Methods of inducing an Anti-HSV b-cell immune response

Abstract

The present disclosure provides a combination comprising ribonucleotide sequences that encode herpes simplex virus (HSV) glycoproteins, including those involved in virus entry and immune evasion and related methods of treating, suppressing, inhibiting, or preventing an HSV infection. The present disclosure further provides a related formulation comprising ribonucleotide sequences that encode HSV glycoproteins, wherein one or more of the ribonucleotides are fully or partially encapsulated within a lipid nanoparticle, wherein the lipid nanoparticle comprises (a) a polymer-conjugated lipid; (b) a cationic lipid; and (c) one or more neutral lipids. Finally, the present disclosure provides methods of inducing an HSV glycoprotein-specific B-cell response in a subject comprising administering to the subject a composition comprising the HSV glycoprotein.

Description

P-634738-PC METHODS OF INDUCING AN ANTI-HSV B-CELL IMMUNE RESPONSESEQUENCE LISTING STATEMENT

[0001] The instant application contains a Sequence Listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on April 3, 2025, is named P-634738-PC-SQL.xml and is 453 kilobytes in size.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under All 39618 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure provides methods of inducing an anti- Herpes Simplex Virus (HSV) B-cell response, comprising administering a combination comprising: (a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof, (b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and (c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof to a subject.BACKGROUND

[0004] A half-billion people worldwide are infected with herpes simplex virus type 2 (HSV-2). Many of these individuals are unaware they are infected, yet they are at risk of transmitting infection to intimate partners. About 20% of infected subjects have frequent, painful recurrent genital lesions. Lifelong daily suppressive therapy with acyclovir or val acyclovir reduces the frequency of recurrences and lowers risk for transmission, but not all people respond or are willing to take daily therapy. Anxiety about transmission to intimate partners is perhaps the greatest concern of people with genital herpes.P-634738-PC

[0005] One of the most dreaded complications of genital herpes is neonatal herpes. This infection is uncommon (1: 3,000 births in the U. S.) but devastating with high morbidity and mortality in newborns. Neonates acquire HSV-1 or HSV-2 infection from mothers who have reactivation infection at the time of labor and delivery, or the infection in the pregnant woman can be a first-time infection late in pregnancy.

[0006] Prophylactic vaccines that are under development are intended to prevent first-time HSV infections, and those vaccines may not be effective in preventing recurrences in people already infected. From a public health perspective, the biggest impact of an effective genital herpes vaccine will be on HIV infection. Genital herpes increases the risk of acquiring or transmitting HIV by 3-4-fold.SUMMARY

[0007] The present disclosure provides methods of treating, suppressing, inhibiting, or preventing a Herpes Simplex Virus (HSV) infection comprising administering a combination comprising: (a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof, (b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and (c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof to a subject, wherein administration of the combination induces an anti-HSV immune response, wherein the anti-HSV immune response comprises a B-cell response, wherein the B-cell response comprises (a) production of antibodies directed against HSV-2 gC, HSV-gE, or a combination thereof (b) a memory B-cell response, or (c) a combination thereof.

[0008] In some embodiments, the present disclosure provides a combination comprising: (a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof, (b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and (c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof. In some embodiments, the first ribonucleotide sequence, the second ribonucleotide sequence, the third ribonucleotide sequence, or any combination thereof is formulated at a dose of 3, 30, or 60 pg per administration or 1, 5, or 50 pg per administrationP-634738-PC

[0009] In some embodiments, the present disclosure provides a composition comprising a combination comprising: (a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof, (b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and (c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof. In some embodiments, the first ribonucleotide sequence, the second ribonucleotide sequence, the third ribonucleotide sequence, or any combination thereof is formulated at a dose of 3, 30, or 60 pg or at a dose of 1, 5, or 50 pg per administration.

[0010] In some embodiments, the present disclosure provides a method of inducing an HSV glycoprotein C (gC)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gC antigen or antigenic fragment thereof.

[0011] In other embodiments, the present disclosure provides a method of inducing an HSV glycoprotein D (gD)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gD antigen or antigenic fragment thereof.

[0012] In some embodiments, the present disclosure provides a method of inducing an HSV glycoprotein E (gE)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gE antigen or antigenic fragment thereof.

[0013] Other features and advantages of the present disclosure will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodimentsP-634738-PC presented herein. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0015] Figure 1. Experimental setup for trivalent vaccine efficacy and immunogenicity testing. BALB / c mice were immunized on days 0 and 28 and infected intravaginally 28 days later using 5xl03PFU HSV-2 (275 LDso). Animals were scored for genital disease, and vaginal swabs were collected on days 2 and 4 post-infection. Dorsal root ganglia were evaluated for HSV-2 DNA copy number by qPCR at the end of the experiment. Control immunogen included poly(C) RNA in lipid nanoparticle (LNP) 307, while experimental immunogens were trivalent RNA vaccines encoding HSV-2 gC (gC2), HSV-2 gD (gD2) and HSV-2 gE (gE2) encapsulated with LNP307 or LNP315.

[0016] Figures 2A-2B. Efficacy of trivalent RNA vaccine formulations. BALB / c mice were immunized on days 0 and 28 and infected intravaginally 28 days later using 5x103PFU HSV-2 (275 LDso) Poly(C) RNA in lipid nanoparticle (LNP) 307 (lOpg) served as a control immunogen. Other groups of mice were treated with trivalent RNA vaccines encoding HSV-2 gC (gC2) antigenic fragment, HSV-2 gD (gD2) antigenic fragment, and HSV-2 gE (gE2) antigenic fragment encapsulated with LNP307 (lug or lOpg) or LNP315 (1 pig, 5ug, or lOpg). The probability for mouse survival in each group was examined overtime (Figure 2A). Animals were scored for genital disease on days 4- 28 after HSV challenge. The percent of days each animal had genital disease is plotted from day 4-28 or until humane euthanasia (Figure 2B). n::::5 mice / group for Poly(C) and n^lO / group for other groups. P value in B was calculated by Mann Whitney test for non-parametric data. P<0.05 was considered significant.

[0017] Figure 3. Day 2 and day 4 vaginal virus titers post challenge. The vaginal cavities of the experimental subjects were swabbed on day 2 and day 4 following viral challenge. The swabs were placed in 1 ml of complete Dulbecco’s modified Eagle’s medium (DMEM), containing HEPES buffer, L-glutamine, and antibiotics and 5% fetal bovine serum (FBS). The presence of virus was determined by placing the media on Vero cell monolayer and determining plaque forming units (PFU) in each well 48 hours later (1). Dorsal root ganglia (DRG) were dissected 28 days post-infection, and DNA was isolated. Using HSV-2 specific Us9 primers and probes, HSV-2 genomic copy number was determined by real time PCR (Awasthi S, et al. Immunization with a vaccine combining herpes simplex virus 2 (HSV-2) glycoprotein C (gC) and gD subunits improves the protection of dorsal root ganglia in mice and reduces the frequency of recurrent vaginal shedding of HSV-2 DNA in guineaP-634738-PC pigs compared to immunization with gD alone. J Virol. 2011;85(20): 10472— 10486, incorporated herein by reference). The viral genomic copies were normalized with mouse housekeeping gene adipsin and expressed as HSV-2 genomic copy number per IO5copies of the adipsin gene. n:::4 mice / group for Poly(C) control and n=10 for other groups. P value was calculated by Mann Whitney test for non-parametric data. P<0.05 was considered significant.

[0018] Figure 4, IgG ELISA binding titers in responses to trivalent RNA vaccine formulations. gC2, gD2 and gE2 binding antibody response were measured by IgG ELISA in the sera collected 3 weeks after the 2nd vaccination (Awasthi S, et al. An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in guinea pigs. PLoS Pathog. 2017; 13(1 ):el006141, incorporated herein by reference). ELISA plates were coated with each immunogen separately and incubated with serial 2-fold dilutions of serum at 1:500-l:512,000 for one hour at room temperature, washed three times with PBS-Tween, and then incubated 30 minutes with 1:2000 of HRP conj ugated anti-mouse IgG at room temperature, followed by ABTS reagent. n=5 mice / group for Poly(C) and n=10 for vaccinated groups.

[0019] Figure 5. Neutralizing antibody titers. Neutralizing antibody titers of the sera collected three weeks post-second immunizations were measured by plaque reduction assay on Veto cells (Awasthi S, et al. Nucleoside-modified RNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. Sci Immunol. 2019;4(39):eaaw7083, incorporated herein by reference). Approximately 100 plaque forming units (PFU) of HSV 2 were incubated with a range of dilutions (1:40-1:10240) of each serum sample in the presence of human complement (HSV1 / 2 sero-negative donor) at 37CC for one hour then transferred onto Vero cells in 24 well tissue culture plate and overt ay ed with 1.5% CM cellulose. Approximately 48 hours later, the CM cellulose layer was aspirated off, and cells were stained with crystal violet to count plaques. The neutralizing Ab titer was defined as the dilution of sera that reduced the number of plaques by > 50% compared to virus incubated with PBS

[0020] Figure 6A. Polyfunctional CD8 -i-T-cell Responses. Female Balb / C mice (n=5) were immunized twice 28 days apart with 10 pg trivalent RNA vaccine encoding exemplary antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) formulated with either LNP307 or LNP315 (Figure 6A). Ten days post-second immunization, spleens were isolated.

[0021] Figures 6B-6D. Representative flow cytometry plot showing fFNy and TNFa cytokine production from CD8+ T cells from splenocytes of one mouse each that was immunized by polyCP-634738-PC RNA (negative control Figure 6B), NA vaccine formulated with LNP307 (LNP A) (Figure 6C), or trivalent RNA vaccine formulated with LNP315 (LNP B) (Figure 6D).

[0022] Figures 6E-6G. CD8+T-cell responses were measured in splenic lymphocytes stimulated with overlapping peptide pools for all three immunogens gC2 (Figure 6E), gD2 (Figure 6F), and gE2 (Figure 6G) by intracellular cytokine staining using flow cytometry, as described previously (Awasthi S, et al. Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models. J Clin Invest 13; (23):el52310, incorporated herein by reference). P value was calculated by Mann Whiney for non-parametric data. P<0.05 was considered significant.

[0023] Figure 7A. Germinal Center B-cell responses. Female BALB / c mice (n=5) were either mock immunized or immunized with 10 pg trivalent RNA vaccine encoding exemplary antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) formulated with LNP315 once or twice 4-weeks apart. Spleens were isolated 2-weeks post- 1stimmunization (Figure 7A, top panel), 40-days post 2ndimmunization (Figure 7A, middle panel), or 6-months post 2ndimmunization (Figure 7A, bottom panel).

[0024] Figure 7B. Representative flow plots. Mice were mock immunized (top panel) or immunized once with 10 pg trivalent RNA vaccine encoding exemplary antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) formulated with LNP315 (bottom panel). gC2 specific (left), gD2 specific (middle), or gE2 specific (right) CD19+B220+IgD-IgM- class switched germinal center B-cells were evaluated in both groups two weeks after the immunization or mock immunization.

[0025] Figures 8A-8C. Quantification of Germinal Center B-cell responses. Mice were mock immunized or immunized with 10 pg trivalent RNA vaccine encoding exemplary antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) formulated with LNP315 once or twice 4-weeks apart. Spleens were isolated 2-weeks post-lstimmunization (Figure 8A), 40-days post 2ndimmunization (Figure 8B), or 6-months post 2ndimmunization (Figure 8C), and flow cytometry was used to assay splenic lymphocytes for gC2, gD2 or gE2 specific class switched germinal center B cells (CD19+ B220+ IgD-IgM-) as described previously (Awasthi S, et al. Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models. J Clin Invest 13; (23):el52310, incorporated herein by reference). Trivalent RNA vaccine specific gC2 IgG, gD2 IgG, and gE2 IgG response are shown at 40 -days post 2ndimmunization (Figure 8D)P-634738-PC and 6 months post 2ndimmunization (Figure 8E). P value was calculated by Mann Whiney for nonparametric data. P<0.05 was considered significant.

[0026] Figures 8D-8E. Vaccine-induced gC2, gD2 and gE2 antibody titers. Mice were mock immunized or immunized with 10 pg trivalent mRNA vaccine formulated with LNP315 once or twice 4-weeks apart. Vaccine-induced gC2, gD2 and gE2 antibody titers were measured with ELISA 40 days post-2ndimmunization (Figure 8D) and 6-months post- 2ndimmunization (Figure 8E) in naive and vaccinated mice. The P value was calculated by Mann Whiney for non-parametric data. P<0.05 was considered significant.

[0027] Figure 9. Epitope-specific antibody responses in HSV-2 RNA-LNP vaccinated guinea pigs: dose escalation. Female Hartley strain guinea pigs were immunized intradermally (ID) three times at one-month intervals with 5pg, lOpg, 20pg, or 50pg each of exemplary nucleoside-modified antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) RNA-LNP or lOpg PolyC RNA-LNP as a control. One month after the third immunization, guinea pig sera were isolated and evaluated for antibody responses.

[0028] Figures 10A-10C. Effects of vaccine dose on serum HSV-2 gC IgG, serum HSV-2 gl) IgG, and serum HSV-2 gE IgG. Serum IgG endpoint titers of female Hartley guinea pigs after intradermal immunization with 5 pg, lOpg, 20pg, or 50ug each of exemplary nucleoside-modified antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2)RNA-LNP vaccine antigens were evaluated by standard ELISA-based assays.

[0029] Figure 10D. Effects of vaccine dose on neutralizing antibody titer. Neutralizing antibody titers of female Hartley guinea pigs after intradermal immunization with 5pg, lOpg, 20ug, or 50pg each of exemplary nucleoside-modified antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2)RNA-LNP vaccine antigens were evaluated using standard plaque reduction assays on Vero cells.

[0030] Figure 11. Antibody responses tn functional epitopes. The generation of epitope-specific antibody responses to three exempl ry nucleoside-modified antigenic fragments of HSV-2 gC (gC2), HSV-2 gD (gD2), or HSV-2 gE (gE2) was evaluated using a high-throughput biosensor-based competition assay. Sixteen sentinel Mabs representing 16 important functional epitopes were printed on a LSA biosensor chip via amine-coupling. Sera from each animal was then incubated with purified gC2, gD2. or gE2 and then evaluated for binding to the Mab printed on the LSA biosensor chip. The percent reduction in gC2, gD2, or gE2 binding to the Mab printed on the LSA biosensor chip comparedP-634738-PC to a control was determined and graphed as % blocking. Data were sorted from most blocked to least blocked Mab.

[0031] Figure 12, The correlation between the number of epitope-specific antibody responses recognized (Fig 11) and the vaccine dose was evaluated. The total number of epitopes on the LSA biosensor chip recognized by each animal’s sera were graphed as a function of vaccine dose.

[0032] Figure 13. The guinea pigs from the experiment described in Figure 9 were then challenged intravaginally with HSV-2 strain MS (fix 105PFU (25 LDso)) and monitored for signs of clinical disease (survival, body weight, and genital disease) and subclinical infection vaginal virus titers and vaginal shedding of HSV-2 DNA post-infection.

[0033] Figures 14A-C. Immunized guinea pigs were challenged intravaginally with HSV-2 strain MS (5><l O' PFU (25 LDso)) and monitored for signs of clinical disease. Survival (Figure 14A) was monitored for 60 days following HSV-2 challenge. Animals were evaluated daily for health and signs of disease. Animals belonging to the PolyC RNA-LNP control group were euthanized upon reaching humane endpoints. Weight loss (Figure 14B) was evaluated during the acute phase of disease days 1- 14 post-infection or longer for animals close to humane endpoints (data not shown). Weight loss was graphed as % body weight on the observation day compared to weight taken just prior to challenge. Genital disease (presence of genital lesions) (Figure 14C) was monitored for up to 60 days following HSV-2 challenge and graphed as the % of observation days with disease. The number of observation days for animals that were humanely euthanized prior to day 60 was appropriately adjusted.

[0034] Figures 15A-C. Immunized guinea pigs were challenged intravaginally with HSV-2 strain MS (5xl05PFU (25 LD50)) and monitored for signs of subclinical infection including vaginal virus titers days 2 (Figure 15A) and 4 (Figure 15B) post-infection Vaginal virus titers in guinea pigs were evaluated days 2 and 4 post-infection by gently swabbing the vaginal cavity and determining the amount of HSV-2 virus present by standard plaque assay on Vero cells (Figures 15A-B). The total number of epitopes recognized by the vaccinated guinea pigs was also evaluated. (Figure 15C).

[0035] Figure 16 -B. Sera were collected from guinea pigs of three groups, i) naive animals immunized with a trivalent gC2 / gD2 / gE2 mRNA-LNP vaccine (naive, immunized), ii) animals infected intranasally with HSV-l and left unvaccinated (HSV-l Hnfected) and iii) animals infected intranasally with HSV-l followed by immunization with the trivalent mRNA vaccine (HSV- 1+infected, immunized). High-throughput biosensor-based competition assay (Figure 16A) of fifteen sentinel Mabs representing 15 important functional epitopes were printed on a LSA biosensor chipP-634738-PC via amine-coupling. Sera from each animal was then incubated with purified gC2, gD2, or gE2 and then evaluated for binding to the Mab printed on the LSA biosensor chip. The number of epitopes blocked > J 5% by each guinea pig was added up and graphed by animal group (Figure 16B).

[0036] Figure 17. Guinea pigs of three groups: i) naive animals immunized with a trivalent gC2 / gD2 / gE2 mRNA-LNP vaccine (naive, immunized), ii) animals infected intranasally with HSV- 1 and left unvaccinated (HSV-1+infected) and iii) animals infected intranasally with HSV-1 followed by immunization with the trivalent mRNA vaccine (HSV-1 + infected, immunized) were challenged intravaginaily with HSV-2 strain MS (5* 105PFU (25 LD50)) and monitored for signs of clinical disease. Genital disease (presence of genital lesions) w7as monitored for up to 60 days following HSV- 2 challenge and graphed as the % of observation days with disease. The number of observation days for animals that were humanely euthanized prior to day 60 was appropriately adjusted.CERTAIN DEFINITIONS

[0037] In general, terminology used herein is in accordance with its understood meaning in the art, unless clearly indicated otherwise. Explicit definitions of certain terms are provided below; meanings of these and other terms in particular instances throughout this specification will be clear to those skilled in the art from context.

[0038] So that the present disclosure may be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0039] About. The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0040] Agent As used herein, the term “agent”, may refer to a physical entity or phenomenon. In some embodiments, an agent may be characterized by a particular feature and / or effect. In some embodiments, an agent may be a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. In some embodiments, the term “agent” may refer to a compound, molecule, orP-634738-PC entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moieties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0041] Amino acid: In its broadest sense, as used herein, the term “amino acid” refers to a compound and / or substance that can be, is, or has been incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally-occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter the relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0042] Antibody agent. As used herein, the term “antibody agent” refers to an agent that specifically binds to a particular antigen. In some embodiments, the term encompasses a polypeptide or polypeptide complex that includes immunoglobulin structural elements sufficient to confer specific binding. For example, in some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or more structural elements recognized by those skilled in the artP-634738-PC as a complementarity determining region (CDR); in some embodiments an antibody agent is or comprises a polypeptide whose amino acid sequence includes at least one CDR (e.g., at least one heavy chain CDR and / or at least one light chain CDR) that is substantially identical to one found in a reference antibody. In some embodiments an included CDR is substantially identical to a reference CDR in that it is either identical in sequence or contains between 1-5 amino acid substitutions as compared with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that 1-5 amino acids within the included CDR are deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical to the reference CDR. In some embodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art as an immunoglobulin variable domain. In some embodiments, an antibody agent in or comprises a polypeptide whose amino acid sequence includes structural elements recognized by those skilled in the art to correspond to CDRsl, 2, and 3 of an antibody variable domain; in some such embodiments, an antibody agent in or comprises a polypeptide or set of polypeptides whose amino acid sequence(s) together include structural elements recognized by those skilled in the art to correspond to both heavy chain and light chain variable region CDRs, e.g., heavy chain CDRs 1, 2, and / or 3 and light chain CDRs 1, 2, and / or 3. In some embodiments, an antibody agent is a polypeptide protein having a binding domain whichP-634738-PC is homologous or largely homologous to an immunoglobulin-binding domain. In some embodiments, an antibody agent may be or comprise a polyclonal antibody preparation. In some embodiments, an antibody agent may be or comprise a monoclonal antibody preparation. In some embodiments, an antibody agent may include one or more constant region sequences that are characteristic of a particular organism, such as a camel, human, mouse, primate, rabbit, rat; in many embodiments, an antibody agent may include one or more constant region sequences that are characteristic of a human. In some embodiments, an antibody agent may include one or more sequence elements that would be recognized by one skilled in the art as a humanized sequence, a primatized sequence, a chimeric sequence, etc. In some embodiments, an antibody agent may be a canonical antibody (e.g., may comprise two heavy chains and two light chains). In some embodiments, an antibody agent may be in a format selected from, but not limited to, intact IgA, IgG, IgE or IgM antibodies; bi- or multi- specific antibodies (e.g., Zybodies®, etc); antibody fragments such as Fab fragments, Fab’ fragments, F(ab’)2 fragments, Fd’ fragments, Fd fragments, and isolated CDRs or sets thereof; single chain Fvs; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); Small Modular ImmunoPharmaceuticals (“SMIPs™ ); single chain or Tandem diabodies (TandAb®); VHHs; Anticalins®; Nanobodies® minibodies; BiTE®s; ankyrin repeat proteins or DARPINs®; Avimers®; DARTs; TCR-like antibodies;, Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; MicroProteins; Fynomers®, Centyrins®; and KALBITOR®s. In some embodiments, an antibody may lack a covalent modification (e.g., attachment of a glycan) that it would have if produced naturally. In some embodiments, an antibody may contain a covalent modification (e.g., attachment of a glycan, a payload (e.g., a detectable moiety, a therapeutic moiety, a catalytic moiety, etc ), or other pendant group (e.g., poly-ethylene glycol, etc.)).

[0043] Antigen: Those skilled in the art, reading the present specification, will appreciate that the term “antigen” refers to a molecule that is recognized by the immune system, e.g., in particular embodiments the adaptive immune system, such that it elicits an antigen-specific immune response. In some embodiments, an antigen-specific immune response may be or comprise generation of antibodies and / or antigen-specific T cells. In some embodiments, an antigen is a peptide or polypeptide that comprises at least one epitope against which an immune response can be generated. In some embodiments, an antigen is presented by cells of the immune system such as antigen presenting cells like dendritic cells or macrophages. In some embodimentss, an antigen or a processedP-634738-PC product thereof such as a T-cell epitope is bound by a T- or B-cell receptor, or by an immunoglobulin molecule such as an antibody. Accordingly, an antigen or a processed product thereof may react specifically with antibodies or T lymphocytes (T cells). In some embodiments, an antigen is a parasitic antigen. In accordance with the present disclosure, in some embodiments, an antigen may be delivered by RNA molecules as provided herein. In some embodiments, a peptide or polypeptide antigen can be 2-100 amino acids, including for example, 5 amino acids, 10 amino acids, 15 amino acids, 20 amino acids, 25 amino acids, 30 amino acids, 35 amino acids, 40 amino acids, 45 amino acids, or 50 amino acids in length. In some embodiments, a peptide or polypeptide antigen can be greater than 50 amino acids. In some embodiments, a peptide or polypeptide antigen can be greater than 100 amino acids. In some embodiments, an antigen is recognized by an immune effector cell. In some embodiments, an antigen if recognized by an immune effector cell is able to induce in the presence of appropriate co-stimulatory signals, stimulation, priming and / or expansion of the immune effector cell carrying an antigen receptor recognizing the antigen. In the context of the embodiments of the present disclosure, in some embodiments, an antigen can be presented or present on the surface of a cell, e.g., an antigen presenting cell. In some embodiments, an antigen is presented by a diseased cell such as a virus-infected cell. In some embodiments, an antigen receptor is a TCR which binds to an epitope of an antigen presented in the context of MHC. In some embodiments, binding of a TCR when expressed by T cells and / or present on T cells to an antigen presented by cells such as antigen presenting cells results in stimulation, priming and / or expansion of said T cells. In some embodiments, binding of a TCR when expressed by T cells and / or present on T cells to an antigen presented on diseased cells results in cytolysis and / or apoptosis of the diseased cells, wherein said T cells preferably release cytotoxic factors, e.g. perforins and granzymes.

[0044] Associated: Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of, susceptibility to, severity of, stage of, etc. the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments,P-634738-PC two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.

[0045] Binding. Those skilled in the art, reading the present specification, will appreciate that the term “binding” typically refers to a non-covalent association between or among entities or moieties. In some embodiments, binding data are expressed in terms of “IC50”. As is understood in the art, IC50 is the concentration of an assessed agent in a binding assay at which 50% inhibition of binding of reference agent known to bind the relevant binding partner is observed. In some embodiments, assays are run under conditions in which the assays are run (e.g., limiting binding target and reference concentrations), these values approximate KD values. Assays for determining binding are well known in the art and are described in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995); and Sette, et al., Mol. Immunol. 31:813 (1994). Alternatively, binding can be expressed relative to binding by a reference standard peptide. For example, can be based on its IC50, relative to the IC50 of a reference standard peptide. Binding can also be determined using other assay systems including those using: live cells (e.g., Ceppellini et al., Nature 339:392 (1989); Christnick et al., Nature 352:67 (1991); Busch et al., Int. Immunol. 2:443 (1990); Hill et al., J. Immunol. 147:189 (1991); del Guercio et al., J. Immunol. 154:685 (1995)), cell free systems using detergent lysates (e.g., Cerundolo et al., J. Immunol 21:2069 (1991)), immobilized purified MHC (e.g., Hill et al., J. Immunol. 152, 2890 (1994); Marshall et al., J. Immunol. 152:4946 (1994)), ELISA systems (e.g., Reay et al., EMBO J. 11:2829 (1992)), surface plasmon resonance (e.g., Khilko et al., J. Biol. Chem. 268:15425 (1993)); high flux soluble phase assays (Hammer et al., J. Exp. Med. 180:2353 (1994)), and measurement of class I MHC stabilization or assembly (e.g., Ljunggren et al., Nature 346:476 (1990); Schumacher et al., Cell 62:563 (1990); Townsend et al., Cell 62:285 (1990); Parker et al., J. Immunol. 149:1896 (1992)).

[0046] Cap. As used herein, the term “cap” refers to a structure comprising or essentially consisting of a nucleoside-5 '-triphosphate that is typically joined to a 5'-end of an uncapped RNA (e.g., an uncapped RNA having a 5'- diphosphate). In some embodiments, a cap is or comprises a guanine nucleotide. In some embodiments, a cap is or comprises a naturally-occurring RNA 5’ cap, including, e.g., but not limited to a 7- methylguanosine cap, which has a structure designated as “m7G.” In some embodiments, a cap is or comprises a synthetic cap analog that resembles an RNA cap structure andP-634738-PC possesses the ability to stabilize RNA if attached thereto, including, e.g., but not limited to anti-reverse cap analogs (ARCAs) known in the art). Those skilled in the art will appreciate that methods for joining a cap to a 5’ end of an RNA are known in the art. For example, in some embodiments, a capped RNA may be obtained by in vitro capping of RNA that has a 5' triphosphate group or RNA that has a 5' diphosphate group with a capping enzyme system (including, e.g., but not limited to vaccinia capping enzyme system or Saccharomyces cerevisiae capping enzyme system). Alternatively, a capped RNA can be obtained by in vitro transcription (IVT) of a single-stranded DNA template in the presence of a dinucleotide or trinucleotide cap analog.

[0047] Cell-mediated immunity “Cell-mediated immunity,” “cellular immunity,” “cellular immune response,” or similar terms are meant to include a cellular response directed to cells characterized by expression of an antigen, in particular characterized by presentation of an antigen with class I or class II MHC. A cellular response relates to immune effector cells, in particular to T cells or T lymphocytes which act as either “helpers” or “killers.” The helper T cells (also termed CD4+T cells or CD4 T cells) play a central role by regulating the immune response and the killer cells (also termed cytotoxic T cells, cytolytic T cells, CD8+T cells, CD8 T cells, or CTLs) kill diseased cells such as virus-infected cells, preventing the production of more diseased cells.

[0048] Co-administration: As used herein, the term “co-administration” refers to use of a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) described herein and an additional therapeutic agent. The combined use of a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) provided herein and an additional therapeutic agent may be performed concurrently or separately (e.g., sequentially in any order). In some embodiments, a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) provided herein and an additional therapeutic agent may be combined in one pharmaceutically-acceptable carrier, or they may be placed in separate carriers and delivered to a target cell or administered to a subject at different times. Each of these situations is contemplated as falling within the meaning of “co-administration” or “combination,” provided that a pharmaceutical composition (e g., immunogenic composition, e.g., vaccine) provided herein and an additional therapeutic agent are delivered or administered sufficiently close in time that there is at least some temporal overlap in biological effect(s) generated by each on a target cell or a subject being treated.

[0049] Codon-optimized As used herein, the term “codon-optimized” refers to alteration of codons in a coding region of a nucleic acid molecule to reflect the typical codon usage of a host organismP-634738-PC without preferably altering the amino acid sequence encoded by the nucleic acid molecule. Within the context of the present disclosure, in some embodiments coding regions are codon-optimized for optimal expression in a subject to be treated using the RNA molecules provided herein. In some embodiments, codon-optimization may be performed such that codons for which frequently occurring tRNAs are available are inserted in place of “rare codons.” In some embodiments, codon-optimization may include increasing guanosine / cytosine (G / C) content of a coding region of RNA described herein as compared to the G / C content of the corresponding coding sequence of a wild-type RNA, wherein the amino acid sequence encoded by the RNA is preferably not modified compared to the amino acid sequence.

[0050] Combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0001] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusionP-634738-PC that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0052] Corresponding to. As used herein, the term “corresponding to” refers to a relationship between two or more entities. For example, the term “corresponding to” may be used to designate the position / identity of a structural element in a compound or composition relative to another compound or composition (e.g., to an appropriate reference compound or composition). For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190thamino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify “corresponding” amino acids. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GL SEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHLLS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and / or nucleic acids in accordance with the present disclosure. Those of skill in the art will also appreciate that, in some instances, the term “corresponding to” may be used to describe an event or entity that shares a relevant similarity with another event or entity (e.g., an appropriate reference event or entity). To give but one example, a gene or protein in one organism may be described as “corresponding to” a gene or protein from another organism in order to indicate, in some embodiments, that it plays an analogous role or performs an analogous function and / or that it shows a particular degree of sequence identity or homology, or shares a particular characteristic sequence element.

[0053] Derived. In the context of an amino acid sequence (peptide or polypeptide) “derived from” a designated amino acid sequence (peptide or polypeptide), it refers to a structural analogue of a designated amino acid sequence. In some embodiments, an amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentiallyP-634738-PC identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a particular amino acid sequence may be variants of that particular sequence or a fragment thereof. For example, it will be understood by one of ordinary skill in the art that the antigens suitable for use herein may be altered such that they vary in sequence from the naturally occurring or native sequences from which they were derived, while retaining the desirable activity of the native sequences.

[0054] Designed: As used herein, the term “designed” refers to an agent (i) whose structure is or was selected by the hand of man; (ii) that is produced by a process requiring the hand of man; and / or (iii) that is distinct from natural substances and other known agents.

[0055] Dosing regimen: Those skilled in the art will appreciate that the term “dosing regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (it?., is a therapeutic dosing regimen).

[0056] Engineered: In general, the term “engineered” refers to the aspect of having been manipulated by the hand of man. For example, a polynucleotide is considered to be “engineered” when two or more sequences that are not linked together in that order in nature are manipulated by the hand of man to be directly linked to one another in the engineered polynucleotide and / or when a particular residue in a polynucleotide is non-naturally occurring and / or is caused through action of the hand of man to be linked with an entity or moiety with which it is not linked in nature.P-634738-PC

[0057] Epitope. As used herein, the term “epitope” refers to a moiety that is specifically recognized by an immunoglobulin (e.g., antibody or receptor) binding component. For example, an epitope may be recognized by a T cell, a B cell, or an antibody. In some embodiments, an epitope is comprised of a plurality of chemical atoms or groups on an antigen. In some embodiments, such chemical atoms or groups are surface-exposed when the antigen adopts a relevant three-dimensional conformation. In some embodiments, such chemical atoms or groups are physically near to each other in space when the antigen adopts such a conformation. In some embodiments, at least some such chemical atoms are groups are physically separated from one another when the antigen adopts an alternative conformation (e.g., is linearized). Accordingly, in some embodiments, an epitope of an antigen may include a continuous or discontinuous portion of the antigen. In some embodiments, an epitope is or comprises a T cell epitope. In some embodiments, an epitope may have a length of about 5 to about 30 amino acids, or about 10 to about 25 amino acids, or about 5 to about 15 amino acids, or about 5 to 12 amino acids, or about 6 to about 9 amino acids.

[0058] Expression: As used herein, the term “expression” of a nucleic acid sequence refers to the generation of a gene product from the nucleic acid sequence. In some embodiments, a gene product can be a transcript. In some embodiments, a gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, etc.); (3) translation of an RNA into a polypeptide or protein; and / or (4) post-translational modification of a polypeptide or protein.

[0059] Five prime untranslated region: As used herein, the terms “five prime untranslated region” or “5' UTR” refer to a sequence of an RNA molecule between a transcription start site and a start codon of a coding region of an RNA. In some embodiments, “5’ UTR” refers to a sequence of an RNA molecule that begins at a transcription start site and ends one nucleotide (nt) before a start codon (usually AUG) of a coding region of an RNA molecule, e.g., in its natural context.

