months prior to the pharmaceutical composition being administered.

In some embodiments, the subject has a cancer.

In some embodiments, the cancer is a B cell cancer.

In some embodiments, the B cell cancer is a B cell lymphoma or a B cell leukemia.

In some embodiments, the subject has an autoimmune disease or condition.

In some embodiments, the autoimmune disease or condition is Addison disease, Anti-NMDA receptor encephalitis, antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders, Celiac disease—sprue, chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, chronic lymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis, Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediated autoimmune diseases, IgG4-related disease, Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus erythematosus, Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, Type I diabetes, Ulcerative colitis, Vasculitis and Vitiligo.

In some embodiments, the subject has congenital agammaglobulinemia or congenital IgA deficiency.

In some embodiments, the subject has HIV or AIDS.

In some embodiments, the subject is receiving an immunosuppressive agent or has received an immunosuppressive agent less than 1 year, less than 6 months or less than 3 months prior to the administering of the pharmaceutical composition.

In some embodiments, the immunosuppressive agent is abatacept, abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan, aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides, anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine, betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, bortezomib, brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab, cetuximab, chidamide, chlorambucil, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine, daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate, doxorubicin, doxorubicin, durvalumab, duvelisib, duvortuxizumab, eculizumab, efalizumab, eftilagimod alpha, a neuropeptide combination of metenkefalin and tridecactide, elezanumab, elotuzumab, encorafenib, enfuvirtida, entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod, firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab, guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, 1d-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole, levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib, lumiliximab, maraviroc, masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil, mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim, peginterferon beta-1a, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide, ravulizimab-cwvz, recombinant il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir, rituximab, ruxolitinib, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod, sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus, talabostat mesylate, talacotuzumab, tanespimycin, tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole, vorinostat, vosaroxin, ziv-aflibercept or any combination thereof.

In some embodiments, the immunosuppressive agent is A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CDid ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

In some embodiments, the subject is greater than 55, 56, 57, 58, 59, 60, 65, 70, 75 or 80 years of age; or wherein the subject is less than 35, 30, 25, 20, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years of age.