CHIMERIC ADENOVIRAL VECTORS

BACKGROUND OF THE DISCLOSURE

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Some symptoms of the disease include, for example, fever, cough, shortness of breath, muscle pain, sputum production, diarrhea, sore throat, loss of smell, and abdominal pain. While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure. The disease currently has no cure and has spread rapidly across several continents, with community outbreaks throughout the world.

SUMMARY OF THE DISCLOSURE

In one aspect, the disclosure provides a chimeric adenoviral expression vector, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist.

In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a nucleic acid encoding a dsRNA. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOS:13-20. In particular embodiments, the nucleic acid encoding the TLR-3 agonist comprises a sequence of SEQ ID NO:13.

Further, the chimeric adenoviral expression vector can comprise additional element (c): a third promoter operably linked to a nucleic acid encoding a second SARS-CoV-2 protein. In some embodiments, element (c) is placed between elements (a) and (b) in the expression cassette. In certain embodiments, the first SARS-CoV-2 protein in (a) and the second SARS-CoV-2 protein in (c) are different. In other embodiments, the SARS-CoV-2 protein in (a) and the SARS-CoV-2 protein in (c) are the same.

In some embodiments of this aspect, the nucleic acid encoding the first SARS-CoV-2 protein in element (a) and/or the nucleic acid encoding the second SARS-CoV-2 protein in element (c) comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:3. In some embodiments, the first and/or second SARS-CoV-2 protein comprises a SARS-CoV-2 S protein having a sequence with at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:1 or SEQ ID NO:21 or SEQ ID NO:22. In some embodiments, the nucleic acid encoding the first SARS-CoV-2 protein in element (a) and/or the nucleic acid encoding the second SARS-CoV-2 protein in element (c) comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:23.

In some embodiments, the nucleic acid encoding the first SARS-CoV-2 protein in element (a) and/or the nucleic acid encoding the second SARS-CoV-2 protein in element (c) comprises a sequence having at least 85%, 90%, 95%, 97%, 99/o, or 100% identity to the sequence of SEQ ID NO:4. In some embodiments, the first and/or the second SARS-CoV-2 protein comprises a SARS-CoV-2 N protein having a sequence with at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:2.

In some embodiments of this aspect, the nucleic acid encoding the first SARS-CoV-2 protein in element (a) and/or the nucleic acid encoding the second SARS-CoV-2 protein in element (c) comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:5. In some embodiments, the first and/or second SARS-CoV-2 protein comprises a fusion protein comprising a S1 region of a SARS-CoV-2 S protein, a furin site, and a SARS-CoV-2 N protein, and wherein the fusion protein comprises a sequence having at least 85% identity to the sequence of SEQ ID NO:12.

Moreover, the first promoter and the second promoter in the chimeric adenoviral vector can be identical or different. For example, the first promoter and the second promoter each can be a CMV promoter.

In some embodiments of the aspect, when all three elements (a)-(c) are present, the first promoter can be a CMV promoter, the second promoter can be a CMV promoter, and the third promoter can be a beta-actin promoter (e.g., a human beta-actin promoter).

In some embodiments of this aspect, the nucleic acid encoding the SARS-CoV-2 S protein comprises the sequence of SEQ ID NO:3. In some embodiments, the SARS-CoV-2 S protein comprises the sequence of SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22.

In some embodiments, the first promoter and the second promoter are each a CMV promoter.

In some embodiments of this aspect, the elements (a) and (b) together are encoded by the sequence of SEQ ID NO:6. Further, the chimeric adenoviral expression vector of this aspect is encoded by the sequence of SEQ ID NO:9.

In another aspect, the disclosure features a chimeric adenoviral expression vector, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 S protein; (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist; and (c) a third promoter operably linked to a nucleic acid encoding a SARS-CoV-2 N protein, optionally in which the order of the elements in the expression cassette from the N-terminus to the C-terminus is: element (a), element (c), and element (b).

In some embodiments of this aspect, the nucleic acid encoding the SARS-CoV-2 S protein comprises the sequence of SEQ ID NO:3. In some embodiments of this aspect, the nucleic acid encoding the SARS-CoV-2 S protein comprises the sequence of SEQ ID NO:23. In some embodiments, the SARS-CoV-2 S protein comprises the sequence of SEQ ID NO:1 or SEQ ID NO:21 or SEQ ID NO:22.

In some embodiments of this aspect, the nucleic acid encoding the SARS-CoV-2 N protein comprises the sequence of SEQ ID NO:4. In some embodiments, the SARS-CoV-2 N protein comprises the sequence of SEQ ID NO:2.

Further, in some embodiments of this aspect, the first promoter in element (a) is a CMV promoter, the second promoter in element (b) is a CMV promoter, and the third promoter in element (c) is a beta-actin promoter (e.g., a human beta-actin promoter).

In some embodiments, the elements (a), (b), and (c) together are encoded by the sequence of SEQ ID NO:7. Further, the chimeric adenoviral expression vector of this aspect is encoded by the sequence of SEQ ID NO:10.

In another aspect, the disclosure features a chimeric adenoviral expression vector, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a SARS-CoV-2 fusion protein, wherein the SARS-CoV-2 fusion protein comprises a S1 region of a SARS-CoV-2 S protein, a furin site, and a SARS-CoV-2 N protein; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist.

In some embodiments of this aspect, the nucleic acid encoding the SARS-CoV-2 fusion protein comprises the sequence of SEQ ID NO:5. In some embodiments, the SARS-CoV-2 fusion protein comprises the sequence of SEQ ID NO:12.

In some embodiments of this aspect, the first promoter and the second promoter are each a CMV promoter.

In some embodiments of this aspect, the elements (a) and (b) together are encoded by the sequence of SEQ ID NO:8. Further, the chimeric adenoviral expression vector of this aspect is encoded by the sequence of SEQ ID NO:11.

In another aspect, the disclosure features an immunogenic composition comprising a chimeric adenoviral expression vector described herein and a pharmaceutically acceptable carrier.

In a further aspect, the disclosure additionally features a chimeric adenoviral expression vector, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist; and (c) a third promoter operably linked to a nucleic acid encoding a SARS-CoV-2 N protein. In some embodiments, the SARS-CoV-2 N protein comprises an amino acid sequence having at least 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, element (c) is situated between elements (a) and (b) in the expression cassette. In some embodiments, the first SARS-CoV-2 protein comprises a SARS-CoV-2 S protein having a sequence with at least 95%, 96%, 97%, 98%, 99%, or 100/6 identity to the sequence of SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a nucleic acid encoding a dsRNA. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOS:13-20. In some embodiments, the nucleic acid encoding the first SARS-CoV-2 protein in element (a) comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:3. In some embodiments, the nucleic acid encoding the SARS-CoV-2 N protein comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% identity to the sequence of SEQ ID NO:4. In some embodiments, the first promoter and the second promoter are identical. In some embodiments, the first promoter and the second promoter are each a CMV promoter. In some embodiments, the first promoter is a CMV promoter, the second promoter is a CMV promoter, and the third promoter is a beta-actin promoter. In some embodiments, element (c) is situated between elements (a) and (b), and elements (a), (c), and (b) together are encoded by a sequence having at least 95% identity to SEQ ID NO:7 or is encoded by the sequence of SEQ ID NO:7. In some embodiments, the chimeric adenoviral expression vector comprises a sequence having at least 95% identity to SEQ ID NO:10 or comprises the sequence of SEQ ID NO:10.

In another aspect, the disclosure provides a method for eliciting an immune response towards a SARS-CoV-2 protein (e.g., a SARS-CoV-2 protein having the sequence of SEQ ID NOS:1, 2, or 12, or a variant thereof as described herein (e.g., having at least 90% or at least 95% identity to SEQ ID NO:1, 2, or 12) in a subject, comprising administering to the subject an immunogenically effective amount of a chimeric adenoviral expression vector described herein or an immunogenic composition described herein. In some embodiments, the route of administration is oral, intranasal, or mucosal (e.g., oral). In certain embodiments, the route of administration is oral delivery by swallowing a tablet.

In some embodiments of the method, the immune response is elicited in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cells, and/or an airway basal cell of the subject. In certain embodiments, the subject is a human.

Also provided is a chimeric polynucleotide (which can be used to induce an immune response in a subject, including but not limited to a CD8 T-cell response), comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist; and (c) a third promoter operably linked to a nucleic acid encoding a SARS-CoV-2 protein or a non-SARS-CoV-2 antigenic protein.

In some embodiments, the chimeric polynucleotide is a chimeric adenoviral expression vector. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a nucleic acid encoding a dsRNA. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOS:13-20 In some embodiments, element (c) is placed between elements (a) and (b) in the expression cassette.

In a further aspect, the disclosure provides a chimeric polynucleotide, comprising an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding an antigenic protein; (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist; and (c) a third promoter operably linked to a nucleic acid encoding a SARS-CoV-2 N-protein. In some embodiments, the SARS-CoV-2 N protein has at least 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO:2. In some embodiments, the chimeric polynucleotide is a chimeric adenoviral expression vector. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a nucleic acid encoding a dsRNA. In some embodiments, the nucleic acid encoding the TLR-3 agonist comprises a sequence selected from the group consisting of: SEQ ID NOS:13-20. In some embodiments, element (c) is placed between elements (a) and (b) in the expression cassette. In some embodiments, the antigenic protein is from a bacteria, fungus, virus, or parasite. In some embodiments, the antigenic protein is a cancer antigen.

In a further aspect, the disclosure provides a method of inducing an immune response in a subject, the method comprising administering a chimeric polynucleotide as seat forth in the preceding paragraph to a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the expression of the antigens in human cells post infection.

FIG. 2 shows the IgG antibody titers to S1 following immunization of mice on days 0 and 14. Titers measured by standard ELISA.

FIGS. 3A and 3B show the IgG antibody titers to S1 and S2 following immunization of mice on days 0 and 14. MSD was used to measure the binding signal at multiple time points for both antigens. There were no significant differences in the signal at early timepoints, but more antibody responses were detected at the higher dose groups at later time points.

FIG. 4A-4D. Transgene inserts developed to test vaccine specific responses. Recombinant adenoviruses were made using these inserts a. rAd-S b. rAd-S-N c. rAd-S1-N d. rAd-S(fixed)-N.

FIGS. 5A-5D. Immunization with candidate rAd vaccines induce serum IgG and lung IgA responses. Antibody titers to S following immunization of Balb/c mice on days 0 and 14 with 1×108 IU rAd expressing full-length S (rAd-S), co-expressing full length S and N (rAd-S-N) or co-expressing a fusion protein comprising the S1 domain and N (rAd-S1-N). (FIG. 5A) IgG serum IgG endpoint titers to S1 were measured by standard ELISA (n=6 per vaccinated group, n=3 for PBS administered group). Symbols represent mean titers and bars represent the standard error) (FIG. 5B) Neutralizing antibody responses comparing rAd-S-N and rAd-S1-N using two different methods, surrogate VNT (sVNT) and cell-based VNT (cVNT). (FIG. 5C) IgA lung antibody titers to S1 and S2 in immunized mice. Endpoint titers were measured by standard ELISA (n=10 per group). Lines represent the median and inter-quartile range. ** p<0.01, *** p<0.001 defined by Mann-Whitney t-test. FIG. 5D. Neutralizing antibodies measured in the lungs post immunization.

FIGS. 6A-6B. Immunization with rAd co-expressing full length S and N vaccines induce IgG responses in a dose-dependent manner. FIGS. 6A and 6B. Balb/c mice were immunized, IN, on days 0 and 14 with 1×10⁷IU, 1×10⁸IU or 7.2×10⁸IU of rAd co-expressing full length S and N (rAd-S-N). The amount of IgG specific for S1 (FIG. 6A) and S2 in serum diluted 1/4000, was evaluated using a Mesoscale binding assay. Points represent the mean and lines represent the standard deviation.

FIGS. 7A-7C. Immunization with rAd co-expressing full length S and N vaccines induce polyfunctional T cell responses in a dose-dependent manner. (FIG. 7A) Balb/c mice were immunized, IN, on days 0 and 14 with 1×10⁸HU (Ad-S-N high), 1×10′ IU (Ad-S-N low) of rAd-S-N. The frequency of CD4+(top panel) or CD8+ T cells (bottom panel) that produced only IFN-γ, TNF-α, IL-2 or IL-4 after stimulation of spleen cells with 1 μg/ml (CD4+) or 5 μg/ml (CD8+) of the S peptide pools, as determined by ICS-FACS. (B) The frequency of polyfunctional CD4+ (top panel) or CD8+ T cells (bottom panel) that produced more than one cytokine after stimulation of spleen cells with 1 μg/ml (CD4+) or 5 μg/ml (CD8+) S peptide pools, Bars represent the mean and the lines represent the standard error of the mean. (C) IFN-γ T cell responses to S protein 4 weeks following immunization on weeks 0 and 4 with 1×10⁶IU, 1×10⁷IU, 1×10⁸LU doses of rAd-S-N were measured by ELISPOT. Bars represent the mean and the lines represent the standard deviation. * p<0.05; one-way non-parametric ANOVA with multiple comparisons.

FIGS. 8A-8B: Antibodies to S were superior when the S protein expressed in the wild-type configuration compared to the fixed version. Balb/c mice were immunized on weeks 0 and 4 with 1e8 IU per mouse (n=6), and antibody titers were measured. (FIG. 8A) IgG antibody titers over time. (FIG. 8B) Neutralizing antibody responses were measured at week 6. Note that 1:1000 was the maximum dilution performed.

FIGS. 9A-9F: (FIG. 9A) (left) Frequency of CD27++CD38++ plasmablasts in peripheral blood before (day 1) and after (day 8) vaccination as measured by flow cytometry. Bars represent median values, while error bars correspond to 95% confidence intervals. Wilcoxon test was used to compare frequencies before and after vaccination; (right) Representative flow cytometry plot showing pre- and day 8 post-vaccination CD27++ CD38++ plasmablasts for one vaccine; (FIG. 9B) Fold change (day 8/day 1) in plasmablast frequencies. A total of 24/35 subjects (69%) showed a 2-fold or higher increase (with a 3.3 median fold change increase overall); (FIG. 9C) Fold change (day 8/day 1) of IgA- and B7-expressing plasmablasts in low and high dose vaccine cohorts. Mann-Whitney test was used to compare frequencies between the two different dose groups; (FIG. 9D) Fold change (day 8/day 1) in the number of IgA-positive antibody-secreting cells (ASC) reactive against the S1 domain of the Sars-CoV-2 spike antigen; (FIG. 9E) Fold change (day 29/day 1) in S-, N-, or RBD-specific IgA antibodies in the serum as measured by MSD platform. Red dotted lines represent median values. Mann-Whitney test was used to compare frequencies between the two different dose groups; (FIG. 9F) Fold change (day 29/day 1) in S-, N-, or RBD-specific IgA antibodies in nasal and saliva samples as measured by MSD platform.

FIGS. 10A-10F: (FIG. 10A) PBMCs pre- and post-immunization were restimulated with SARS-CoV-2 peptides, surface stained for CD4, CD8 and degranulation marker CD107a and intracellularly stained for cytokines. IFNγ, TNFα, and CD107a percent of CD8 T cells increase over background post immunization in response to SARS-CoV-2 Spike protein; (FIG. 10B) IFNγ, TNFα, and CD107a percent of CD4 T cells increase over background post immunization in response to SARS-CoV-2 Spike protein; (FIG. 10C) Increase in IFNγ-producing CD8 T cells post immunization on day 8 versus day 1: (FIG. 10D) Polarization toward Th1 responses versus Th2 responses in subjects immunized by VXA-CoV2-1. Fold change over baseline is displayed; (FIG. 10E) IFNγ, TNFα, and CD107a percent of CD8 T cells increase over background post immunization in response to SARS-CoV-2 Nucleoprotein; (FIG. 10F) IFNγ, TNFα, and CD107a percent of CD4 T cells increase over background post immunization in response to SARS-CoV-2 Nucleoprotein.

FIG. 11: IFNγ, TNFα, and CD107a percent of CD8 T cells increase over background post immunization in response to S&N peptides from 4 endemic coronaviruses

FIGS. 12A-12D. Oral VXA-CoV-2 elicits anti-viral CD8 T cells of higher magnitude than intramuscular mRNA vaccines. PBMCs pre- and post-immunization were restimulated with SARS-CoV-2 peptides, surface stained for CD4, CD8 and degranulation marker CD107a and intracellularly stained for cytokines. PBMCs from all 3 vaccines were evaluated at the same time. (FIG. 12A) Graph shows IFNγ, TNFα, and CD107a percent of CD8 T cells increase over background post immunization in response to SARS-CoV-2 Spike protein (FIG. 12B) IFNγ data from (FIG. 12A) is plotted alongside vaxart cohort and convalescents. Convalescent subjects are not day 1 subtracted due to no pre-infection samples obtained. (FIG. 12C) Representative facs plots comparing the three vaccines. FIG. 12 (D) Timecourse of Pfizer and Moderna vaccines

DETAILED DESCRIPTION OF THE DISCLOSURE
I. Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a mucosal viral pathogen that infects the epithelial cells of the lungs and possibly even the intestine (9). Some symptoms of the disease include, for example, fever, cough, shortness of breath, muscle pain, sputum production, diarrhea, sore throat, loss of smell, and abdominal pain. While the majority of cases result in mild symptoms, some progress to viral pneumonia and multi-organ failure.

The virus is spread mainly through close contact and via respiratory droplets produced when people cough or sneeze. People may also contract COVID-19 by touching a contaminated surface and then their face. The infection is most contagious when people are symptomatic, although spread may be possible before symptoms appear. Currently, there is no vaccine or specific antiviral treatment for COVID-19. Managing the disease involves treatment of symptoms, supportive care, isolation, and some experimental measures.

The genome of SARS-CoV-2 virus encodes four major structural proteins including spike (S), nucleocapsid (N), membrane (M), and envelope (E), which are required to make a complete virus particle. After viral entry, 16 non-structural proteins are formed from two large precursor proteins. These viruses have a relatively large positive sense RNA strand (26-32 kb), and without erroneous editing, the RNA can mutate, evolve, and undergo homologous recombination with other family members to create new viral species (6). The S protein is believed to be the major antibody target for coronavirus vaccines, as the protein is responsible for receptor binding, membrane fusion, and tissue tropism. When comparing SARS-CoV-2 Wu-1 (GenBank Accession No. QHD43416.1) to SARS-CoV (GenBank Accession No. AY525636.1), the S protein was found to have 76.2% identity, 87.2% similarity, and 2% gaps in 1273 positions (7). Both SARS-CoV and SARS-CoV-2 are believed to use the same receptor for cell entry: the angiotensin-converting enzyme 2 receptor (ACE2), which is expressed on some human cell types (8). As discussed in the article by Xu, et al., high expression levels of ACE2 are present in type II alveolar cells the lungs, absorptive enterocytes of the ileum and colon, and possibly even in oral tissues such as the tongue (9).

Provided herein are vaccines, immunogenic compositions, and methods for treating COVID-19 that involve the use of chimeric adenoviral vectors that contain one or more nucleic acids encoding one or more SARS-CoV-2 proteins and a nucleic acid encoding a TLR-3 agonist.

II. Definitions

The term “chimeric” or “recombinant” as used herein with reference, e.g., to a nucleic acid, protein, or vector, indicates that the nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein. Thus, for example, chimeric and and recombinant vectors include nucleic acid sequences that are not found within the native (non-chimeric or non-recombinant) form of the vector. A chimeric adenoviral expression vector refers to an adenoviral expression vector comprising a nucleic acid sequence encoding a heterologous polypeptide, such as a SARS-CoV-2 protein.

The term “expression vector” refers to a nucleic acid construct, generated recombinantly or synthetically, with a series of specified nucleic acid elements that permit transcription of a particular nucleic acid in a host cell. The expression vector can be part of a plasmid, virus, or nucleic acid fragment. Typically, the expression vector includes a nucleic acid to be transcribed operably linked to a promoter.

The term “promoter” refers to an array of nucleic acid control sequences that direct transcription of a nucleic acid. As used herein, a promoter includes necessary nucleic acid sequences near the start site of transcription, such as, in the case of a polymerase II type promoter, a TATA element. A promoter also optionally includes distal enhancer or repressor elements, which can be located as many as several thousand base pairs from the start site of transcription. Promoters include constitutive and inducible promoters. A “constitutive” promoter is a promoter that is active under most environmental and developmental conditions. An “inducible” promoter is a promoter that is active under environmental or developmental regulation. The term “operably linked” refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter, or array of transcription factor binding sites) and a second nucleic acid sequence, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence.

The term “SARS-CoV-2” or “severe acute respiratory syndrome coronavirus 2” refers to a coronavirus within a large genus of betacoronaviruses from the viral family of Coronaviridae. Genbank Accession No. MN908947.3 is a published DNA sequence of SARS-CoV-2. The virus is spread mainly through close contact and via respiratory droplets produced when people cough or sneeze.

The term “SARS-CoV-2 protein” refers to a protein encoded by the nucleic acid of SARS-CoV-2 (e.g., Genbank Accession No. MN908947.3) or a fragment of the protein. In some embodiments, a fragment of the SARS-CoV-2 protein comprises at least 10, 20, or more contiguous amino acids from the full-length protein encoded by the sequence of Genbank Accession No. MN908947.3. For example, a SARS-CoV-2 protein can be a structural protein of the full-length protein encoded by the nucleic acid of the SARS-CoV-2 virus, such as a SARS-CoV-2 S protein (surface glycoprotein; e.g., SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g., that are at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO:1 or or SEQ ID NO: 21 or SEQ ID NO:22) or a SARS-CoV-2 N protein (nucleocapsid phosphoprotein, SEQ ID NO:2). A SARS-CoV-2 protein can also be a fusion protein that contains different portions of the full-length protein encoded by the nucleic acid of the SARS-CoV-2 virus. For example, a SARS-CoV-2 fusion protein can contain a S1 region of a SARS-CoV-2 S protein, a furin site, and a SARS-CoV-2 N protein (e.g., SEQ ID NO:12).

The term “COVID-19” or “coronavirus disease 2019” refers to an infectious disease caused by the SARS-CoV-2 virus.

The term “TLR agonist” or “Toll-like receptor agonist” as used herein refers to a compound that binds and stimulates a Toll-like receptor including, e.g., TLR-2, TLR-3, TLR-6, TLR-7, or TLR-8. TLR agonists are reviewed in MacKichan, IAVI Report. 9:1-5 (2005) and Abreu et al., J Immmol, 174(8), 4453-4460 (2005). Agonists induce signal transduction following binding to their receptor.

The term “TLR-3 agonist” or “Toll-like receptor 3 agonist” as used herein refers to a compound that binds and stimulates the TLR-3. TLR-3 agonists have been identified including double-stranded RNA, virally derived dsRNA, several chemically synthesized analogs to double-stranded RNA including polyinosine-polycytidylic acid (poly I:C)-polyadenylic-polyuridylic acid (poly A:U) and poly I:poly C, and antibodies (or cross-linking of antibodies) to TLR-3 that lead to IFN-beta production (Matsumoto, M, et al, Biochem Biophys Res Commun 24:1364 (2002), de Bouteiller, et al, J Biol Chem 18:38133-45 (2005)). In some embodiments, a TLR-3 agonist comprises a sequence of any one of SEQ ID NOS:13-20. In some embodiments, a TLR-3 agonist is a dsRNA (e.g., dsRNA encoded by a nucleic acid comprising a sequence set forth in SEQ ID NO:13).

The term “heterologous” when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs).

Unless otherwise indicated, a particular nucleic acid sequence also encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.

The term “antigen” refers to a protein or part of a polypeptide chain that can be recognized by T cell receptors and/or antibodies. Typically, antigens are derived from bacterial, viral, or fungal proteins.

The term “immunogenically effective dose or amount” of the compositions of the present disclosure is an amount that elicits or modulates an immune response specific for the SARS-CoV-2 protein. Immune responses include humoral immune responses and cell-mediated immune responses. An immunogenic composition can be used therapeutically or prophylactically to treat or prevent disease at any stage. Humoral immune responses are generally mediated by cell free components of the blood, i.e., plasma or serum; transfer of the serum or plasma from one individual to another transfers immunity. Cell mediated immune responses are generally mediated by antigen specific lymphocytes; transfer of the antigen specific lymphocytes from one individual to another transfers immunity.

The term “therapeutic dose” or “therapeutically effective amount” or “effective amount” of a chimeric adenoviral vector or a composition comprising a chimeric adenoviral vector refers to an amount of the vector or composition comprising the vector which prevents, alleviates, abates, or reduces the severity of symptoms of diseases and disorders associated with the source of the SARS-CoV-2 protein (e.g., a SARS-CoV-2 virus).

The term “adjuvant” refers to a non-specific immune response enhancer. Suitable adjuvants include, for example, cholera toxin, monophosphoryl lipid A (MPL), Freund's Complete Adjuvant, Freund's Incomplete Adjuvant, Quil A, and Al(OH). Adjuvants can also be those substances that cause antigen-presenting cell activation and enhanced presentation of T cells through secondary signaling molecules likeToll-like receptors. Examples of Toll-like receptors include the receptors that recognize double-stranded RNA, bacterial flagella, LPS, CpG DNA, and bacterial lipopeptide (Reviewed recently in Abreu et al., J Immunol, 174(8), 4453-4460 (2005)).

The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.

The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.

Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

As used herein, the term “percent identity” or “percent identical,” used in the context of nucleic acids or polypeptides, refers to a sequence that has at least 50% sequence identity with a reference sequence. Alternatively, percent identity can be any integer from 50% to 100%. In some embodiments, a sequence is substantially identical to a reference sequence if the sequence has at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the reference sequence as determined using the methods described herein; preferably BLAST using standard parameters, as described below. Percent identity may also be determined by manual alignment.

For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

A comparison window includes reference to a segment of any one of the number of contiguous positions, e.g., a segment of at least 10 residues. In some embodiments, the comparison window has from 10 to 600 residues, e.g., about 10 to about 30 residues, about 10 to about 20 residues, about 50 to about 200 residues, or about 100 to about 150 residues, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

Algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990). J. Mol. Biol. 215: 403-410 and Altschul et al. (1977) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (NCBI) web site. The algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al, supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word size (W) of 28, an expectation (E) of 10, M=1, N=−2, and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word size (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff& Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, an amino acid sequence is considered similar to a reference sequence if the smallest sum probability in a comparison of the test amino acid sequence to the reference amino acid sequence is less than about 0.01, more preferably less than about 10′, and most preferably less than about 10′.

III. Compositions and Methods of the Present Disclosure

The disclosure provides compositions comprising chimeric adenoviral vectors. The chimeric adenoviral vectors can include one or more nucleic acids encoding one or more SARS-CoV-2 proteins. The chimeric adenoviral vectors can also include a nucleic acid encoding a toll-like receptor (TLR) agonist (e.g., a TLR-3 agonist), which can serve as an effective adjuvant when administered in conjunction with viral vectors.

In some embodiments, the chimeric adenoviral vectors of the disclosure comprise an expression cassette comprising the following elements: (a) a first promoter operably linked to a nucleic acid encoding a first SARS-CoV-2 protein; and (b) a second promoter operably linked to a nucleic acid encoding a toll-like receptor-3 (TLR-3) agonist. The first SARS-CoV-2 protein can be a full-length protein (or a substantially identical protein thereof) encoded by the nucleic acid of SARS-CoV-2 (e.g., Genbank Accession No. MN908947.3) or a fragment of the protein. For example, a first SARS-CoV-2 protein can be a structural protein of the full-length protein encoded by the nucleic acid of the SARS-CoV-2 virus, such as a SARS-CoV-2 S protein (surface glycoprotein; e.g., SEQ ID NO:1 or a substantially identical protein thereof, e.g., SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g., that are at least 90%, or at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22); or a SARS-CoV-2 N protein (nucleocapsid phosphoprotein; SEQ ID NO:2 or a substantially identical protein thereof, e.g., a variant thereof, e.g., that has at least 90%, or at least 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:2). In other embodiments, a first SARS-CoV-2 protein can be a protein encoded by other parts of the nucleic acid of the SARS-CoV-2 virus, such as a protein encoded by the ORF1ab gene, a protein encoded by the ORF3a gene, a protein encoded by the E gene (encoding an envelope protein), a protein encoded by the M gene (encoding a membrane glycoprotein), a protein encoded by the ORF6 gene, a protein encoded by the ORF7a gene, a protein encoded by the ORF8 gene, or a protein encoded by the ORF10 gene.

In further embodiments, a first SARS-CoV-2 protein can be a fusion protein that contains different portions of the full-length protein encoded by the nucleic acid of the SARS-CoV-2 virus. For example, a SARS-CoV-2 fusion protein can contain a S1 region of a SARS-CoV-2 S protein, a furin site, and a SARS-CoV-2 N protein (e.g., SEQ ID NO:12).

A nucleic acid that encodes a first SARS-CoV-2 protein in element (a) can comprise a sequence having at least 85%, 90%, 95%, 96%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:3, which encodes the amino acid sequence of the SARS-CoV-2 S protein (SEQ ID NO:1). In some embodiments, a first SARS-CoV-2 protein in element (a) can comprise a sequence having at least 85%, 90%, 95%, 96%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:3 and encode a SARS-CoV-2 S protein of SEQ ID NO: 21 or SEQ ID NO:22. In some embodiments, a first SARS-CoV-2 protein in element (a) can comprise a sequence having at least 85%, 90%, 95%, 96%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, or 99%) identity to the sequence of SEQ ID NO:3 and encodes a SARS-CoV-2 S protein variant at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO:1 or or SEQ ID NO: 21 or SEQ ID NO:22. In other embodiments, a nucleic acid that encodes a first SARS-CoV-2 protein in element (a) can comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:4, which encodes the amino acid sequence of the SARS-CoV-2 N protein (SEQ ID NO:2). In some embodiments, a first SARS-CoV-2 protein in element (a) can comprise a sequence having at least 85%, 90%, 95%, 96%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, or 99%) identity to the sequence of SEQ ID NO:4 and encodes a SARS-CoV-2 N protein variant at least 90% identical, or at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2. In further embodiments, a nucleic acid that encodes a first SARS-CoV-2 protein in element (a) can comprises a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:5, which encodes the amino acid sequence of the SARS-CoV-2 fusion protein that contains a S1 region of a SARS-CoV-2 S protein, a furin site, and a SARS-CoV-2 N protein (SEQ ID NO:12).

In addition to a first SARS-CoV-2 protein, the chimeric adenoviral vectors of the disclosure can further comprise element (c) a third promoter operably linked to a nucleic acid encoding a second SARS-CoV-2 protein. In particular embodiments, the order of the elements in the expression cassette from the N-terminus to the C-terminus is: element (a), element (c), and element (b). In some embodiments, the first and second SARS-CoV-2 proteins encoded by their respective nucleic acids in elements (a) and (c) in the expression cassette are the same. In some embodiments, the first and second SARS-CoV-2 proteins encoded by their respective nucleic acids in elements (a) and (c) in the expression cassette are different.

For example, the first SARS-CoV-2 protein can be a SARS-CoV-2 S protein (e.g., SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g. that are at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99/o, or 100%) identity to the sequence of SEQ ID NO:3) and the second SARS-CoV-2 protein can be a SARS-CoV-2 N protein (e.g., SEQ ID NO:2, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 96%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:4). In another example, the first SARS-CoV-2 protein can be a SARS-CoV-2 N protein (e.g., SEQ ID NO:2, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:4) and the second SARS-CoV-2 protein can be a SARS-CoV-2 S protein (e.g., SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g that are at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO:1 or or SEQ ID NO: 21 or SEQ ID NO:22, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:3).

In another example, the first SARS-CoV-2 protein can be a SARS-CoV-2 N protein (e.g., SEQ ID NO:2; or a variant thereof, e.g., having at least 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:2) or a SARS-CoV-2 S protein (e.g., SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g that are at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO:1 or or SEQ ID NO: 21 or SEQ ID NO:22) and the second SARS-CoV-2 protein can be a SARS-CoV-2 fusion protein (e.g., SEQ ID NO:12, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:5).

In yet another example, the first SARS-CoV-2 protein can be a SARS-CoV-2 fusion protein (e.g., SEQ ID NO:12, which is encoded by a nucleic acid sequence having at least 85%, 90%, 95%, 97%, 99%, or 100% (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to the sequence of SEQ ID NO:5) and the second SARS-CoV-2 protein can be a SARS-CoV-2 N protein (e.g., SEQ ID NO:2; or a variant at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2) or a SARS-CoV-2 S protein (e.g., SEQ ID NO:1 or SEQ ID NO: 21 or SEQ ID NO:22, or variants thereof, e.g., that are at least 90%, 95%, 97%, 98%, or 99% identical to SEQ ID NO:1 or or SEQ ID NO: 21 or SEQ ID NO:22).

One of skill understands that variants of SARS-CoV-2 proteins, e.g., variants of the SARS-CoV-2 S protein, emerge rapidly. Examples of two variant S protein sequences, UK B.1.1.1.7 variant and South African B.1.351 501Y.V2 variant, are provided in SEQ ID NOS:21 and 22, respectively. Other S protein variants are known, including a Brazil variant, P.1 (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I); and an Indian variant B.1.617 (L452R, E484Q, D614G), among others. Thus, in some embodiments, the SARS-CoV-2 S protein sequence is a variant sequence identified in a patient population.

In addition to the above-described vectors triggering an immune response to SARS-CoV-2 protein, in view of the data shown in Example 6, provided herein are embodiments in which co-introduction of a SARS-CoV-2 N protein with any second antigen, which can be from a non-SARS-CoV-2 antigen source, can be used to stimulate a CD8 T-cell immune response to the second antigen.

Accordingly the disclosure also provides for polynucleotides encoding a SARS-CoV-2 N protein (e.g., SEQ ID NO:2 or a variant thereof having at least 90% identity, or at least 95% identity, to SEQ ID NO:2, or a fragment thereof) and encoding a second antigenic protein from any source. For example the second antigenic protein can be from a non-SARS-CoV-2 virus, a bacterium, other pathogen or cancer. For example, in some embodiments, the second antigen is a protein or fragment thereof from Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpes virus, type 8; Human papillomavirus; BK virus; JC virus; Smallpox; polio virus; Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; Yellow Fever virus; Dengue virus; West Nile virus; Rubella virus; Hepatitis E virus; Human Immunodeficiency virus (HIV); Influenza virus; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabia virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytialvirus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Banna virus; Human Enterovirus; Hanta virus; West Nile virus; Middle East Respiratory Syndrome Corona Virus; Japanese encephalitis virus; Vesicular exanthernavirus; or Eastern equine encephalitis. See, also, U.S. Pat. No. 8,222,224 for a list of antigens that can be used.

Particular examples of second antigens that can be used as described herein in combination with a SARS-CoV-2 N protein include but are not limited to those derived from norovirus (e.g., VP1), Respiratory syncytial virus (RSV), the influenza virus (e.g., HA, NA, M1, NP), human immunodeficiency virus (HIV, e.g., gag, pol, env, etc.), human papilloma virus (HPV, e.g., capsid proteins such as L1), Venezuelan Equine Encephalomyelitis (VEE) virus, Epstein Barr virus, herpes simplex virus (HSV), human herpes virus, rhinoviruses, cocksackieviruses, enteroviruses, hepatitis A, B, C, E, and G (HAV, HBV, HCV, HEV, HGV e.g., surface antigen), mumps virus, rubella virus, measles virus, poliovirus, smallpox virus, rabies virus, and Varicella-zoster virus.

Suitable viral antigens useful as second antigens as described herein also include viral nonstructural proteins, e.g., proteins encoded by viral nucleic acid that do not encode for structural polypeptides, in contrast to those that make capsid or the protein surrounding a virus. Non-structural proteins include those proteins that promote viral nucleic acid replication, viral gene expression, or post-translational processing, such as, for example, Nonstructural proteins 1, 2, 3, and 4 (NS1, NS2, NS3, and NS4, respectively) from Venezuelan Equine encephalitis (VEE), Eastern Equine Encephalitis (EEE), or Semliki Forest.

Bacterial antigens useful as second antigens as described herein can be derived from, for example, Staphylococcus aureus, Staphylococcus epidermis, Helicobacter pylori, Streptococcus bovis, Streptococcus pyogenes, Streptococcus pneumoniae, Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium leprae, Corynebacterium diphtheriae, Borrelia burgdorferi, Bacillus anthracis, Bacillus cereus, Clostridium botulinum, Clostridium difficile, Salmonella typhi, Vibrio chloerae, Haemophilus influenzae, Bordetella pertussis, Yersinia pestis, Neisseria gonorrhoeae, Treponema pallidum, Mycoplasm sp., Legionella pneumophila, Rickettsia typhi, Chlamydia trachomatis, and Shigella dysenteriae, Vibrio cholera (e.g., Cholera toxin subunit B, cholera toxin-coregulated pilus (TCP)); Helicobacter pylorii (e.g., VacA, CagA, NAP, Hsp, catalase, urease); E. coli (e.g., heat-labile enterotoxin, fimbrial antigens).

Parasite antigens useful as second antigens as described herein can be derived from, for example, Giardia lamblia, Leishmania sp., Trypanosoma sp., Trichomonas sp., Plasmodium sp. (e.g., P. falciparum surface protein antigens such as pfs25, pfs28, pfs45, pfs84, pfs 48/45, pfs 230, Pvs25, and Pvs28); Schistosoma sp.; Mycobacterium tuberculosis (e.g., Ag85, MPT64, ESAT-6, CFP10, R8307, MTB-32 MTB-39, CSP, LSA-1, LSA-3, EXP1, SSP-2, SALSA, STARP, GLURP, MSP-1, MSP-2, MSP-3, MSP-4, MSP-5, MSP-8, MSP-9, AMA-1, Type 1 integral membrane protein, RESA, EBA-175, and DBA).

Fungal antigens useful as second antigens as described herein can be derived from, for example, Tinea pedis, Tinea corporus, Tinea cruris, Tinea unguium, Cladosporium carionii, Coccidioides immitis, Candida sp., Aspergillus fumigatus, and Pneumocystis carinii.

Cancer antigens useful as second antigens as described herein include, for example, antigens expressed or over-expressed in colon cancer, stomach cancer, pancreatic cancer, lung cancer, ovarian cancer, prostate cancer, breast cancer, skin cancer (e.g., melanoma), leukemia, or lymphoma. Exemplary cancer antigens include, for example, HPV L1, HPV L2, HPV E1, HPV E2, placental alkaline phosphatase, AFP, BRCA1, Her2/neu, CA 15-3, CA 19-9, CA-125, CEA, Hcg, urokinase-type plasminogen activator (Upa), plasminogen activator inhibitor, CD53, CD30, CD25, C5, CD11a, CD33, CD20, ErbB2, CTLA-4. See Sliwkowski & Mellman (2013) Science 341:6151 for additional cancer targets.

While an attenuated adenovirus can be used to express a SARS-CoV-2 N protein and second antigenic protein (e.g., to generate a CD8 T-cell response), other polynucleotides or vectors can also be used. Expression vectors can include, for example, virally-derived vectors, e.g., recombinant adeno-associated virus (AA V) vectors, retroviral vectors, adenoviral vectors, modified vaccinia Ankara (MVA) vectors, and lentiviral (e.g., HSV-1-derived) vectors (see, e.g., Brouard et al. (2009) British J. Pharm. 157:153). In other embodiments, the SARS-CoV-2 N protein (e.g., SEQ ID NO:2) and second antigenic protein can be encoded by a polynucleotide, e.g., naked or encapsulated DNA or RNA, e.g., mRNA (see, e.g., U.S. Patent Publication No. 2020/0254086 for details of various aspects for RNA-based vaccines).

In some embodiments a vector that comprises a region encoding a SAR-CoV-2 N protein and a region encoding a second antigenic protein, further comprises a nucleic acid encoding a TLR agonist (e.g., a TLR-3 agonist), which can serve as an effective adjuvant when administered in conjunction with vectors, such as viral vectors.

In some embodiments, a vector, e.g., a viral vector, encodes a SARS-Co-V2 N protein (e.g., an N protein sequence of SEQ ID NO:2, or a variant thereof, e.g., at least 90% identical, or at least 95% identical to SEQ ID NO:2) and a second antigenic protein, in which expression of the N protein and second antigenic protein is driven by different promoters. In further embodiments, the vector comprises a ribosomal skipping element situated between the region of the nucleic acid that encode the N protein and the region encoding the second antigenic protein. In some embodiments, the vector comprises an IRES situated between the N protein and second antigenic protein to produce a bicistronic transcript. In some embodiments, the ribosomal skipping element is a sequence encoding a virus 2A peptide (T2A), a porcine teschovirus-1 2A peptide (P2A), a foot-and-mouth disease virus 2A peptide (F2A), equine rhinitis A virus 2A peptide (E2A), a cytoplasmic polyhedrosis virus 2A peptide (BmCPV 2A), or a flacherie virus of B. mori 2A peptide (BmIFV 2A); situated between the N protein and the second antigenic protein. In some embodiments, the construct further encodes a TLR agonist.

In some embodiments, the vector comprises a first promoter operably linked to polynucleotide sequence encoding a SARS-CoV-2 N protein and a second promoter operably linked to the second antigenic protein. In some embodiments, the vector, e.g., a viral vector, can further comprise a third promoter operably linked to a TLR agonist, e.g., a TLR-3 agonist.

In particular embodiments, the order of the elements in the expression cassette from the N-terminus to the C-terminus is: a sequence encoding an antigenic protein, a sequence encoding a SARS-Co-V2 N protein and a sequence encoding a TLR agonist, e.g., a TLR 3 agonist.

In further embodiments, an antigenic protein can be fused to the N protein sequence For example, a fusion protein can contain an antigenic protein, a furin site, and a SARS-CoV-2 N protein, or variant thereof, e.g., at least 90% identical, or at least 95% identical to SEQ ID NO:2.

In some embodiments, a SARS-CoV-2 N protein encoded by a vector has at least 90% identity to SEQ ID NO:2. In some embodiments, the N protein encoded by the vector has at least 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:2.

In some embodiments, the vector comprises an expression cassette as described herein in which a second antigenic protein replaces a SARS-CoV-2 S protein in the constructs provided herein that encode both the N protein and SARS-CoV-2 S proteins. Thus, for example, in some embodiments, the vector comprises sequences as follows (5′-3): CMV-second antigenic protein-BGH-Actin-N protein-SPA-BGH-CM-dsRNA-SPA in which “CMV” is a CMV promoter; “second antigenic protein” is a nucleic acid sequence encoding a second antigenic protein, e.g., from an infectious disease agent or a cancer antigen as described herein, “BGH” is a bovine growth hormone polyadenylation signal sequence”; “βActin” is a beta-actin promoter, e.g., a human beta-actin promoter; “N-protein” is a nucleic acid sequence encoding a SARS-CoV2 N protein as described herein, e.g., SEQ ID NO:2, or a protein having at least 90% identity or at least 95% identity to SEQ ID NO:2, “SPA” is a synthetic polyA sequence, and “dsRNA” is a nucleic acid sequence encoding a TLR agonist, e.g., a TLR-3 agonist.

In some embodiments, an N protein from an alternative coronavirus is employed in place of the SARS-CoV-2 N protein in constructs comprising an N protein and an antigenic protein, such as an infection disease antigen or cancer antigen. Thus, for example, in some embodiments, such a construct can comprise a SARS-CoV or MERS N protein.

In some embodiments, the vector is an adenoviral vector, e.g., an adenovirus 5(Ad5) vector as described below.

Suitable Adenoviral Vectors

In some embodiments, an adenoviral vector as described herein is adenovirus 5 (Ad5), which can include, for example, Ad5 with deletions of the E1/E3 regions and Ad5 with a deletion of the E4 region. Other suitable adenoviral vectors include strains 2, orally tested strains 4 and 7, enteric adenoviruses 40 and 41, and other strains (e.g. Ad34) that are sufficient for delivering an antigen and eliciting an adaptive immune response to the transgene antigen (Lubeck el al., Proc Natl Acad Sci USA, 86(17), 6763-6767 (1989); Shen et al., J Virol, 75(9), 4297-4307 (2001); Bailey et al., Virology, 202(2), 695-706 (1994)). In some embodiments, the adenoviral vector is a live, replication incompetent adenoviral vector (such as E1 and E3 deleted rAd5), live and attenuated adenoviral vector (such as the E1B55K deletion viruses), or a live adenoviral vector with wild-type replication.

The transcriptional and translational control sequences in expression vectors to be used in transforming vertebrate cells in vivo may be provided by viral sources. For example, commonly used promoters and enhancers are derived, e.g., from beta-actin, adenovirus, simian virus (SV40), and human cytomegalovirus (CMV). For example, vectors allowing expression of proteins under the direction of the CMV promoter, beta-actin promoter, SV40 early promoter, SV40 later promoter, metallothionein promoter, murine mammary tumor virus promoter, Rous sarcoma virus promoter, transducer promoter, or other promoters shown effective for expression in mammalian cells are suitable. Further viral genomic promoter, control and/or signal sequences may be used, provided such control sequences are compatible with the host cell chosen.

Various promoters can be used in the chimeric adenoviral vectors described herein. The promoters used for elements (a), (b), and/or (c) can be identical or different. For example, in some embodiments, the first promoter used in element (a) and the second promoter used in element (b) can both be a CMV promoter. In other embodiments, when element (c) is included, the third promoter can be identical or different from the first and/or second promoter. For example, the first promoter and the second promoter can both be a CMV promoter and the third promoter can be a beta-actin promoter (e.g., a human beta-actin promoter).

TLR Agonists

The chimeric adenoviral vectors described herein can also include a nucleic acid encoding a toll-like receptor (TLR) agonist, which can serve as an effective adjuvant when administered in conjunction with viral vectors. TLR agonists can be used to enhance the immune response to the SARS-CoV-2 protein. In some embodiments, TLR-3 agonists are used. In some embodiments, the TLR agonists described herein can be delivered simultaneously with the expression vector encoding an antigen of interest (e.g., a SARS-CoV-2 protein). In other embodiments, the TLR agonists can be delivered separately (i.e., temporally or spatially) from the expression vector encoding an antigen of interest (e.g., a SARS-CoV-2 protein). For example, the expression vector can be administered via a non-parenteral route (e.g., orally, intranasally, or mucosally), while the TLR agonist can be delivered by a parenteral route (e.g., intramuscularly, intraperitoneally, or subcutaneously).

In particular embodiments, a TLR-3 agonist is can be used to stimulate immune recognition of an antigen of interest. TLR-3 agonists include, for example, short hairpin RNA, virally derived RNA, short segments of RNA that can form double-strands or short hairpin RNA, and short interfering RNA (siRNA). In one embodiment of the disclosure, the TLR-3 agonist is virally derived dsRNA, such as for example, a dsRNA derived from a Sindbis virus or dsRNA viral intermediates (Alexopoulou et al, Nature 413:732-8 (2001)). In some embodiments, the TLR-3 agonist is a short hairpin RNA. Short hairpin RNA sequences typically comprise two complementary sequences joined by a linker sequence. The particular linker sequence is not a critical aspect of the disclosure. Any appropriate linker sequence can be used so long as it does not interfere with the binding of the two complementary sequences to form a dsRNA.

In some embodiments, the TLR-3 agonist can comprise a sequence having at least 85%, 90%, 95%, 97%, 99%, or 100/a (e.g., 85%, 87%, 89%, 91%, 93%, 95%, 97%, 99%, or 100%) identity to a sequence set forth in SEQ ID NOS:13-20. In particular embodiments, the TLR-3 agonists comprises the sequence of SEQ ID NO:13. In certain embodiments, dsRNA that is a TLR-3 agonist does not encode a particular polypeptide, but produces a pro-inflammatory cytokine (e.g. IL-6, IL-8, TNF-alpha, IFN-alpha, IFN-beta) when contacted with a responder cell (e.g., a dendritic cell, a peripheral blood mononuclear cell, or a macrophage) in vitro or in-vivo.

In particular embodiments, the TLR agonist (e.g., TLR-3 agonist) described herein can be delivered simultaneously within the same the expression vector that encodes a SARS-CoV-2 protein. In other embodiments, the TLR agonist (e.g., TLR-3 agonist) can be delivered separately (i.e., temporally or spatially) from the expression vector that encodes a SARS-CoV-2 protein. In some cases when the TLR-3 agonist is delivered separately from the expression vector, the nucleic acid encoding the TLR-3 agonist (e.g., an expressed dsRNA) and the chimeric adenoviral vector comprising a nucleic acid encoding a SARS-CoV-2 protein can be administered in the same formulation. In other cases the nucleic acid encoding the TLR-3 agonist and the chimeric adenoviral vector comprising a nucleic acid encoding a SARS-CoV-2 protein can be administered in different formulations. When the nucleic acid encoding the TLR-3 agonist and the adenoviral vector comprising a nucleic acid encoding a SARS-CoV-2 protein are administered in different formulations, their administration may be simultaneous or sequential. For example, the nucleic acid encoding the TLR-3 agonist may be administered first, followed by the chimeric adenoviral vector (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, 2, 4, 6, 8, or 10 days later). Alternatively, the adenoviral vector may be administered first, followed by the nucleic acid encoding the TLR-3 agonist (e.g., 1, 2, 4, 8, 12, 16, 20, or 24 hours, 2, 4, 6, 8, or 10 days later). In some embodiment, the nucleic acid encoding the TLR-3 agonist and the nucleic acid encoding the SARS-CoV-2 protein are under the control of the same promoter. In other embodiments, the nucleic acid encoding the TLR-3 agonist and the nucleic acid encoding the SARS-CoV-2 protein are under the control of different promoters.

IV. Pharmaceutical Compositions and Routes of Administration

An immunogenic pharmaceutical composition can contain a chimeric adenoviral vector described herein and a pharmaceutically acceptable carrier. Suitable carriers include, for example, water, saline, alcohol, a fat, a wax, a buffer, a solid carrier, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, and magnesium carbonate, or biodegradable microspheres (e.g., polylactate polyglycolate). Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883. The immunogenic polypeptide and/or carrier expression vector can be encapsulated within the biodegradable microsphere or associated with the surface of the microsphere.