[0060] Humoral immunity: As used herein, the term “humoral immunity” or “humoral immune response” refers to antibody production and the accessory processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antibodies, which include pathogen neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.P-634738-PC

[0061] Identity: As used herein, the term “identity” refers to the overall relatedness between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules. In some embodiments, polynucleotide molecules e.g., DNA molecules and / or RNA molecules) and / or between polypeptide molecules are considered to be “substantially identical” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical. Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or substantially 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller, 1989, which has been incorporated into the ALIGN program (version 2.0). In some exemplary embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna. CMP matrix.

[0062] Increased, Induced, or Reduced: As used herein, these terms or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with a provided pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) may be “increased” relative to that obtained with a comparable reference pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine). Alternatively or additionally, in some embodiments, an assessed value achieved in aP-634738-PC subject may be “increased” relative to that obtained in the same subject under different conditions (e.g., prior to or after an event; or presence or absence of an event such as administration of a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) as provided herein, or in a different, comparable subject (e.g., in a comparable subject that differs from the subject of interest in prior exposure to a condition, e.g., absence of administration of a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) as provided herein.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance. In some embodiments, the term “reduced” or equivalent terms refers to a reduction in the level of an assessed value by at least 5%, at least 10%, at least 20%, at least 50%, at least 75% or higher, as compared to a comparable reference. In some embodiments, the term “reduced” or equivalent terms refers to a complete or essentially complete inhibition, i.e., a reduction to zero or essentially to zero. In some embodiments, the term “increased” or “induced” refers to an increase in the level of an assessed value by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 80%, at least 100%, at least 200%, at least 500%, or higher, as compared to a comparable reference.

[0063] Ionizable. The term “ionizable” refers to a compound or group or atom that is charged at a certain pH. In the context of an ionizable amino lipid, such a lipid or a function group or atom thereof bears a positive charge at a certain pH. In some embodiments, an ionizable amino lipid is positively charged at an acidic pH. In some embodiments, an ionizable amino lipid is predominately neutral at physiological pH values, e.g., in some embodiments about 7.0-7.4, but becomes positively charged at lower pH values. In some embodiments, an ionizable amino lipid may have a pKa within a range of about 5 to about 7.

[0064] Isolated: The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated”, but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated”. An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.

[0065] RNA lipid nanoparticle. As used herein, the term “RNA lipid nanoparticle” refers to a nanoparticle comprising at least one lipid and RNA molecule(s). In some embodiments, an RNA lipidP-634738-PC nanoparticle comprises at least one ionizable amino lipid. In some embodiments, an RNA lipid nanoparticle comprises at least one ionizable amino lipid, at least one helper lipid, and at least one polymer-conjugated lipid (e.g., PEG-conjugated lipid). In various embodiments, RNA lipid nanoparticles as described herein can have an average size (e.g., Z-average) of about 100 nm to 1000 nm, or about 200 nm to 900 nm, or about 200 nm to 800 nm, or about 250 nm to about 700 nm. In some embodiments of the present disclosure, RNA lipid nanoparticles can have a particle size (e.g., Z-average) of about 30 nm to about 200 nm, or about 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 to about 90 nm, about 80 nm to about 90 nm, or about 70 nm to about 80 nm. In some embodiments, an average size of lipid nanoparticles is determined by measuring the particle diameter. In some embodiments, RNA lipid nanoparticles may be prepared by mixing lipids with RNA molecules provided herein.

[0066] Lipidoid: As used herein, a “lipidoid” refers to a lipid-like molecule. In some embodiments, a lipoid is an amphiphilic molecule with one or more lipid-like physical properties. In the context of the present disclosure, the term lipid is considered to encompass lipidoids.

[0067] Nanoparticle: As used herein, the term “nanoparticle” refers to a particle having an average size suitable for parenteral administration. In some embodiments, a nanoparticle has a longest dimension (e.g., a diameter) of less than 1,000 nanometers (nm). In some embodiments, a nanoparticle may be characterized by a longest dimension (e.g., a diameter) of less than 300 nm. In some embodiments, a nanoparticle may be characterized by a longest dimension (e.g., a diameter) of less than 100 nm. In many embodiments, a nanoparticle may be characterized by a longest dimension between about 1 nm and about 100 nm, or between about 1 nm and about 500 nm, or between about 1 nm and 1,000 nm. In many embodiments, a population of nanoparticles is characterized by an average size (e.g., longest dimension) that is below about 1,000 nm, about 500 nm, about 100 nm, about 50 nm, about 40 nm, about 30 nm, about 20 nm, or about 10 nm and often above about 1 nm. In many embodiments, a nanoparticle may be substantially spherical so that its longest dimension may be its diameter. In some embodiments, a nanoparticle has a diameter of less than 100 nm as defined by the National Institutes of Health.

[0068] Naturally occurring: The term “naturally occurring” as used herein refers to an entity that can be found in nature. For example, a peptide or nucleic acid that is present in an organism (includingP-634738-PC viruses) and can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally occurring.

[0069] Neutralization: As used herein, the term “neutralization” refers to an event in which binding agents such as antibodies bind to a biological active site of a virus such as a receptor binding protein, thereby inhibiting the parasitic infection of cells. In some embodiments, the term “neutralization” refers to an event in which binding agents eliminate or significantly reduce ability of infecting cells.

[0070] Nucleic acid particle. A “nucleic acid particle” can be used to deliver nucleic acid to a target site of interest (e.g., cell, tissue, organ, and the like). A nucleic acid particle may comprise at least one cationic or cationically ionizable lipid or lipid-like material, at least one cationic polymer such as protamine, or a mixture thereof and nucleic acid. In some embodiments, a nucleic acid particle is a lipid nanoparticle. In some embodiments, a nucleic acid particle is a lipoplex particle.

[0071] Nucleic acid / Polynucleotide. As used herein, the term “nucleic acid” refers to a polymer of at least 10 nucleotides or more. In some embodiments, a nucleic acid is or comprises DNA. In some embodiments, a nucleic acid is or comprises RNA. In some embodiments, a nucleic acid is or comprises peptide nucleic acid (PNA). In some embodiments, a nucleic acid is or comprises a single stranded nucleic acid. In some embodiments, a nucleic acid is or comprises a double-stranded nucleic acid. In some embodiments, a nucleic acid comprises both single and double-stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, a nucleic acid may comprise a backbone that comprises one or more phosphorothioate or 5'-N-phosphoramidite linkages and / or one or more peptide bonds, e.g., as in a “peptide nucleic acid”. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises on or more, or all, non-natural residues. In some embodiments, a non-natural residue comprises a nucleoside analog (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3 -methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5 -propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaad enosine, 7-deazaguanosine, 8-oxoadenosine, 8 -oxoguanosine, 6-O-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a non-natural residue comprises one or moreP-634738-PC modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared to those in natural residues. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in vivo or in vitro, reproduction in a recombinant cell or system, or chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10.500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16.500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, or 20,000 or more residues or nucleotides long.

[0072] Nucleotide: As used herein, the term “nucleotide” refers to its art-recognized meaning. When a number of nucleotides is used as an indication of size, e.g., of a polynucleotide, a certain number of nucleotides refers to the number of nucleotides on a single strand, e.g., of a polynucleotide.

[0073] Patient: As used herein, the term “patient” refers to any organism who is suffering or at risk of a disease or disorder or condition. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more diseases or disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disease or disorder or condition. In some embodiments, a patient has been diagnosed with one or more diseases or disorders or conditions. In some embodiments, a disease or disorder or condition that is amenable to provided technologies is or includes an HSV infection. In some embodiments, a patient is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition. In some embodiments, a patient is a patient suffering from or susceptible to an HSV infection.

[0074] PEG-conjugated lipid. The term “PEG-conjugated lipid" refers to a molecule comprising a lipid portion and a polyethylene glycol portion.

[0075] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, active agent is present in unit dose amount appropriate for administration in aP-634738-PC therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection as, for example, a sterile solution or suspension formulation.

[0076] Pharmaceutically effective amount: The term “pharmaceutically effective amount” or “therapeutically effective amount” refers to the amount which achieves a desired reaction or a desired effect alone or together with further doses. In the case of the treatment of a particular disease, a desired reaction in some embodiments relates to inhibition of the course of the disease. In some embodiments, such inhibition may comprise slowing down the progress of a disease and / or interrupting or reversing the progress of the disease. In some embodiments, a desired reaction in a treatment of a disease may be or comprise delay or prevention of the onset of a disease or a condition. An effective amount of pharmaceutical compositions (e.g., immunogenic compositions, e.g., vaccines) provided herein will depend, for example, on a disease or condition to be treated, the severity of such a disease or condition, individual parameters of the patient, including, e.g., age, physiological condition, size and weight, the duration of treatment, the type of an accompanying therapy (if present), the specific route of administration and similar factors. Accordingly, doses of pharmaceutical compositions (e.g., immunogenic compositions, e.g., vaccines) provided herein may depend on various of such parameters. In the case that a reaction in a patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used.

[0077] Poly(A) sequence: As used herein, the term “poly(A) sequence” or “poly-A tail” refers to an uninterrupted or interrupted sequence of adenylate residues which is typically located at the 3'-end of an RNA molecule. Poly(A) sequences are known to those of skill in the art and may follow the 3’-UTR in the RNAs provided herein. An uninterrupted poly(A) sequence is characterized by consecutive adenylate residues. In nature, an uninterrupted poly(A) sequence is typical. RNAs disclosed herein can have a poly(A) sequence attached to the free 3'-end of the RNA by a templateindependent RNA polymerase after transcription or a poly(A) sequence encoded by DNA and transcribed by a template-dependent RNA polymerase.

[0078] Polypeptide: As used herein, the term “polypeptide” refers to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In someP-634738-PC embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications comprise acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it is used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in some embodiments, aP-634738-PC conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide.

[0079] Prevent: As used herein, the term “prevent” or “prevention” when used in connection with the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0080] Recombinant: The term “recombinant” in the context of the present disclosure means “made through genetic engineering”. In some embodiments, a “recombinant” entity such as a recombinant nucleic acid in the context of the present disclosure is not naturally occurring.

[0081] Reference: As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0082] Risk: As will be understood from context, “risk” of a disease, disorder, and / or condition refers to a likelihood that a particular individual will develop the disease, disorder, and / or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%. In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some embodiments, a reference sample or group of reference samples have a known risk of a disease, disorder, condition and / or event. In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual. In some embodiments, relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. In some embodiments, risk may reflect one or more genetic attributes, e.g., which may predispose an individual toward development (or not) of aP-634738-PC particular disease, disorder and / or condition. In some embodiments, risk may reflect one or more epigenetic events or attributes and / or one or more lifestyle or environmental events or attributes.

[0083] RNA lipoplex particle. As used herein, the term “RNA lipoplex particle” refers to a complex comprising liposomes, in particular cationic liposomes, and RNA molecules. Without wishing to bound by a particular theory, electrostatic interactions between positively charged liposomes and negatively charged RNA results in complexation and spontaneous formation of RNA lipoplex particles. In some embodiments, positively charged liposomes may comprise a cationic lipid, such as in some embodiments DOTMA, and additional lipids, such as in some embodiments DOPE. In some embodiments, an RNA lipoplex particle is a nanoparticle.

[0084] Selective or specific: The term “selective” or “specific”, when used herein in reference to an agent having an activity, is understood by those skilled in the art to mean that the agent discriminates between potential target entities, states, or cells. For example, in some embodiments, an agent is said to bind “specifically” to its target if it binds preferentially with that target in the presence of one or more competing alternative targets. In many embodiments, specific interaction is dependent upon the presence of a particular structural feature of the target entity (e.g., an epitope, a cleft, a binding site). It is to be understood that specificity need not be absolute. In some embodiments, specificity may be evaluated relative to that of a target-binding moiety for one or more other potential target entities (e.g., competitors). In some embodiments, specificity is evaluated relative to that of a reference specific binding moiety. In some embodiments, specificity is evaluated relative to that of a reference nonspecific binding moiety.

[0085] Stable: As used herein, the term “stable” in the context of the present disclosure refers to a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) as a whole and / or components thereof meeting or exceeding pre-determined acceptance criteria. For example, in some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) exhibits no unacceptable levels of microbial growth, and substantially no or no breakdown or degradation of the active biological molecule component(s). In some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to the integrity of RNA molecules being maintained at least above 90% or more. In some embodiments, a stable pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to at least 90% or more (including, e.g., at least 95%, at least 96%, at least 97%, or more) of RNA molecules being maintained to be encapsulated within lipid nanoparticles. In some embodiments, a stableP-634738-PC pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) refers to a formulation that remains capable of eliciting a desired immunologic response when administered to a subject. In some embodiments, a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) remains stable for a specified period of time under certain conditions.

[0086] Subject. As used herein, the term “subject” refers to an organism to be administered with a composition described herein, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, domestic pets, etc.) and humans. In some embodiments, a subject is a human subject. In some embodiments, a subject is suffering from a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject is susceptible to a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject displays one or more non-specific symptoms of a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition (e.g., an HSV infection). In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0087] Suffering from. An individual who is “suffering from” a disease, disorder, and / or condition has been diagnosed with and / or displays one or more symptoms of a disease, disorder, and / or condition.

[0088] Susceptible to. An individual who is “susceptible to” a disease, disorder, and / or condition is one who has a higher risk of developing the disease, disorder, and / or condition than does a member of the general public. In some embodiments, an individual who is susceptible to a disease, disorder and / or condition may not have been diagnosed with the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition may not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individualP-634738-PC who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0089] Synthetic: As used herein, the term “synthetic” refers to an entity that is artificial, or that is made with human intervention, or that results from synthesis rather than naturally occurring. For example, in some embodiments, a synthetic nucleic acid or polynucleotide refers to a nucleic acid molecule that is chemically synthesized, e.g., in some embodiments by solid-phase synthesis. In some embodiments, the term “synthetic” refers to an entity that is made outside of biological cells. For example, in some embodiments, a synthetic nucleic acid or polynucleotide refers to a nucleic acid molecule (e.g., an RNA) that is produced by in vitro transcription using a template.

[0090] Therapy: The term “therapy” refers to an administration or delivery of an agent or intervention that has a therapeutic effect and / or elicits a desired biological and / or pharmacological effect (e.g., has been demonstrated to be statistically likely to have such effect when administered to a relevant population). In some embodiments, a therapeutic agent or therapy is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. In some embodiments, a therapeutic agent or therapy is a medical intervention (e.g., surgery, radiation, phototherapy) that can be performed to alleviate, relieve, inhibit, present, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition.

[0091] Three prime untranslated region: As used herein, the terms “three prime untranslated region” or “3' UTR” refer to a sequence of an RNA molecule that begins following a stop codon of a coding region of an open reading frame sequence. In some embodiments, the 3' UTR begins immediately after a stop codon of a coding region of an open reading frame sequence, e.g., in its natural context. In other embodiments, the 3' UTR does not begin immediately after stop codon of the coding region of an open reading frame sequence, e.g., in its natural context.

[0092] Threshold level (e.g., acceptance criteria): As used herein, the term “threshold level” refers to a level that are used as a reference to attain information on and / or classify the results of a measurement, for example, the results of a measurement attained in an assay. For example, in some embodiments, a threshold level means a value measured in an assay that defines the dividing line between two subsets of a population (e.g. a batch that satisfy quality control criteria vs. a batch that does not satisfy quality control criteria). Thus, a value that is equal to or higher than the thresholdP-634738-PC level defines one subset of the population, and a value that is lower than the threshold level defines the other subset of the population. A threshold level can be determined based on one or more control samples or across a population of control samples. A threshold level can be determined prior to, concurrently with, or after the measurement of interest is taken. In some embodiments, a threshold level can be a range of values.

[0093] Treat: As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject at a later-stage of disease, disorder, and / or condition.

[0094] Vaccination. As used herein, the term “vaccination” refers to the administration of a composition intended to generate an immune response, for example to a disease-associated (e.g., disease-causing) agent. In some embodiments, vaccination can be administered before, during, and / or after exposure to a disease-associated agent, and in certain embodiments, before, during, and / or shortly after exposure to the agent. In some embodiments, vaccination includes multiple administrations, appropriately spaced in time, of a vaccine composition. In some embodiments, vaccination generates an immune response to an infectious agent.

[0095] Vaccine: As used herein, the term “vaccine” refers to a composition that induces an immune response upon administration to a subject. In some embodiments, an induced immune response provides protective immunity.

[0096] Variant: As used herein in the context of molecules, e.g., nucleic acids, proteins, or small molecules, the term “variant” refers to a molecule that shows significant structural identity with a reference molecule but differs structurally from the reference molecule, e.g., in the presence or absence or in the level of one or more chemical moi eties as compared to the reference entity. In some embodiments, a variant also differs functionally from its reference molecule. In general, whether a particular molecule is properly considered to be a “variant” of a reference molecule is based on its degree of structural identity with the reference molecule. As will be appreciated by those skilled inP-634738-PC the art, any biological or chemical reference molecule has certain characteristic structural elements. A variant, by definition, is a distinct molecule that shares one or more such characteristic structural elements but differs in at least one aspect from the reference molecule. In some embodiments, a variant polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in amino acid or nucleotide sequence and / or one or more differences in chemical moieties (e.g., carbohydrates, lipids, phosphate groups) that are covalently components of the polypeptide or nucleic acid (e.g., that are attached to the polypeptide or nucleic acid backbone). In some embodiments, a variant polypeptide or nucleic acid shows an overall sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a variant polypeptide or nucleic acid does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a variant polypeptide or nucleic acid shares one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid lacks one or more of the biological activities of the reference polypeptide or nucleic acid. In some embodiments, a variant polypeptide or nucleic acid shows a reduced level of one or more biological activities as compared to the reference polypeptide or nucleic acid. In some embodiments, a polypeptide or nucleic acid of interest is considered to be a “variant” of a reference polypeptide or nucleic acid if it has an amino acid or nucleotide sequence that is identical to that of the reference but for a small number of sequence alterations at particular positions. Typically, fewer than about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, or about 2% of the residues in a variant are substituted, inserted, or deleted, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises about 10, about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 substituted residues as compared to a reference. Often, a variant polypeptide or nucleic acid comprises a very small number (e.g., fewer than about 5, about 4, about 3, about 2, or about 1) number of substituted, inserted, or deleted, functional residues (i.e., residues that participate in a particular biological activity) relative to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises not more than about 5, about 4, about 3, about 2, or about 1 addition or deletion, and, in some embodiments, comprises no additions or deletions, as compared to the reference. In some embodiments, a variant polypeptide or nucleic acid comprises fewer than about 25, about 20, about 19, about 18, about 17, about 16, aboutP-634738-PC 15, about 14, about 13, about 10, about 9, about 8, about 7, about 6, and commonly fewer than about 5, about 4, about 3, or about 2 additions or deletions as compared to the reference. In some embodiments, a reference polypeptide or nucleic acid is one found in nature.

[0097] Vector, as used herein, refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments may be ligated. Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “expression vectors.” In some embodiments, known techniques may be used, for example, for generation or manipulation of recombinant DNA, for oligonucleotide synthesis, and for tissue culture and transformation (e.g., electroporation, lipofection). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (2012)), which is incorporated herein by reference for any purpose.

[0098] All literature and similar material cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and web pages, regardless of the format of such literature and similar materials, are expressly incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described in any way.P-634738-PC DETAILED DESCRIPTIONCompositions

[0099] In some embodiments, the present disclosure provides compositions comprising one or more RNAs (also referred to herein as “polyribonucleotides”). In some embodiments, one or more RNAs encode one or more Herpes Simplex Virus (HSV) glycoproteins or antigenic fragments thereof. In some embodiments, an RNA is a modified RNA as described herein below.

[0100] In some embodiments, an antigenic fragment of an HSV glycoprotein comprises the ectodomain of the glycoprotein or a portion thereof. In another embodiment, an antigenic fragment consists of the ectodomain of the glycoprotein or a portion thereof.

[0101] In some embodiments, the present disclosure provides a composition comprising one or more nucleoside-modified RNAs, wherein each of said modified RNAs encodes a Herpes Simplex Virus (HSV) glycoprotein or antigenic fragment thereof, and wherein said modified RNA comprises one or more pseudouridine or pseudouridine family residues.

[0102] In some embodiments, an HSV glycoprotein comprises glycoprotein D (gD), glycoprotein C (gC), glycoprotein E (gE), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L (gL) glycoprotein I (gl), or a combination thereof.

[0103] Thus, in some embodiments, the present disclosure provides a composition comprising one or more modified RNAs encoding HSV gD, gC, gE, gB, gH, gL, gl, or antigenic fragments thereof. In some embodiments, the modified RNAs comprise pseudouridine-modified RNAs.

[0104] In some embodiments, the present disclosure provides compositions comprising an RNA encoding HSV gD or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gC or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gE or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gB or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gH or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gL or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV gl or an antigenic fragment thereof.P-634738-PC

[0105] In some embodiments, the present disclosure provides a composition comprising: (a) an RNA encoding HSV gD or an antigenic fragment thereof; and (b) an RNA encoding HSV gC or an antigenic fragment thereof.

[0106] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV gD or an antigenic fragment thereof; and (b) an RNA encoding HSV gE or an antigenic fragment thereof.

[0107] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV gC or an antigenic fragment thereof; and (b) an RNA encoding HSV gE or an antigenic fragment thereof.

[0108] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV gD or an antigenic fragment thereof; (b) an RNA encoding HSV gC or an antigenic fragment thereof, and (c) an RNA encoding HSV gE or an antigenic fragment thereof.

[0109] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV gD or an antigenic fragment thereof; (b) an RNA encoding HSV gC or an antigenic fragment thereof, (c) an RNA encoding HSV gE or an antigenic fragment thereof; and (d) an RNA encoding HSV gB or an antigenic fragment thereof.

[0110] In some embodiments, the present disclosure provides a composition as described herein and further comprising one or more polyribonucleotides encoding: (a) HSV glycoprotein B (gB) or antigenic fragment thereof; (b) HSV glycoprotein H (gH) or antigenic fragment thereof; (c) HSV glycoprotein L (gL) or antigenic fragment thereof; (d) HSV glycoprotein I (gl) or antigenic fragment thereof; or (e) any combination thereof.

[0111] In some embodiments, an HSV gB antigen or antigenic fragment thereof as provided herein comprises one or more mutations that stabilize the HSV gB antigen or antigenic fragment thereof relative to a comparable HSV gB antigen or antigenic fragment thereof that does not comprise the one or more mutations. In some embodiments, the one or more mutations are one or more amino acid substitutions. In some embodiments, the one or more amino acid substitutions comprise 251C, 718C, or a combination thereof, wherein the numbering is with reference to SEQ ID NO: 25.

[0112] In some embodiments, the ribonucleotide sequence encodes an HSV gB antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gB antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in any one of SEQ ID NOs: 22-32 and 92. In some embodiments, the ribonucleotide sequence encodes an HSV gH antigen or antigenic fragmentP-634738-PC thereof and wherein the amino acid sequence of said HSV gH antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 49.

[0113] In some embodiments, the ribonucleotide sequence encodes an HSV gL antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gL antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 48.

[0114] In some embodiments, the ribonucleotide sequence encodes an HSV gl antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gl antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 47.

[0115] In some embodiments, the HSV glycoproteins are HSV-2 glycoproteins or antigenic fragments thereof. In another embodiment, the HSV glycoproteins are HSV-1 glycoproteins or antigenic fragments thereof. In some embodiments, the HSV glycoproteins comprise both HSV-2 glycoproteins or antigenic fragments thereof and HSV-1 glycoproteins or antigenic fragments thereof. In another embodiment, the HSV glycoproteins comprise a mixture of HSV-2 glycoproteins, or antigenic fragments thereof, and HSV-1 glycoproteins or antigenic fragments thereof.

[0116] In some embodiments, the present disclosure provides compositions comprising an RNA encoding HSV-2 gD or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gC or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gE or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gE or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gB or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gH or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gL or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-2 gl or an antigenic fragment thereof.

[0117] In some embodiments, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-2 gD or an antigenic fragment thereof; and (b) an RNA encoding HSV-2 gC or an antigenic fragment thereof.P-634738-PC

[0118] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-2 gD or an antigenic fragment thereof; and (b) an RNA encoding HSV-2 gE or an antigenic fragment thereof.

[0119] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-2 gC or an antigenic fragment thereof; and (b) an RNA encoding HSV-2 gE or an antigenic fragment thereof.

[0120] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-2 gD or an antigenic fragment thereof; (b) an RNA encoding HSV-2 gC or an antigenic fragment thereof, and (c) an RNA encoding HSV-2 gE or an antigenic fragment thereof.

[0121] In some embodiments, the present disclosure provides compositions comprising an RNA encoding HSV-1 gD or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gC or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gE or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gE or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gB or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gH or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gL or an antigenic fragment thereof. In another embodiment, the present disclosure provides compositions comprising an RNA encoding HSV-1 gl or an antigenic fragment thereof.

[0122] In some embodiments, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-1 gD or fragment thereof; and (b) an RNA encoding HSV-1 gC or fragment thereof.

[0123] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-1 gD or an antigenic fragment thereof; and (b) an RNA encoding HSV-1 gE or an antigenic fragment thereof.

[0124] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-1 gC or an antigenic fragment thereof; and (b) an RNA encoding HSV-1 gE or an antigenic fragment thereof.P-634738-PC

[0125] In another embodiment, the present disclosure provides a composition comprising: (a) an RNA encoding HSV-1 gD or an antigenic fragment thereof; (b) an RNA encoding HSV-1 gC or an antigenic fragment thereof, and (c) an RNA encoding HSV-1 gE or an antigenic fragment thereof.

[0126] In some embodiments, any of the compositions as provided herein consists essentially of one or more RNAs, wherein each of said RNAs encodes an HSV glycoprotein antigen or antigenic fragment thereof. In another embodiment, any of the compositions as provided herein consists of one or more RNAs, wherein each of said RNAs encodes an HSV glycoprotein antigen or antigenic fragment thereof.

[0127] In another embodiment, the present disclosure provides compositions comprising an RNA encoding an HSV gD protein or an antigenic fragment thereof, an RNA encoding an HSV gC protein or an antigenic fragment thereof, an RNA encoding an HSV gE protein or an antigenic fragment thereof and RNAs encoding one or more additional HSV glycoproteins or an antigenic fragment thereof. In some embodiments, said additional HSV glycoproteins comprise gB or an antigenic fragment thereof, gH or an antigenic fragment thereof, gL or an antigenic fragment thereof, gl or an antigenic fragment thereof, or any combination thereof. In some embodiments, said additional HSV glycoproteins comprise glycoprotein M (gM), glycoprotein N (gN), glycoprotein K (gK), glycoprotein G (gG), glycoprotein J (gj), or an antigenic fragment(s) thereof.

[0128] In some embodiments, compositions of the present disclosure and for use in the methods of the present disclosure comprise both HSV-2 glycoproteins or immunogenic glycoprotein fragments and HSV-1 glycoproteins or immunogenic glycoprotein fragments. In another embodiment, compositions of the present disclosure and for use in the methods of the present disclosure comprise a mixture of HSV-2 glycoproteins or immunogenic glycoprotein fragments and HSV-1 glycoproteins or immunogenic glycoprotein fragments. For example, in some embodiments, a composition of the present disclosure comprises HSV-2 gC, HSV-1 gD, and HSV-2 gE, or antigenic fragments thereof. In another embodiment, a composition of the present disclosure comprises HSV-1 gC, HSV-2 gD, and HSV-2 gE, or antigenic fragments thereof. In another embodiment, a composition of the present disclosure comprises HSV-2 gC, HSV-2 gD, and HSV-1 gE, or antigenic fragments thereof. In another embodiment, a composition of the present disclosure comprises HSV-1 gC, HSV-1 gD, and HSV-2 gE, or antigenic fragments thereof. In another embodiment, a composition of the present disclosure comprises HSV-1 gC, HSV-2 gD, and HSV-1 gE, or antigenic fragments thereof. In anotherP-634738-PC embodiment, a composition of the present disclosure comprises HSV-2 gC, HSV-1 gD, and HSV-1 gE, or antigenic fragments thereof.

[0129] In another embodiment, compositions of the present disclosure comprise one or more additional HSV-1 glycoproteins or antigenic fragments thereof, or HSV-2 glycoproteins orboth HSV-1 and HSV-2 glycoproteins, as provided herein. For example, in some embodiments, a composition of the present disclosure comprising HSV-2 gC or an antigenic fragment thereof, HSV-1 gD or an antigenic fragment thereof and HSV-2 gE or an antigenic fragment thereof may further comprise HSV-1 gl or an antigenic fragment thereof. In another embodiment, a composition of the present disclosure comprising HSV-2 gC or an antigenic fragment thereof, HSV-2 gD or an antigenic fragment thereof, and HSV-2 gE or an antigenic fragment thereof may further comprise HSV-1 gB or an antigenic fragment thereof. Each of the possible combinations of HSV-1 and HSV-2 glycoproteins, or antigenic fragments thereof, represents a separate embodiment of the disclosure.

[0130] In some embodiments, the present disclosure provides an RNA construct comprising one or more coding sequences, a 5’UTR, a 3’UTR, a polyA tail, a cap, or a combination thereof. In some embodiments, the 5’UTR is from tobacco etch virus. In some embodiments, the 3’UTR is from Xenopus beta globin.

[0131] As used herein, “encoding” refers to an RNA molecule that contains a gene that encodes a protein of interest, or a fragment thereof. In another embodiment, an RNA molecule comprises a protein coding sequence that encodes a protein of interest, or a fragment thereof. In another embodiment, one or more other proteins, or a fragments thereof is also encoded. In another embodiment, the protein of interest, or a fragment thereof, is the only protein encoded. Each possibility represents a separate embodiment of the present disclosure.

[0132] “Antigenic fragment” refers, in another embodiment, to a portion of a protein that is immunogenic and elicits a protective immune response when administered to a subject.

[0133] In some embodiments, “immunogenicity” or “immunogenic” is used herein to refer to the innate ability of a protein, peptide, protein fragment, nucleic acid, antigen or organism to elicit an immune response in an animal when the protein, peptide, protein fragment, nucleic acid, antigen or organism is administered to the animal. Thus, “enhancing the immunogenicity” in some embodiments, refers to increasing the ability of a protein, peptide, nucleic acid, antigen or organism to elicit an immune response in an animal when the protein, peptide, protein fragment, nucleic acid, antigen or organism is administered to an animal. The increased ability of a protein, peptide, protein fragment,P-634738-PC nucleic acid, antigen or organism to elicit an immune response can be measured by, in some embodiments, a greater number of antibodies to a protein, peptide, protein fragment, nucleic acid, antigen or organism, a greater diversity of antibodies to an antigen or organism, a greater number of T-cells specific for a protein, peptide, protein fragment, nucleic acid, antigen or organism, a greater cytotoxic or helper T-cell response to a protein, peptide, nucleic acid, antigen or organism, and the like.

[0134] In some embodiments, a protein, peptide, protein fragment, nucleic acid or organism can be antigenic. “Antigenic” refers, in another embodiment, to a protein, peptide, protein fragment, nucleic acid, or organism capable of specifically interacting with an antigen recognition molecule of the immune system, e.g., an immunoglobulin (antibody) or T cell antigen receptor. An antigenic protein, peptide, or protein fragment contains, in another embodiment, an epitope of at least about 8 amino acids (AAs). An antigenic portion of a a protein, peptide, protein fragment, nucleic acid, or organism, also called herein an epitope, can be a portion that is immunodominant for antibody or T cell receptor recognition, or it can be a portion used to generate an antibody to the molecule by conjugating an antigenic portion to a carrier polypeptide for immunization. A molecule that is antigenic need not itself be immunogenic, i.e., capable of eliciting an immune response without a carrier.

[0135] In some embodiments, “functional” is used herein to refer to the innate ability of a protein, peptide, nucleic acid, fragment or a variant thereof to exhibit a biological activity or function. In some embodiments, such a biological function is its binding property to an interaction partner, e.g., a membrane-associated receptor, and in another embodiment, its trimerization property. In the case of functional fragments and the functional variants of the disclosure, these biological functions may in fact be changed, e.g., with respect to their specificity or selectivity, but with retention of the basic biological function.

[0136] In some embodiments, the term “fragment” is used herein to refer to a protein or polypeptide that is shorter or comprises fewer amino acids than the full-length protein or polypeptide. In another embodiment, fragment refers to a nucleic acid encoding the protein fragment that is shorter or comprises fewer nucleotides than the full-length nucleic acid. In another embodiment, the fragment is an N-terminal fragment. In another embodiment, the fragment is a C-terminal fragment. In some embodiments, the fragment is an intrasequential section of the protein, peptide, or nucleic acid. In another embodiment, the fragment is an immunogenic intrasequential section of the protein, peptide or nucleic acid. In another embodiment, the fragment is a functional intrasequential section within theP-634738-PC protein, peptide or nucleic acid. In another embodiment, the fragment is an N-terminal antigenic fragment. In some embodiments, the fragment is a C-terminal antigenic fragment. In another embodiment, the fragment is an N-terminal functional fragment. In another embodiment, the fragment is a C-terminal functional fragment. In another embodiment, the fragment contains pieces of the protein linked together or pieces of multiple proteins linked together. In some embodiments, the fragment of the HSV protein is the ectodomain of the protein. In another embodiment, the fragment is 1,2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids shorter than the full-length protein. In another embodiment, the fragment is 50-100, 100-150, 150-300, or 300-600 amino acids shorter than the full-length protein. In another embodiment, the fragment comprises 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% of the full-length protein. In another embodiment, the fragment comprises approximately 42%, 83%, 78%, or 66% of the full-length protein (excluding the signal sequence), as is provided herein, in some embodiments, for HSV-2 gE, gC, gD, and gl. In some embodiments, a fragment is a domain (e.g., an ectodomain).

[0137] In some embodiments, an “antigenic fragment” of a glycoprotein as provided in the present disclosure refers to a portion of the glycoprotein that is immunogenic. In some embodiments, an antigenic fragment elicits a protective immune response when administered to a subject.

[0138] In another aspect, the present disclosure provides compositions comprising RNAs, wherein each of said RNAs encodes a) HSV glycoprotein D (gD) or an antigenic fragment thereof, b) HSV glycoprotein C (gC) or an antigenic fragment thereof, c) HSV glycoprotein E (gE) or an antigenic fragment thereof, or any combination thereof.

[0139] In some embodiments, the present disclosure provides a composition comprising an RNA encoding an HSV gD or an antigenic fragment thereof, an RNA encoding an HSV gC or an antigenic fragment thereof, and an RNA encoding an HSV gE or an antigenic fragment thereof.

[0140] In another embodiment, inclusion of an RNA encoding gC or an antigenic fragment thereof, and / or an RNA encoding gE or an antigenic fragment thereof, in the composition of the present disclosure increases the efficaciousness of anti-gD antibodies elicited by the composition.

[0141] In another embodiment, inclusion of an RNA encoding gC or an antigenic fragment thereof, and / or an RNA encoding gE or an antigenic fragment thereof in the composition of the present disclosure enhances the effectiveness of an innate immune response. In another embodiment, the innate immune response is an antibody-mediated immune response. In another embodiment, the innate immune response is a non-antibody-mediated immune response. In another embodiment, the innateP-634738-PC immune response is an NK (natural killer) cell response. In another embodiment, the innate immune response is any other innate immune response known in the art.

[0142] In some embodiments, inclusion of an RNA encoding gC antigen or an antigenic fragment thereof, and / or an RNA encoding gE antigen or an antigenic fragment thereof, in the composition of the present disclosure increases the efficaciousness of antibodies elicited by the composition against one of the glycoproteins provided herein. In some embodiments, inclusion of an RNA encoding gC antigen or an antigenic fragment thereof, and / or an RNA encoding gE antigen or an antigenic fragment thereof, in the composition of the present disclosure decreases the dose of one of the above glycoproteins required to elicit antibodies that inhibit binding of the glycoprotein to a cellular receptor thereof, when a dose of one of the glycoproteins is administered separately from one of the other glycoproteins.

[0143] In some embodiments, a composition comprises one or more RNAs encoding HSV glycoprotein antigens or antigenic fragments thereof and lipid nanoparticles, polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes.

[0144] In some embodiments, the present disclosure provides a formulation comprising a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof, a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof, wherein one or more of the ribonucleotides are fully or partially encapsulated within a lipid nanoparticle, wherein the lipid nanoparticle comprises (a) a polymer-conjugated lipid; (b) a cationic lipid; and (c) one or more neutral lipids.

[0145] In some embodiments, the present disclosure provides a composition comprising a formulation as described herein.Glycoprotein C

[0146] In some embodiments, the present disclosure provides an RNA encoding a polypeptide comprising an HSV glycoprotein C (gC) antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, the present disclosure provides a composition comprising an RNA encoding a polypeptide comprising an HSV gC antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof (e.g., ectodomain) comprises an amino acid sequence that is at least 95% identical to the amino acidP-634738-PC sequence of SEQ ID NO: 12. In some embodiments, an RNA encoding a polypeptide comprising an HSV-2 gC antigen or antigenic fragment thereof (e.g., ectodomain) comprises a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 36 or 37.

[0147] In some embodiments, the present disclosure provides a composition comprising a combination as described herein. In some embodiments, a combination comprises RNA encoding HSV glycoprotein antigens or antigenic fragments thereof at the doses provided herein. In some embodiments, doses comprise 1, 3, 5, 30, 50, or 60 qg per administration.

[0148] In some embodiments, a polyribonucleotide (e.g., a polyribonucleotide encoding a polypeptide comprising an HSV glycoprotein C (gC) antigen or an antigenic fragment thereof) is an isolated polyribonucleotide.HSV-1 gC

[0149] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-1 glycoprotein C (gC) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-1 gC antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-1 gC. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.

[0150] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-1 gC antigen or antigenic fragment thereof comprises: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGGCCAUCUCCGGCGUGCCCGUGC UGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCCGCCCAGGAGUCCUGGGCCGAGA CCGCCUCCACCGGCCCCACCAUCACCGCCGGCGCCGUGACCAACGCCUCCGAGGCCCC CACCUCCGGCUCCCCCGGCUCCGCCGCCUCCCCCGAGGUGACCCCCACCUCCACCCCC AACCCCAACAACGUGACCCAGAACAAGACCACCCCCACCGAGCCCGCCUCCCCCCCCA CCACCCCCAAGCCCACCUCCACCCCCAAGUCCCCCCCCACCUCCACCCCCGACCCCAA GCCCAAGAACAACACCACCCCCGCCAAGUCCGGCCGCCCCACCAAGCCCCCCGGCCCC GUGUGGUGCGACCGCCGCGACCCCCUGGCCCGCUACGGCUCCCGCGUGCAGAUCCGC UGCCGCUUCCGCAACUCCACCCGCAUGGAGUUCCGCCUGCAGAUCUGGCGCUACUCC AUGGGCCCCUCCCCCCCCAUCGCCCCCGCCCCCGACCUGGAGGAGGUGCUGACCAACA UCACCGCCCCCCCCGGCGGCCUGCUGGUGUACGACUCCGCCCCCAACCUGACCGACCCP-634738-PC CCACGUGCUGUGGGCCGAGGGCGCCGGCCCCGGCGCCGACCCCCCCCUGUACUCCGU GACCGGCCCCCUGCCCACCCAGCGCCUGAUCAUCGGCGAGGUGACCCCCGCCACCCAG GGCAUGUACUACCUGGCCUGGGGCCGCAUGGACUCCCCCCACGAGUACGGCACCUGG GUGCGCGUGCGCAUGUUCCGCCCCCCCUCCCUGACCCUGCAGCCCCACGCCGUGAUG GAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCGCCUACUACCCCCGCAACCCCG UGGAGUUCGACUGGUUCGAGGACGACCGCCAGGUGUUCAACCCCGGCCAGAUCGACA CCCAGACCCACGAGCACCCCGACGGCUUCACCACCGUGUCCACCGUGACCUCCGAGGC CGUGGGCGGCCAGGUGCCCCCCCGCACCUUCACCUGCCAGAUGACCUGGCACCGCGA CUCCGUGACCUUCUCCCGCCGCAACGCCACCGGCCUGGCCCUGGUGCUGCCCCGCCCC ACCAUCACCAUGGAGUUCGGCGUGCGCCACGUGGUGUGCACCGCCGGCUGCGUGCCC GAGGGCGUGACCUUCGCCUGGUUCCUGGGCGACGACCCCUCCCCCGCCGCCAAGUCC GCCGUGACCGCCCAGGAGUCCUGCGACCACCCCGGCCUGGCCACCGUGCGCUCCACCC UGCCCAUCUCCUACGACUACUCCGAGUACAUCUGCCGCCUGACCGGCUACCCCGCCG GC AJCCCCGGGGGGGKGCKCCKCGKKCUAGUAGUGAGUGACUAGGAUCUGGUUAGCAC UAAACCAGCCUCAAGAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCAACUUACACU UACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUGCUCCUAA UAAAAAGAAAGUU UCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAC (SEQ ID NO: 42)

[0151] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 69). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0152] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-1 gC antigen or antigenic fragment thereof lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments, a sequence encoding a polypeptide comprising an HSV-1 gC antigenic fragment is as set forth in SEQ ID NO: 35.

[0153] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises amino acids 27-457 of gC from HSV-1 (e.g., KOS strain), as set forth in the following amino acid sequence:P-634738-PC ETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPASPPTTPKP TSTPKSPPTSTPDPKPKNNTTPAKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRM EFRLQIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYDSAPNLTDPHVLWAEGAGPGAD PPL YS VTGPLPTQRLIIGEVTPATQGMYYL AWGRMD SPHEYGTWVRVRMFRPP SLTLQPHA VMEGQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTSEA VGGQVPPRTFTCQMTWHRDSVTFSRRNATGLALVLPRPTITMEFGVRHVVCTAGCVPEGV TFAWFLGDDPSPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYICRLTGYPAGIPVLEHH(SEQ ID NO: 6).

[0154] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 6. In some embodiments, an HSV-1 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 6.

[0155] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 27-457 of gC from an HSV-1 strain.

[0156] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 25-457 of gC from HSV-1 (e.g., KOS strain), as set forth in the following amino acid sequence:GSETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPASPPTTP KPTSTPKSPPTSTPDPKPKNNTTPAKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNST RMEFRLQIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYDSAPNLTDPHVLWAEGAGPG ADPPLYSVTGPLPTQRLIIGEVTPATQGMYYLAWGRMDSPHEYGTWVRVRMFRPPSLTLQP HAVMEGQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTS EAVGGQVPPRTFTCQMTWHRDSVTFSRRNATGLALVLPRPTITMEFGVRHVVCTAGCVPE GVTFAWFLGDDPSPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYICRLTGYPAGIPVLE HH (SEQ ID NO: 7).

[0157] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to theP-634738-PC amino acid sequence SEQ ID NO: 7. In some embodiments, an HSV-1 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 7.

[0158] In some embodiments, an HSV-1 gC antigen or antigen fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises the following amino acid sequence:

[0159] MAPGRVGLAVVLWGLLWLGAGVAGGSETASTGPTITAGAVTNASEAPTSGSPGSA ASPEVTPTSTPNPNNVTQNKTTPTEPASPPTTPKPTSTPKSPPTSTPDPKPKNNTTPAKSGRPT KPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEFRLQIWRYSMGPSPPIAPAPDLEEVLTN ITAPPGGLLVYDSAPNLTDPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQGMYY LAWGRMD SPHEYGTWVRVRMFRPP SLTLQPHAVMEGQPFKATCT AAAYYPRNP VEFD WF EDDRQVFNPGQIDTQTHEHPDGFTTVSTVTSEAVGGQVPPRTFTCQMTWHRDSVTFSRRNA TGLALVLPRPTITMEFGVRHVVCTAGCVPEGVTFAWFLGDDPSPAAKSAVTAQESCDHPGL ATVRSTLPISYDYSEYICRLTGYPAGIPVLEHHGSHQPPPRDPTERQVIEAIEWVGIGIGVLAA GVLVVTAIVYVVRTSQSRQRHRR (SEQ ID NO: 8).

[0160] In some embodiments, an HSV-1 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 8. In some embodiments, an HSV-1 gC has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 8.

[0161] In another embodiment, the HSV-1 gC antigen or antigenic fragment thereof, encoded by RNA utilized in methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any of the following GenBank Accession Numbers: AAA45779.1, AAA96680.1, ABI63505.1, ABM52973.1, ABM52976.1, ABM52977.1, ACM62267.1, ADD60042.1, ADD60119.1, ADM22367.1, ADM22444.1, ADM22520.1, ADM22597.1, ADM22674.1, ADM22751.1, ADM22827.1, ADM22904.1, ADM22981.1, ADM23057.1, ADM23133.1, ADM23210.1, ADM23287.1, ADM23361.1, ADM23435.1, ADM23509.1, ADM23583.1, ADM23658.1, ADM23733.1, ADM23809.1, AEQ77075.1, AEQ77099.1, AER37628.1, AER37697.1, AER37767.1, AER37838.1, AER37910.1, AER37981.1, AER38051.2, AFA36179.1, AFA36180.1, AFA36181.1, AFA36182.1, AFA36183.1, AFA36184.1, AFA36185.1, AFA36186.1, AFA36187.1, AFA36188.1, AFA36189.1, AFA36190.1, AFA36191.1, AFA36192.1, AFA36193.1, AFA36194.1, AFA36195.1, AFA36196.1, AFA36197.1, AFA36198.1, AFA36199.1,P-634738-PC AFA36200.1, AFA36201.1, AFA36202.1, AFA36203.1, AFE62872.1, AFH78104.1, AFI23635.1, AFK50391.1, AFP86408.1, AGZ01906.1, AIR95840.1, AJE59989.1, AJE60060.1, AJE6013E1, AJE60202.1, AKE48623.1, AKE98415.1, AKE98416.1, AKE98417.1, AKE98418.1, AKE98419.1, AKE98420.1, AKE9842E1, AKE98422.1, AKE98423.1, AKE98424.1, AKE98425.1, AKE98426.1, AKE98427.1, AKE98428.1, AKE98429.1, AKE98430.1, AKE9843E1, AKE98432.1, AKE98433.1, AKE98434.1, AKE98435.1, AKG59227.1, AKG59299.1, AKG59372.1, AKG59444.1, AKG59516.1, AKG5959E1, AKG59663.1, AKG59736.1, AKG59807.1, AKG59879.1, AKG59953.1, AKG60027.1, AKG60099.1, AKG60170.1, AKG60243.1, AKG60316.1, AKG60386.1, AKG60456.1, AKG60528.1, AKG6060E1, AKG60674.1, AKG60745.1, AKG60817.1, AKG60887.1, AKG60959.1, AKG61032.1, AKG61104.1, AKG61175.1, AKG61248.1, AKG6132E1, AKG61392.1, AKG61464.1, AKG61537.1, AKG6161E1, AKG61684.1, AKG61756.1, AKG61828.1, AKG61902.1, AKG61974.1, AKH80444.1, AKH80517.1, AKM76368.1, ALM22613.1, ALM22687.1, ALM2276E1, ALM22835.1, ALO1864E1, ALO18717.1, AMB65642.1, AMB65715.1, AMB65862.1, AMN09813.1, ANN83942.1, ANN84019.1, ANN84095.1, ANN84172.1, ANN84249.1, ANN84326.1, ANN84403.1, ANN84478.1, ANN84555.1, ANN84632.1, ANN84708.1, ANN84785.1, ANN8486E1, ANN84938.1, ANN85014.1, ANN8509E1, ANN85167.1, ANN85242.1, ANN85319.1, ANN85396.1, ANN85472.1, ANN85549.1, ANN85626.1, ANN85703.1, ANN85779.1, AOY34308.1, AOY36663.1, AOY36687.1, ARB08935.1, ARO38059.1, AR038060.1, ARO3806E1, ARO38062.1, ARO38063.1, ARO38064.1, ARO38065.1, ARO38066.1, ASM47642.1, ASM47719.1, ASM47796.1, ASM4787E1, BAM73394.1, CAA32294.1, CAB40083.1, CAD13356.1, CAD13357.1, CAD13358.1, CAD13359.1, CAD13360.1, CAD1336E1, CAD13362.1, CAD13363.1, CAD13364.1, CAD13365.1, CAD13366.1, CAD13367.1, CAD13368.1, CAD13369.1, CAD13370.1, CAD1337E1, CAD13372.1, CAD13373.1, CAD13374.1, CAD13375.1, CAD13376.1, CAD13377.1, CAD13378.1, P04290.1, P04488.1, P09855.1, P10228.1, P28986.1, SBO07729.1, SBO07793.1, SBO07798.1, SBO07812.1, SB007880.1, SBS69375.1, SBS69379.1, SBS69440.1, SBS69448.1, SBS69560.1, SBS69599.1, SBS69602.1, SBS69637.1, SBS69790.1, SBT69374.1, SCL76887.1, YP 009137119.1, or YP 009137143. EP-634738-PC HSV-2 gC

[0162] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-2 glycoprotein C (gC) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-2 gC antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-2 gC. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.

[0163] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-2 gC antigen or antigenic fragment thereof comprises:GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGCUGCUGCUGA UCGCCCUGUCCCUGGCCCUGGUGACCAACUCCGCCUCCCCCGGCCGCACCAUCACC GUGGGCCCCCGCGGCAACGCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACGCCU CCGCCCCCCGCACCACCCCCACCCCCCCCCAGCCCCGCAAGGCCACCAAGUCCAAGGC CUCCACCGCCAAGCCCGCCCCCCCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCGAG CCCGUGCGCUGCAACCGCCACGACCCCCUGGCCCGCUACGGCUCCCGCGUGCAGAUCC GCUGCCGCUUCCCCAACUCCACCCGCACCGAGUUCCGCCUGCAGAUCUGGCGCUACG CCACCGCCACCGACGCCGAGAUCGGCACCGCCCCCUCCCUGGAGGAGGUGAUGGUGA ACGUGUCCGCCCCCCCCGGCGGCCAGCUGGUGUACGACUCCGCCCCCAACCGCACCGA CCCCCACGUGAUCUGGGCCGAGGGCGCCGGCCCCGGCGCCUCCCCCCGCCUGUACUCC GUGGUGGGCCCCCUGGGCCGCCAGCGCCUGAUCAUCGAGGAGCUGACCCUGGAGACC CAGGGCAUGUACUACUGGGUGUGGGGCCGCACCGACCGCCCCUCCGCCUACGGCACC UGGGUGCGCGUGCGCGUGUUCCGCCCCCCCUCCCUGACCAUCCACCCCCACGCCGUGC UGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCACCUACUACCCCGGCAACC GCGCCGAGUUCGUGUGGUUCGAGGACGGCCGCCGCGUGUUCGACCCCGCCCAGAUCC ACACCCAGACCCAGGAGAACCCCGACGGCUUCUCCACCGUGUCCACCGUGACCUCCG CCGCCGUGGGCGGCCAGGGCCCCCCCCGCACCUUCACCUGCCAGCUGACCUGGCACCG CGACUCCGUGUCCUUCUCCCGCCGCAACGCCUCCGGCACCGCCUCCGUGCUGCCCCGC CCCACCAUCACCAUGGAGUUCACCGGCGACCACGCCGUGUGCACCGCCGGCUGCGUG CCCGAGGGCGUGACCUUCGCCUGGUUCCUGGGCGACGACUCCUCCCCCGCCGAGAAG GUGGCCGUGGCCUCCCAGACCUCCUGCGGCCGCCCCGGCACCGCCACCAUCCGCUCCAP-634738-PC CCCUGCCCGUGUCCUACGAGCAGACCGAGUACAUCUGCCGCCUGGCCGGCUACCCCG ACGGCAGCCCCGUGCUGGAGCACCACGAACUAGUAGUGACUGACUAGGAUCUGGUUAC CACUAAACCAGCCUCAAGAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCAACUUACA CUUACAAAA UGUUGUCCCCCAAAA UGUAGCCAUUCGUA UCUGCUCCUAA UAAAAAGAAAG UUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAC (SEQ ID NO: 43).

[0164] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 70). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0165] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-2 gC antigen or antigenic fragment thereof lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments, a sequence of the HSV-2 gC antigenic fragment is as set forth in SEQ ID NO: 36.

[0166] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises amino acids 27-426 of gC from HSV-2 (e g., strain 333 or UL44), as set forth in the following amino acid sequence:ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKT SSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNV SAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMYY WVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFE DGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNAS GTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTA TIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 9)

[0167] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 9. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 9.P-634738-PC

[0168] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises the following amino acid sequence:ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKT SSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNV SAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMYY W VWGRTDRP S AYGT WVRVRVFRPP SLTIHPH AVLEGQPFK ATCT AAT YYPGNRAEF VWFE DGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNAS GTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTA TIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 10).

[0169] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 10. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 10.

[0170] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 28-426 of gC from HSV-2 (e.g., strain 333 or UL44), as set forth in the following amino acid sequence:SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTS SEPVRCNRHDPLARYGSRVQIRCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVS APPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMYYW VWGRTDRP S A YGT WVRVRVFRPP SLTIHPHAVLEGQPFK ATCT AAT YYPGNRAEF VWFED GRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASG TASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTAT IRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 11).

[0171] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 11. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 11.

[0172] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises the following amino acid sequence:P-634738-PC SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTS SEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVS APPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMYYW VWGRTDRP S AYGTWVRVRVFRPP SLTIHPHAVLEGQPFK ATCT AAT YYPGNRAEF VWFED GRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASG TASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTAT IRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 12).

[0173] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 12. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 12.

[0174] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 26-426 of gC from HSV-2 (e.g., strain 333 or UL44), as set forth in the following amino acid sequence:SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPK TSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVN VSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMY YW VWGRTDRP S AYGTWVRVRVFRPP SLTIHPHAVLEGQPFK ATCT AAT YYPGNRAEF VWF EDGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNA SGTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGT ATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 13).

[0175] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 13. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 13.

[0176] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises the following amino acid sequence:SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPK TSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNP-634738-PC VSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMY YW VWGRTDRP S AYGTWVRVRVFRPP SLTIHPHAVLEGQPFKATCT AAT YYPGNRAEF VWF EDGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNA SGTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGT ATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 14).

[0177] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 14. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 14.

[0178] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises the following amino acid sequence:MALGRVGLAVGLWGLLWVGVVVVLANASPGRTITVGPRGNASNAAPSASPRNASAPRTTP TPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEF RLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASP RLYSVVGPLGRQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAV LEGQPFKATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVG GQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFA WFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHHGSH QPPPRDPTERQVIRAVEGAGIGVAVLVAVVLAGTAVVYLTHASSVRYRRLR (SEQ ID NO: 15).

[0179] In some embodiments, an HSV-2 gC antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 15. In some embodiments, an HSV-2 gC antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 15.

[0180] In another embodiment, an HSV-2 gC or an antigenic fragment thereof, encoded by RNA utilized in methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any of the following GenBank Accession Numbers: AAA20532.1, AAA66442.1, AAB60549.1, AAB60550.1, AAB60551.1, AAB72101.1, ABU45429.1, ABU45430.1,P-634738-PC ABU45431.1, ABU45432.1, ABU45459.1, ABU45460.1, AEV91348.1, AEV91383.1, AEV91407.1, AFM93864.1, AHG54708.1, AKC42808.1, AKC59285.1, AKC59357.1, AKC59428.1, AKC59499.1, AKC59570.1, AMB66008.1, AMB66079.1, AMB66151.1, AMB66224.1, AMB66252.1, AMB66253.1, AMB66368.1, AMB66441.1, AQZ55735.2, AQZ55806.1, AQZ55877.1, AQZ55948.1, AQZ56019.1, AQZ56090.1, AQZ56161.2, AQZ56232.2, AQZ56303.2, AQZ56374.2, AQZ56445.1, AQZ56516.1, AQZ56587.1, AQZ56658.1, AQZ56729.2, AQZ56800.1, AQZ56871.1, AQZ56942.2, AQZ57013.1, AQZ57084.2, AQZ57155.1, AQZ57226.1, AQZ57297.1, AQZ57368.1, AQZ57439.1, AQZ57510.1, AQZ57581.1, AQZ57652.1, AQZ57723.1, AQZ57794.2, AQZ57865.2, AQZ57936.1, AQZ58007.2, AQZ58078.1, AQZ58149.2, AQZ58220.1, AQZ58291.1, AQZ58362.1, AQZ58433.1, AQZ58504.1, AQZ58575.1, AQZ58646.1, AQZ58717.2, AQZ58788.2, AQZ58859.2, AQZ58930.1, AQZ59001.2, AQZ59072.1, AQZ59143.1, ARO38067.1, ARO38068.1, ARO38069.1, AR038070.1, ARO38071.1, ARO38072.1, CAA25687.1, CAA26025.1, CAB06730.1, CAB06734.1, CAB96544.1, P03173.1, P06475.1, P89475.1, Q89730.1, YP 009137161.1, YP 009137196.1, or YP_009137220.1.

[0181] In some embodiments, a polypeptide encoded by RNA utilized in methods and compositions of the present disclosure comprises a properdin interfering domain. “Properdin-interfering domain” refers, in some embodiments, to a domain that blocks or inhibits binding of a host C3b molecule with a host properdin molecule. In some embodiments, a properdin interfering domain blocks or inhibits an interaction of a host C3b molecule with a host properdin molecule.

[0182] In some embodiments, a polypeptide encoded by RNA utilized in methods and compositions of the present disclosure comprises a C5 interfering domain or a portion thereof. In some embodiments, a polypeptide provided by the present disclosure comprises a portion of a C5 interfering domain. “C5-interf ering domain” refers, in some embodiments, to a domain that interferes with binding of a host C3b molecule with a host C5 molecule. In some embodiments, a C5 interfering domain interferes with the interaction of a host C3b molecule with a host C5 molecule.

[0183] Each RNA encoding HSV-1 gC or HSV-2 gC antigen or antigenic fragment thereof represents a separate embodiment of the present disclosure.

[0184] In some embodiments, a gC antigen or antigenic fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure is an antigenic fragment. In some embodiments, a gC immunoprotective antigen need not be the entire protein (e.g., glycoprotein). In some embodiments, a protective immune response is or comprises an antibody response. In someP-634738-PC embodiments, mutants, sequence conservative variants, and / or functional conservative variants of gC (e.g., HSV-1 gC, or HSV-2 gC, or both) are useful in methods and compositions of the present disclosure, provided that all such variants retain the required immuno-protective effect. In some embodiments, an antigenic fragment can comprise an immuno-protective gC antigen from a HSV strain. In some embodiments, an antigenic fragment comprises sequence variants of HSV (e.g., as found in infected individuals).Glycoprotein D

[0185] In some embodiments, the present disclosure provides an RNA encoding a polypeptide comprising an HSV glycoprotein D (gD) antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, the present disclosure provides a composition comprising an RNA encoding a polypeptide comprising an HSV gD antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof (e.g., ectodomain) comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, an RNA encoding a polypeptide comprising an HSV-2 gD ectodomain comprises a nucleic acid sequence of SEQ ID NO: 39. In some embodiments, a ribonucleotide sequence encodes a polypeptide comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82.

[0186] In some embodiments, a polyribonucleotide (e g., a polyribonucleotide encoding a polypeptide comprising an HSV glycoprotein D (gD) antigen or an antigenic fragment thereof) is an isolated polyribonucleotide.HSV-1 gD

[0187] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-1 glycoprotein D (gD) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-1 gD antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-1 gD. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.

[0188] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-1 gD fragment comprises:GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGCUGCUGCUGAP-634738-PC UCGCCCUGUCCCUGGCCCUGGUGACCAACUCCAAGUACGCCCUGGCCGACGCCUCC CUGAAGAUGGCCGACCCCAACCGCUUCCGCGGCAAGGACCUGCCCGUGCUGGACCAG CUGACCGACCCCCCCGGCGUGCGCCGCGUGUACCACAUCCAGGCCGGCCUGCCCGACC CCUUCCAGCCCCCCUCCCUGCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCGCCUG CCGCUCCGUGCUGCUGAACGCCCCCUCCGAGGCCCCCCAGAUCGUGCGCGGCGCCUCC GAGGACGUGCGCAAGCAGCCCUACAACCUGACCAUCGCCUGGUUCCGCAUGGGCGGC AACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAGUGCUCCUACAACAAGUCC CUGGGCGCCUGCCCCAUCCGCACCCAGCCCCGCUGGAACUACUACGACUCCUUCUCCG CCGUGUCCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCCGCCUUCGAGACCGCCG GCACCUACCUGCGCCUGGUGAAGAUCAACGACUGGACCGAGAUCACCCAGUUCAUCC UGGAGCACCGCGCCAAGGGCUCCUGCAAGUACGCCCUGCCCCUGCGCAUCCCCCCCUC CGCCUGCCUGUCCCCCCAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGCAU GCUGCCCCGCUUCAUCCCCGAGAACCAGCGCACCGUGGCCGUGUACUCCCUGAAGAU CGCCGGCUGGCACGGCCCCAAGGCCCCCUACACCUCCACCCUGCUGCCCCCCGAGCUG UCCGAGACCCCCAACGCCACCCAGCCCGAGCUGGCCCCCGAGGACCCCGAGGACUCCG CCCUGCUGGAGGACCCCGUGGGCACCGUGGCCCCCCAGAUCCCCCCCAACUGGCACA GCCCCGCCMJCCKGGKCGCCGCCKCCCCGG CGKKCUAGUAGUGACUGACUAGGAUCU GGUUACCACUAAACCAGCCUCAAGAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCA ACUUACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUGCUCCUAA UAAA AAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAC (SEQ ID NO: 44)

[0189] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 70). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0190] In some embodiments, a nucleotide sequence encoding a polypeptide comprises an HSV-1 gD antigen or antigenic fragment thereof lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments,P-634738-PC a polynucleotide sequence encoding a polypeptide comprising an HSV-1 gD fragment is as set forth in SEQ ID NO: 38.

[0191] In some embodiments, an HSV-1 gD antigen or antigenic fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 26-331 of gD (e.g., from HSV-1 Patton strain), as set forth in the following amino acid sequence:KYALADASLKMADPNRFRGKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPITVYYAV LERACRSVLLNAPSEAPQIVRGASEDVRKQPYNLTIAWFRMGGNCAIPITVMEYTECSYNKS LGACPIRTQPRWNYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRA KGSCKYALPLRIPP S ACL SPQ AYQQGVTVD SIGMLPRFIPENQRT VA VYSLKIAGWHGPK AP YTSTLLPPELSETPNATQPELAPEDPEDSALLEDPVGTVAPQIPPNWHIPSIQDAATPY (SEQ ID NO: 16)

[0192] In some embodiments, an HSV-1 gD antigen or antigen fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 16. In some embodiments, an HSV-1 gD antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 16.

[0193] In some embodiments, an HSV-1 gD antigen or antigen fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure comprises the following amino acid sequence:MGGAAARLGAVILFVVIVGLHGVRGKYALADASLKLADPNRFRRKDLPVLDQLTDPPGVR RVYHIQAGLPDPFQPPSLPITVYYAVLERACRSVLLNAPSEAPQIVRGASEDVRKQPYNLTIA WFRMGGNCAIPITVMEYTECSYNKSLGACPIRTQPRWNYYDSFSAVSEDNLGFLMHAPAFE TAGTYLRLVKINDWTEITQFILEHRAKGSCKYALPLRIPPSACLSPQAYQQGVTVDSIGMLP RFIPENQRTVAVYSLKIAGWHGPKAPYTSTLLPPELSETPNATQPELAPEAPEDSALLEDPVG TVAPQIPPNWHIPSIQDAATPYHPPATPNNMGLIAGAVGGSLLAALVICGIVYWMRRRTQK APKRIRLPHIREDDQPSSHQPLFY (SEQ ID NO: 17)

[0194] In some embodiments, an HSV-1 gD antigen or antigen fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 17. In some embodiments, an HSV-1 gD antigen fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 17.P-634738-PC

[0195] In another embodiment, an HSV-1 gD antigen or antigenic fragment thereof, encoded by RNA utilized in methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any one of the following GenBank Accession Numbers: AAL90884.1 (KHS2 strain), AAL90883.1 (KHS1 strain), AAK93950.1 (F strain), AAB59754.1 (F strain), AAA19631.1 (mutant strain not identified), AAAI 9630.1 (mutant strain not identified), or AAA19629.1 (strain not identified).