The ingredients in an immunogenic pharmaceutical composition are closely related to factors such as, but are not limited to, the route of administration of the immunogenic pharmeutical composition, the timeline and/or duration of drug release, and the targeted delivery site. In some embodiments, a delayed release coating or an additional coating of the formulation can contain other film-forming polymers being non-sensitive to luminal conditions for technical reasons or chronographic control of the drug release. Materials to be used for such purpose includes, but are not limited to; sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures.

Additives such as dispersants, colorants, pigments, additional polymers, e.g., poly(ethylacrylat, methylmethacrylat), anti-tacking and anti-foaming agents can be included into a coating layer. Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the core material. The coating layers can also contain pharmaceutically acceptable plasticizers to obtain desired mechanical properties. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, glycerol monoesters, polysorbates or other plasticizers and mixtures thereof. The amount of plasticizer can be optimised for each formula, and in relation to the selected polymer(s), selected plasticizer(s) and the applied amount of said polymer(s).

Such immunogenic pharmaceutical compositions can also comprise non-immunogenic buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, bacteriostats, chelating agents such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide), suspending agents, thickening agents and/or preservatives. Alternatively, compositions of the present disclosure may be formulated as a lyophilate. Compounds may also be encapsulated within liposomes using well known technology.

Further, pharmaceutical compositions can be prepared to protect against stomach degradation such that the administered immunogenic biological agent reach the desired location. Methods for microencapsulation of DNA and drugs for oral delivery are described, e.g., in US2004043952. For the oral environment, several of these are available including the Eudragit and the TimeClock release systems as well as other methods specifically designed for adenovirus (Lubeck et al., Proc Natl Acad Sci USA, 86(17), 6763-6767 (1989); Chourasia and Jain, J Pharm Pharm Sci, 6(1), 33-66 (2003)). In some embodiments, the Eudragit system can be used to to deliver the chimeric adenoviral vector to the lower small intestine.

In particular embodiments, the immunogenic composition is in the form of a tablet or capsule, e.g., in the form of a compressed tablet covered by enteric coating. In some embodiments, the immunogenic composition is encapsulated in a polymeric capsule comprising gelatin, hydroxypropylmethylcellulose, starch, or pullulan. In some embodiments, the immunogenic composition is in the form of microparticles less than 2 mm in diameter, e.g., each microparticle covered with enteric coating as described herein. In particular embodiments, the immunogenic composition in the form of a tablet, a capsule, or a microparticle can be orally administered. In some embodiments, site-specific delivery can be achieved via tablets or capsules that release upon an externally generated signal. Early models released for a high-frequency (HF) signal, as disclosed in Digenis et al. (1998) Pharm. Sci. Tech. Today 1:160. The original HF capsule concept has since been updated and the result marketed as InteliSite®. The updated capsule is a radio-frequency activated, non-disintegrating delivery system. Radiolabeling of the capsule permits the determination of the capsule location within a specific region of the GI tract via gamma scintigraphy. When the capsule reaches the desired location in the GI tract, external activation opens a series of windows to the capsule drug reservoir.

In some embodiments, the immunogenic composition can be enclosed in a radio-controlled capsule, so that the capsule is tracked and signaled once it reaches the delivery site. In some embodiments, the capsule is signaled at a given time after administration that corresponds to when the capsule is expected to arrive at the delivery site, with or without detecting.

The compositions described herein may be administered as part of a sustained release formulation (i.e., a formulation such as a capsule or sponge that effects a slow release of compound following administration). Such formulations may generally be prepared using well known technology (see, e.g., Coombes et al. (1996) Vaccine 14:1429-1438). Sustained-release formulations may contain a polypeptide, polynucleotide or antibody dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane.

Carriers for use within such formulations are biocompatible and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. Such carriers include microparticles of poly(lactide-co-glycolide), as well as polyacrylate, latex, starch, cellulose and dextran. Other delayed-release carriers include supramolecular biovectors, which comprise a non-liquid hydrophilic core (e.g., a cross-linked polysaccharide or oligosaccharide) and, optionally, an external layer comprising an amphiphilic compound (see, e.g., WO 94/20078; WO 94/23701; and WO 96/06638). The amount of active compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.

In some embodiments, the immunogenic compositions are presented in unit-dose or multi-dose containers, such as sealed ampoules or vials. Such containers are preferably hermetically sealed to preserve sterility of the formulation until use. In general, formulations can be stored as suspensions, solutions, or emulsions in oily or aqueous vehicles. Alternatively, an immunogenic composition may be stored in a freeze-dried condition requiring only the addition of a sterile liquid carrier immediately prior to use.

Compositions for Targeted Delivery

In some embodiments of targeted delivery, enteric coatings are used to shield substances from the low pH environment of the stomach and delay release of the enclosed substance until it reaches a desired target later in the digestive tract. Enteric coatings are known, and commercially available. Examples include pH-sensitive polymers, bio-degradable polymers, hydrogels, time-release systems, and osmotic delivery systems (see, e.g., Chourasia & Jain (2003) J. Pharm. Pharmaceutical Sci. 6:33).

In some embodiments, the targeted delivery site is the ileum. The pH of the gastrointestinal tract (GIT) progresses from very acidic in the stomach (pH˜2), to more neutral in the ileum (pH˜5.8-7.0). pH sensitive coatings can be used that dissolve in the ileum or just before the ileum. Examples include Eudragit® L and S polymers (threshold pH's ranging from 5.5-7.0); polyvinyl acetate phthalate (pH 5.0), hydroxypropyl methylcellulose phthalate 50 and 55 (pH 5.2 and 5.4, respectively), and cellulose acetate phthalate (pH 5.0). Thakral et al. (2013) Expert Opin. Drug Deliv. 10:131 review Euragit® formulations for ileal delivery, in particular, combinations of L and S that ensure delivery at pH-7.0. Crotts el al. (2001) Eur. J Pharm. Biol. 51:71 describe Eudragit® formulations with appropriate disintegration properties. Vijay et al. (2010) J. Mater. Sci. Mater. Med. 21:2583 review acrylic acid (AA)-methyl methacrylate (MMA) based copolymers for ileal delivery at pH 6.8.

For ileal delivery, the polymer coating typically dissolves at about pH 6.8 and allows complete release within about 40 min (see, e.g., Huyghebaert et al. (2005) Int. J. Pharm. 298:26). To accomplish this, a therapeutic substance can be covered in layers of different coatings, e.g., so that the outermost layer protects the substance through low pH conditions and is dissolved when the tablet leaves the stomach, and at least one inner layer that dissolves as the tablet passes into increasing pH. Examples of layered coatings for delivery to the distal ileum are described, e.g., in WO 2015/127278, WO 2016/200951, and WO 2013/148258.

Biodegradable polymers (e.g., pectin, azo polymers) typically rely on the enzymatic activity of microflora living in the GIT. The ileum harbors larger numbers of bacteria than earlier stages, including lactobacilli and enterobacteria.

Osmotic-controlled Release Oral delivery Systems (OROS®; Alza) is an example of an osmotic system that degrades over time in aqueous conditions. Such materials can be manipulated with other coatings, or in varying thicknesses, to deliver specifically to the ileum (see, e.g., Conley el al. (2006) Curr. Med. Res. Opin. 22:1879).

Combination polymers for delivery to the ileum are reported in WO2000062820. Examples include Eudragit® L100-55 (25 mg/capsule) with triethyl citrate (2.4 mg/capsule), and Povidone K-25 (20 mg/tablet) followed by Eudragit®FS30D (30 mg/tablet). pH sensitive polymers can be applied to effect delivery to the ileum, as described above and, e.g., methacrylic acid copolymers (e.g., poly(methacylic acid-co-methyl methacrylate) 1:1), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl-cellulose, shellac or other suitable polymer(s). The coating layer can also be composed of film-forming polymers being sensitive to other luminal components than pH, such as bacterial degradation or a component that has such a sensitivity when it is mixed with another film-forming polymer Examples of such components providing delayed release to the ileum are polymers comprising azo bond(s), polysaccharides such as pectin and its salts, galactomannans, amylose and chondroitin, disulphide polymers and glycosides.

Components with varying pH, water, and enzymatic sensitivities can be used in combination to target a therapeutic composition to the ileum. The thickness of the coating can also be used to control release. The components can also be used to form a matrix, in which the therapeutic composition is embedded. See generally, Frontiers in Drug Design & Discovery (Bentham Science Pub. 2009) vol. 4.

Adjuvant

In some embodiments of the present disclosure, in addition to the TLR agonist (e.g., TLR-3 agonist) encoded in the chimeric adenoviral vector, the compositions can further comprise additional adjuvants. Suitable adjuvants include, for example, the lipids and non-lipid compounds, cholera toxin (CT), CT subunit B, CT derivative CTK63, E. coli heat labile enterotoxin (LT), LT derivative LTK63, Al(OH)₃, and polyionic organic acids as described in e.g., WO 04/020592, Anderson and Crowle, Infect. Immun. 31(1):413-418 (1981), Roterman et al., J. Physiol. Pharmacol., 44(3):213-32 (1993), Arora and Crowle, J. Reliculoendothel. 24(3):271-86 (1978), and Crowle and May, Infect. Immun. 38(3):932-7 (1982)). Suitable polyionic organic acids include for example, 6,6′-[3,3′-demithyl[1,1′-biphenyl]-4,4′-diyl]bis(azo)bis[4-amino-5-hydroxy-1,3-naphthalene-disulfonic acid] (Evans Blue) and 3,3′-[1,1′biphenyl]-4,4′-diylbis(azo)bis[4-amino-1-naphthalenesulfonic acid] (Congo Red). It will be appreciated by those of skill in the art that the polyionic organic acids may be used for any genetic vaccination method in conjunction with any type of administration.

Other suitable adjuvants include topical immunomodulators such as, members of the imidazoquinoline family such as, for example, imiquimod and resiquimod (see, e.g., Hengge et al., Lancet Infect. Dis. 1(3):189-98 (2001).

Additional suitable adjuvants are commercially available as, for example, additional alum-based adjuvants (e.g., Alhydrogel, Rehydragel, aluminum phosphate, Algammulin); oil based adjuvants (Freund's Incomplete Adjuvant and Complete Adjuvant (Difco Laboratories, Detroit, Mich.), Specol, RIBI, TiterMax, Montanide ISA50 or Seppic MONTANIDE ISA 720): nonionic block copolymer-based adjuvants, cytokines (e.g., GM-CSF or Flat3-ligand); Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.); AS-2 (SmithKline Beecham, Philadelphia, Pa.); salts of calcium, iron or zinc; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; monophosphoryl lipid A and Quil A. Cytokines, such as GM-CSF or interleukin-2, -7, or -12, are also suitable adjuvants. Hemocyanins (e.g., keyhole limpet hemocyanin) and hemoerythrins may also be used in the disclosure. Polysaccharide adjuvants such as, for example, chitin, chitosan, and deacetylated chitin are also suitable as adjuvants. Other suitable adjuvants include muramyl dipeptide (MDP, N acetylmuramyl L alanyl D isoglutamine) bacterial peptidoglycans and their derivatives (e.g., threonyl-MDP, and MTPPE). BCG and BCG cell wall skeleton (CWS) may also be used as adjuvants in the disclosure, with or without trehalose dimycolate. Trehalose dimycolate may be used itself (see, e.g., U.S. Pat. No. 4,579,945). Detoxified endotoxins are also useful as adjuvants alone or in combination with other adjuvants (see, e.g., U.S. Pat. Nos. 4,866,034; 4,435,386; 4,505,899; 4,436,727; 4,436,728; 4,505,900; and 4,520,019. The saponins QS21, QS17, QS7 are also useful as adjuvants (see, e.g., U.S. Pat. No. 5,057,540; EP 0362279; WO 96/33739; and WO 96/11711). Other suitable adjuvants include Montanide ISA 720 (Seppic, France), SAF (Chiron, Calif., United States), ISCOMS (CSL), MF-59 (Chiron), the SBAS series of adjuvants (e.g., SBAS-2, SBAS-4 or SBAS-6 or variants thereof, available from SmithKline Beecham, Rixensart, Belgium), Detox (Corixa, Hamilton, Mont.), and RC-529 (Corixa, Hamilton, Mont.).

Within the pharmaceutical compositions provided herein, the adjuvant composition can be designed to induce, e.g., an immune response predominantly of the Th1 or Th2 type. High levels of Th1-type cytokines (e.g., IFN-gamma, TNF-alpha, IL-2 and IL-12) tend to favor the induction of cell mediated immune responses to an administered antigen. In contrast, high levels of Th2-type cytokines (e.g., IL-4, IL-5, IL-6 and IL-10) tend to favor the induction of humoral immune responses. Following oral delivery of a composition comprising an immunogenic polypeptide as provided herein, an immune response that includes Th1- and Th2-type responses will typically be elicited.

Routes of Administration

A composition comprising the chimeric adenoviral vector can be administered by any non-parenteral route (e.g., orally, intranasally, or mucosally via, for example, the vagina, lungs, salivary glands, nasal cavities, small intestine, colon, rectum, tonsils, or Peyer's patches). The composition may be administered alone or with an adjuvant as described above. In particular embodiments, the immunogenic composition is administered orally in the form of a tablet or capsule. In further embodiments, the immunogenic composition is administered orally for targeted delivery in the ileum in the form of a tablet or capsule.

V. Therapeutic Uses

One aspect of the present disclosure involves using the immunogenic compositions described herein to elicit an antigen specific immune response towards a SARS-CoV-2 protein (e.g., a SARS-CoV-2 protein having the sequence of SEQ ID NOS:1, 2, or 12) in a subject. In some embodiments, the immune response is elicited in an alveolar cell, an absorptive enterocyte, a ciliated cell, a goblet cell, a club cells, and/or an airway basal cell of the subject. As used herein, a “subject” refers to any warm-blooded animal, such as, for example, a rodent, a feline, a canine, or a primate, preferably a human. The immunogenic compositions can be used before the subject developed COVID-19 to prevent disease. The disease can be diagnosed using criteria generally accepted in the art. For example, viral infection can be diagnosed by the measurement of viral titer in a biological sample (e.g., a nostril swab or mucosal sample) from the subject.

As shown in the examples, vaccines described herein can be particularly effective in triggering a CD8⁺ T-cell immune response. In some embodiments, this significant CD8 response may be triggered by the presence of the SARS-CoV-2 N protein (e.g., SEQ ID NO:2 os substantially identical variants thereof), which acts to stimulate a CD8⁺ T-cell response to a second antigenic protein (which in the example was SARS-CoV-2 S protein, but which could be a different SARS-CoV-2 protein, or as discussed in more detail below, a non-SARS-CoV-2 protein). Accordingly, in some embodiments, a vaccine as described herein resulting in expression of a SARS-CoV-2 N protein as well as a second antigenic protein, can be used to trigger an immune response, which includes a CD8⁺ T-cell response, in a subject, e.g., a human subject. In some embodiments, the human subject is a subject with less ability to develop an antibody-based immune response or would otherwise benefit from a CD8⁺ T-cell immune response. Exemplary subjects can include, but are not limited to: elderly humans, e.g., at least 50, at least 60 or at least 70 years old, or that has an antibody deficiency disorder (see, e.g., Angel A. Justiz Vaillant; Kamleshun Ramphul, ANTIBODY DEFICIENCY DISORER (Treasure Island (FL): StatPearls Publishing: 2020) for a descrition thereof), which can include but is not limited to subjects with X-linked agammaglobulinemia (Bruton disease), transient hypogammaglobulinemia of newborn, Selective Ig immunodeficiencies, for example, IgA selective deficiency, Super IgM syndrome, and common variable immunodeficiency disord.

Immunotherapy is typically active immunotherapy, in which treatment relies on the in vivo stimulation of the endogenous host immune system to react against, e.g., virally infected cells, with the administration of immunogenic composition comprising the chimeric adenoviral vectors described herein.

Frequency of administration of the immunogenic composition described herein, as well as dosage, will vary from individual to individual, and may be readily established using standard techniques. In some embodiments, between 1 and 10 (e.g., between 2 and 10, between 3 and 10, between 4 and 10, between 5 and 10, between 6 and 10, between 7 and 10, between 8 and 10, between 9 and 10, between 1 and 9, between 1 and 8, between 1 and 7, between 1 and 6, between 1 and 5, between 1 and 4, between 1 and 3, or between 1 and 2) doses may be administered over a 52 week period. In some embodiments, 2 or 3 doses are administered at intervals of 1 month; or for example, 2-3 doses are administered every 2-3 months. It is possible that the intervals will be once a year for certain therapies. Booster vaccinations may be given periodically thereafter.

A suitable dose is an amount of a compound for example that, when administered as described above, is capable of promoting an anti-viral immune response, and is at least 10-50% above the basal (i.e., untreated) level. Such response can be monitored by measuring the anti-viral antibodies in a patient or by vaccine-dependent generation of cytolytic T cells capable of killing, e.g., the patient's virus-infected cells in vitro. Immunogenic responses can also be measured by detecting immunocomplexes formed between the immunogenic polypeptides and antibodies in body fluid which are specific for the immunogenic polypeptides. Samples of body fluid taken from an individual prior to and subsequent to initiation of therapy may be analyzed for the immunocomplexes. Briefly, the number of immunocomplexes detected in both samples can be compared. A substantial change in the number of immunocomplexes in the second sample (post-therapy initiation) relative to the first sample (pre-therapy) reflects successful therapy. Such vaccines should also be capable of causing an immune response that leads to prevention of the COVID-19 disease in vaccinated patients as compared to non-vaccinated patients.

Exemplary dosages can be measured in infectious units (I.U.). A replication-deficient recombinant Ad5 vector can be tittered and quantified using I.U. units. This is accomplished through performance of an IU assay in the adherent human embryonic kidney (HEK) 293 cell line, which is permissive for growth of replication-deficient Ad5. HEK293 cells are plated in a 24-well sterile tissue culture plate and allowed to adhere. The viral material is diluted in sequential 10-fold dilutions and infected into individual wells of plated HEK293 cells in an appropriate number of replicates, usually in duplicate or triplicate. Infection is allowed to proceed via incubation for ˜40-42 hours at 37 C, 5% C02. Cells are then fixed with methanol to allow permeability, washed, and blocked with a buffer solution containing bovine serum albumin (BSA). Cells are then incubated with a rabbit-derived primary antibody against the Ad5 hexon surface protein, washed, and probed again with an HRP-conjugated anti-rabbit secondary antibody. Infected cells are then stained via incubation with 3,3′-diaminobenzidine tetrahydrochloride (DAB) and hydrogen peroxide. Infected cells are visualized using phase-contrast microscopy and a dilution is chosen that exhibits discreet individual infection events—these are visible as darkly stained cells that are highly visible against the semi-transparent monolayer of uninfected cells. Total infected cells are counted per field-of-vision in at least ten fields-of-vision of the appropriate dilution. Viral titer can be calculated using the average number of these counts in conjunction with the total number of fields-of-vision for the objective lens/eyepiece magnification used and multiplying by the dilution factor used in the counts.

In some embodiments, the vaccines administered can have a dosage of 10⁷-10¹¹, e.g., 10⁸-10¹¹, 10⁹-10¹¹, 5×10⁹-5×10¹⁰I.U. Suitable dose sizes will vary with the size of the patient, but will typically range from about 0.01 ml to about 10 ml for an injected vaccine, more typically from about 0.025 to about 7.5 ml, most typically from about 0.05 to about 5 ml. For a tablet or capsule final product, the size would be between 10 mg to 1000 mg, most typically between 100-400 mg. Those of skill in the art will appreciate that the dose size may be adjusted based on the particular patient or the particular disease or disorder being treated.

EXAMPLES

The following examples are intended to illustrate, but not to limit the present disclosure.

Example 1. Generation of Recombinant Adenoviral Constructs

Several different recombinant adenoviral (rAd) constructs to prevent SARS-CoV-2 infection were developed, using the same vector platform that was previously evaluated clinically (14, 15), with the exception that different antigens were used. Several rAd SARS-CoV-2 vaccines were generated by standard methods (e.g., as described by He, et al (17)).

Three vaccine constructs were created based on the published DNA sequence of SARS-CoV-2 publicly available as Genbank Accession No. MN908947.3. Specifically, the published amino acid sequence of the SARS-CoV-2 S protein (or surface glycoprotein; SEQ 1 below) and the SARS-CoV-2 N protein (or nucleocapsid phosphoprotein; SEQ 2 below) were used to synthesize nucleic acid sequences codon optimized for expression in Homo sapiens cells. Codon optimized nucleic acid sequences for the SARS-CoV-2 S gene and SARS-CoV-2 N gene are shown in SEQ ID NOS:3 and 4, respectively. These sequences were used to create recombinant plasmids containing transgenes cloned into the E1 region of Adenovirus Type 5 (pAd).

Two recombinant pAd plasmids were constructed using sequences from SARS-CoV-2.

1. ED81.4.1: pAd-CMV-SARS-CoV-2-S-BGH-CMV-dsRNA-SPA. Recombinant Ad5 vector containing SEQ ID NO:3 under control of the CMV promoter. Sequence of the entire transgene cassette from initial CMV promoter through the SPA following the dsRNA adjuvant is included as SEQ ID NO:6. Sequence of the entire recombinant adenoviral genome containing this transgene construct is included as SEQ ID NO:9.

2. ED84A6.4.1: pAd-CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-CMV-dsRNA-SPA. Recombinant Ad5 vector containing SEQ ID NO:3 under control of the CMV promoter and SEQ ID NO:4 under control of the beta-actin promoter. Sequence of the entire transgene cassette from initial CMV promoter through the SPA following the dsRNA adjuvant is included as SEQ ID NO:7. Sequence of the entire recombinant adenoviral genome containing this transgene construct is included as SEQ ID NO: 10.

In addition, a third pAd plasmid was constructed using a fusion sequence (SEQ ID NO:5) combining the S1 region of SARS-CoV-2 S gene (including the native furin site between S1 and S2) with the full-length SARS-CoV-2 N gene:

3. ST05.1.3.3: pAd-CMV-SARS-CoV-2-S1-Furin-N-BGH-CMV-dsRNA-SPA. Recombinant Ad5 vector containing SEQ ID NO:5 under control of the CMV promoter. Sequence of the entire transgene cassette from initial CMV promoter through the SPA following the dsRNA adjuvant is included as SEQ ID NO:8. Sequence of the entire recombinant adenoviral genome containing this transgene construct is included as SEQ ID NO:11.

Sequences were cloned into a shuttle plasmid using the restriction sites (e.g., Sthl and Sgfl). The shuttle plasmid was used to lock the transgenes onto a plasmid (pAd) containing the full sequence of Adenovirus Type 5 deleted for the E1 gene (pAd). The pAd plasmid was transfected into human cells providing the E1 gene product in trans to allow replication and purification of recombinant adenovirus to be used as API in vaccines.

Example 2. Expression of the Antigen Proteins

Three different candidates were evaluated for expression by intracellular staining/flow cytometry. HEK293 cells were placed in tissue culture at 3e5 cells/well in a 24-well plate. Four hrs later, the cells were infected with the various constructs at a MOI of 1. Cells were harvested 40 hours later, and human monoclonal antibodies that recognize the S1 or N proteins (Genscript) were used to stain separate wells. An anti-human IgG PE secondary antibody was used to visualize expression on the fixed cells. The candidate (rAd-S; plasmid pAd-CMV-SARS-CoV-2-S-BGH-CMV-dsRNA-SPA described above) that expressed full length SARS-CoV-2 S protein, but not the N protein clearly showed such expression patterns. The candidate (rAd-S1-N; plasmid pAd-CMV-SARS-CoV-2-S1-Furin-N-BGH-CMV-dsRNA-SPA as described above) that expressed a fusion protein of S1-N expressed both S and N proteins, as did the candidate (rAd-S-N; plasmid pAd-CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-CMV-dsRNA-SPA as described above) that expressed S and N off separate promoters (FIG. 1).

Example 3. Immunogenicity in Mice

The primary objective of the initial mouse immunogenicity studies was to determine which of the rAd vectors induced significant antibody responses. The results were used to determine which candidate vaccine would be selected for GMP manufacturing. Animals were immunized by i.n. (N=6) and the antibody titers were measured over time. The rAd vector expressing both S and N off separate promoters (plasmid pAd-CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-CMV-dsRNA-SPA as described above) produced equivalent titers to the S1 component of the S protein from SARS-CoV-2. The rAd-S-N vector had slightly higher S1 antibody responses than the fusion protein expressing rAd-S1-N (FIG. 2).

A dose response of the chosen vaccine rAd-S-N was then performed to test immunogenicity. Three different dose levels were tested, and the antibody responses to both S1 and S2 were measured using the Mesoscale device. Similar responses were seen at all three dose levels at early timepoints, but the higher dose groups had improved antibody responses at later time points (FIGS. 3A and 3B).

Example 4. Immunogenicity in Humans

The rAd-S-N plasmid (pAd-CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-CMV-dsRNA-SPA as described above) will be manufactured in a GMP facility, dried, and placed into tablets. A human trial will evaluate the ability of the rAd-S-N to elicit immune responses in humans at different dose levels.

Example 5. Pre-Clinical Studies of a Recombinant Adenoviral Mucosal Vaccine to Prevent Sars-Cov-2 Infection
Introduction

The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 disease, in 2019, has led to a global pandemic and significant morbidity, mortality and socio-economic disruption not seen in a century. Coronavirus disease 2019 (COVID-19) is a respiratory illness of variably severity; ranging from asymptomatic infection to mild infection, with fever and cough to severe pneumonia and acute respiratory distress1. Current reports suggest that asymptomatic spread is substantial (2), and SARS-CoV-2 infection induces a transient antibody response in most individuals (3). Therefore, development of successful interventions is an immediate requirement to protect the global population against infection and transmission of this virus and its associated clinical and societal consequences. Mass immunization with efficacious vaccines has been highly successful to prevent the spread of many other infectious diseases and can also prevent disease in the vulnerable through the induction of herd immunity. Significant effort and resources are being invested in urgently identifying efficacious SARS-CoV-2 vaccines. A number of different vaccine platforms have demonstrated pre-clinical immunogenicity and efficacy against pneumonia (4, 5). Several vaccines have demonstrated phase I or phase II safety and immunogenicity (6-8). However, at this time, no vaccine has demonstrated efficacy in the field.

The most advanced SARS-CoV-2 vaccine candidates are all given by the intramuscular (IM) route, with some requiring −80° C. storage. This is a major barrier for vaccine dissemination and deployment during a pandemic in which people are asked to practice social distancing and avoid congregation. The ultimate goal of any vaccine campaign is to protect against disease by providing enough herd immunity to inhibit viral spread, not to make a set number of doses of vaccine. An injected solution takes a long period of time to administer and distribute and requires costly logistics, which means dose availability does not immediately translate to immunity. Further, systemic immunization can induce immunity in the periphery and lower respiratory tract. However, these vaccines cannot induce mucosal immunity in the upper respiratory tract, as evidenced by the poor mucosal IgA reported from van Doremalen, et al., 4 Mucosal IgA (with the polymeric structure and addition of the secretory component), creates more potent viral neutralization (9), can block viral transmission (10, 11), and in general, is more likely to create sterilizing immunity given that this is the first line of defense for a respiratory pathogen.

Mucosal vaccines can induce mucosal immune responses, antibodies and T cells at wet surfaces. We are developing oral vaccines for multiple indications, including influenza and noroviruses, delivered in a tablet form for people. Our vaccine platform is a replication-defective adenovirus type-5 vectored vaccine that expresses antigen along with a novel toll-like receptor 3 agonist as an adjuvant. These vaccines have been well tolerated, and able to generate robust humoral and cellular immune responses to the expressed antigens (12-14). Protective efficacy in humans was demonstrated against a respiratory virus 90 days or more post vaccination, as shown in a well characterized experimental influenza infection model (15). Furthermore, the vaccine also has the advantage of room temperature stability and needle-free, ease of administration, providing several advantages over injected vaccine approaches with respect to vaccine deployment and access.

Here, we describe the pre-clinical development of a SARS-CoV-2 vaccine based on Vaxart's oral adenovirus platform. The key approach was to develop several vaccine candidates in parallel, in order to create premanufacturing seeds while initial immunogenicity experiments were in progress. Given that the vaccines were made during the pandemic, rapid decisions were required to keep the manufacturing and regulatory timelines from slipping. We assessed the relative immunogenicity of four candidate vaccines that expressed antigens based on the spike (S) and nucleocapsid (N) SARS-CoV-2 proteins. These proteins have been well characterized as antigens for related coronaviruses, such as SARS-CoV and MERS (reviewed in Yong, et al., (16)) and, increasingly, for SARS-CoV-2 spike. The aim of our vaccine is to induce immunogenicity on three levels; firstly, to induce potent serum neutralizing antibodies to S, secondly to induce mucosal immune responses, and thirdly to induce T cell responses to both vaccine antigens. This three-fold approach aims to induce robust and broad immunity capable of protecting the individual from virus infection as well as disease, promote rapid dissemination of vaccine during a pandemic, and to protect the population from virus transmission through herd immunity.

Here, we report the induction of neutralizing antibody (Nab), IgG and IgA antibody responses, and T cell responses in mice following immunization of rAd vectors expressing one or more SARS-CoV-2 antigens.

Results
Vector Construction

Initially, three different rAd vectors were constructed to express different SARS-CoV-2 antigens. These were a vector expressing the full-length S protein (rAd-S), a vector expressing the S protein and the N protein (rAd-S-N), and a vector expressing a fusion protein of the S1 domain with the N protein (rAd-S1-N). The N protein of rAd-S-N was expressed under control of the human beta actin promoter, which is much more potent in human cells than mouse cells. An additional construct where the expressed S protein was fixed in a prefusion conformation (rAd-S(fixed)-N) was constructed at a later date as a control for exploring neutralizing antibody responses. These are described in FIG. 4. Expression of the various transgenes was confirmed following infection of 293 cells using flow cytometry and monoclonal antibodies to the S or N protein.

Immunogenicity of rAd Vectors Expressing S and N Antigens

The primary objective of the initial mouse immunogenicity studies was to determine which of the rAd vectors induced significant antibody responses to S, and to obtain those results rapidly enough to provide a GMP seed in time for manufacturing. We and others (17) have observed that transgene expression by vaccine vectors orally administered to mice can be suppressed in their intestinal environment, so immunogenicity was assessed following intranasal (i.n.) immunization. Animals were immunized i.n. and the antibody titers were measured over time by IgG ELISA. All three rAd vectors induced nearly equivalent anti-S1 IgG titers, at weeks 2 and 4 and the IgG titer in all animals was significantly boosted by the second immunization (p<0.05 Mann Whitney t-tests) (FIG. 5A). However, the vector expressing full-length S (rAd-S-N) induced higher neutralizing titers compared to the vector expressing only S1 (FIG. 5B). This was measured by two different neutralizing assays, one based on SARS-CoV-2 infection of Vero cells (cVNT) and one based on a surrogate neutralizing assay (sVNT). Furthermore, rAd-S-N induced higher lung IgA responses to S1 and unsurprisingly, to S2 (FIG. 5C) compared to rAd-S1-N two weeks after the final immunization. Notably, neutralizing titers in the lung were also significantly higher when rAd-S-N was used compared to the S1-containing vaccine (rAd-S1-N) (FIG. 5D). This demonstrated that the rAd-S-N candidate induced greater functional responses (NAb and IgA) compared to the vaccine containing the just the S1 domain. Because the N protein is much more highly conserved than the S protein, and is a target of long term T cell responses induced by infection (18), the vector rAd-S-N was chosen for GMP manufacturing.

Three dose levels of rAd-S-N were then tested to understand the dose responsiveness of this vaccine. The antibody responses to both S1 (FIG. 6A) and S2 (FIG. 6B) were measured. Similar responses were seen at all three dose levels at all timepoints. Responses to S1 and S2 were significantly increased at week 6 compared to earlier times, in all groups.

The induction of S-specific T cells by rAd-S-N at different doses was then assessed. Induction of antigen-specific CD4+ and CD8+ T cells that produced effector cytokines such as IFN-γ, TNF-α and IL-2 was observed two weeks after 2 immunizations (FIG. 7A). Notably, little IL-4 was induced by this vaccine and only in CD4+ T cells; providing a level of assurance that the risk for vaccine dependent enhancement of disease was very low. Furthermore, immunization with rAd-S-N induced double and triple positive, multi-functional IFN-γ, TNF-α and IL-2 CD4+ T cells (FIG. 7B). A second dose response experiment was performed to focus on T cell responses to the S protein, 4 weeks after the final immunization (week 8 of the study). Splenocytes were stimulated overnight with a peptide library to the S protein, divided in two separate peptide pools. T cell responses in the two pools were summed and plotted (FIG. 7C). Animals administered the 1e7 IU and the 1e8 IU dose levels had significantly higher T cell responses compared to the untreated animals but produced a similar number of IFN-γ secreting cells to each other, demonstrating a dose plateau at the 1e7 IU dose. Notably, this T cell analysis was conducted 4 weeks after the second immunization, potentially after the peak of T cell responses.

rAd-Expressed Wild-Type S Induces a Superior Neutralizing Response Compared to Stabilized Pre-Fusion S.

An additional study was performed to compare rAd-S-N to a vaccine candidate with the S-protein stabilized and with the transmembrane region removed (rAd-S(fixed)-N). A stabilized version of the S protein has been proposed as a way to improve neutralizing antibody responses and produce less non-neutralizing antibodies. The S protein was stabilized through modifications as described by Amanat et al., (19). rAd-S-N induced higher serum IgG titers to S1 (FIG. 8A) at both timepoints tested, although these were not statistically significant at week 6 by Mann-Whitney (p=0.067). However, rAd-S-N induced significantly higher neutralizing antibody responses (FIG. 8B) than the stabilized version (p=0.0152). These results suggest that a wild-type version of the S protein is superior for a rAd based vaccine in mice.

Discussion

The endgame to the COVID-19 pandemic requires the identification and manufacture of a safe and effective vaccine and a subsequent global immunization campaign. A number of vaccine candidates have accelerated to phase III global efficacy testing and, if sufficiently successful in these trials, may form the first generation of an immunization campaign. However, all of these advanced candidates are S-based vaccines that are injected. Such an approach will unlikely prevent virus transmission, but should prevent pneumonia and virus growth and damage in the lower respiratory tract and periphery, as evidenced in macaque challenge studies (4, 5).

One key constraint in a global COVID-19 immunization campaign will be the cold chain distribution logistics and a bottleneck of requiring suitably trained health care workers (HCWs) to inject the vaccine. Current logistics costs, including cold chain and training, can double the cost of fully immunizing an individual in a low-middle income country (LMIC) (20). Implementing a mass immunization campaign, requiring trained HCWs for injection-based vaccines, will have a significant impact on healthcare resources in all countries. The need for cold chain, biohazardous sharps waste disposal and training will result in increased cost, inequitable vaccine access, delayed vaccine uptake and prolongation of this pandemic. These costs will be magnified if vaccines are unable to provide long-term protection (natural immunity to other beta-coronaviruses is short-lived (21)), and annual injection-based campaigns are needed. Vaxart's oral tablet vaccine platform provides a solution to these immunological as well as logistic, economic, access and acceptability problems. In this study we demonstrate, in an animal pre-clinical model, the immunogenicity of a SARS-CoV-2 vaccine using Vaxart's vaccine platform; namely the induction of serum and mucosal neutralising antibodies and poly-functional T cells.

Mouse studies were designed to test immunogenicity of candidate vaccines rapidly in the spring of 2020, before moving onto manufacturing and clinical studies critical to addressing the pandemic. Vaxart's oral tablet vaccine platform has previously proven to be able to create reliable mucosal (respiratory and intestinal), T cell, and antibody responses against several different pathogens in humans (12, 14, 22, 23). We know from our prior human influenza virus challenge study that oral immunization was able to induce protective efficacy 90 days post immunization; on par with the commercial quadrivalent inactivated vaccine (15). These features provide confidence that the adoption of the platform to COVID-19 could translate to efficacy against this pathogenic coronavirus and could provide durable protection against virus infection. Finally, a tablet vaccine campaign is much easier because qualified medical support is not needed to administer it. This ease of administration will result in increased vaccine access and potentially, acceptability, as has been evidenced by the success of easy-to-administer, oral polio vaccine, in the elimination of polio virus (24). These features could be even more important during SARS-CoV-2 immunization campaigns compared to other vaccines, as substantially more resources may be required to ensure uptake of this vaccine, given the global levels of COVID-19 denialism, mistrust and increased vaccine hesitancy (25, 26). The tablet vaccine does not need refrigerators or freezers, does not require needles or vials, and can potentially be shipped via standard mail or by a delivery drone. These qualities significantly enhance deployment and distribution logistics, even permitting access to isolated regions with fewer technical resources. Finally, from an immunological perspective, oral administration of this adenovirus is not compromised by pre-existing immunity to adenoviruses or creates substantial anti-vector immunity (12, 13), issues that have been shown to cause significantly decreased vaccine potency in an rAd5 based SARS-CoV2 vaccine (27) and can prevent durable increased immunity when the same adenovirus platform is re-administered by the IM route (28).

The choice of antigen can be difficult during a novel pandemic, a time in which key decisions are needed quickly. The S protein is believed to be the major neutralizing antibody target for coronavirus vaccines, as the protein is responsible for receptor binding, membrane fusion, and tissue tropism. When comparing SARS-CoV-2 Wu-1 to SARS-CoV, the S protein was found to have 76.2% identity (29). Both SARS-CoV and SARS-CoV-2 are believed to use the same receptor for cell entry: the angiotensin-converting enzyme 2 receptor (ACE2), which is expressed on some human cell types30. Thus, SARS-CoV-2 S protein is being used as the leading target antigen in vaccine development so far and is an ideal target given that it functions as the key mechanism for viral binding to target cells. However, the overall reliance on the S protein and an IgG serum response in the vaccines could eventually lead to viral escape. For influenza, small changes in the hemagglutinin binding protein, including a single glycosylation site, can greatly affect the ability of injected vaccines to protect (31). SARS-CoV-2 appears to be more stable than most RNA viruses, but S protein mutations have already been observed without the selective pressure of a widely distributed vaccine. Once vaccine pressure begins, escape mutations might emerge. We took two approaches to address this issue; firstly to include the more conserved N protein in the vaccine and secondly to induce broader immune responses, namely through mucosal IgA.

High expression levels of ACE2 are present in type II alveolar cells of the lungs, absorptive enterocytes of the ileum and colon, and possibly even in oral tissues such as the tongue (32). Transmission of the virus is believed to occur primarily through respiratory droplets and fomites between unprotected individuals in close contact (33), although there is some evidence of transmission via the oral-fecal route as seen with both SARS-CoV and MERS-CoV viruses where coronaviruses can be secreted in fecal samples from infected humans (34). There is also evidence that a subset of individuals exist that have gastrointestinal symptoms, rather than respiratory symptoms, are more likely to shed virus longer (35). Driving immune mucosal immune responses to S at both the respiratory and the intestinal tract may be able provide broader immunity and a greater ability to block transmission, than simply targeting one mucosal site alone. Blocking transmission, rather than just disease, will be essential to reducing infection rates and eventually eradicating SARS-CoV-2. We have previously demonstrated that an oral, tableted rAd-based vaccine can induce protection against respiratory infection and shedding following influenza virus challenge (15) as well as intestinal immunity to norovirus antigens in humans (12). Furthermore, mucosal IgA is more likely to be able address any heterogeneity of the S proteins in circulating viruses than a monomeric IgG response. mIgA has also been found to be more potent at cross reactivity than IgG for other respiratory pathogens (36). IgA may also be a more neutralizing isotype than IgG in COVID-19 infection, and in fact neutralizing IgA dominates the early immune response (37). Notably, we saw a higher ratio between neutralizing to non-neutralizing antibodies in our lung versus serum antibody results in our mouse study as well, which supports the concept that IgA may have more potency compared to IgG. Polymeric IgA, through multiple binding interactions to the antigen and to Fc receptors can turn a weak single interaction into a higher overall affinity binding and activation signal, creating more cross-protection against heterologous viruses (38).

Our second strategy to mitigate this potential vaccine-driven escape problem was to include the N protein in the vaccine construct. The N protein is highly conserved among β-coronaviruses, (greater than 90% identical) contains several immunodominant T cell epitopes, and long-term memory to N can be found in SARS-CoV recovered subjects as well as people with no known exposure to SARS-CoV or SARS-CoV-2 (18, 39). In an infection setting, T cell responses to the N protein seem to correlate to increased neutralizing antibody responses (40). All of these reasons led us to add N to our vaccine approach. The protein was expressed in 293A cells. However, as the human beta actin promoter is more active in human cells than mice, we did not explore immune responses in Balb/c mice, but will examine them more carefully in future NHP and human studies.

The optimum sequence and structure of the S protein to be included in a SARS-CoV-2 vaccine is a subject of debate. Several labs have suggested that reducing the S protein to the key neutralizing domains within the receptor binding domain (RBD) would promote higher neutralizing antibody responses, and fewer non-neutralizing antibodies (41, 42). We made a vaccine candidate composed of the S1 domain, which includes the RBD, in an attempt to promote this approach. Although the S1-based vaccine produced similar IgG binding titers to S1, neutralizing antibody responses were significantly lower compared to the full-length S antigen. Other gene-based vaccines have also shown the reductionist approach to S does not work so well, demonstrating that the DNA vaccine expressing the full-length S-protein produced higher neutralizing antibodies than shorter S segments (5). In agreement with these macaque studies, we observed that the sequence of the Ad-encoded antigen had a significant impact on antibody function, here with respect to neutralization. While reducing the potential for exposing non-neutralizing antibody epitopes seems reasonable in theory, this might reduce the T cell help that allows for greater neutralizing antibodies to develop. Indeed, of the spike protein T cell responses, which make up 54% of the responses to SARS-CoV-2, only 11% map to receptor binding domain (43). Stabilizing the S protein might be important for a protein vaccine, but not necessarily for a gene-based vaccine. The former is produced in vitro and it is produced to retain a homogenous, defined structure, ready for injection. In contrast, the latter, is expressed on the surface of a cell, in vivo, like natural infection, substantially in a prefusion form, and the additional stabilization may be unnecessary for B cells to create antibodies against the key neutralizing epitopes. We directly compared a stabilized version of S to the wild-type version in construct encoding the S and N proteins as described in this example. The wild-type version was significantly better at inducing neutralizing antibody responses. Of interest, this was also observed in a DNA vaccine study in NHPs, where the stabilized version appeared to induce lower neutralizing antibody (NAb) titers compared to the wild-type S5. A slightly different result was observed in studies of rAd26 vectors by Mercado, et al in NHPs, where expressing a stabilized version of the S protein appeared to improve NAb but lower T cell responses (44). In summary, stabilization doesn't universally improve the immune responses in gene-based or vector-based vaccines.

Multiple vaccine candidates are in, or are about to begin, clinical testing. Due to known safety and immunogenicity for epidemic pathogens such as Ebola virus, two leading candidate vaccines are based on recombinant adenovirus vectors; University of Oxford's ChAdOx1-nCov and Janssen Pharmaceutical's AdVac platforms (45-48). We saw stronger serum IgG and NAb titers in our study compared to a ChAdOx1-nCov in Balb/c mice. (4) However, this might reflect differences in assay components. An rAd36 vaccine study was performed by Hassan, et al., where doses of 1e10 VP were given by intranasal delivery (49). The results were significant from the standpoint of blocking lung infection in a mouse SARS-CoV-2 challenge model. They reported titers of serum antibody titers of 1e4 above the background titers, similar to our results, despite using doses 2- to 3-log fold higher compared to our study. Indeed, in our study, equivalently strong T cell and antibody responses were observed using 1e7 IU and 1e8 IU by the intranasal route. Using these doses, we observed high percentages of CD8+ T cell responses (up to 14%) secreting IFN-γ and TNF-α and strong CD4+ T cells after peptide restimulation. Although we did not evaluate the trafficking properties of these antigen-specific T cells, we know that oral administration of this Ad-based vaccine in humans induces high levels of mucosal homing lymphocytes (12, 15). A proportion of the antigen-specific CD4+ and CD8+ T cells were polyfunctional in this mouse study. Vaccine-induced T cells possessing multiple functions may provide more effective elimination of virus subsequent to infection and therefore could be involved in the prevention of disease, however it is uncertain at this time what is the optimum T cell phenotype required for protection against disease.

In summary, these studies in mice represent were our first step in creating a vaccine candidate, demonstrating the immunogenicity of the construct at even low vaccine doses and the elucidation of the full-length spike protein as a leading candidate antigen to induce T cell responses and superior systemic and mucosal neutralizing antibody. Future work will focus on the immune responses in humans.

Methods
Vaccine Constructs

For this study, four recombinant adenoviral vaccine constructs were created based on the published DNA sequence of SARS-CoV-2 publicly available as Genbank Accession No. MN908947.3. Specifically, the published amino acid sequences of the SARS-CoV-2 spike protein (S protein) and the SARS-CoV-2 Nucleocapsid protein (N protein) were used to synthesize nucleic acid sequences codon optimized for expression in Homo sapiens cells (Blue Heron Biotechnology, Bothell, Wash.). These sequences were used to create recombinant plasmids containing transgenes cloned into the E1 region of Adenovirus Type 5 (rAd5), as described by He, et al. (50), using the same vector backbone used in prior clinical trials for oral rAd tablets (12, 15). As shown in FIG. 4, the following four constructs were created:

a. rAd-S: rAd5 vector containing full-length SARS-CoV-2 S gene under control of the CMV promoter.

b. rAd-S-N: rAd5 vector containing full-length SARS-CoV-2 S gene under control of the CMV promoter and full-length SARS-CoV-2 N gene under control of the human beta-actin promoter.

c. rAd-S1-N: rAd5 vector using a fusion sequence combining the S1 region of SARS-CoV-2 S gene (including the native furin site between S1 and S2) with the full-length SARS-CoV-2 N gene.

d. rAd-S(fixed)-N: rAd5 vector containing a stabilized S gene with the transmembrane region removed under the control of the CMV promoter and full-length SARS-CoV-2 N gene under control of the human beta-actin promoter. The S gene is stabilized through the following modifications:

a) Arginine residues at aa positions 682, 683, 685 were deleted to remove the native furin cleavage site

b) Two stabilizing mutations were introduced: K986P and V987P

c) Transmembrane region was removed following P1213 and replaced with bacteriophage T4 fibritin trimerization foldon domain sequence (51) (GYIPEAPRDGQAYVRKDGEWVLLSTFL)

All vaccines were grown in the Expi293F suspension cell-line (Thermo Fisher Scientific), purified by CsCl density centrifugation and provided in a liquid form for animal experiments.

Animal Experiments

Studies were approved for ethics by the Animal Care and Use Committees (IACUC). All of the procedures were carried out in accordance with local, state and federal guidelines and regulations. Female 6-8 week old Balb/c mice were purchased from Jackson labs (Bar Harbor, Me.). Because mice do not swallow pills, liquid formulations were instilled intranasally in 10 μl per nostril, 20 μl per mouse in order to test immunogenicity of the various constructs. Serum was acquired by cheek puncture at various timepoints.

Antibody Assessment
ELISAs.

Specific antibody titers to proteins were measured similarly to methods described previously (52). Briefly, microtiter plates (MaxiSorp: Nunc) were coated in 1 carbonate buffer (0.1 M at pH 9.6) with 1.0 ug/ml S1 protein (GenScript). The plates were incubated overnight at 4° C. in a humidified chamber and then blocked in PBS plus 0.05% Tween 20 (PBST) plus 1% BSA solution for 1 h before washing. Plasma samples were serially diluted in PBST. After a 2-h incubation, the plates were washed with PBST at least 5 times. Antibodies were then added as a mixture of anti-mouse IgG1-horseradish peroxidase (HRP) and anti-mouse IgG2a-HRP (Bethyl Laboratories, Montgomery, Tex.). Each secondary antibody was used at a 1:5,000 dilution. The plates were washed at least 5 times after a 1-h incubation. Antigen-specific mouse antibodies were detected with 3,3=,5,5=-tetramethyl-benzidine (TMB) substrate (Rockland, Gilbertsville, Pa.) and H2SO4 was used as a stop solution. The plates were read at 450 nm on a Spectra Max M2 Microplate Reader. Average antibody titers were reported as the reciprocal dilution giving an absorbance value greater than the average background plus 2 standard deviations, unless otherwise stated.

Antibody Binding Antibodies

To measure responses to both S1 and S2 simultaneously, A MULTI-SPOT® 96-well, 2-Spot Plate (Mesoscale Devices; MSD) was coated with SARS CoV-2 antigens. Proteins were commercially acquired from a source (Native Antigen Company) that produced them in mammalian cells (293 cells). These were biotinylated and adhered to their respective spots by their individual U-PLEX linkers. To measure IgG antibodies, plates were blocked with MSD Blocker B for 1 hour with shaking, then washed three times prior to the addition of samples, diluted 1:4000. After incubation for 2 hours with shaking, the plates were washed three times. The plates were then incubated for 1 hour with the detection antibody at 1 μg/mL (MSD SULFO-TAG™ Anti-mouse IgG). After washing 3 times, the Read Buffer was added and the plates were read on the Meso QuickPlex SQ 120.