[0196] In another embodiment, an HSV-1 gD antigen or antigenic fragment thereof, encoded by RNA utilized in methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any of the following GenBank Accession Numbers: A1Z0Q5.2, AAA45780.1, AAA45785.1, AAA45786.1, AAA96682.1, AAK19597.1, AAN74642.1, AB 163524.1, ABM52978.1, ABM52979.1, ABM52980.1, ABM52981.1, ABM66847.1, ABM66848.1, ACM62295.1, ADD60053.1, ADD60130.1, ADM22389.1, ADM22466.1, ADM22542.1, ADM22619.1, ADM22696.1, ADM22773.1, ADM22849.1, ADM22926.1, ADM23003.1, ADM23079.1, ADM23155.1, ADM23231.1, ADM23309.1, ADM23383.1, ADM23457.1, ADM23531.1, ADM23605.1, ADM23680.1, ADM23755.1, ADM23831.1, AEQ77097.1, AER37647.1, AER37715.1, AER37786.1, AER37857.1, AER37929.1, AER38000.1, AER38070.1, AFE62894.1, AFH41180.1, AFI23657.1, AFK50415.1, AFP86430.1, AGZ01928.1, AIR95858.1, AJE60009.1, AJE60080.1, AJE6015E1, AJE60222.1, AJE60293.1, AJE60439.1, AKE48645.1, AKG59246.1, AKG59318.1, AKG59391.1, AKG59462.1, AKG59536.1, AKG59609.1 AKG59682.1, AKG59755.1, AKG59826.1, AKG59898.1, AKG59972.1, AKG60046.1 AKG60118.1, AKG60189.1, AKG60261.1, AKG60334.1, AKG60404.1, AKG60474.1 AKG60546.1, AKG60620.1, AKG60692.1, AKG60763.1, AKG60835.1, AKG60906.1 AKG60978.1, AKG61050.1, AKG61123.1, AKG61194.1, AKG61267.1, AKG61339.1 AKG61411.1, AKG61484.1, AKG61556.1, AKG61629.1, AKG61703.1, AKG61774.1 AKG61847.1, AKG61920.1, AKG61993.1, AKH80463.1, AKH80536.1, ALM22635.1 ALM22709.1, ALM22783.1, ALM22857.1, ALO 18662.1, ALO18738.1, AMB65662.1 AMB65735.1, AMB65809.1, AMB65885.1, AMB65956.1, AMN09832.1, ANN83964.1 ANN84041.1, ANN84117.1, ANN84194.1, ANN84271.1, ANN84348.1, ANN84424.1 ANN84500.1, ANN84577.1, ANN84653.1, ANN84730.1, ANN84806.1, ANN84883.1 ANN84959.1, ANN85036.1, ANN85112.1, ANN85187.1, ANN85264.1, ANN85341.1 ANN85416.1, ANN85494.1, ANN85571.1, ANN85648.1, ANN85724.1, ANN85801.1P-634738-PC AOY34093.1, AOY34141.1, AOY34243.1, AOY34271.1, AOY34337.1, AOY36685.1, ARB08957.1, ARO37961.1, ARO37962.1, ARO37963.1, ARO37964.1, ARO37965.1, ARO37966.1, ARO37967.1, ARO37968.1, AR037969.1, AR037970.1, ARO37971.1, ARO37972.1 ARO37973.1, ARO37974.1, ARO37975.1, ARO37976.1, ARO37977.1, ARO37978.1 ARO37979.1, ARO37980.1, ARO37981.1, ARO37982.1, ARO37983.1, ARO37984.1 ARO37985.1, ARO37986.1, ARO37987.1, ARO37988.1, ARO37989.1, ARO37990.1 ARO37991.1, ARO37992.1, ARO37993.1, ARO37994.1, ARO37995.1, ARO37996.1 ARO37997.1, ARO37998.1, ARO37999.1, ASM47664.1, ASM47741.1, ASM47818.1 ASM47893.1, BAM73419.1, CAA26060.1, CAA32283.1, CAA32284.1, CAA32289.1 CAA38245.1, CAT05431.1, P06476.1, P36318.1, P57083.1, P68331.1, Q05059.1, Q69091.1, SBO07792.1, SBO07819.1, SBO07855.1, SBO07869.1, SBO07887.1, SB007908.1, SBS69553.1, SBS69561.1, SBS69579.1, SBS69625.1, SBS69688.1, SBS69694.1, SBS69717.1, SBS69727.1, SBS69811.1, SBT69395.1, SCL76902.1, VGBEDZ, or YP 009137141.1.HSV-2 gD

[0197] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-2 glycoprotein D (gD) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-2 gD antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-2 gD. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.

[0198] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-2 gD antigen or antigenic fragment thereof comprises:GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGGGCCGCCUGACCUCCGGCGUGG GCACCGCCGCCCUGCUGGUGGUGGCCGUGGGCCUGCGCGUGGUGUGCGCCAGUA CGCCCUGGCCGACCCCUCCCUGAAGAUGGCCGACCCCAACCGCUUCCGCGGCAAGAA CCUGCCCGUGCUGGACCAGCUGACCGACCCCCCCGGCGUGAAGCGCGUGUACCACAU CCAGCCCUCCCUGGAGGACCCCUUCCAGCCCCCCUCCAUCCCCAUCACCGUGUACUAC GCCGUGCUGGAGCGCGCCUGCCGCUCCGUGCUGCUGCACGCCCCCUCCGAGGCCCCCC AGAUCGUGCGCGGCGCCUCCGACGAGGCCCGCAAGCACACCUACAACCUGACCAUCG CCUGGUACCGCAUGGGCGACAACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGP-634738-PC AGUGCCCCUACAACAAGUCCCUGGGCGUGUGCCCCAUCCGCACCCAGCCCCGCUGGU CCUACUACGACUCCUUCUCCGCCGUGUCCGAGGACAACCUGGGCUUCCUGAUGCACG CCCCCGCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGAUCAACGACUGGA CCGAGAUCACCCAGUUCAUCCUGGAGCACCGCGCCCGCGCCUCCUGCAAGUACGCCC UGCCCCUGCGCAUCCCCCCCGCCGCCUGCCUGACCUCCAAGGCCUACCAGCAGGGCGU GACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUCCCCGAGAACCAGCGCACCGU GGCCCUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGCCCCCCUACACCUCC ACCCUGCUGCCCCCCGAGCUGUCCGACACCACCAACGCCACCCAGCCCGAGCUGGUGC CCGAGGACCCCGAGGACUCCGCCCUGCUGGAGGACCCCGCCGGCACCGUGUCCUCCC AGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGUGGCCCCCCACCACUAAC7 / AGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAG UCUCUAAGCUACA UAA UACCAACUUACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUGCUCCUAA UAAAAAGAAAGUUUCUUCACA UUCUAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAC (SEQ ID NO: 45)

[0199] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 71). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0200] In some embodiments, a nucleotide sequence encoding a polypeptide comprising an HSV-2 gD antigen or antigenic fragment thereof lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments, a sequence encoding a polypeptide comprising an HSV-2 gD antigenic fragment is as set forth in SEQ ID NO: 39.

[0201] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises amino acids 26-331 of gD (e.g., from HSV-2 strain 333 or US6), as set forth in the following amino acid sequence:KYALADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVL ERACRSVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKS LGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRAP-634738-PC RASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPP YTSTLLPPELSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 18).

[0202] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 18. In some embodiments, an HSV-2 gD antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 18.

[0203] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises amino acids 30-331 of gD from HSV-2(e.g., strain 333 or US6), as set forth in the following amino acid sequence:ADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVLERAC RSVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVC PIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRARASC KYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTST LLPPELSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 19).

[0204] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 19. In some embodiments, an HSV-2 gD antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 19.

[0205] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises amino acids 31-331 of gD from HSV-2 (e g., strain 333 or US6), as set forth in the following amino acid sequence:DP SLKMADPNRFRGKNLP VLDQLTDPPGVKRVYHIQP SLEDPFQPP SIPIT VYYAVLERACR SVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPI RTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRARASCK YALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTL LPPELSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 20).P-634738-PC

[0206] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 20. In some embodiments, an HSV-2 gD antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 20.

[0207] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof encoded by RNA utilized in methods and compositions of the present disclosure comprises the following amino acid sequence:MGRLTSGVGTAALLVVAVGLRVVCAKYALADPSLKMADPNRFRGKNLPVLDQLTDPPGV KRVYHIQPSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEARKHTYNLTI AWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAF ETAGTYLRLVKINDWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGML PRFIPENQRT V ALYSLKIAGWHGPKPP YT STLLPPEL SDTTNATQPEL VPEDPED S ALLEDP A GTVSSQIPPNWHIPSIQDVAPHHAPAAPSNPGLIIGALAGSTLAVLVIGGIAFWVRRRAQMAP KRLRLPHIRDDDAPPSHQPLFY (SEQ ID NO: 21).

[0208] In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 21. In some embodiments, an HSV-2 gD antigenic fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 21. In some embodiments, an HSV-2 gD antigen or antigenic fragment thereof, encoded by RNA utilized in methods and compositions of the present disclosure comprises the amino acid sequences as set forth in GenBank Accession Numbers: 1003204A, AAA45841.1, AAA45842.1, AAB60552.1, AAB60553.1, AAB60554.1, AAB60555.1, AAB72102.1, AAS01730.1, AAW23130.1, AAW23131.1, AAW23132.1, AAW23133.1, AAW23134.1, ABS84899.1, ABU45433.1, ABU45434.1, ABU45435.1, ABU45461.1, ABU45462.1, ACA28831.1, AEV91405.1, AFM93876.1, AFS18198.1, AFS18199.1, AFS18200.1, AFS18201.1, AFS18202.1, AFS18203.1, AFS18204.1, AFS18205.1, AFS18206.1, AFS18207.1, AFS18208.1, AFS18209.1, AFS18210.1, AFS18211.1, AFS18212.1, AFS18213.1, AFS18214.1, AFS18215.1, AFS18216.1, AFS18217.1, AFS18218.1, AFS18219.1, AFS18220.1, AFS18221.1, AHG54730.1, AIL27720.1, AIL27721.1, AIL27722.1, AIL27723.1, AIL27724.1, AIL27725.1, AIL27726.1, AIL27727.1, AIL27728.1,P-634738-PC AIL27729.1, AIL27730.1, AIL27731.1, AIL28069.1, AIL28070.1, AKC42828.1, AKC59305.1, AKC59376.1, AKC59447.1, AKC59518.1, AKC59589.1, AMB66102.1, AMB66171.1, AMB66244.1, AMB66321.1, AMB66394.1, AMB66463.1, AQZ55754.1, AQZ55825.1, AQZ55896.1, AQZ55967.1, AQZ56038.1, AQZ56109.1, AQZ56180.1, AQZ56251.1, AQZ56322.1, AQZ56393.1, AQZ56464.1, AQZ56535.1, AQZ56606.1, AQZ56677.1, AQZ56748.1, AQZ56819.1, AQZ56890.1, AQZ56961.1, AQZ57032.1, AQZ57103.1, AQZ57174.1, AQZ57245.1, AQZ57316.1, AQZ57387.1, AQZ57458.1, AQZ57529.1, AQZ57600.1, AQZ57671.1, AQZ57742.1, AQZ57813.1, AQZ57884.1, AQZ57955.1, AQZ58026.1, AQZ58097.1, AQZ58168.1, AQZ58239.1, AQZ58310.1, AQZ58381.1, AQZ58452.1, AQZ58523.1, AQZ58594.1, AQZ58665.1, AQZ58736.1, AQZ58807.1, AQZ58878.1, AQZ58949.1, AQZ59020.1, AQZ59091.1, AQZ59162.1, AR038000.1, AR038001.1, AR038002.1, ARO38003.1, ARO38004.1, ARO38005.1, ARO38006.1, ARO38007.1 AR038008.1, ARO38009.1, AR038010.1, ARO38011.1, ARO38012.1, ARO38013.1 ARO38014.1, ARO38015.1, ARO38016.1, ARO38017.1, ARO38018.1, ARO38019.1 ARO38020.1, ARO38021.1, ARO38022.1, ARO38023.1, ARO38024.1, ARO38025.1 ARO38026.1, ARO38027.1, ARO38028.1, ARO38029.1, AR038030.1, ARO38031.1 ARO38032.1, ARO38033.1, ARO38034.1, ARO38035.1, ARO38036.1, ARO38037.1 ARO38038.1, ARO38039.1, ARO38040.1, ARO38041.1, ARO38042.1, ARO38043.1 ARO38044.1, CAA26025.1, CAB06713.1, CAC33573.1, CAT05432.1, P03172.2, Q69467.1, or YP 009137218.1.

[0209] In some embodiments, a gD antigen or fragment (e.g., antigenic fragment) includes Y63 with reference to SEQ ID NO: 21. In another embodiment, a gD antigen or fragment (e.g., antigenic fragment) includes R159 with reference to SEQ ID NO: 21. In another embodiment, a gD antigen or fragment (e.g., antigenic fragment) includes D240 with reference to SEQ ID NO: 21. In another embodiment, a gD antigen or fragment (e.g., antigenic fragment) includes P246 with reference to SEQ ID NO: 21. In another embodiment, a gD antigen or fragment (e.g., antigenic fragment) includes a residue selected from Y63, R159, D240, P246, or a combination thereof with reference to SEQ ID NO: 21. In another embodiment, inclusion of one of these residues elicits antibodies that inhibit binding to nectin-1.

[0210] The nomenclature used herein for gD amino acid residues includes the residues of the signal peptide encoded by the signal sequence. Thus, residue one of the mature protein is referred to as “26.”P-634738-PC

[0211] Each RNA encoding HSV-1 gD and HSV-2 gD protein or fragment thereof represents a separate embodiment of the present disclosure.

[0212] In another embodiment, the HSV gD, gC, and gE proteins, and fragments thereof, encoded by the modified RNA as disclosed herein are described in US Patent Publication No. 2013-0028925-Al, which is incorporated by reference herein in its entirety.

[0213] In another embodiment, a gD antigen or fragment thereof encoded by RNA utilized in the methods and compositions of the present disclosure is an antigenic fragment. In another embodiment, a gD immunoprotective antigen need not be the entire protein. The protective immune response generally involves, in another embodiment, an antibody response. In another embodiment, mutants, sequence conservative variants, and functional conservative variants of gD are useful in methods and compositions of the present disclosure, provided that all such variants retain the required immunoprotective effect. In another embodiment, the antigenic fragment can comprise an immuno-protective gD antigen from any strain of HSV. In another embodiment, the antigenic fragment can comprise sequence variants of HSV, as found in infected individuals.

[0214] In some embodiments, an RNA of the present disclosure encodes an HSV polypeptide, or fragment thereof, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 1.

[0215] In some embodiments, methods of the present disclosure comprise administering to a subject an HSV polypeptide, or fragment thereof, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 1.Glycoprotein E

[0216] In some embodiments, the present disclosure provides an RNA encoding a polypeptide comprising an HSV glycoprotein E (gE) antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, the present disclosure provides a composition comprising an RNA encoding a polypeptide comprising an HSV gE antigen or an antigenic fragment thereof (e.g., an ectodomain). In some embodiments, an HSV-2 gE antigen or antigenic fragment thereof (e.g., ectodomain) comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, an RNA encoding a polypeptide comprising anP-634738-PC HSV-2 gE antigen or antigenic fragment thereof (e.g., ectodomain) comprises a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 34.

[0217] In some embodiments, the present disclosure provides a composition comprising a combination as described herein. In some embodiments, a combination comprises RNA encoding HSV glycoprotein antigens or antigenic fragments thereof at the doses provided herein. In some embodiments, doses comprise 1, 3, 5, 30, 50, or 60 pg per administration.

[0218] In some embodiments, a polyribonucleotide (e g., a polyribonucleotide encoding a polypeptide comprising an HSV glycoprotein E (gE) antigen or an antigenic fragment thereof) is an isolated polyribonucleotide.HSV-1 gE

[0219] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-1 glycoprotein E (gE) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-1 gE antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-1 gE. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.

[0220] In some embodiments, a nucleotide sequence of the RNA encoding an HSV-1 gE fragment comprises:GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGCUGCUGCUGA UCGCCCUGUCCCUGGCCCUGGUGACCAACUCCAAGACCUCCUGGCGCCGCGUGUCC GUGGGCGAGGACGUGUCCCUGCUGCCCGCCCCCGGCCCCACCGGCCGCGGCCCCACCC AGAAGCUGCUGUGGGCCGUGGAGCCCCUGGACGGCUGCGGCCCCCUGCACCCCUCCU GGGUGUCCCUGAUGCCCCCCAAGCAGGUGCCCGAGACCGUGGUGGACGCCGCCUGCA UGCGCGCCCCCGUGCCCCUGGCCAUGGCCUACGCCCCCCCCGCCCCCUCCGCCACCGG CGGCCUGCGCACCGACUUCGUGUGGCAGGAGCGCGCCGCCGUGGUGAACCGCUCCCU GGUGAUCUACGGCGUGCGCGAGACCGACUCCGGCCUGUACACCCUGUCCGUGGGCGA CAUCAAGGACCCCGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGCAGCCCGCCCC CGUGCCCACCCCCCCCCCCACCCCCGCCGACUACGACGAGGACGACAACGACGAGGGC GAGGGCGAGGACGAGUCCCUGGCCGGCACCCCCGCCUCCGGCACCCCCCGCCUGCCCC CCUCCCCCGCCCCCCCCCGCUCCUGGCCCUCCGCCCCCGAGGUGUCCCACGUGCGCGGP-634738-PC CGUGACCGUGCGCAUGGAGACCCCCGAGGCCAUCCUGUUCUCCCCCGGCGAGGCCUU CUCCACCAACGUGUCCAUCCACGCCAUCGCCCACGACGACCAGACCUACACCAUGGA CGUGGUGUGGCUGCGCUUCGACGUGCCCACCUCCUGCGCCGAGAUGCGCAUCUACGA GUCCUGCCUGUACCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGC GCCGCCUCCACCUGGACCUCCCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCA CCAACCCCCCCCCCCGCUGCUCCGCCGAGGCCCACAUGGAGCCCUUCCCCGGCCUGGC CUGGCAGGCCGCCUCCGUGAACCUGGAGUUCCGCGACGCCUCCCCCCAGCACUCCGG CCUGUACCUGUGCGUGGUGUACGUGAACGACCACAUCCACGCCUGGGGCCACAUCAC CAUCAACACCGCCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCCCCUGCCCCAGCG CGGCGCCGACCUGGCCGAGCCCACCCACCCCCACGUGGGCGCCUAACt7 / lGt4Gt7GAC{7 GACUAGGA UCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAA UGGAGUCUCUAAGCU ACA UAAUACCAACUUACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUG CUCCUAA UAAAAAGAAAGUUUCUUCACA UUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAC (SEQ ID NO: 40).

[0221] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 70). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0222] In another embodiment, a nucleotide sequence of the RNA encoding an HSV-1 gE fragment lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments, the sequence of the HSV-1 gE fragment is as set forth in SEQ ID NO: 33.

[0223] In some embodiments, an HSV-1 gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 24-409 of gE from HSV-1 (e.g., NS strain), as set forth in the following amino acid sequence:KTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVPETV VDAACMRAPVPLAMAYAPPAPSATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGLYTLS VGDIKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGEGEDESLAGTPASGTPRLPPS PAPPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHAIAHDDQTYTMDVVWLRFP-634738-PC DVPTSCAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAGCSRTNPPPRCSAEA HMEPFPGLAWQAASVNLEFRDASPQHSGLYLCVVYVNDHIHAWGHITINTAAQYRNAVVE QPLPQRGADLAEPTHPHVGA (SEQ ID NO: 1).

[0224] In some embodiments, an HSV-1 gE fragment comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 1. In some embodiments, an HSV-1 gE fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 1.

[0225] In some embodiments, the gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 24-409 of gE from an HSV-1 strain (e g., SEQ ID NO: 1).

[0226] In some embodiments, the HSV-1 gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 21-409 of gE from HSV-1 (e.g., NS strain or US8), as set forth in the following amino acid sequence:GTPKTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVP ETVVDAACMRAPVPLAMAYAPPAPSATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGL YTLSVGDIKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGEGEDESLAGTPASGTP RLPPSPAPPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHAIAHDDQTYTMDV VWLRFDVPTSCAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAGCSRTNPPP RCSAEAHMEPFPGLAWQAASVNLEFRDASPQHSGLYLCVVYVNDHIHAWGHITINTAAQY RNAVVEQPLPQRGADLAEPTHPHVGA (SEQ ID NO: 2).

[0227] In some embodiments, an HSV-1 gE fragment comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 2. In some embodiments, an HSV-1 gE fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 2.

[0228] In some embodiments, the gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 21-409 of gE from an HSV-1 strain (e g., SEQ ID NO: 2).

[0229] In some embodiments, an HSV-1 gE encoded by RNA utilized in the methods and compositions of the present disclosure comprises the following amino acid sequence:P-634738-PC MDRGAVVGFLLGVCVVSCLAGTPKTSWRRVSVGEDVSLLPAPGPTGRGPTQKLL WAVEPL DGCGPLHPSWVSLMPPKQVPETVVDAACMRAPVPLAMAYAPPAPSATGGLRTDFVWQER AAVVNRSLVIYGVRETDSGLYTLSVGDIKDPARQVASWLVVQPAPVPTPPPTPADYDEDD NDEGEGEDESL AGTP ASGTPRLPP SP APPRSWP S APEVSHVRGVT VRMETPEAILF SPGEAF S TNVSIHAIAHDDQTYTMDVVWLRFDVPTSCAEMRIYESCLYHPQLPECLSPADAPCAASTW TSRLAVRSYAGCSRTNPPPRCSAEAHMEPFPGLAWQAASVNLEFRDASPQHSGLYLCVVY VNDHIHAWGHITINTAAQYRNAVVEQPLPQRGADLAEPTHPHVGAPPHAPPTHGALRLGA VMGA ALLL S ALGL S VW ACMTC WRRRAWR A VK SRA S GKGPT Y I R V AD SEL Y AD W S SD SE GERDQVPWLAPPERPDSPSTNGSGFEILSPTAPSVYPRSDGHQSRRQLTTFGSGRPDRRYSQ ASDSSVFW (SEQ ID NO: 3).

[0230] In some embodiments, an HSV-1 gE comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 3. In some embodiments, an HSV-1 gE has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 3.

[0231] In another embodiment, the HSV-1 gE or an antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any of the following GenBank Accession Numbers: AAA45779.1, AAA96680.1, ABI63526.1, ACM62297.1, ADD60055.1, ADD60132.1, ADM22391.1, ADM22468.1, ADM22544.1, ADM22621.1, ADM22698.1, ADM22775.1, ADM22851.1, ADM22928.1, ADM23005.1, ADM23081.1, ADM23157.1, ADM23233.1, ADM23311.1, ADM23385.1, ADM23459.1, ADM23533.1, ADM23607.1, ADM23682.1, ADM23757.1, ADM23833.1, ADN34689.1, ADN34692.1, ADN34695.1, AEQ77099.1, AER37649.1, AER37717.1, AER37788.1, AER37859.1, AER37931.1, AER38002.1, AER38072.1, AFA36179.1, AFA36180.1, AFA36181.1, AFA36182.1, AFA36183.1, AFA36184.1, AFA36185.1, AFA36186.1, AFA36187.1, AFA36188.1, AFA36189.1, AFA36190.1, AFA36191.1, AFA36192.1, AFA36193.1, AFA36194.1, AFA36195.1, AFA36196.1, AFA36197.1, AFA36198.1, AFA36199.1, AFA36200.1, AFA36201.1, AFA36202.1, AFA36203.1, AFE62896.1, AFI23659.1, AFK50417.1, AFP86432.1, AGZ01930.1, AIR95859.1, AJE60011.1, AJE60082.1, AJE60153.1, AJE60224.1, AJE60295.1, AKE48647.1, AKE98373.1, AKE98374.1, AKE98375.1, AKE98376.1, AKE98377.1, AKE98378.1, AKE98379.1, AKE98380.1, AKE98381.1, AKE98382.1, AKE98383.1, AKE98384.1, AKE98385.1, AKE98386.1, AKE98387.1,P-634738-PC AKE98388.1, AKE98389.1, AKE98390.1, AKE98391.1, AKE98392.1, AKE98393.1, AKG59248.1, AKG59320.1, AKG59393.1, AKG59464.1, AKG59538.1, AKG59611.1, AKG59684.1 AKG59757.1, AKG59828.1, AKG59900.1, AKG59974.1, AKG60048.1, AKG60120.1 AKG60191.1, AKG60263.1, AKG60336.1, AKG60406.1, AKG60476.1, AKG60548.1 AKG60622.1, AKG60694.1, AKG60765.1, AKG60837.1, AKG60908.1, AKG60980.1 AKG61052.1, AKG61125.1, AKG61196.1, AKG61269.1, AKG61341.1, AKG61413.1 AKG61486.1, AKG61558.1, AKG61631.1, AKG61705.1, AKG61776.1, AKG61849.1 AKG61922.1, AKG61995.1, AKH80465.1, AKH80538.1, ALM22637.1, ALM22711.1 ALM22785.1, ALM22859.1, ALO 18664.1, ALO18740.1, AMB65664.1, AMB65737.1 AMB65811.1, AMB65887.1, AMB65958.1, AMN09834.1, ANN83966.1, ANN84043.1 ANN84119.1, ANN84196.1, ANN 84273.1, ANN84350.1, ANN84426.1, ANN84502.1 ANN84579.1, ANN84655.1, ANN84732.1, ANN84808.1, ANN84885.1, ANN84961.1 ANN85038.1, ANN85114.1, ANN85189.1, ANN85266.1, ANN85343.1, ANN85418.1 ANN85496.1, ANN85573.1, ANN85650.1, ANN85726.1, ANN85803.1, AOY34085.1 AOY36687.1, ARB08959.1, ARO38073.1, ARO38074.1, ARO38075.1, ARO38076.1 ARO38077.1, ARO38078.1, ARO38079.1, ARO38080.1, ASM47642.1, ASM47666.1 ASM47743.1, ASM47820.1, ASM47895.1, BAM73421.1, CAA26062.1, CAA32272.1 CAF24756.1, CAF24757.1, CAF24758.1, CAF24759.1, CAF24760.1, CAF24761.1, CAF24762.1, CAF24763.1, CAF24764.1, CAF24765.1, CAF24766.1, CAF24767.1, CAF24768.1, CAF24769.1, CAF24770.1, CAF24771.1, CAF24772.1, CAF24773.1, CAF24774.1, CAF24775.1, CAF24776.1, CAF24777.1, CAF24778.1, CAF24779.1, CAF24780.1, CAF24781.1, CAF24782.1, CAF24783.1, CAF24784.1, CAF24785.1, P04290.1, P04488.1, P28986.1, Q703F0.1, SB007910.1, SBS69571.1, SBS69576.1, SBS69595.1, SBS69636.1, SBS69693.1, SBS69701.1, SBS69722.1, SBS69732.1, SBS69813.1, SBT69397.1, or YP 009137143.1.HSV-2 gE

[0232] In some embodiments, a nucleotide sequence as provided herein encodes a polypeptide comprising an HSV-2 glycoprotein E (gE) antigen or antigenic fragment thereof. In some embodiments, the nucleotide sequence encodes an HSV-2 gE antigen. In other embodiments, the nucleotide sequence encodes a fragment of HSV-2 gE. In some embodiments, the fragment is an antigenic fragment, an immunogenic fragment, or a combination thereof.P-634738-PC

[0233] In some embodiments, a nucleotide sequence of the RNA encoding an HSV-2 gE fragment comprises:GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGC AUUCUACUUCUAUUGCAGCAAUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUC UGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGCUGCUGCUGA UCGCCCUGUCCCUGGCCCUGGUGACCAACUCCCGCACCUCCUGGAAGCGCGUGACC UCCGGCGAGGACGUGGUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACCCGC GCCCACAAGCUGCUGUGGGCCGCCGAGCCCCUGGACGCCUGCGGCCCCCUGCGCCCCU CCUGGGUGGCCCUGUGGCCCCCCCGCCGCGUGCUGGAGACCGUGGUGGACGCCGCCU GCAUGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCCCCCCCCUUCCCCGCCGGCGA CGAGGGCCUGUACUCCGAGCUGGCCUGGCGCGACCGCGUGGCCGUGGUGAACGAGUC CCUGGUGAUCUACGGCGCCCUGGAGACCGACUCCGGCCUGUACACCCUGUCCGUGGU GGGCCUGUCCGACGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCCCGC CCCCGUGCCCACCCCCACCCCCGACGACUACGACGAGGAGGACGACGCCGGCGUGUCC GAGCGCACCCCCGUGUCCGUGCCCCCCCCCACCCCCCCCCGCCGCCCCCCCGUGGCCC CCCCCACCCACCCCCGCGUGAUCCCCGAGGUGUCCCACGUGCGCGGCGUGACCGUGCA CAUGGAGACCCCCGAGGCCAUCCUGUUCGCCCCCGGCGAGACCUUCGGCACCAACGU GUCCAUCCACGCCAUCGCCCACGACGACGGCCCCUACGCCAUGGACGUGGUGUGGAU GCGCUUCGACGUGCCCUCCUCCUGCGCCGAGAUGCGCAUCUACGAGGCCUGCCUGUA CCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCGUGUCCUCC UGGGCCUACCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCACCACCCCCCCCC CCCGCUGCUUCGCCGAGGCCCGCAUGGAGCCCGUGCCCGGCCUGGCCUGGCUGGCCU CCACCGUGAACCUGGAGUUCCAGCACGCCUCCCCCCAGCACGCCGGCCUGUACCUGU GCGUGGUGUACGUGGACGACCACAUCCACGCCUGGGGCCACAUGACCAUCUCCACCG CCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCACCUGCCCCAGCGCCAGCCCGAGC CCGUGGAGCCCACCCGCCCCCACGGGCGCGCCUAACUAGUAGUGACUGACUAGGAUCU GGUUACCACUAAACCAGCCUCAAGAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCA ACUUACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUGCUCCUAA UAAA AAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAC (SEQ ID NO: 41).P-634738-PC

[0234] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 89). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 70). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 90) and poly adenylation tail (SEQ ID NO: 91).

[0235] In another embodiment, a nucleotide sequence of the RNA encoding an HSV-2 gE fragment lacks the 5’ untranslated sequences, the signal sequence, the 3’ untranslated sequences, the poly adenylation tail, or a combination thereof. In some embodiments, the sequence of the HSV-2 gE fragment is as set forth in SEQ ID NO: 34.

[0236] In some embodiments, an HSV-2 gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises amino acids 24-405 of gE from HSV-2 (e.g., strain 2.12 or US8) as set forth in the following amino acid sequence:RTSWKRVTSGEDVVLLPAPAGPEERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLET VVDAACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLS VVGLSDEARQVASVVLVVEPAPVPTPTPDDYDEEDDAGVSERTPVSVPPPTPPRRPPVAPPT HPRVIPEVSHVRGVTVHMETPEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMRFDVPS SCAEMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARME PVPGLAWLASTVNLEFQHASPQHAGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVVEQH LPQRQPEPVEPTRPHVRA (SEQ ID NO: 4).

[0237] In some embodiments, an HSV-2 gE fragment comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 4. In some embodiments, an HSV-2 gE fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 4.

[0238] In some embodiments, an HSV-2 gE encoded by RNA utilized in the methods and compositions of the present disclosure comprises the following amino acid sequence:MARGAGLVFFVGVWVVSCLAAAPRTSWKRVTSGEDVVLLPAPAERTRAHKLLWAAEPLD ACGPLRPSWVALWPPRRVLETWDAACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVA VVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLWEPAPVPTPTPDDYDEEDDAGV TNARRSAFPPQPPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETLEAILFAPGETFGTNVSIHAI AHDDGPYAMDVVWMRFDVPSSCADMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVP-634738-PC RSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQHAGLYLCVVYVDDHIH AWGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRAPHPAPSARGPLRLGAVLGAAL LLAALGLSAWACMTCWRRRSWRAVKSRASATGPTYIRVADSELYADWSSDSEGERDGSL WQDPPERPDSPSTNGSGFEILSPTAPSVYPHSEGRKSRRPLTTFGSGSPGRRHSQASYPSVLW(SEQ IDNO: 5).

[0239] In some embodiments, an HSV-2 gE comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 5. In some embodiments, an HSV-2 gE has an amino acid sequence that is identical to the amino acid sequence SEQ IDNO: 5.

[0240] In another embodiment, the HSV-2 gE or an antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure comprises the amino acid sequences as set forth in any of the following GenBank Accession Numbers: ABU45436.1, ABU45437.1, ABU45438.1, ABU45439.1, ABW83306.1, ABW83308.1, ABW83310.1, ABW83312.1, ABW83314.1, ABW83316.1, ABW83318.1, ABW83320.1, ABW83322.1, ABW83324.1, ABW83326.1, ABW83328.1, ABW83330.1, ABW83332.1, ABW83334.1, ABW83336.1, ABW83338.1, ABW83340.1, ABW83342.1, ABW83344.1, ABW83346.1, ABW83348.1, ABW83350.1, ABW83352.1, ABW83354.1, ABW83356.1, ABW83358.1, ABW83360.1, ABW83362.1, ABW83364.1, ABW83366.1, ABW83368.1, ABW83370.1, ABW83372.1, ABW83374.1, ABW83376.1, ABW83378.1, ABW83380.1, ABW83382.1, ABW83384.1, ABW83386.1, ABW83388.1, ABW83390.1, ABW83392.1, ABW83394.1, ABW83396.1, ABW83398.1, ABW83400.1, ABZ04069.1, AEV91407.1, AHG54732.1, AKC42830.1, AKC59307.1, AKC59378.1, AKC59449.1, AKC59520.1, AKC59591.1, AMB66104.1, AMB66173.1, AMB66246.1, AMB66465.1, AQZ55756.1, AQZ55827.1, AQZ55898.1, AQZ55969.2, AQZ56040.2, AQZ56111.2, AQZ56182.1, AQZ56253.2, AQZ56324.1, AQZ56395.1, AQZ56466.2, AQZ56537.1, AQZ56608.1, AQZ56679.1, AQZ56750.1, AQZ56821.2, AQZ56892.1, AQZ56963.2, AQZ57034.2, AQZ57105.1, AQZ57176.1, AQZ57247.2, AQZ57318.2, AQZ57389.2, AQZ57460.2, AQZ57531.2, AQZ57602.2, AQZ57673.1, AQZ57744.2, AQZ57815.1, AQZ57886.1, AQZ57957.2, AQZ58028.2, AQZ58099.1, AQZ58170.2, AQZ58241.2, AQZ58312.2, AQZ58383.2, AQZ58454.2, AQZ58525.2, AQZ58596.1, AQZ58667.1, AQZ58738.2, AQZ58809.2, AQZ58880.2,P-634738-PC AQZ58951.2, AQZ59022.2, AQZ59093.1, AQZ59164.1, ARO38081.1, ARO38082.1, ARO38083.1, ARO38084.1, ARO38085.1, ARO38086.1, CAB06715.1, P89436.1, P89475.1, or YP_009137220.1.

[0241] In another embodiment, a gE fragment encoded by RNA utilized in the methods and compositions of the present disclosure comprises an IgG Fc-binding domain of the gE protein. In another embodiment, the gE domain encoded by RNA utilized in the methods and compositions of the present disclosure is any other gE domain known in the art to mediate binding to IgG Fc.

[0242] In another embodiment, a gE protein encoded by RNA utilized in the methods and compositions of the present disclosure comprises a gE domain involved in cell-to-cell spread.

[0243] In another embodiment, a gE fragment encoded by RNA fragment utilized in the methods and compositions of the present disclosure comprises an immune evasion domain. In another embodiment, a gE fragment encoded by RNA fragment utilized in the methods and compositions of the present disclosure comprises a portion of an immune evasion domain.

[0244] Each RNA encoding HSV-1 gE or HSV-2 gE protein or fragment thereof represents a separate embodiment of the present disclosure.

[0245] In another embodiment, a gE protein fragment encoded by RNA utilized in the methods and compositions of the present disclosure is an antigenic fragment. In another embodiment, a gE immunoprotective antigen need not be the entire protein. The protective immune response generally involves, in another embodiment, an antibody response. In another embodiment, mutants, sequence conservative variants, and functional conservative variants of gE are useful in methods and compositions of the present disclosure, provided that all such variants retain the required immunoprotective effect. In another embodiment, the antigenic fragment can comprise an immuno-protective gE antigen from any strain of HSV. In another embodiment, the antigenic fragment can comprise sequence variants of HSV, as found in infected individuals.

[0246] In some embodiments, the present disclosure provides a nucleoside-modified RNA encoding the ectodomain of HSV gE which comprises a sequence that is at least 95% identical to any one of SEQ IDNOs: 33-34.P-634738-PC TABLE 1: Exemplary amino acid sequences of HSV immunogensSequenceAmino Acid Sequence SEQ ID NO: NameHSV-1 gE KTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCG 1(24-409) PLHPSWVSLMPPKQVPETVVDAACMRAPVPLAMA YAPP APS ATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGLYTLSVGD IKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGEGED ESLAGTPASGTPRLPPSPAPPRSWPSAPEVSHVRGVTVRMETP EAILFSPGEAFSTNVSIHAIAHDDQTYTMDVVWLRFDVPTSC AEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAG C SRTNPPPRC S AEAHMEPFPGLAWQAAS VNLEFRD ASPQHSG LYLCVVYVNDHIHAWGHITINTAAQYRNAVVEQPLPQRGAD LAEPTHPHVGA HSV-1 gE GTPKTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLD 2(21-409) GCGPLHPSWVSLMPPKQVPETWDAACMRAPVPLAMAYAPPAPS ATGGLRTDF VWQER A A VVNRSL VIYGVRETD S GL YTL S VGDIKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGE GEDESLAGTPASGTPRLPPSPAPPRSWPSAPEVSHVRGVTVR METPEAILF SPGEAF S TNVSIHAIAHDDQT YTMDVVWLRFD V PTSCAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRS YAGCSRTNPPPRCSAEAHMEPFPGLAWQAASVNLEFRDASP QHSGLYLCVVYVNDHIHAWGHITINTAAQYRNAVVEQPLPQ RGADLAEPTHPHVGA HSV-1 gE MDRGAVVGFLLGVCVVSCLAGTPKTSWRRVSVGEDVSLLPA 3Full- PGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVPETlength VVDAACMRAPVPLAMAYAPPAPSATGGLRTDFVWQERAAV VNRSLVIYGVRETDSGLYTLSVGDIKDPARQVASWLVVQPA PVPTPPPTPADYDEDDNDEGEGEDESLAGTPASGTPRLPPSPA PPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHAI AHDDQTYTMDVVWLRFDVPTSCAEMRIYESCLYHPQLPECLP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameSPADAPC AASTWTSRLAVRSYAGC SRTNPPPRC S AEAHMEPF PGLAWQAASVNLEFRDASPQHSGLYLCVVYVNDHIHAWGHI TINTAAQYRNAWEQPLPQRGADLAEPTHPHVGAPPHAPPTH GALRLGA VMGAALLL S ALGL S VWACMTC WRRRAWRA VK S RASGKGPTYIRVAD SEL YADWS SD SEGERDQ VPWL APPERPD SPSTNGSGFEILSPTAPSVYPRSDGHQSRRQLTTFGSGRPDRR YSQASDSSVFW HSV-2 gE RTSWKRVTSGEDVVLLPAPAGPEERTRAHKLLWAAEPLDAC 4(24-405) GPLRPSWVALWPPRRVLETWDAACMRAPEPLAIAYSPPFPA GDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVG LSDEARQVASWLVVEPAPVPTPTPDDYDEEDDAGVSERTPV SVPPPTPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETPEAILFA PGETFGTNVSIHAIAHDDGP YAMD VVWMRFD VP S SC AEMRI YEACL YHPQLPECL SPADAPC A VS S W AYRL A VRS YAGC SRT TPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQHAGLYLC VVYVDDHIHAWGHMTISTAAQYRNAVVEQHLPQRQPEPVEP TRPHVRA HSV-2 gE MARGAGLVFFVGVWVVSCLAAAPRTSWKRVTSGEDVVLLP 5Full- APAERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVlength VDAACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVN ESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPV PTPTPDDYDEEDDAGVTNARRSAFPPQPPPRRPPVAPPTHPRV IPEVSHVRGVTVHMETLEAILFAPGETFGTNVSIHAIAHDDGP YAMDVVWMRFDVPSSCADMRIYEACLYHPQLPECLSPADAP CAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAW LASTVNLEFQHASPQHAGLYLCVVYVDDHIHAWGHMTISTA AQYRNAWEQHLPQRQPEPVEPTRPHVRAPHPAPSARGPLRL GAVLGAALLLAALGLSAWACMTCWRRRSWRAVKSRASATP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameGPTYIRVADSELYADWSSDSEGERDGSLWQDPPERPDSPSTN GSGFEILSPTAPSVYPHSEGRKSRRPLTTFGSGSPGRRHSQASY PSVLW HSV-1 gC ETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNN 6(27-457) VTQNKTTPTEPASPPTTPKPTSTPKSPPTSTPDPKPKNNTTPAK SGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEFRL QIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYDSAPNLT DPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQGM YYLAWGRMDSPHEYGTWVRVRMFRPPSLTLQPHAVMEGQP FKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHP DGFTTVSTVTSEAVGGQVPPRTFTCQMTWHRDSVTFSRRNA TGLALVLPRPTITMEFGVRHWCTAGCVPEGVTFAWFLGDDP SPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYICRLTGYP AGIPVLEHH HSV-1 gC GSETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNP 7(25-457) NNVTQNKTTPTEPASPPTTPKPTSTPKSPPTSTPDPKPKNNTTP AKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEF RLQIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYDSAPN LTDPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQ GMYYL AWGRMD SPHEYGTWVRVRMFRPP SLTLQPHAVME GQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTH EHPDGFTTVSTVTSEAVGGQVPPRTFTCQMTWHRDSVTFSRR NATGLALVLPRPTITMEFGVRHWCTAGCVPEGVTFAWFLG DDPSPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYICRLT GYPAGIPVLEHH HSV-1 gC MAPGRVGLAVVLWGLLWLGAGVAGGSETASTGPTITAGAV 8Full- TNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPASlength PPTTPKPTSTPKSPPTSTPDPKPKNNTTPAKSGRPTKPPGPVWCP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameDRRDPLARYGSRVQIRCRFRNSTRMEFRLQIWRYSMGPSPPIA PAPDLEEVLTNITAPPGGLLVYDSAPNLTDPHVLWAEGAGPG ADPPLYSVTGPLPTQRLIIGEVTPATQGMYYLAWGRMDSPHE YGTWVRVRMFRPPSLTLQPHAVMEGQPFKATCTAAAYYPR NPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTSEAV GGQ VPPRTFTCQMTWHRD S VTF SRRN ATGL AL VLPRPTITME FGVRHVVCTAGCVPEGVTFAWFLGDDPSPAAKSAVTAQESC DHPGLATVRSTLPISYDYSEYICRLTGYPAGIPVLEHHGSHQP PPRDPTERQVIEAIEWVGIGIGVLAAGVLVVTAIVYVVRTSQS RQRHRR HSV-2 gC ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKAT 9(27-426) KSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIR CRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSAPP GGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQ RLI IEELTLETQGM Y Y W V WGRTDRP S A YGTW VRVRVFRPP S LTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVF DPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTW HRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPE GVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSY EQTEYICRLAGYPDGIPVLEHH HSV-2 gC ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKAT 10 S123F KSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIRVariant CRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPP(27-426) GGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQ RLIIEELTLETQGMYYW VWGRTDRP SA YGTW VRVRVFRPP S LTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVF DPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTW HRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPEP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSY EQTEYICRLAGYPDGIPVLEHH HSV-2 gC SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATK 11(28-426) SKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIRC RFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPG GQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQR LIIEELTLETQGMYYWVWGRTDRP S AYGTWVRVRVFRPP SL TIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVFDP AQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHR DSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPEGV TFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQ TEYICRLAGYPDGIPVLEHH HSV-2 gC SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATK 12 S123F SKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIRCVariant RFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPG(28-426) GQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGRQR LIIEELTLETQGMYYWVWGRTDRP S AYGTWVRVRVFRPP SL TIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVFDP AQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHR DSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPEGV TFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQ TEYICRLAGYPDGIPVLEHH HSV-2 gC SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKA 13(26-426) TKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQI RCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSA PPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLG RQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRP P SLTIHPHAVLEGQPFKATC T AATYYPGNRAEF VWFEDGRRVP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLT WHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVP EGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVS YEQTEYICRLAGYPDGIPVLEHH HSV-2 gC SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKA 14 S123F TKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIVariant RCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSA(26-426) PPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLG RQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRP PSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRV FDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLT WHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVP EGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVS YEQTEYICRLAGYPDGIPVLEHH HSV-2 gC MALGRVGLAVGLWGLLWVGVVVVLANASPGRTITVGPRGN 15Full- ASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKlength TGPPKTSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEFRLQI WRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRT DPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGM YYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPF KATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQTQENPD GFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASG TASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSP AEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDG IPVLEHHGSHQPPPRDPTERQVIRAVEGAGIGVAVLVAVVLA GT A WYLTHAS S VRYRRLR HSV-1 gD KYALADASLKMADPNRFRGKDLPVLDQLTDPPGVRRVYHIQ 16(26-331) AGLPDPFQPPSLPITVYYAVLERACRSVLLNAPSEAPQIVRGAP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameSED VRKQP YNLTIAWFRMGGNC AIPIT VMEYTEC S YNK SLGA CPIRTQPRWNYYD SF S A VSEDNLGFLMHAP AFET AGT YLRL V KINDWTEITQFILEHRAKGSCKYALPLRIPPSACLSPQAYQQG VTVDSIGMLPRFIPENQRTVAVYSLKIAGWHGPKAPYTSTLLP PEL SETPNATQPEL APEDPED S ALLEDP VGT VAPQIPPNWHIP S IQDAATPY HSV-1 gD MGGAAARLGAVILFVVIVGLHGVRGKYALADASLKLADPNR 17Full- FRRKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPITVYYlength AVLERACRSVLLNAPSEAPQIVRGASEDVRKQPYNLTIAWFRMGGNC AIPIT VMEYTEC S YNKSLGACPIRTQPRWNYYDSF SA VSEDNLGFLMHAP AFET AGT YLRL VKINDWTEITQFILEHRA KGSCKYALPLRIPPSACLSPQAYQQGVTVDSIGMLPRFIPENQ RT VAVYSLKIAGWHGPKAP YT STLLPPEL SETPNATQPEL APE APEDSALLEDPVGTVAPQIPPNWHIPSIQDAATPYHPPATPNN MGLIAGAVGGSLLAALVICGIVYWMRRRTQKAPKRIRLPHIR EDDQPSSHQPLFY HSV-2 gD KYALADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQ 18(26-331) PSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGAS DEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGV CPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLV KINDWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQG VTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLP PELSDTTNATQPELVPEDPED S ALLEDP AGTVS SQIPPNWHIPS IQDVAPHH HSV-2 gD ADP SLKMADPNRFRGKNLP VLDQLTDPPGVKRVYHIQP SLED 19(30-331) PFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEARK HTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQ PRWS YYD SF SA VSEDNLGFLMHAP AFET AGT YLRL VKINDWP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSI GMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDT TNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAP HH HSV-2 gD DP SLKMADPNRFRGKNLP VLDQLTDPPGVKRVYHIQP SLEDP 20(31-331) FQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEARK HTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQ PRW S Y YD SF S A VSEDNLGFLMHAP AFET AGT YLRL VKIND W TEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSI GMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDT TNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAP HH HSV-2 gD MGRLT S GVGT A ALL V V A VGLRVVC AKY AL ADP SLKM ADPN 21Full- RFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYlength AVLERACRSVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNC AIPIT VMEYTECP YNK SLGVCPIRTQPRW S Y YD SF S A VSEDNLGFLMHAP AFETAGTYLRLVKINDWTEITQFILEHRA RASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQ RTVALYSLKIAGWHGPKPPYTSTLLPPELSDTTNATQPELVPE DPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHHAPAAPSNP GLIIGALAGSTLAVLVIGGIAFWVRRRAQMAPKRLRLPHIRDD DAPPSHQPLFY HSV-1 gB MHQGAPSWGRRWFVVWALLGLTLGVLVASAAPTSPGTPGV 22 UL27AAATQAANGGPATPAPPPLGAAPTGDPKPKKNKKPKNPTPPR PAGDNATVAAGHATLREHLRDIKAENTDANFYVCPPPTGAT VVQFEQPRRCPTRPEGQNYTEGIAVVFKENIAPYKFKATMYY KDVTVSQVWFGHRYSQFMGIFEDRAPVPFEEVIDKINAKGVC RSTAKYVRNNLETTAFHRDDHETDMELKPANAATRTSRGWP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameHTTDLKYNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEFVL ATGDFVYMSPFYGYREGSHTEHTTYAADRFKQVDGFYARDL TTKARATAPTTRNLLTTPKFTVAWDWVPKRPSVCTMTKWQ EVDEMLRSEYGGSFRF S SDAISTTFTTNLTEYPLSRVDLGDCI GKDARDAMDRIFARRYNATHIKVGQPQYYQANGGFLIAYQP LLSNTLAELYVREHLREQSRKPPNPTPPPPGASANASVERIKT T S S IFF ARLQFT YNHIQRHVNDMLGRVAIAWCELQNHELTLW NEARKLNPNAIASVTVGRRVSARMLGDVMAVSTCVPVAAD NVIVQNSMRISSRPGACYSRPLVSFRYEDQGPLVEGQLGENN ELRLTRDAIEPCTVGHRRYFTFGGGYVYFEEYAYSHQLSRAD ITTVSTFIDLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTEVQR RNQLHDLRFADIDTVIHADANAAMFAGLGAFFEGMGDLGRA VGKVVMGIVGGVVSAVSGVSSFMSNPFGALAVGLLVLAGLA AAFFAFRYVMRLQSNPMKALYPLTTKELKNPTNPDASGEGE EGGDFDEAKLAEAREMIRYMALVSAMERTEHKAKKKGTSA LLSAKVTDMVMRKRRNTNYTQVPNKDGDADEDDL HSV-2 gB MRGGGLIC AL VVGALV AA VA S AAP AAP AAPRA SGGVAATV 23 UL27 / HG AANGGPASRPPPVPSPATTKARKRKTKKPPKRPEATPPPDAN52 ATVAAGHATLRAHLREIKVENADAQFYVCPPPTGATVVQFE QPRRCPTRPEGQNYTEGIAVVFKENIAPYKFKATMYYKDVTV SQVWFGHRYSQFMGIFEDRAPVPFEEVIDKINTKGVCRSTAK YVRNNMETTAFHRDDHETDMELKPAKVATRTSRGWHTTDL KYNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEFVLATGDF VYMSPFYGYREGSHTEHTSYAADRFKQVDGFYARDLTTKAR ATSPTTRNLLTTPKFTVAWDWVPKRPAVCTMTKWQEVDEM LRAEYGGSFRFSSDAISTTFTTNLTEYSLSRVDLGDCIGRDAR EAIDRMFARKYNATHIKVGQPQYYLATGGFLIAYQPLLSNTL AELYVREYMREQDRKPRNATPAPLREAPSANASVERIKTTSSIP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameEFARLQFTYNHIQRHVNDMLGRIAVAWCELQNHELTLWNEA RKLNPNAIASATVGRRVSARMLGDVMAVSTCVPVAPDNVIV QNSMRVSSRPGTCYSRPLVSFRYEDQGPLIEGQLGENNELRL TRDALEPCTVGHRRYFIFGGGYVYFEEYAYSHQLSRADVTTV STFIDLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTEVQRRNQ LHDLRFADIDTVIRADANAAMFAGLCAFFEGMGDLGRAVGK VVMGVVGGVVSAVSGVSSFMSNPFGALAVGLLVLAGLVAA FFAFRYVLQLQRNPMKALYPLTTKELKTSDPGGVGGEGEEG AEGGGFDEAKLAEAR EMIR YM AL VS AMERTEHKARKKGTS ALLS SKVTNMVLRKR NKA RYSPLHNEDEAGDEDEL HSV-2 gB APAAPAAPRASGGVAATVAANGGPASRPPPVPSPATTKARK 24RKTKKPPKRPEATPPPDANATVAAGHATLRAHLREIKVENAD AQFYVCPPPTGATVVQFEQPRRCPTRPEGQNYTEGIAVVFKE NIAPYKFKATMYYKDVTVSQVWFGHRYSQFMGIFEDRAPVP FEEVIDKIN AKGVCRSTAKYVRNNMETTAFHRDDHETDMEL KPAKVATRTSRGWHTTDLKYNPSRVEAFHRYGTTVNCIVEE VDARSVYPYDEFVLATGDFVYMSPFYGYREGSHTEHTSYAA DRFKQVDGFYARDLTTKARATSPTTRNLLTTPKFTVAWDWV PKRPAVCTMTKWQEVDEMLRAEYGGSFRFSSDAISTTFTTNL TQYSLSRVDLGDCIGRDAREAIDRMFARKYNATHIKVGQPQ YYLATGGFLIAYQPLLSNTLAELYVREYMREQDRKPRNATPA PLREAPSANASVERIKTTSSIEFARLQFTYNHIQRHVNDMLGR IAVAWCELQNHELTLWNEARKLNPNAIASATVGRRVSARML GDVMAVSTCVPVAPDNVIVQNSMRVSSRPGTCYSRPLVSFR YEDQGPLIEGQLGENNELRLTRDALEPCTVGHRRYFIFGGGY VYFEEYAYSHQLSRADVTTVSTFIDLNITMLEDHEFVPLEVYT RHEIKDSGLLDYTEVQRRNQLHDLRFADIDTVIRADANAAP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameHSV-2 gB MRGGGLICALVVGALVAAVASAAPAAPAAPRASGGVAATV 25 UL27 / 333 AANGGPASRPPPVPSPATTKARKRKTKKPPKRPEATPPPDAN ATVAAGHATLRAHLREIKVENADAQFYVCPPPTGATVVQFE QPRRCPTRPEGQNYTEGIAVVFKENIAPYKFKATMYYKDVTV SQVWFGHRYSQFMGIFEDRAPVPFEEVIDKINAKGVCRSTAK YVRNNMETTAFHRDDHETDMELKPAKVATRTSRGWHTTDL KYNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEFVLATGDF VYMSPFYGYREGSHTEHTSYAADRFKQVDGFYARDLTTKAR ATSPTTRNLLTTPKFTVAWDWVPKRPAVCTMTKWQEVDEM LRAEYGGSFRF S SDAISTTFTTNLTQYSLSRVDLGDCIGRDAR EAIDRMFARKYNATHIKVGQPQYYLATGGFLIAYQPLLSNTL AELYVREYMREQDRKPRNATPAPLREAPSANASVERIKTTSSI EFARLQFTYNHIQRHVNDMLGRIAVAWCELQNHELTLWNEA RKLNPNAIASATVGRRVSARMLGDVMAVSTCVPVAPDNVIV QNSMRVSSRPGTCYSRPLVSFRYEDQGPLIEGQLGENNELRL TRDALEPCTVGHRRYFIFGGGYVYFEEYAYSHQLSRADVTTV STFIDLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTEVQRRNQ LHDLRFADIDTVIRADANAAMFAGLCAFFEGMGDLGRAVGK VVMGVVGGVVSAVSGVSSFMSNPFGALAVGLLVLAGLVAA FFAFRYVLQLQRNPMKALYPLTTKELKTSDPGGVGGEGEEG AEGGGFDEAKLAEAREMIRYMALVSAMERTEHKARKKGTS ALLSSKVTNMVLRKRNKARYSPLHNEDEAGDEDEL HSV-2 gB MRGGGLICALVVGALVAAVASAAPAAPRASGGVAATVAAN 26 UL27 / GGPAPQPPPVPSPATTKARKRKTKKPPKRPEATPPPDANATVMS AAGHATLRAHLREIKVENADAQFYVCPPPTGATWQFEQPR RCPTRPEGQNYTEGIAVVFKENIAPYKFKATMYYKDVTVSQ VWFGHRYSQFMGIFEDRAPVPFEEVIDKINAKGVCRSTAKYV RNNMETTAFHRDDHETDMELKPAKVATRTSRGWHTTDLKYP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEFVLATGDFVY MSPFYGYREGSHTEHTSYAADRFKQVDGFYARDLTTKAQAT SPTTRNLLTTPKFTVAWDWVPKRPAVCTMTKWQEVDEMLR AEYGGSFRFSSDAISTTFTTNLTEYSLSRVDLGDCIGRDAREAI DRMFARKYNATHIKVGQPQYYLATGGFLIAYQPLLSNTLAEL YVREYMREQDRKPRNATPAPLREAPSANASVERIKTTSSIEFA RLQFTYNHIQRHVNDMLGRIAVAWCELQNHELTLWNEARK LNPNAIASATVGRRVSARMLGDVMAVSTCVPVAPDNVIVQN SMRVSSRPGTCYSRPLVSFRYEDQGPLIEGQLGENNELRLTRD ALEPCTVGHRRYFIFGGGYVYFEEYAYSHQLSRADVTTVSTFI DLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTEVQRRNQLHD LRFADIDTVIRADANAAMFAGLCAFFEGMGDLGRAVGKVV MGVVGGVVSAVSGVSSFMSNPFGALAVGLLVLAGLVAAFFA FRYVLQLQRNPMKALYPLTTKELKTSDPGGVGGEGEEGAEG GGFDEAKLAEARQMIRYMALVSAMERTEHKARKKGTSALLS SKVTNMVLRKRNKARYSPLHNEDEAGDEDEL HSV-1 gB MHQGAPSWGRRWFVVWALLGLTLGVLVASAAPSSPGTPGV 27 UL27 / AAATQAANGGPATPAPPALGAAPTGDPKPKKNKKPKNPTPPKOS RPAGDNATVAAGHATLREHLRDIKAENTDANFYVCPPPTGA TWQFEQPRRCPTRPEGQNYTEGIAVVFKENIAPYKFKATMY YKDVTVSQVWFGHRYSQFMGIFEDRAPVPFEE VIDKIN AKGV CRSTAKYVRNNLETTAFHRDDHETDMELKPANAATRTSRG WHTTDLKYNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEF VLATGDFVYMSPFYGYREGSHTEHTSYAADRFKQVDGFYAR DLTTKARAT APTTRNLLTTPKFT VAWDWVPKRP S VC TMTK WQEVDEMLRSEYGGSFRFSSDAISTTFTTNLTEYPLSRVDLG DCIGKDARDAMDRIFARRYNATHIKVGQPQYYLANGGFLIA YQPLLSNTLAELYVREHLREQSRKPPNPTPPPPGASANASVERP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameIKTT S S IEF ARLQFT YNHIQRHVNDMLGRVAIAWCELQNHEL TLWNEARKLNPNAIASVTVGRRVSARMLGDVMAVSTCVPV AADNVIVQNSMRISSRPGACYSRPLVSFRYEDQGPLVEGQLG ENNELRLTRDAIEPCTVGHRRYFTFGGGYVYFEEYAYSHQLS RADITTVSTFIDLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTE VQRRNQLHDLRFADIDTVIHADANAAMFAGLGAFFEGMGDL GRAVGKWMGIVGGVVSAVSGVSSFMSNPFGALAVGLLVLA GLAAAFFAFRYVMRLQSNPMKALYPLTTKELKNPTNPDASG EGEEGGDFDEAI< LAEAREMIRYMALVSAMERTEHI< AI< I< I< G TSALLSAKVTDMVMRKRRNTNYTQVPNKDGDADEDDL HSV-2 gB MRGGGLICALVVGALVAAVASAAPAAPAAPRASGGVAATV 28 UL27 / AANGGPASRPPPVPSPATTKARKRKTKKPPKRPEATPPPDANHG52 ATVAAGHATLRAHLREIKVENADAQFYVCPPPTGATVVQFE QPRRCPTRPEGQNYTEGIAVVFKENIAPYKFKATMYYKDVTV SQVWFGHRYSQFMGIFEDRAPVPFEEVIDKINAKGVCRSTAK YVRNNMETTAFHRDDHETDMELKPAKVATRTSRGWHTTDL KYNPSRVEAFHRYGTTVNCIVEEVDARSVYPYDEFVLATGDF VYMSPFYGYREGSHTEHTSYAADRFKQVDGFYARDLTTKAR ATSPTTRNLLTTPKFTVAWDWVPKRPAVCTMTKWQEVDEM LRAEYGGSFRFSSDAISTTFTTNLTEYSLSRVDLGDCIGRDAR EAIDRMFARKYNATHIKVGQPQYYLATGGFLIAYQPLLSNTL AELYVREYMREQDRKPRNATPAPLREAPSANASVERIKTTSSI EFARLQFTYNHIQRHVNDMLGRIAVAWCELQNHELTLWNEA RKLNPNAIASATVGRRVSARMLGDVMAVSTCVPVAPDNVIV QNSMRVSSRPGTCYSRPLVSFRYEDQGPLIEGQLGENNELRL TRDALEPCTVGHRRYFIFGGGYVYFEEYAYSHQLSRADVTTV STFIDLNITMLEDHEFVPLEVYTRHEIKDSGLLDYTEVQRRNQ LHDLRFADIDTVIRADANAAMFAGLCAFFEGMGDLGRAVGKP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameVVMGVVGGVVSAVSGVSSFMSNPFGALAVGLLVLAGLVAA FFAFRYVLQLQRNPMKALYPLTTKELKTSDPGGVGGEGEEG AEGGGFDEAKLAEAREMIRYMALVSAMERTEHKARKKGTS ALL S SKVTNMVLRKRNKARYSPLHNEDEAGDEDEL HSV-1 gB APTSPGTPGVAAATQAANGGPATPAPPPLGAAPTGDPKPKKN 29 KOS full KKPKNPTPPRPAGDNATVAAGHATLREHLRDIKAENTDANFlength YVCPPPTGATWQFEQPRRCPTRPEGQNYTEGIAVVFKENIAP(884 aa) YKFKATMYYKDVTVSQVWFGHRYSQFMGIFEDRAPVPFEEVwith IDKINAKGVCRSTAKYVRNNLETTAFHRDDHETDMELKPANH516P AATRT SRGWHTTDLKYNP SRVEAFHRYGTT VNCIVEEVD ARmutation SVYPYDEFVLATGDFVYMSPFYGYREGSHTEHTTYAADRFK QVDGFYARDLTTKARATAPTTRNLLTTPKFTVAWDWVPKRP SVCTMTKWQEVDEMLRSEYGGSFRFSSDAISTTFTTNLTEYP LSRVDLGDCIGKDARDAMDRIFARRYNATHIKVGQPQYYQA NGGFLIA YQPLL SNTLAEL YVREHLREQ SRKPPNPTPPPPGAS ANASVERIKTTSSIEFARLQFTYNHIQRHVND HSV-1 gB APTSPGTPGVAAATQAANGGPATPAPPPLGAAPTGDPKPKKN 30 KOS KKPKNPTPPRPAGDNATVAAGHATLREHLRDIKAENTDANFwildtype YVCPPPTGATWQFEQPRRCPTRPEGQNYTEGIAVVFKENIAPfull-length YKFKATMYYKDVTVSQVWFGHRYSQFMGIFEDRAPVPFEEV(874 aa) IDKINAKGVCRSTAKYVRNNLETTAFHRDDHETDMELKPANAATRT SRGWHTTDLKYNP SRVEAFHRYGTT VNCIVEEVD AR SVYPYDEFVLATGDFVYMSPFYGYREGSHTEHTTYAADRFK QVDGFYARDLTTKARATAPTTRNLLTTPKFTVAWDWVPKRP SVCTMTKWQEVDEMLRSEYGGSFRFSSDAISTTFTTNLTEYP LSRVDLGDCIGKDARDAMDRIFARRYNATHIKVGQPQYYQA NGGFLIA YQPLL SNTLAEL YVREHLREQ SRKPPNPTPPPPGAS ANAS VERIKTT S SIEF ARLQFT YNHIQRHVNDP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameHSV-1 gB APTSPGTPGVAAATQAANGGPATPAPPPLGAAPTGDPKPKKN 31 KOS KKPKNPTPPRPAGDNATVAAGHATLREHLRDIKAENTDANFtruncated YVCPPPTGATWQFEQPRRCPTRPEGQNYTEGIAVVFKENIAP(814 aa) YKFKATMYYKDVTVSQVWFGHRYSQFMGIFEDRAPVPFEEVwith IDKINAKGVCRSTAKYVRNNLETTAFHRDDHETDMELKPANH516P AATRT SRGWHTTDLK YNP SRVEAFHRYGTT VNCI VEEVD ARmutation SVYPYDEFVLATGDFVYMSPFYGYREGSHTEHTTYAADRFK QVDGFYARDLTTKARATAPTTRNLLTTPKFTVAWDWVPKRP SVCTMTKWQEVDEMLRSEYGGSFRFSSDAISTTFTTNLTEYP LSRVDLGDCIGKDARDAMDRIFARRYNATHIKVGQPQYYQA NGGFLI A YQPLL SNTLAEL YVREHLREQ SRKPPNPTPPPPGAS ANASVERIKTTSSIEFARLQFTYNHIQRPVNDMLGRVAIAWCE LQNHELTLWNEARKLNPNAIASVTVGRRVSARMLGDVMAV STCVPVAADNVIVQNSMRISSRPGACYSRPLVSFRYEDQGPL VEGQLGENNELRLTRDAIEPCTVGHRRYFTFGGGYVYFEEYA YSHQLSRADITTVSTFIDLNITMLEDHEFVPLEVYTRHEIKDSG LLDYTEVQRRNQLHDERFADIDTVIHADANAAAFFAFRYVM RLQSNPMKALYPLTTKELKNPTNPDASGEGEEGGDFDEAKL AEAREMIRYMALVSAMERTEHI< AI< I< I< GTSALLSAI< VTDMV MRKRRNTNYTQVPNKDGDADEDDL HSV-1 gB APTSPGTPGVAAATQAANGGPATPAPPPLGAAPTGDPKPKKN 32(700 aa) KKPKNPTPPRPAGDNATVAAGHATLREHLRDIKAENTDANF YVCPPPTGATWQFEQPRRCPTRPEGQNYTEGIAVVFKENIAP YKFKATMYYKDVTVSQVWFGHRYSQFMGIFEDRAPVPFEEV IDKINAKGVCRSTAKYVRNNLETTAFHRDDHETDMELKPAN AATRT SRGWHTTDLKYNP SRVEAFHRYGTT VNCIVEEVD AR SVYPYDEFVLATGDFVYMSPFYGYREGSHTEHTTYAADRFK QVDGFYARDLTTKARATAPTTRNLLTTPKFTVAWDWVPKRPP-634738-PC SequenceAmino Acid Sequence SEQ ID NO: NameSVCTMTKWQEVDEMLRSEYGGSFRFSSDAISTTFTTNLTEYP LSRVDLGDCIGKDARDAMDRIFARRYNATHIKVGQPQYYQA NGGFLIAYQPLLSNTLAELYVREHLREQSRKPPNPTPPPPGAS ANAS VERIK FT S S IEF ARLQFT YN H IQ RH VN DMLGR V A I A WC ELQNHELTLWNEARKLNPNAIASVTVGRRVSARMLGDVMA VSTCVPVAADNVIVQNSMRISSRPGACYSRPLVSFRYEDQGP LVEGQLGENNELRLTRDAIEPCTVGHRRYFTFGGGYVYFEEY A YSHQL SRADITT VSTFIDLNITMLEDHEF VPLEVYTRHEIKD S GLLDYTEVQRRNQLHDLRFADIDTVIHADANAA

[0247] In some embodiments, an RNA of the present disclosure comprises a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 2.