SARS-CoV-2 Neutralization Assays

Neutralizing antibodies were routinely detected based on the SARS-CoV-2 Surrogate Virus Neutralization Test (sVNT) kit (GenScript). This ELISA-based kit detects antibodies that hinder the interaction between the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein and the ACE2 receptor on host cells, and is highly correlated to conventional virus neutralizing titers for SARS-CoV-2 infection of Vero cells (53). The advantage of this approach is that the assay can be done in a BSL-2 laboratory. Sera from mice immunized with the candidate vaccines was diluted at 1:20, 1:100, 1:300, 1:500, 1:750 and 1:1000 using the provided sample dilution buffer. Sera from non-immunized mice was diluted 1:20. Lung samples were diluted 1:5, 1:20, and 1:100. Positive and negative controls were prepared at a 1:9 volume ratio following the provided protocol. After dilution, sera or lung samples were individually incubated at a 1:1 ratio with HRP-RBD solution for 30 minutes at 37° C. Following incubation, 100 μl of the each HRP-RBD and sample or control mixture was added to the corresponding wells in the hACE2-precoated capture plate and once again incubated at 37° C. for 15 minutes. Afterwards, wells were thoroughly washed and 100 μl of the provided TMB (3,3=,5,5=-tetramethyl-benzidine) solution was added to each well and left to incubate for 15 minutes at room temperature (20-25° C.). Lastly 50 μl of Stop Solution was added to each well, and the plate was read on a Spectra Max M2 Microplate Reader at 450 nm. The absorbance of a given sample is inversely related on the titer of anti-SARS-CoV-2 RBD neutralizing antibody in a given sample. Per test kit protocol, a cut-off of 20% inhibition when comparing the OD of the sample versus the OD of the negative control was determined to be positive for the presence of neutralizing antibodies. Samples that were negative at the lowest dilution were set equal to ½ of the lowest dilution tested, either 10 for sera or 2.5 for lung samples.

Additional neutralizing antibodies responses were measured in some studies using a cVNT assay at Visimederi under BSL3 conditions. The cVNT assay has a readout of Cytopathic Effect (CPE) to detect specific neutralizing antibodies against live SARS-COV-2 in animal or human samples. The cVNT/CPE assay permits the virus to makes multiples cycles of infection and release from cells; its exponential grow in few days (usually 72 hours of incubation) causes the partial or complete cell monolayer detachment from the surface of the support, clearly identifiable as CPE. Serum samples are heat inactivated for 30 min at 56°; two-fold dilutions, starting from 1:10 are performed then mixed with an equal volume of viral solution containing 100 TCID50 of SARS-CoV-2. The serum-virus mixture is incubated for 1 hour at 37° in humidified atmosphere with 5% CO2. After incubation, 100 μL of the mixture at each dilution are added in duplicate to a cell plate containing a semiconfluent Vero E6 monolayer. After 72 hours of incubation the plates are inspected by an inverted optical microscope. The highest serum dilution that protect more than 50% of cells from CPE is taken as the neutralization titer.

Lung IgA ELISAs.

Two weeks after the final immunization (day 28 of the study), mice were sacrificed and bled via cardiac puncture. Lungs were removed and snap frozen at −80° C. On thawing, lungs were weighed. Lungs were homogenized in 150 μl DPBS using pellet pestles (Sigma Z359947). Homogenates were centrifuged at 1300 rpm for 3 minutes and supernatants were frozen. The total protein content in lung homogenate was evaluated using a Bradford assay to ensure equivalent amounts of tissue in all samples before evaluation of IgA content. Antigen-specific IgA titers in lungs were detected using a mouse IgA ELISA kit (Mabtech) and pNPP substrate (Mabtech). Briefly, MaxiSorp plates (Nunc) were coated with S1 or S2 (The Native Antigen Company; 50 ng/well) in PBS for overnight adsorption at 4° C. and then blocked in PBS plus 0.05% Tween 20 (PBST) plus 0.1% BSA (PBS/T/B) solution for 1 h before washing. Lung homogenates were serially diluted in PBS/T/B, starting at a 1:30 dilution. After 2 hours incubation and washing, bound IgA was detected using MT39A-ALP conjugated antibody (1:1000), according to the manufacturer's protocol. Plates were read at 415 nm. Endpoint titers were taken as the x-axis intercept of the dilution curve at an absorbance value 3× standard deviations greater than the absorbance for naïve mouse serum. Non-responding animals were set a titer of 15 or ½ the value of the lowest dilution tested.

T Cell Responses

Spleens were removed and placed in 5 ml Hanks Balanced Salt Solution (with 1M HEPES and 5% FBS) before pushing through a sterile strainer with a 5 ml syringe. After RBC lysis (Ebiosolutions), resuspension, and counting, the cells were ready for analysis. Cells were cultured at 5e5 cells/well with two peptide pools representing the full-length S protein at 1 μg/ml (Genscript) overnight in order to stimulate the cells. The culture media consisted of RPMI media (Lonza) with 0.01M HEPES, 1×l-glutamine, 1×MEM basic amino acids, 1× penstrep, 10% FBS, and 5.5e-5 mole/l beta-mercaptoethanol. Antigen specific IFN-γ ELISPOTs were measured using a Mabtech kit. Flow cytometric analysis was performed using an Attune Flow cytometer and Flow Jo version 10.7.1, after staining with the appropriate antibodies. For flow cytometry, 2e6 splenocytes per well were incubated for 18 hours at 37° C. with peptide pools representing full-length S at either 1 or 5 ug/ml, adding Brefeldin A (ThermoFisher) for the last 4 hours of incubation. The antibodies used were APC-H7 conjugated CD4, FITC conjugated CD8, BV650 conjugated CD3, PerCP-Cy5.5 conjugated IFN-γ, BV421 conjugated IL-2, PE-Cy7 conjugated TNFα, APC conjugated IL-4, Alexa Fluor conjugated CD44, and PE conjugated CD62L (BD biosciences).

References for Example 5

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4. van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020.

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6. Folegatti P M, Ewer K J, Aley P K, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020.

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36. Muramatsu M, Yoshida R, Yokoyama A, et al. Comparison of antiviral activity between IgA and IgG specific to influenza virus hemagglutinin: increased potential of IgA for heterosubtypic immunity. PLoS One 2014; 9(1): e85582.

37. Sterlin D, Mathian A, Miyara M, et al. IgA dominates the early neutralizing antibody response to SARS-CoV-2. medRxiv 2020: 2020.06.10.20126532.

38. Tamura S, Funato H, Hirabayashi Y, et al. Cross-protection against influenza A virus infection by passively transferred respiratory tract IgA antibodies to different hemagglutinin molecules. Eur J Immunol 1991; 21(6): 1337-44.

39. Le Bert N, Tan A T, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020; 584(7821): 457-62.

40. Ni L, Ye F, Cheng M L, et al. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity 2020; 52(6): 971-7 e3.

41. Tai W, Zhang X, Drelich A, et al. A novel receptor-binding domain (RBD)-based mRNA vaccine against SARS-CoV-2. Cell Res 2020.

42. Zha L, Zhao H, Mohsen M O, et al. Development of a COVID-19 vaccine based on the receptor binding domain displayed on virus-like particles. bioRxiv 2020: 2020.05.06.079830.

43. Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 2020: eabd3871.

44. Mercado N B, Zahn R, Wegmann F, et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 2020.

45. Mutua G, Anzala O, Luhn K, et al. Safety and Immunogenicity of a 2-Dose Heterologous Vaccine Regimen With Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: 12-Month Data From a Phase 1 Randomized Clinical Trial in Nairobi, Kenya. J Infect Dis 2019; 220(1): 57-67.

46. Anywaine Z, Whitworth H, Kaleebu P, et al. Safety and Immunogenicity of a 2-Dose Heterologous Vaccination Regimen With Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: 12-Month Data From a Phase 1 Randomized Clinical Trial in Uganda and Tanzania. J Infect Dis 2019; 220(1): 46-56.

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52. Tucker S N, Lin K, Stevens S, Scollay R, Bennett M J, Olson D C. Systemic and mucosal antibody responses following retroductal gene transfer to the salivary gland. Mol Therapy 2003: 8: 392-9.

53. Tan C W, Chia W N, Qin X, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol 2020.

Example 6

Study VXA-COV2-101 was a Phase 1 open-label, dose-ranging trial to evaluate the safety and immunogenicity of a SARS-CoV-2 oral tableted vaccine (rAd-S-N, SEQ ID NO:10), which is referred to in Examples 6 and 7 as VXA-CoV2-1, administered to healthy adult subjects 18-55 years of age.

The objectives of this study were to evaluate the safety and immunogenicity of VXA-CoV2-1 oral vaccine delivered by enteric tablet.

Subjects were enrolled at a single phase I unit in Southern California. Following completion of screening assessment and confirmation of eligibility 35 subjects were enrolled into this trial; Cohort 1 sentinel subjects (n=5) were vaccinated at Day 1 and have a repeat dose at Day 29. Cohort 2 and 3 subjects received a single vaccination at Day 1. The study design is shown in the table below-.

VXA-COV2-101 Study Design

Dose
No. of
No of

Group
Vaccine
(IU ± 0.5 log)*
Doses
Subjects

Cohort 1
VXA-CoV2-1
1 × 10¹⁰
2
5

(Sentinels)

SMC Review of Safety Data through Day 8 Visit

Cohort 2
VXA-CoV2-1
1 × 10¹⁰
1
15

Cohort 3
VXA-CoV2-1
5 × 10¹⁰
1
15

Total
35

Cohort 1 sentinel subjects received a second dose (boost) at same dose level as the first at Day 29

B Cell Antibody Analysis

The ability of VXA-CoV2-1 in promoting B cells with high antibody-making potential was assessed using both flow cytometry-based measurements and an antibody-secreting cell (ASC) assay by ELISPOT. It has been previously well established that B cells responding to vaccination become activated at the site of administration and in local draining lymph nodes, where they differentiate into plasmablasts following germinal center reactions. Between 6 and 8 days after immunization, a significant proportion of plasmablasts leave the germinal centers and appear transiently in the peripheral circulation, where they can be found highly enriched for vaccine antigen-specific antibody-secreting cells (ASC). Accordingly, flow cytometry analysis of fixed whole blood samples collected pre- and post-vaccination in the VXA-COV2-101 study revealed a significant expansion in the overall CD27++ CD38++ plasmablast population 8 days following vaccination, with roughly 70% (24/35) of the vaccines showing a 2-fold or higher increase in plasmablast frequencies compared to baseline levels (FIG. 9A-B). Further investigation indicated upregulation of both IgA and the mucosal homing receptor α4β7 on the surface of circulating plasmablasts post vaccination, particularly in the cohort who received VXA-CoV2-1 at a higher dose level (FIG. 9C), thus suggesting vaccine-induced migration of this IgA-producing B cell population to mucosal tissues (Mora and von Andrian, 2008). Overall, these results are consistent with previous data published by the company in the context of a phase 2 Influenza A challenge study in humans, where generation of IgA plasmablasts with similar mucosal features following oral influenza vaccination was found to be a strong indicator of vaccine-induced protection (Liebowitz et al., 2020).

Additionally, an ELISpot assay was used to measure the ability of VXA-CoV2-1 to induce circulating antibody-secreting B cells that could recognize and bind the S1 domain of the SARS-CoV-2 spike (S) antigen. This analysis indicated significant vaccine-induced generation of S1-reactive, IgA-secreting ASC on day 8 post first immunization (p=0.0002 by Wilcoxon test), with an overall median 4-fold increase over baseline levels (FIG. 9D). More specifically, 8/12 (67%) subjects in the lower dose vaccine group for which both day 1 and day 8 ASC measurements were available were here classified as “responders”, as indicated by a median 2-fold or higher increase in day 8 post-vaccination IgA-secreting ASC numbers per million cells versus pre-vaccination levels (median fold increase of 2.67; 95% CI: 1.0-13.32). A slightly higher percentage of responders (11/15 subjects, 73%) was recorded in the higher vaccine dose cohort (median fold increase of 4; 95% CI: 1.3-13.32).

Levels of IgA antibodies specific to different SARS-CoV-2 antigens were measured in serum, saliva, and nasal samples pre- and post-immunization using the Meso Scale Discovery (MSD) platform. In agreement with the mucosal features of the B cell responses observed via flow cytometry and ELISPOT, IgA antibodies targeting SARS-CoV-2 spike (S), Nucleoprotein (N), and the spike receptor binding domain (RBD) could be found in both serum and mucosal compartments. Overall, 23% (8/35) of the vaccines showed a 50% or higher vaccine-specific IgA increase in the serum by day 29, with 6/8 of these subjects producing IgA targeting all three SARS-CoV-2 antigens in analysis. Consistent with the IgA+ B7+ plasmablast measurements, subjects in the higher dose cohort showed higher IgA antibody responses specific to S in the serum (FIG. 9). As we expected, given the unique characteristics of the VXA-CoV2-1 oral vaccine candidate, a higher percentage of vaccines mounted SARS-COV-2-specific IgA antibody responses in the mucosal compartments versus serum, with 54% of vaccines (19/35) reaching a 2-fold or higher increase in mucosal IgA in either saliva or nasal samples (FIG. 9F. More specifically, 10/35 (29%) of vaccines had a 2-fold or higher increase in IgA antibodies in their saliva, while 12/35 (35%) reached the same threshold in their nasal compartment by d29 post vaccination. No significant differences in vaccine-specific IgA responses in the saliva or nasal samples between the two dose groups could be observed (FIG. 9F). Measuring the ability of IgA to neutralize is difficult with the limitations of mucosal samples, but preliminary findings suggest that the subjects that had a two-fold increase in specific nasal IgA also had the ability to neutralize in a surrogate neutralization assay that measured ACE2 binding to spike protein (FIG. 9F). Secretory IgA has been shown to have higher neutralizing ability then IgG to SARS-CoV-2 as reported by Sterlin, et al, (Sterlin et al., 2021).

These findings are promising since several reports have highlighted the potential of mucosal immunity and generation of IgA antibodies in contributing to protection against COVID-19 (Ejemel et al., 2020; Russell et al., 2020; Sterlin et al., 2021). Notably, while injectable vaccines are not designed to effectively induce IgA antibodies in the respiratory mucosa, oral vaccination strategies might offer this advantage (Jeyanathan et al., 2020). Induction of SARS-CoV-2-specific IgA responses at key mucosal surfaces might also elicit sterlizing immunity and have a greater ability to block viral transmission, highly desirable features, particularly in a scenario where novel SARS-CoV-2 variants can replicate in vaccinated subjects undetected.

Analysis of IgG antibodies in the serum post-vaccination indicated an absence of an increase in SARS-CoV-2 specific antibody responses. Similarly, no significant SARS-CoV-2 antibody-mediated neutralization in the serum was observed. While the underlying reasons for the lack of vaccine-specific IgG and antibody neutralization in the serum are not defined at present, it is possible that a single oral dose of VXA-CoV2-1 at the dose levels used in this study were not sufficient to elicit robust vaccine-specific IgG neutralizing responses. Additionally, it cannot be excluded that the presence of a gene encoding for N in the VXA-CoV2-1 construct may have skewed the immunogenicity profile of this vaccine candidate away from serum neutralizing antibodies towards T cell-mediated immunity.

T Cell Analysis

Besides B cells and antibodies, T cells also play a crucial role in the generation of protective immune responses against many microbial infections. In the context of COVID-19, T cells have been shown to target multiple SARS-CoV-2 proteins in convalescent subjects, while they also appear to be less vulnerable to SARS-CoV-2 variants compared to antibodies (Grifoni et al., 2020; Ledford, 2021; Tarke et al., 2021).

Induction of SARS-CoV-2-specific T cells and Th1/Th2 polarization following vaccination with VXA-CoV2-1 were measured using a restimulation assay using peripheral blood mononuclear cells (PBMCs) from 26 pairs of samples collected pre- and day 8 post-vaccination were cultured with SARS-CoV-2 peptides from either S or N, and Th1/Th2 cytokine responses assessed. PBMCs were thawed, rested overnight and cultured in Immunocult media (Stemcell Technologies) at a concentration of 1×10⁷cells/ml in a 96 well round bottom plate for 5 hours at 37 degrees celsius with either the S or N peptide libraries (Miltenyi) in the presence of Brefeldin A (Invitrogen) and Monensin (Biolegend). Cells were harvested, surface stained with CD4-BV605, CD8-BV785 and zombie near-IR viability dye (Biolegend). After fixing with 4% PFA (biotium) and permeabilising with Cytoperm (BD Biosciences), antibodies to the cytokines IFNγ-BV510 (Biolegend), TNFα-e450 (Thermofisher), IL-2-APC (Thermofisher), IL-4-PerCP (biolegend), IL-5-PE (Biolegend), IL-13 (Biolegend), and CD107a-Alexa488 (Thermofisher) were used to assess the intracellular cytokine response and analysed using an Attune (Thermofisher) flow cytometer to evaluate.

No significant increase of Th2 responses, defined as intracellular production of IL5/1L4/IL13 cytokines by CD4⁺ T cells, was observed in response to S or N in any of the post vaccination samples compared to pre-vaccination levels. This is important since early reports in the field hypothesized potential adverse events related to antibody-dependent enhancement (ADE) following Th2 polarization (Lee et al., 2020).

Strikingly, the majority of vaccines in this study strikingly had a strong increase in Th1 responses on day 8 post vaccination, defined as intracellular production of IFNγ/TNFα cytokines and the degranulation marker CD107a, particularly from CD8⁺T cells (FIG. 10A, C) but also CD4⁺T cells (FIG. 10 B) in response to restimulation with S peptides. Particularly, 13/26 (50%) subjects had a 2-fold or higher increase in Th1 cytokines in response to S, with 19/26 (73%) subjects overall showing measurable cytokine-producing CD8⁺T cell responses above baseline levels (FIG. 10D). Increase in the production of Th1 cytokines post vaccination were also found following restimulation with SARS-COV-2 N peptides (FIG. 10E-F), particularly for CD8⁺T cells, although of lower magnitude compared to S-specific responses. More specifically, 9/26 (35%) of subjects reached a 2-fold or higher increase in CD8⁺ T cell production of Th1 cytokines following N restimulation on day 8 compared to baseline levels. Overall, the percentage of T cells that show markers of anti-viral functionality in response to SARS-CoV-2 peptides, particularly IFNγ-producing CD8⁺T cells, induced following oral immunization with VXA-CoV2-1 is remarkable. This percentage of responding CD8 T cells has not been reported with mRNA vaccines currently in use against COVID-19. This might represent a crucial advantage because CD8⁺T cells with cytotoxic ability are uniquely positioned to clear virally infected cells and could also be helpful in reducing transmission by decreasing viral loads in infected patients (Ledford, 2021). Follow-up analyses will focus on a more direct comparison of vaccine-induced T cell immunity between VXA-CoV2-1 and the SARS-CoV-2 mRNA vaccines that have received EUA in the US.

In conclusion, VXA-CoV2-1 engaged both the humoral and cellular arms of the immune system by inducing SARS-CoV-2-specific IgA antibodies at key mucosal sites, as well as vaccine-specific T cells, particularly IFNγ-producing CD8⁺ T cells directed against both SARS-CoV-2 vaccine antigens S and N.

Another general goal of coronavirus vaccines is not only to protect against current strains, but to provide protection against circulating strains of other human coronaviruses, creating a pancoronavirus vaccine. To investigate this, we evaluated whether VXA-CoV2-1 induced T cells that were specific to the four endemic human coronaviruses—229E, HKU1, OC43 and NL63. We found that there was an increase over pre-vaccination levels for all four endemic human coronaviruses (FIG. 11), suggesting that the T cells induced are cross-reactive with the circulating human coronaviruses.

Example 7

To compare the responses induced by VXA-COV2-1 with the current leading intramuscular covid vaccines, we recruited subjects that were due to be vaccinated with mRNA vaccines to donate PBMCs. PBMCs were taken at the same timepoints as our vaccines, pre and 7 days post vaccination, and T cell activity was measured in the same in vitro assay alongside PBMCs from the VXA-COV1-101 trial. Samples from all 3 vaccines were run in the same assay and subject to the same analysis to control for assay variability.

Surprisingly we found that subjects that took the VXA-COV2-1 tablets had T cell responses that were typically an order of magnitude higher than those that were vaccinated intramuscularly with either the Pfizer or Moderna vaccines approved under Emergency Use Authorization.

IFNγ and TNFα release from CD8 T cells were significantly increased (FIG. 12A), with CD107a degranulation showing a smaller increase over pre-vaccination baseline. The average percent increase above day 1 of IFNγ from CD8 T cells for the vaccines was 0.4/0.09/2.3 for Pfizer/Moderna/Vaxart vaccines respectively. This amounts to a >5 fold increase of those that took VXA-CoV-2 tablets versus the intramuscular vaccines.

As only a small subset of seven subjects were tested in the same assay as the other vaccines, to account for potential bias in selection of subjects, the whole cohort that was measured previously is graphed alongside for comparison, with significance still seen when comparing the whole cohort to the comparator experiment (FIG. 12B). With the average of the whole cohort including the non-responders being measured at 1.5%, a >3.5 fold increase was still seen over the intramuscular vaccines. The average IFNγ response of the four convalescent subjects was 0.8. Representative facs plots are shown in FIG. 12C, displaying the increase in VXA-CoV2-1 subjects at d7 post inoculation. The reported T cell measurements from the intramuscular vaccines were taken at a timepoint 7 days post second dose vaccine. To account for this, PBMCs were also measured at 7 days post second dose in the same assay and found to have responses of equal magnitude at both timepoints with the exception of one subject that had particularly good T cell responses that increased at both timepoints (FIG. 12D). This is similar to the data that was reported by Pfizer (Sahin et al. Nature 2021).

Additional References Cited in Examples 5-7

Ejemel, M., Li, Q., Hou, S., Schiller, Z. A., Tree, J. A., Wallace, A., Amcheslavsky, A., Kurt Yilmaz, N., Buttigieg, K. R., Elmore, M. J., et al. (2020). A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction. Nat Commun 11, 4198.

Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., et al. (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489-1501 e1415.

He, X. S., Sasaki, S., Narvaez, C. F., Zhang, C., Liu, H., Woo, J. C., Kemble, G. W., Dekker, C. L., Davis, M. M., and Greenberg, H. B. (2011). Plasmablast-derived polyclonal antibody response after influenza vaccination. J Immunol Methods 365, 67-75.

Jeyanathan, M., Afkhami, S., Smaill, F., Miller, M. S., Lichty, B. D., and Xing, Z. (2020). Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol 20, 615-632.

Ledford, H. (2021). How ‘killer’ T cells could boost COVID immunity in face of new variants. Nature 590, 374-375.

Lee, W. S., Wheatley, A. K., Kent, S. J., and DeKosky, B. J. (2020). Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol 5, 1185-1191.

Liebowitz, D., Gottlieb, K., Kolhatkar, N. S., Garg, S. J., Asher, J. M., Nazareno, J., Kim, K., Mcllwain, D. R., and Tucker, S. N. (2020). Efficacy, immunogenicity, and safety of an oral influenza vaccine: a placebo-controlled and active-controlled phase 2 human challenge study. Lancet Infect Dis 20, 435-444.

Mora, J. R., and von Andrian, U. H. (2008). Differentiation and homing of IgA-secreting cells. Mucosal immunology 1, 96-109.

Russell, M. W., Moldoveanu, Z., Ogra, P. L., and Mestecky, J. (2020). Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection. Front Immunol 11, 611337.

Sterlin, D., Mathian, A., Miyara, M., Mohr, A., Anna, F., Claer, L., Quentric, P., Fadlallah, J., Devilliers, H., Ghillani, P., et al. (2021). IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci Transl Med 13.

Tarke, A., Sidney, J., Methot, N., Zhang, Y., Dan, J. M., Goodwin, B., Rubiro, P., Sutherland, A., da Silva Antunes, R., Frazier, A., et al. (2021). Negligible impact of SARS-CoV-2 variants on CD4 (+) and CD8 (+) T cell reactivity in COVID-19 exposed donors and vaccines. bioRxiv.

TABLE OF SEQUENCES

SEQ ID NO: 1: SARS-CoV-2 S Protein (surface glycoprotein) amino acid sequence

MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPF

FSNVTWFHAIHVSGTNGTKRFDNPVLPINDGVYFASTEKSNIIRGWIFGTTLDSKTQS

LLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVS

QPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLP

IGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDA

VDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRF

ASVYAWNRKMSNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRG

DEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSN

LKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELL

HAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTD

AVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPT

WRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVAS

QSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTEC

SNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILP

DPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKINGLTVLPPLLT

DEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLI

ANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDIL

SRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSK

RVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGV

FVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEEL

DKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYI

KWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKG

VKLHYT*

SEQ ID NO: 2: SARS-CoV-2 N Protein (nucleocapsid phosphoprotein) amino acid

sequence

MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTAL

TQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYY

LGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPK

GFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDR

LNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQ

TQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIK

LDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTL

LPAADLDDFSKQLQQSMSSADSTQA*

SEQ ID NO: 3: SARS-CoV-2 S Protein (surface glycoprotein) nucleic acid sequence

ggtaccgccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCA

ATCTGACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGG

TGTTTACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGAC

CTCTTCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGC

ACCAACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTA

TATTTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTA

CCCTGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGT

GATCAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATC

ACAAAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGA

ATAATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAA

GCAGGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTAC

TTCAAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGG

GCTTTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAG

ATTTCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTT

CCGGATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAAC

CTTTCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCC

CTGGACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAG

GGGATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGC

TTTCCTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATT

CGCTTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTAT

AGTGTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCC

TACCAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATC

AGAGGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGAT

TATAATTACAAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTA

ACAATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAG

AAAAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGC

CGGGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAG

TCTTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCG

TGCTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTC

CACCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGG

ACCGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCC

GCGATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCT

CGATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAAC

ACAAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCA

GTGGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGG

TCCAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACA

ATTCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGAC

CCAGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGC

ATATACAATGTCCCTGGGAGCTGAGAATTCAGTCGCGTATTCAAACAATTCCATT

GCTATTCCTACTAATTTCACTATCTCCGTCACGACCGAGATCCTGCCAGTTTCCAT

GACTAAGACTTCTGTTGACTGCACCATGTATATCTGTGGCGATAGCACCGAGTGC

AGTAATCTGCTTCTGCAGTACGGCTCCTTCTGCACACAACTCAATCGAGCACTGA

CCGGTATTGCAGTTGAGCAGGACAAGAACACACAGGAGGTCTTTGCACAGGTCA

AACAAATTTACAAAACCCCCCCCATAAAAGACTTTGGTGGGTTCAACTTCAGCCA

AATCCTCCCAGATCCCAGCAAGCCCTCCAAAAGATCCTTCATCGAAGACCTTTTG

TTCAATAAGGTAACCCTGGCCGACGCAGGCTTCATCAAACAATATGGCGATTGCC

TTGGAGACATTGCTGCGCGCGATTTGATCTGTGCTCAGAAATTTAACGGTTTGAC

CGTGCTGCCCCCACTTCTGACTGATGAGATGATAGCACAGTATACTTCTGCTCTT

CTGGCAGGAACAATCACTTCCGGGTGGACCTTTGGCGCTGGTGCAGCACTGCAA

ATCCCCTTCGCAATGCAAATGGCCTACCGATTCAATGGTATTGGTGTTACCCAGA

ACGTGCTCTATGAGAATCAGAAACTCATCGCCAATCAGTTCAATAGCGCTATTGG

CAAGATTCAGGATTCCCTCAGCTCTACCGCCAGCGCTCTGGGGAAGCTCCAGGAC

GTGGTGAACCAAAATGCTCAAGCGCTCAATACCCTTGTGAAACAGCTCAGCTCC

AATTTTGGCGCAATTAGCAGCGTTCTGAATGATATTCTGTCCCGGCTGGACAAGG

TAGAAGCAGAAGTCCAGATCGACAGGCTGATCACCGGGCGGTTGCAGAGTCTCC

AGACCTATGTCACACAACAGCTGATCCGCGCCGCCGAGATCAGGGCTTCCGCTA

ACCTGGCCGCCACTAAGATGTCCGAATGCGTGTTGGGGCAGAGTAAGCGGGTCG

ACTTTTGCGGGAAGGGATACCATCTGATGAGCTTCCCTCAGTCTGCACCCCACGG

AGTAGTGTTCCTCCACGTCACATATGTGCCCGCTCAGGAAAAGAATTTCACAACC

GCACCTGCTATCTGTCACGACGGCAAGGCCCACTTTCCTAGAGAAGGAGTTTTCG

TATCTAACGGCACCCACTGGTTCGTGACACAGCGGAACTTTTACGAGCCTCAGAT

TATAACTACGGACAACACTTTCGTGTCAGGCAACTGTGACGTGGTGATTGGGATC

GTGAACAACACAGTCTACGACCCATTGCAGCCCGAGTTGGACTCCTTCAAAGAG

GAGCTTGATAAGTATTTCAAGAACCATACCTCTCCCGACGTGGACCTGGGGGAC

ATTAGCGGCATCAATGCATCCGTTGTGAATATCCAGAAAGAAATCGATAGGCTG

AATGAGGTCGCAAAAAATCTTAATGAGTCACTGATTGATCTGCAGGAACTCGGC

AAATATGAGCAGTATATTAAGTGGCCGTGGTACATATGGCTCGGCTTTATCGCCG

GTCTGATTGCCATCGTGATGGTGACCATTATGCTGTGTTGTATGACAAGCTGCTG

TTCATGTCTCAAAGGATGCTGCTCCTGCGGTAGCTGCTGTAAGTTCGATGAAGAC

GACAGTGAGCCCGTGCTCAAAGGAGTGAAACTCCACTACACATAAcgatcg

SEQ ID NO: 4: SARS-CoV-2 N Protein (nacleocapsid phosphoprotein) nucleic arid

sequence

ggtaccgccaccATGTCCGATAACGGCCCCCAGAATCAGAGAAACGCTCCCCGCATCA

CGTTCGGCGGACCAAGTGACAGCACAGGCAGTAACCAGAACGGAGAACGCTCCG

GTGCTCGCTCCAAGCAGCGACGGCCGCAAGGGCTTCCCAACAATACCGCCAGCT

GGTTTACGGCTCTGACCCAACACGGGAAAGAAGATCTTAAATTCCCCAGGGGCC

AGGGCGTCCCTATCAATACTAACTCCAGCCCGGATGATCAGATAGGCTACTATAG

ACGCGCTACCCGACGGATACGAGGGGGGGACGGCAAAATGAAGGACCTTTCCCC

CCGGTGGTATTTCTATTACTTGGGCACCGGACCAGAAGCCGGACTGCCTTACGGC

GCTAACAAAGACGGAATAATCTGGGTTGCGACGGAGGGCGCCCTGAATACACCT

AAAGACCATATCGGCACAAGAAATCCTGCTAACAATGCCGCGATTGTGCTCCAG

CTGCCTCAGGGAACCACGCTGCCTAAAGGGTTTTACGCTGAGGGGTCAAGGGGG

GGGAGTCAAGCGTCTAGTAGGTCATCCTCTCGCTCTCGCAATAGTTCCCGGAACT

CAACCCCAGGCAGCAGCAGAGGAACCTCTCCCGCACGGATGGCTGGCAATGGGG

GAGATGCTGCCCTTGCTCTCCTTCTGCTGGATCGCCTTAACCAGCTCGAATCAAA

GATGTCTGGAAAAGGTCAGCAGCAGCAAGGCCAGACCGTGACAAAGAAGAGTG

CAGCTGAAGCTAGTAAAAAGCCACGCCAAAAACGGACCGCAACTAAGGCATATA

ACGTAACACAGGCCTTCGGCAGAAGAGGTCCAGAACAAACACAGGGAAACTTTG

GCGATCAAGAGCTGATTAGACAGGGCACAGATTACAAACACTGGCCACAGATCG

CGCAGTTTGCACCAAGCGCCTCTGCATTCTTCGGGATGAGTCGGATTGGGATGGA

AGTCACTCCATCCGGGACCTGGCTTACCTACACAGGGGCAATAAAACTCGACGA

CAAAGACCCAAACTTTAAAGATCAGGTCATCCTGCTGAATAAACACATCGATGC

CTACAAAACTTTCCCCCCAACCGAACCAAAGAAAGACAAGAAAAAAAAGGCAG

ACGAAACGCAAGCGCTCCCTCAGCGCCAGAAGAAGCAGCAGACCGTTACACTGT

TGCCAGCAGCAGATCTGGATGATTTTTCCAAGCAGCTTCAACAGAGTATGTCAAG

CGCTGACAGCACTCAGGCTTGAcgatcg

SEQ ID NO: 5: SARS-CoV-2 Fusion: S1-Furin-N nucleic acid sequence

ggtaccgccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCA

ATCTGACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGG

TGTTTACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGAC

CTCTTCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGC

ACCAACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTA

TATTTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTA

CCCTGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGT

GATCAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATC

ACAAAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGA

ATAATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAA

GCAGGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTAC

TTCAAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGG

GCTTTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAG

ATTTCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTT

CCGGATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAAC

CTTTCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCC

CTGGACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAG

GGGATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGC

TTTCCTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATT

CGCTTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTAT

AGTGTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCC

TACCAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATC

AGAGGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGAT

TATAATTACAAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTA

ACAATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAG

AAAAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGC

CGGGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAG

TCTTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCG

TGCTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTC

CACCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGG

ACCGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCC

GCGATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCT

CGATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAAC

ACAAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCA

GTGGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGG

TCCAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACA

ATTCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGAC

CCAGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGC

ATATACAATGATGTCCGATAACGGCCCCCAGAATCAGAGAAACGCTCCCCGCAT

CACGTTCGGCGGACCAAGTGACAGCACAGGCAGTAACCAGAACGGAGAACGCTC

CGGTGCTCGCTCCAAGCAGCGACGGCCGCAAGGGCTTCCCAACAATACCGCCAG

CTGGTTTACGGCTCTGACCCAACACGGGAAAGAAGATCTTAAATTCCCCAGGGG

CCAGGGCGTCCCTATCAATACTAACTCCAGCCCGGATGATCAGATAGGCTACTAT

AGACGCGCTACCCGACGGATACGAGGGGGGGACGGCAAAATGAAGGACCTTTCC

CCCCGGTGGTATTTCTATTACTTGGGCACCGGACCAGAAGCCGGACTGCCTTACG

GCGCTAACAAAGACGGAATAATCTGGGTTGCGACGGAGGGCGCCCTGAATACAC

CTAAAGACCATATCGGCACAAGAAATCCTGCTAACAATGCCGCGATTGTGCTCC

AGCTGCCTCAGGGAACCACGCTGCCTAAAGGGTTTTACGCTGAGGGGTCAAGGG

GGGGGAGTCAAGCGTCTAGTAGGTCATCCTCTCGCTCTCGCAATAGTTCCCGGAA

CTCAACCCCAGGCAGCAGCAGAGGAACCTCTCCCGCACGGATGGCTGGCAATGG

GGGAGATGCTGCCCTTGCTCTCCTTCTGCTGGATCGCCTTAACCAGCTCGAATCA

AAGATGTCTGGAAAAGGTCAGCAGCAGCAAGGCCAGACCGTGACAAAGAAGAG

TGCAGCTGAAGCTAGTAAAAAGCCACGCCAAAAACGGACCGCAACTAAGGCATA

TAACGTAACACAGGCCTTCGGCAGAAGAGGTCCAGAACAAACACAGGGAAACTT

TGGCGATCAAGAGCTGATTAGACAGGGCACAGATTACAAACACTGGCCACAGAT

CGCGCAGTTTGCACCAAGCGCCTCTGCATTCTTCGGGATGAGTCGGATTGGGATG

GAAGTCACTCCATCCGGGACCTGGCTTACCTACACAGGGGCAATAAAACTCGAC

GACAAAGACCCAAACTTTAAAGATCAGGTCATCCTGCTGAATAAACACATCGAT

GCCTACAAAACTTTCCCCCCAACCGAACCAAAGAAAGACAAGAAAAAAAAGGC

AGACGAAACGCAAGCGCTCCCTCAGCGCCAGAAGAAGCAGCAGACCGTTACACT

GTTGCCAGCAGCAGATCTGGATGATTTTTCCAAGCAGCTTCAACAGAGTATGTCA

AGCGCTGACAGCACTCAGGCTTGAcgatcg

SEQ ID NO: 6: CMV-SARS-CoV-2-S-BGH-CMV-dSRNA-SPA

TAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTA

CATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATT

GACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA

CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGT

ATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTG

GCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTAC

GTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGC

GTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAA

TGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAAC

TCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATA

AGCAGAGCTCGTTTAGTGAACCGTCAGatcgcctggagacgccatccacgctgttttgacctccatagaaga

caccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaaga

caggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattgg

tctattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGATGggtacc

gccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCAATCT

GACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGGTGTT

TACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGACCTCT

TCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGCACC

AACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTATAT

TTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTACCC

TGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGTGAT

CAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATCACA

AAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGAATA

ATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAAGCA

GGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTACTTC

AAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGGGCT

TTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAGATT

TCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTTCCG

GATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAACCTT

TCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCCCTG

GACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAGGGG

ATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGCTTTC

CTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATTCGC

TTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTATAGT

GTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCCTAC

CAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATCAGA

GGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGATTAT

AATTACAAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTAAC

AATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAGAA

AAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGCCG

GGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAGTC

TTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCGTG

CTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTCCA

CCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGGAC

CGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCCGC

GATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCTCG

ATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAACAC

AAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCAGT

GGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGGTC

CAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACAAT

TCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGACCC

AGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGCAT

ATACAATGTCCCTGGGAGCTGAGAATTCAGTCGCGTATTCAAACAATTCCATTGC

TATTCCTACTAATTTCACTATCTCCGTCACGACCGAGATCCTGCCAGTTTCCATGA

CTAAGACTTCTGTTGACTGCACCATGTATATCTGTGGCGATAGCACCGAGTGCAG

TAATCTGCTTCTGCAGTACGGCTCCTTCTGCACACAACTCAATCGAGCACTGACC

GGTATTGCAGTTGAGCAGGACAAGAACACACAGGAGGTCTTTGCACAGGTCAAA

CAAATTTACAAAACCCCCCCCATAAAAGACTTTGGTGGGTTCAACTTCAGCCAAA

TCCTCCCAGATCCCAGCAAGCCCTCCAAAAGATCCTTCATCGAAGACCTTTTGTT

CAATAAGGTAACCCTGGCCGACGCAGGCTTCATCAAACAATATGGCGATTGCCTT

GGAGACATTGCTGCGCGCGATTTGATCTGTGCTCAGAAATTTAACGGTTTGACCG

TGCTGCCCCCACTTCTGACTGATGAGATGATAGCACAGTATACTTCTGCTCTTCTG

GCAGGAACAATCACTTCCGGGTGGACCTTTGGCGCTGGTGCAGCACTGCAAATC

CCCTTCGCAATGCAAATGGCCTACCGATTCAATGGTATTGGTGTTACCCAGAACG

TGCTCTATGAGAATCAGAAACTCATCGCCAATCAGTTCAATAGCGCTATTGGCAA

GATTCAGGATTCCCTCAGCTCTACCGCCAGCGCTCTGGGGAAGCTCCAGGACGTG

GTGAACCAAAATGCTCAAGCGCTCAATACCCTTGTGAAACAGCTCAGCTCCAATT

TTGGCGCAATTAGCAGCGTTCTGAATGATATTCTGTCCCGGCTGGACAAGGTAGA

AGCAGAAGTCCAGATCGACAGGCTGATCACCGGGCGGTTGCAGAGTCTCCAGAC

CTATGTCACACAACAGCTGATCCGCGCCGCCGAGATCAGGGCTTCCGCTAACCTG

GCCGCCACTAAGATGTCCGAATGCGTGTTGGGGCAGAGTAAGCGGGTCGACTTT

TGCGGGAAGGGATACCATCTGATGAGCTTCCCTCAGTCTGCACCCCACGGAGTA

GTGTTCCTCCACGTCACATATGTGCCCGCTCAGGAAAAGAATTTCACAACCGCAC

CTGCTATCTGTCACGACGGCAAGGCCCACTTTCCTAGAGAAGGAGTTTTCGTATC

TAACGGCACCCACTGGTTCGTGACACAGCGGAACTTTTACGAGCCTCAGATTATA

ACTACGGACAACACTTTCGTGTCAGGCAACTGTGACGTGGTGATTGGGATCGTGA

ACAACACAGTCTACGACCCATTGCAGCCCGAGTTGGACTCCTTCAAAGAGGAGC

TTGATAAGTATTTCAAGAACCATACCTCTCCCGACGTGGACCTGGGGGACATTAG

CGGCATCAATGCATCCGTTGTGAATATCCAGAAAGAAATCGATAGGCTGAATGA

GGTCGCAAAAAATCTTAATGAGTCACTGATTGATCTGCAGGAACTCGGCAAATA

TGAGCAGTATATTAAGTGGCCGTGGTACATATGGCTCGGCTTTATCGCCGGTCTG

ATTGCCATCGTGATGGTGACCATTATGCTGTGTTGTATGACAAGCTGCTGTTCAT

GTCTCAAAGGATGCTGCTCCTGCGGTAGCTGCTGTAAGTTCGATGAAGACGACA

GTGAGCCCGTGCTCAAAGGAGTGAAACTCCACTACACATAAcgatcgGATATCGCT

AGCGTACCGGCGGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCTCGCTG

ATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCG

TGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGA

GGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTG

GGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGA

TGCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAAAGCTTAcgcgttagttattaata

GTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACA

TAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGA

CGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACG

TCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTAT

CATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGC

ATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGT

ATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGT

GGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATG

GGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTC

CGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAG

CAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGAGATATCGGGCCACTGCAGG

AAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCTCTAGAAA

TAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTG

SEQ ID NO: 7: CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-CMV-

dsRNA-SPA

TAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTA

CATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATT

GACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA

CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGT

ATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTG

GCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTAC

GTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGC

GTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAA

TGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAAC

TCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATA

AGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTT

TTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTGACTCTAGCCTAGCTCTG

AAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTacaagacaggtttaaggagacca

atagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtctattttcccaccctt

aggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGATGggtaccgccaccATGTTT

GTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCATCTGACTACCCG

GACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGGTGTTTACTACCCA

GACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGACCTCTTCCTCCCTTT

TTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGCACCAACGGCACC

AAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTATATTTTGCCTCTA

CTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTACCCTGGACTCAA

AAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGTGATCAAAGTCTG

TGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATCACAAAAATAACA

AATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGAATAATTGCACCTT

CGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAAGCAGGGCAATTTT

AAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTACTTCAAGATTTACT

CCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGGGCTTTTCTGCATT

GGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAGATTTCAGACTTTG

CTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTTCCGGATGGACCG

CTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAACCTTTCTTTTGAA

GTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCCCTGGACCCCCT

GTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAGGGGATATACCA

GACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGCTTTCCTAATATA

ACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATTCGCTTCCGTCT

ACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTATAGTGTTTTGTA

CAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCCTACCAAACTG

AACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATCAGAGGAGACG

AGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGATTATAATTACAA

ACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTAACAATCTTGAC

TCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAGAAAAAGCAATT

TGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGCCGGGTCCACTC

CATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAGTCTTATGGATTC

CAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCGTGCTCAGCTTCG

AGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTCCACCAATCTTGT

TAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGGACCGGCGTTCTG

ACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCCGCGATATTGCTG

ACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCTCGATATCACACC

TTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAACACAAGCAACCA

GGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCAGTGGCCATCCAC

GCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGGTCCAATGTTTTTC

AGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACAATTCCTACGAGT

GTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGACCCAGACTAATAG

CCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGCATATACAATGTCC

CTGGGAGCTGAGAATTCAGTCGCGTATTCAAACAATTCCATTGCTATTCCTACTA

ATTTCACTATCTCCGTCACGACCGAGATCCTGCCAGTTTCCATGACTAAGACTTCT

GTTGACTGCACCATGTATATCTGTGGCGATAGCACCGAGTGCAGTAATCTGCTTC

TGCAGTACGGCTCCTTCTGCACACAACTCAATCGAGCACTGACCGGTATTGCAGT

TGAGCAGGACAAGAACACACAGGAGGTCTTTGCACAGGTCAAACAAATTTACAA

AACCCCCCCCATAAAAGACTTTGGTGGGTTCAACTTCAGCCAAATCCTCCCAGAT

CCCAGCAAGCCCTCCAAAAGATCCTTCATCGAAGACCTTTTGTTCAATAAGGTAA

CCCTGGCCGACGCAGGCTTCATCAAACAATATGGCGATTGCCTTGGAGACATTGC

TGCGCGCGATTTGATCTGTGCTCAGAAATTTAACGGTTTGACCGTGCTGCCCCCA

CTTCTGACTGATGAGATGATAGCACAGTATACTTCTGCTCTTCTGGCAGGAACAA

TCACTTCCGGGTGGACCTTTGGCGCTGGTGCAGCACTGCAAATCCCCTTCGCAAT

GCAAATGGCCTACCGATTCAATGGTATTGGTGTTACCCAGAACGTGCTCTATGAG

AATCAGAAACTCATCGCCAATCAGTTCAATAGCGCTATTGGCAAGATTCAGGATT

CCCTCAGCTCTACCGCCAGCGCTCTGGGGAAGCTCCAGGACGTGGTGAACCAAA

ATGCTCAAGCGCTCAATACCCTTGTGAAACAGCTCAGCTCCAATTTTGGCGCAAT

TAGCAGCGTTCTGAATGATATTCTGTCCCGGCTGGACAAGGTAGAAGCAGAAGT

CCAGATCGACAGGCTGATCACCGGGCGGTTGCAGAGTCTCCAGACCTATGTCAC

ACAACAGCTGATCCGCGCCGCCGAGATCAGGGCTTCCGCTAACCTGGCCGCCAC

TAAGATGTCCGAATGCGTGTTGGGGCAGAGTAAGCGGGTCGACTTTTGCGGGAA

GGGATACCATCTGATGAGCTTCCCTCAGTCTGCACCCCACGGAGTAGTGTTCCTC

CACGTCACATATGTGCCCGCTCAGGAAAAGAATTTCACAACCGCACCTGCTATCT

GTCACGACGGCAAGGCCCACTTTCCTAGAGAAGGAGTTTTCGTATCTAACGGCAC

CCACTGGTTCGTGACACAGCGGAACTTTTACGAGCCTCAGATTATAACTACGGAC

AACACTTTCGTGTCAGGCAACTGTGACGTGGTGATTGGGATCGTGAACAACACA

GTCTACGACCCATTGCAGCCCGAGTTGGACTCCTTCAAAGAGGAGCTTGATAAGT

ATTTCAAGAACCATACCTCTCCCGACGTGGACCTGGGGGACATTAGCGGCATCA

ATGCATCCGTTGTGAATATCCAGAAAGAAATCGATAGGCTGAATGAGGTCGCAA

AAAATCTTAATGAGTCACTGATTGATCTGCAGGAACTCGGCAAATATGAGCAGT

ATATTAAGTGGCCGTGGTACATATGGCTCGGCTTTATCGCCGGTCTGATTGCCAT

CGTGATGGTGACCATTATGCTGTGTTGTATGACAAGCTGCTGTTCATGTCTCAAA

GGATGCTGCTCCTGCGGTAGCTGCTGTAAGTTCGATGAAGACGACAGTGAGCCC

GTGCTCAAAGGAGTGAAACTCCACTACACATAAcgatcgacgcgtAGAGCTCGCTGATC

AGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGC

CTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGA

AATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGG

CAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGC

GGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAaagcttgcggccgcGCCCAGCACC

CCAAGGCGGCCAACGCCAAAACTCTCCCTCCTCCTCTTCCTCAATCTCGCTCTCG

CTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAGGGGGTAAAAAAATGCTGCACTGT

GCGGCGAAGCCGGTGAGTGAGCGGCGCGGGGCCAATCAGCGTGCGCCGTTCCGA

AAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGGCGCCCTATAAAACCCAGCGG

CGCGACGCGCCACCACCGCCGAGACcctgcaggccgccaccATGTCCGATAACGGCCCCC

AGAATCAGAGAAACGCTCCCCGCATCACGTTCGGCGGACCAAGTGACAGCACAG

GCAGTAACCAGAACGGAGAACGCTCCGGTGCTCGCTCCAAGCAGCGACGGCCGC

AAGGGCTTCCCAACAATACCGCCAGCTGGTTTACGGCTCTGACCCAACACGGGA

AAGAAGATCTTAAATTCCCCAGGGGCCAGGGCGTCCCTATCAATACTAACTCCA

GCCCGGATGATCAGATAGGCTACTATAGACGCGCTACCCGACGGATACGAGGGG

GGGACGGCAAAATGAAGGACCTTTCCCCCCGGTGGTATTTCTATTACTTGGGCAC

CGGACCAGAAGCCGGACTGCCTTACGGCGCTAACAAAGACGGAATAATCTGGGT

TGCGACGGAGGGCGCCCTGAATACACCTAAAGACCATATCGGCACAAGAAATCC

TGCTAACAATGCCGCGATTGTGCTCCAGCTGCCTCAGGGAACCACGCTGCCTAAA

GGGTTTTACGCTGAGGGGTCAAGGGGGGGGAGTCAAGCGTCTAGTAGGTCATCC

TCTCGCTCTCGCAATAGTTCCCGGAACTCAACCCCAGGCAGCAGCAGAGGAACC

TCTCCCGCACGGATGGCTGGCAATGGGGGAGATGCTGCCCTTGCTCTCCTTCTGC

TGGATCGCCTTAACCAGCTCGAATCAAAGATGTCTGGAAAAGGTCAGCAGCAGC

AAGGCCAGACCGTGACAAAGAAGAGTGCAGCTGAAGCTAGTAAAAAGCCACGC

CAAAAACGGACCGCAACTAAGGCATATAACGTAACACAGGCCTTCGGCAGAAGA

GGTCCAGAACAAACACAGGGAAACTTTGGCGATCAAGAGCTGATTAGACAGGGC

ACAGATTACAAACACTGGCCACAGATCGCGCAGTTTGCACCAAGCGCCTCTGCA

TTCTTCGGGATGAGTCGGATTGGGATGGAAGTCACTCCATCCGGGACCTGGCTTA

CCTACACAGGGGCAATAAAACTCGACGACAAAGACCCAAACTTTAAAGATCAGG

TCATCCTGCTGAATAAACACATCGATGCCTACAAAACTTTCCCCCCAACCGAACC

AAAGAAAGACAAGAAAAAAAAGGCAGACGAAACGCAAGCGCTCCCTCAGCGCC

AGAAGAAGCAGCAGACCGTTACACTGTTGCCAGCAGCAGATCTGGATGATTTTT

CCAAGCAGCTTCAACAGAGTATGTCAAGCGCTGACAGCACTCAGGCTTGAggcgcg

ccgctgaccgatAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGT

GacgcgttagttattaataGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGT

TCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCC

CCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACT

TTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTAC

ATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATG

GCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAG

TACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACAT

CAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATT

GACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTC

GTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGG

TCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGAGATATCGGGC

CACTGCAGGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTT

CTCTAGAAATAAAATATCTTTATTTTCATTACATCTGTGTGTGGTTTTTTGTGTG

SEQ ID NO: 8: CMV-SARS-CoV-2-S1-Furin-N-BGH-CMV-dsRNA-SPA

TAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTA

CATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATT

GACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGA

CGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGT

ATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTG

GCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTAC

GTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGC

GTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAA

TGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAAC

TCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATA

AGCAGAGCTCGTTTAGTGAACCGTCAGatcgcctggagacgccatccacgctgttttgacctccatagaaga

caccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggttacaaga

caggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattgg

tctattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGATGggtacc

gccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCAATCT

GACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGGTGTT

TACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGACCTCT

TCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGCACC

AACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTATAT

TTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTACCC

TGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGTGAT

CAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATCACA

AAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGAATA

ATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAAGCA

GGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTACTTC

AAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGGGCT

TTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAGATT

TCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTTCCG

GATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAACCTT

TCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCCCTG

GACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAGGGG

ATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGCTTTC

CTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATTCGC

TTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTATAGT

GTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCCTAC

CAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATCAGA

GGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGATTAT

AATTACAAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTAAC

AATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAGAA

AAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGCCG

GGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAGTC

TTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCGTG

CTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTCCA

CCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGGAC

CGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCCGC

GATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCTCG

ATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAACAC

AAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCAGT

GGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGGTC

CAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACAAT

TCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGACCC

AGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGCAT

ATACAATGATGTCCGATAACGGCCCCCAGAATCAGAGAAACGCTCCCCGCATCA

CGTTCGGCGGACCAAGTGACAGCACAGGCAGTAACCAGAACGGAGAACGCTCCG

GTGCTCGCTCCAAGCAGCGACGGCCGCAAGGGCTTCCCAACAATACCGCCAGCT

GGTTTACGGCTCTGACCCAACACGGGAAAGAAGATCTTAAATTCCCCAGGGGCC

AGGGCGTCCCTATCAATACTAACTCCAGCCCGGATGATCAGATAGGCTACTATAG

ACGCGCTACCCGACGGATACGAGGGGGGGACGGCAAAATGAAGGACCTTTCCCC

CCGGTGGTATTTCTATTACTTGGGCACCGGACCAGAAGCCGGACTGCCTTACGGC

GCTAACAAAGACGGAATAATCTGGGTTGCGACGGAGGGCGCCCTGAATACACCT

AAAGACCATATCGGCACAAGAAATCCTGCTAACAATGCCGCGATTGTGCTCCAG

CTGCCTCAGGGAACCACGCTGCCTAAAGGGTTTTACGCTGAGGGGTCAAGGGGG

GGGAGTCAAGCGTCTAGTAGGTCATCCTCTCGCTCTCGCAATAGTTCCCGGAACT

CAACCCCAGGCAGCAGCAGAGGAACCTCTCCCGCACGGATGGCTGGCAATGGGG

GAGATGCTGCCCTTGCTCTCCTTCTGCTGGATCGCCTTAACCAGCTCGAATCAAA

GATGTCTGGAAAAGGTCAGCAGCAGCAAGGCCAGACCGTGACAAAGAAGAGTG

CAGCTGAAGCTAGTAAAAAGCCACGCCAAAAACGGACCGCAACTAAGGCATATA

ACGTAACACAGGCCTTCGGCAGAAGAGGTCCAGAACAAACACAGGGAAACTTTG

GCGATCAAGAGCTGATTAGACAGGGCACAGATTACAAACACTGGCCACAGATCG

CGCAGTTTGCACCAAGCGCCTCTGCATTCTTCGGGATGAGTCGGATTGGGATGGA

AGTCACTCCATCCGGGACCTGGCTTACCTACACAGGGGCAATAAAACTCGACGA

CAAAGACCCAAACTTTAAAGATCAGGTCATCCTGCTGAATAAACACATCGATGC

CTACAAAACTTTCCCCCCAACCGAACCAAAGAAAGACAAGAAAAAAAAGGCAG

ACGAAACGCAAGCGCTCCCTCAGCGCCAGAAGAAGCAGCAGACCGTTACACTGT

TGCCAGCAGCAGATCTGGATGATTTTTCCAAGCAGCTTCAACAGAGTATGTCAAG

CGCTGACAGCACTCAGGCTTGAcgatcgGATATCGCTAGCGTACCGGCGGCCGCCCT

ATTCTATAGTGTCACCTAAATGCTAGAGCTCGCTGATCAGCCTCGACTGTGCCTT

CTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAA

GGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTC

TGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGG

AGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTT

CTGAGGCGGAAAGAACCAAAGCTTAcgcgttagttattaataGTAATCAATTACGGGGTCAT

TAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCC

GCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTT

CCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTAC

GGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCC

TATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACC

TTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCAT

GGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGG

GGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAA

ATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGG

GCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACC

GTCAGATCCGCTAGAGATATCGGGCCACTGCAGGAAACGATATGGGCTGAATAC

GGATCCGTATTCAGCCCATATCGTTTCTCTAGAAATAAAATATCTTTATTTTCATT

ACATCTGTGTGTTGGTTTTTTGTGTG

SEQ ID NO: 9: rAd-CMV-SARS-CoV-2-S-BGH-CMV-dsRNA-SPA

TAAGGATCCCATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAA

TGAGGGGGTGGAGTTTGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGAC

GTAGTAGTGTGGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTAAGCG

ACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCCGGTGTACACAGGAAGTGA

CAATTTTCGCGCGGTTTTAGGCGGATGTTGTAGTAAATTTGGGCGTAACCGAGTA

AGATTTGGCCATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATCTGAATAA

TTTTGTGTTACTCATAGCGCGTAATACTGCTAGAGATTGGCGAAAGGGGGATGT

GCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTA

AAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTG

GCCACAGGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATT

TATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTA

TTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGC

GTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCC

CATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCA

TTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAA

GTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG

CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACAT

CTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAAT

GGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACG

TCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAA

CAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTA

TATAAGCAGAGCTCGTTTAGTGAACCGTCAGatcgcctggagacgccatccacgctgttttgacctccat

agaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggtt

acaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgc

ctattggtctattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGAT

GggtaccgccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTC

AATCTGACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAG

GTGTTTACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGA

CCTCTTCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGG

CACCAACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGT

ATATTTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACT

ACCCTGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGG

TGATCAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTAT

CACAAAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCG

AATAATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGA

AGCAGGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTT

ACTTCAAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCA

GGGCTTTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACA

AGATTTCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTT

CTTCCGGATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCG

AACCTTTCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGC

GCCCTGGACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAG

AAGGGGATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTG

CGCTTTCCTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTA

GATTCGCTTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGA

CTATAGTGTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGA

GCCCTACCAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGT

TATCAGAGGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGC

TGATTATAATTACAAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAAC

AGTAACAATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGT

TCAGAAAAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATC

AGGCCGGGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATT

GCAGTCTTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTT

GTCGTGCTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGA

AGTCCACCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGAC

CGGGACCGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTC

GGCCGCGATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAA

ATTCTCGATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAA

CTAACACAAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGG

TGCCAGTGGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCAC

AGGGTCCAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTC

AACAATTCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATC

AGACCCAGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCA

TTGCATATACAATGTCCCTGGGAGCTGAGAATTCAGTCGCGTATTCAAACAATTC

CATTGCTATTCCTACTAATTTCACTATCTCCGTCACGACCGAGATCCTGCCAGTTT

CCATGACTAAGACTTCTGTTGACTGCACCATGTATATCTGTGGCGATAGCACCGA

GTGCAGTAATCTGCTTCTGCAGTACGGCTCCTTCTGCACACAACTCAATCGAGCA

CTGACCGGTATTGCAGTTGAGCAGGACAAGAACACACAGGAGGTCTTTGCACAG

GTCAAACAAATTTACAAAACCCCCCCCATAAAAGACTTTGGTGGGTTCAACTTCA

GCCAAATCCTCCCAGATCCCAGCAAGCCCTCCAAAAGATCCTTCATCGAAGACCT

TTTGTTCAATAAGGTAACCCTGGCCGACGCAGGCTTCATCAAACAATATGGCGAT

TGCCTTGGAGACATTGCTGCGCGCGATTTGATCTGTGCTCAGAAATTTAACGGTT

TGACCGTGCTGCCCCCACTTCTGACTGATGAGATGATAGCACAGTATACTTCTGC

TCTTCTGGCAGGAACAATCACTTCCGGGTGGACCTTTGGCGCTGGTGCAGCACTG

CAAATCCCCTTCGCAATGCAAATGGCCTACCGATTCAATGGTATTGGTGTTACCC

AGAACGTGCTCTATGAGAATCAGAAACTCATCGCCAATCAGTTCAATAGCGCTAT

TGGCAAGATTCAGGATTCCCTCAGCTCTACCGCCAGCGCTCTGGGGAAGCTCCAG

GACGTGGTGAACCAAAATGCTCAAGCGCTCAATACCCTTGTGAAACAGCTCAGC

TCCAATTTTGGCGCAATTAGCAGCGTTCTGAATGATATTCTGTCCCGGCTGGACA

AGGTAGAAGCAGAAGTCCAGATCGACAGGCTGATCACCGGGCGGTTGCAGAGTC

TCCAGACCTATGTCACACAACAGCTGATCCGCGCCGCCGAGATCAGGGCTTCCGC

TAACCTGGCCGCCACTAAGATGTCCGAATGCGTGTTGGGGCAGAGTAAGCGGGT

CGACTTTTGCGGGAAGGGATACCATCTGATGAGCTTCCCTCAGTCTGCACCCCAC

GGAGTAGTGTTCCTCCACGTCACATATGTGCCCGCTCAGGAAAAGAATTTCACAA

CCGCACCTGCTATCTGTCACGACGGCAAGGCCCACTTTCCTAGAGAAGGAGTTTT

CGTATCTAACGGCACCCACTGGTTCGTGACACAGCGGAACTTTTACGAGCCTCAG

ATTATAACTACGGACAACACTTTCGTGTCAGGCAACTGTGACGTGGTGATTGGGA

TCGTGAACAACACAGTCTACGACCCATTGCAGCCCGAGTTGGACTCCTTCAAAGA

GGAGCTTGATAAGTATTTCAAGAACCATACCTCTCCCGACGTGGACCTGGGGGA

CATTAGCGGCATCAATGCATCCGTTGTGAATATCCAGAAAGAAATCGATAGGCT

GAATGAGGTCGCAAAAAATCTTAATGAGTCACTGATTGATCTGCAGGAACTCGG

CAAATATGAGCAGTATATTAAGTGGCCGTGGTACATATGGCTCGGCTTTATCGCC

GGTCTGATTGCCATCGTGATGGTGACCATTATGCTGTGTTGTATGACAAGCTGCT

GTTCATGTCTCAAAGGATGCTGCTCCTGCGGTAGCTGCTGTAAGTTCGATGAAGA

CGACAGTGAGCCCGTGCTCAAAGGAGTGAAACTCCACTACACATAAcgatcgGATA

TCGCTAGCGTACCGGCGGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCT

CGCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTC

CCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAA

ATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGG

GGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTG

GGGATGCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAAAGCTTAcgcgttagt

tattaataGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGT

TACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCA

TTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATT

GACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGT

GTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCC

TGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCT

ACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGG

GCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTC

AATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACA

ACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATA

TAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGAGATATCGGGCCACTG

CAGGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCTCTA

GAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGAATCG

ATAGTACTAACATACGCTCTCCATCTCGAGCCTAAGCTTGTCGACTCGAAGATCT

GGGCGTGGTTAAGGGTGGGAAAGAATATATAAGGTGGGGGTCTTATGTAGTTTT

GTATCTGTTTTGCAGCAGCCGCCGCCGCCATGAGCACCAACTCGTTTGATGGAAG

CATTGTGAGCTCATATTTGACAACGCGCATGCCCCCATGGGCCGGGGTGCGTCAG

AATGTGATGGGCTCCAGCATTGATGGTCGCCCCGTCCTGCCCGCAAACTCTACTA

CCTTGACCTACGAGACCGTGTCTGGAACGCCGTTGGAGACTGCAGCCTCCGCCGC

CGCTTCAGCCGCTGCAGCCACCGCCCGCGGGATTGTGACTGACTTTGCTTTCCTG

AGCCCGCTTGCAAGCAGTGCAGCTTCCCGTTCATCCGCCCGCGATGACAAGTTGA

CGGCTCTTTTGGCACAATTGGATTCTTTGACCCGGGAACTTAATGTCGTTTCTCAG

CAGCTGTTGGATCTGCGCCAGCAGGTTTCTGCCCTGAAGGCTTCCTCCCCTCCCA

ATGCGGTTTAAAACATAAATAAAAAACCAGACTCTGTTTGGATTTGGATCAAGCA

AGTGTCTTGCTGTCTTTATTTAGGGGTTTTGCGCGCGCGGTAGGCCCGGGACCAG

CGGTCTCGGTCGTTGAGGGTCCTGTGTATTTTTTCCAGGACGTGGTAAAGGTGAC

TCTGGATGTTCAGATACATGGGCATAAGCCCGTCTCTGGGGTGGAGGTAGCACC

ACTGCAGAGCTTCATGCTGCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGG

AGCGCTGGGCGTGGTGCCTAAAAATGTCTTTCAGTAGCAAGCTGATTGCCAGGG

GCAGGCCCTTGGTGTAAGTGTTTACAAAGCGGTTAAGCTGGGATGGGTGCATAC

GTGGGGATATGAGATGCATCTTGGACTGTATTTTTAGGTTGGCTATGTTCCCAGC

CATATCCCTCCGGGGATTCATGTTGTGCAGAACCACCAGCACAGTGTATCCGGTG

CACTTGGGAAATTTGTCATGTAGCTTAGAAGGAAATGCGTGGAAGAACTTGGAG

ACGCCCTTGTGACCTCCAAGATTTTCCATGCATTCGTCCATAATGATGGCAATGG

GCCCACGGGCGGCGGCCTGGGCGAAGATATTTCTGGGATCACTAACGTCATAGT

TGTGTTCCAGGATGAGATCGTCATAGGCCATTTTTACAAAGCGCGGGCGGAGGG

TGCCAGACTGCGGTATAATGGTTCCATCCGGCCCAGGGGCGTAGTTACCCTCACA

GATTTGCATTTCCCACGCTTTGAGTTCAGATGGGGGGATCATGTCTACCTGCGGG

GCGATGAAGAAAACGGTTTCCGGGGTAGGGGAGATCAGCTGGGAAGAAAGCAG

GTTCCTGAGCAGCTGCGACTTACCGCAGCCGGTGGGCCCGTAAATCACACCTATT

ACCGGCTGCAACTGGTAGTTAAGAGAGCTGCAGCTGCCGTCATCCCTGAGCAGG

GGGGCCACTTCGTTAAGCATGTCCCTGACTCGCATGTTTTCCCTGACCAAATCCG

CCAGAAGGCGCTCGCCGCCCAGCGATAGCAGTTCTTGCAAGGAAGCAAAGTTTT

TCAACGGTTTGAGACCGTCCGCCGTAGGCATGCTTTTGAGCGTTTGACCAAGCAG

TTCCAGGCGGTCCCACAGCTCGGTCACCTGCTCTACGGCATCTCGATCCAGCATA

TCTCCTCGTTTCGCGGGTTGGGGCGGCTTTCGCTGTACGGCAGTAGTCGGTGCTC

GTCCAGACGGGCCAGGGTCATGTCTTTCCACGGGCGCAGGGTCCTCGTCAGCGTA

GTCTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGCGCGCTGGCCAGGGTGCGC

TTGAGGCTGGTCCTGCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGG

CCAGGTAGCATTTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGCGTGGCCCTT

GGCGCGCAGCTTGCCCTTGGAGGAGGCGCCGCACGAGGGGCAGTGCAGACTTTT

GAGGGCGTAGAGCTTGGGCGCGAGAAATACCGATTCCGGGGAGTAGGCATCCGC

GCCGCAGGCCCCGCAGACGGTCTCGCATTCCACGAGCCAGGTGAGCTCTGGCCG

TTCGGGGTCAAAAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCTGG

TTTCCATGAGCCGGTGTCCACGCTCGGTGACGAAAAGGCTGTCCGTGTCCCCGTA

TACAGACTTGAGAGGCCTGTCCTCGAGCGGTGTTCCGCGGTCCTCCTCGTATAGA

AACTCGGACCACTCTGAGACAAAGGCTCGCGTCCAGGCCAGCACGAAGGAGGCT

AAGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACTCGCTCCAGGGTG

TGAAGACACATGTCGCCCTCTTCGGCATCAAGGAAGGTGATTGGTTTGTAGGTGT

AGGCCACGTGACCGGGTGTTCCTGAAGGGGGGCTATAAAAGGGGGTGGGGGCGC

GTTCGTCCTCACTCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGA

GTACTCCCTCTGAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAA

AACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCC

GCATCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGGTGGCAAACG

ACCCGTAGAGGGCGTTGGACAGCAACTTGGCGATGGAGCGCAGGGTTTGGTTTT

TGTCGCGATCGGCGCGCTCCTTGGCCGCGATGTTTAGCTGCACGTATTCGCGCGC

AACGCACCGCCATTCGGGAAAGACGGTGGTGCGCTCGTCGGGCACCAGGTGCAC

GCGCCAACCGCGGTTGTGCAGGGTGACAAGGTCAACGCTGGTGGCTACCTCTCC

GCGTAGGCGCTCGTTGGTCCAGCAGAGGCGGCCGCCCTTGCGCGAGCAGAATGG

CGGTAGGGGGTCTAGCTGCGTCTCGTCCGGGGGGTCTGCGTCCACGGTAAAGAC

CCCGGGCAGCAGGCGCGCGTCGAAGTAGTCTATCTTGCATCCTTGCAAGTCTAGC

GCCTGCTGCCATGCGCGGGCGGCAAGCGCGCGCTCGTATGGGTTGAGTGGGGGA

CCCCATGGCATGGGGTGGGTGAGCGCGGAGGCGTACATGCCGCAAATGTCGTAA

ACGTAGAGGGGCTCTCTGAGTATTCCAAGATATGTAGGGTAGCATCTTCCACCGC

GGATGCTGGCGCGCACGTAATCGTATAGTTCGTGCGAGGGAGCGAGGAGGTCGG

GACCGAGGTTGCTACGGGCGGGCTGCTCTGCTCGGAAGACTATCTGCCTGAAGA

TGGCATGTGAGTTGGATGATATGGTTGGACGCTGGAAGACGTTGAAGCTGGCGT

CTGTGAGACCTACCGCGTCACGCACGAAGGAGGCGTAGGAGTCGCGCAGCTTGT

TGACCAGCTCGGCGGTGACCTGCACGTCTAGGGCGCAGTAGTCCAGGGTTTCCTT

GATGATGTCATACTTATCCTGTCCCTTTTTTTTCCACAGCTCGCGGTTGAGGACAA

ACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGAAACCCGTCGGCCTCCGAACG

GTAAGAGCCTAGCATGTAGAACTGGTTGACGGCCTGGTAGGCGCAGCATCCCTTT

TCTACGGGTAGCGCGTATGCCTGCGCGGCCTTCCGGAGCGAGGTGTGGGTGAGC

GCAAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTATTTGAAGTCAGTGTCGT

CGCATCCGCCCTGCTCCCAGAGCAAAAAGTCCGTGCGCTTTTTGGAACGCGGATT

TGGCAGGGCGAAGGTGACATCGTTGAAGAGTATCTTTCCCGCGCGAGGCATAAA

GTTGCGTGTGATGCGGAAGGGTCCCGGCACCTCGGAACGGTTGTTAATTACCTGG

GCGGCGAGCACGATCTCGTCAAAGCCGTTGATGTTGTGGCCCACAATGTAAAGTT

CCAAGAAGCGCGGGATGCCCTTGATGGAAGGCAATTTTTTAAGTTCCTCGTAGGT

GAGCTCTTCAGGGGAGCTGAGCCCGTGCTCTGAAAGGGCCCAGTCTGCAAGATG

AGGGTTGGAAGCGACGAATGAGCTCCACAGGTCACGGGCCATTAGCATTTGCAG

GTGGTCGCGAAAGGTCCTAAACTGGCGACCTATGGCCATTTTTTCTGGGGTGATG

CAGTAGAAGGTAAGCGGGTCTTGTTCCCAGCGGTCCCATCCAAGGTTCGCGGCTA

GGTCTCGCGCGGCAGTCACTAGAGGCTCATCTCCGCCGAACTTCATGACCAGCAT

GAAGGGCACGAGCTGCTTCCCAAAGGCCCCCATCCAAGTATAGGTCTCTACATC

GTAGGTGACAAAGAGACGCTCGGTGCGAGGATGCGAGCCGATCGGGAAGAACT

GGATCTCCCGCCACCAATTGGAGGAGTGGCTATTGATGTGGTGAAAGTAGAAGT

CCCTGCGACGGGCCGAACACTCGTGCTGGCTTTTGTAAAAACGTGCGCAGTACTG

GCAGCGGTGCACGGGCTGTACATCCTGCACGAGGTTGACCTGACGACCGCGCAC

AAGGAAGCAGAGTGGGAATTTGAGCCCCTCGCCTGGCGGGTTTGGCTGGTGGTC

TTCTACTTCGGCTGCTTGTCCTTGACCGTCTGGCTGCTCGAGGGGAGTTACGGTG

GATCGGACCACCACGCCGCGCGAGCCCAAAGTCCAGATGTCCGCGCGCGGCGGT

CGGAGCTTGATGACAACATCGCGCAGATGGGAGCTGTCCATGGTCTGGAGCTCC

CGCGGCGTCAGGTCAGGCGGGAGCTCCTGCAGGTTTACCTCGCATAGACGGGTC

AGGGCGCGGGCTAGATCCAGGTGATACCTAATTTCCAGGGGCTGGTTGGTGGCG

GCGTCGATGGCTTGCAAGAGGCCGCATCCCCGCGGCGCGACTACGGTACCGCGC

GGCGGGCGGTGGGCCGCGGGGGTGTCCTTGGATGATGCATCTAAAAGCGGTGAC

GCGGGCGAGCCCCCGGAGGTAGGGGGGGCTCCGGACCCGCCGGGAGAGGGGGC

AGGGGCACGTCGGCGCCGCGCGCGGGCAGGAGCTGGTGCTGCGCGCGTAGGTTG

CTGGCGAACGCGACGACGCGGCGGTTGATCTCCTGAATCTGGCGCCTCTGCGTGA

AGACGACGGGCCCGGTGAGCTTGAACCTGAAAGAGAGTTCGACAGAATCAATTT

CGGTGTCGTTGACGGCGGCCTGGCGCAAAATCTCCTGCACGTCTCCTGAGTTGTC

TTGATAGGCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGGAGATCTCCG

CGTCCGGCTCGCTCCACGGTGGCGGCGAGGTCGTTGGAAATGCGGGCCATGAGC

TGCGAGAAGGCGTTGAGGCCTCCCTCGTTCCAGACGCGGCTGTAGACCACGCCC

CCTTCGGCATCGCGGGCGCGCATGACCACCTGCGCGAGATTGAGCTCCACGTGCC

GGGCGAAGACGGCGTAGTTTCGCAGGCGCTGAAAGAGGTAGTTGAGGGTGGTGG

CGGTGTGTTCTGCCACGAAGAAGTACATAACCCAGCGTCGCAACGTGGATTCGTT

GATATCCCCCAAGGCCTCAAGGCGCTCCATGGCCTCGTAGAAGTCCACGGCGAA

GTTGAAAAACTGGGAGTTGCGCGCCGACACGGTTAACTCCTCCTCCAGAAGACG

GATGAGCTCGGCGACAGTGTCGCGCACCTCGCGCTCAAAGGCTACAGGGGCCTC

TTCTTCTTCTTCAATCTCCTCTTCCATAAGGGCCTCCCCTTCTTCTTCTTCTGGCGG

CGGTGGGGGAGGGGGGACACGGCGGCGACGACGGCGCACCGGGAGGCGGTCGA

CAAAGCGCTCGATCATCTCCCCGCGGCGACGGCGCATGGTCTCGGTGACGGCGC

GGCCGTTCTCGCGGGGGCGCAGTTGGAAGACGCCGCCCGTCATGTCCCGGTTATG

GGTTGGCGGGGGGCTGCCATGCGGCAGGGATACGGCGCTAACGATGCATCTCAA

CAATTGTTGTGTAGGTACTCCGCCGCCGAGGGACCTGAGCGAGTCCGCATCGACC

GGATCGGAAAACCTCTCGAGAAAGGCGTCTAACCAGTCACAGTCGCAAGGTAGG

CTGAGCACCGTGGCGGGCGGCAGCGGGCGGCGGTCGGGGTTGTTTCTGGCGGAG

GTGCTGCTGATGATGTAATTAAAGTAGGCGGTCTTGAGACGGCGGATGGTCGAC

AGAAGCACCATGTCCTTGGGTCCGGCCTGCTGAATGCGCAGGCGGTCGGCCATG

CCCCAGGCTTCGTTTTGACATCGGCGCAGGTCTTTGTAGTAGTCTTGCATGAGCC

TTTCTACCGGCACTTCTTCTTCTCCTTCCTCTTGTCCTGCATCTCTTGCATCTATCG

CTGCGGCGGCGGCGGAGTTTGGCCGTAGGTGGCGCCCTCTTCCTCCCATGCGTGT

GACCCCGAAGCCCCTCATCGGCTGAAGCAGGGCTAGGTCGGCGACAACGCGCTC

GGCTAATATGGCCTGCTGCACCTGCGTGAGGGTAGACTGGAAGTCATCCATGTCC

ACAAAGCGGTGGTATGCGCCCGTGTTGATGGTGTAAGTGCAGTTGGCCATAACG

GACCAGTTAACGGTCTGGTGACCCGGCTGCGAGAGCTCGGTGTACCTGAGACGC

GAGTAAGCCCTCGAGTCAAATACGTAGTCGTTGCAAGTCCGCACCAGGTACTGG

TATCCCACCAAAAAGTGCGGCGGCGGCTGGCGGTAGAGGGGCCAGCGTAGGGTG

GCCGGGGCTCCGGGGGCGAGATCTTCCAACATAAGGCGATGATATCCGTAGATG

TACCTGGACATCCAGGTGATGCCGGCGGCGGTGGTGGAGGCGCGCGGAAAGTCG

CGGACGCGGTTCCAGATGTTGCGCAGCGGCAAAAAGTGCTCCATGGTCGGGACG

CTCTGGCCGGTCAGGCGCGCGCAATCGTTGACGCTCTAGCGTGCAAAAGGAGAG

CCTGTAAGCGGGCACTCTTCCGTGGTCTGGTGGATAAATTCGCAAGGGTATCATG

GCGGACGACCGGGGTTCGAGCCCCGTATCCGGCCGTCCGCCGTGATCCATGCGG

TTACCGCCCGCGTGTCGAACCCAGGTGTGCGACGTCAGACAACGGGGGAGTGCT

CCTTTTGGCTTCCTTCCAGGCGCGGCGGCTGCTGCGCTAGCTTTTTTGGCCACTGG

CCGCGCGCAGCGTAAGCGGTTAGGCTGGAAAGCGAAAGCATTAAGTGGCTCGCT

CCCTGTAGCCGGAGGGTTATTTTCCAAGGGTTGAGTCGCGGGACCCCCGGTTCGA

GTCTCGGACCGGCCGGACTGCGGCGAACGGGGGTTTGCCTCCCCGTCATGCAAG

ACCCCGCTTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTTTTGCTTTTCCC

AGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCTCCTCAGCAGCGGCAAGAGC

AAGAGCAGCGGCAGACATGCAGGGCACCCTCCCCTCCTCCTACCGCGTCAGGAG

GGGCGACATCCGCGGTTGACGCGGCAGCAGATGGTGATTACGAACCCCCGCGGC

GCCGGGCCCGGCACTACCTGGACTTGGAGGAGGGCGAGGGCCTGGCGCGGCTAG

GAGCGCCCTCTCCTGAGCGGCACCCAAGGGTGCAGCTGAAGCGTGATACGCGTG

AGGCGTACGTGCCGCGGCAGAACCTGTTTCGCGACCGCGAGGGAGAGGAGCCCG

AGGAGATGCGGGATCGAAAGTTCCACGCAGGGCGCGAGCTGCGGCATGGCCTGA

ATCGCGAGCGGTTGCTGCGCGAGGAGGACTTTGAGCCCGACGCGCGAACCGGGA

TTAGTCCCGCGCGCGCACACGTGGCGGCCGCCGACCTGGTAACCGCATACGAGC

AGACGGTGAACCAGGAGATTAACTTTCAAAAAAGCTTTAACAACCACGTGCGTA

CGCTTGTGGCGCGCGAGGAGGTGGCTATAGGACTGATGCATCTGTGGGACTTTGT

AAGCGCGCTGGAGCAAAACCCAAATAGCAAGCCGCTCATGGCGCAGCTGTTCCT

TATAGTGCAGCACAGCAGGGACAACGAGGCATTCAGGGATGCGCTGCTAAACAT

AGTAGAGCCCGAGGGCCGCTGGCTGCTCGATTTGATAAACATCCTGCAGAGCAT

AGTGGTGCAGGAGCGCAGCTTGAGCCTGGCTGACAAGGTGGCCGCCATCAACTA

TTCCATGCTTAGCCTGGGCAAGTTTTACGCCCGCAAGATATACCATACCCCTTAC

GTTCCCATAGACAAGGAGGTAAAGATCGAGGGGTTCTACATGCGCATGGCGCTG

AAGGTGCTTACCTTGAGCGACGACCTGGGCGTTTATCGCAACGAGCGCATCCAC

AAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTCAGCGACCGCGAGCTGATGCAC

AGCCTGCAAAGGGCCCTGGCTGGCACGGGCAGCGGCGATAGAGAGGCCGAGTCC

TACTTTGACGCGGGCGCTGACCTGCGCTGGGCCCCAAGCCGACGCGCCCTGGAG

GCAGCTGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCGCGCGCTGGCAACGTC

GGCGGCGTGGAGGAATATGACGAGGACGATGAGTACGAGCCAGAGGACGGCGA

GTACTAAGCGGTGATGTTTCTGATCAGATGATGCAAGACGCAACGGACCCGGCG

GTGCGGGCGGCGCTGCAGAGCCAGCCGTCCGGCCTTAACTCCACGGACGACTGG

CGCCAGGTCATGGACCGCATCATGTCGCTGACTGCGCGCAATCCTGACGCGTTCC

GGCAGCAGCCGCAGGCCAACCGGCTCTCCGCAATTCTGGAAGCGGTGGTCCCGG

CGCGCGCAAACCCCACGCACGAGAAGGTGCTGGCGATCGTAAACGCGCTGGCCG

AAAACAGGGCCATCCGGCCCGACGAGGCCGGCCTGGTCTACGACGCGCTGCTTC

AGCGCGTGGCTCGTTACAACAGCGGCAACGTGCAGACCAACCTGGACCGGCTGG

TGGGGGATGTGCGCGAGGCCGTGGCGCAGCGTGAGCGCGCGCAGCAGCAGGGC

AACCTGGGCTCCATGGTTGCACTAAACGCCTTCCTGAGTACACAGCCCGCCAACG

TGCCGCGGGGACAGGAGGACTACACCAACTTTGTGAGCGCACTGCGGCTAATGG

TGACTGAGACACCGCAAAGTGAGGTGTACCAGTCTGGGCCAGACTATTTTTTCCA

GACCAGTAGACAAGGCCTGCAGACCGTAAACCTGAGCCAGGCTTTCAAAAACTT

GCAGGGGCTGTGGGGGGTGCGGGCTCCCACAGGCGACCGCGCGACCGTGTCTAG

CTTGCTGACGCCCAACTCGCGCCTGTTGCTGCTGCTAATAGCGCCCTTCACGGAC

AGTGGCAGCGTGTCCCGGGACACATACCTAGGTCACTTGCTGACACTGTACCGCG

AGGCCATAGGTCAGGCGCATGTGGACGAGCATACTTTCCAGGAGATTACAAGTG

TCAGCCGCGCGCTGGGGCAGGAGGACACGGGCAGCCTGGAGGCAACCCTAAACT

ACCTGCTGACCAACCGGCGGCAGAAGATCCCCTCGTTGCACAGTTTAAACAGCG

AGGAGGAGCGCATTTTGCGCTACGTGCAGCAGAGCGTGAGCCTTAACCTGATGC

GCGACGGGGTAACGCCCAGCGTGGCGCTGGACATGACCGCGCGCAACATGGAAC

CGGGCATGTATGCCTCAAACCGGCCGTTTATCAACCGCCTAATGGACTACTTGCA

TCGCGCGGCCGCCGTGAACCCCGAGTATTTCACCAATGCCATCTTGAACCCGCAC

TGGCTACCGCCCCCTGGTTTCTACACCGGGGGATTCGAGGTGCCCGAGGGTAACG

ATGGATTCCTCTGGGACGACATAGACGACAGCGTGTTTTCCCCGCAACCGCAGAC

CCTGCTAGAGTTGCAACAGCGCGAGCAGGCAGAGGCGGCGCTGCGAAAGGAAA

GCTTCCGCAGGCCAAGCAGCTTGTCCGATCTAGGCGCTGCGGCCCCGCGGTCAG

ATGCTAGTAGCCCATTTCCAAGCTTGATAGGGTCTCTTACCAGCACTCGCACCAC

CCGCCCGCGCCTGCTGGGCGAGGAGGAGTACCTAAACAACTCGCTGCTGCAGCC

GCAGCGCGAAAAAAACCTGCCTCCGGCATTTCCCAACAACGGGATAGAGAGCCT

AGTGGACAAGATGAGTAGATGGAAGACGTACGCGCAGGAGCACAGGGACGTGC

CAGGCCCGCGCCCGCCCACCCGTCGTCAAAGGCACGACCGTCAGCGGGGTCTGG

TGTGGGAGGACGATGACTCGGCAGACGACAGCAGCGTCCTGGATTTGGGAGGGA

GTGGCAACCCGTTTGCGCACCTTCGCCCCAGGCTGGGGAGAATGTTTTAAAAAA

AAAAAAGCATGATGCAAAATAAAAAACTCACCAAGGCCATGGCACCGAGCGTTG

GTTTTCTTGTATTCCCCTTAGTATGCGGCGCGCGGCGATGTATGAGGAAGGTCCT

CCTCCCTCCTACGAGAGTGTGGTGAGCGCGGCGCCAGTGGCGGCGGCGCTGGGT

TCTCCCTTCGATGCTCCCCTGGACCCGCCGTTTGTGCCTCCGCGGTACCTGGGGCC

TACCGGGGGGAGAAACAGCATCCGTTACTCTGAGTTGGCACCCCTATTCGACACC

ACCCGTGTGTACCTGGTGGACAACAAGTCAACGGATGTGGCATCCCTGAACTAC

CAGAACGACCACAGCAACTTTCTGACCACGGTCATTCAAAACAATGACTACAGC

CCGGGGGAGGCAAGCACACAGACCATCAATCTTGACGACCGGTCGCACTGGGGC

GGCGACCTGAAAACCATCCTGCATACCAACATGCCAAATGTGAACGAGTTCATG

TTTACCAATAAGTTTAAGGCGCGGGTGATGGTGTCGCGCTTGCCTACTAAGGACA

ATCAGGTGGAGCTGAAATACGAGTGGGTGGAGTTCACGCTGCCCGAGGGCAACT

ACTCCGAGACCATGACCATAGACCTTATGAACAACGCGATCGTGGAGCACTACT

TGAAAGTGGGCAGACAGAACGGGGTTCTGGAAAGCGACATCGGGGTAAAGTTTG

ACACCCGCAACTTCAGACTGGGGTTTGACCCCGTCACTGGTCTTGTCATGCCTGG

GGTATATACAAACGAAGCCTTCCATCCAGACATCATTTTGCTGCCAGGATGCGGG

GTGGACTTCACCCACAGCCGCCTGAGCAACTTGTTGGGCATCCGCAAGCGGCAA

CCCTTCCAGGAGGGCTTTAGGATCACCTACGATGATCTGGAGGGTGGTAACATTC

CCGCACTGTTGGATGTGGACGCCTACCAGGCGAGCTTGAAAGATGACACCGAAC

AGGGCGGGGGTGGCGCAGGCGGCAGCAACAGCAGTGGCAGCGGCGCGGAAGAG

AACTCCAACGCGGCAGCCGCGGCAATGCAGCCGGTGGAGGACATGAACGATCAT

GCCATTCGCGGCGACACCTTTGCCACACGGGCTGAGGAGAAGCGCGCTGAGGCC

GAAGCAGCGGCCGAAGCTGCCGCCCCCGCTGCGCAACCCGAGGTCGAGAAGCCT

CAGAAGAAACCGGTGATCAAACCCCTGACAGAGGACAGCAAGAAACGCAGTTA

CAACCTAATAAGCAATGACAGCACCTTCACCCAGTACCGCAGCTGGTACCTTGCA

TACAACTACGGCGACCCTCAGACCGGAATCCGCTCATGGACCCTGCTTTGCACTC

CTGACGTAACCTGCGGCTCGGAGCAGGTCTACTGGTCGTTGCCAGACATGATGCA

AGACCCCGTGACCTTCCGCTCCACGCGCCAGATCAGCAACTTTCCGGTGGTGGGC

GCCGAGCTGTTGCCCGTGCACTCCAAGAGCTTCTACAACGACCAGGCCGTCTACT

CCCAACTCATCCGCCAGTTTACCTCTCTGACCCACGTGTTCAATCGCTTTCCCGAG

AACCAGATTTTGGCGCGCCCGCCAGCCCCCACCATCACCACCGTCAGTGAAAAC

GTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCGCAACAGCATCGGAGGA

GTCCAGCGAGTGACCATTACTGACGCCAGACGCCGCACCTGCCCCTACGTTTACA

AGGCCCTGGGCATAGTCTCGCCGCGCGTCCTATCGAGCCGCACTTTTTGAGCAAG

CATGTCCATCCTTATATCGCCCAGCAATAACACAGGCTGGGGCCTGCGCTTCCCA

AGCAAGATGTTTGGCGGGGCCAAGAAGCGCTCCGACCAACACCCAGTGCGCGTG

CGCGGGCACTACCGCGCGCCCTGGGGCGCGCACAAACGCGGCCGCACTGGGCGC

ACCACCGTCGATGACGCCATCGACGCGGTGGTGGAGGAGGCGCGCAACTACACG

CCCACGCCGCCACCAGTGTCCACAGTGGACGCGGCCATTCAGACCGTGGTGCGC

GGAGCCCGGCGCTATGCTAAAATGAAGAGACGGCGGAGGCGCGTAGCACGTCGC

CACCGCCGCCGACCCGGCACTGCCGCCCAACGCGCGGCGGCGGCCCTGCTTAAC

CGCGCACGTCGCACCGGCCGACGGGCGGCCATGCGGGCCGCTCGAAGGCTGGCC

GCGGGTATTGTCACTGTGCCCCCCAGGTCCAGGCGACGAGCGGCCGCCGCAGCA

GCCGCGGCCATTAGTGCTATGACTCAGGGTCGCAGGGGCAACGTGTATTGGGTG

CGCGACTCGGTTAGCGGCCTGCGCGTGCCCGTGCGCACCCGCCCCCCGCGCAACT

AGATTGCAAGAAAAAACTACTTAGACTCGTACTGTTGTATGTATCCAGCGGCGGC

GGCGCGCAACGAAGCTATGTCCAAGCGCAAAATCAAAGAAGAGATGCTCCAGGT

CATCGCGCCGGAGATCTATGGCCCCCCGAAGAAGGAAGAGCAGGATTACAAGCC

CCGAAAGCTAAAGCGGGTCAAAAAGAAAAAGAAAGATGATGATGATGAACTTG

ACGACGAGGTGGAACTGCTGCACGCTACCGCGCCCAGGCGACGGGTACAGTGGA

AAGGTCGACGCGTAAAACGTGTTTTGCGACCCGGCACCACCGTAGTCTTTACGCC

CGGTGAGCGCTCCACCCGCACCTACAAGCGCGTGTATGATGAGGTGTACGGCGA

CGAGGACCTGCTTGAGCAGGCCAACGAGCGCCTCGGGGAGTTTGCCTACGGAAA

GCGGCATAAGGACATGCTGGCGTTGCCGCTGGACGAGGGCAACCCAACACCTAG

CCTAAAGCCCGTAACACTGCAGCAGGTGCTGCCCGCGCTTGCACCGTCCGAAGA

AAAGCGCGGCCTAAAGCGCGAGTCTGGTGACTTGGCACCCACCGTGCAGCTGAT

GGTACCCAAGCGCCAGCGACTGGAAGATGTCTTGGAAAAAATGACCGTGGAACC

TGGGCTGGAGCCCGAGGTCCGCGTGCGGCCAATCAAGCAGGTGGCGCCGGGACT

GGGCGTGCAGACCGTGGACGTTCAGATACCCACTACCAGTAGCACCAGTATTGC

CACCGCCACAGAGGGCATGGAGACACAAACGTCCCCGGTTGCCTCAGCGGTGGC

GGATGCCGCGGTGCAGGCGGTCGCTGCGGCCGCGTCCAAGACCTCTACGGAGGT

GCAAACGGACCCGTGGATGTTTCGCGTTTCAGCCCCCCGGCGCCCGCGCCGTTCG

AGGAAGTACGGCGCCGCCAGCGCGCTACTGCCCGAATATGCCCTACATCCTTCCA

TTGCGCCTACCCCCGGCTATCGTGGCTACACCTACCGCCCCAGAAGACGAGCAAC

TACCCGACGCCGAACCACCACTGGAACCCGCCGCCGCCGTCGCCGTCGCCAGCC

CGTGCTGGCCCCGATTTCCGTGCGCAGGGTGGCTCGCGAAGGAGGCAGGACCCT

GGTGCTGCCAACAGCGCGCTACCACCCCAGCATCGTTTAAAAGCCGGTCTTTGTG

GTTCTTGCAGATATGGCCCTCACCTGCCGCCTCCGTTTCCCGGTGCCGGGATTCC

GAGGAAGAATGCACCGTAGGAGGGGCATGGCCGGCCACGGCCTGACGGGCGGC

ATGCGTCGTGCGCACCACCGGCGGCGGCGCGCGTCGCACCGTCGCATGCGCGGC

GGTATCCTGCCCCTCCTTATTCCACTGATCGCCGCGGCGATTGGCGCCGTGCCCG

GAATTGCATCCGTGGCCTTGCAGGCGCAGAGACACTGATTAAAAACAAGTTGCA

TGTGGAAAAATCAAAATAAAAAGTCTGGACTCTCACGCTCGCTTGGTCCTGTAAC

TATTTTGTAGAATGGAAGACATCAACTTTGCGTCTCTGGCCCCGCGACACGGCTC

GCGCCCGTTCATGGGAAACTGGCAAGATATCGGCACCAGCAATATGAGCGGTGG

CGCCTTCAGCTGGGGCTCGCTGTGGAGCGGCATTAAAAATTTCGGTTCCACCGTT

AAGAACTATGGCAGCAAGGCCTGGAACAGCAGCACAGGCCAGATGCTGAGGGA

TAAGTTGAAAGAGCAAAATTTCCAACAAAAGGTGGTAGATGGCCTGGCCTCTGG

CATTAGCGGGGTGGTGGACCTGGCCAACCAGGCAGTGCAAAATAAGATTAACAG

TAAGCTTGATCCCCGCCCTCCCGTAGAGGAGCCTCCACCGGCCGTGGAGACAGT

GTCTCCAGAGGGGCGTGGCGAAAAGCGTCCGCGCCCCGACAGGGAAGAAACTCT

GGTGACGCAAATAGACGAGCCTCCCTCGTACGAGGAGGCACTAAAGCAAGGCCT

GCCCACCACCCGTCCCATCGCGCCCATGGCTACCGGAGTGCTGGGCCAGCACAC

ACCCGTAACGCTGGACCTGCCTCCCCCCGCCGACACCCAGCAGAAACCTGTGCTG

CCAGGCCCGACCGCCGTTGTTGTAACCCGTCCTAGCCGCGCGTCCCTGCGCCGCG

CCGCCAGCGGTCCGCGATCGTTGCGGCCCGTAGCCAGTGGCAACTGGCAAAGCA

CACTGAACAGCATCGTGGGTCTGGGGGTGCAATCCCTGAAGCGCCGACGATGCT

TCTGATAGCTAACGTGTCGTATGTGTGTCATGTATGCGTCCATGTCGCCGCCAGA

GGAGCTGCTGAGCCGCCGCGCGCCCGCTTTCCAAGATGGCTACCCCTTCGATGAT

GCCGCAGTGGTCTTACATGCACATCTCGGGCCAGGACGCCTCGGAGTACCTGAG

CCCCGGGCTGGTGCAGTTTGCCCGCGCCACCGAGACGTACTTCAGCCTGAATAAC

AAGTTTAGAAACCCCACGGTGGCGCCTACGCACGACGTGACCACAGACCGGTCC

CAGCGTTTGACGCTGCGGTTCATCCCTGTGGACCGTGAGGATACTGCGTACTCGT

ACAAGGCGCGGTTCACCCTAGCTGTGGGTGATAACCGTGTGCTGGACATGGCTTC

CACGTACTTTGACATCCGCGGCGTGCTGGACAGGGGCCCTACTTTTAAGCCCTAC

TCTGGCACTGCCTACAACGCCCTGGCTCCCAAGGGTGCCCCAAATCCTTGCGAAT

GGGATGAAGCTGCTACTGCTCTTGAAATAAACCTAGAAGAAGAGGACGATGACA

ACGAAGACGAAGTAGACGAGCAAGCTGAGCAGCAAAAAACTCACGTATTTGGG

CAGGCGCCTTATTCTGGTATAAATATTACAAAGGAGGGTATTCAAATAGGTGTCG

AAGGTCAAACACCTAAATATGCCGATAAAACATTTCAACCTGAACCTCAAATAG

GAGAATCTCAGTGGTACGAAACAGAAATTAATCATGCAGCTGGGAGAGTCCTAA

AAAAGACTACCCCAATGAAACCATGTTACGGTTCATATGCAAAACCCACAAATG

AAAATGGAGGGCAAGGCATTCTTGTAAAGCAACAAAATGGAAAGCTAGAAAGT

CAAGTGGAAATGCAATTTTTCTCAACTACTGAGGCAGCCGCAGGCAATGGTGAT

AACTTGACTCCTAAAGTGGTATTGTACAGTGAAGATGTAGATATAGAAACCCCA

GACACTCATATTTCTTACATGCCCACTATTAAGGAAGGTAACTCACGAGAACTAA

TGGGCCAACAATCTATGCCCAACAGGCCTAATTACATTGCTTTTAGGGACAATTT

TATTGGTCTAATGTATTACAACAGCACGGGTAATATGGGTGTTCTGGCGGGCCAA

GCATCGCAGTTGAATGCTGTTGTAGATTTGCAAGACAGAAACACAGAGCTTTCAT

ACCAGCTTTTGCTTGATTCCATTGGTGATAGAACCAGGTACTTTTCTATGTGGAAT

CAGGCTGTTGACAGCTATGATCCAGATGTTAGAATTATTGAAAATCATGGAACTG

AAGATGAACTTCCAAATTACTGCTTTCCACTGGGAGGTGTGATTAATACAGAGAC

TCTTACCAAGGTAAAACCTAAAACAGGTCAGGAAAATGGATGGGAAAAAGATGC

TACAGAATTTTCAGATAAAAATGAAATAAGAGTTGGAAATAATTTTGCCATGGA

AATCAATCTAAATGCCAACCTGTGGAGAAATTTCCTGTACTCCAACATAGCGCTG

TATTTGCCCGACAAGCTAAAGTACAGTCCTTCCAACGTAAAAATTTCTGATAACC

CAAACACCTACGACTACATGAACAAGCGAGTGGTGGCTCCCGGGCTAGTGGACT

GCTACATTAACCTTGGAGCACGCTGGTCCCTTGACTATATGGACAACGTCAACCC

ATTTAACCACCACCGCAATGCTGGCCTGCGCTACCGCTCAATGTTGCTGGGCAAT

GGTCGCTATGTGCCCTTCCACATCCAGGTGCCTCAGAAGTTCTTTGCCATTAAAA

ACCTCCTTCTCCTGCCGGGCTCATACACCTACGAGTGGAACTTCAGGAAGGATGT

TAACATGGTTCTGCAGAGCTCCCTAGGAAATGACCTAAGGGTTGACGGAGCCAG

CATTAAGTTTGATAGCATTTGCCTTTACGCCACCTTCTTCCCCATGGCCCACAACA

CCGCCTCCACGCTTGAGGCCATGCTTAGAAACGACACCAACGACCAGTCCTTTAA

CGACTATCTCTCCGCCGCCAACATGCTCTACCCTATACCCGCCAACGCTACCAAC

GTGCCCATATCCATCCCCTCCCGCAACTGGGCGGCTTTCCGCGGCTGGGCCTTCA

CGCGCCTTAAGACTAAGGAAACCCCATCACTGGGCTCGGGCTACGACCCTTATTA

CACCTACTCTGGCTCTATACCCTACCTAGATGGAACCTTTTACCTCAACCACACCT

TTAAGAAGGTGGCCATTACCTTTGACTCTTCTGTCAGCTGGCCTGGCAATGACCG

CCTGCTTACCCCCAACGAGTTTGAAATTAAGCGCTCAGTTGACGGGGAGGGTTAC

AACGTTGCCCAGTGTAACATGACCAAAGACTGGTTCCTGGTACAAATGCTAGCTA

ACTATAACATTGGCTACCAGGGCTTCTATATCCCAGAGAGCTACAAGGACCGCAT

GTACTCCTTCTTTAGAAACTTCCAGCCCATGAGCCGTCAGGTGGTGGATGATACT

AAATACAAGGACTACCAACAGGTGGGCATCCTACACCAACACAACAACTCTGGA

TTTGTTGGCTACCTTGCCCCCACCATGCGCGAAGGACAGGCCTACCCTGCTAACT

TCCCCTATCCGCTTATAGGCAAGACCGCAGTTGACAGCATTACCCAGAAAAAGTT

TCTTTGCGATCGCACCCTTTGGCGCATCCCATTCTCCAGTAACTTTATGTCCATGG

GCGCACTCACAGACCTGGGCCAAAACCTTCTCTACGCCAACTCCGCCCACGCGCT

AGACATGACTTTTGAGGTGGATCCCATGGACGAGCCCACCCTTCTTTATGTTTTG

TTTGAAGTCTTTGACGTGGTCCGTGTGCACCAGCCGCACCGCGGCGTCATCGAAA

CCGTGTACCTGCGCACGCCCTTCTCGGCCGGCAACGCCACAACATAAAGAAGCA

AGCAACATCAACAACAGCTGCCGCCATGGGCTCCAGTGAGCAGGAACTGAAAGC

CATTGTCAAAGATCTTGGTTGTGGGCCATATTTTTTGGGCACCTATGACAAGCGC

TTTCCAGGCTTTGTTTCTCCACACAAGCTCGCCTGCGCCATAGTCAATACGGCCG

GTCGCGAGACTGGGGGCGTACACTGGATGGCCTTTGCCTGGAACCCGCACTCAA

AAACATGCTACCTCTTTGAGCCCTTTGGCTTTTCTGACCAGCGACTCAAGCAGGT

TTACCAGTTTGAGTACGAGTCACTCCTGCGCCGTAGCGCCATTGCTTCTTCCCCCG

ACCGCTGTATAACGCTGGAAAAGTCCACCCAAAGCGTACAGGGGCCCAACTCGG

CCGCCTGTGGACTATTCTGCTGCATGTTTCTCCACGCCTTTGCCAACTGGCCCCAA

ACTCCCATGGATCACAACCCCACCATGAACCTTATTACCGGGGTACCCAACTCCA

TGCTCAACAGTCCCCAGGTACAGCCCACCCTGCGTCGCAACCAGGAACAGCTCT

ACAGCTTCCTGGAGCGCCACTCGCCCTACTTCCGCAGCCACAGTGCGCAGATTAG

GAGCGCCACTTCTTTTTGTCACTTGAAAAACATGTAAAAATAATGTACTAGAGAC

ACTTTCAATAAAGGCAAATGCTTTTATTTGTACACTCTCGGGTGATTATTTACCCC

CACCCTTGCCGTCTGCGCCGTTTAAAAATCAAAGGGGTTCTGCCGCGCATCGCTA

TGCGCCACTGGCAGGGACACGTTGCGATACTGGTGTTTAGTGCTCCACTTAAACT

CAGGCACAACCATCCGCGGCAGCTCGGTGAAGTTTTCACTCCACAGGCTGCGCA

CCATCACCAACGCGTTTAGCAGGTCGGGCGCCGATATCTTGAAGTCGCAGTTGGG

GCCTCCGCCCTGCGCGCGCGAGTTGCGATACACAGGGTTGCAGCACTGGAACAC

TATCAGCGCCGGGTGGTGCACGCTGGCCAGCACGCTCTTGTCGGAGATCAGATCC

GCGTCCAGGTCCTCCGCGTTGCTCAGGGCGAACGGAGTCAACTTTGGTAGCTGCC

TTCCCAAAAAGGGCGCGTGCCCAGGCTTTGAGTTGCACTCGCACCGTAGTGGCAT

CAAAAGGTGACCGTGCCCGGTCTGGGCGTTAGGATACAGCGCCTGCATAAAAGC

CTTGATCTGCTTAAAAGCCACCTGAGCCTTTGCGCCTTCAGAGAAGAACATGCCG

CAAGACTTGCCGGAAAACTGATTGGCCGGACAGGCCGCGTCGTGCACGCAGCAC

CTTGCGTCGGTGTTGGAGATCTGCACCACATTTCGGCCCCACCGGTTCTTCACGA

TCTTGGCCTTGCTAGACTGCTCCTTCAGCGCGCGCTGCCCGTTTTCGCTCGTCACA

TCCATTTCAATCACGTGCTCCTTATTTATCATAATGCTTCCGTGTAGACACTTAAG

CTCGCCTTCGATCTCAGCGCAGCGGTGCAGCCACAACGCGCAGCCCGTGGGCTC

GTGATGCTTGTAGGTCACCTCTGCAAACGACTGCAGGTACGCCTGCAGGAATCGC

CCCATCATCGTCACAAAGGTCTTGTTGCTGGTGAAGGTCAGCTGCAACCCGCGGT

GCTCCTCGTTCAGCCAGGTCTTGCATACGGCCGCCAGAGCTTCCACTTGGTCAGG

CAGTAGTTTGAAGTTCGCCTTTAGATCGTTATCCACGTGGTACTTGTCCATCAGC

GCGCGCGCAGCCTCCATGCCCTTCTCCCACGCAGACACGATCGGCACACTCAGCG

GGTTCATCACCGTAATTTCACTTTCCGCTTCGCTGGGCTCTTCCTCTTCCTCTTGC

GTCCGCATACCACGCGCCACTGGGTCGTCTTCATTCAGCCGCCGCACTGTGCGCT

TACCTCCTTTGCCATGCTTGATTAGCACCGGTGGGTTGCTGAAACCCACCATTTGT

AGCGCCACATCTTCTCTTTCTTCCTCGCTGTCCACGATTACCTCTGGTGATGGCGG

GCGCTCGGGCTTGGGAGAAGGGCGCTTCTTTTTCTTCTTGGGCGCAATGGCCAAA

TCCGCCGCCGAGGTCGATGGCCGCGGGCTGGGTGTGCGCGGCACCAGCGCGTCT

TGTGATGAGTCTTCCTCGTCCTCGGACTCGATACGCCGCCTCATCCGCTTTTTTGG

GGGCGCCCGGGGAGGCGGCGGCGACGGGGACGGGGACGACACGTCCTCCATGG

TTGGGGGACGTCGCGCCGCACCGCGTCCGCGCTCGGGGGTGGTTTCGCGCTGCTC

CTCTTCCCGACTGGCCATTTCCTTCTCCTATAGGCAGAAAAAGATCATGGAGTCA

GTCGAGAAGAAGGACAGCCTAACCGCCCCCTCTGAGTTCGCCACCACCGCCTCC

ACCGATGCCGCCAACGCGCCTACCACCTTCCCCGTCGAGGCACCCCCGCTTGAGG

AGGAGGAAGTGATTATCGAGCAGGACCCAGGTTTTGTAAGCGAAGACGACGAGG

ACCGCTCAGTACCAACAGAGGATAAAAAGCAAGACCAGGACAACGCAGAGGCA

AACGAGGAACAAGTCGGGCGGGGGGACGAAAGGCATGGCGACTACCTAGATGT

GGGAGACGACGTGCTGTTGAAGCATCTGCAGCGCCAGTGCGCCATTATCTGCGA

CGCGTTGCAAGAGCGCAGCGATGTGCCCCTCGCCATAGCGGATGTCAGCCTTGCC

TACGAACGCCACCTATTCTCACCGCGCGTACCCCCCAAACGCCAAGAAAACGGC

ACATGCGAGCCCAACCCGCGCCTCAACTTCTACCCCGTATTTGCCGTGCCAGAGG

TGCTTGCCACCTATCACATCTTTTTCCAAAACTGCAAGATACCCCTATCCTGCCGT

GCCAACCGCAGCCGAGCGGACAAGCAGCTGGCCTTGCGGCAGGGCGCTGTCATA

CCTGATATCGCCTCGCTCAACGAAGTGCCAAAAATCTTTGAGGGTCTTGGACGCG

ACGAGAAGCGCGCGGCAAACGCTCTGCAACAGGAAAACAGCGAAAATGAAAGT

CACTCTGGAGTGTTGGTGGAACTCGAGGGTGACAACGCGCGCCTAGCCGTACTA

AAACGCAGCATCGAGGTCACCCACTTTGCCTACCCGGCACTTAACCTACCCCCCA

AGGTCATGAGCACAGTCATGAGTGAGCTGATCGTGCGCCGTGCGCAGCCCCTGG

AGAGGGATGCAAATTTGCAAGAACAAACAGAGGAGGGCCTACCCGCAGTTGGC

GACGAGCAGCTAGCGCGCTGGCTTCAAACGCGCGAGCCTGCCGACTTGGAGGAG

CGACGCAAACTAATGATGGCCGCAGTGCTCGTTACCGTGGAGCTTGAGTGCATG

CAGCGGTTCTTTGCTGACCCGGAGATGCAGCGCAAGCTAGAGGAAACATTGCAC

TACACCTTTCGACAGGGCTACGTACGCCAGGCCTGCAAGATCTCCAACGTGGAG

CTCTGCAACCTGGTCTCCTACCTTGGAATTTTGCACGAAAACCGCCTTGGGCAAA

ACGTGCTTCATTCCACGCTCAAGGGCGAGGCGCGCCGCGACTACGTCCGCGACT

GCGTTTACTTATTTCTATGCTACACCTGGCAGACGGCCATGGGCGTTTGGCAGCA

GTGCTTGGAGGAGTGCAACCTCAAGGAGCTGCAGAAACTGCTAAAGCAAAACTT

GAAGGACCTATGGACGGCCTTCAACGAGCGCTCCGTGGCCGCGCACCTGGCGGA

CATCATTTTCCCCGAACGCCTGCTTAAAACCCTGCAACAGGGTCTGCCAGACTTC

ACCAGTCAAAGCATGTTGCAGAACTTTAGGAACTTTATCCTAGAGCGCTCAGGA

ATCTTGCCCGCCACCTGCTGTGCACTTCCTAGCGACTTTGTGCCCATTAAGTACCG

CGAATGCCCTCCGCCGCTTTGGGGCCACTGCTACCTTCTGCAGCTAGCCAACTAC

CTTGCCTACCACTCTGACATAATGGAAGACGTGAGCGGTGACGGTCTACTGGAGT

GTCACTGTCGCTGCAACCTATGCACCCCGCACCGCTCCCTGGTTTGCAATTCGCA

GCTGCTTAACGAAAGTCAAATTATCGGTACCTTTGAGCTGCAGGGTCCCTCGCCT

GACGAAAAGTCCGCGGCTCCGGGGTTGAAACTCACTCCGGGGCTGTGGACGTCG

GCTTACCTTCGCAAATTTGTACCTGAGGACTACCACGCCCACGAGATTAGGTTCT

ACGAAGACCAATCCCGCCCGCCTAATGCGGAGCTTACCGCCTGCGTCATTACCCA

GGGCCACATTCTTGGCCAATTGCAAGCCATCAACAAAGCCCGCCAAGAGTTTCTG

CTACGAAAGGGACGGGGGGTTTACTTGGACCCCCAGTCCGGCGAGGAGCTCAAC

CCAATCCCCCCGCCGCCGCAGCCCTATCAGCAGCAGCCGCGGGCCCTTGCTTCCC

AGGATGGCACCCAAAAAGAAGCTGCAGCTGCCGCCGCCACCCACGGACGAGGA

GGAATACTGGGACAGTCAGGCAGAGGAGGTTTTGGACGAGGAGGAGGAGGACA

TGATGGAAGACTGGGAGAGCCTAGACGAGGAAGCTTCCGAGGTCGAAGAGGTGT

CAGACGAAACACCGTCACCCTCGGTCGCATTCCCCTCGCCGGCGCCCCAGAAATC

GGCAACCGGTTCCAGCATGGCTACAACCTCCGCTCCTCAGGCGCCGCCGGCACTG

CCCGTTCGCCGACCCAACCGTAGATGGGACACCACTGGAACCAGGGCCGGTAAG

TCCAAGCAGCCGCCGCCGTTAGCCCAAGAGCAACAACAGCGCCAAGGCTACCGC

TCATGGCGCGGGCACAAGAACGCCATAGTTGCTTGCTTGCAAGACTGTGGGGGC

AACATCTCCTTCGCCCGCCGCTTTCTTCTCTACCATCACGGCGTGGCCTTCCCCCG

TAACATCCTGCATTACTACCGTCATCTCTACAGCCCATACTGCACCGGCGGCAGC

GGCAGCAACAGCAGCGGCCACACAGAAGCAAAGGCGACCGGATAGCAAGACTC

TGACAAAGCCCAAGAAATCCACAGCGGCGGCAGCAGCAGGAGGAGGAGCGCTG

CGTCTGGCGCCCAACGAACCCGTATCGACCCGCGAGCTTAGAAACAGGATTTTTC

CCACTCTGTATGCTATATTTCAACAGAGCAGGGGCCAAGAACAAGAGCTGAAAA

TAAAAAACAGGTCTCTGCGATCCCTCACCCGCAGCTGCCTGTATCACAAAAGCG

AAGATCAGCTTCGGCGCACGCTGGAAGACGCGGAGGCTCTCTTCAGTAAATACT

GCGCGCTGACTCTTAAGGACTAGTTTCGCGCCCTTTCTCAAATTTAAGCGCGAAA

ACTACGTCATCTCCAGCGGCCACACCCGGCGCCAGCACCTGTTGTCAGCGCCATT

ATGAGCAAGGAAATTCCCACGCCCTACATGTGGAGTTACCAGCCACAAATGGGA

CTTGCGGCTGGAGCTGCCCAAGACTACTCAACCCGAATAAACTACATGAGCGCG

GGACCCCACATGATATCCCGGGTCAACGGAATACGCGCCCACCGAAACCGAATT

CTCCTGGAACAGGCGGCTATTACCACCACACCTCGTAATAACCTTAATCCCCGTA

GTTGGCCCGCTGCCCTGGTGTACCAGGAAAGTCCCGCTCCCACCACTGTGGTACT

TCCCAGAGACGCCCAGGCCGAAGTTCAGATGACTAACTCAGGGGCGCAGCTTGC

GGGCGGCTTTCGTCACAGGGTGCGGTCGCCCGGGCAGGGTATAACTCACCTGAC

AATCAGAGGGCGAGGTATTCAGCTCAACGACGAGTCGGTGAGCTCCTCGCTTGG

TCTCCGTCCGGACGGGACATTTCAGATCGGCGGCGCCGGCCGCTCTTCATTCACG

CCTCGTCAGGCAATCCTAACTCTGCAGACCTCGTCCTCTGAGCCGCGCTCTGGAG

GCATTGGAACTCTGCAATTTATTGAGGAGTTTGTGCCATCGGTCTACTTTAACCC

CTTCTCGGGACCTCCCGGCCACTATCCGGATCAATTTATTCCTAACTTTGACGCG

GTAAAGGACTCGGCGGACGGCTACGACTGAATGTTAAGTGGAGAGGCAGAGCA

ACTGCGCCTGAAACACCTGGTCCACTGTCGCCGCCACAAGTGCTTTGCCCGCGAC

TCCGGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCATATCGAGGGCCcGGCGC

ACGGCGTCCGGCTTACCGCCCAGGGAGAGCTTGCCCGTAGCCTGATTCGGGAGTT

TACCCAGCGCCCCCTGCTAGTTGAGCGGGACAGGGGACCCTGTGTTCTCACTGTG

ATTTGCAACTGTCCTAACCCTGGATTACATCAAGATCCTCTAGTTAATGTCAGGT

CGCCTAAGTCGATTAACTAGAGTACCCGGGGATCTTATTCCCTTTAACTAATAAA

AAAAAATAATAAAGCATCACTTACTTAAAATCAGTTAGCAAATTTCTGTCCAGTT

TATTCAGCAGCACCTCCTTGCCCTCCTCCCAGCTCTGGTATTGCAGCTTCCTCCTG

GCTGCAAACTTTCTCCACAATCTAAATGGAATGTCAGTTTCCTCCTGTTCCTGTCC

ATCCGCACCCACTATCTTCATGTTGTTGCAGATGAAGCGCGCAAGACCGTCTGAA

GATACCTTCAACCCCGTGTATCCATATGACACGGAAACCGGTCCTCCAACTGTGC

CTTTTCTTACTCCTCCCTTTGTATCCCCCAATGGGTTTCAAGAGAGTCCCCCTGGG

GTACTCTCTTTGCGCCTATCCGAACCTCTAGTTACCTCCAATGGCATGCTTGCGCT

CAAAATGGGCAACGGCCTCTCTCTGGACGAGGCCGGCAACCTTACCTCCCAAAA

TGTAACCACTGTGAGCCCACCTCTCAAAAAAACCAAGTCAAACATAAACCTGGA

AATATCTGCACCCCTCACAGTTACCTCAGAAGCCCTAACTGTGGCTGCCGCCGCA

CCTCTAATGGTCGCGGGCAACACACTCACCATGCAATCACAGGCCCCGCTAACC

GTGCACGACTCCAAACTTAGCATTGCCACCCAAGGACCCCTCACAGTGTCAGAA

GGAAAGCTAGCCCTGCAAACATCAGGCCCCCTCACCACCACCGATAGCAGTACC

CTTACTATCACTGCCTCACCCCCTCTAACTACTGCCACTGGTAGCTTGGGCATTGA

CTTGAAAGAGCCCATTTATACACAAAATGGAAAACTAGGACTAAAGTACGGGGC

TCCTTTGCATGTAACAGACGACCTAAACACTTTGACCGTAGCAACTGGTCCAGGT

GTGACTATTAATAATACTTCCTTGCAAACTAAAGTTACTGGAGCCTTGGGTTTTG

ATTCACAAGGCAATATGCAACTTAATGTAGCAGGAGGACTAAGGATTGATTCTC

AAAACAGACGCCTTATACTTGATGTTAGTTATCCGTTTGATGCTCAAAACCAACT

AAATCTAAGACTAGGACAGGGCCCTCTTTTTATAAACTCAGCCCACAACTTGGAT

ATTAACTACAACAAAGGCCTTTACTTGTTTACAGCTTCAAACAATTCCAAAAAGC

TTGAGGTTAACCTAAGCACTGCCAAGGGGTTGATGTTTGACGCTACAGCCATAGC

CATTAATGCAGGAGATGGGCTTGAATTTGGTTCACCTAATGCACCAAACACAAAT

CCCCTCAAAACAAAAATTGGCCATGGCCTAGAATTTGATTCAAACAAGGCTATG

GTTCCTAAACTAGGAACTGGCCTTAGTTTTGACAGCACAGGTGCCATTACAGTAG

GAAACAAAAATAATGATAAGCTAACTTTGTGGACCACACCAGCTCCATCTCCTA

ACTGTAGACTAAATGCAGAGAAAGATGCTAAACTCACTTTGGTCTTAACAAAAT

GTGGCAGTCAAATACTTGCTACAGTTTCAGTTTTGGCTGTTAAAGGCAGTTTGGC

TCCAATATCTGGAACAGTTCAAAGTGCTCATCTTATTATAAGATTTGACGAAAAT

GGAGTGCTACTAAACAATTCCTTCCTGGACCCAGAATATTGGAACTTTAGAAATG

GAGATCTTACTGAAGGCACAGCCTATACAAACGCTGTTGGATTTATGCCTAACCT

ATCAGCTTATCCAAAATCTCACGGTAAAACTGCCAAAAGTAACATTGTCAGTCAA

GTTTACTTAAACGGAGACAAAACTAAACCTGTAACACTAACCATTACACTAAAC

GGTACACAGGAAACAGGAGACACAACTCCAAGTGCATACTCTATGTCATTTTCAT

GGGACTGGTCTGGCCACAACTACATTAATGAAATATTTGCCACATCCTCTTACAC

TTTTTCATACATTGCCCAAGAATAAAGAATCGTTTGTGTTATGTTTCAACGTGTTT

ATTTTTCAATTGCAGAAAATTTCAAGTCATTTTTCATTCAGTAGTATAGCCCCACC

ACCACATAGCTTATACAGATCACCGTACCTTAATCAAACTCACAGAACCCTAGTA

TTCAACCTGCCACCTCCCTCCCAACACACAGAGTACACAGTCCTTTCTCCCCGGC

TGGCCTTAAAAAGCATCATATCATGGGTAACAGACATATTCTTAGGTGTTATATT

CCACACGGTTTCCTGTCGAGCCAAACGCTCATCAGTGATATTAATAAACTCCCCG

GGCAGCTCACTTAAGTTCATGTCGCTGTCCAGCTGCTGAGCCACAGGCTGCTGTC

CAACTTGCGGTTGCTTAACGGGCGGCGAAGGAGAAGTCCACGCCTACATGGGGG

TAGAGTCATAATCGTGCATCAGGATAGGGCGGTGGTGCTGCAGCAGCGCGCGAA

TAAACTGCTGCCGCCGCCGCTCCGTCCTGCAGGAATACAACATGGCAGTGGTCTC

CTCAGCGATGATTCGCACCGCCCGCAGCATAAGGCGCCTTGTCCTCCGGGCACAG

CAGCGCACCCTGATCTCACTTAAATCAGCACAGTAACTGCAGCACAGCACCACA

ATATTGTTCAAAATCCCACAGTGCAAGGCGCTGTATCCAAAGCTCATGGCGGGG

ACCACAGAACCCACGTGGCCATCATACCACAAGCGCAGGTAGATTAAGTGGCGA

CCCCTCATAAACACGCTGGACATAAACATTACCTCTTTTGGCATGTTGTAATTCA

CCACCTCCCGGTACCATATAAACCTCTGATTAAACATGGCGCCATCCACCACCAT

CCTAAACCAGCTGGCCAAAACCTGCCCGCCGGCTATACACTGCAGGGAACCGGG

ACTGGAACAATGACAGTGGAGAGCCCAGGACTCGTAACCATGGATCATCATGCT

CGTCATGATATCAATGTTGGCACAACACAGGCACACGTGCATACACTTCCTCAGG

ATTACAAGCTCCTCCCGCGTTAGAACCATATCCCAGGGAACAACCCATTCCTGAA

TCAGCGTAAATCCCACACTGCAGGGAAGACCTCGCACGTAACTCACGTTGTGCAT

TGTCAAAGTGTTACATTCGGGCAGCAGCGGATGATCCTCCAGTATGGTAGCGCG

GGTTTCTGTCTCAAAAGGAGGTAGACGATCCCTACTGTACGGAGTGCGCCGAGA

CAACCGAGATCGTGTTGGTCGTAGTGTCATGCCAAATGGAACGCCGGACGTAGT

CATATTTCCTGAAGCAAAACCAGGTGCGGGCGTGACAAACAGATCTGCGTCTCC

GGTCTCGCCGCTTAGATCGCTCTGTGTAGTAGTTGTAGTATATCCACTCTCTCAAA

GCATCCAGGCGCCCCCTGGCTTCGGGTTCTATGTAAACTCCTTCATGCGCCGCTG

CCCTGATAACATCCACCACCGCAGAATAAGCCACACCCAGCCAACCTACACATT

CGTTCTGCGAGTCACACACGGGAGGAGCGGGAAGAGCTGGAAGAACCATGTTTT

TTTTTTTATTCCAAAAGATTATCCAAAACCTCAAAATGAAGATCTATTAAGTGAA

CGCGCTCCCCTCCGGTGGCGTGGTCAAACTCTACAGCCAAAGAACAGATAATGG

CATTTGTAAGATGTTGCACAATGGCTTCCAAAAGGCAAACGGCCCTCACGTCCAA

GTGGACGTAAAGGCTAAACCCTTCAGGGTGAATCTCCTCTATAAACATTCCAGCA

CCTTCAACCATGCCCAAATAATTCTCATCTCGCCACCTTCTCAATATATCTCTAAG

CAAATCCCGAATATTAAGTCCGGCCATTGTAAAAATCTGCTCCAGAGCGCCCTCC

ACCTTCAGCCTCAAGCAGCGAATCATGATTGCAAAAATTCAGGTTCCTCACAGAC

CTGTATAAGATTCAAAAGCGGAACATTAACAAAAATACCGCGATCCCGTAGGTC

CCTTCGCAGGGCCAGCTGAACATAATCGTGCAGGTCTGCACGGACCAGCGCGGC

CACTTCCCCGCCAGGAACCATGACAAAAGAACCCACACTGATTATGACACGCAT

ACTCGGAGCTATGCTAACCAGCGTAGCCCCGATGTAAGCTTGTTGCATGGGCGGC

GATATAAAATGCAAGGTGCTGCTCAAAAAATCAGGCAAAGCCTCGCGCAAAAAA

GAAAGCACATCGTAGTCATGCTCATGCAGATAAAGGCAGGTAAGCTCCGGAACC

ACCACAGAAAAAGACACCATTTTTCTCTCAAACATGTCTGCGGGTTTCTGCATAA

ACACAAAATAAAATAACAAAAAAACATTTAAACATTAGAAGCCTGTCTTACAAC

AGGAAAAACAACCCTTATAAGCATAAGACGGACTACGGCCATGCCGGCGTGACC

GTAAAAAAACTGGTCACCGTGATTAAAAAGCACCACCGACAGCTCCTCGGTCAT

GTCCGGAGTCATAATGTAAGACTCGGTAAACACATCAGGTTGATTCACATCGGTC

AGTGCTAAAAAGCGACCGAAATAGCCCGGGGGAATACATACCCGCAGGCGTAG

AGACAACATTACAGCCCCCATAGGAGGTATAACAAAATTAATAGGAGAGAAAA

ACACATAAACACCTGAAAAACCCTCCTGCCTAGGCAAAATAGCACCCTCCCGCT

CCAGAACAACATACAGCGCTTCCACAGCGGCAGCCATAACAGTCAGCCTTACCA

GTAAAAAAGAAAACCTATTAAAAAAACACCACTCGACACGGCACCAGCTCAATC

AGTCACAGTGTAAAAAAGGGCCAAGTGCAGAGCGAGTATATATAGGACTAAAA

AATGACGTAACGGTrAAAGTCCACAAAAAACACCCAGAAAACCGCACGCGAACC

TACGCCCAGAAACGAAAGCCAAAAAACCCACAACTTCCTCAAATCGTCACTTCC

GTTTTCCCACGTTACGTCACTTCCCATTTTAAGAAAACTACAATTCCCAACACAT

ACAAGTTACTCCGCCCTAAAACCTACGTCACCCGCCCCGTTCCCACGCCCCGCGC

CACGTCACAAACTCCACCCCCTCATTATCATATTGGCTTCAATCCAAAATAAGGT

ATATT

SEQ ID NO: 10: rAd-CMV-SARS-CoV-2-S-BGH-bActin-SARS-CoV-2-N-SPA-BGH-

CMV-dsRNA-SPA

TAAGGATCCCATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAA

TGAGGGGGTGGAGTTTGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGAC

GTAGTAGTGTGGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTAAGCG

ACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCCGGTGTACACAGGAAGTGA

CAATTTTCGCGCGGTTTTAGGCGGATGTTGTAGTAAATTTGGGCGTAACCGAGTA

AGATTTGGCCATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATCTGAATAA

TTTTGTGTTACTCATAGCGCGTAATACTGCTAGAGATCTGGCGAAAGGGGGATGT

GCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTA

AAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTG

GCCACAGGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATT

TATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTA

TTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGC

GTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCC

CATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCA

TTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAA

GTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG

CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACAT

CTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAAT

GGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACG

TCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAA

CAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTA

TATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGAGACGCCATCCACG

CTGTTTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTGACTCTAGCCTAG

CTCTGAAGTTGGTGGTGAGGCCCTGGGCAGGTTGGTATCAAGGTTacaagacaggtttaag

gagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgcctattggtctattttccc

acccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGATGggtaccgccaccA

TGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTCAATCTGACTA

CCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAGGTGTTTACTAC

CCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGACCTCTTCCTCC

CTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGGCACCAACGGC

ACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGTATATTTTGCCT

CTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACTACCCTGGACTC

AAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGGTGATCAAAGTC

TGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTATCACAAAAATAA

CAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCGAATAATTGCACC

TTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGAAGCAGGGCAATT

TTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTTACTTCAAGATTTA

CTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCAGGGCTTTTCTGCA

TTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACAAGATTTCAGACTT

TGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTTCTTCCGGATGGAC

CGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCGAACCTTTCTTTTG

AAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGCGCCCTGGACCCC

CTGrCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAGAAGGGGATATAC

CAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTGCGCTTTCCTAATA

TAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTAGATTCGCTTCCGT

CTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGACTATAGTGTTTTG

TACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGAGCCCTACCAAAC

TGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGTTATCAGAGGAGA

CGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGCTGATTATAATTAC

AAACTGCCCGACGACTTTACAGGATGTGTGATCGCGTGGAACAGTAACAATCTT

GACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGTTCAGAAAAAGCA

ATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATCAGGCCGGGTCCA

CTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATTGCAGTCTTATGGA

TTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTTGTCGTGCTCAGCT

TCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGAAGTCCACCAATCT

TGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGACCGGGACCGGCGTT

CTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTCGGCCGCGATATTG

CTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAAATTCTCGATATCAC

ACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAACTAACACAAGCAAC

CAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGGTGCCAGTGGCCATCC

ACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCACAGGGTCCAATGTTTT

TCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTCAACAATTCCTACGA

GTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATCAGACCCAGACTAAT

AGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCATTGCATATACAATGT

CCCTGGGAGCTGAGAATTCAGTCGCGTATTCAAACAATTCCATTGCTATTCCTAC

TAATTTCACTATCTCCGTCACGACCGAGATCCTGCCAGTTTCCATGACTAAGACT

TCTGTTGACTGCACCATGTATATCTGTGGCGATAGCACCGAGTGCAGTAATCTGC

TTCTGCAGTACGGCTCCTTCTGCACACAACTCAATCGAGCACTGACCGGTATTGC

AGTTGAGCAGGACAAGAACACACAGGAGGTCTTTGCACAGGTCAAACAAATTTA

CAAAACCCCCCCCATAAAAGACTTTGGTGGGTTCAACTTCAGCCAAATCCTCCCA

GATCCCAGCAAGCCCTCCAAAAGATCCTTCATCGAAGACCTTTTGTTCAATAAGG

TAACCCTGGCCGACGCAGGCTTCATCAAACAATATGGCGATTGCCTTGGAGACAT

TGCTGCGCGCGATTTGATCTGTGCTCAGAAATTTAACGGTTTGACCGTGCTGCCC

CCACTTCTGACTGATGAGATGATAGCACAGTATACTTCTGCTCTTCTGGCAGGAA

CAATCACTTCCGGGTGGACCTTTGGCGCTGGTGCAGCACTGCAAATCCCCTTCGC

AATGCAAATGGCCTACCGATTCAATGGTATTGGTGTTACCCAGAACGTGCTCTAT

GAGAATCAGAAACTCATCGCCAATCAGTTCAATAGCGCTATTGGCAAGATTCAG

GATTCCCTCAGCTCTACCGCCAGCGCTCTGGGGAAGCTCCAGGACGTGGTGAACC

AAAATGCTCAAGCGCTCAATACCCTTGTGAAACAGCTCAGCTCCAATTTTGGCGC

AATTAGCAGCGTTCTGAATGATATTCTGTCCCGGCTGGACAAGGTAGAAGCAGA

AGTCCAGATCGACAGGCTGATCACCGGGCGGTTGCAGAGTCTCCAGACCTATGT

CACACAACAGCTGATCCGCGCCGCCGAGATCAGGGCTTCCGCTAACCTGGCCGC

CACTAAGATGTCCGAATGCGTGTTGGGGCAGAGTAAGCGGGTCGACTTTTGCGG

GAAGGGATACCATCTGATGAGCTTCCCTCAGTCTGCACCCCACGGAGTAGTGTTC

CTCCACGTCACATATGTGCCCGCTCAGGAAAAGAATTTCACAACCGCACCTGCTA

TCTGTCACGACGGCAAGGCCCACTTTCCTAGAGAAGGAGTTTTCGTATCTAACGG

CACCCACTGGTTCGTGACACAGCGGAACTTTTACGAGCCTCAGATTATAACTACG

GACAACACTTTCGTGTCAGGCAACTGTGACGTGGTGATTGGGATCGTGAACAAC

ACAGTCTACGACCCATTGCAGCCCGAGTTGGACTCCTTCAAAGAGGAGCTTGATA

AGTATTTCAAGAACCATACCTCTCCCGACGTGGACCTGGGGGACATTAGCGGCAT

CAATGCATCCGTTGTGAATATCCAGAAAGAAATCGATAGGCTGAATGAGGTCGC

AAAAAATCTTAATGAGTCACTGATTGATCTGCAGGAACTCGGCAAATATGAGCA

GTATATTAAGTGGCCGTGGTACATATGGCTCGGCTTTATCGCCGGTCTGATTGCC

ATCGTGATGGTGACCATTATGCTGTGTTGTATGACAAGCTGCTGTTCATGTCTCA

AAGGATGCTGCTCCTGCGGTAGCTGCTGTAAGTTCGATGAAGACGACAGTGAGC

CCGTGCTCAAAGGAGTGAAACTCCACTACACATAAcgatcgacgcgtAGAGCTCGCTGA

TCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGT

GCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAG

GAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGG

GGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGAT

GCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAaagcttgcggccgcGCCCAGCA

CCCCAAGGCGGCCAACGCCAAAACTCTCCCTCCTCCTCTTCCTCAATCTCGCTCTC

GCTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAGGGGGTAAAAAAATGCTGCACTG

TGCGGCGAAGCCGGTGAGTGAGCGGCGCGGGGCCAATCAGCGTGCGCCGTTCCG

AAAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGGCGCCCTATAAAACCCAGCG

GCGCGACGCGCCACCACCGCCGAGACcctgcaggccgccaccATGTCCGATAACGGCCCC

CAGAATCAGAGAAACGCTCCCCGCATCACGTTCGGCGGACCAAGTGACAGCACA

GGCAGTAACCAGAACGGAGAACGCTCCGGTGCTCGCTCCAAGCAGCGACGGCCG

CAAGGGCTTCCCAACAATACCGCCAGCTGGTTTACGGCTCTGACCCAACACGGG

AAAGAAGATCTTAAATTCCCCAGGGGCCAGGGCGTCCCTATCAATACTAACTCC

AGCCCGGATGATCAGATAGGCTACTATAGACGCGCTACCCGACGGATACGAGGG

GGGGACGGCAAAATGAAGGACCTTTCCCCCCGGTGGTATTTCTATTACTTGGGCA

CCGGACCAGAAGCCGGACTGCCTTACGGCGCTAACAAAGACGGAATAATCTGGG

TTGCGACGGAGGGCGCCCTGAATACACCTAAAGACCATATCGGCACAAGAAATC

CTGCTAACAATGCCGCGATTGTGCTCCAGCTGCCTCAGGGAACCACGCTGCCTAA

AGGGTTTTACGCTGAGGGGTCAAGGGGGGGGAGTCAAGCGTCTAGTAGGTCATC

CTCTCGCTCTCGCAATAGTTCCCGGAACTCAACCCCAGGCAGCAGCAGAGGAAC

CTCTCCCGCACGGATGGCTGGCAATGGGGGAGATGCTGCCCTTGCTCTCCTTCTG

CTGGATCGCCTTAACCAGCTCGAATCAAAGATGTCTGGAAAAGGTCAGCAGCAG

CAAGGCCAGACCGTGACAAAGAAGAGTGCAGCTGAAGCTAGTAAAAAGCCACG

CCAAAAACGGACCGCAACTAAGGCATATAACGTAACACAGGCCTTCGGCAGAAG

AGGTCCAGAACAAACACAGGGAAACTTTGGCGATCAAGAGCTGATTAGACAGGG

CACAGATTACAAACACTGGCCACAGATCGCGCAGTTTGCACCAAGCGCCTCTGC

ATTCTTCGGGATGAGTCGGATTGGGATGGAAGTCACTCCATCCGGGACCTGGCTT

ACCTACACAGGGGCAATAAAACTCGACGACAAAGACCCAAACTTTAAAGATCAG

GTCATCCTGCTGAATAAACACATCGATGCCTACAAAACTTTCCCCCCAACCGAAC

CAAAGAAAGACAAGAAAAAAAAGGCAGACGAAACGCAAGCGCTCCCTCAGCGC

CAGAAGAAGCAGCAGACCGTTACACTGTTGCCAGCAGCAGATCTGGATGATTTT

TCCAAGCAGCTTCAACAGAGTATGTCAAGCGCTGACAGCACTCAGGCTTGAggcgC

gccgctgaccgatAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTG

TGacgcgttagttattaataGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAG

TTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACC

CCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGAC

TTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTA

CATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAAT

GGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCA

GTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTAC

ATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCA

TTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATG

TCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGA

GGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCCGCTAGAGATATCG

GGCCACTGCAGGAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATC

GTTTCTCTAGAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGT

GTGAATCGATAGTACTAACATACGCTCTCCATCTCGAGCCTAAGCTTGTCGACTC

GAAGATCTGGGCGTGGTTAAGGGTGGGAAAGAATATATAAGGTGGGGGTCTTAT

GTAGTTTTGTATCTGTTTTGCAGCAGCCGCCGCCGCCATGAGCACCAACTCGTTT

GATGGAAGCATTGTGAGCTCATATTTGACAACGCGCATGCCCCCATGGGCcGGG

GTGCGTCAGAATGTGATGGGCTCCAGCATTGATGGTCGCCCCGTCCTGCCCGCAA

ACTCTACTACCTTGACCTACGAGACCGTGTCTGGAACGCCGTTGGAGACTGCAGC

CTCCGCCGCCGCTTCAGCCGCTGCAGCCACCGCCCGCGGGATTGTGACTGACTTT

GCTTTCCTGAGCCCGCTTGCAAGCAGTGCAGCTTCCCGTTCATCCGCCCGCGATG

ACAAGTTGACGGCTCTTTTGGCACAATTGGATTCTTTGACCCGGGAACTTAATGT

CGTTTCTCAGCAGCTGTTGGATCTGCGCCAGCAGGTTTCTGCCCTGAAGGCTTCC

TCCCCTCCCAATGCGGTTTAAAACATAAATAAAAAACCAGACTCTGTTTGGATTT

GGATCAAGCAAGTGTCTTGCTGTCTTTATTTAGGGGTTTTGCGCGCGCGGTAGGC

CCGGGACCAGCGGTCTCGGTCGTTGAGGGTCCTGTGTATTTTTTCCAGGACGTGG

TAAAGGTGACTCTGGATGTTCAGATACATGGGCATAAGCCCGTCTCTGGGGTGG

AGGTAGCACCACTGCAGAGCTTCATGCTGCGGGGTGGTGTTGTAGATGATCCAGT

CGTAGCAGGAGCGCTGGGCGTGGTGCCTAAAAATGTCTTTCAGTAGCAAGCTGA