[0248] In some embodiments, methods of the present disclosure comprise administering to a subject an RNA comprising a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 2.TABLE 2: Exemplary nucleic acid sequences of HSV immunogensSequenceNucleic Acid Sequence SEQ ID NO: NameHSV-1 gE AAGACCUCCUGGCGCCGCGUGUCCGUGGGCGAGGACGUG 33(24-409) UCCCUGCUGCCCGCCCCCGGCCCCACCGGCCGCGGCCCCA CCCAGAAGCUGCUGUGGGCCGUGGAGCCCCUGGACGGCU GCGGCCCCCUGCACCCCUCCUGGGUGUCCCUGAUGCCCC CCAAGCAGGUGCCCGAGACCGUGGUGGACGCCGCCUGCA UGCGCGCCCCCGUGCCCCUGGCCAUGGCCUACGCCCCCC CCGCCCCCUCCGCCACCGGCGGCCUGCGCACCGACUUCGP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameUGUGGCAGGAGCGCGCCGCCGUGGUGAACCGCUCCCUGG UGAUCUACGGCGUGCGCGAGACCGACUCCGGCCUGUACA CCCUGUCCGUGGGCGACAUCAAGGACCCCGCCCGCCAGG UGGCCUCCGUGGUGCUGGUGGUGCAGCCCGCCCCCGUGC CCACCCCCCCCCCCACCCCCGCCGACUACGACGAGGACGA CAACGACGAGGGCGAGGGCGAGGACGAGUCCCUGGCCGG CACCCCCGCCUCCGGCACCCCCCGCCUGCCCCCCUCCCCC GCCCCCCCCCGCUCCUGGCCCUCCGCCCCCGAGGUGUCCC ACGUGCGCGGCGUGACCGUGCGCAUGGAGACCCCCGAGG CCAUCCUGUUCUCCCCCGGCGAGGCCUUCUCCACCAACG UGUCCAUCCACGCCAUCGCCCACGACGACCAGACCUACA CCAUGGACGUGGUGUGGCUGCGCUUCGACGUGCCCACCU CCUGCGCCGAGAUGCGCAUCUACGAGUCCUGCCUGUACC ACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCC CCUGCGCCGCCUCCACCUGGACCUCCCGCCUGGCCGUGC GCUCCUACGCCGGCUGCUCCCGCACCAACCCCCCCCCCCG CUGCUCCGCCGAGGCCCACAUGGAGCCCUUCCCCGGCCU GGCCUGGCAGGCCGCCUCCGUGAACCUGGAGUUCCGCGA CGCCUCCCCCCAGCACUCCGGCCUGUACCUGUGCGUGGU GUACGUGAACGACCACAUCCACGCCUGGGGCCACAUCAC CAUCAACACCGCCGCCCAGUACCGCAACGCCGUGGUGGA GCAGCCCCUGCCCCAGCGCGGCGCCGACCUGGCCGAGCC CACCCACCCCCACGUGGGCGCCUAA HSV-2 gE CGCACCUCCUGGAAGCGCGUGACCUCCGGCGAGGACGUG 34 [US8] GUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACC(24-405) CGCGCCCACAAGCUGCUGUGGGCCGCCGAGCCCCUGGACWT GCCUGCGGCCCCCUGCGCCCCUCCUGGGUGGCCCUGUGG CCCCCCCGCCGCGUGCUGGAGACCGUGGUGGACGCCGCCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameUGCAUGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCC CCCCCCUUCCCCGCCGGCGACGAGGGCCUGUACUCCGAG CUGGCCUGGCGCGACCGCGUGGCCGUGGUGAACGAGUCC CUGGUGAUCUACGGCGCCCUGGAGACCGACUCCGGCCUG UACACCCUGUCCGUGGUGGGCCUGUCCGACGAGGCCCGC CAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCCCGCCCCC GUGCCCACCCCCACCCCCGACGACUACGACGAGGAGGAC GACGCCGGCGUGUCCGAGCGCACCCCCGUGUCCGUGCCC CCCCCCACCCCCCCCCGCCGCCCCCCCGUGGCCCCCCCCA CCCACCCCCGCGUGAUCCCCGAGGUGUCCCACGUGCGCG GCGUGACCGUGCACAUGGAGACCCCCGAGGCCAUCCUGU UCGCCCCCGGCGAGACCUUCGGCACCAACGUGUCCAUCC ACGCCAUCGCCCACGACGACGGCCCCUACGCCAUGGACG UGGUGUGGAUGCGCUUCGACGUGCCCUCCUCCUGCGCCG AGAUGCGCAUCUACGAGGCCUGCCUGUACCACCCCCAGC UGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCG UGUCCUCCUGGGCCUACCGCCUGGCCGUGCGCUCCUACG CCGGCUGCUCCCGCACCACCCCCCCCCCCCGCUGCUUCGC CGAGGCCCGCAUGGAGCCCGUGCCCGGCCUGGCCUGGCU GGCCUCCACCGUGAACCUGGAGUUCCAGCACGCCUCCCC CCAGCACGCCGGCCUGUACCUGUGCGUGGUGUACGUGGA CGACCACAUCCACGCCUGGGGCCACAUGACCAUCUCCAC CGCCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCACCU GCCCCAGCGCCAGCCCGAGCCCGUGGAGCCCACCCGCCC CCACGUGCGCGCCUAA HSV-1 gC GAGACCGCCUCCACCGGCCCCACCAUCACCGCCGGCGCC 35(27-457) GUGACCAACGCCUCCGAGGCCCCCACCUCCGGCUCCCCCWT GGCUCCGCCGCCUCCCCCGAGGUGACCCCCACCUCCACCCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCCAACCCCAACAACGUGACCCAGAACAAGACCACCCCCA CCGAGCCCGCCUCCCCCCCCACCACCCCCAAGCCCACCUC CACCCCCAAGUCCCCCCCCACCUCCACCCCCGACCCCAAG CCCAAGAACAACACCACCCCCGCCAAGUCCGGCCGCCCC ACCAAGCCCCCCGGCCCCGUGUGGUGCGACCGCCGCGAC CCCCUGGCCCGCUACGGCUCCCGCGUGCAGAUCCGCUGC CGCUUCCGCAACUCCACCCGCAUGGAGUUCCGCCUGCAG AUCUGGCGCUACUCCAUGGGCCCCUCCCCCCCCAUCGCC CCCGCCCCCGACCUGGAGGAGGUGCUGACCAACAUCACC GCCCCCCCCGGCGGCCUGCUGGUGUACGACUCCGCCCCC AACCUGACCGACCCCCACGUGCUGUGGGCCGAGGGCGCC GGCCCCGGCGCCGACCCCCCCCUGUACUCCGUGACCGGC CCCCUGCCCACCCAGCGCCUGAUCAUCGGCGAGGUGACC CCCGCCACCCAGGGCAUGUACUACCUGGCCUGGGGCCGC AUGGACUCCCCCCACGAGUACGGCACCUGGGUGCGCGUG CGCAUGUUCCGCCCCCCCUCCCUGACCCUGCAGCCCCAC GCCGUGAUGGAGGGCCAGCCCUUCAAGGCCACCUGCACC GCCGCCGCCUACUACCCCCGCAACCCCGUGGAGUUCGAC UGGUUCGAGGACGACCGCCAGGUGUUCAACCCCGGCCAG AUCGACACCCAGACCCACGAGCACCCCGACGGCUUCACC ACCGUGUCCACCGUGACCUCCGAGGCCGUGGGCGGCCAG GUGCCCCCCCGCACCUUCACCUGCCAGAUGACCUGGCAC CGCGACUCCGUGACCUUCUCCCGCCGCAACGCCACCGGC CUGGCCCUGGUGCUGCCCCGCCCCACCAUCACCAUGGAG UUCGGCGUGCGCCACGUGGUGUGCACCGCCGGCUGCGUG CCCGAGGGCGUGACCUUCGCCUGGUUCCUGGGCGACGAC CCCUCCCCCGCCGCCAAGUCCGCCGUGACCGCCCAGGAG UCCUGCGACCACCCCGGCCUGGCCACCGUGCGCUCCACCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCUGCCCAUCUCCUACGACUACUCCGAGUACAUCUGCCGC CUGACCGGCUACCCCGCCGGCAUCCCCGUGCUGGAGCAC CACUAA HSV-2 gC GCCUCCCCCGGCCGCACCAUCACCGUGGGCCCCCGCGGC 36 [UL44] AACGCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACG(27-426) CCUCCGCCCCCCGCACCACCCCCACCCCCCCCCAGCCCCGWT CAAGGCCACCAAGUCCAAGGCCUCCACCGCCAAGCCCGC CCCCCCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCGAG CCCGUGCGCUGCAACCGCCACGACCCCCUGGCCCGCUAC GGCUCCCGCGUGCAGAUCCGCUGCCGCUUCCCCAACUCC ACCCGCACCGAGUUCCGCCUGCAGAUCUGGCGCUACGCC ACCGCCACCGACGCCGAGAUCGGCACCGCCCCCUCCCUG GAGGAGGUGAUGGUGAACGUGUCCGCCCCCCCCGGCGGC CAGCUGGUGUACGACUCCGCCCCCAACCGCACCGACCCC CACGUGAUCUGGGCCGAGGGCGCCGGCCCCGGCGCCUCC CCCCGCCUGUACUCCGUGGUGGGCCCCCUGGGCCGCCAG CGCCUGAUCAUCGAGGAGCUGACCCUGGAGACCCAGGGC AUGUACUACUGGGUGUGGGGCCGCACCGACCGCCCCUCC GCCUACGGCACCUGGGUGCGCGUGCGCGUGUUCCGCCCC CCCUCCCUGACCAUCCACCCCCACGCCGUGCUGGAGGGC CAGCCCUUCAAGGCCACCUGCACCGCCGCCACCUACUAC CCCGGCAACCGCGCCGAGUUCGUGUGGUUCGAGGACGGC CGCCGCGUGUUCGACCCCGCCCAGAUCCACACCCAGACC CAGGAGAACCCCGACGGCUUCUCCACCGUGUCCACCGUG ACCUCCGCCGCCGUGGGCGGCCAGGGCCCCCCCCGCACC UUCACCUGCCAGCUGACCUGGCACCGCGACUCCGUGUCC UUCUCCCGCCGCAACGCCUCCGGCACCGCCUCCGUGCUG CCCCGCCCCACCAUCACCAUGGAGUUCACCGGCGACCACP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameGCCGUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGACC UUCGCCUGGUUCCUGGGCGACGACUCCUCCCCCGCCGAG AAGGUGGCCGUGGCCUCCCAGACCUCCUGCGGCCGCCCC GGCACCGCCACCAUCCGCUCCACCCUGCCCGUGUCCUAC GAGCAGACCGAGUACAUCUGCCGCCUGGCCGGCUACCCC GACGGCAUCCCCGUGCUGGAGCACCACUAA HSV-2 gC UCCCCCGGCCGCACCAUCACCGUGGGCCCCCGCGGCAAC 37 [UL44] GCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACGCCU(28-426) CCGCCCCCCGCACCACCCCCACCCCCCCCCAGCCCCGCAAWT GGCCACCAAGUCCAAGGCCUCCACCGCCAAGCCCGCCCC CCCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCGAGCCC GUGCGCUGCAACCGCCACGACCCCCUGGCCCGCUACGGC UCCCGCGUGCAGAUCCGCUGCCGCUUCCCCAACUCCACC CGCACCGAGUUCCGCCUGCAGAUCUGGCGCUACGCCACC GCCACCGACGCCGAGAUCGGCACCGCCCCCUCCCUGGAG GAGGUGAUGGUGAACGUGUCCGCCCCCCCCGGCGGCCAG CUGGUGUACGACUCCGCCCCCAACCGCACCGACCCCCAC GUGAUCUGGGCCGAGGGCGCCGGCCCCGGCGCCUCCCCC CGCCUGUACUCCGUGGUGGGCCCCCUGGGCCGCCAGCGC CUGAUCAUCGAGGAGCUGACCCUGGAGACCCAGGGCAUG UACUACUGGGUGUGGGGCCGCACCGACCGCCCCUCCGCC UACGGCACCUGGGUGCGCGUGCGCGUGUUCCGCCCCCCC UCCCUGACCAUCCACCCCCACGCCGUGCUGGAGGGCCAG CCCUUCAAGGCCACCUGCACCGCCGCCACCUACUACCCC GGCAACCGCGCCGAGUUCGUGUGGUUCGAGGACGGCCGC CGCGUGUUCGACCCCGCCCAGAUCCACACCCAGACCCAG GAGAACCCCGACGGCUUCUCCACCGUGUCCACCGUGACC UCCGCCGCCGUGGGCGGCCAGGGCCCCCCCCGCACCUUCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameACCUGCCAGCUGACCUGGCACCGCGACUCCGUGUCCUUC UCCCGCCGCAACGCCUCCGGCACCGCCUCCGUGCUGCCC CGCCCCACCAUCACCAUGGAGUUCACCGGCGACCACGCC GUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGACCUUC GCCUGGUUCCUGGGCGACGACUCCUCCCCCGCCGAGAAG GUGGCCGUGGCCUCCCAGACCUCCUGCGGCCGCCCCGGC ACCGCCACCAUCCGCUCCACCCUGCCCGUGUCCUACGAG CAGACCGAGUACAUCUGCCGCCUGGCCGGCUACCCCGAC GGCAUCCCCGUGCUGGAGCACCACUAA HSV-1 gD AAGUACGCCCUGGCCGACGCCUCCCUGAAGAUGGCCGAC 38(26-331) CCCAACCGCUUCCGCGGCAAGGACCUGCCCGUGCUGGACWT CAGCUGACCGACCCCCCCGGCGUGCGCCGCGUGUACCAC AUCCAGGCCGGCCUGCCCGACCCCUUCCAGCCCCCCUCCC UGCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCGCCU GCCGCUCCGUGCUGCUGAACGCCCCCUCCGAGGCCCCCC AGAUCGUGCGCGGCGCCUCCGAGGACGUGCGCAAGCAGC CCUACAACCUGACCAUCGCCUGGUUCCGCAUGGGCGGCA ACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAGU GCUCCUACAACAAGUCCCUGGGCGCCUGCCCCAUCCGCA CCCAGCCCCGCUGGAACUACUACGACUCCUUCUCCGCCG UGUCCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCCG CCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGA UCAACGACUGGACCGAGAUCACCCAGUUCAUCCUGGAGC ACCGCGCCAAGGGCUCCUGCAAGUACGCCCUGCCCCUGC GCAUCCCCCCCUCCGCCUGCCUGUCCCCCCAGGCCUACCA GCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCCCG CUUCAUCCCCGAGAACCAGCGCACCGUGGCCGUGUACUC CCUGAAGAUCGCCGGCUGGCACGGCCCCAAGGCCCCCUAP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCACCUCCACCCUGCUGCCCCCCGAGCUGUCCGAGACCCC CAACGCCACCCAGCCCGAGCUGGCCCCCGAGGACCCCGA GGACUCCGCCCUGCUGGAGGACCCCGUGGGCACCGUGGC CCCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCA GGACGCCGCCACCCCCUACUAA HSV-2 gD AAGUACGCCCUGGCCGACCCCUCCCUGAAGAUGGCCGAC 39(26-331) CCCAACCGCUUCCGCGGCAAGAACCUGCCCGUGCUGGACWT CAGCUGACCGACCCCCCCGGCGUGAAGCGCGUGUACCAC AUCCAGCCCUCCCUGGAGGACCCCUUCCAGCCCCCCUCC AUCCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCGCC UGCCGCUCCGUGCUGCUGCACGCCCCCUCCGAGGCCCCC CAGAUCGUGCGCGGCGCCUCCGACGAGGCCCGCAAGCAC ACCUACAACCUGACCAUCGCCUGGUACCGCAUGGGCGAC AACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAG UGCCCCUACAACAAGUCCCUGGGCGUGUGCCCCAUCCGC ACCCAGCCCCGCUGGUCCUACUACGACUCCUUCUCCGCC GUGUCCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCC GCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAG AUCAACGACUGGACCGAGAUCACCCAGUUCAUCCUGGAG CACCGCGCCCGCGCCUCCUGCAAGUACGCCCUGCCCCUG CGCAUCCCCCCCGCCGCCUGCCUGACCUCCAAGGCCUAC CAGCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCC CGCUUCAUCCCCGAGAACCAGCGCACCGUGGCCCUGUAC UCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGCCCCCC UACACCUCCACCCUGCUGCCCCCCGAGCUGUCCGACACC ACCAACGCCACCCAGCCCGAGCUGGUGCCCGAGGACCCC GAGGACUCCGCCCUGCUGGAGGACCCCGCCGGCACCGUGP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameUCCUCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUC CAGGACGUGGCCCCCCACCACUAAComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 40HSV-1 gE AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGC AGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGU GACCAACUCCAAGACCUCCUGGCGCCGCGUGUCCGUGG GCGAGGACGUGUCCCUGCUGCCCGCCCCCGGCCCCACCG GCCGCGGCCCCACCCAGAAGCUGCUGUGGGCCGUGGAGC CCCUGGACGGCUGCGGCCCCCUGCACCCCUCCUGGGUGU CCCUGAUGCCCCCCAAGCAGGUGCCCGAGACCGUGGUGG ACGCCGCCUGCAUGCGCGCCCCCGUGCCCCUGGCCAUGG CCUACGCCCCCCCCGCCCCCUCCGCCACCGGCGGCCUGCG CACCGACUUCGUGUGGCAGGAGCGCGCCGCCGUGGUGAA CCGCUCCCUGGUGAUCUACGGCGUGCGCGAGACCGACUC CGGCCUGUACACCCUGUCCGUGGGCGACAUCAAGGACCC CGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGCAGCC CGCCCCCGUGCCCACCCCCCCCCCCACCCCCGCCGACUAC GACGAGGACGACAACGACGAGGGCGAGGGCGAGGACGA GUCCCUGGCCGGCACCCCCGCCUCCGGCACCCCCCGCCUG CCCCCCUCCCCCGCCCCCCCCCGCUCCUGGCCCUCCGCCC CCGAGGUGUCCCACGUGCGCGGCGUGACCGUGCGCAUGG AGACCCCCGAGGCCAUCCUGUUCUCCCCCGGCGAGGCCU UCUCCACCAACGUGUCCAUCCACGCCAUCGCCCACGACG ACCAGACCUACACCAUGGACGUGGUGUGGCUGCGCUUCG ACGUGCCCACCUCCUGCGCCGAGAUGCGCAUCUACGAGU CCUGCCUGUACCACCCCCAGCUGCCCGAGUGCCUGUCCCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCCGCCGACGCCCCCUGCGCCGCCUCCACCUGGACCUCCCG CCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCACCAA CCCCCCCCCCCGCUGCUCCGCCGAGGCCCACAUGGAGCCC UUCCCCGGCCUGGCCUGGCAGGCCGCCUCCGUGAACCUG GAGUUCCGCGACGCCUCCCCCCAGCACUCCGGCCUGUAC CUGUGCGUGGUGUACGUGAACGACCACAUCCACGCCUGG GGCCACAUCACCAUCAACACCGCCGCCCAGUACCGCAAC GCCGUGGUGGAGCAGCCCCUGCCCCAGCGCGGCGCCGAC CUGGCCGAGCCCACCCACCCCCACGUGGGCGCCUAACDL4 GUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCU CAAGAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCAA CUUACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUC GUA UCUGCUCCUAA UAAAAAGAAAGUUUCUUCACA UUCUAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAACComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 41HSV-2 gE AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGC AGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGU GACCAACUCCCGCACCUCCUGGAAGCGCGUGACCUCCGG CGAGGACGUGGUGCUGCUGCCCGCCCCCGCCGGCCCCGA GGAGCGCACCCGCGCCCACAAGCUGCUGUGGGCCGCCGA GCCCCUGGACGCCUGCGGCCCCCUGCGCCCCUCCUGGGU GGCCCUGUGGCCCCCCCGCCGCGUGCUGGAGACCGUGGU GGACGCCGCCUGCAUGCGCGCCCCCGAGCCCCUGGCCAU CGCCUACUCCCCCCCCUUCCCCGCCGGCGACGAGGGCCUP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameGUACUCCGAGCUGGCCUGGCGCGACCGCGUGGCCGUGGU GAACGAGUCCCUGGUGAUCUACGGCGCCCUGGAGACCGA CUCCGGCCUGUACACCCUGUCCGUGGUGGGCCUGUCCGA CGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGA GCCCGCCCCCGUGCCCACCCCCACCCCCGACGACUACGAC GAGGAGGACGACGCCGGCGUGUCCGAGCGCACCCCCGUG UCCGUGCCCCCCCCCACCCCCCCCCGCCGCCCCCCCGUGG CCCCCCCCACCCACCCCCGCGUGAUCCCCGAGGUGUCCCA CGUGCGCGGCGUGACCGUGCACAUGGAGACCCCCGAGGC CAUCCUGUUCGCCCCCGGCGAGACCUUCGGCACCAACGU GUCCAUCCACGCCAUCGCCCACGACGACGGCCCCUACGC CAUGGACGUGGUGUGGAUGCGCUUCGACGUGCCCUCCUC CUGCGCCGAGAUGCGCAUCUACGAGGCCUGCCUGUACCA CCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCC UGCGCCGUGUCCUCCUGGGCCUACCGCCUGGCCGUGCGC UCCUACGCCGGCUGCUCCCGCACCACCCCCCCCCCCCGCU GCUUCGCCGAGGCCCGCAUGGAGCCCGUGCCCGGCCUGG CCUGGCUGGCCUCCACCGUGAACCUGGAGUUCCAGCACG CCUCCCCCCAGCACGCCGGCCUGUACCUGUGCGUGGUGU ACGUGGACGACCACAUCCACGCCUGGGGCCACAUGACCA UCUCCACCGCCGCCCAGUACCGCAACGCCGUGGUGGAGC AGCACCUGCCCCAGCGCCAGCCCGAGCCCGUGGAGCCCA CCCGCCCGCACGGGCGCGCCGWCUAGUAGUGACUGACUA GGA UCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAA U GGAGUCUCUAAGCUACA UAA UACCAACUUACACUUACAAAA UGUUGUCCCCCAAAA UG UAGCCA UUCGUA UCUGCUCCUAA UAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 42HSV-1 gC AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGGCCAUCU CCGGCGUGCCCGUGCUGGGCUUCUUCAUCAUCGCCGU GCUGAUGUCCGCCCAGGAGUCCUGGGCCGAGACCGCC UCCACCGGCCCCACCAUCACCGCCGGCGCCGUGACCAAC GCCUCCGAGGCCCCCACCUCCGGCUCCCCCGGCUCCGCCG CCUCCCCCGAGGUGACCCCCACCUCCACCCCCAACCCCAA CAACGUGACCCAGAACAAGACCACCCCCACCGAGCCCGC CUCCCCCCCCACCACCCCCAAGCCCACCUCCACCCCCAAG UCCCCCCCCACCUCCACCCCCGACCCCAAGCCCAAGAACA ACACCACCCCCGCCAAGUCCGGCCGCCCCACCAAGCCCCC CGGCCCCGUGUGGUGCGACCGCCGCGACCCCCUGGCCCG CUACGGCUCCCGCGUGCAGAUCCGCUGCCGCUUCCGCAA CUCCACCCGCAUGGAGUUCCGCCUGCAGAUCUGGCGCUA CUCCAUGGGCCCCUCCCCCCCCAUCGCCCCCGCCCCCGAC CUGGAGGAGGUGCUGACCAACAUCACCGCCCCCCCCGGC GGCCUGCUGGUGUACGACUCCGCCCCCAACCUGACCGAC CCCCACGUGCUGUGGGCCGAGGGCGCCGGCCCCGGCGCC GACCCCCCCCUGUACUCCGUGACCGGCCCCCUGCCCACCC AGCGCCUGAUCAUCGGCGAGGUGACCCCCGCCACCCAGG GCAUGUACUACCUGGCCUGGGGCCGCAUGGACUCCCCCC ACGAGUACGGCACCUGGGUGCGCGUGCGCAUGUUCCGCC CCCCCUCCCUGACCCUGCAGCCCCACGCCGUGAUGGAGG GCCAGCCCUUCAAGGCCACCUGCACCGCCGCCGCCUACUP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameACCCCCGCAACCCCGUGGAGUUCGACUGGUUCGAGGACG ACCGCCAGGUGUUCAACCCCGGCCAGAUCGACACCCAGA CCCACGAGCACCCCGACGGCUUCACCACCGUGUCCACCG UGACCUCCGAGGCCGUGGGCGGCCAGGUGCCCCCCCGCA CCUUCACCUGCCAGAUGACCUGGCACCGCGACUCCGUGA CCUUCUCCCGCCGCAACGCCACCGGCCUGGCCCUGGUGC UGCCCCGCCCCACCAUCACCAUGGAGUUCGGCGUGCGCC ACGUGGUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGA CCUUCGCCUGGUUCCUGGGCGACGACCCCUCCCCCGCCG CCAAGUCCGCCGUGACCGCCCAGGAGUCCUGCGACCACC CCGGCCUGGCCACCGUGCGCUCCACCCUGCCCAUCUCCU ACGACUACUCCGAGUACAUCUGCCGCCUGACCGGCUACC CCGCCGGCAUCCCCGUGCUGGAGCACCACUAACt4Gt4G UGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGA ACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCAACUUAC ACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UC UGCUCCUAA UAAAAAGAAAGUUUCUUCACA UUCUAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAACComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 43HSV-2 gC AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGC AGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGU GACCAACUCCGCCUCCCCCGGCCGCACCAUCACCGUGGG CCCCCGCGGCAACGCCUCCAACGCCGCCCCCUCCGCCUCC CCCCGCAACGCCUCCGCCCCCCGCACCACCCCCACCCCCCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCCCAGCCCCGCAAGGCCACCAAGUCCAAGGCCUCCACCG CCAAGCCCGCCCCCCCCCCCAAGACCGGCCCCCCCAAGAC CUCCUCCGAGCCCGUGCGCUGCAACCGCCACGACCCCCU GGCCCGCUACGGCUCCCGCGUGCAGAUCCGCUGCCGCUU CCCCAACUCCACCCGCACCGAGUUCCGCCUGCAGAUCUG GCGCUACGCCACCGCCACCGACGCCGAGAUCGGCACCGC CCCCUCCCUGGAGGAGGUGAUGGUGAACGUGUCCGCCCC CCCCGGCGGCCAGCUGGUGUACGACUCCGCCCCCAACCG CACCGACCCCCACGUGAUCUGGGCCGAGGGCGCCGGCCC CGGCGCCUCCCCCCGCCUGUACUCCGUGGUGGGCCCCCU GGGCCGCCAGCGCCUGAUCAUCGAGGAGCUGACCCUGGA GACCCAGGGCAUGUACUACUGGGUGUGGGGCCGCACCGA CCGCCCCUCCGCCUACGGCACCUGGGUGCGCGUGCGCGU GUUCCGCCCCCCCUCCCUGACCAUCCACCCCCACGCCGUG CUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCC ACCUACUACCCCGGCAACCGCGCCGAGUUCGUGUGGUUC GAGGACGGCCGCCGCGUGUUCGACCCCGCCCAGAUCCAC ACCCAGACCCAGGAGAACCCCGACGGCUUCUCCACCGUG UCCACCGUGACCUCCGCCGCCGUGGGCGGCCAGGGCCCC CCCCGCACCUUCACCUGCCAGCUGACCUGGCACCGCGAC UCCGUGUCCUUCUCCCGCCGCAACGCCUCCGGCACCGCC UCCGUGCUGCCCCGCCCCACCAUCACCAUGGAGUUCACC GGCGACCACGCCGUGUGCACCGCCGGCUGCGUGCCCGAG GGCGUGACCUUCGCCUGGUUCCUGGGCGACGACUCCUCC CCCGCCGAGAAGGUGGCCGUGGCCUCCCAGACCUCCUGC GGCCGCCCCGGCACCGCCACCAUCCGCUCCACCCUGCCCG UGUCCUACGAGCAGACCGAGUACAUCUGCCGCCUGGCCG GCUACCCCGACGGCAUCCCCGUGCUGGAGCACCACUAACP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 44HSV-1 gD AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGC AGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGU GACCAACUCCAAGUACGCCCUGGCCGACGCCUCCCUGAA GAUGGCCGACCCCAACCGCUUCCGCGGCAAGGACCUGCC CGUGCUGGACCAGCUGACCGACCCCCCCGGCGUGCGCCG CGUGUACCACAUCCAGGCCGGCCUGCCCGACCCCUUCCA GCCCCCCUCCCUGCCCAUCACCGUGUACUACGCCGUGCU GGAGCGCGCCUGCCGCUCCGUGCUGCUGAACGCCCCCUC CGAGGCCCCCCAGAUCGUGCGCGGCGCCUCCGAGGACGU GCGCAAGCAGCCCUACAACCUGACCAUCGCCUGGUUCCG CAUGGGCGGCAACUGCGCCAUCCCCAUCACCGUGAUGGA GUACACCGAGUGCUCCUACAACAAGUCCCUGGGCGCCUG CCCCAUCCGCACCCAGCCCCGCUGGAACUACUACGACUC CUUCUCCGCCGUGUCCGAGGACAACCUGGGCUUCCUGAU GCACGCCCCCGCCUUCGAGACCGCCGGCACCUACCUGCG CCUGGUGAAGAUCAACGACUGGACCGAGAUCACCCAGUU CAUCCUGGAGCACCGCGCCAAGGGCUCCUGCAAGUACGC CCUGCCCCUGCGCAUCCCCCCCUCCGCCUGCCUGUCCCCCP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGC AUGCUGCCCCGCUUCAUCCCCGAGAACCAGCGCACCGUG GCCGUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCC AAGGCCCCCUACACCUCCACCCUGCUGCCCCCCGAGCUG UCCGAGACCCCCAACGCCACCCAGCCCGAGCUGGCCCCC GAGGACCCCGAGGACUCCGCCCUGCUGGAGGACCCCGUG GGCACCGUGGCCCCCCAGAUCCCCCCCAACUGGCACAUC CCCUCCAUCCAGGACGCCGCCACCCCCUACUAACM4GM4 GUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAA GAACACCCGAA UGGAGUCUCUAAGCUACA UAA UACCAACUU ACACUUACAAAA UGUUGUCCCCCAAAA UGUAGCCA UUCGUA UCUGCUCCUAA UAAAAAGAAA GUUUCUUCACA UUCUAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAACComplete GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACG 45HSV-2 gD AAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCA AUUUAAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUG AAAAUUUUCACCAUUUACGAACGAUAGCAUGGGCCGCC UGACCUCCGGCGUGGGCACCGCCGCCCUGCUGGUGGU GGCCGUGGGCCUGCGCGUGGUGUGCGCCAAGUACGCC CUGGCCGACCCCUCCCUGAAGAUGGCCGACCCCAACCGC UUCCGCGGCAAGAACCUGCCCGUGCUGGACCAGCUGACC GACCCCCCCGGCGUGAAGCGCGUGUACCACAUCCAGCCC UCCCUGGAGGACCCCUUCCAGCCCCCCUCCAUCCCCAUC ACCGUGUACUACGCCGUGCUGGAGCGCGCCUGCCGCUCC GUGCUGCUGCACGCCCCCUCCGAGGCCCCCCAGAUCGUG CGCGGCGCCUCCGACGAGGCCCGCAAGCACACCUACAACP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: NameCUGACCAUCGCCUGGUACCGCAUGGGCGACAACUGCGCC AUCCCCAUCACCGUGAUGGAGUACACCGAGUGCCCCUAC AACAAGUCCCUGGGCGUGUGCCCCAUCCGCACCCAGCCC CGCUGGUCCUACUACGACUCCUUCUCCGCCGUGUCCGAG GACAACCUGGGCUUCCUGAUGCACGCCCCCGCCUUCGAG ACCGCCGGCACCUACCUGCGCCUGGUGAAGAUCAACGAC UGGACCGAGAUCACCCAGUUCAUCCUGGAGCACCGCGCC CGCGCCUCCUGCAAGUACGCCCUGCCCCUGCGCAUCCCC CCCGCCGCCUGCCUGACCUCCAAGGCCUACCAGCAGGGC GUGACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUC CCCGAGAACCAGCGCACCGUGGCCCUGUACUCCCUGAAG AUCGCCGGCUGGCACGGCCCCAAGCCCCCCUACACCUCC ACCCUGCUGCCCCCCGAGCUGUCCGACACCACCAACGCC ACCCAGCCCGAGCUGGUGCCCGAGGACCCCGAGGACUCC GCCCUGCUGGAGGACCCCGCCGGCACCGUGUCCUCCCAG AUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGUG GCCCCCCACCACVAACUAGUAGUGACUGACUAGGAUCUGG UUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUC UAAGCUACA UAA UACCAACUUACACUUACAAAA UGUUGUCC CCCAAAA UGUA GCCA UUCGUA UCUGCUCCUAA UAAAAAGAA AGUUUCUUCACA UUCUAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA A AAA AAA AAA A A A AAAAAAAAAAAAAAAA CTruncated gcccccgccgcccccgccgccccccgcgcctccggcggcgtggccgccaccgtggccgcc 46HSV-2 gB aacggcggccccgcctcccgccccccccccgtgccctcccccgccaccaccaaggcccgca(1-7271) agcgcaagaccaagaagccccccaagcgccccgaggccacccccccccccgacgccaacgccaccgtggccgccggccacgccaccctgcgcgcccacctgcgcgagatcaaggtggagaaIncluding native signal sequenceP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Namecgccgacgcccagttctacgtgtgccccccccccaccggcgccaccgtggtgcagttcgagca gccccgccgctgccccacccgccccgagggccagaactacaccgagggcatcgccgtggtgt tcaaggagaacatcgccccctacaagttcaaggccaccatgtactacaaggacgtgaccgtgtc ccaggtgtggttcggccaccgctactcccagttcatgggcatcttcgaggaccgcgcccccgtg cccttcgaggaggtgatcgacaagatcaacgccaagggcgtgtgccgctccaccgccaagtac gtgcgcaacaacatggagaccaccgccttccaccgcgacgaccacgagaccgacatggagct gaagcccgccaaggtggccacccgcacctcccgcggctggcacaccaccgacctgaagtaca acccctcccgcgtggaggccttccaccgctacggcaccaccgtgaactgcatcgtggaggagg tggacgcccgctccgtgtacccctacgacgagttcgtgctggccaccggcgacttcgtgtacat gtcccccttctacggctaccgcgagggctcccacaccgagcacacctcctacgccgccgaccg cttcaagcaggtggacggcttctacgcccgcgacctgaccaccaaggcccgcgccacctcccc caccacccgcaacctgctgaccacccccaagttcaccgtggcctgggactgggtgcccaagcg ccccgccgtgtgcaccatgaccaagtggcaggaggtggacgagatgctgcgcgccgagtacg gcggctccttccgcttctcctccgacgccatctccaccaccttcaccaccaacctgacccagtact ccctgtcccgcgtggacctgggcgactgcatcggccgcgacgcccgcgaggccatcgaccgc atgttcgcccgcaagtacaacgccacccacatcaaggtgggccagccccagtactacctggcc accggcggcttcctgatcgcctaccagcccctgctgtccaacaccctggccgagctgtacgtgc gcgagtacatgcgcgagcaggaccgcaagccccgcaacgccacccccgcccccctgcgcga ggccccctccgccaacgcctccgtggagcgcatcaagaccacctcctccatcgagttcgcccg cctgcagttcacctacaaccacatccagcgccacgtgaacgacatgctgggccgcatcgccgtg gcctggtgcgagctgcagaaccacgagctgaccctgtggaacgaggcccgcaagctgaaccc caacgccatcgcctccgccaccgtgggccgccgcgtgtccgcccgcatgctgggcgacgtgat ggccgtgtccacctgcgtgcccgtggcccccgacaacgtgatcgtgcagaactccatgcgcgt gtcctcccgccccggcacctgctactcccgccccctggtgtccttccgctacgaggaccagggc cccctgatcgagggccagctgggcgagaacaacgagctgcgcctgacccgcgacgccctgg agccctgcaccgtgggccaccgccgctacttcatcttcggcggcggctacgtgtacttcgagga gtacgcctactcccaccagctgtcccgcgccgacgtgaccaccgtgtccaccttcatcgacctga acatcaccatgctggaggaccacgagttcgtgcccctggaggtgtacacccgccacgagatcaP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Nameaggactccggcctgctggactacaccgaggtgcagcgccgcaaccagctgcacgacctgcgc ttcgccgacatcgacaccgtgatccgcgccgacgccaacgccgccTruncated ggccccaccgtgtccctggtgtccgactccctggtggacgccggcgccgtgggcccccaggg 47HSV-2 gl cttcgtggaggaggacctgcgcgtgttcggcgagctgcacttcgtgggcgcccaggtgcccca(1-254)2caccaactactacgacggcatcatcgagctgttccactaccccctgggcaaccactgcccccgc gtggtgcacgtggtgaccctgaccgcctgcccccgccgccccgccgtggccttcaccctgtgc cgctccacccaccacgcccactcccccgcctaccccaccctggagctgggcctggcccgcca gcccctgctgcgcgtgcgcaccgccacccgcgactacgccggcctgtacgtgctgcgcgtgtg ggtgggctccgccaccaacgcctcccgcttcgtgctgggcgtggccctgtccgccaacggcac cttcgtgtacaacggctccgactacggctcctgcgaccccgcccagctgcccttctccgcccccc gcctgggcccctcctccgtgtacacccccggcgcctcccgccccacccccccccgcaccacca cccccccctcctccccccgcgaccccacccccgcccccggcgacaccggcacccccgcccc cgcctccggcgagatcgccccccccaactccacccgctccgcctccgagtcccgccaccgcTruncated ggctcccaggccaccgagtacgtgctgcgctccgtgatcgccaaggaggtgggcgacatcctg 48HSV-2 gL cgcgtgccctgcatgcgcacccccgccgacgacgtgtcctggcgctacgaggccccctccgtg(1-224)3atcgactacgcccgcatcgacggcatcttcctgcgctaccactgccccggcctggacaccttcct gtgggaccgccacgcccagcgcgcctacctggtgaaccccttcctgttcgccgccggcttcctg gaggacctgtcccactccgtgttccccgccgacacccaggagaccaccacccgccgcgccct gtacaaggagatccgcgacgccctgggctcccgcaagcaggccgtgtcccacgcccccgtgc gcgccggctgcgtgaacttcgactactcccgcacccgccgctgcgtgggccgccgcgacctgc gccccgccaacaccacctccacctgggagccccccgtgtcctccgacgacgaggcctcctccc agtccaagcccctggccacccagccccccgtgctggccctgtccaacgcccccccccgccgc gtgtcccccacccgcggccgccgccgccacacccgcctgcgccgcaacTruncated cacgacacctactggaccgagcagatcgacccctggttcctgcacggcctgggcctggcccgc 49HSV-2 gH acctactggcgcgacaccaacaccggccgcctgtggctgcccaacacccccgacgcctccga(1-803)4cccccagcgcggccgcctggccccccccggcgagctgaacctgaccaccgcctccgtgcccaIncluding native signal sequenceIncluding native signal sequenceIncluding native signal sequenceP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Nametgctgcgctggtacgccgagcgcttctgcttcgtgctggtgaccaccgccgagttcccccgcga ccccggccagctgctgtacatccccaagacctacctgctgggccgcccccgcaacgcctccct gcccgagctgcccgaggccggccccacctcccgcccccccgccgaggtgacccagctgaag ggcctgtcccacaaccccggcgcctccgccctgctgcgctcccgcgcctgggtgaccttcgcc gccgcccccgaccgcgagggcctgaccttcccccgcggcgacgacggcgccaccgagcgc caccccgacggccgccgcaacgcccccccccccggcccccccgccggcaccccccgccac cccaccaccaacctgtccatcgcccacctgcacaacgcctccgtgacctggctggccgcccgc ggcctgctgcgcacccccggccgctacgtgtacctgtccccctccgcctccacctggcccgtgg gcgtgtggaccaccggcggcctggccttcggctgcgacgccgccctggtgcgcgcccgctac ggcaagggcttcatgggcctggtgatctccatgcgcgactccccccccgccgagatcatcgtgg tgcccgccgacaagaccctggcccgcgtgggcaaccccaccgacgagaacgcccccgccgt gctgcccggcccccccgccggcccccgctaccgcgtgttcgtgctgggcgcccccacccccg ccgacaacggctccgccctggacgccctgcgccgcgtggccggctaccccgaggagtccacc aactacgcccagtacatgtcccgcgcctacgccgagttcctgggcgaggaccccggctccggc accgacgcccgcccctccctgttctggcgcctggccggcctgctggcctcctccggcttcgcctt cgtgaacgccgcccacgcccacgacgccatccgcctgtccgacctgctgggcttcctggccca ctcccgcgtgctggccggcctggccgcccgcggcgccgccggctgcgccgccgactccgtgt tcctgaacgtgtccgtgctggaccccgccgcccgcctgcgcctggaggcccgcctgggccacc tggtggccgccatcctggagcgcgagcagtccctggccgcccacgccctgggctaccagctg gccttcgtgctggactcccccgccgcctacggcgccgtggccccctccgccgcccgcctgatc gacgccctgtacgccgagttcctgggcggccgcgccctgaccgcccccatggtgcgccgcgc cctgttctacgccaccgccgtgctgcgcgcccccttcctggccggcgccccctccgccgagca gcgcgagcgcgcccgccgcggcctgctgatcaccaccgccctgtgcacctccgacgtggccg ccgccacccacgccgacctgcgcgccgccctggcccgcaccgaccaccagaagaacctgtc tggctgcccgaccacttctccccctgcgccgcctccctgcgcttcgacctggccgagggcggct tcatcctggacgccctggccatggccacccgctccgacatccccgccgacgtgatggcccagc agacccgcggcgtggcctccgtgctgacccgctgggcccactacaacgccctgatccgcgcct tcgtgcccgaggccacccaccagtgctccggcccctcccacaacgccgagccccgcatcctgP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Namegtgcccatcacccacaacgcctcctacgtggtgacccacacccccctgccccgcggcatcggc tacaagctgaccggcgtggacgtgcgccgccccctgttcatcacctacctgaccgccacctgcg agggccacgcccgcgagatcgagcccaagcgcctggtgcgcaccgagaaccgccgcgacct gggcctggtgggcgccgtgttcctgcgctacacccccgccggcgaggtgatgtccgtgctgct ggtggacaccgacgccacccagcagcagctggcccagggccccgtggccggcacccccaa cgtgttctcctccgacgtgccctccgtggccctgctgctgttccccaacggcaccgtgatccacct gctggccttcgacaccctgcccatcgccaccatcgcccccComplete agcataaaagtctcaacacaacatatacaaaacaaacgaatctcaagcaatcaagcattct 50 gB2 acttctattgcagcaatttaaatcatttcttttaaagcaaaagcaattttctgaaaattttcacsequence catttacgaacgatagcgctatgcgcatgcagctgctgctgctgatcgccctgtccctggccct ggtgaccaactccgcccccgccgcccccgccgccccccgcgcctccggcggcgtggccgcc accgtggccgccaacggcggccccgcctcccgccccccccccgtgccctcccccgccacca ccaaggcccgcaagcgcaagaccaagaagccccccaagcgccccgaggccaccccccccc ccgacgccaacgccaccgtggccgccggccacgccaccctgcgcgcccacctgcgcgagat caaggtggagaacgccgacgcccagttctacgtgtgccccccccccaccggcgccaccgtgg tgcagttcgagcagccccgccgctgccccacccgccccgagggccagaactacaccgaggg catcgccgtggtgttcaaggagaacatcgccccctacaagttcaaggccaccatgtactacaag gacgtgaccgtgtcccaggtgtggttcggccaccgctactcccagttcatgggcatcttcgagga ccgcgcccccgtgcccttcgaggaggtgatcgacaagatcaacgccaagggcgtgtgccgct ccaccgccaagtacgtgcgcaacaacatggagaccaccgccttccaccgcgacgaccacgag accgacatggagctgaagcccgccaaggtggccacccgcacctcccgcggctggcacacca ccgacctgaagtacaacccctcccgcgtggaggccttccaccgctacggcaccaccgtgaact gcatcgtggaggaggtggacgcccgctccgtgtacccctacgacgagttcgtgctggccaccg gcgacttcgtgtacatgtcccccttctacggctaccgcgagggctcccacaccgagcacacctc ctacgccgccgaccgcttcaagcaggtggacggcttctacgcccgcgacctgaccaccaagg cccgcgccacctcccccaccacccgcaacctgctgaccacccccaagttcaccgtggcctggg actgggtgcccaagcgccccgccgtgtgcaccatgaccaagtggcaggaggtggacgagatg ctgcgcgccgagtacggcggctccttccgcttctcctccgacgccatctccaccaccttcaccacP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Namecaacctgacccagtactccctgtcccgcgtggacctgggcgactgcatcggccgcgacgcccg cgaggccatcgaccgcatgttcgcccgcaagtacaacgccacccacatcaaggtgggccagc cccagtactacctggccaccggcggcttcctgatcgcctaccagcccctgctgtccaacaccct ggccgagctgtacgtgcgcgagtacatgcgcgagcaggaccgcaagccccgcaacgccacc cccgcccccctgcgcgaggccccctccgccaacgcctccgtggagcgcatcaagaccacctc ctccatcgagttcgcccgcctgcagttcacctacaaccacatccagcgccacgtgaacgacatg ctgggccgcatcgccgtggcctggtgcgagctgcagaaccacgagctgaccctgtggaacga ggcccgcaagctgaaccccaacgccatcgcctccgccaccgtgggccgccgcgtgtccgccc gcatgctgggcgacgtgatggccgtgtccacctgcgtgcccgtggcccccgacaacgtgatcg tgcagaactccatgcgcgtgtcctcccgccccggcacctgctactcccgccccctggtgtccttc cgctacgaggaccagggccccctgatcgagggccagctgggcgagaacaacgagctgcgcc tgacccgcgacgccctggagccctgcaccgtgggccaccgccgctacttcatcttcggcggcg gctacgtgtacttcgaggagtacgcctactcccaccagctgtcccgcgccgacgtgaccaccgt gtccaccttcatcgacctgaacatcaccatgctggaggaccacgagttcgtgcccctggaggtgt acacccgccacgagatcaaggactccggcctgctggactacaccgaggtgcagcgccgcaac cagctgcacgacctgcgcttcgccgacatcgacaccgtgatccgcgccgacgccaacgccgc ctaataaactagtagtgactgactaggatctggttaccactarzczccagcc / c«aga«ctzcccga atggagtctctaagctacataataccaacttacacttacaaaatgttgtcccccaaaatgtagc ccillcglcilclgctcclcialciciciaagaacigitlcltcac&ttcta&&a^&&&^&&&a?i&&?ia&& aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaComplete agcataaaagtctcaacacaacatatacaaaacaaacgaatctcaagcaatcaagcattct 51 gI2 acttctattgcagcaatttaaatcatttcttttaaagcaaaagcaattttctgaaaattttcacsequence catttacgaacgataacgccaccatggccatctccggcgtgcccgtgctgggcttcttcatcatc gccgtgctgatgtccgcccaggagtcctgggccggccccaccgtgtccctggtgtccgactcc ctggtggacgccggcgccgtgggcccccagggcttcgtggaggaggacctgcgcgtgttcgg cgagctgcacttcgtgggcgcccaggtgccccacaccaactactacgacggcatcatcgagct gttccactaccccctgggcaaccactgcccccgcgtggtgcacgtggtgaccctgaccgcctgP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Namecccccgccgccccgccgtggccttcaccctgtgccgctccacccaccacgcccactcccccgc ctaccccaccctggagctgggcctggcccgccagcccctgctgcgcgtgcgcaccgccaccc gcgactacgccggcctgtacgtgctgcgcgtgtgggtgggctccgccaccaacgcctcccgct tcgtgctgggcgtggccctgtccgccaacggcaccttcgtgtacaacggctccgactacggctc ctgcgaccccgcccagctgcccttctccgccccccgcctgggcccctcctccgtgtacaccccc ggcgcctcccgccccacccccccccgcaccaccacccccccctcctccccccgcgaccccac ccccgcccccggcgacaccggcacccccgcccccgcctccggcgagatcgccccccccaac tccacccgctccgcctccgagtcccgccaccgctaaactagtagtgactgactaggatctggtta ccactaaaccagcctcaagaacacccgaatggagtctctaagctacataataccaacttaca cttacaaaatgttgtcccccaaaatgtagccattcgtatctgctcctaataaaaagaaagtttctt cacattctaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaComplete agcataaaagtctcaacacaacatatacaaaacaaacgaatctcaagcaatcaagcattct 52 gL2 acttctattgcagcaatttaaatcatttcttttaaagcaaaagcaattttctgaaaattttcacsequence catttacgaacgatagcgctatgcgcatgcagctgctgctgctgatcgccctgtccctggccct ggtgaccaactccggctcccaggccaccgagtacgtgctgcgctccgtgatcgccaaggaggt gggcgacatcctgcgcgtgccctgcatgcgcacccccgccgacgacgtgtcctggcgctacg aggccccctccgtgatcgactacgcccgcatcgacggcatcttcctgcgctaccactgccccgg cctggacaccttcctgtgggaccgccacgcccagcgcgcctacctggtgaaccccttcctgttc gccgccggcttcctggaggacctgtcccactccgtgttccccgccgacacccaggagaccacc acccgccgcgccctgtacaaggagatccgcgacgccctgggctcccgcaagcaggccgtgtc ccacgcccccgtgcgcgccggctgcgtgaacttcgactactcccgcacccgccgctgcgtgg gccgccgcgacctgcgccccgccaacaccacctccacctgggagccccccgtgtcctccgac gacgaggcctcctcccagtccaagcccctggccacccagccccccgtgctggccctgtccaac gcccccccccgccgcgtgtcccccacccgcggccgccgccgccacacccgcctgcgccgca actaataaactagtagtgactgactaggatctggttaccacta£z«cc«gccfca<7gaacacccg aatggagtctctaagctacataataccaacttacacttacaaaatgttgtcccccaaaatgtagccattcgtatctgctcctaataaaaagaaagtttcttcacattctaaaaaaaaaaaaaaaaaaaaP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Nameaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaaComplete agcataaaagtctcaacacaacatatacaaaacaaacgaatctcaagcaatcaagcattct 53 gH2 acttctattgcagcaatttaaatcatttcttttaaagcaaaagcaattttctgaaaattttcacsequence catttacgaacgatagcgctatgcscatgcagctgctgctgctgatcgccctstccctggccct ggtgaccaactcccacgacacctactggaccgagcagatcgacccctggttcctgcacggcct gggcctggcccgcacctactggcgcgacaccaacaccggccgcctgtggctgcccaacaccc ccgacgcctccgacccccagcgcggccgcctggccccccccggcgagctgaacctgaccac cgcctccgtgcccatgctgcgctggtacgccgagcgcttctgcttcgtgctggtgaccaccgcc gagttcccccgcgaccccggccagctgctgtacatccccaagacctacctgctgggccgcccc cgcaacgcctccctgcccgagctgcccgaggccggccccacctcccgcccccccgccgagg tgacccagctgaagggcctgtcccacaaccccggcgcctccgccctgctgcgctcccgcgcct gggtgaccttcgccgccgcccccgaccgcgagggcctgaccttcccccgcggcgacgacgg cgccaccgagcgccaccccgacggccgccgcaacgcccccccccccggcccccccgccgg caccccccgccaccccaccaccaacctgtccatcgcccacctgcacaacgcctccgtgacctg gctggccgcccgcggcctgctgcgcacccccggccgctacgtgtacctgtccccctccgcctc cacctggcccgtgggcgtgtggaccaccggcggcctggccttcggctgcgacgccgccctgg tgcgcgcccgctacggcaagggcttcatgggcctggtgatctccatgcgcgactccccccccg ccgagatcatcgtggtgcccgccgacaagaccctggcccgcgtgggcaaccccaccgacga gaacgcccccgccgtgctgcccggcccccccgccggcccccgctaccgcgtgttcgtgctgg gcgcccccacccccgccgacaacggctccgccctggacgccctgcgccgcgtggccggcta ccccgaggagtccaccaactacgcccagtacatgtcccgcgcctacgccgagttcctgggcga ggaccccggctccggcaccgacgcccgcccctccctgttctggcgcctggccggcctgctgg cctcctccggcttcgccttcgtgaacgccgcccacgcccacgacgccatccgcctgtccgacct gctgggcttcctggcccactcccgcgtgctggccggcctggccgcccgcggcgccgccggct gcgccgccgactccgtgttcctgaacgtgtccgtgctggaccccgccgcccgcctgcgcctgg aggcccgcctgggccacctggtggccgccatcctggagcgcgagcagtccctggccgcccacgccctgggctaccagctggccttcgtgctggactcccccgccgcctacggcgccgtggccccP-634738-PC SequenceNucleic Acid Sequence SEQ ID NO: Namectccgccgcccgcctgatcgacgccctgtacgccgagttcctgggcggccgcgccctgaccg cccccatggtgcgccgcgccctgttctacgccaccgccgtgctgcgcgcccccttcctggccg gcgccccctccgccgagcagcgcgagcgcgcccgccgcggcctgctgatcaccaccgccct gtgcacctccgacgtggccgccgccacccacgccgacctgcgcgccgccctggcccgcacc gaccaccagaagaacctgttctggctgcccgaccacttctccccctgcgccgcctccctgcgctt cgacctggccgagggcggcttcatcctggacgccctggccatggccacccgctccgacatccc cgccgacgtgatggcccagcagacccgcggcgtggcctccgtgctgacccgctgggcccact acaacgccctgatccgcgccttcgtgcccgaggccacccaccagtgctccggcccctcccaca acgccgagccccgcatcctggtgcccatcacccacaacgcctcctacgtggtgacccacaccc ccctgccccgcggcatcggctacaagctgaccggcgtggacgtgcgccgccccctgttcatca cctacctgaccgccacctgcgagggccacgcccgcgagatcgagcccaagcgcctggtgcg caccgagaaccgccgcgacctgggcctggtgggcgccgtgttcctgcgctacacccccgccg gcgaggtgatgtccgtgctgctggtggacaccgacgccacccagcagcagctggcccagggc cccgtggccggcacccccaacgtgttctcctccgacgtgccctccgtggccctgctgctgttccc caacggcaccgtgatccacctgctggccttcgacaccctgcccatcgccaccatcgccccctaa taaactagtagtgactgactaggatctggtaccactaaaccagcclcaagaacacccgaatg gagtctctaagctacataataccaacttacacttacaaaatgttgtcccccaaaatgtagccat tcgtatctgctcctaataaaaagaacigtttcttcaca\icX.aaaaaaaaaaaaa3Laaaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaa aaaaaaaaa aaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaa

[0249] In another embodiment, an HSV glycoprotein protein fragment encoded by RNA utilized in the methods and compositions of the present disclosure is an antigenic fragment. In another embodiment, an HSV glycoprotein protein fragment encoded by RNA utilized in the methods and compositions of the present disclosure is an immunoprotective antigen. In some embodiments, an immunoprotective antigen need not be the entire protein. The protective immune response generally involves, in another embodiment, an antibody response. In another embodiment, mutants, sequence conservative variants, and functional conservative variants of glycoproteins provided herein are useful in methods and compositions of the present disclosure, provided that all such variants retain theP-634738-PC required immuno-protective effect. In another embodiment, the antigenic fragment can comprise an immuno-protective antigen from any strain of HSV. In another embodiment, the antigenic fragment can comprise sequence variants of HSV, as found in infected individuals.

[0250] In some embodiments, an HSV glycoprotein antigen or antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure is a homologue of a sequence provided herein. In another embodiment, an HSV glycoprotein antigen or antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure is an isoform of the sequence provided herein. In another embodiment, an HSV glycoprotein antigen or antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure is a variant of the sequence provided herein. In another embodiment, an HSV glycoprotein antigen or antigenic fragment thereof, encoded by RNA utilized in the methods and compositions of the present disclosure is a fragment of the sequence provided herein.

[0251] In another embodiment, the glycoprotein fragment encoded by RNA of the methods and compositions of the present disclosure comprises the ectodomain of the glycoprotein or antigenic fragment thereof. In another embodiment, the glycoprotein fragment encoded by RNA of the methods and compositions of the present disclosure consists of the ectodomain of the glycoprotein or antigenic fragment thereof. In another embodiment, the glycoprotein fragment encoded by RNA of the methods and compositions of the present disclosure comprises a fragment of the ectodomain of the glycoprotein. In another embodiment, the glycoprotein fragment may be any glycoprotein fragment known in the art.

[0252] In another embodiment, the glycoprotein or antigenic fragment encoded by an RNA utilized in the methods and compositions of the present disclosure may be from any strain of HSV. In another embodiment, the antigenic fragment encoded by RNA utilized in the methods and compositions of the present disclosure may comprise sequence variants of HSV, as found in infected individuals.

[0253] In some embodiments, “variant” refers to an amino acid or nucleic acid sequence (or in other embodiments, an organism or tissue) that is different from the majority of the population but is still sufficiently similar to the common mode to be considered to be one of them, for example splice variants. In some embodiments, the variant may a sequence conservative variant, while in another embodiment, the variant may be a functional conservative variant. In some embodiments, a variant may comprise an addition, deletion or substitution of one or more amino acids.P-634738-PC

[0254] “Immune evasion domain” refers, in some embodiments, to a domain that interferes with or reduces in vivo anti-HSV efficacy of anti-HSV antibodies (e.g. anti-gD antibodies). In another embodiment, the domain interferes or reduces in vivo anti-HSV efficacy of an anti-HSV immune response. In another embodiment, the domain reduces the immunogenicity of an HSV protein (e.g. gD) during subsequent infection. In another embodiment, the domain reduces the immunogenicity of an HSV protein during subsequent challenge. In another embodiment, the domain reduces the immunogenicity of HSV during subsequent challenge. In another embodiment, the domain reduces the immunogenicity of an HSV protein in the context of ongoing HSV infection. In another embodiment, the domain reduces the immunogenicity of HSV in the context of ongoing HSV infection. In another embodiment, the domain functions as an IgG Fc receptor. In another embodiment, the domain promotes antibody bipolar bridging, which in some embodiments, is a term that refers to an antibody molecule binding by its Fab domain to an HSV antigen and by its Fc domain to a separate HSV antigen, such as in some embodiments, gE, thereby blocking the ability of the Fc domain to activate complement.

[0255] The present disclosure also provides for modified RNA encoding analogs of HSV proteins or polypeptides, or fragments thereof. Analogs may differ from naturally occurring proteins or peptides by conservative amino acid sequence substitutions or by modifications which do not affect sequence, or by both.

[0256] In another embodiment, an HSV glycoprotein encoded by modified RNA of the present disclosure is homologous to a sequence set forth hereinabove, either expressly or by reference to a GenBank entry. The terms “homology,” “homologous,” etc, when in reference to any protein or peptide, refer, in some embodiments, to a percentage of amino acid residues in the candidate sequence that are identical with the residues of a corresponding native polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology, and not considering any conservative substitutions as part of the sequence identity. Methods and computer programs for the alignment are well known in the art.

[0257] In another embodiment, “homology” refers to identity of a protein sequence encoded by an RNA to a sequence disclosed herein of greater than 70%. In another embodiment, the identity is greater than 72%. In another embodiment, the identity is greater than 75%. In another embodiment, the identity is greater than 78%. In another embodiment, the identity is greater than 80%. In another embodiment, the identity is greater than 82%. In another embodiment, the identity is greater than 83%.P-634738-PC In another embodiment, the identity is greater than 85%. In another embodiment, the identity is greater than 87%. In another embodiment, the identity is greater than 88%. In another embodiment, the identity is greater than 90%. In another embodiment, the identity is greater than 92%. In another embodiment, the identity is greater than 93%. In another embodiment, the identity is greater than 95%. In another embodiment, the identity is greater than 96%. In another embodiment, the identity is greater than 97%. In another embodiment, the identity is greater than 98%. In another embodiment, the identity is greater than 99%. In another embodiment, the identity is 100%.

[0258] In some embodiments, “isoform” refers to a version of a molecule, for example, a protein, with only slight differences to another isoform of the same protein. In some embodiments, isoforms may be produced from different but related genes, or in another embodiment, may arise from the same gene by alternative splicing. In another embodiment, isoforms are caused by single nucleotide polymorphisms.

[0259] In another embodiment, an RNA encoding a glycoprotein antigen or antigenic fragment thereof as provided herein further encodes an antigenic tag. In some embodiments, the tag is a histidine (“His”) tag. In some embodiments, the His tag comprises 5 histidine residues. In another embodiment, the His tag comprises 6 histidine residues.

[0260] In another embodiment, methods and compositions of the present disclosure utilize a chimeric molecule, comprising a fusion of an RNA encoding an HSV protein or antigenic fragment thereof, with an RNA encoding a tag polypeptide that provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is placed, in other embodiments, at the amino- or carboxyl-terminus of the protein or in an internal location therein. The presence of such epitope-tagged forms of the recombinant HSV protein or antigenic fragment thereof, is detected, in another embodiment, using an antibody against the tag polypeptide. In another embodiment, inclusion of the epitope tag enables the recombinant HSV protein or antigenic fragment thereof, to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are known in the art.

[0261] In some embodiments, the compositions of the present disclosure comprise an adjuvant, while in another embodiment, the compositions do not comprise an adjuvant. “Adjuvant” refers, in another embodiment, to compounds that, when administered to an individual or tested in vitro, increase the immune response to an antigen in the individual or test system to which the antigen is administered. In another embodiment, an immune adjuvant enhances an immune response to an antigen that isP-634738-PC weakly immunogenic when administered alone, i.e., inducing no or weak antibody titers or cell-mediated immune response. In another embodiment, the adjuvant increases antibody titers to the antigen. In another embodiment, the adjuvant lowers the dose of the antigen effective to achieve an immune response in the individual. Multiple types of adjuvants are known in the art and described in detail in U. S. Patent Publication 2013 / 0028925 which is hereby incorporated by reference herein.Secretory Signals - Signal Sequences and Signal Peptides

[0262] In some embodiments, an RNA encoding a glycoprotein as provided herein comprises a secretory signal sequence encoding a signal peptide, e.g., that is functional in mammalian cells. In some embodiments, a signal sequence encodes a modified signal peptide (e.g., comprising amino acid substitutions or amino acid additions). In some embodiments, a signal sequence is a codon optimized signal sequence.

[0263] In some embodiments, a utilized secretory signal is a heterologous secretory signal. In some embodiments, a heterologous secretory signal comprises or consists of a non-human secretory signal. In some embodiments, a heterologous secretory signal comprises or consists of a viral secretory signal. In some embodiments, a viral secretory signal comprises or consists of anHSV secretory signal (e.g., an HSV-1 or HSV-2 secretory signal). In some embodiments, a secretory signal comprises or consists of an HSV-1 secretory signal. In some embodiments, a secretory signal comprises or consists of an HSV-2 secretory signal. In some embodiments, a secretory signal encodes a signal peptide characterized by a length of about 15 to 30 amino acids. In some embodiments, a secretory signal encodes a signal peptide that preferably allows transport of an HSV-1 glycoprotein, or antigenic fragment thereof, an HSV-2 glycoprotein, or antigenic fragment thereof, or both, with which it is associated into a defined cellular compartment, preferably a cell surface, endoplasmic reticulum (ER) or endosomal-lysosomal compartment.

[0264] In some embodiments, a signal sequence is the native signal sequence of the encoded glycoprotein. In some embodiments, a signal sequence is or comprises an HSV glycoprotein D (gD) signal sequence (e.g., an HSV-1 or HSV-2 gD signal sequence).

[0265] In some embodiments, a signal sequence is or comprises an HSV glycoprotein C (gC) signal sequence (e.g., an HSV-1 or HSV-2 gC signal sequence). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gC signal peptide (SEQ ID NO: 56). In another embodiment, a signal peptide encoded by a signal sequence is or comprises an HSV-1 gC signal peptide (SEQ ID NO:57).P-634738-PC

[0266] In some embodiments, a signal sequence is or comprises an HSV glycoprotein E (gE) signal sequence (e.g., an HSV-1 or HSV-2 gE signal sequence). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gE signal peptide (SEQ ID NO: 58).

[0267] In some embodiments, a signal sequence is or comprises an HSV gB signal sequence (e.g., an HSV-1 or HSV-2 gB signal sequence). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gB signal peptide (SEQ ID NO: 60). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-1 gB signal peptide (SEQ ID NO: 61).

[0268] In some embodiments, a signal sequence is or comprises an HSV gl signal sequence (e.g., an HSV-1 or HSV-2 gl signal sequence). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gl signal peptide (SEQ ID NO: 62). In some embodiments, an HSV-2 gl signal peptide comprises amino acid residues 1-18 of the wild-type peptide (SEQ ID NO: 63). In some embodiments, a signal peptide is or comprises an HSV-1 gl signal peptide (SEQ ID NO: 64).

[0269] In other embodiments, a signal sequence is a heterologous signal sequence. In some embodiments, a heterologous signal peptide encoded by a heterologous signal sequence comprises an IL-2 signal peptide (SEQ ID NO: 65). In some embodiments, a heterologous signal peptide encoded by a heterologous signal sequence comprises or consists of an azurocidin signal peptide (SEQ ID NO: 66). In some embodiments, a heterologous signal peptide encoded by a heterologous signal sequence comprises or consists of an MHC Class II signal peptide (SEQ ID NO: 67). In some embodiments, a signal sequence comprises or consists of an Ebola virus signal sequence. In some embodiments, an Ebola virus signal peptide encoded by an Ebola virus signal sequence comprises or consists of an Ebola virus spike glycoprotein (SGP) signal peptide (SEQ ID NO: 68). In other embodiments, an RNA encoding a glycoprotein as provided herein does not comprise a signal sequence. In some embodiments, an RNA as provided herein only encodes an ectodomain without a signal peptide.