TTGCCAGGGGCAGGCCCTTGGTGTAAGTGTTTACAAAGCGGTTAAGCTGGGATG

GGTGCATACGTGGGGATATGAGATGCATCTTGGACTGTATTTTTAGGTTGGCTAT

GTTCCCAGCCATATCCCTCCGGGGATTCATGTTGTGCAGAACCACCAGCACAGTG

TATCCGGTGCACTTGGGAAATTTGTCATGTAGCTTAGAAGGAAATGCGTGGAAG

AACTTGGAGACGCCCTTGTGACCTCCAAGATTTTCCATGCATTCGTCCATAATGA

TGGCAATGGGCCCACGGGCGGCGGCCTGGGCGAAGATATTTCTGGGATCACTAA

CGTCATAGTTGTGTTCCAGGATGAGATCGTCATAGGCCATTTTTACAAAGCGCGG

GCGGAGGGTGCCAGACTGCGGTATAATGGTTCCATCCGGCCCAGGGGCGTAGTT

ACCCTCACAGATTTGCATTTCCCACGCTTTGAGTTCAGATGGGGGGATCATGTCT

ACCTGCGGGGCGATGAAGAAAACGGTTTCCGGGGTAGGGGAGATCAGCTGGGA

AGAAAGCAGGTTCCTGAGCAGCTGCGACTTACCGCAGCCGGTGGGCCCGTAAAT

CACACCTATTACCGGCTGCAACTGGTAGTTAAGAGAGCTGCAGCTGCCGTCATCC

CTGAGCAGGGGGGCCACTTCGTTAAGCATGTCCCTGACTCGCATGTTTTCCCTGA

CCAAATCCGCCAGAAGGCGCTCGCCGCCCAGCGATAGCAGTTCTTGCAAGGAAG

CAAAGTTTTTCAACGGTTTGAGACCGTCCGCCGTAGGCATGCTTTTGAGCGTTTG

ACCAAGCAGTTCCAGGCGGTCCCACAGCTCGGTCACCTGCTCTACGGCATCTCGA

TCCAGCATATCTCCTCGTTTCGCGGGTTGGGGCGGCTTTCGCTGTACGGCAGTAG

TCGGTGCTCGTCCAGACGGGCCAGGGTCATGTCTTTCCACGGGCGCAGGGTCCTC

GTCAGCGTAGTCTGGGTCACGGTGAAGGGGTGCGCTCCGGGCTGCGCGCTGGCC

AGGGTGCGCTTGAGGCTGGTCCTGCTGGTGCTGAAGCGCTGCCGGTCTTCGCCCT

GCGCGTCGGCCAGGTAGCATTTGACCATGGTGTCATAGTCCAGCCCCTCCGCGGC

GTGGCCCTTGGCGCGCAGCTTGCCCTTGGAGGAGGCGCCGCACGAGGGGCAGTG

CAGACTTTTGAGGGCGTAGAGCTTGGGCGCGAGAAATACCGATTCCGGGGAGTA

GGCATCCGCGCCGCAGGCCCCGCAGACGGTCTCGCATTCCACGAGCCAGGTGAG

CTCTGGCCGTTCGGGGTCAAAAACCAGGTTTCCCCCATGCTTTTTGATGCGTTTCT

TACCTCTGGTTTCCATGAGCCGGTGTCCACGCTCGGTGACGAAAAGGCTGTCCGT

GTCCCCGTATACAGACTTGAGAGGCCTGTCCTCGAGCGGTGTTCCGCGGTCCTCC

TCGTATAGAAACTCGGACCACTCTGAGACAAAGGCTCGCGTCCAGGCCAGCACG

AAGGAGGCTAAGTGGGAGGGGTAGCGGTCGTTGTCCACTAGGGGGTCCACTCGC

TCCAGGGTGTGAAGACACATGTCGCCCTCTTCGGCATCAAGGAAGGTGATTGGTT

TGTAGGTGTAGGCCACGTGACCGGGTGTTCCTGAAGGGGGGCTATAAAAGGGGG

TGGGGGCGCGTTCGTCCTCACTCTCTTCCGCATCGCTGTCTGCGAGGGCCAGCTG

TTGGGGTGAGTACTCCCTCTGAAAAGCGGGCATGACTTCTGCGCTAAGATTGTCA

GTTTCCAAAAACGAGGAGGATTTGATATTCACCTGGCCCGCGGTGATGCCTTTGA

GGGTGGCCGCATCCATCTGGTCAGAAAAGACAATCTTTTTGTTGTCAAGCTTGGT

GGCAAACGACCCGTAGAGGGCGTTGGACAGCAACTTGGCGATGGAGCGCAGGGT

TTGGTTTTTGTCGCGATCGGCGCGCTCCTTGGCCGCGATGTTTAGCTGCACGTATT

CGCGCGCAACGCACCGCCATTCGGGAAAGACGGTGGTGCGCTCGTCGGGCACCA

GGTGCACGCGCCAACCGCGGTTGTGCAGGGTGACAAGGTCAACGCTGGTGGCTA

CCTCTCCGCGTAGGCGCTCGTTGGTCCAGCAGAGGCGGCCGCCCTTGCGCGAGCA

GAATGGCGGTAGGGGGTCTAGCTGCGTCTCGTCCGGGGGGTCTGCGTCCACGGT

AAAGACCCCGGGCAGCAGGCGCGCGTCGAAGTAGTCTATCTTGCATCCTTGCAA

GTCTAGCGCCTGCTGCCATGCGCGGGCGGCAAGCGCGCGCTCGTATGGGTTGAG

TGGGGGACCCCATGGCATGGGGTGGGTGAGCGCGGAGGCGTACATGCCGCAAAT

GTCGTAAACGTAGAGGGGCTCTCTGAGTATTCCAAGATATGTAGGGTAGCATCTT

CCACCGCGGATGCTGGCGCGCACGTAATCGTATAGTTCGTGCGAGGGAGCGAGG

AGGTCGGGACCGAGGTTGCTACGGGCGGGCTGCTCTGCTCGGAAGACTATCTGC

CTGAAGATGGCATGTGAGTTGGATGATATGGTTGGACGCTGGAAGACGTTGAAG

CTGGCGTCTGTGAGACCTACCGCGTCACGCACGAAGGAGGCGTAGGAGTCGCGC

AGCTTGTTGACCAGCTCGGCGGTGACCTGCACGTCTAGGGCGCAGTAGTCCAGG

GTTTCCTTGATGATGTCATACTTATCCTGTCCCTTTTTTTTCCACAGCTCGCGGTTG

AGGACAAACTCTTCGCGGTCTTTCCAGTACTCTTGGATCGGAAACCCGTCGGCCT

CCGAACGGTAAGAGCCTAGCATGTAGAACTGGTTGACGGCCTGGTAGGCGCAGC

ATCCCTTTTCTACGGGTAGCGCGTATGCCTGCGCGGCCTTCCGGAGCGAGGTGTG

GGTGAGCGCAAAGGTGTCCCTGACCATGACTTTGAGGTACTGGTATTTGAAGTCA

GTGTCGTCGCATCCGCCCTGCTCCCAGAGCAAAAAGTCCGTGCGCTTTTTGGAAC

GCGGATTTGGCAGGGCGAAGGTGACATCGTTGAAGAGTATCTTTCCCGCGCGAG

GCATAAAGTTGCGTGTGATGCGGAAGGGTCCCGGCACCTCGGAACGGTTGTTAA

TTACCTGGGCGGCGAGCACGATCTCGTCAAAGCCGTTGATGTTGTGGCCCACAAT

GTAAAGTTCCAAGAAGCGCGGGATGCCCTTGATGGAAGGCAATTTTTTAAGTTCC

TCGTAGGTGAGCTCTTCAGGGGAGCTGAGCCCGTGCTCTGAAAGGGCCCAGTCT

GCAAGATGAGGGTTGGAAGCGACGAATGAGCTCCACAGGTCACGGGCCATTAGC

ATTTGCAGGTGGTCGCGAAAGGTCCTAAACTGGCGACCTATGGCCATTTTTTCTG

GGGTGATGCAGTAGAAGGTAAGCGGGTCTTGTTCCCAGCGGTCCCATCCAAGGT

TCGCGGCTAGGTCTCGCGCGGCAGTCACTAGAGGCTCATCTCCGCCGAACTTCAT

GACCAGCATGAAGGGCACGAGCTGCTTCCCAAAGGCCCCCATCCAAGTATAGGT

CTCTACATCGTAGGTGACAAAGAGACGCTCGGTGCGAGGATGCGAGCCGATCGG

GAAGAACTGGATCTCCCGCCACCAATTGGAGGAGTGGCTATTGATGTGGTGAAA

GTAGAAGTCCCTGCGACGGGCCGAACACTCGTGCTGGCTTTTGTAAAAACGTGC

GCAGTACTGGCAGCGGTGCACGGGCTGTACATCCTGCACGAGGTTGACCTGACG

ACCGCGCACAAGGAAGCAGAGTGGGAATTTGAGCCCCTCGCCTGGCGGGTTTGG

CTGGTGGTCTTCTACTTCGGCTGCTTGTCCTTGACCGTCTGGCTGCTCGAGGGGA

GTTACGGTGGATCGGACCACCACGCCGCGCGAGCCCAAAGTCCAGATGTCCGCG

CGCGGCGGTCGGAGCTTGATGACAACATCGCGCAGATGGGAGCTGTCCATGGTC

TGGAGCTCCCGCGGCGTCAGGTCAGGCGGGAGCTCCTGCAGGTTTACCTCGCATA

GACGGGTCAGGGCGCGGGCTAGATCCAGGTGATACCTAATTTCCAGGGGCTGGT

TGGTGGCGGCGTCGATGGCTTGCAAGAGGCCGCATCCCCGCGGCGCGACTACGG

TACCGCGCGGCGGGCGGTGGGCCGCGGGGGTGTCCTTGGATGATGCATCTAAAA

GCGGTGACGCGGGCGAGCCCCCGGAGGTAGGGGGGGCTCCGGACCCGCCGGGA

GAGGGGGCAGGGGCACGTCGGCGCCGCGCGCGGGCAGGAGCTGGTGCTGCGCG

CGTAGGTTGCTGGCGAACGCGACGACGCGGCGGTTGATCTCCTGAATCTGGCGC

CTCTGCGTGAAGACGACGGGCCCGGTGAGCTTTGAACCTGAAAGAGAGTTCGAGA

GAATCAATTTCGGTGTCGTTGACGGCGGCCTGGCGCAAAATCTCCTGCACGTCTC

CTGAGTTGTCTTGATAGGCGATCTCGGCCATGAACTGCTCGATCTCTTCCTCCTGG

AGATCTCCGCGTCCGGCTCGCTCCACGGTGGCGGCGAGGTCGTTGGAAATGCGG

GCCATGAGCTGCGAGAAGGCGTTGAGGCCTCCCTCGTTCCAGACGCGGCTGTAG

ACCACGCCCCCTTCGGCATCGCGGGCGCGCATGACCACCTGCGCGAGATTGAGC

TCCACGTGCCGGGCGAAGACGGCGTAGTTTCGCAGGCGCTGAAAGAGGTAGTTG

AGGGTGGTGGCGGTGTGTTCTGCCACGAAGAAGTACATAACCCAGCGTCGCAAC

GTGGATTCGTTGATATCCCCCAAGGCCTCAAGGCGCTCCATGGCCTCGTAGAAGT

CCACGGCGAAGTTGAAAAACTGGGAGTTGCGCGCCGACACGGTTAACTCCTCCT

CCAGAAGACGGATGAGCTCGGCGACAGTGTCGCGCACCTCGCGCTCAAAGGCTA

CAGGGGCCTCTTCTTCTTCTTCAATCTCCTCTTCCATAAGGGCCTCCCCTTCTTCTT

CTTCTGGCGGCGGTGGGGGAGGGGGGACACGGCGGCGACGACGGCGCACCGGG

AGGCGGTCGACAAAGCGCTCGATCATCTCCCCGCGGCGACGGCGCATGGTCTCG

GTGACGGCGCGGCCGTTCTCGCGGGGGCGCAGTTGGAAGACGCCGCCCGTCATG

TCCCGGTTATGGGTTGGCGGGGGGCTGCCATGCGGCAGGGATACGGCGCTAACG

ATGCATCTCAACAATTGTTGTGTAGGTACTCCGCCGCCGAGGGACCTGAGCGAGT

CCGCATCGACCGGATCGGAAAACCTCTCGAGAAAGGCGTCTAACCAGTCACAGT

CGCAAGGTAGGCTGAGCACCGTGGCGGGCGGCAGCGGGCGGCGGTCGGGGTTGT

TTCTGGCGGAGGTGCTGCTGATGATGTAATTAAAGTAGGCGGTCTTGAGACGGCG

GATGGTCGACAGAAGCACCATGTCCTTGGGTCCGGCCTGCTGAATGCGCAGGCG

GTCGGCCATGCCCCAGGCTTCGTTTTGACATCGGCGCAGGTCTTTGTAGTAGTCT

TGCATGAGCCTTTCTACCGGCACTTCTTCTTCTCCTTCCTCTTGTCCTGCATCTCTT

GCATCTATCGCTGCGGCGGCGGCGGAGTTTGGCCGTAGGTGGCGCCCTCTTCCTC

CCATGCGTGTGACCCCGAAGCCCCTCATCGGCTGAAGCAGGGCTAGGTCGGCGA

CAACGCGCTCGGCTAATATGGCCTGCTGCACCTGCGTGAGGGTAGACTGGAAGT

CATCCATGTCCACAAAGCGGTGGTATGCGCCCGTGTTGATGGTGTAAGTGCAGTT

GGCCATAACGGACCAGTTAACGGTCTGGTGACCCGGCTGCGAGAGCTCGGTGTA

CCTGAGACGCGAGTAAGCCCTCGAGTCAAATACGTAGTCGTTGCAAGTCCGCAC

CAGGTACTGGTATCCCACCAAAAAGTGCGGCGGCGGCTGGCGGTAGAGGGGCCA

GCGTAGGGTGGCCGGGGCTCCGGGGGCGAGATCTTCCAACATAAGGCGATGATA

TCCGTAGATGTACCTGGACATCCAGGTGATGCCGGCGGCGGTGGTGGAGGCGCG

CGGAAAGTCGCGGACGCGGTTCCAGATGTTGCGCAGCGGCAAAAAGTGCTCCAT

GGTCGGGACGCTCTGGCCGGTCAGGCGCGCGCAATCGTTGACGCTCTAGCGTGC

AAAAGGAGAGCCTGTAAGCGGGCACTCTTCCGTGGTCTGGTGGATAAATTCGCA

AGGGTATCATGGCGGACGACCGGGGTTCGAGCCCCGTATCCGGCCGTCCGCCGT

GATCCATGCGGTTACCGCCCGCGTGTCGAACCCAGGTGTGCGACGTCAGACAAC

GGGGGAGTGCTCCTTTTGGCTTCCTTCCAGGCGCGGCGGCTGCTGCGCTAGCTTT

TTTGGCCACTGGCCGCGCGCAGCGTAAGCGGTTAGGCTGGAAAGCGAAAGCATT

AAGTGGCTCGCTCCCTGTAGCCGGAGGGTTATTTTCCAAGGGTTGAGTCGCGGGA

CCCCCGGTTCGAGTCTCGGACCGGCCGGACTGCGGCGAACGGGGGTTTGCCTCCC

CGTCATGCAAGACCCCGCTTGCAAATTCCTCCGGAAACAGGGACGAGCCCCTTTT

TTGCTTTTCCCAGATGCATCCGGTGCTGCGGCAGATGCGCCCCCCTCCTCAGCAG

CGGCAAGAGCAAGAGCAGCGGCAGACATGCAGGGCACCCTCCCCTCCTCCTACC

GCGTCAGGAGGGGCGACATCCGCGGTTGACGCGGCAGCAGATGGTGATTACGAA

CCCCCGCGGCGCCGGGCCCGGCACTACCTGGACTTGGAGGAGGGCGAGGGCCTG

GCGCGGCTAGGAGCGCCCTCTCCTGAGCGGCACCCAAGGGTGCAGCTGAAGCGT

GATACGCGTGAGGCGTACGTGCCGCGGCAGAACCTGTTTCGCGACCGCGAGGGA

GAGGAGCCCGAGGAGATGCGGGATCGAAAGTTCCACGCAGGGCGCGAGCTGCG

GCATGGCCTGAATCGCGAGCGGTTGCTGCGCGAGGAGGACTTTGAGCCCGACGC

GCGAACCGGGATTAGTCCCGCGCGCGCACACGTGGCGGCCGCCGACCTGGTAAC

CGCATACGAGCAGACGGTGAACCAGGAGATTAACTTTCAAAAAAGCTTTAACAA

CCACGTGCGTACGCTTGTGGCGCGCGAGGAGGTGGCTATAGGACTGATGCATCT

GTGGGACTTTGTAAGCGCGCTGGAGCAAAACCCAAATAGCAAGCCGCTCATGGC

GCAGCTGTTCCTTATAGTGCAGCACAGCAGGGACAACGAGGCATTCAGGGATGC

GCTGCTAAACATAGTAGAGCCCGAGGGCCGCTGGCTGCTCGATTTGATAAACAT

CCTGCAGAGCATAGTGGTGCAGGAGCGCAGCTTGAGCCTGGCTGACAAGGTGGC

CGCCATCAACTATTCCATGCTTAGCCTGGGCAAGTTTTACGCCCGCAAGATATAC

CATACCCCTTACGTTCCCATAGACAAGGAGGTAAAGATCGAGGGGTTCTACATG

CGCATGGCGCTGAAGGTGCTTACCTTGAGCGACGACCTGGGCGTTTATCGCAACG

AGCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCGCGAGCTCAGCGACCGCG

AGCTGATGCACAGCCTGCAAAGGGCCCTGGCTGGCACGGGCAGCGGCGATAGAG

AGGCCGAGTCCTACTTTGACGCGGGCGCTGACCTGCGCTGGGCCCCAAGCCGAC

GCGCCCTGGAGGCAGCTGGGGCCGGACCTGGGCTGGCGGTGGCACCCGCGCGCG

CTGGCAACGTCGGCGGCGTGGAGGAATATGACGAGGACGATGAGTACGAGCCA

GAGGACGGCGAGTACTAAGCGGTGATGTTTCTGATCAGATGATGCAAGACGCAA

CGGACCCGGCGGTGCGGGCGGCGCTGCAGAGCCAGCCGTCCGGCCTTAACTCCA

CGGACGACTGGCGCCAGGTCATGGACCGCATCATGTCGCTGACTGCGCGCAATC

CTGACGCGTTCCGGCAGCAGCCGCAGGCCAACCGGCTCTCCGCAATTCTGGAAG

CGGTGGTCCCGGCGCGCGCAAACCCCACGCACGAGAAGGTGCTGGCGATCGTAA

ACGCGCTGGCCGAAAACAGGGCCATCCGGCCCGACGAGGCCGGCCTGGTCTACG

ACGCGCTGCTTCAGCGCGTGGCTCGTTACAACAGCGGCAACGTGCAGACCAACC

TGGACCGGCTGGTGGGGGATGTGCGCGAGGCCGTGGCGCAGCGTGAGCGCGCGC

AGCAGCAGGGCAACCTGGGCTCCATGGTTGCACTAAACGCCTTCCTGAGTACAC

AGCCCGCCAACGTGCCGCGGGGACAGGAGGACTACACCAACTTTGTGAGCGCAC

TGCGGCTAATGGTGACTGAGACACCGCAAAGTGAGGTGTACCAGTCTGGGCCAG

ACTATTTTTTCCAGACCAGTAGACAAGGCCTGCAGACCGTAAACCTGAGCCAGG

CTTTCAAAAACTTGCAGGGGCTGTGGGGGGTGCGGGCTCCCACAGGCGACCGCG

CGACCGTGTCTAGCTTGCTGACGCCCAACTCGCGCCTGTTGCTGCTGCTAATAGC

GCCCTTCACGGACAGTGGCAGCGTGTCCCGGGACACATACCTAGGTCACTTGCTG

ACACTGTACCGCGAGGCCATAGGTCAGGCGCATGTGGACGAGCATACTTTCCAG

GAGATTACAAGTGTCAGCCGCGCGCTGGGGCAGGAGGACACGGGCAGCCTGGA

GGCAACCCTAAACTACCTGCTGACCAACCGGCGGCAGAAGATCCCCTCGTTGCA

CAGTTTAAACAGCGAGGAGGAGCGCATTTTGCGCTACGTGCAGCAGAGCGTGAG

CCTTAACCTGATGCGCGACGGGGTAACGCCCAGCGTGGCGCTGGACATGACCGC

GCGCAACATGGAACCGGGCATGTATGCCTCAAACCGGCCGTTTATCAACCGCCT

AATGGACTACTTGCATCGCGCGGCCGCCGTGAACCCCGAGTATTTCACCAATGCC

ATCTTGAACCCGCACTGGCTACCGCCCCCTGGTTTCTACACCGGGGGATTCGAGG

TGCCCGAGGGTAACGATGGATTCCTCTGGGACGACATAGACGACAGCGTGTTTTC

CCCGCAACCGCAGACCCTGCTAGAGTTGCAACAGCGCGAGCAGGCAGAGGCGGC

GCTGCGAAAGGAAAGCTTCCGCAGGCCAAGCAGCTTGTCCGATCTAGGCGCTGC

GGCCCCGCGGTCAGATGCTAGTAGCCCATTTCCAAGCTTGATAGGGTCTCTTACC

AGCACTCGCACCACCCGCCCGCGCCTGCTGGGCGAGGAGGAGTACCTAAACAAC

TCGCTGCTGCAGCCGCAGCGCGAAAAAAACCTGCCTCCGGCATTTCCCAACAAC

GGGATAGAGAGCCTAGTGGACAAGATGAGTAGATGGAAGACGTACGCGCAGGA

GCACAGGGACGTGCCAGGCCCGCGCCCGCCCACCCGTCGTCAAAGGCACGACCG

TCAGCGGGGTCTGGTGTGGGAGGACGATGACTCGGCAGACGACAGCAGCGTCCT

GGATTTGGGAGGGAGTGGCAACCCGTTTGCGCACCTTCGCCCCAGGCTGGGGAG

AATGTTTTAAAAAAAAAAAAGCATGATGCAAAATAAAAAACTCACCAAGGCCAT

GGCACCGAGCGTTGGTTTTCTTGTATTCCCCTTAGTATGCGGCGCGCGGCGATGT

ATGAGGAAGGTCCTCCTCCCTCCTACGAGAGTGTGGTGAGCGCGGCGCCAGTGG

CGGCGGCGCTGGGTTCTCCCTTCGATGCTCCCCTGGACCCGCCGTTTGTGCCTCC

GCGGTACCTGCGGCCTACCGGGGGGAGAAACAGCATCCGTTACTCTGAGTTGGC

ACCCCTATTCGACACCACCCGTGTGTACCTGGTGGACAACAAGTCAACGGATGTG

GCATCCCTGAACTACCAGAACGACCACAGCAACTTTCTGACCACGGTCATTCAAA

ACAATGACTACAGCCCGGGGGAGGCAAGCACACAGACCATCAATCTTGACGACC

GGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCATACCAACATGCCAAATG

TGAACGAGTTCATGTTTACCAATAAGTTTAAGGCGCGGGTGATGGTGTCGCGCTT

GCCTACTAAGGACAATCAGGTGGAGCTGAAATACGAGTGGGTGGAGTTCACGCT

GCCCGAGGGCAACTACTCCGAGACCATGACCATAGACCTTATGAACAACGCGAT

CGTGGAGCACTACTTGAAAGTGGGCAGACAGAACGGGGTTCTGGAAAGCGACAT

CGGGGTAAAGTTTGACACCCGCAACTTCAGACTGGGGTTTGACCCCGTCACTGGT

CTTGTCATGCCTGGGGTATATACAAACGAAGCCTTCCATCCAGACATCATTTTGC

TGCCAGGATGCGGGGTGGACTTCACCCACAGCCGCCTGAGCAACTTGTTGGGCA

TCCGCAAGCGGCAACCCTTCCAGGAGGGCTTTAGGATCACCTACGATGATCTGG

AGGGTGGTAACATTCCCGCACTGTTGGATGTGGACGCCTACCAGGCGAGCTTGA

AAGATGACACCGAACAGGGCGGGGGTGGCGCAGGCGGCAGCAACAGCAGTGGC

AGCGGCGCGGAAGAGAACTCCAACGCGGCAGCCGCGGCAATGCAGCCGGTGGA

GGACATGAACGATCATGCCATTCGCGGCGACACCTTTGCCACACGGGCTGAGGA

GAAGCGCGCTGAGGCCGAAGCAGCGGCCGAAGCTGCCGCCCCCGCTGCGCAACC

CGAGGTCGAGAAGCCTCAGAAGAAACCGGTGATCAAACCCCTGACAGAGGACA

GCAAGAAACGCAGTTACAACCTAATAAGCAATGACAGCACCTTCACCCAGTACC

GCAGCTGGTACCTTGCATACAACTACGGCGACCCTCAGACCGGAATCCGCTCATG

GACCCTGCTTTGCACTCCTGACGTAACCTGCGGCTCGGAGCAGGTCTACTGGTCG

TTGCCAGACATGATGCAAGACCCCGTGACCTTCCGCTCCACGCGCCAGATCAGCA

ACTTTCCGGTGGTGGGCGCCGAGCTGTTGCCCGTGCACTCCAAGAGCTTCTACAA

CGACCAGGCCGTCTACTCCCAACTCATCCGCCAGTTTACCTCTCTGACCCACGTG

TTCAATCGCTTTCCCGAGAACCAGATTTTGGCGCGCCCGCCAGCCCCCACCATCA

CCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACGCTACCGCTGCG

CAACAGCATCGGAGGAGTCCAGCGAGTGACCATTACTGACGCCAGACGCCGCAC

CTGCCCCTACGTTTACAAGGCCCTGGGCATAGTCTCGCCGCGCGTCCTATCGAGC

CGCACTTTTTGAGCAAGCATGTCCATCCTTATATCGCCCAGCAATAACACAGGCT

GGGGCCTGCGCTTCCCAAGCAAGATGTTTGGCGGGGCCAAGAAGCGCTCCGACC

AACACCCAGTGCGCGTGCGCGGGCACTACCGCGCGCCCTGGGGCGCGCACAAAC

GCGGCCGCACTGGGCGCACCACCGTCGATGACGCCATCGACGCGGTGGTGGAGG

AGGCGCGCAACTACACGCCCACGCCGCCACCAGTGTCCACAGTGGACGCGGCCA

TTCAGACCGTGGTGCGCGGAGCCCGGCGCTATGCTAAAATGAAGAGACGGCGGA

GGCGCGTAGCACGTCGCCACCGCCGCCGACCCGGCACTGCCGCCCAACGCGCGG

CGGCGGCCCTGCTTAACCGCGCACGTCGCACCGGCCGACGGGCGGCCATGCGGG

CCGCTCGAAGGCTGGCCGCGGGTATTGTCACTGTGCCCCCCAGGTCCAGGCGAC

GAGCGGCCGCCGCAGCAGCCGCGGCCATTAGTGCTATGACTCAGGGTCGCAGGG

GCAACGTGTATTGGGTGCGCGACTCGGTTAGCGGCCTGCGCGTGCCCGTGCGCAC

CCGCCCCCCGCGCAACTAGATTGCAAGAAAAAACTACTTAGACTCGTACTGTTGT

ATGTATCCAGCGGCGGCGGCGCGCAACGAAGCTATGTCCAAGCGCAAAATCAAA

GAAGAGATGCTCCAGGTCATCGCGCCGGAGATCTATGGCCCCCCGAAGAAGGAA

GAGCAGGATTACAAGCCCCGAAAGCTAAAGCGGGTCAAAAAGAAAAAGAAAGA

TGATGATGATGAACTTGACGACGAGGTGGAACTGCTGCACGCTACCGCGCCCAG

GCGACGGGTACAGTGGAAAGGTCGACGCGTAAAACGTGTTTTGCGACCCGGCAC

CACCGTAGTCTTTACGCCCGGTGAGCGCTCCACCCGCACCTACAAGCGCGTGTAT

GATGAGGTGTACGGCGACGAGGACCTGCTTGAGCAGGCCAACGAGCGCCTCGGG

GAGTTTGCCTACGGAAAGCGGCATAAGGACATGCTGGCGTTGCCGCTGGACGAG

GGCAACCCAACACCTAGCCTAAAGCCCGTAACACTGCAGCAGGTGCTGCCCGCG

CTTGCACCGTCCGAAGAAAAGCGCGGCCTAAAGCGCGAGTCTGGTGACTTGGCA

CCCACCGTGCAGCTGATGGTACCCAAGCGCCAGCGACTGGAAGATGTCTTGGAA

AAAATGACCGTGGAACCTGGGCTGGAGCCCGAGGTCCGCGTGCGGCCAATCAAG

CAGGTGGCGCCGGGACTGGGCGTGCAGACCGTGGACGTTCAGATACCCACTACC

AGTAGCACCAGTATTGCCACCGCCACAGAGGGCATGGAGACACAAACGTCCCCG

GTTGCCTCAGCGGTGGCGGATGCCGCGGTGCAGGCGGTCGCTGCGGCCGCGTCC

AAGACCTCTACGGAGGTGCAAACGGACCCGTGGATGTTTCGCGTTTCAGCCCCCC

GGCGCCCGCGCCGTTCGAGGAAGTACGGCGCCGCCAGCGCGCTACTGCCCGAAT

ATGCCCTACATCCTTCCATTGCGCCTACCCCCGGCTATCGTGGCTACACCTACCG

CCCCAGAAGACGAGCAACTACCCGACGCCGAACCACCACTGGAACCCGCCGCCG

CCGTCGCCGTCGCCAGCCCGTGCTGGCCCCGATTTCCGTGCGCAGGGTGGCTCGC

GAAGGAGGCAGGACCCTGGTGCTGCCAACAGCGCGCTACCACCCCAGCATCGTT

TAAAAGCCGGTCTTTGTGGTTCTTGCAGATATGGCCCTCACCTGCCGCCTCCGTTT

CCCGGTGCCGGGATTCCGAGGAAGAATGCACCGTAGGAGGGGCATGGCCGGCCA

CGGCCTGACGGGCGGCATGCGTCGTGCGCACCACCGGCGGCGGCGCGCGTCGCA

CCGTCGCATGCGCGGCGGTATCCTGCCCCTCCTTATTCCACTGATCGCCGCGGCG

ATTGGCGCCGTGCCCGGAATTGCATCCGTGGCCTTGCAGGCGCAGAGACACTGA

TTAAAAACAAGTTGCATGTGGAAAAATCAAAATAAAAAGTCTGGACTCTCACGC

TCGCTTGGTCCTGTAACTATTTTGTAGAATGGAAGACATCAACTTTGCGTCTCTGG

CCCCGCGACACGGCTCGCGCCCGTTCATGGGAAACTGGCAAGATATCGGCACCA

GCAATATGAGCGGTGGCGCCTTCAGCTGGGGCTCGCTGTGGAGCGGCATTAAAA

ATTTCGGTTCCACCGTTAAGAACTATGGCAGCAAGGCCTGGAACAGCAGCACAG

GCCAGATGCTGAGGGATAAGTTGAAAGAGCAAAATTTCCAACAAAAGGTGGTAG

ATGGCCTGGCCTCTGGCATTAGCGGGGTGGTGGACCTGGCCAACCAGGCAGTGC

AAAATAAGATTAACAGTAAGCTTGATCCCCGCCCTCCCGTAGAGGAGCCTCCAC

CGGCCGTGGAGACAGTGTCTCCAGAGGGGCGTGGCGAAAAGCGTCCGCGCCCCG

ACAGGGAAGAAACTCTGGTGACGCAAATAGACGAGCCTCCCTCGTACGAGGAGG

CACTAAAGCAAGGCCTGCCCACCACCCGTCCCATCGCGCCCATGGCTACCGGAG

TGCTGGGCCAGCACACACCCGTAACGCTGGACCTGCCTCCCCCCGCCGACACCCA

GCAGAAACCTGTGCTGCCAGGCCCGACCGCCGTTGTTGTAACCCGTCCTAGCCGC

GCGTCCCTGCGCCGCGCCGCCAGCGGTCCGCGATCGTTGCGGCCCGTAGCCAGTG

GCAACTGGCAAAGCACACTGAACAGCATCGTGGGTCTGGGGGTGCAATCCCTGA

AGCGCCGACGATGCTTCTGATAGCTAACGTGTCGTATGTGTGTCATGTATGCGTC

CATGTCGCCGCCAGAGGAGCTGCTGAGCCGCCGCGCGCCCGCTTTCCAAGATGG

CTACCCCTTCGATGATGCCGCAGTGGTCTTACATGCACATCTCGGGCCAGGACGC

CTCGGAGTACCTGAGCCCCGGGCTGGTGCAGTTTGCCCGCGCCACCGAGACGTA

CTTCAGCCTGAATAACAAGTTTAGAAACCCCACGGTGGCGCCTACGCACGACGT

GACCACAGACCGGTCCCAGCGTTTGACGCTGCGGTTCATCCCTGTGGACCGTGAG

GATACTGCGTACTCGTACAAGGCGCGGTTCACCCTAGCTGTGGGTGATAACCGTG

TGCTGGACATGGCTTCCACGTACTTTGACATCCGCGGCGTGCTGGACAGGGGCCC

TACTTTTAAGCCCTACTCTGGCACTGCCTACAACGCCCTGGCTCCCAAGGGTGCC

CCAAATCCTTGCGAATGGGATGAAGCTGCTACTGCTCTTGAAATAAACCTAGAA

GAAGAGGACGATGACAACGAAGACGAAGTAGACGAGCAAGCTGAGCAGCAAAA

AACTCACGTATTTGGGCAGGCGCCTTATTCTGGTATAAATATTACAAAGGAGGGT

ATTCAAATAGGTGTCGAAGGTCAAACACCTAAATATGCCGATAAAACATTTCAA

CCTGAACCTCAAATAGGAGAATCTCAGTGGTACGAAACAGAAATTAATCATGCA

GCTGGGAGAGTCCTAAAAAAGACTACCCCAATGAAACCATGTTACGGTTCATAT

GCAAAACCCACAAATGAAAATGGAGGGCAAGGCATTCTTGTAAAGCAACAAAAT

GGAAAGCTAGAAAGTCAAGTGGAAATGCAATTTTTCTCAACTACTGAGGCAGCC

GCAGGCAATGGTGATAACTTGACTCCTAAAGTGGTATTGTACAGTGAAGATGTA

GATATAGAAACCCCAGACACTCATATTTCTTACATGCCCACTATTAAGGAAGGTA

ACTCACGAGAACTAATGGGCCAACAATCTATGCCCAACAGGCCTAATTACATTG

CTTTTAGGGACAATTTTATTGGTCTAATGTATTACAACAGCACGGGTAATATGGG

TGTTCTGGCGGGCCAAGCATCGCAGTTGAATGCTGTTGTAGATTTGCAAGACAGA

AACACAGAGCTTTCATACCAGCTTTTGCTTGATTCCATTGGTGATAGAACCAGGT

ACTTTTCTATGTGGAATCAGGCTGTTGACAGCTATGATCCAGATGTTAGAATTAT

TGAAAATCATGGAACTGAAGATGAACTTCCAAATTACTGCTTTCCACTGGGAGGT

GTGATTAATACAGAGACTCTTACCAAGGTAAAACCTAAAACAGGTCAGGAAAAT

GGATGGGAAAAAGATGCTACAGAATTTTCAGATAAAAATGAAATAAGAGTTGGA

AATAATTTTGCCATGGAAATCAATCTAAATGCCAACCTGTGGAGAAATTTCCTGT

ACTCCAACATAGCGCTGTATTTGCCCGACAAGCTAAAGTACAGTCCTTCCAACGT

AAAAATTTCTGATAACCCAAACACCTACGACTACATGAACAAGCGAGTGGTGGC

TCCCGGGCTAGTGGACTGCTACATTAACCTTGGAGCACGCTGGTCCCTTGACTAT

ATGGACAACGTCAACCCATTTAACCACCACCGCAATGCTGGCCTGCGCTACCGCT

CAATGTTGCTGGGCAATGGTCGCTATGTGCCCTTCCACATCCAGGTGCCTCAGAA

GTTCTTTGCCATTAAAAACCTCCTTCTCCTGCCGGGCTCATACACCTACGAGTGG

AACTTCAGGAAGGATGTTAACATGGTTCTGCAGAGCTCCCTAGGAAATGACCTA

AGGGTTGACGGAGCCAGCATTAAGTTTGATAGCATTTGCCTTTACGCCACCTTCT

TCCCCATGGCCCACAACACCGCCTCCACGCTTGAGGCCATGCTTAGAAACGACAC

CAACGACCAGTCCTTTAACGACTATCTCTCCGCCGCCAACATGCTCTACCCTATA

CCCGCCAACGCTACCAACGTGCCCATATCCATCCCCTCCCGCAACTGGGCGGCTT

TCCGCGGCTGGGCCTTCACGCGCCTTAAGACTAAGGAAACCCCATCACTGGGCTC

GGGCTACGACCCTTATTACACCTACTCTGGCTCTATACCCTACCTAGATGGAACC

TTTTACCTCAACCACACCTTTAAGAAGGTGGCCATTACCTTTGACTCTTCTGTCAG

CTGGCCTGGCAATGACCGCCTGCTTACCCCCAACGAGTTTGAAATTAAGCGCTCA

GTTGACGGGGAGGGTTACAACGTTGCCCAGTGTAACATGACCAAAGACTGGTTC

CTGGTACAAATGCTAGCTAACTATAACATTGGCTACCAGGGCTTCTATATCCCAG

AGAGCTACAAGGACCGCATGTACTCCTTCTTTAGAAACTTCCAGCCCATGAGCCG

TCAGGTGGTGGATGATACTAAATACAAGGACTACCAACAGGTGGGCATCCTACA

CCAACACAACAACTCTGGATTTGTTGGCTACCTTGCCCCCACCATGCGCGAAGGA

CAGGCCTACCCTGCTAACTTCCCCTATCCGCTTATAGGCAAGACCGCAGTTGACA

GCATTACCCAGAAAAAGTTTCTTTGCGATCGCACCCTTTGGCGCATCCCATTCTC

CAGTAACTTTATGTCCATGGGCGCACTCACAGACCTGGGCCAAAACCTTCTCTAC

GCCAACTCCGCCCACGCGCTAGACATGACTTTTGAGGTGGATCCCATGGACGAG

CCCACCCTTCTTTATGTTTTGTTTGAAGTCTTTGACGTGGTCCGTGTGCACCAGCC

GCACCGCGGCGTCATCGAAACCGTGTACCTGCGCACGCCCTTCTCGGCCGGCAAC

GCCACAACATAAAGAAGCAAGCAACATCAACAACAGCTGCCGCCATGGGCTCCA

GTGAGCAGGAACTGAAAGCCATTGTCAAAGATCTTGGTTGTGGGCCATATTTTTT

GGGCACCTATGACAAGCGCTTTCCAGGCTTTGTTTCTCCACACAAGCTCGCCTGC

GCCATAGTCAATACGGCCGGTCGCGAGACTGGGGGCGTACACTGGATGGCCTTT

GCCTGGAACCCGCACTCAAAAACATGCTACCTCTTTGAGCCCTTTGGCTTTTCTG

ACCAGCGACTCAAGCAGGTTTACCAGTTTGAGTACGAGTCACTCCTGCGCCGTAG

CGCCATTGCTTCTTCCCCCGACCGCTGTATAACGCTGGAAAAGTCCACCCAAAGC

GTACAGGGGCCCAACTCGGCCGCCTGTGGACTATTCTGCTGCATGTTTCTCCACG

CCTTTGCCAACTGGCCCCAAACTCCCATGGATCACAACCCCACCATGAACCTTAT

TACCGGGGTACCCAACTCCATGCTCAACAGTCCCCAGGTACAGCCCACCCTGCGT

CGCAACCAGGAACAGCTCTACAGCTTCCTGGAGCGCCACTCGCCCTACTTCCGCA

GCCACAGTGCGCAGATTAGGAGCGCCACTTCTTTTTGTCACTTGAAAAACATGTA

AAAATAATGTACTAGAGACACTTTCAATAAAGGCAAATGCTTTTATTTGTACACT

CTCGGGTGATTATTTACCCCCACCCTTGCCGTCTGCGCCGTTTAAAAATCAAAGG

GGTTCTGCCGCGCATCGCTATGCGCCACTGGCAGGGACACGTTGCGATACTGGTG

TTTAGTGCTCCACTTAAACTCAGGCACAACCATCCGCGGCAGCTCGGTGAAGTTT

TCACTCCACAGGCTGCGCACCATCACCAACGCGTTTAGCAGGTCGGGCGCCGAT

ATCTTGAACTCGCAGTTGGGGCCTCCGCCCTCCGCGCGCGAGTTCGATACACAG

GGTTGCAGCACTGGAACACTATCAGCGCCGGGTGGTGCACGCTGGCCAGCACGC

TCTTGTCGGAGATCAGATCCGCGTCCAGGTCCTCCGCGTTGCTCAGGGCGAACGG

AGTCAACTTTGGTAGCTGCCTTCCCAAAAAGGGCGCGTGCCCAGGCTTTGAGTTG

CACTCGCACCGTAGTGGCATCAAAAGGTGACCGTGCCCGGTCTGGGCGTTAGGA

TACAGCGCCTGCATAAAAGCCTTGATCTGCTTAAAAGCCACCTGAGCCTTTGCGC

CTTCAGAGAAGAACATGCCGCAAGACTTGCCGGAAAACTGATTGGCCGGACAGG

CCGCGTCGTGCACGCAGCACCTTGCGTCGGTGTTGGAGATCTGCACCACATTTCG

GCCCCACCGGTTCTTCACGATCTTGGCCTTGCTAGACTGCTCCTTCAGCGCGCGCT

GCCCGTTTTCGCTCGTCACATCCATTTCAATCACGTGCTCCTTATTTATCATAATG

CTTCCGTGTAGACACTTAAGCTCGCCTTCGATCTCAGCGCAGCGGTGCAGCCACA

ACGCGCAGCCCGTGGGCTCGTGATGCTTGTAGGTCACCTCTGCAAACGACTGCAG

GTACGCCTGCAGGAATCGCCCCATCATCGTCACAAAGGTCTTGTTGCTGGTGAAG

GTCAGCTGCAACCCGCGGTGCTCCTCGTTCAGCCAGGTCTTGCATACGGCCGCCA

GAGCTTCCACTTGGTCAGGCAGTAGTTTGAAGTTCGCCTTTAGATCGTTATCCAC

GTGGTACTTGTCCATCAGCGCGCGCGCAGCCTCCATGCCCTTCTCCCACGCAGAC

ACGATCGGCACACTCAGCGGGTTCATCACCGTAATTTCACTTTCCGCTTCGCTGG

GCTCTTCCTCTTCCTCTTGCGTCCGCATACCACGCGCCACTGGGTCGTCTTCATTC

AGCCGCCGCACTGTGCGCTTACCTCCTTTGCCATGCTTGATTAGCACCGGTGGGT

TGCTGAAACCCACCATTTGTAGCGCCACATCTTCTCTTTCTTCCTCGCTGTCCACG

ATTACCTCTGGTGATGGCGGGCGCTCGGGCTTGGGAGAAGGGCGCTTCTTTTTCT

TCTTGGGCGCAATGGCCAAATCCGCCGCCGAGGTCGATGGCCGCGGGCTGGGTG

TGCGCGGCACCAGCGCGTCTTGTGATGAGTCTTCCTCGTCCTCGGACTCGATACG

CCGCCTCATCCGCTTTTTTGGGGGCGCCCGGGGAGGCGGCGGCGACGGGGACGG

GGACGACACGTCCTCCATGGTTGGGGGACGTCGCGCCGCACCGCGTCCGCGCTC

GGGGGTGGTTTCGCGCTGCTCCTCTTCCCGACTGGCCATTTCCTTCTCCTATAGGC

AGAAAAAGATCATGGAGTCAGTCGAGAAGAAGGACAGCCTAACCGCCCCCTCTG

AGTTCGCCACCACCGCCTCCACCGATGCCGCCAACGCGCCTACCACCTTCCCCGT

CGAGGCACCCCCGCTTGAGGAGGAGGAAGTGATTATCGAGCAGGACCCAGGTTT

TGTAAGCGAAGACGACGAGGACCGCTCAGTACCAACAGAGGATAAAAAGCAAG

ACCAGGACAACGCAGAGGCAAACGAGGAACAAGTCGGGCGGGGGGACGAAAGG

CATGGCGACTACCTAGATGTGGGAGACGACGTGCTGTTGAAGCATCTGCAGCGC

CAGTGCGCCATTATCTGCGACGCGTTGCAAGAGCGCAGCGATGTGCCCCTCGCCA

TAGCGGATGTCAGCCTTGCCTACGAACGCCACCTATTCTCACCGCGCGTACCCCC

CAAACGCCAAGAAAACGGCACATGCGAGCCCAACCCGCGCCTCAACTTCTACCC

CGTATTTGCCGTGCCAGAGGTGCTTGCCACCTATCACATCTTTTTCCAAAACTGC

AAGATACCCCTATCCTGCCGTGCCAACCGCAGCCGAGCGGACAAGCAGCTGGCC

TTGCGGCAGGGCGCTGTCATACCTGATATCGCCTCGCTCAACGAAGTGCCAAAA

ATCTTTGAGGGTCTTGGACGCGACGAGAAGCGCGCGGCAAACGCTCTGCAACAG

GAAAACAGCGAAAATGAAAGTCACTCTGGAGTGTTGGTGGAACTCGAGGGTGAC

AACGCGCGCCTAGCCGTACTAAAACGCAGCATCGAGGTCACCCACTTTGCCTACC

CGGCACTTAACCTACCCCCCAAGGTCATGAGCACAGTCATGAGTGAGCTGATCGT

GCGCCGTGCGCAGCCCCTGGAGAGGGATGCAAATTTGCAAGAACAAACAGAGG

AGGGCCTACCCGCAGTTGGCGACGAGCAGCTAGCGCGCTGGCTTCAAACGCGCG

AGCCTGCCGACTTGGAGGAGCGACGCAAACTAATGATGGCCGCAGTGCTCGTTA

CCGTGGAGCTTGAGTGCATGCAGCGGTTCTTTGCTGACCCGGAGATGCAGCGCA

AGCTAGAGGAAACATTGCACTACACCTTTCGACAGGGCTACGTACGCCAGGCCT

GCAAGATCTCCAACGTGGAGCTCTGCAACCTGGTCTCCTACCTTGGAATTTTGCA

CGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCACGCTCAAGGGCGAGGCGCG

CCGCGACTACGTCCGCGACTGCGTTTACTTATTTCTATGCTACACCTGGCAGACG

GCCATGGGCGTTTGGCAGCAGTGCTTGGAGGAGTGCAACCTCAAGGAGCTGCAG

AAACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACGAGCGCTCC

GTGGCCGCGCACCTGGCGGACATCATTTTCCCCGAACGCCTGCTTAAAACCCTGC

AACAGGGTCTGCCAGACTTCACCAGTCAAAGCATGTTGCAGAACTTTAGGAACTT

TATCCTAGAGCGCTCAGGAATCTTGCCCGCCACCTGCTGTGCACTTCCTAGCGAC

TTTGTGCCCATTAAGTACCGCGAATGCCCTCCGCCGCTTTGGGGCCACTGCTACC

TTCTGCAGCTAGCCAACTACCTTGCCTACCACTCTGACATAATGGAAGACGTGAG

CGGTGACGGTCTACTGGAGTGTCACTGTCGCTGCAACCTATGCACCCCGCACCGC

TCCCTGGTTTGCAATTCGCAGCTGCTTAACGAAAGTCAAATTATCGGTACCTTTG

AGCTGCAGGGTCCCTCGCCTGACGAAAAGTCCGCGGCTCCGGGGTTGAAACTCA

CTCCGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTACCTGAGGACTACCA

CGCCCACGAGATTAGGTTCTACGAAGACCAATCCCGCCCGCCTAATGCGGAGCTT

ACCGCCTGCGTCATTACCCAGGGCCACATTCTTGGCCAATTGCAAGCCATCAACA

AAGCCCGCCAAGAGTTTCTGCTACGAAAGGGACGGGGGGTTTACTTGGACCCCC

AGTCCGGCGAGGAGCTCAACCCAATCCCCCCGCCGCCGCAGCCCTATCAGCAGC

AGCCGCGGGCCCTTGCTTCCCAGGATGGCACCCAAAAAGAAGCTGCAGCTGCCG

CCGCCACCCACGGACGAGGAGGAATACTGGGACAGTCAGGCAGAGGAGGTTTTG

GACGAGGAGGAGGAGGACATGATGGAAGACTGGGAGAGCCTAGACGAGGAAGC

TTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTCACCCTCGGTCGCATTCCCC

TCGCCGGCGCCCCAGAAATCGGCAACCGGTTCCAGCATGGCTACAACCTCCGCTC

CTCAGGCGCCGCCGGCACTGCCCGTTCGCCGACCCAACCGTAGATGGGACACCA

CTGGAACCAGGGCCGGTAAGTCCAAGCAGCCGCCGCCGTTAGCCCAAGAGCAAC

AACAGCGCCAAGGCTACCGCTCATGGCGCGGGCACAAGAACGCCATAGTTGCTT

GCTTGCAAGACTGTGGGGGCAACATCTCCTTCGCCCGCCGCTTTCTTCTCTACCAT

CACGGCGTGGCCTTCCCCCGTAACATCCTGCATTACTACCGTCATCTCTACAGCC

CATACTGCACCGGCGGCAGCGGCAGCAACAGCAGCGGCCACACAGAAGCAAAG

GCGACCGGATAGCAAGACTCTGACAAAGCCCAAGAAATCCACAGCGGCGGCAG

CAGCAGGAGGAGGAGCGCTGCGTCTGGCGCCCAACGAACCCGTATCGACCCGCG

AGCTTAGAAACAGGATTTTTCCCACTCTGTATGCTATATTTCAACAGAGCAGGGG

CCAAGAACAAGAGCTGAAAATAAAAAACAGGTCTCTGCGATCCCTCACCCGCAG

CTGCCTGTATCACAAAAGCGAAGATCAGCTTCGGCGCACGCTGGAAGACGCGGA

GGCTCTCTTCAGTAAATACTGCGCGCTGACTCTTAAGGACTAGTTTCGCGCCCTTT

CTCAAATTTAAGCGCGAAAACTACGTCATCTCCAGCGGCCACACCCGGCGCCAG

CACCTGTTGTCAGCGCCATTATGAGCAAGGAAATTCCCACGCCCTACATGTGGAG

TTACCAGCCACAAATGGGACTTGCGGCTGGAGCTGCCCAAGACTACTCAACCCG

AATAAACTACATGAGCGCGGGACCCCACATGATATCCCGGGTCAACGGAATACG

CGCCCACCGAAACCGAATTCTCCTGGAACAGGCGGCTATTACCACCACACCTCGT

AATAACCTTAATCCCCGTAGTTGGCCCGCTGCCCTGGTGTACCAGGAAAGTCCCG

CTCCCACCACTGTGGTACTTCCCAGAGACGCCCAGGCCGAAGTTCAGATGACTAA

CTCAGGGGCGCAGCTTGCGGGCGGCTTTCGTCACAGGGTGCGGTCGCCCGGGCA

GGGTATAACTCACCTGACAATCAGAGGGCGAGGTATTCAGCTCAACGACGAGTC

GGTGAGCTCCTCGCTTGGTCTCCGTCCGGACGGGACATTTCAGATCGGCGGCGCC

GGCCGCTCTTCATTCACGCCTCGTCAGGCAATCCTAACTCTGCAGACCTCGTCCT

CTGAGCCGCGCTCTGGAGGCATTGGAACTCTGCAATTTATTGAGGAGTTTGTGCC

ATCGGTCTACTTTAACCCCTTCTCGGGACCTCCCGGCCACTATCCGGATCAATTTA

TTCCTAACTTTGACGCGGTAAAGGACTCGGCGGACGGCTACGACTGAATGTTAA

GTGGAGAGGCAGAGCAACTGCGCCTGAAACACCTGGTCCACTGTCGCCGCCACA

AGTGCTTTGCCCGCGACTCCGGTGAGTTTTGCTACTTTGAATTGCCCGAGGATCA

TATCGAGGGCCCGGCGCACGGCGTCCGGCTTACCGCCCAGGGAGAGCTTGCCCG

TAGCCTGATTCGGGAGTTTACCCAGCGCCCCCTGCTAGTTGAGCGGGACAGGGG

ACCCTGTGTTCTCACTGTGATTTGCAACTGTCCTAACCCTGGATTACATCAAGATC

CTCTAGTTAATGTCAGGTCGCCTAAGTCGATTAACTAGAGTACCCGGGGATCTTA

TTCCCTTTAACTAATAAAAAAAAATAATAAAGCATCACTTACTTAAAATCAGTTA

GCAAATTTCTGTCCAGTTTATTCAGCAGCACCTCCTTGCCCTCCTCCCAGCTCTGG

TATTGCAGCTTCCTCCTGGCTGCAAACTTTCTCCACAATCTAAATGGAATGTCAG

TTTCCTCCTGTTCCTGTCCATCCGCACCCACTATCTTCATGTTGTTGCAGATGAAG

CGCGCAAGACCGTCTGAAGATACCTTCAACCCCGTGTATCCATATGACACGGAA

ACCGGTCCTCCAACTGTGCCTTTTCTTACTCCTCCCTTTGTATCCCCCAATGGGTT

TCAAGAGAGTCCCCCTGGGGTACTCTCTTTGCGCCTATCCGAACCTCTAGTTACC

TCCAATGGCATGCTTGCGCTCAAAATGGGCAACGGCCTCTCTCTGGACGAGGCCG

GCAACCTTACCTCCCAAAATGTAACCACTGTGAGCCCACCTCTCAAAAAAACCA

AGTCAAACATAAACCTGGAAATATCTGCACCCCTCACAGTTACCTCAGAAGCCCT

AACTGTGGCTGCCGCCGCACCTCTAATGGTCGCGGGCAACACACTCACCATGCA

ATCACAGGCCCCGCTAACCGTGCACGACTCCAAACTTAGCATTGCCACCCAAGG

ACCCCTCACAGTGTCAGAAGGAAAGCTAGCCCTGCAAACATCAGGCCCCCTCAC

CACCACCGATAGCAGTACCCTTACTATCACTGCCTCACCCCCTCTAACTACTGCC

ACTGGTAGCTTGGGCATTGACTTGAAAGAGCCCATTTATACACAAAATGGAAAA

CTAGGACTAAAGTACGGGGCTCCTTTGCATGTAACAGACGACCTAAACACTTTGA

CCGTAGCAACTGGTCCAGGTGTGACTATTAATAATACTTCCTTGCAAACTAAAGT

TACTGGAGCCTTGGGTTTTGATTCACAAGGCAATATGCAACTTAATGTAGCAGGA

GGACTAAGGATTGATTCTCAAAACAGACGCCTTATACTTGATGTTAGTTATCCGT

TTGATGCTCAAAACCAACTAAATCTAAGACTAGGACAGGGCCCTCTTTTTATAAA

CTCAGCCCACAACTTGGATATTAACTACAACAAAGGCCTTTACTTGTTTACAGCT

TCAAACAATTCCAAAAAGCTTGAGGTTAACCTAAGCACTGCCAAGGGGTTGATG

TTTGACGCTACAGCCATAGCCATTAATGCAGGAGATGGGCTTGAATTTGGTTCAC

CTAATGCACCAAACACAAATCCCCTCAAAACAAAAATTGGCCATGGCCTAGAAT

TTGATTCAAACAAGGCTATGGTTCCTAAACTAGGAACTGGCCTTAGTTTTGACAG

CACAGGTGCCATTACAGTAGGAAACAAAAATAATGATAAGCTAACTTTGTGGAC

CACACCAGCTCCATCTCCTAACTGTAGACTAAATGCAGAGAAAGATGCTAAACT

CACTTTGGTCTTAACAAAATGTGGCAGTCAAATACTTGCTACAGTTTCAGTTTTG

GCTGTTAAAGGCAGTTTGGCTCCAATATCTGGAACAGTTCAAAGTGCTCATCTTA

TTATAAGATTTGACGAAAATGGAGTGCTACTAAACAATTCCTTCCTGGACCCAGA

ATATTGGAACTTTAGAAATGGAGATCTTACTGAAGGCACAGCCTATACAAACGC

TGTTGGATTTATGCCTAACCTATCAGCTTATCCAAAATCTCACGGTAAAACTGCC

AAAAGTAACATTGTCAGTCAAGTTTACTTAAACGGAGACAAAACTAAACCTGTA

ACACTAACCATTACACTAAACGGTACACAGGAAACAGGAGACACAACTCCAAGT

GCATACTCTATGTCATTTTCATGGGACTGGTCTGGCCACAACTACATTAATGAAA

TATTTGCCACATCCTCTTACACTTTTTCATACATTGCCCAAGAATAAAGAATCGTT

TGTGTTATGTTTCAACGTGTTTATTTTTCAATTGCAGAAAATTTCAAGTCATTTTT

CATTCAGTAGTATAGCCCCACCACCACATAGCTTATACAGATCACCGTACCTTAA

TCAAACTCACAGAACCCTAGTATTCAACCTGCCACCTCCCTCCCAACACACAGAG

TACACAGTCCTTTCTCCCCGGCTGGCCTTAAAAAGCATCATATCATGGGTAACAG

ACATATTCTTAGGTGTTATATTCCACACGGTTTCCTGTCGAGCCAAACGCTCATC

AGTGATATTAATAAACTCCCCGGGCAGCTCACTTAAGTTCATGTCGCTGTCCAGC

TGCTGAGCCACAGGCTGCTGTCCAACTTGCGGTTGCTTAACGGGCGGCGAAGGA

GAAGTCCACGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGATAGGGCGG

TGGTGCTGCAGCAGCGCGCGAATAAACTGCTGCCGCCGCCGCTCCGTCCTGCAG

GAATACAACATGGCAGTGGTCTCCTCAGCGATGATTCGCACCGCCCGCAGCATA

AGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCTGATCTCACTTAAATCAGCAC

AGTAACTGCAGCACAGCACCACAATATTGTTCAAAATCCCACAGTGCAAGGCGC

TGTATCCAAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCATACCACA

AGCGCAGGTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATAAACATTA

CCTCTTTTGGCATGTTGTAATTCACCACCTCCCGGTACCATATAAACCTCTGATTA

AACATGGCGCCATCCACCACCATCCTAAACCAGCTGGCCAAAACCTGCCCGCCG

GCTATACACTGCAGGGAACCGGGACTGGAACAATGACAGTGGAGAGCCCAGGA

CTCGTAACCATGGATCATCATGCTCGTCATGATATCAATGTTGGCACAACACAGG

CACACGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAACCATAT

CCCAGGGAACAACCCATTCCTGAATCAGCGTAAATCCCACACTGCAGGGAAGAC

CTCGCACGTAACTCACGTTGTGCATTGTCAAAGTGTTACATTCGGGCAGCAGCGG

ATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTCTCAAAAGGAGGTAGACGATCC

CTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGTAGTGTCATGC

CAAATGGAACGCCGGACGTAGTCATATTTCCTGAAGCAAAACCAGGTGCGGGCG

TGACAAACAGATCTGCGTCTCCGGTCTCGCCGCTTAGATCGCTCTGTGTAGTAGT

TGTAGTATATCCACTCTCTCAAAGCATCCAGGCGCCCCCTGGCTTCGGGTTCTAT

GTAAACTCCTTCATGCGCCGCTGCCCTGATAACATCCACCACCGCAGAATAAGCC

ACACCCAGCCAACCTACACATTCGTTCTGCGAGTCACACACGGGAGGAGCGGGA

AGAGCTGGAAGAACCATGTTTTTTTTTTTATTCCAAAAGATTATCCAAAACCTCA

AAATGAAGATCTATTAAGTGAACGCGCTCCCCTCCGGTGGCGTGGTCAAACTCTA

CAGCCAAAGAACAGATAATGGCATTTGTAAGATGTTGCACAATGGCTTCCAAAA

GGCAAACGGCCCTCACGTCCAAGTGGACGTAAAGGCTAAACCCTTCAGGGTGAA

TCTCCTCTATAAACATTCCAGCACCTTCAACCATGCCCAAATAATTCTCATCTCGC

CACCTTCTCAATATATCTCTAAGCAAATCCCGAATATTAAGTCCGGCCATTGTAA

AAATCTGCTCCAGAGCGCCCTCCACCTTCAGCCTCAAGCAGCGAATCATGATTGC

AAAAATTCAGGTTCCTCACAGACCTGTATAAGATTCAAAAGCGGAACATTAACA

AAAATACCGCGATCCCGTAGGTCCCTTCGCAGGGCCAGCTGAACATAATCGTGC

AGGTCTGCACGGACCAGCGCGGCCACTTCCCCGCCAGGAACCATGACAAAAGAA

CCCACACTGATTATGACACGCATACTCGGAGCTATGCTAACCAGCGTAGCCCCGA

TGTAAGCTTGTTGCATGGGCGGCGATATAAAATGCAAGGTGCTGCTCAAAAAAT

CAGGCAAAGCCTCGCGCAAAAAAGAAAGCACATCGTAGTCATGCTCATGCAGAT

AAAGGCAGGTAAGCTCCGGAACCACCACAGAAAAAGACACCATTTTTCTCTCAA

ACATGTCTGCGGGTTTCTGCATAAACACAAAATAAAATAACAAAAAAACATTTA

AACATTAGAAGCCTGTCTTACAACAGGAAAAACAACCCTTATAAGCATAAGACG

GACTACGGCCATGCCGGCGTGACCGTAAAAAAACTGGTCACCGTGATTAAAAAG

CACCACCGACAGCTCCTCGGTCATGTCCGGAGTCATAATGTAAGACTCGGTAAAC

ACATCAGGTTGATTCACATCGGTCAGTGCTAAAAAGCGACCGAAATAGCCCGGG

GGAATACATACCCGCAGGCGTAGAGACAACATTACAGCCCCCATAGGAGGTATA

ACAAAATTAATAGGAGAGAAAAACACATAAACACCTGAAAAACCCTCCTGCCTA

GGCAAAATAGCACCCTCCCGCTCCAGAACAACATACAGCGCTTCCACAGCGGCA

GCCATAACAGTCAGCCTTACCAGTAAAAAAGAAAACCTATTAAAAAAACACCAC

TCGACACGGCACCAGCTCAATCAGTCACAGTGTAAAAAAGGGCCAAGTGCAGAG

CGAGTATATATAGGACTAAAAAATGACGTAACGGTTAAAGTCCACAAAAAACAC

CCAGAAAACCGCACGCGAACCTACGCCCAGAAACGAAAGCCAAAAAACCCACA

ACTTCCTCAAATCGTCACTTCCGTTTTCCCACGTTACGTCACTTCCCATTTTAAGA

AAACTACAATTCCCAACACATACAAGTTACTCCGCCCTAAAACCTACGTCACCCG

CCCCGTTCCCACGCCCCGCGCCACGTCACAAACTCCACCCCCTCATTATCATATT

GGCTTCAATCCAAAATAAGGTATATT

SEQ ID NO: 11: rAd-CMV-SARS-CoV-2-S1-Furin-N-BGH-CMV-dsRNA-SPA

TAAGGATCCCATCATCAATAATATACCTTATTTTGGATTGAAGCCAATATGATAA

TGAGGGGGTGGAGTTTGTGACGTGGCGCGGGGCGTGGGAACGGGGCGGGTGAC

GTAGTAGTGTGGCGGAAGTGTGATGTTGCAAGTGTGGCGGAACACATGTAAGCG

ACGGATGTGGCAAAAGTGACGTTTTTGGTGTGCGCCGGTGTACACAGGAAGTGA

CAATTTTCGCGCGGTTTTAGGCGGATGTTGTAGTAAATTTGGGCGTAACCGAGTA

AGATTTGGCCATTTTCGCGGGAAAACTGAATAAGAGGAAGTGAAATCTGAATAA

TTTTGTGTTACTCATAGCGCGTAATACTGCTAGAGATCTGGCGAAAGGGGGATGT

GCTGCAAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTA

AAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGAATTGGGTACTG

GCCACAGGAGCTTGGCCCATTGCATACGTTGTATCCATATCATAATATGTACATT

TATATTGGCTCATGTCCAACATTACCGCCATGTTGACATTGATTATTGACTAGTTA

TTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGC

GTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCC

CATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCA

TTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAA

GTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCG

CCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACAT

CTACGTATTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAAT

GGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACG

TCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAA

CAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTA

TATAAGCAGAGCTCGTTTAGTGAACCGTCAGatcgcctggagacgccatccacgctgttttgacctccat

agaagacaccgggaccgatccagcctgactctagCctAGCTCtgaagttggtggtgaggccctgggcaggttggtatcaaggtt

acaagacaggtttaaggagaccaatagaaactgggcatgtggagacagagaagactcttgggtttctgataggcactgactctctctgc

ctattggtctattttcccacccttaggctgctggtctgagcctagGAGATCTCTCGAGGTCGACGGTATCGAT

GggtaccgccaccATGTTTGTTTTTCTCGTACTCCTGCCCCTGGTTTCCTCCCAATGTGTC

AATCTGACTACCCGGACCCAACTTCCTCCCGCCTACACCAATTCCTTTACCCGAG

GTGTTTACTACCCAGACAAAGTGTTCAGGTCATCCGTCCTCCATAGTACCCAAGA

CCTCTTCCTCCCTTTTTTTTCTAACGTTACCTGGTTTCACGCTATTCACGTTAGCGG

CACCAACGGCACCAAAAGATTCGATAACCCCGTACTGCCGTTCAACGACGGGGT

ATATTTTGCCTCTACTGAAAAATCAAACATCATACGCGGATGGATCTTTGGGACT

ACCCTGGACTCAAAAACTCAGTCCCTGCTGATTGTGAATAACGCTACCAACGTGG

TGATCAAAGTCTGTGAATTCCAGTTTTGCAACGATCCTTTTCTCGGCGTTTATTAT

CACAAAAATAACAAATCCTGGATGGAGAGCGAGTTCCGGGTGTACTCCTCCGCG

AATAATTGCACCTTCGAATATGTGTCTCAGCCATTCCTCATGGACCTCGAGGGGA

AGCAGGGCAATTTTAAGAATCTGCGAGAATTCGTGTTCAAGAATATAGACGGTT

ACTTCAAGATTTACTCCAAACACACCCCGATTAACCTGGTTAGGGACTTGCCTCA

GGGCTTTTCTGCATTGGAGCCCCTCGTGGACCTCCCAATCGGCATAAACATTACA

AGATTTCAGACTTTGCTTGCATTGCACAGGAGCTATTTGACACCCGGCGATTCTT

CTTCCGGATGGACCGCTGGAGCAGCTGCTTATTACGTGGGCTATCTGCAGCCTCG

AACCTTTCTTTTGAAGTACAACGAAAATGGAACTATCACCGATGCAGTTGACTGC

GCCCTGGACCCCCTGTCCGAAACTAAGTGCACGCTCAAAAGTTTCACAGTAGAG

AAGGGGATATACCAGACTAGCAATTTCCGCGTTCAGCCAACCGAAAGTATAGTG

CGCTTTCCTAATATAACTAACCTGTGTCCTTTCGGGGAAGTGTTTAACGCCACTA

GATTCGCTTCCGTCTACGCCTGGAATAGAAAGAGGATCTCAAATTGCGTTGCTGA

CTATAGTGTTTTGTACAATTCCGCCTCTTTCTCAACCTTCAAATGTTACGGGGTGA

GCCCTACCAAACTGAACGACCTGTGCTTTACAAACGTATACGCCGACAGCTTTGT

TATCAGAGGAGACGAGGTTCGCCAGATTGCTCCGGGTCAGACAGGCAAGATTGC

TGATrATAATrACAAACTGCCCGACGACTTrACAGGATGTGTGATCGCGTGGAAC

AGTAACAATCTTGACTCAAAGGTTGGGGGTAATTATAATTATCTTTACCGGCTGT

TCAGAAAAAGCAATTTGAAACCCTTCGAAAGGGACATATCCACCGAGATCTATC

AGGCCGGGTCCACTCCATGCAATGGTGTGGAAGGTTTTAATTGCTACTTCCCATT

GCAGTCTTATGGATTCCAACCAACCAATGGCGTAGGCTACCAGCCGTATCGCGTT

GTCGTGCTCAGCTTCGAGCTGCTCCACGCCCCCGCGACCGTATGCGGTCCTAAGA

AGTCCACCAATCTTGTTAAGAACAAGTGTGTAAACTTTAACTTTAACGGGCTGAC

CGGGACCGGCGTTCTGACTGAATCTAACAAAAAATTCCTGCCTTTCCAGCAGTTC

GGCCGCGATATTGCTGACACCACTGACGCTGTAAGAGACCCTCAGACCCTTGAA

ATTCTCGATATCACACCTTGCAGCTTTGGGGGCGTGTCCGTCATCACTCCAGGAA

CTAACACAAGCAACCAGGTGGCAGTGTTGTACCAGGATGTTAATTGTACCGAGG

TGCCAGTGGCCATCCACGCCGATCAATTGACACCTACCTGGAGGGTTTACAGCAC

AGGGTCCAATGTTTTTCAGACAAGAGCCGGATGTCTGATCGGTGCCGAGCATGTC

AACAATTCCTACGAGTGTGATATCCCCATTGGTGCGGGAATTTGTGCATCATATC

AGACCCAGACTAATAGCCCAAGAAGAGCTAGATCCGTCGCTAGTCAATCCATCA

TTGCATATACAATGATGTCCGATAACGGCCCCCAGAATCAGAGAAACGCTCCCC

GCATCACGTTCGGCGGACCAAGTGACAGCACAGGCAGTAACCAGAACGGAGAA

CGCTCCGGTGCTCGCTCCAAGCAGCGACGGCCGCAAGGGCTTCCCAACAATACC

GCCAGCTGGTTTACGGCTCTGACCCAACACGGGAAAGAAGATCTTAAATTCCCC

AGGGGCCAGGGCGTCCCTATCAATACTAACTCCAGCCCGGATGATCAGATAGGC

TACTATAGACGCGCTACCCGACGGATACGAGGGGGGGACGGCAAAATGAAGGA

CCTTTCCCCCCGGTGGTATTTCTATTACTTGGGCACCGGACCAGAAGCCGGACTG

CCTTACGGCGCTAACAAAGACGGAATAATCTGGGTTGCGACGGAGGGCGCCCTG

AATACACCTAAAGACCATATCGGCACAAGAAATCCTGCTAACAATGCCGCGATT

GTGCTCCAGCTGCCTCAGGGAACCACGCTGCCTAAAGGGTTTTACGCTGAGGGGT

CAAGGGGGGGGAGTCAAGCGTCTAGTAGGTCATCCTCTCGCTCTCGCAATAGTTC

CCGGAACTCAACCCCAGGCAGCAGCAGAGGAACCTCTCCCGCACGGATGGCTGG

CAATGGGGGAGATGCTGCCCTTGCTCTCCTTCTGCTGGATCGCCTTAACCAGCTC

GAATCAAAGATGTCTGGAAAAGGTCAGCAGCAGCAAGGCCAGACCGTGACAAA

GAAGAGTGCAGCTGAAGCTAGTAAAAAGCCACGCCAAAAACGGACCGCAACTA

AGGCATATAACGTAACACAGGCCTTCGGCAGAAGAGGTCCAGAACAAACACAG

GGAAACTTTGGCGATCAAGAGCTGATTAGACAGGGCACAGATTACAAACACTGG

CCACAGATCGCGCAGTTTGCACCAAGCGCCTCTGCATTCTTCGGGATGAGTCGGA

TTGGGATGGAAGTCACTCCATCCGGGACCTGGCTTACCTACACAGGGGCAATAA

AACTCGACGACAAAGACCCAAACTTTAAAGATCAGGTCATCCTGCTGAATAAAC

ACATCGATGCCTACAAAACTTTCCCCCCAACCGAACCAAAGAAAGACAAGAAAA

AAAAGGCAGACGAAACGCAAGCGCTCCCTCAGCGCCAGAAGAAGCAGCAGACC

GTTACACTGTTGCCAGCAGCAGATCTGGATGATTTTTCCAAGCAGCTTCAACAGA

GTATGTCAAGCGCTGACAGCACTCAGGCTTGAcgatcgGATATCGCTAGCGTACCGG

CGGCCGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCTCGCTGATCAGCCTCG

ACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTT

GACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCA

TCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACA

GCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGC

TCTATGGCTTCTGAGGCGGAAAGAACCAAAGCTTAcgcgttagttattaataGTAATCAATT

ACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGG

TAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAAT

GACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTG

GAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAA

GTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCA

GTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATC

GCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGT

TTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTT

TTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTG

ACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGT

TTAGTGAACCGTCAGATCCGCTAGAGATATCGGGCCACTGCAGGAAACGATATG

GGCTGAATACGGATCCGTATTCAGCCCATATCGTTTCTCTAGAAATAAAATATCT

TTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGAATCGATAGTACTAACATA

CGCTCTCCATCTCGAGCCTAAGCTTGTCGACTCGAAGATCTGGGCGTGGTTAAGG

GTGGGAAAGAATATATAAGGTGGGGGTCTTATGTAGTTTTGTATCTGTTTTGCAG

CAGCCGCCGCCGCCATGAGCACCAACTCGTTTGATGGAAGCATTGTGAGCTCATA

TTTGACAACGCGCATGCCCCCATGGGCCGGGGTGCGTCAGAATGTGATGGGCTC

CAGCATTGATGGTCGCCCCGTCCTGCCCGCAAACTCTACTACCTTGACCTACGAG

ACCGTGTCTGGAACGCCGTTGGAGACTGCAGCCTCCGCCGCCGCTTCAGCCGCTG

CAGCCACCGCCCGCGGGATTGTGACTGACTTTGCTTTCCTGAGCCCGCTTGCAAG

CAGTGCAGCTTCCCGTTCATCCGCCCGCGATGACAAGTTGACGGCTCTTTTGGCA

CAATTGGATTCTTTGACCCGGGAACTTAATGTCGTTTCTCAGCAGCTGTTGGATCT

GCGCCAGCAGGTTTCTGCCCTGAAGGCTTCCTCCCCTCCCAATGCGGTTTAAAAC

ATAAATAAAAAACCAGACTCTGTTTGGATTTGGATCAAGCAAGTGTCTTGCTGTC

TTTATTTAGGGGTTTTGCGCGCGCGGTAGGCCCGGGACCAGCGGTCTCGGTCGTT

GAGGGTCCTGTGTATTTTTTCCAGGACGTGGTAAAGGTGACTCTGGATGTTCAGA

TACATGGGCATAAGCCCGTCTCTGGGGTGGAGGTAGCACCACTGCAGAGCTTCA

TGCTGCGGGGTGGTGTTGTAGATGATCCAGTCGTAGCAGGAGCGCTGGGCGTGG

TGCCTAAAAATGTCTTTCAGTAGCAAGCTGATTGCCAGGGGCAGGCCCTTGGTGT

AAGTGTTTACAAAGCGGTTAAGCTGGGATGGGTGCATACGTGGGGATATGAGAT

GCATCTTGGACTGTATTTTTAGGTTGGCTATGTTCCCAGCCATATCCCTCCGGGGA

TTCATGTTGTGCAGAACCACCAGCACAGTGTATCCGGTGCACTTGGGAAATTTGT

CATGTAGCTTAGAAGGAAATGCGTGGAAGAACTTGGAGACGCCCTTGTGACCTC

CAAGATTTTCCATGCATTCGTCCATAATGATGGCAATGGGCCCACGGGCGGCGGC

CTGGGCGAAGATATTTCTGGGATCACTAACGTCATAGTTGTGTTCCAGGATGAGA

TCGTCATAGGCCATTTTTACAAAGCGCGGGCGGAGGGTGCCAGACTGCGGTATA

ATGGTTCCATCCGGCCCAGGGGCGTAGTTACCCTCACAGATTTGCATTTCCCACG

CTTTGAGTTCAGATGGGGGGATCATGTCTACCTGCGGGGCGATGAAGAAAACGG

TTTCCGGGGTAGGGGAGATCAGCTGGGAAGAAAGCAGGTTCCTGAGCAGCTGCG

ACTTACCGCAGCCGGTGGGCCCGTAAATCACACCTATTACCGGCTGCAACTGGTA

GTTAAGAGAGCTGCAGCTGCCGTCATCCCTGAGCAGGGGGGCCACTTCGTTAAG

CATGTCCCTGACTCGCATGTTTTCCCTGACCAAATCCGCCAGAAGGCGCTCGCCG

CCCAGCGATAGCAGTTCTTGCAAGGAAGCAAAGTTTTTCAACGGTTTGAGACCGT

CCGCCGTAGGCATGCTTTTGAGCGTTTGACCAAGCAGTTCCAGGCGGTCCCACAG

CTCGGTCACCTGCTCTACGGCATCTCGATCCAGCATATCTCCTCGTTTCGCGGGTT

GGGGCGGCTTTCGCTGTACGGCAGTAGTCGGTGCTCGTCCAGACGGGCCAGGGT

CATGTCTTTCCACGGGCGCAGGGTCCTCGTCAGCGTAGTCTGGGTCACGGTGAAG

GGGTGCGCTCCGGGCTGCGCGCTGGCCAGGGTGCGCTTGAGGCTGGTCCTGCTG

GTGCTGAAGCGCTGCCGGTCTTCGCCCTGCGCGTCGGCCAGGTAGCATTTGACCA

TGGTGTCATAGTCCAGCCCCTCCGCGGCGTGGCCCTTGGCGCGCAGCTTGCCCTT

GGAGGAGGCGCCGCACGAGGGGCAGTGCAGACTTTTGAGGGCGTAGAGCTTGGG

CGCGAGAAATACCGATTCCGGGGAGTAGGCATCCGCGCCGCAGGCCCCGCAGAC

GGTCTCGCATTCCACGAGCCAGGTGAGCTCTGGCCGTTCGGGGTCAAAAACCAG

GTTTCCCCCATGCTTTTTGATGCGTTTCTTACCTCTGGTTTCCATGAGCCGGTGTC

CACGCTCGGTGACGAAAAGGCTGTCCGTGTCCCCGTATACAGACTTGAGAGGCC

TGTCCTCGAGCGGTGTTCCGCGGTCCTCCTCGTATAGAAACTCGGACCACTCTGA

GACAAAGGCTCGCGTCCAGGCCAGCACGAAGGAGGCTAAGTGGGAGGGGTAGC

GGTCGTTGTCCACTAGGGGGTCCACTCGCTCCAGGGTGTGAAGACACATGTCGCC

CTCTTCGGCATCAAGGAAGGTGATTGGTTTGTAGGTGTAGGCCACGTGACCGGGT

GTTCCTGAAGGGGGGCTATAAAAGGGGGTGGGGGCGCGTTCGTCCTCACTCTCTT

CCGCATCGCTGTCTGCGAGGGCCAGCTGTTGGGGTGAGTACTCCCTCTGAAAAGC

GGGCATGACTTCTGCGCTAAGATTGTCAGTTTCCAAAAACGAGGAGGATTTGATA

TTCACCTGGCCCGCGGTGATGCCTTTGAGGGTGGCCGCATCCATCTGGTCAGAAA

AGACAATCTTTTTGTTGTCAAGCTTGGTGGCAAACGACCCGTAGAGGGCGTTGGA

CAGCAACTTGGCGATGGAGCGCAGGGTTTGGTTTTTGTCGCGATCGGCGCGCTCC

TTGGCCGCGATGTTTAGCTGCACGTATTCGCGCGCAACGCACCGCCATTCGGGAA

AGACGGTGGTGCGCTCGTCGGGCACCAGGTGCACGCGCCAACCGCGGTTGTGCA

GGGTGACAAGGTCAACGCTGGTGGCTACCTCTCCGCGTAGGCGCTCGTTGGTCCA

GCAGAGGCGGCCGCCCTTGCGCGAGCAGAATGGCGGTAGGGGGTCTAGCTGCGT

CTCGTCCGGGGGGTCTGCGTCCACGGTAAAGACCCCGGGCAGCAGGCGCGCGTC

GAAGTAGTCTATCTTGCATCCTTGCAAGTCTAGCGCCTGCTGCCATGCGCGGGCG

GCAAGCGCGCGCTCGTATGGGTTGAGTGGGGGACCCCATGGCATGGGGTGGGTG

AGCGCGGAGGCGTACATGCCGCAAATGTCGTAAACGTAGAGGGGCTCTCTGAGT

ATTCCAAGATATGTAGGGTAGCATCTTCCACCGCGGATGCTGGCGCGCACGTAAT

CGTATAGTTCGTGCGAGGGAGCGAGGAGGTCGGGACCGAGGTTGCTACGGGCGG

GCTGCTCTGCTCGGAAGACTATCTGCCTGAAGATGGCATGTGAGTTGGATGATAT

GGTTGGACGCTGGAAGACGTTGAAGCTGGCGTCTGTGAGACCTACCGCGTCACG

CACGAAGGAGGCGTAGGAGTCGCGCAGCTTGTTGACCAGCTCGGCGGTGACCTG

CACGTCTAGGGCGCAGTAGTCCAGGGTTTCCTTGATGATGTCATACTTATCCTGT

CCCTTTTTTTTCCACAGCTCGCGGTTGAGGACAAACTCTTCGCGGTCTTTCCAGTA

CTCTTGGATCGGAAACCCGTCGGCCTCCGAACGGTAAGAGCCTAGCATGTAGAA

CTGGTTGACGGCCTGGTAGGCGCAGCATCCCTTTTCTACGGGTAGCGCGTATGCC

TGCGCGGCCTTCCGGAGCGAGGTGTGGGTGAGCGCAAAGGTGTCCCTGACCATG

ACTTTGAGGTACTGGTATTTGAAGTCAGTGTCGTCGCATCCGCCCTGCTCCCAGA

GCAAAAAGTCCGTGCGCTTTTTGGAACGCGGATTTGGCAGGGCGAAGGTGACAT

CGTTGAAGAGTATCTTTCCCGCGCGAGGCATAAAGTTGCGTGTGATGCGGAAGG

GTCCCGGCACCTCGGAACGGTTGTTAATTACCTGGGCGGCGAGCACGATCTCGTC

AAAGCCGTTGATGTTGTGGCCCACAATGTAAAGTTCCAAGAAGCGCGGGATGCC

CTTGATGGAAGGCAATTTTTTAAGTTCCTCGTAGGTGAGCTCTTCAGGGGAGCTG

AGCCCGTGCTCTGAAAGGGCCCAGTCTGCAAGATGAGGGTTGGAAGCGACGAAT

GAGCTCCACAGGTCACGGGCCATTAGCATTTGCAGGTGGTCGCGAAAGGTCCTA

AACTGGCGACCTATGGCCATTTTTTCTGGGGTGATGCAGTAGAAGGTAAGCGGGT

CTTGTTCCCAGCGGTCCCATCCAAGGTTCGCGGCTAGGTCTCGCGCGGCAGTCAC

TAGAGGCTCATCTCCGCCGAACTTCATGACCAGCATGAAGGGCACGAGCTGCTTC

CCAAAGGCCCCCATCCAAGTATAGGTCTCTACATCGTAGGTGACAAAGAGACGC

TCGGTGCGAGGATGCGAGCCGATCGGGAAGAACTGGATCTCCCGCCACCAATTG

GAGGAGTGGCTATTGATGTGGTGAAAGTAGAAGTCCCTGCGACGGGCCGAACAC

TCGTGCTGGCTTTTGTAAAAACGTGCGCAGTACTGGCAGCGGTGCACGGGCTGTA

CATCCTGCACGAGGTTGACCTGACGACCGCGCACAAGGAAGCAGAGTGGGAATT

TGAGCCCCTCGCCTGGCGGGTTTGGCTGGTGGTCTTCTACTTCGGCTGCTTGTCCT

TGACCGTCTGGCTGCTCGAGGGGAGTTACGGTGGATCGGACCACCACGCCGCGC

GAGCCCAAAGTCCAGATGTCCGCGCGCGGCGGTCGGAGCTTGATGACAACATCG

CGCAGATGGGAGCTGTCCATGGTCTGGAGCTCCCGCGGCGTCAGGTCAGGCGGG

AGCTCCTGCAGGTTTACCTCGCATAGACGGGTCAGGGCGCGGGCTAGATCCAGG

TGATACCTAATTTCCAGGGGCTGGTTGGTGGCGGCGTCGATGGCTTGCAAGAGGC

CGCATCCCCGCGGCGCGACTACGGTACCGCGCGGCGGGCGGTGGGCCGCGGGGG

TGTCCTTGGATGATGCATCTAAAAGCGGTGACGCGGGCGAGCCCCCGGAGGTAG

GGGGGGCTCCGGACCCGCCGGGAGAGGGGGCAGGGGCACGTCGGCGCCGCGCG

CGGGCAGGAGCTGGTGCTGCGCGCGTAGGTTGCTGGCGAACGCGACGACGCGGC

GGTTGATCTCCTGAATCTGGCGCCTCTGCGTGAAGACGACGGGCCCGGTGAGCTT

GAACCTGAAAGAGAGTTCGACAGAATCAATTTCGGTGTCGTTGACGGCGGCCTG

GCGCAAAATCTCCTGCACGTCTCCTGAGTTGTCTTGATAGGCGATCTCGGCCATG

AACTGCTCGATCTCTTCCTCCTGGAGATCTCCGCGTCCGGCTCGCTCCACGGTGG

CGGCGAGGTCGTTGGAAATGCGGGCCATGAGCTGCGAGAAGGCGTTGAGGCCTC

CCTCGTTCCAGACGCGGCTGTAGACCACGCCCCCTTCGGCATCGCGGGCGCGCAT

GACCACCTGCGCGAGATTGAGCTCCACGTGCCGGGCGAAGACGGCGTAGTTTCG

CAGGCGCTGAAAGAGGTAGTTGAGGGTGGTGGCGGTGTGTTCTGCCACGAAGAA

GTACATAACCCAGCGTCGCAACGTGGATTCGTTGATATCCCCCAAGGCCTCAAGG

CGCTCCATGGCCTCGTAGAAGTCCACGGCGAAGTTGAAAAACTGGGAGTTGCGC

GCCGACACGGTTAACTCCTCCTCCAGAAGACGGATGAGCTCGGCGACAGTGTCG

CGCACCTCGCGCTCAAAGGCTACAGGGGCCTCTTCTTCTTCTTCAATCTCCTCTTC

CATAAGGGCCTCCCCTTCTTCTTCTTCTGGCGGCGGTGGGGGAGGGGGGACACGG

CGGCGACGACGGCGCACCGGGAGGCGGTCGACAAAGCGCTCGATCATCTCCCCG

CGGCGACGGCGCATGGTCTCGGTGACGGCGCGGCCGTTCTCGCGGGGGCGCAGT

TGGAAGACGCCGCCCGTCATGTCCCGGTTATGGGTTGGCGGGGGGCTGCCATGC

GGCAGGGATACGGCGCTAACGATGCATCTCAACAATTGTTGTGTAGGTACTCCGC

CGCCGAGGGACCTGAGCGAGTCCGCATCGACCGGATCGGAAAACCTCTCGAGAA

AGGCGTCTAACCAGTCACAGTCGCAAGGTAGGCTGAGCACCGTGGCGGGCGGCA

GCGGGCGGCGGTCGGGGTTGTTTCTGGCGGAGGTGCTGCTGATGATGTAATTAAA

GTAGGCGGTCTTGAGACGGCGGATGGTCGACAGAAGCACCATGTCCTTGGGTCC

GGCCTGCTGAATGCGCAGGCGGTCGGCCATGCCCCAGGCTTCGTTTTGACATCGG

CGCAGGTCTTTGTAGTAGTCTTGCATGAGCCTTTCTACCGGCACTTCTTCTTCTCC

TTCCTCTTGTCCTGCATCTCTTGCATCTATCGCTGCGGCGGCGGCGGAGTTTGGCC

GTAGGTGGCGCCCTCTTCCTCCCATGCGTGTGACCCCGAAGCCCCTCATCGGCTG

AAGCAGGGCTAGGTCGGCGACAACGCGCTCGGCTAATATGGCCTGCTGCACCTG

CGTGAGGGTAGACTGGAAGTCATCCATGTCCACAAAGCGGTGGTATGCGCCCGT

GTTGATGGTGTAAGTGCAGTTGGCCATAACGGACCAGTTAACGGTCTGGTGACCC

GGCTGCGAGAGCTCGGTGTACCTGAGACGCGAGTAAGCCCTCGAGTCAAATACG

TAGTCGTTGCAAGTCCGCACCAGGTACTGGTATCCCACCAAAAAGTGCGGCGGC

GGCTGGCGGTAGAGGGGCCAGCGTAGGGTGGCCGGGGCTCCGGGGGCGAGATCT

TCCAACATAAGGCGATGATATCCGTAGATGTACCTGGACATCCAGGTGATGCCG

GCGGCGGTGGTGGAGGCGCGCGGAAAGTCGCGGACGCGGTTCCAGATGTTGCGC

AGCGGCAAAAAGTGCTCCATGGTCGGGACGCTCTGGCCGGTCAGGCGCGCGCAA

TCGTTGACGCTCTAGCGTGCAAAAGGAGAGCCTGTAAGCGGGCACTCTTCCGTG

GTCTGGTGGATAAATTCGCAAGGGTATCATGGCGGACGACCGGGGTTCGAGCCC

CGTATCCGGCCGTCCGCCGTGATCCATGCGGTTACCGCCCGCGTGTCGAACCCAG

GTGTGCGACGTCAGACAACGGGGGAGTGCTCCTTTTGGCTTCCTTCCAGGCGCGG

CGGCTGCTGCGCTAGCTTTTTTGGCCACTGGCCGCGCGCAGCGTAAGCGGTTAGG

CTGGAAAGCGAAAGCATTAAGTGGCTCGCTCCCTGTAGCCGGAGGGTTATTTTCC

AAGGGTTGAGTCGCGGGACCCCCGGTTCGAGTCTCGGACCGGCCGGACTGCGGC

GAACGGGGGTTTGCCTCCCCGTCATGCAAGACCCCGCTTGCAAATTCCTCCGGAA

ACAGGGACGAGCCCCTTTTTTGCTTTTCCCAGATGCATCCGGTGCTGCGGCAGAT

GCGCCCCCCTCCTCAGCAGCGGCAAGAGCAAGAGCAGCGGCAGACATGCAGGGC

ACCCTCCCCTCCTCCTACCGCGTCAGGAGGGGCGACATCCGCGGTTGACGCGGCA

GCAGATGGTGATTACGAACCCCCGCGGCGCCGGGCCCGGCACTACCTGGACTTG

GAGGAGGGCGAGGGCCTGGCGCGGCTAGGAGCGCCCTCTCCTGAGCGGCACCCA

AGGGTGCAGCTGAAGCGTGATACGCGTGAGGCGTACGTGCCGCGGCAGAACCTG

TTTCGCGACCGCGAGGGAGAGGAGCCCGAGGAGATGCGGGATCGAAAGTTCCAC

GCAGGGCGCGAGCTGCGGCATGGCCTGAATCGCGAGCGGTTGCTGCGCGAGGAG

GACTTTGAGCCCGACGCGCGAACCGGGATTAGTCCCGCGCGCGCACACGTGGCG

GCCGCCGACCTGGTAACCGCATACGAGCAGACGGTGAACCAGGAGATTAACTTT

CAAAAAAGCTTTAACAACCACGTGCGTACGCTTGTGGCGCGCGAGGAGGTGGCT

ATAGGACTGATGCATCTGTGGGACTTTGTAAGCGCGCTGGAGCAAAACCCAAAT

AGCAAGCCGCTCATGGCGCAGCTGTTCCTTATAGTGCAGCACAGCAGGGACAAC

GAGGCATTCAGGGATGCGCTGCTAAACATAGTAGAGCCCGAGGGCCGCTGGCTG

CTCGATTTGATAAACATCCTGCAGAGCATAGTGGTGCAGGAGCGCAGCTTGAGC

CTGGCTGACAAGGTGGCCGCCATCAACTATTCCATGCTTAGCCTGGGCAAGTTTT

ACGCCCGCAAGATATACCATACCCCTTACGTTCCCATAGACAAGGAGGTAAAGA

TCGAGGGGTTCTACATGCGCATGGCGCTGAAGGTGCTTACCTTGAGCGACGACCT

GGGCGTTTATCGCAACGAGCGCATCCACAAGGCCGTGAGCGTGAGCCGGCGGCG

CGAGCTCAGCGACCGCGAGCTGATGCACAGCCTGCAAAGGGCCCTGGCTGGCAC

GGGCAGCGGCGATAGAGAGGCCGAGTCCTACTTTGACGCGGGCGCTGACCTGCG

CTGGGCCCCAAGCCGACGCGCCCTGGAGGCAGCTGGGGCCGGACCTGGGCTGGC

GGTGGCACCCGCGCGCGCTGGCAACGTCGGCGGCGTGGAGGAATATGACGAGGA

CGATGAGTACGAGCCAGAGGACGGCGAGTACTAAGCGGTGATGTTTCTGATCAG

ATGATGCAAGACGCAACGGACCCGGCGGTGCGGGCGGCGCTGCAGAGCCAGCC

GTCCGGCCTTAACTCCACGGACGACTGGCGCCAGGTCATGGACCGCATCATGTCG

CTGACTGCGCGCAATCCTGACGCGTTCCGGCAGCAGCCGCAGGCCAACCGGCTC

TCCGCAATTCTGGAAGCGGTGGTCCCGGCGCGCGCAAACCCCACGCACGAGAAG

GTGCTGGCGATCGTAAACGCGCTGGCCGAAAACAGGGCCATCCGGCCCGACGAG

GCCGGCCTGGTCTACGACGCGCTGCTTCAGCGCGTGGCTCGTTACAACAGCGGCA

ACGTGCAGACCAACCTGGACCGGCTGGTGGGGGATGTGCGCGAGGCCGTGGCGC

AGCGTGAGCGCGCGCAGCAGCAGGGCAACCTGGGCTCCATGGTTGCACTAAACG

CCTTCCTGAGTACACAGCCCGCCAACGTGCCGCGGGGACAGGAGGACTACACCA

ACTTTGTGAGCGCACTGCGGCTAATGGTGACTGAGACACCGCAAAGTGAGGTGT

ACCAGTCTGGGCCAGACTATTTTTTCCAGACCAGTAGACAAGGCCTGCAGACCGT

AAACCTGAGCCAGGCTTTCAAAAACTTGCAGGGGCTGTGGGGGGTGCGGGCTCC

CACAGGCGACCGCGCGACCGTGTCTAGCTTGCTGACGCCCAACTCGCGCCTGTTG

CTGCTGCTAATAGCGCCCTTCACGGACAGTGGCAGCGTGTCCCGGGACACATACC

TAGGTCACTTGCTGACACTGTACCGCGAGGCCATAGGTCAGGCGCATGTGGACG

AGCATACTTTCCAGGAGATTACAAGTGTCAGCCGCGCGCTGGGGCAGGAGGACA

CGGGCAGCCTGGAGGCAACCCTAAACTACCTGCTGACCAACCGGCGGCAGAAGA

TCCCCTCGTTGCACAGTTTAAACAGCGAGGAGGAGCGCATTTTGCGCTACGTGCA

GCAGAGCGTGAGCCTTAACCTGATGCGCGACGGGGTAACGCCCAGCGTGGCGCT

GGACATGACCGCGCGCAACATGGAACCGGGCATGTATGCCTCAAACCGGCCGTT

TATCAACCGCCTAATGGACTACTTGCATCGCGCGGCCGCCGTGAACCCCGAGTAT

TTCACCAATGCCATCTTGAACCCGCACTGGCTACCGCCCCCTGGTTTCTACACCG

GGGGATTCGAGGTGCCCGAGGGTAACGATGGATTCCTCTGGGACGACATAGACG

ACAGCGTGTTTTCCCCGCAACCGCAGACCCTGCTAGAGTTGCAACAGCGCGAGC

AGGCAGAGGCGGCGCTGCGAAAGGAAAGCTTCCGCAGGCCAAGCAGCTTGTCCG

ATCTAGGCGCTGCGGCCCCGCGGTCAGATGCTAGTAGCCCATTTCCAAGCTTGAT

AGGGTCTCTTACCAGCACTCGCACCACCCGCCCGCGCCTGCTGGGCGAGGAGGA

GTACCTAAACAACTCGCTGCTGCAGCCGCAGCGCGAAAAAAACCTGCCTCCGGC

ATTTCCCAACAACGGGATAGAGAGCCTAGTGGACAAGATGAGTAGATGGAAGAC

GTACGCGCAGGAGCACAGGGACGTGCCAGGCCCGCGCCCGCCCACCCGTCGTCA

AAGGCACGACCGTCAGCGGGGTCTGGTGTGGGAGGACGATGACTCGGCAGACGA

CAGCAGCGTCCTGGATTTGGGAGGGAGTGGCAACCCGTTTGCGCACCTTCGCCCC

AGGCTGGGGAGAATGTTTTAAAAAAAAAAAAGCATGATGCAAAATAAAAAACTC

ACCAAGGCCATGGCACCGAGCGTTGGTTTTCTTGTATTCCCCTTAGTATGCGGCG

CGCGGCGATGTATGAGGAAGGTCCTCCTCCCTCCTACGAGAGTGTGGTGAGCGC

GGCGCCAGTGGCGGCGGCGCTGGGTTCTCCCTTCGATGCTCCCCTGGACCCGCCG

TTTGTGCCTCCGCGGTACCTGCGGCCTACCGGGGGGAGAAACAGCATCCGTTACT

CTGAGTTGGCACCCCTATTCGACACCACCCGTGTGTACCTGGTGGACAACAAGTC

AACGGATGTGGCATCCCTGAACTACCAGAACGACCACAGCAACTTTCTGACCAC

GGTCATTCAAAACAATGACTACAGCCCGGGGGAGGCAAGCACACAGACCATCAA

TCTTGACGACCGGTCGCACTGGGGCGGCGACCTGAAAACCATCCTGCATACCAA

CATGCCAAATGTGAACGAGTTCATGTTTACCAATAAGTTTAAGGCGCGGGTGATG

GTGTCGCGCTTGCCTACTAAGGACAATCAGGTGGAGCTGAAATACGAGTGGGTG

GAGTTCACGCTGCCCGAGGGCAACTACTCCGAGACCATGACCATAGACCTTATG

AACAACGCGATCGTGGAGCACTACTTGAAAGTGGGCAGACAGAACGGGGTTCTG

GAAAGCGACATCGGGGTAAAGTTTGACACCCGCAACTTCAGACTGGGGTTTGAC

CCCGTCACTGGTCTTGTCATGCCTGGGGTATATACAAACGAAGCCTTCCATCCAG

ACATCATTTTGCTGCCAGGATGCGGGGTGGACTTCACCCACAGCCGCCTGAGCAA

CTTGTTGGGCATCCGCAAGCGGCAACCCTTCCAGGAGGGCTTTAGGATCACCTAC

GATGATCTGGAGGGTGGTAACATTCCCGCACTGTTGGATGTGGACGCCTACCAG

GCGAGCTTGAAAGATGACACCGAACAGGGCGGGGGTGGCGCAGGCGGCAGCAA

CAGCAGTGGCAGCGGCGCGGAAGAGAACTCCAACGCGGCAGCCGCGGCAATGC

AGCCGGTGGAGGACATGAACGATCATGCCATTCGCGGCGACACCTTTGCCACAC

GGGCTGAGGAGAAGCGCGCTGAGGCCGAAGCAGCGGCCGAAGCTGCCGCCCCC

GCTGCGCAACCCGAGGTCGAGAAGCCTCAGAAGAAACCGGTGATCAAACCCCTG

ACAGAGGACAGCAAGAAACGCAGTTACAACCTAATAAGCAATGACAGCACCTTC

ACCCAGTACCGCAGCTGGTACCTTGCATACAACTACGGCGACCCTCAGACCGGA

ATCCGCTCATGGACCCTGCTTTGCACTCCTGACGTAACCTGCGGCTCGGAGCAGG

TCTACTGGTCGTTGCCAGACATGATGCAAGACCCCGTGACCTTCCGCTCCACGCG

CCAGATCAGCAACTTTCCGGTGGTGGGCGCCGAGCTGTTGCCCGTGCACTCCAAG

AGCTTCTACAACGACCAGGCCGTCTACTCCCAACTCATCCGCCAGTTTACCTCTC

TGACCCACGTGTTCAATCGCTTTCCCGAGAACCAGATTTTGGCGCGCCCGCCAGC

CCCCACCATCACCACCGTCAGTGAAAACGTTCCTGCTCTCACAGATCACGGGACG

CTACCGCTGCGCAACAGCATCGGAGGAGTCCAGCGAGTGACCATTACTGACGCC

AGACGCCGCACCTGCCCCTACGTTTACAAGGCCCTGGGCATAGTCTCGCCGCGCG

TCCTATCGAGCCGCACTTTTTGAGCAAGCATGTCCATCCTTATATCGCCCAGCAA

TAACACAGGCTGGGGCCTGCGCTTCCCAAGCAAGATGTTTGGCGGGGCCAAGAA

GCGCTCCGACCAACACCCAGTGCGCGTGCGCGGGCACTACCGCGCGCCCTGGGG

CGCGCACAAACGCGGCCGCACTGGGCGCACCACCGTCGATGACGCCATCGACGC

GGTGGTGGAGGAGGCGCGCAACTACACGCCCACGCCGCCACCAGTGTCCACAGT

GGACGCGGCCATTCAGACCGTGGTGCGCGGAGCCCGGCGCTATGCTAAAATGAA

GAGACGGCGGAGGCGCGTAGCACGTCGCCACCGCCGCCGACCCGGCACTGCCGC

CCAACGCGCGGCGGCGGCCCTGCTTAACCGCGCACGTCGCACCGGCCGACGGGC

GGCCATGCGGGCCGCTCGAAGGCTGGCCGCGGGTATTGTCACTGTGCCCCCCAG

GTCCAGGCGACGAGCGGCCGCCGCAGCAGCCGCGGCCATTAGTGCTATGACTCA

GGGTCGCAGGGGCAACGTGTATTGGGTGCGCGACTCGGTTAGCGGCCTGCGCGT

GCCCGTGCGCACCCGCCCCCCGCGCAACTAGATTGCAAGAAAAAACTACTTAGA

CTCGTACTGTTGTATGTATCCAGCGGCGGCGGCGCGCAACGAAGCTATGTCCAAG

CGCAAAATCAAAGAAGAGATGCTCCAGGTCATCGCGCCGGAGATCTATGGCCCC

CCGAAGAAGGAAGAGCAGGATTACAAGCCCCGAAAGCTAAAGCGGGTCAAAAA

GAAAAAGAAAGATGATGATGATGAACTTGACGACGAGGTGGAACTGCTGCACGC

TACCGCGCCCAGGCGACGGGTACAGTGGAAAGGTCGACGCGTAAAACGTGTTTT

GCGACCCGGCACCACCGTAGTCTTTACGCCCGGTGAGCGCTCCACCCGCACCTAC

AAGCGCGTGTATGATGAGGTGTACGGCGACGAGGACCTGCTTGAGCAGGCCAAC

GAGCGCCTCGGGGAGTTTGCCTACGGAAAGCGGCATAAGGACATGCTGGCGTTG

CCGCTGGACGAGGGCAACCCAACACCTAGCCTAAAGCCCGTAACACTGCAGCAG

GTGCTGCCCGCGCTTGCACCGTCCGAAGAAAAGCGCGGCCTAAAGCGCGAGTCT

GGTGACTTGGCACCCACCGTGCAGCTGATGGTACCCAAGCCCCAGCGACTGGAA

GATGTCTTGGAAAAAATGACCGTGGAACCTGGGCTGGAGCCCGAGGTCCGCGTG

CGGCCAATCAAGCAGGTGGCGCCGGGACTGGGCGTGCAGACCGTGGACGTTCAG

ATACCCACTACCAGTAGCACCAGTATTGCCACCGCCACAGAGGGCATGGAGACA

CAAACGTCCCCGGTTGCCTCAGCGGTGGCGGATGCCGCGGTGCAGGCGGTCGCT

GCGGCCGCGTCCAAGACCTCTACGGAGGTGCAAACGGACCCGTGGATGTTTCGC

GTTTCAGCCCCCCGGCGCCCGCGCCGTTCGAGGAAGTACGGCGCCGCCAGCGCG

CTACTGCCCGAATATGCCCTACATCCTTCCATTGCGCCTACCCCCGGCTATCGTG

GCTACACCTACCGCCCCAGAAGACGAGCAACTACCCGACGCCGAACCACCACTG

GAACCCGCCGCCGCCGTCGCCGTCGCCAGCCCGTGCTGGCCCCGATTTCCGTGCG

CAGGGTGGCTCGCGAAGGAGGCAGGACCCTGGTGCTGCCAACAGCGCGCTACCA

CCCCAGCATCGTTTAAAAGCCGGTCTTTGTGGTTCTTGCAGATATGGCCCTCACC

TGCCGCCTCCGTTTCCCGGTGCCGGGATTCCGAGGAAGAATGCACCGTAGGAGG

GGCATGGCCGGCCACGGCCTGACGGGCGGCATGCGTCGTGCGCACCACCGGCGG

CGGCGCGCGTCGCACCGTCGCATGCGCGGCGGTATCCTGCCCCTCCTTATTCCAC

TGATCGCCGCGGCGATTGGCGCCGTGCCCGGAATTGCATCCGTGGCCTTGCAGGC

GCAGAGACACTGATTAAAAACAAGTTGCATGTGGAAAAATCAAAATAAAAAGTC

TGGACTCTCACGCTCGCTTGGTCCTGTAACTATTTTGTAGAATGGAAGACATCAA

CTTTGCGTCTCTGGCCCCGCGACACGGCTCGCGCCCGTTCATGGGAAACTGGCAA

GATATCGGCACCAGCAATATGAGCGGTGGCGCCTTCAGCTGGGGCTCGCTGTGG

AGCGGCATTAAAAATTTCGGTTCCACCGTTAAGAACTATGGCAGCAAGGCCTGG

AACAGCAGCACAGGCCAGATGCTGAGGGATAAGTTGAAAGAGCAAAATTTCCAA

CAAAAGGTGGTAGATGGCCTGGCCTCTGGCATTAGCGGGGTGGTGGACCTGGCC

AACCAGGCAGTGCAAAATAAGATTAACAGTAAGCTTGATCCCCGCCCTCCCGTA

GAGGAGCCTCCACCGGCCGTGGAGACAGTGTCTCCAGAGGGGCGTGGCGAAAAG

CGTCCGCGCCCCGACAGGGAAGAAACTCTGGTGACGCAAATAGACGAGCCTCCC

TCGTACGAGGAGGCACTAAAGCAAGGCCTGCCCACCACCCGTCCCATCGCGCCC

ATGGCTACCGGAGTGCTGGGCCAGCACACACCCGTAACGCTGGACCTGCCTCCC

CCCGCCGACACCCAGCAGAAACCTGTGCTGCCAGGCCCGACCGCCGTTGTTGTA

ACCCGTCCTAGCCGCGCGTCCCTGCGCCGCGCCGCCAGCGGTCCGCGATCGTTGC

GGCCCGTAGCCAGTGGCAACTGGCAAAGCACACTGAACAGCATCGTGGGTCTGG

GGGTGCAATCCCTGAAGCGCCGACGATGCTTCTGATAGCTAACGTGTCGTATGTG

TGTCATGTATGCGTCCATGTCGCCGCCAGAGGAGCTGCTGAGCCGCCGCGCGCCC

GCTTTCCAAGATGGCTACCCCTTCGATGATGCCGCAGTGGTCTTACATGCACATC

TCGGGCCAGGACGCCTCGGAGTACCTGAGCCCCGGGCTGGTGCAGTTTGCCCGC

GCCACCGAGACGTACTTCAGCCTGAATAACAAGTTTAGAAACCCCACGGTGGCG

CCTACGCACGACGTGACCACAGACCGGTCCCAGCGTTTGACGCTGCGGTTCATCC

CTGTGGACCGTGAGGATACTGCGTACTCGTACAAGGCGCGGTTCACCCTAGCTGT

GGGTGATAACCGTGTGCTGGACATGGCTTCCACGTACTTTGACATCCGCGGCGTG

CTGGACAGGGGCCCTACTTTTAAGCCCTACTCTGGCACTGCCTACAACGCCCTGG

CTCCCAAGGGTGCCCCAAATCCTTGCGAATGGGATGAAGCTGCTACTGCTCTTGA

AATAAACCTAGAAGAAGAGGACGATGACAACGAAGACGAAGTAGACGAGCAAG

CTGAGCAGCAAAAAACTCACGTATTTGGGCAGGCGCCTTATTCTGGTATAAATAT

TACAAAGGAGGGTATTCAAATAGGTGTCGAAGGTCAAACACCTAAATATGCCGA

TAAAACATTTCAACCTGAACCTCAAATAGGAGAATCTCAGTGGTACGAAACAGA

AATTAATCATGCAGCTGGGAGAGTCCTAAAAAAGACTACCCCAATGAAACCATG

TTACGGTTCATATGCAAAACCCACAAATGAAAATGGAGGGCAAGGCATTCTTGT

AAAGCAACAAAATGGAAAGCTAGAAAGTCAAGTGGAAATGCAATTTTTCTCAAC

TACTGAGGCAGCCGCAGGCAATGGTGATAACTTGACTCCTAAAGTGGTATTGTAC

AGTGAAGATGTAGATATAGAAACCCCAGACACTCATATTTCTTACATGCCCACTA

TTAAGGAAGGTAACTCACGAGAACTAATGGGCCAACAATCTATGCCCAACAGGC

CTAATTACATTGCTTTTAGGGACAATTTTATTGGTCTAATGTATTACAACAGCACG

GGTAATATGGGTGTTCTGGCGGGCCAAGCATCGCAGTTGAATGCTGTTGTAGATT

TGCAAGACAGAAACACAGAGCTTTCATACCAGCTTTTGCTTGATTCCATTGGTGA

TAGAACCAGGTACTTTTCTATGTGGAATCAGGCTGTTGACAGCTATGATCCAGAT

GTTAGAATTATTGAAAATCATGGAACTGAAGATGAACTTCCAAATTACTGCTTTC

CACTGGGAGGTGTGATTAATACAGAGACTCTTACCAAGGTAAAACCTAAAACAG

GTCAGGAAAATGGATGGGAAAAAGATGCTACAGAATTTTCAGATAAAAATGAAA

TAAGAGTTGGAAATAATTTTGCCATGGAAATCAATCTAAATGCCAACCTGTGGAG

AAATTTCCTGTACTCCAACATAGCGCTGTATTTGCCCGACAAGCTAAAGTACAGT

CCTTCCAACGTAAAAATTTCTGATAACCCAAACACCTACGACTACATGAACAAGC

GAGTGGTGGCTCCCGGGCTAGTGGACTGCTACATTAACCTTGGAGCACGCTGGTC

CCTTGACTATATGGACAACGTCAACCCATTTAACCACCACCGCAATGCTGGCCTG

CGCTACCGCTCAATGTTGCTGGGCAATGGTCGCTATGTGCCCTTCCACATCCAGG

TGCCTCAGAAGTTCTTTGCCATTAAAAACCTCCTTCTCCTGCCGGGCTCATACACC

TACGAGTGGAACTTCAGGAAGGATGTTAACATGGTTCTGCAGAGCTCCCTAGGA

AATGACCTAAGGGTTGACGGAGCCAGCATTAAGTTTGATAGCATTTGCCTTTACG

CCACCTTCTTCCCCATGGCCCACAACACCGCCTCCACGCTTGAGGCCATGCTTAG

AAACGACACCAACGACCAGTCCTTTAACGACTATCTCTCCGCCGCCAACATGCTC

TACCCTATACCCGCCAACGCTACCAACGTGCCCATATCCATCCCCTCCCGCAACT

GGGCGGCTTTCCGCGGCTGGGCCTTCACGCGCCTTAAGACTAAGGAAACCCCATC

ACTGGGCTCGGGCTACGACCCTTATTACACCTACTCTGGCTCTATACCCTACCTA

GATGGAACCTTTTACCTCAACCACACCTTTAAGAAGGTGGCCATTACCTTTGACT

CTTCTGTCAGCTGGCCTGGCAATGACCGCCTGCTTACCCCCAACGAGTTTGAAAT

TAAGCGCTCAGTTGACGGGGAGGGTTACAACGTTGCCCAGTGTAACATGACCAA

AGACTGGTTCCTGGTACAAATGCTAGCTAACTATAACATTGGCTACCAGGGCTTC

TATATCCCAGAGAGCTACAAGGACCGCATGTACTCCTTCTTTAGAAACTTCCAGC

CCATGAGCCGTCAGGTGGTGGATGATACTAAATACAAGGACTACCAACAGGTGG

GCATCCTACACCAACACAACAACTCTGGATTTGTTGGCTACCTTGCCCCCACCAT

GCGCGAAGGACAGGCCTACCCTGCTAACTTCCCCTATCCGCTTATAGGCAAGACC

GCAGTTGACAGCATTACCCAGAAAAAGTTTCTTTGCGATCGCACCCTTTGGCGCA

TCCCATTCTCCAGTAACTTTATGTCCATGGGCGCACTCACAGACCTGGGCCAAAA

CCTTCTCTACGCCAACTCCGCCCACGCGCTAGACATGACTTTTGAGGTGGATCCC

ATGGACGAGCCCACCCTTCTTTATGTTTTGTTTGAAGTCTTTGACGTGGTCCGTGT

GCACCAGCCGCACCGCGGCGTCATCGAAACCGTGTACCTGCGCACGCCCTTCTCG

GCCGGCAACGCCACAACATAAAGAAGCAAGCAACATCAACAACAGCTGCCGCC

ATGGGCTCCAGTGAGCAGGAACTGAAAGCCATTGTCAAAGATCTTGGTTGTGGG

CCATATTTTTTGGGCACCTATGACAAGCGCTTTCCAGGCTTTGTTTCTCCACACAA

GCTCGCCTGCGCCATAGTCAATACGGCCGGTCGCGAGACTGGGGGCGTACACTG

GATGGCCTTTGCCTGGAACCCGCACTCAAAAACATGCTACCTCTTTGAGCCCTTT

GGCTTTTCTGACCAGCGACTCAAGCAGGTTTACCAGTTTGAGTACGAGTCACTCC

TGCGCCGTAGCGCCATTGCTTCTTCCCCCGACCGCTGTATAACGCTGGAAAAGTC

CACCCAAAGCGTACAGGGGCCCAACTCGGCCGCCTGTGGACTATTCTGCTGCATG

TTTCTCCACGCCTTTGCCAACTGGCCCCAAACTCCCATGGATCACAACCCCACCA

TGAACCTTATTACCGGGGTACCCAACTCCATGCTCAACAGTCCCCAGGTACAGCC

CACCCTGCGTCGCAACCAGGAACAGCTCTACAGCTTCCTGGAGCGCCACTCGCCC

TACTTCCGCAGCCACAGTGCGCAGATTAGGAGCGCCACTTCTTTTTGTCACTTGA

AAAACATGTAAAAATAATGTACTAGAGACACTTTCAATAAAGGCAAATGCTTTT

ATTTGTACACTCTCGGGTGATTATTTACCCCCACCCTTGCCGTCTGCGCCGTTTAA

AAATCAAAGGGGTTCTGCCGCGCATCGCTATGCGCCACTGGCAGGGACACGTTG

CGATACTGGTGTTTAGTGCTCCACTTAAACTCAGGCACAACCATCCGCGGCAGCT

CGGTGAAGTTTTCACTCCACAGGCTGCGCACCATCACCAACGCGTTTAGCAGGTC

GGGCGCCGATATCTTGAAGTCGCAGTTGGGGCCTCCGCCCTGCGCGCGCGAGTTG

CGATACACAGGGTTGCAGCACTGGAACACTATCAGCGCCGGGTGGTGCACGCTG

GCCAGCACGCTCTTGTCGGAGATCAGATCCGCGTCCAGGTCCTCCGCGTTGCTCA

GGGCGAACGGAGTCAACTTTGGTAGCTGCCTTCCCAAAAAGGGCGCGTGCCCAG

GCTTTGAGTTGCACTCGCACCGTAGTGGCATCAAAAGGTGACCGTGCCCGGTCTG

GGCGTTAGGATACAGCGCCTGCATAAAAGCCTTGATCTGCTTAAAAGCCACCTG

AGCCTTTGCGCCTTCAGAGAAGAACATGCCGCAAGACTTGCCGGAAAACTGATT

GGCCGGACAGGCCGCGTCGTGCACGCAGCACCTTGCGTCGGTGTTGGAGATCTG

CACCACATTTCGGCCCCACCGGTTCTTCACGATCTTGGCCTTGCTAGACTGCTCCT

TCAGCGCGCGCTGCCCGTTTTCGCTCGTCACATCCATTTCAATCACGTGCTCCTTA

TTTATCATAATGCTTCCGTGTAGACACTTAAGCTCGCCTTCGATCTCAGCGCAGC

GGTGCAGCCACAACGCGCAGCCCGTGGGCTCGTGATGCTTGTAGGTCACCTCTGC

AAACGACTGCAGGTACGCCTGCAGGAATCGCCCCATCATCGTCACAAAGGTCTT

GTTGCTGGTGAAGGTCAGCTGCAACCCGCGGTGCTCCTCGTTCAGCCAGGTCTTG

CATACGGCCGCCAGAGCTTCCACTTGGTCAGGCAGTAGTTTGAAGTTCGCCTTTA

GATCGTTATCCACGTGGTACTTGTCCATCAGCGCGCGCGCAGCCTCCATGCCCTT

CTCCCACGCAGACACGATCGGCACACTCAGCGGGTTCATCACCGTAATTTCACTT

TCCGCTTCGCTGGGCTCTTCCTCTTCCTCTTGCGTCCGCATACCACGCGCCACTGG

GTCGTCTTCATTCAGCCGCCGCACTGTGCGCTTACCTCCTTTGCCATGCTTGATTA

GCACCGGTGGGTTGCTGAAACCCACCATTTGTAGCGCCACATCTTCTCTTTCTTCC

TCGCTGTCCACGATTACCTCTGGTGATGGCGGGCGCTCGGGCTTGGGAGAAGGG

CGCTTCTTTTTCTTCTTGGGCGCAATGGCCAAATCCGCCGCCGAGGTCGATGGCC

GCGGGCTGGGTGTGCGCGGCACCAGCGCGTCTTGTGATGAGTCTTCCTCGTCCTC

GGACTCGATACGCCGCCTCATCCGCTTTTTTGGGGGCGCCCGGGGAGGCGGCGG

CGACGGGGACGGGGACGACACGTCCTCCATGGTTGGGGGACGTCGCGCCGCACC

GCGTCCGCGCTCGGGGGTGGTTTCGCGCTGCTCCTCTTCCCGACTGGCCATTTCCT

TCTCCTATAGGCAGAAAAAGATCATGGAGTCAGTCGAGAAGAAGGACAGCCTAA

CCGCCCCCTCTGAGTTCGCCACCACCGCCTCCACCGATGCCGCCAACGCGCCTAC

CACCTTCCCCGTCGAGGCACCCCCGCTTGAGGAGGAGGAAGTGATTATCGAGCA

GGACCCAGGTTTTGTAAGCGAAGACGACGAGGACCGCTCAGTACCAACAGAGGA

TAAAAAGCAAGACCAGGACAACGCAGAGGCAAACGAGGAACAAGTCGGGCGGG

GGGACGAAAGGCATGGCGACTACCTAGATGTGGGAGACGACGTGCTGTTGAAGC

ATCTGCAGCGCCAGTGCGCCATTATCTGCGACGCGTTGCAAGAGCGCAGCGATG

TGCCCCTCGCCATAGCGGATGTCAGCCTTGCCTACGAACGCCACCTATTCTCACC

GCGCGTACCCCCCAAACGCCAAGAAAACGGCACATGCGAGCCCAACCCGCGCCT

CAACTTCTACCCCGTATTTGCCGTGCCAGAGGTGCTTGCCACCTATCACATCTTTT

TCCAAAACTGCAAGATACCCCTATCCTGCCGTGCCAACCGCAGCCGAGCGGACA

AGCAGCTGGCCTTGCGGCAGGGCGCTGTCATACCTGATATCGCCTCGCTCAACGA

AGTGCCAAAAATCTTTGAGGGTCTTGGACGCGACGAGAAGCGCGCGGCAAACGC

TCTGCAACAGGAAAACAGCGAAAATGAAAGTCACTCTGGAGTGTTGGTGGAACT

CGAGGGTGACAACGCGCGCCTAGCCGTACTAAAACGCAGCATCGAGGTCACCCA

CTTTGCCTACCCGGCACTTAACCTACCCCCCAAGGTCATGAGCACAGTCATGAGT

GAGCTGATCGTGCGCCGTGCGCAGCCCCTGGAGAGGGATGCAAATTTGCAAGAA

CAAACAGAGGAGGGCCTACCCGCAGTTGGCGACGAGCAGCTAGCGCGCTGGCTT

CAAACGCGCGAGCCTGCCGACTTGGAGGAGCGACGCAAACTAATGATGGCCGCA

GTGCTCGTTACCGTGGAGCTTGAGTGCATGCAGCGGTTCTTTGCTGACCCGGAGA

TGCAGCGCAAGCTAGAGGAAACATTGCACTACACCTTTCGACAGGGCTACGTAC

GCCAGGCCTGCAAGATCTCCAACGTGGAGCTCTGCAACCTGGTCTCCTACCTTGG

AATTTTGCACGAAAACCGCCTTGGGCAAAACGTGCTTCATTCCACGCTCAAGGGC

GAGGCGCGCCGCGACTACGTCCGCGACTGCGTTTACTTATTTCTATGCTACACCT

GGCAGACGGCCATGGGCGTTTGGCAGCAGTGCTTGGAGGAGTGCAACCTCAAGG

AGCTGCAGAAACTGCTAAAGCAAAACTTGAAGGACCTATGGACGGCCTTCAACG

AGCGCTCCGTGGCCGCGCACCTGGCGGACATCATTTTCCCCGAACGCCTGCTTAA

AACCCTGCAACAGGGTCTGCCAGACTTCACCAGTCAAAGCATGTTGCAGAACTTT

AGGAACTTTATCCTAGAGCGCTCAGGAATCTTGCCCGCCACCTGCTGTGCACTTC

CTAGCGACTTTGTGCCCATTAAGTACCGCGAATGCCCTCCGCCGCTTTGGGGCCA

CTGCTACCTTCTGCAGCTAGCCAACTACCTTGCCTACCACTCTGACATAATGGAA

GACGTGAGCGGTGACGGTCTACTGGAGTGTCACTGTCGCTGCAACCTATGCACCC

CGCACCGCTCCCTGGTTTGCAATTCGCAGCTGCTTAACGAAAGTCAAATTATCGG

TACCTTTGAGCTGCAGGGTCCCTCGCCTGACGAAAAGTCCGCGGCTCCGGGGTTG

AAACTCACTCCGGGGCTGTGGACGTCGGCTTACCTTCGCAAATTTGTACCTGAGG

ACTACCACGCCCACGAGATTAGGTTCTACGAAGACCAATCCCGCCCGCCTAATGC

GGAGCTTACCGCCTGCGTCATTACCCAGGGCCACATTCTTGGCCAATTGCAAGCC

ATCAACAAAGCCCGCCAAGAGTTTCTGCTACGAAAGGGACGGGGGGTTTACTTG

GACCCCCAGTCCGGCGAGGAGCTCAACCCAATCCCCCCGCCGCCGCAGCCCTAT

CAGCAGCAGCCGCGGGCCCTTGCTTCCCAGGATGGCACCCAAAAAGAAGCTGCA

GCTGCCGCCGCCACCCACGGACGAGGAGGAATACTGGGACAGTCAGGCAGAGG

ACGTTTTGGACGAGGAGGAGGAGGACATGATGGAAGACTGGGAGAGCCTAGAC

GAGGAAGCTTCCGAGGTCGAAGAGGTGTCAGACGAAACACCGTCACCCTCGGTC

GCATTCCCCTCGCCGGCGCCCCAGAAATCGGCAACCGGTTCCAGCATGGCTACA

ACCTCCGCTCCTCAGGCGCCGCCGGCACTGCCCGTTCGCCGACCCAACCGTAGAT

GGGACACCACTGGAACCAGGGCCGGTAAGTCCAAGCAGCCGCCGCCGTTAGCCC

AAGAGCAACAACAGCGCCAAGGCTACCGCTCATGGCGCGGGCACAAGAACGCC

ATAGTTGCTTGCTTGCAAGACTGTGGGGGCAACATCTCCTTCGCCCGCCGCTTTC

TTCTCTACCATCACGGCGTGGCCTTCCCCCGTAACATCCTGCATTACTACCGTCAT

CTCTACAGCCCATACTGCACCGGCGGCAGCGGCAGCAACAGCAGCGGCCACACA

GAAGCAAAGGCGACCGGATAGCAAGACTCTGACAAAGCCCAAGAAATCCACAG

CGGCGGCAGCAGCAGGAGGAGGAGCGCTGCGTCTGGCGCCCAACGAACCCGTAT

CGACCCGCGAGCTTAGAAACAGGATTTTTCCCACTCTGTATGCTATATTTCAACA

GAGCAGGGGCCAAGAACAAGAGCTGAAAATAAAAAACAGGTCTCTGCGATCCCT

CACCCGCAGCTGCCTGTATCACAAAAGCGAAGATCAGCTTCGGCGCACGCTGGA

AGACGCGGAGGCTCTCTTCAGTAAATACTGCGCGCTGACTCTTAAGGACTAGTTT

CGCGCCCTTTCTCAAATTTAAGCGCGAAAACTACGTCATCTCCAGCGGCCACACC

CGGCGCCAGCACCTGTTGTCAGCGCCATTATGAGCAAGGAAATTCCCACGCCCTA

CATGTGGAGTTACCAGCCACAAATGGGACTTGCGGCTGGAGCTGCCCAAGACTA

CTCAACCCGAATAAACTACATGAGCGCGGGACCCCACATGATATCCCGGGTCAA

CGGAATACGCGCCCACCGAAACCGAATTCTCCTGGAACAGGCGGCTATTACCAC

CACACCTCGTAATAACCTTAATCCCCGTAGTTGGCCCGCTGCCCTGGTGTACCAG

GAAAGTCCCGCTCCCACCACTGTGGTACTTCCCAGAGACGCCCAGGCCGAAGTTC

AGATGACTAACTCAGGGGCGCAGCTTGCGGGCGGCTTTCGTCACAGGGTGCGGT

CGCCCGGGCAGGGTATAACTCACCTGACAATCAGAGGGCGAGGTATTCAGCTCA

ACGACGAGTCGGTGAGCTCCTCGCTTGGTCTCCGTCCGGACGGGACATTTCAGAT

CGGCGGCGCCGGCCGCTCTTCATTCACGCCTCGTCAGGCAATCCTAACTCTGCAG

ACCTCGTCCTCTGAGCCGCGCTCTGGAGGCATTGGAACTCTGCAATTTATTGAGG

AGTTTGTGCCATCGGTCTACTTTAACCCCTTCTCGGGACCTCCCGGCCACTATCCG

GATCAATTTATTCCTAACTTTGACGCGGTAAAGGACTCGGCGGACGGCTACGACT

GAATGTTAAGTGGAGAGGCAGAGCAACTGCGCCTGAAACACCTGGTCCACTGTC

GCCGCCACAAGTGCTTTGCCCGCGACTCCGGTGAGTTTTGCTACTTTGAATTGCC

CGAGGATCATATCGAGGGCCCGGCGCACGGCGTCCGGCTTACCGCCCAGGGAGA

GCTTGCCCGTAGCCTGATTCGGGAGTTTACCCAGCGCCCCCTGCTAGTTGAGCGG

GACAGGGGACCCTGTGTTCTCACTGTGATTTGCAACTGTCCTAACCCTGGATTAC

ATCAAGATCCTCTAGTTAATGTCAGGTCGCCTAAGTCGATTAACTAGAGTACCCG

GGGATCTTATTCCCTTTAACTAATAAAAAAAAATAATAAAGCATCACTTACTTAA

AATCAGTTAGCAAATTTCTGTCCAGTTTATTCAGCAGCACCTCCTTGCCCTCCTCC

CAGCTCTGGTATTGCAGCTTCCTCCTGGCTGCAAACTTTCTCCACAATCTAAATG

GAATGTCAGTTTCCTCCTGTTCCTGTCCATCCGCACCCACTATCTTCATGTTGTTG

CAGATGAAGCGCGCAAGACCGTCTGAAGATACCTTCAACCCCGTGTATCCATAT

GACACGGAAACCGGTCCTCCAACTGTGCCTTTTCTTACTCCTCCCTTTGTATCCCC

CAATGGGTTTCAAGAGAGTCCCCCTGGGGTACTCTCTTTGCGCCTATCCGAACCT

CTAGTTACCTCCAATGGCATGCTTGCGCTCAAAATGGGCAACGGCCTCTCTCTGG

ACGAGGCCGGCAACCTTACCTCCCAAAATGTAACCACTGTGAGCCCACCTCTCAA

AAAAACCAAGTCAAACATAAACCTGGAAATATCTGCACCCCTCACAGTTACCTC

AGAAGCCCTAACTGTGGCTGCCGCCGCACCTCTAATGGTCGCGGGCAACACACT

CACCATGCAATCACAGGCCCCGCTAACCGTGCACGACTCCAAACTTAGCATTGCC

ACCCAAGGACCCCTCACAGTGTCAGAAGGAAAGCTAGCCCTGCAAACATCAGGC

CCCCTCACCACCACCGATAGCAGTACCCTTACTATCACTGCCTCACCCCCTCTAA

CTACTGCCACTGGTAGCTTGGGCATTGACTTGAAAGAGCCCATTTATACACAAAA

TGGAAAACTAGGACTAAAGTACGGGGCTCCTTTGCATGTAACAGACGACCTAAA

CACTTTGACCGTAGCAACTGGTCCAGGTGTGACTATTAATAATACTTCCTTGCAA

ACTAAAGTTACTGGAGCCTTGGGTTTTGATTCACAAGGCAATATGCAACTTAATG

TAGCAGGAGGACTAAGGATTGATTCTCAAAACAGACGCCTTATACTTGATGTTAG

TTATCCGTTTGATGCTCAAAACCAACTAAATCTAAGACTAGGACAGGGCCCTCTT

TTTATAAACTCAGCCCACAACTTGGATATTAACTACAACAAAGGCCTTTACTTGT

TTACAGCTTCAAACAATTCCAAAAAGCTTGAGGTTAACCTAAGCACTGCCAAGG

GGTTGATGTTTGACGCTACAGCCATAGCCATTAATGCAGGAGATGGGCTTGAATT

TGGTTCACCTAATGCACCAAACACAAATCCCCTCAAAACAAAAATTGGCCATGG

CCTAGAATTTGATTCAAACAAGGCTATGGTTCCTAAACTAGGAACTGGCCTTAGT

TTTGACAGCACAGGTGCCATTACAGTAGGAAACAAAAATAATGATAAGCTAACT

TTGTGGACCACACCAGCTCCATCTCCTAACTGTAGACTAAATGCAGAGAAAGAT

GCTAAACTCACTTTGGTCTTAACAAAATGTGGCAGTCAAATACTTGCTACAGTTT

CAGTTTTGGCTGTTAAAGGCAGTTTGGCTCCAATATCTGGAACAGTTCAAAGTGC

TCATCTTATTATAAGATTTGACGAAAATGGAGTGCTACTAAACAATTCCTTCCTG

GACCCAGAATATTGGAACTTTAGAAATGGAGATCTTACTGAAGGCACAGCCTAT

ACAAACGCTGTTGGATTTATGCCTAACCTATCAGCTTATCCAAAATCTCACGGTA

AAACTGCCAAAAGTAACATTGTCAGTCAAGTTTACTTAAACGGAGACAAAACTA

AACCTGTAACACTAACCATTACACTAAACGGTACACAGGAAACAGGAGACACAA

CTCCAAGTGCATACTCTATGTCATTTTCATGGGACTGGTCTGGCCACAACTACAT

TAATGAAATATTTGCCACATCCTCTTACACTTTTTCATACATTGCCCAAGAATAA

AGAATCGTTTGTGTTATGTTTCAACGTGTTTATTTTTCAATTGCAGAAAATTTCAA

GTCATTTTTCATTCAGTAGTATAGCCCCACCACCACATAGCTTATACAGATCACC

GTACCTTAATCAAACTCACAGAACCCTAGTATTCAACCTGCCACCTCCCTCCCAA

CACACAGAGTACACAGTCCTTTCTCCCCGGCTGGCCTTAAAAAGCATCATATCAT

GGGTAACAGACATATTCTTAGGTGTTATATTCCACACGGTTTCCTGTCGAGCCAA

ACGCTCATCAGTGATATTAATAAACTCCCCGGGCAGCTCACTTAAGTTCATGTCG

CTGTCCAGCTGCTGAGCCACAGGCTGCTGTCCAACTTGCGGTTGCTTAACGGGCG

GCGAAGGAGAAGTCCACGCCTACATGGGGGTAGAGTCATAATCGTGCATCAGGA

TAGGGCGGTGGTGCTGCAGCAGCGCGCGAATAAACTGCTGCCGCCGCCGCTCCG

TCCTGCAGGAATACAACATGGCAGTGGTCTCCTCAGCGATGATTCGCACCGCCCG

CAGCATAAGGCGCCTTGTCCTCCGGGCACAGCAGCGCACCCTGATCTCACTTAAA

TCAGCACAGTAACTGCAGCACAGCACCACAATATTGTTCAAAATCCCACAGTGC

AAGGCGCTGTATCCAAAGCTCATGGCGGGGACCACAGAACCCACGTGGCCATCA

TACCACAAGCGCAGGTAGATTAAGTGGCGACCCCTCATAAACACGCTGGACATA

AACATTACCTCTTTTGGCATGTTGTAATTCACCACCTCCCGGTACCATATAAACCT

CTGATTAAACATGGCGCCATCCACCACCATCCTAAACCAGCTGGCCAAAACCTGC

CCGCCGGCTATACACTGCAGGGAACCGGGACTGGAACAATGACAGTGGAGAGCC

CAGGACTCGTAACCATGGATCATCATGCTCGTCATGATATCAATGTTGGCACAAC

ACAGGCACACGTGCATACACTTCCTCAGGATTACAAGCTCCTCCCGCGTTAGAAC

CATATCCCAGGGAACAACCCATTCCTGAATCAGCGTAAATCCCACACTGCAGGG

AAGACCTCGCACGTAACTCACGTTGTGCATTGTCAAAGTGTTACATTCGGGCAGC

AGCGGATGATCCTCCAGTATGGTAGCGCGGGTTTCTGTCTCAAAAGGAGGTAGA

CGATCCCTACTGTACGGAGTGCGCCGAGACAACCGAGATCGTGTTGGTCGTAGT

GTCATGCCAAATGGAACGCCGGACGTAGTCATATTTCCTGAAGCAAAACCAGGT

GCGGGCGTGACAAACAGATCTGCGTCTCCGGTCTCGCCGCTTAGATCGCTCTGTG

TAGTAGTTGTAGTATATCCACTCTCTCAAAGCATCCAGGCGCCCCCTGGCTTCGG

GTTCTATGTAAACTCCTTCATGCGCCGCTGCCCTGATAACATCCACCACCGCAGA

ATAAGCCACACCCAGCCAACCTACACATTCGTTCTGCGAGTCACACACGGGAGG

AGCGGGAAGAGCTGGAAGAACCATGTTTTTTTTTTTATTCCAAAAGATTATCCAA

AACCTCAAAATGAAGATCTATTAAGTGAACGCGCTCCCCTCCGGTGGCGTGGTCA

AACTCTACAGCCAAAGAACAGATAATGGCATTTGTAAGATGTTGCACAATGGCT

TCCAAAAGGCAAACGGCCCTCACGTCCAAGTGGACGTAAAGGCTAAACCCTTCA

GGGTGAATCTCCTCTATAAACATTCCAGCACCTTCAACCATGCCCAAATAATTCT

CATCTCGCCACCTTCTCAATATATCTCTAAGCAAATCCCGAATATTAAGTCCGGC

CATTGTAAAAATCTGCTCCAGAGCGCCCTCCACCTTCAGCCTCAAGCAGCGAATC

ATGATTGCAAAAATTCAGGTTCCTCACAGACCTGTATAAGATTCAAAAGCGGAA

CATTAACAAAAATACCGCGATCCCGTAGGTCCCTTCGCAGGGCCAGCTGAACAT

AATCGTGCAGGTCTGCACGGACCAGCGCGGCCACTTCCCCGCCAGGAACCATGA

CAAAAGAACCCACACTGATTATGACACGCATACTCGGAGCTATGCTAACCAGCG

TAGCCCCGATGTAAGCTTGTTGCATGGGCGGCGATATAAAATGCAAGGTGCTGCT

CAAAAAATCAGGCAAAGCCTCGCGCAAAAAAGAAAGCACATCGTAGTCATGCTC

ATGCAGATAAAGGCAGGTAAGCTCCGGAACCACCACAGAAAAAGACACCATTTT

TCTCTCAAACATGTCTGCGGGTTTCTGCATAAACACAAAATAAAATAACAAAAA

AACATTTAAACATTAGAAGCCTGTCTTACAACAGGAAAAACAACCCTTATAAGC

ATAAGACGGACTACGGCCATGCCGGCGTGACCGTAAAAAAACTGGTCACCGTGA

TTAAAAAGCACCACCGACAGCTCCTCGGTCATGTCCGGAGTCATAATGTAAGACT

CGGTAAACACATCAGGTTGATTCACATCGGTCAGTGCTAAAAAGCGACCGAAAT

AGCCCGGGGGAATACATACCCGCAGGCGTAGAGACAACATTACAGCCCCCATAG

GAGGTATAACAAAATTAATAGGAGAGAAAAACACATAAACACCTGAAAAACCC

TCCTGCCTAGGCAAAATAGCACCCTCCCGCTCCAGAACAACATACAGCGCTTCCA

CAGCGGCAGCCATAACAGTCAGCCTTACCAGTAAAAAAGAAAACCTATTAAAAA

AACACCACTCGACACGGCACCAGCTCAATCAGTCACAGTGTAAAAAAGGGCCAA

GTGCAGAGCGAGTATATATAGGACTAAAAAATGACGTAACGGTTAAAGTCCACA

AAAAACACCCAGAAAACCGCACGCGAACCTACGCCCAGAAACGAAAGCCAAAA

AACCCACAACTTCCTCAAATCGTCACTTCCGTTTTCCCACGTTACGTCACTTCCCA

TTTTAAGAAAACTACAATTCCCAACACATACAAGTTACTCCGCCCTAAAACCTAC

GTCACCCGCCCCGTTCCCACGCCCCGCGCCACGTCACAAACTCCACCCCCTCATT

ATCATATTGGCTTCAATCCAAAATAAGGTATATT

SEQ ID NO: 12: Amino Sequence of S1-N

MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPF

FSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQS

LLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVS

QPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLP

IGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDA

VDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRF

ASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRG

DEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSN

LKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELL

HAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTD

AVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPT

WRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVAS

QSIIAYTMMSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNT

ASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSP

RWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLP

QGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAAL

ALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAF

GRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWL

TYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKK

QQTVTLLPAADLDDFSKQLQQSMSSADSTQA

SEQ ID NO: 13: TLR-3 agonist sequence

GAAACGATATGGGCTGAATACTTAAGTATTCAGCCCATATCGTTTC

SEQ ID NO: 14: TLR-3 agonist sequence

CGGGCCCCCCCTCGAGGTCGACGGTATCGATAAGCTTGATATCGAATTCGCCCTT

AGATATCGTCGACGCCCAGCACCCCAAGGCGGCCAACGCCAAAACTCTCCCTCC

TCCTCTTCCTCAATCTCGCTCTCGCTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAG

GGGGTAAAAAAATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCGCGGG

GCCAATCAGCGTGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGG

CGGCGCCCTATAAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGACATCGAT

GATATCTAAAGGGCGAATTCCTGCAGCCCGGGGGATCCACTAGTCTAGATGCAT

GCTCGAGCGGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTCAGCTGCGG

ATCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCT

CTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTT

GGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAAT

TGTAATACGACTCACTATAGGGCGAATTGGGTACCGGGCCCCCCCTCGAGGTCG

ACGGTATCGATAAGCTTGATATCGAATTCCTGCAGCCCGGGGGATCCACTAGTTT

CTAGAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGGC

GGCCGCCACCGCGGTGGAGCTATCGAATTCAAGCTTGTCGACTCGAAGATCCTA

GACTAGTGGATCCCCCGGGCTGCAGGAATTCGCCCTTTAGATATCATCGATGTCT

CGGCGGTGGTGGCGCGTCGCGCCGCTGGGTTTTATAGGGCGCCGCCGCGGCCGC

TCGAGCCATAAAAGGCAACTTTCGGAACGGCGCACGCTGATTGGCCCCGCGCCG

CTCACTCACCGGCTTCGCCGCACAGTGCAGCATTTTTTTACCCCCTCTCCCCTCCT

TTTGCGAAAAAAAAAAAGAGCGAGAGCGAGATTGAGGAAGAGGAGGAGGGAGA

GTTTTGGCGTTGGCCGCCTTGGGGTGCTGGGCGTCGACGATATCTAAGGGCGAAT

TCGATATCAAGCTTATCGATACCGTCGACCTCGAGGGGGGGCCCG

SEQ ID NO: 15: TLR-3 agonist sequence

CGGGCCCCCCCTCGAGGTCGACGGTATCGATAAGCTTGATATCGAATTCGCCCTT

AGATATCGTCGACGCCCAGCACCCCAAGGCGGCCAACGCCAAAACTCTCCCTCC

TCCTCTTCCTCAATCTCGCTCTCGCTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAG

GGGGTAAAAAAATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCGCGGG

GCCAATCAGCGTGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGG

CGGCGCCCTATAAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGACATCGAT

GATATCTAAAGGGCGAATTCCTGCAGCCCGGGGGATCCACTAGTCTAGATGCAT

GCTCGAGCGGCCGCCAGTGTGATGGATATCTGCAGAATTCGCCCTTCAGCTGCGG

ATCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCGGTGCGGGCCT

CTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGCAAGGCGATTAAGTT

GGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTAAAACGACGGCCAGTGAAT

TGTAATACGACTCACTATAGGGCGAATTGGGTACCGGGCCCCCCCTCGAGGTCG

ACGGTATCGATAAGCTTGATATCGAATTCCTGCAGCCCGGGGGATCCACTAGTTT

CTAGAAATAAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGGC

GGCCGCCACCGCGGTGGAGCTATCGAATTCAAGCTTGTCGACTCGAAGATCGTA

CACAGGAAGTGACAATTTTCGCGCGGTTTTAGGCGGATGTTGTAGTAAATTTGGG

CGTAACCGAGTAAGATTTGGCCATTTTCGCGGGAAAACTGAATAAGAGGAAGTG

AAATCTGAATAATTTTGTGTTACTCATAGCGCGTAATACTGGTACCGGGCCCCCC

CTCGAGGTCGACGGTATCGATAAGCTTGATATCGAATTCGCCCTTAGATATCGTC

GACGCCCAGCACCCCAAGGCGGCCAACGCCAAAACTCTCCCTCCTCCTCTTCCTC

AATCTCGCTCTCGCTCTTTTTTTTTTTCGCAAAAGGAGGGGAGAGGGGGTAAAAA

AATGCTGCACTGTGCGGCGAAGCCGGTGAGTGAGCGGCGCGGGGCCAATCAGCG

TGCGCCGTTCCGAAAGTTGCCTTTTATGGCTCGAGCGGCCGCGGCGGCGCCCTAT

AAAACCCAGCGGCGCGACGCGCCACCACCGCCGAGACATCGATGATATCTAAAG

GGCGAATTCCTGCAGCCCGGGGGATCCACTAGTCTAGAACTAGTGGATCCCCCG

GGCTGCAGGAATTCGATATCAAGCTTATCGATACCGTCGACCTCGAGGGGGGGC

CCGGTACCCAATTCGCCCTATAGTGAGTCGTATTACAATTCACTGGCCGTCGTTTT

ACAACGTCGTGACTGGGAAAACCCTGGCGTTACCCAACTTAATCGCCTTGCAGCA

CATCCCCCTTTCGCCAGCTGGCGTAATAGCGAAGAGGCCCGCACCGATCGCCCTT

CCCAACAGTTGCGCAGCCTGAATGGCGAATGGATCCGCAGCTGAAGGGCGAATT

CTGCAGATATCCATCACACTGGCGGCCGCTCGAGCATGCATCTAGAAATAAAAT

ATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGGCGGCCGCCACCGCG

GTGGAGCTA

SEQ ID NO: 16: TLR-3 agonist sequence

GATGGTGCTTCAAGCTAGTACTTAAGTACTAGCTTGAAGCACCATC

SEQ ID NO: 17: TLR-3 agonist sequence

GATGGTGCTTCAAGCTAGTACGGATCCGTACTAGCTTGAAGCACCATC

SEQ ID NO: 18: TLR-3 agonist sequence

GAAACGATATGGGCTGAATACGGATCCGTATTCAGCCCATATCGTTTC

SEQ ID NO: 19: TLR-3 agonist sequence

CCTAATAATTATCAAAATGTGGATCCACATTTTGATAATTATTAGG

SEQ ID NO: 20: TLR-3 agonist sequence

CCTAATAATTATCAAAATGTAATTACATTTTGATAATTATTAGG

SEQ ID NO: 21

UK B.1.1.7 S Protein Variant

GISAID Accession #EPI_ISL_601443

MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPF

FSNVTWFHAISGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLI

VNNATNVVIKVCEFQFCNDPFLGVYHKNNKSWMESEFRVYSSANNCTFEYVSQPFL

MDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINI

TRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDC

ALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV

YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEV

RQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKP

FERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTYGVGYQPYRVVVLSFELLHAP

ATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIDDTTDAVR

DPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRV

YSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSHRRARSVASQSIIA

YTMSLGAENSVAYSNNSIAIPINFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLL

QYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKP

SKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLTPLLTDEMI

AQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQ

FNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILARL

DKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVD

FCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVS

NGTHWFVTQRNFYEPQIITTHNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKY

FKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWP

WYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL

HYT*

SEQ ID NO: 22

S. African B.1.351 501Y.V2 S Protein Variant

GISAID Accession #EPI_ISL_678597

MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPF

FSNVTWFHAIHVSGTNGTKRFANPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQS

LLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVS

QPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRGLPQGFSALEPLVDLP

IGINITRFQTLHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDC

ALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASV

YAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEV

RQIAPGQTGNIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRIFRKSNLKP

FERDISTEIYQAGSTPCNGVKGFNCYFPLQSYGFQPTYGVGYQPYRVVVLSFELLHAP

ATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVR

DPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRV

YSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIA

YTMSLGVENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLL

LQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSK

PSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMI

AQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQ

FNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRL

DKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVD

FCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVS

NGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKY

FKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWP

WYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKL

HYT*

SEQ ID NO: 23

UK B.1.1.7 S protein variant GISAID accession #epi_isl_601443, human codon-optimized

nucleic acid sequence:

ATGTTTGTTTTCTTGGTGCTCCTTCCACTGGTGTCCTCCCAGTGTGTGAACCTCAC

CACTCGCACGCAACTGCCCCCAGCCTACACGAACTCTTTCACCCGAGGGGTATAT

TACCCTGATAAAGTCTTCAGGTCCTCTGTTCTCCATAGCACTCAGGATCTTTTCCT

GCCTTTCTTTAGCAACGTAACTTGGTTTCACGCAATTTCAGGCACGAACGGCACG

AAGAGATTTGATAACCCAGTGCTCCCTTTCAATGACGGCGTTTACTTCGCTTCTA

CCGAGAAAAGCAACATCATCAGGGGATGGATTTTCGGGACAACATTGGATTCAA

AGACCCAGAGCCTTCTCATTGTGAATAATGCCACGAACGTGGTAATCAAGGTGT

GCGAGTTCCAGTTCTGCAACGACCCATTCCTTGGAGTTTACCACAAAAACAATAA

GAGCTGGATGGAGAGCGAGTTTAGAGTGTATAGCAGCGCCAACAACTGCACCTT

TGAGTACGTTAGCCAACCCTTTCTGATGGACCTGGAGGGCAAACAGGGAAACTT

TAAGAACCTCCGCGAATTCGTTTTCAAGAACATTGATGGGTATTTTAAGATATAC

TCTAAGCATACCCCTATTAACTTGGTGCGAGATCTTCCTCAGGGGTTCAGCGCGC

TCGAACCTCTCGTGGACTTGCCTATTGGTATCAACATCACCCGATTCCAGACCCT

GCTGGCTCTGCACAGGTCATACTTGACTCCCGGCGATTCATCCAGCGGATGGACT

GCGGGTGCCGCCGCATATTATGTGGGCTACTTGCAGCCACGAACCTTTCTTTTGA

AATATAACGAGAATGGCACAATCACCGACGCCGTTGATTGCGCCCTGGATCCCCT

TTCCGAGACGAAGTGTACGCTGAAGTCTTTCACAGTGGAAAAGGGAATCTACCA

GACATCAAACTTCCGCGTCCAACCTACCGAGTCAATAGTGCGCTTCCCAAATATC

ACCAATCTCTGCCCCTTTGGGGAAGTGTTTAATGCCACCCGGTTCGCTTCTGTCTA

TGCCTGGAACAGGAAGCGCATTTCAAACTGCGTTGCTGACTATTCCGTGCTGTAT

AACTCTGCAAGCTTTTCTACCTTTAAGTGCTATGGTGTTAGTCCGACAAAACTGA

ATGATCTGTGCTTTACCAACGTTTACGCCGACTCATTCGTGATTCGAGGAGATGA

GGTCAGACAAATTGCTCCTGGGCAGACCGGCAAAATCGCCGACTACAACTATAA

GTTGCCTGATGACTTCACCGGCTGCGTGATTGCCTGGAACTCTAACAACCTTGAT

TCTAAAGTCGGAGGGAACTATAATTACCTCTATCGCCTCTTTAGAAAGTCTAATC

TGAAGCCGTTTGAGAGAGATATCTCTACGGAAATATACCAGGCCGGATCAACTC

CTTGTAACGGCGTAGAGGGCTTCAACTGCTATTTTCCACTGCAATCCTACGGGTT

CCAACCTACTTACGGAGTGGGCTATCAACCCTACAGGGTTGTGGTGCTGTCATTT

GAGCTGCTCCACGCACCTGCTACCGTGTGCGGTCCCAAGAAGTCAACCAACCTG

GTCAAGAACAAGTGCGTGAATTTCAATTTTAACGGTCTGACCGGAACAGGGGTG

CTCACAGAGTCAAACAAGAAGTTTCTGCCCTTCCAGCAGTTCGGGCGCGATATTG

ATGACACTACCGACGCAGTTCGCGACCCTCAGACTCTTGAGATTCTTGATATCAC

TCCCTGCAGCTTTGGGGGGGTTTCAGTCATCACCCCAGGCACTAACACATCCAAT

CAAGTGGCCGTGCTGTATCAGGGAGTCAATTGCACCGAGGTCCCAGTGGCAATC

CACGCGGATCAACTCACACCAACATGGAGAGTGTACAGCACCGGGTCTAATGTG

TTCCAAACTAGAGCCGGTTGTCTCATTGGCGCAGAACACGTGAACAACAGCTAC

GAGTGCGACATTCCAATTGGAGCCGGAATCTGTGCCTCTTACCAAACACAGACC

AACTCCCACAGACGGGCTCGATCTGTGGCCTCCCAAAGCATTATCGCTTACACGA

TGAGTCTGGGTGCAGAGAATAGCGTTGCCTACAGTAATAATTCTATCGCTATACC

TATCAATTTCACCATCTCTGTAACCACTGAGATCCTTCCAGTCAGTATGACGAAG

ACTTCTGTTGACTGCACAATGTATATATGCGGAGATTCCACAGAGTGCAGTAACC

TGCTGCTGCAATATGGCTCCTTTTGCACTCAGCTCAATAGGGCCCTTACAGGAAT

CGCCGTGGAGCAAGACAAGAATACTCAAGAAGTCTTCGCGCAGGTGAAGCAGAT

CTACAAAACGCCTCCTATAAAAGACTTTGGCGGGTTCAATTTTTCCCAGATCTTG

CCTGATCCCTCAAAACCCTCTAAGAGATCCTTCATCGAGGATCTTCTGTTTAATA

AGGTCACCCTGGCAGACGCAGGCTTCATTAAGCAGTACGGAGACTGCCTCGGGG

ACATCGCTGCAAGAGACCTTATTTGTGCCCAGAAGTTTAATGGACTCACCGTACT

TCCACCACTGCTCACAGATGAGATGATTGCACAGTACACCTCTGCCCTGCTTGCC

GGCACTATCACCAGCGGCTGGACTTTCGGAGCCGGAGCTGCCCTTCAGATCCCTT

TCGCCATGCAGATGGCATATAGATTCAACGGGATCGGAGTCACCCAGAACGTGC

TTTACGAAAATCAGAAACTGATCGCGAACCAATTCAACAGTGCCATCGGCAAGA

TCCAGGATAGCCTCTCATCCACTGCGAGTGCGTTGGGGAAACTGCAAGATGTGGT

CAATCAGAATGCGCAGGCCCTCAACACGCTGGTGAAGCAGCTCTCCTCTAATTTC

GGGGCTATCAGCTCTGTTCTGAACGATATCTTGGCTAGACTGGATAAGGTGGAGG

CTGAAGTTCAGATTGATAGATTGATTACTGGCCGGCTGCAGTCACTCCAGACTTA

TGTTACGCAGCAGTTGATTCGCGCTGCGGAGATACGGGCCTCAGCTAATCTTGCC

GCTACTAAGATGTCCGAGTGTGTGTTGGGGCAATCCAAACGCGTGGATTTCTGCG

GCAAAGGTTACCATCTTATGTCATTCCCCCAGAGCGCCCCTCACGGAGTGGTTTT

TCTCCATGTGACATATGTCCCAGCCCAGGAAAAAAATTTTACCACAGCCCCAGCT

ATATGCCACGACGGCAAAGCTCACTTTCCTCGCGAGGGGGTCTTCGTATCCAACG

GCACACACTGGTTTGTAACCCAGAGGAATTTCTACGAACCGCAGATCATCACAA

CTCATAACACGTTTGTTTCCGGTAATTGTGATGTAGTAATCGGCATCGTTAATAAT

ACAGTGTATGATCCTCTTCAACCCGAACTGGATAGCTTCAAGGAGGAACTCGATA

AGTACTTCAAGAATCACACTTCTCCTGACGTGGACCTTGGTGATATATCCGGCAT

AAATGCTAGTGTGGTGAACATCCAAAAAGAGATAGACAGGCTCAATGAGGTTGC

TAAGAATTTGAACGAATCTCTTATCGACCTCCAGGAGCTCGGCAAGTACGAGCA

GTATATTAAGTGGCCTTGGTACATCTGGCTGGGTTTCATCGCTGGCTTGATAGCA

ATCGTAATGGTCACCATTATGTTGTGCTGCATGACTTCCTGTTGTAGCTGTCTCAA

AGGGTGTTGCAGCTGTGGCTCATGCTGCAAATTTGACGAAGATGACTCTGAACCA

GTCCTCAAGGGCGTCAAGCTTCACTACACGTGA

ADDITIONAL REFERENCES

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3. Han C, Duan C, Zhang S, Spiegel B, Shi H, Wang W, Zhang L, Lin R, Liu J, Ding Z, Hou X. 2020. Digestive Symptoms in COVID-19 Patients with Mild Disease Severity: Clinical Presentation, Stool Viral RNA Testing, and Outcomes. American Journal of Gastroenterology.

4. Kam Y W, Kien F, Roberts A, Cheung Y C, Lamirande E W, Vogel L, Chu S L, Tse J, Guarner J, Zaki S R, Subbarao K, Peiris M, Nal B, Altmeyer R. 2007. Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcgammaRII-dependent entry into B cells in vitro. Vaccine 25:729-40.

5. Wang Q, Zhang L, Kuwahara K, Li L, Liu Z, Li T, Zhu H, Liu J, Xu Y, Xie J, Morioka H, Sakaguchi N, Qin C, Liu G. 2016. Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates. ACS Infect Dis 2:361-76.

6. Ji W, Wang W, Zhao X, Zai J, Li X. 2020. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol 92:433-440.

7. Kumar S, Maurya V K, Prasad A K, Bhatt M L B, Saxena S K. 2020. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). Virusdisease 31:13-21.

8. Wan Y, Shang J, Graham R, Baric R S, Li F. 2020. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol 94.

9. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. 2020. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 12:8.

10. Okba N M, Raj V S, Haagmans B L. 2017. Middle East respiratory syndrome coronavirus vaccines: current status and novel approaches. Curr Opin Virol 23:49-58.

11. Wang L, Shi W, Joyce M G, Modjarrad K, Zhang Y, Leung K, Lees C R, Zhou T, Yassine H M, Kanekiyo M, Yang Z Y, Chen X, Becker M M, Freeman M, Vogel L, Johnson J C, Olinger G, Todd J P, Bagci U, Solomon J, Mollura D J, Hensley L, Jahrling P, Denison M R, Rao S S, Subbarao K, Kwong P D, Mascola J R, Kong W P, Graham B S. 2015. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 6:7712.

12. Adney D R, Wang L, van Doremalen N, Shi W, Zhang Y, Kong W P, Miller M R, Bushmaker T, Scott D, de Wit E, Modjarrad K, Petrovsky N, Graham B S, Bowen R A, Munster V J. 2019. Efficacy of an Adjuvanted Middle East Respiratory Syndrome Coronavirus Spike Protein Vaccine in Dromedary Camels and Alpacas. Viruses 11.

13. Haagmans B L, van den Brand J M, Raj V S, Volz A, Wohlsein P, Smits S L, Schipper D, Bestebroer T M, Okba N, Fux R, Bensaid A, Solanes Foz D, Kuiken T, Baumgartner W, Segales J, Sutter G, Osterhaus A D. 2016. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 351:77-81.

14. Liebowitz D, Gottlieb K, Kolhatkar N S, Garg S J, Asher J M, Nazareno J, Kim K, McIIwain DR, Tucker S N. 2020. Efficacy and immune correlates of protection induced by an oral influenza vaccine evaluated in a phase 2, placebo-controlled human experimental infection study. Lancet Infect Dis 20:435-444.

15. Kim L, Liebowitz D, Lin K, Kasparek K, Pasetti M F, Garg S J, Gottlieb K, Trager G, Tucker S N. 2018. Safety and immunogenicity of an oral tablet norovirus vaccine, a phase I randomized, placebo-controlled trial. JCI Insight 3:e121077.

16. Kim L, Martinez C J, Hodgson K A, Trager G R, Brandl J R, Sandefer E P, Doll W J, Liebowitz D, Tucker S N. 2016. Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule. Scientific Reports 6:37295.

17. He T C, Zhou S, da Costa L T, Yu J, Kinzler K W, Vogelstein B. 1998. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95:2509-14.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Number	Date	Country
63035490	Jun 2020	US
63045710	Jun 2020	US
63074954	Sep 2020	US
63144339	Feb 2021	US

CHIMERIC ADENOVIRAL VECTORS

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