[0270] In some embodiments, a signal sequence encodes a signal peptide listed in Table 3, or a signal peptide having 1, 2, 3, 4, or 5 amino acid differences thereto. In some embodiments, a signal peptide is selected from those listed in Table 3 and functionally connected to the N-terminus of an HSV immunogen selected from those listed in Table 1.P-634738-PC TABLE 3: Exemplary signal peptidesSequence Name Amino Acid Sequence SEQ ID NO:HSV-2 gD Signal MGRLTSGVGTAALLVVAVGLRVVCA 54 SequenceHSV-1 gD Signal MGGAAARLGAVILFVVIVGLHGVRG 55 SequenceHSV-2 gC Signal MALGRVGLAVGLWGLLWVGVVVVLANA 56 SequenceHSV-1 gC Signal MDRGAVVGFL LGVCVVSCLA 57 SequenceHSV-2 gE Signal MARGAGLVFFVGVWVVSCLAAAP 58 SequenceHSV-1 gE Signal MDRGAVVGFLLGVCVVSCLA 59 SequenceHSV-2 gB Signal MRGGGLICALVVGALVAAVASA 60 SequenceHSV-1 gB Signal MHQGAPSWGRRWFVVWALLGLTLGVLVASA 61 SequenceHSV-2 gl Signal MPGRSLQGLAILGLWVCATG 62 SequenceHSV-2 gl Signal MPGRSLQGLAILGLWVCA 63 Sequence (1-18)HSV-1 gl Signal MPCRPLQGLVLVGLWVCATS 64 SequenceIL2 Signal Sequence MRMQLLLLIALSLALVTNS 65 Azurocidin Signal MTRLTVLALLAGLLAS SRA 66 SequenceMHCII Signal MA1SGVPVLGFFIIAVLMSAQESWA 67SequenceP-634738-PCSequence Name Amino Acid Sequence SEQ ID NO:EBV SGP Signal MGVTGILQLPRDRFKRTSFFLWVIILFQRTFSIP 68Sequence

[0271] In some embodiments, a signal sequence comprises a sequence listed in Table 4, or a signal sequence at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence listed in Table 4. In some embodiments, a signal sequence is selected from those listed in Table 4 and functionally connected (i.e., in frame) to the 5' end of an HSV immunogen nucleic acid sequence selected from those listed in Table 2.TABLE 4: Exemplary signal sequencesSequence Name Version Nucleic Acid Sequence SEQ ID NO:HSV-2 gD WT AUGGGCCGCCUGACCUCCGGCGUGGGCA 69CCGCCGCCCUGCUGGUGGUGGCCGUGGG CCUGCGCGUGGUGUGCGCC IL2 WT AUGCGCAUGCAGCUGCUGCUGCUGAUC 70GCCCUGUCCCUGGCCCUGGUGACCAACU CCAzurocidin WT AUGACCCGCCUGACCGUGCUGGCCCUGC 71UGGCCGGCCUGCUGGCCUCCUCCCGCGC C MHCII WT AUGGCCAUCUCCGGCGUGCCCGUGCUGG 72GCUUCUUCAUCAUCGCCGUGCUGAUGUC CGCCCAGGAGUCCUGGGCC

[0272] In some embodiments, a signal sequence of the RNA as provided herein encodes a signal peptide comprising an amino acid sequence of any one of SEQ ID NOs: 54-68. In some embodiments, a signal sequence of the RNA as provided herein comprises a nucleic acid sequence of any one of SEQ ID NOs: 69-72. In some embodiments, the signal sequence of the RNA as described herein comprises:P-634738-PC a) AUGGGCCGCCUGACCUCCGGCGUGGGCACCGCCGCCCUGCUGGUGGUGGCCGUGGGC CUGCGCGUGGUGUGCGCC (SEQ ID NO: 69),b) AUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCC(SEQ ID NO: 70), orc) AUGGCCAUCUCCGGCGUGCCCGUGCUGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCC GCCCAGGAGUCCUGGGCC (SEQ ID NO: 72).Exemplary signal peptide and HSV immnuogen combinations

[0273] The present disclosure also provides RNA comprising a nucleotide sequence encoding a protein, wherein the protein comprises an HSV (e.g., HSV-1, HSV-2, or both) glycoprotein or antigenic fragment thereof, and a signal peptide. In some embodiments, a nucleotide sequence encodes a protein, wherein the protein comprises an HSV-2 glycoprotein, and a signal peptide.

[0274] Exemplary proteins comprising signal peptides and HSV-2 immunogens are shown in Table 5. In some embodiments, a protein of the present disclosure comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 5TABLE 5: Exemplary signal peptide / HSV-2 immunogen combinationsSEQ Signal HSVAmino Acid SequenceID NO: Peptide Glycoprotein73 IL2 HSV-2 gC (27- MRMQLLLLIALSLALVTNSASPGRTITVGPRGNA 426) SNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAK P APPPKTGPPKT S SEPVRCNRHDPL ARYGSRVQIRC RFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVM VNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGA SPRLYSVVGPLGRQRLIIEELTLETQGMYYWVWGR TDRP S AYGTWVRVRVFRPP S LT IH PH A VLEGQPFK ATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQP-634738-PC SEQ Signal HSVAmino Acid SequenceID NO: Peptide Glycoprotein TQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWH RDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCT AGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGR PGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH74 IL2 HSV-2 gC (28- MRMQLLLLIALSLALVTNSSPGRTITVGPRGNAS 426) NAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKP APPPKTGPPKT S SEP VRCNRHDPLARYGSRVQIRCR FPN STRTEFRLQIWRYAT ATD AEIGT AP SLEEVMV NVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGAS PRLYSVVGPLGRQRLIIEELTLETQGMYYWVWGR TDRP S AYGTW VRVRVFRPP SLTIHPHA VLEGQPFK ATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQ TQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWH RDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCT AGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGR PGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH77 HSV-2 HSV-2 gC (28- MALGRVGLAVGLWGLLWVGVWVLANASPGR gc 426) TITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRK ATK SKASTAKP APPPKTGPPKT S SEP VRCNRHDPL ARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDAEI GTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVI WAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQ GMYYWVWGRTDRP S A YGTW VRVRVFRPP S LTIH P HAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRR VFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPP RTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITM EFTGDHAVCT AGC VPEGVTF AWFLGDD S SP AEKVP-634738-PC SEQ Signal HSVAmino Acid SequenceID NO: Peptide Glycoprotein AVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGY PDGIPVLEHH78 HSV-2 HSV-2 gC (27- MALGRVGLAVGLWGLLWVGVVVVLANAASPG gc 426) RTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPR KATKSKASTAKPAPPPKTGPPKTS SEPVRCNRHDP LARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDA EIGTAP SLEEVMVNVS APPGGQLVYD S APNRTDPH VIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLET QGMYYWVWGRTDRP S AYGT WVRVRVFRPP SLTI HPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDG RRVFDP AQIHTQTQENPDGF STV ST VT S A A VGGQG PPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTIT MEFTGDHA VCTAGC VPEGVTF AWFLGDD S SP AEK VAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAG YPDGIPVLEHH79 IL2 HSV-2 gD MRMQLLLLIALSLALVTNSADPSLKMADPNRFR (30-331) GKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPI T VY YA VEER ACRSVLLH APSE APQIVRGASDEARK HTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLG VCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFET AGTYLRLVKINDWTEITQFILEHRARASCKYALPL RIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTV ALYSLKIAGWHGPKPPYTSTLLPPELSDTTNATQPE LVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVA PHH80 IL2 HSV-2 gD MRMQLLLLIALSLALVTNSKYALADPSLKMADP (26-331) NRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQ PP SIPIT VYYA VLERACRS VLLHAP SEAPQIVRGASP-634738-PC SEQ Signal HSVAmino Acid SequenceID NO: Peptide GlycoproteinDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECP YNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMH APAFETAGTYLRLVKINDWTEITQFILEHRARASCK YALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPE NQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDTT NATQPEL VPEDPED S ALLEDPAGTVS SQIPPNWHIP SIQDVAPHH81 HSV-2 HSV-2 gD (SO- MGRLTSGVGTAALL VVA VGLRVVC A ADP SLKM gD 331) ADPNRFRGKNLP VLDQLTDPPGVKRV YHIQP SLED PFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRG ASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTE CPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFL MHAPAFETAGTYLRLVKINDWTEITQFILEHRARA SCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPR FIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELS DTTNATQPEL VPEDPED S ALLEDPAGTVS SQIPPNW HIP SIQDVAPHH82 HSV-2 HSV-2 gD (26- MGRLTSGVGTAALL VVA VGLRVVCAKYAL ADP gD 331) SLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQ P SLEDPFQPPSIPIT VYYA VLERACRS VLLHAP SEAP QIVRGASDEARKHTYNLTIAWYRMGDNCAIPITV MEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSED NLGFLMHAPAFETAGTYLRLVKINDWTEITQFILE HRARASCKYALPLRIPPAACLTSKAYQQGVTVDSI GMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTL LPPEL SDTTNATQPEL VPEDPED S ALLEDPAGTVS S QIPPNWHIP SIQDVAPHHP-634738-PC SEQ Signal HSVAmino Acid SequenceID NO: Peptide Glycoprotein83 IL2 HSV-2 gE MRMQLLLLIALSLALVTNSRTSWKRVTSGEDVV (24-405) LLPAPAGPEERTRAHKLLWAAEPLDACGPLRPSW VALWPPRRVLETVVDAACMRAPEPLAIAYSPPFPA GDEGLYSELAWRDRVAVVNESLVIYGALETDSGL YTLSVVGLSDEARQVASVVLWEPAPVPTPTPDDY DEEDDAGVSERTPVSVPPPTPPRRPPVAPPTHPRVIP EVSHVRGVTVHMETPEAILFAPGETFGTNVSIHAIA HDDGP YAMDVVWMRFD VP S SC AEMRIYEACL YH PQLPECL SP AD APC AVS S W AYRLA VRS YAGC SRTT PPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQH AGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVV EQHLPQRQPEPVEPTRPHVRA85 HSV-2 HSV-2 gE MARGAGLVFFVGVWVVSCLAAAPRTSWKRVTS gE (24-405) GEDWLLPAPAGPEERTRAHKLLWAAEPLDACGP LRP S W V ALWPPRR VLET VVDAAC MR APEPL AIA Y SPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALE TDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTP TPDDYDEEDDAGVSERTPVSVPPPTPPRRPPVAPPT HPRVIPEVSHVRGVTVHMETPEAILFAPGETFGTNV SIHAIAHDDGPYAMDVVWMRFDVPSSCAEMRIYE ACLYHPQLPECLSP AD APCAVSSW AYRLA VRSYA GC SRTTPPPRCF AEARMEPVPGLAWLASTVNLEFQ HASPQHAGLYLCVVYVDDHIHAWGHMTISTAAQ YRNAWEQHLPQRQPEPVEPTRPHVRA

[0275] In some embodiments, a polypeptide provided herein comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 73 or SEQ ID NO: 74 or a portion thereof.P-634738-PC

[0276] In some embodiments, a polypeptide provided herein comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 79, 80, 81, or 82 or a portion thereof.

[0277] In some embodiments, a polypeptide provided herein comprises an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%>, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 83 or a portion thereof.Exemplary signal sequence and HSV immunogen nucleotide sequence combinations

[0278] The present disclosure also provides RNAs comprising nucleotide sequences as provided herein. In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gC protein or antigenic fragment thereof. In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gD protein or antigenic fragment thereof. In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gE protein or antigenic fragment thereof.

[0279] Exemplary RNA comprising a signal sequence (i.e., encoding a signal peptide) and a sequence encoding an HSV-2 glycoprotein are shown in Table 6 below. In some embodiments, an RNA of the present disclosure comprises a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 6.TABLE 6: Exemplary signal sequence / HSV-2 glycoprotein sequence combinationsSEQ SignalImmunogen Nucleotide SequenceID NO: Sequence86 IL2 HSV-2 gC AUGCGCAUGCAGCUGCUGCUGCUGAU (27-426) CGCCCUGUCCCUGGCCCUGGUGACCA ACUCCGCCUCCCCCGGCCGCACCAUC ACCGUGGGCCCCCGCGGCAACGCCUC CAACGCCGCCCCCUCCGCCUCCCCCCG CAACGCCUCCGCCCCCCGCACCACCCC CACCCCCCCCCAGCCCCGCAAGGCCACP-634738-PC SEQ SignalImmunogen Nucleotide SequenceID NO: SequenceCAAGUCCAAGGCCUCCACCGCCAAGC CCGCCCCCCCCCCCAAGACCGGCCCCC CCAAGACCUCCUCCGAGCCCGUGCGC UGCAACCGCCACGACCCCCUGGCCCG CUACGGCUCCCGCGUGCAGAUCCGCU GCCGCUUCCCCAACUCCACCCGCACC GAGUUCCGCCUGCAGAUCUGGCGCUA CGCCACCGCCACCGACGCCGAGAUCG GCACCGCCCCCUCCCUGGAGGAGGUG AUGGUGAACGUGUCCGCCCCCCCCGG CGGCCAGCUGGUGUACGACUCCGCCC CCAACCGCACCGACCCCCACGUGAUC UGGGCCGAGGGCGCCGGCCCCGGCGC CUCCCCCCGCCUGUACUCCGUGGUGG GCCCCCUGGGCCGCCAGCGCCUGAUC AUCGAGGAGCUGACCCUGGAGACCCA GGGCAUGUACUACUGGGUGUGGGGCC GCACCGACCGCCCCUCCGCCUACGGC ACCUGGGUGCGCGUGCGCGUGUUCCG CCCCCCCUCCCUGACCAUCCACCCCCA CGCCGUGCUGGAGGGCCAGCCCUUCA AGGCCACCUGCACCGCCGCCACCUAC UACCCCGGCAACCGCGCCGAGUUCGU GUGGUUCGAGGACGGCCGCCGCGUGU UCGACCCCGCCCAGAUCCACACCCAG ACCCAGGAGAACCCCGACGGCUUCUC CACCGUGUCCACCGUGACCUCCGCCG CCGUGGGCGGCCAGGGCCCCCCCCGCP-634738-PC SEQ SignalImmunogen Nucleotide SequenceID NO: SequenceACCUUCACCUGCCAGCUGACCUGGCA CCGCGACUCCGUGUCCUUCUCCCGCC GCAACGCCUCCGGCACCGCCUCCGUG CUGCCCCGCCCCACCAUCACCAUGGA GUUCACCGGCGACCACGCCGUGUGCA CCGCCGGCUGCGUGCCCGAGGGCGUG ACCUUCGCCUGGUUCCUGGGCGACGA CUCCUCCCCCGCCGAGAAGGUGGCCG UGGCCUCCCAGACCUCCUGCGGCCGC CCCGGCACCGCCACCAUCCGCUCCACC CUGCCCGUGUCCUACGAGCAGACCGA GUACAUCUGCCGCCUGGCCGGCUACC CCGACGGCAUCCCCGUGCUGGAGCAC CACUAA87 HSV-2 gD HSV-2 gD AUGGGCCGCCUGACCUCCGGCGUGGG (26-331) CACCGCCGCCCUGCUGGUGGUGGCCG UGGGCCUGCGCGUGGUGUGCGCCAAG UACGCCCUGGCCGACCCCUCCCUGAA GAUGGCCGACCCCAACCGCUUCCGCG GCAAGAACCUGCCCGUGCUGGACCAG CUGACCGACCCCCCCGGCGUGAAGCG CGUGUACCACAUCCAGCCCUCCCUGG AGGACCCCUUCCAGCCCCCCUCCAUC CCCAUCACCGUGUACUACGCCGUGCU GGAGCGCGCCUGCCGCUCCGUGCUGC UGCACGCCCCCUCCGAGGCCCCCCAG AUCGUGCGCGGCGCCUCCGACGAGGC CCGCAAGCACACCUACAACCUGACCAP-634738-PC SEQ SignalImmunogen Nucleotide SequenceID NO: SequenceUCGCCUGGUACCGCAUGGGCGACAAC UGCGCCAUCCCCAUCACCGUGAUGGA GUACACCGAGUGCCCCUACAACAAGU CCCUGGGCGUGUGCCCCAUCCGCACC CAGCCCCGCUGGUCCUACUACGACUC CUUCUCCGCCGUGUCCGAGGACAACC UGGGCUUCCUGAUGCACGCCCCCGCC UUCGAGACCGCCGGCACCUACCUGCG CCUGGUGAAGAUCAACGACUGGACCG AGAUCACCCAGUUCAUCCUGGAGCAC CGCGCCCGCGCCUCCUGCAAGUACGC CCUGCCCCUGCGCAUCCCCCCCGCCGC CUGCCUGACCUCCAAGGCCUACCAGC AGGGCGUGACCGUGGACUCCAUCGGC AUGCUGCCCCGCUUCAUCCCCGAGAA CCAGCGCACCGUGGCCCUGUACUCCC UGAAGAUCGCCGGCUGGCACGGCCCC AAGCCCCCCUACACCUCCACCCUGCU GCCCCCCGAGCUGUCCGACACCACCA ACGCCACCCAGCCCGAGCUGGUGCCC GAGGACCCCGAGGACUCCGCCCUGCU GGAGGACCCCGCCGGCACCGUGUCCU CCCAGAUCCCCCCCAACUGGCACAUC CCCUCCAUCCAGGACGUGGCCCCCCA CCACUAA88 IL2 HSV-2 gE AUGCGCAUGCAGCUGCUGCUGCUGAU (24-405) CGCCCUGUCCCUGGCCCUGGUGACCAACUCCCGCACCUCCUGGAAGCGCGUGP-634738-PC SEQ SignalImmunogen Nucleotide SequenceID NO: SequenceACCUCCGGCGAGGACGUGGUGCUGCU GCCCGCCCCCGCCGGCCCCGAGGAGC GCACCCGCGCCCACAAGCUGCUGUGG GCCGCCGAGCCCCUGGACGCCUGCGG CCCCCUGCGCCCCUCCUGGGUGGCCC UGUGGCCCCCCCGCCGCGUGCUGGAG ACCGUGGUGGACGCCGCCUGCAUGCG CGCCCCCGAGCCCCUGGCCAUCGCCU ACUCCCCCCCCUUCCCCGCCGGCGACG AGGGCCUGUACUCCGAGCUGGCCUGG CGCGACCGCGUGGCCGUGGUGAACGA GUCCCUGGUGAUCUACGGCGCCCUGG AGACCGACUCCGGCCUGUACACCCUG UCCGUGGUGGGCCUGUCCGACGAGGC CCGCCAGGUGGCCUCCGUGGUGCUGG UGGUGGAGCCCGCCCCCGUGCCCACC CCCACCCCCGACGACUACGACGAGGA GGACGACGCCGGCGUGUCCGAGCGCA CCCCCGUGUCCGUGCCCCCCCCCACCC CCCCCCGCCGCCCCCCCGUGGCC- CCCCCCACCCACCCCCGCGUGAUCCCC GAGGUGUCCCACGUGCGCGGCGUGAC CGUGCACAUGGAGACCCCCGAGGCCA UCCUGUUCGCCCCCGGCGAGACCUUC GGCACCAACGUGUCCAUCCACGCCAU CGCCCACGACGACGGCCCCUACGCCA UGGACGUGGUGUGGAUGCGCUUCGAC GUGCCCUCCUCCUGCGCCGAGAUGCGP-634738-PC SEQ SignalImmunogen Nucleotide SequenceID NO: SequenceCAUCUACGAGGCCUGCCUGUACCACC CCCAGCUGCCCGAGUGCCUGUCCCCC GCCGACGCCCCCUGCGCCGUGUCCUC CUGGGCCUACCGCCUGGCCGUGCGCU CCUACGCCGGCUGCUCCCGCACCACC CCCCCCCCCCGCUGCUUCGCCGAGGCC CGCAUGGAGCCCGUGCCCGGCCUGGC CUGGCUGGCCUCCACCGUGAACCUGG AGUUCCAGCACGCCUCCCCCCAGCAC GCCGGCCUGUACCUGUGCGUGGUGUA CGUGGACGACCACAUCCACGCCUGGG GCCACAUGACCAUCUCCACCGCCGCC CAGUACCGCAACGCCGUGGUGGAGCA GCACCUGCCCCAGCGCCAGCCCGAGC CCGUGGAGCCCACCCGCCCCCACGUG CGCGCCUAA

[0280] In some embodiments, a first ribonucleotide provided herein comprises a ribonucleic acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the ribonucleic acid sequence of SEQ ID NO: 73 or a portion thereof.

[0281] In some embodiments, a second ribonucleotide provided herein comprises a ribonucleic acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the ribonucleic acid sequence of SEQ ID NO: 74 or a portion thereof.Exemplary Nucleotide Sequence Features

[0282] In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gC protein or antigenic fragment thereof and a signal sequence. In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gDP-634738-PC protein or antigenic fragment thereof and a signal sequence. In some embodiments, an RNA provided herein comprises a nucleotide sequence that encodes an HSV-2 gE protein or antigenic fragment thereof and a signal sequence.

[0283] In some embodiments, nucleotide sequences provided herein can comprise a nucleotide sequence that encodes a 5’UTR and / or a 3’ UTR. In some embodiments, polynucleotides provided herein can comprise a nucleotide sequence that encodes a polyA tail. In some embodiments, nucleotide sequences provided herein may comprise a 5’ cap, which may be incorporated during transcription, or joined to a nucleotide sequence post-transcription.

[0284] In some embodiments, a nucleotide sequence provided herein encodes one or more glycoprotein antigens (e.g., gC, gD, gE, or a combination thereof) or antigenic fragments thereof. In some embodiments, an RNA comprises a 5’ cap, a 5’UTR, a nucleotide sequence that encodes one or more glycoprotein antigens (e.g., gC, gD, gE, or a combination thereof), or antigenic fragments thereof, a 3’ UTR, and a polyA tail.1. 5' Cap

[0285] A structural feature of messenger RNA (mRNA) is a cap structure at the five-prime end (5'). Natural eukaryotic mRNA comprise a 7-methylguanosine cap linked to the mRNA via a 5' to 5'-triphosphate bridge resulting in a capO structure (m7GpppN). In most eukaryotic mRNA and some viral mRNA, further modifications can occur at the 2'-hydroxyl-group (2’ -OH) (e.g., the 2'-hydroxyl group may be methylated to form 2'-O-Me) of the first and subsequent nucleotides producing “capl” and “cap2” five-prime ends, respectively). Diamond, et al., (2014) Cytokine & growth Factor Reviews, 25:543-550, which is incorporated herein by reference in its entirety, reported that capO-mRNA cannot be translated as efficiently as capl -mRNA in which the role of 2'-0-Me in the penultimate position at the mRNA 5’ end is determinant. Lack of the 2'-O-met has been shown to trigger innate immunity and activate an interferon (IFN) response. Daffis, et al. (2010) Nature, 468:452-456; and Ziist et al. (2011) Nature Immunology, 12:137-143, each of which is incorporated herein by reference in its entirety.

[0286] RNA capping is well researched and is described, e.g., in Decroly E et al. (2012) Nature Reviews 10: 51-65; and in Ramanathan A. et al., (2016) Nucleic Acids Res; 44(16): 7511-7526, the entire contents of each of which are hereby incorporated by reference. For example, in some embodiments, a 5 ’-cap structure which may be suitable in the context of the present disclosure is a capO (methylation of the first nucleobase, e.g., m7GpppN), capl (additional methylation of the riboseP-634738-PC of the adjacent nucleotide of m7GpppN), cap2 (additional methylation of the ribose of the 2nd nucleotide downstream of the m7GpppN), cap3 (additional methylation of the ribose of the 3rd nucleotide downstream of the m7GpppN), cap4 (additional methylation of the ribose of the 4th nucleotide downstream of the m7GpppN), ARCA (“anti-reverse cap analogue”), modified ARCA (e.g. phosphothioate modified ARCA), inosine, N1 -methyl-guanosine, 2 ’-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.

[0287] The term “5'-cap” as used herein refers to a structure found on the 5'-end of an RNA, e.g., mRNA, and generally includes a guanosine nucleotide connected to an RNA, e.g., mRNA, via a 5'-to 5'-triphosphate linkage (also referred to as Gppp or G(5')ppp(5')). In some embodiments, a guanosine nucleoside included in a 5’ cap may be modified, for example, by methylation at one or more positions (e.g., at the 7-position) on a base (guanine), and / or by methylation at one or more positions of a ribose. In some embodiments, a guanosine nucleoside included in a 5’ cap comprises a 3’0 methylation at a ribose (3’0MeG). In some embodiments, a guanosine nucleoside included in a 5' cap comprises methylation at the 7-position of guanine (m7G). In some embodiments, a guanosine nucleoside included in a 5' cap comprises methylation at the 7'-position of guanine and a 3' O methylation at a ribose (m7(3'OMeG)). It will be understood that the notation used in the above paragraph, e.g., “(m27,3'-O)G” or “m7(3'OMeG)”, applies to other structures provided herein.

[0288] In some embodiments, providing an RNA with a 5'-cap disclosed herein may be achieved by in vitro transcription, in which a 5'-cap is co-transcriptionally incorporated into an RNA strand, or may be attached to an RNA post-transcriptionally using capping enzymes. In some embodiments, co-transcriptional capping with a cap disclosed herein improves the capping efficiency of an RNA compared to co-transcriptional capping with an appropriate reference comparator. In some embodiments, improving capping efficiency can increase a translation efficiency and / or translation rate of an RNA, and / or increase expression of an encoded protein. In some embodiments, alterations to polynucleotides generate a non-hydrolyzable cap structure which can, for example, prevent decapping and increase RNA half-life.

[0289] In some embodiments, a utilized 5' cap is a capO, a capl, or cap2 structure. See, e.g., Fig. 1 of Ramanathan A et al., and Fig. 1 of Decroly E et al., each of which is incorporated herein by reference in its entirety. In some embodiments, an RNA provided herein comprises a capl structure. In some embodiments, an RNA provided herein comprises a cap2 structure.P-634738-PC

[0290] In some embodiments, an RNA provided herein comprises a capO structure. In some embodiments, a capO structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G). In some embodiments, such a capO structure is connected to an RNA via a 5'- to 5'-triphosphate linkage and is also referred to herein as (m7)Gppp. In some embodiments, a capO structure comprises a guanosine nucleoside methylated at the 2'-position of the ribose of guanosine. In some embodiments, a capO structure comprises a guanosine nucleoside methylated at the 3 '-position of the ribose of guanosine. In some embodiments, a guanosine nucleoside included in a 5' cap comprises methylation at the 7-position of guanine and at the 2'-position of the ribose ((m27,2'-O)G). In some embodiments, a guanosine nucleoside included in a 5' cap comprises methylation at the 7-position of guanine and at the 2'-position of the ribose ((m27,3'-O)G).

[0291] In some embodiments, a capl structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G) and optionally methylated at the 2' or 3' position of the ribose, and a 2'0 methylated first nucleotide in an RNA ((m2'-0)Nl). In some embodiments, a capl structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G) and the 3' position of the ribose, and a 2'0 methylated first nucleotide in an RNA ((m2'-0)Nl). In some embodiments, a capl structure is connected to an RNA via a 5'- to 5 '-triphosphate linkage and is also referred to herein as, e.g., ((m7)Gppp(2'-O)Nl) or (m27,3’-O)Gppp(2'-O)Nl), wherein N1 is as defined and provided herein. In some embodiments, a capl structure comprises a second nucleotide, N2, which is at position 2 and is chosen from A, G, C, or U, e.g., (m7)Gppp(2'-O)NlpN2 or (m27,3’-O)Gppp(2'-O)NlpN2, wherein each of N1 and N2 is as defined and provided herein.

[0292] In some embodiments, a cap2 structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G) and optionally methylated at the 2' or 3' position of the ribose, and 2'0 methylated first and second nucleotides in an RNA ((m2’-O)Nlp(m2’-O)N2). In some embodiments, a cap2 structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G) and the 3' position of the ribose, and 2'0 methylated first and second nucleotides in an RNA. In some embodiments, a cap2 structure is connected to an RNA via a 5'- to 5'-triphosphate linkage and is also referred to herein as, e.g., ((m7)Gppp(2'-O)Nlp(2'-O)N2) or (m27,3’-O)Gppp(2'-O)Nlp(2'-O)N2), wherein each of N1 and N2 is as defined and provided herein.

[0293] In some embodiments, the 5' cap is a dinucleotide cap structure. In some embodiments, the 5' cap is a dinucleotide cap structure comprising Nl, wherein N1 is as defined and provided herein.P-634738-PC In some embodiments, the 5' cap is a dinucleotide cap G*N1, wherein N1 is as defined above and herein, and G* comprises a structure of formula (I):(I)or a salt thereof,wherein each R2 and R3 is -OH or -0CH3; and X is O or S.

[0294] In some embodiments, R2 is -OH. In some embodiments, R2 is -OCH3. In some embodiments, R3 is -OH. In some embodiments, R3 is -OCH3. In some embodiments, R2 is -OH and R3 is -OH. In some embodiments, R2 is -OH and R3 is -CH3. In some embodiments, R2 is -CH3 and R3 is -OH. In some embodiments, R2 is -CH3 and R3 is -CH3.

[0295] In some embodiments, X is O. In some embodiments, X is S.

[0296] In some embodiments, the 5' cap is a dinucleotide capO structure (e.g., (m7)GpppNl, (m27,2’-O)GpppNl, (m27,3’-O)GpppNl, (m7)GppSpNl, (m27,2’-O)GppSpNl, or (m27,3’-O)GppSpNl), wherein N1 is as defined and provided herein. In some embodiments, the 5' cap is a dinucleotide capO structure (e.g., (m7)GpppNl, (m27,2’-O)GpppNl, (m27,3’-O)GpppNl, (m7)GppSpNl, (m27,2’-O)GppSpNl, or (m27,3’-O)GppSpNl), wherein N1 is G. In some embodiments, the 5' cap is a dinucleotide capO structure (e.g., (m7)GpppNl, (m27,2’-O)GpppNl, (m27,3’-O)GpppNl, (m7)GppSpNl, (m27,2’-O)GppSpNl, or (m27,3’-O)GppSpNl), wherein N1 is A, U, or C. In some embodiments, the 5' cap is a dinucleotide capl structure (e.g., (m7)Gppp(m2’-O)N1, (m27,2’-O)Gppp(m2’-O)Nl, (m27,3’-O)Gppp(m2’-O)Nl, (m7)GppSp(m2’-O)Nl, (m27,2’-O)GppSp(m2’-O)Nl, or (m27,3’-O)GppSp(m2’-O)Nl), wherein N1 is as defined and provided herein. In some embodiments, the 5' cap is selected from the group consisting of (m7)GpppG (“EcapO”), (m7)Gppp(m2’-O)G (“Ecapl”), (m27,3’-O)GpppG (“ARCA” or “DI”), and (m27,2’-O)GppSpG (“beta-S-ARCA”). In some embodiments, the 5' cap is (m7)GpppG (“EcapO”), having a structure of formula (II):P-634738-PC OH OH(II)or a salt thereof.

[0297] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)G (“Ecapl”), having a structure of formula (III):OH OH(HI)or a salt thereof.

[0298] In some embodiments, the 5' cap is (m27,3’-O)GpppG (“ARCA” or “DI”), having a structure of formula (IV):OH Ox(IV)or a salt thereof.

[0299] In some embodiments, the 5' cap is (m27,2’-O)GppSpG (“beta-S-ARCA”), having a structure of formula (V):P-634738-PC OH(V)or a salt thereof.

[0300] In some embodiments, the 5' cap is a trinucleotide cap structure. In some embodiments, the 5' cap is a trinucleotide cap structure comprising NlpN2, wherein N1 and N2 are as defined and provided herein. In some embodiments, the 5' cap is a dinucleotide cap G*NlpN2, wherein N1 and N2 are as defined above and herein, and G* comprises a structure of formula (VI):or a salt thereof, wherein R2, R3, and X are as defined and provided herein.

[0301] In some embodiments, the 5' cap is a trinucleotide capO structure (e.g., (m7)GpppNlpN2, (m27,2’-O)GpppNlpN2, or (m27,3’-O)GpppNlpN2), wherein N1 and N2 are as defined and provided herein). In some embodiments, the 5' cap is a trinucleotide capl structure (e.g., (m7)Gppp(m2’-O)NlpN2, (m27,2’-O)Gppp(m2’-O)NlpN2, (m27,3’-O)Gppp(m2’-O)NlpN2), wherein N1 and N2 are as defined and provided herein. In some embodiments, the 5' cap is a trinucleotide cap2 structure (e.g., (m7)Gppp(m2’-O)Nlp(m2’-O)N2, (m27,2’-O)Gppp(m2’-O)Nlp(m2’-O)N2, (m27,3’-O)Gppp(m2’-O)Nlp(m2’-O)N2), wherein N1 andN2 are as defined and provided herein. In some embodiments, the 5' cap is selected from the group consisting of (m27,3’-O)Gppp(m2’-O)ApG (“CleanCap AG”, “CC413”), (m27,3’-O)Gppp(m2’-O)GpG (“CleanCap GG”),P-634738-PC (m7)Gppp(m2’-O)ApG, (m7)Gppp(m2’-O)GpG, (m27,3’-O)Gppp(m26,2’-O)ApG, and (m7)Gppp(m2’-O)ApU.

[0302] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m2’-O)ApG (“CleanCap AG”, “CC413”), having a structure of formula (VII):(VII)or a salt thereof.

[0303] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m2’-O)GpG (“CleanCap GG”), having a structure of formula (VIII):(VIII)P-634738-PC or a salt thereof.

[0304] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)ApG, having a structure of formula(IX)or a salt thereof.

[0305] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)GpG, having a structure of formula (X):OH OH(X)or a salt thereof.P-634738-PC

[0306] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m26,2’-O)ApG, having a structure of formula (XI):(XI)or a salt thereof.

[0307] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)ApU, having a structure of formula (XII):(XII)or a salt thereof.P-634738-PC

[0308] In some embodiments, the 5' cap is a tetranucleotide cap structure. In some embodiments, the 5' cap is a tetranucleotide cap structure comprising NlpN2pN3, whereinNl, N2, andN3 are as defined and provided herein. In some embodiments, the 5' cap is a tetranucleotide cap G*NlpN2pN3, wherein Nl, N2, and N3 are as defined above and herein, and G* comprises a structure of formula (XIII):or a salt thereof, wherein R2, R3, and X are as defined and provided herein.

[0309] In some embodiments, the 5' cap is a tetranucleotide capO structure (e.g. (m7)GpppNlpN2pN3, (m27’2’°)GpppNipN2pN3, or (m27’3’°)GpppNiN2pN3), wherein Ni, N2, and N3 are as defined and provided herein). In some embodiments, the 5’ cap is a tetranucleotide Capl structure (e.g., (m7)Gppp(m2'°)NipN2pN3, (m27’2'°)Gppp(m2'°)NipN2pN3, (m273'°)Gppp(m2’ °)NipN2N3), wherein Ni, N2, and N3 are as defined and provided herein. In some embodiments, the 5' cap is a tetranucleotide Cap2 structure (e.g., (m7)Gppp(m2'°)Nip(m2'°)N2pN3, (m27’2'°)Gppp(m2' °)Nip(m2-o)N2pN3, (m27’3'°)Gppp(m2'o)Nip(m2'o)N2pN3), wherein Ni, N2, and N3 are as defined and provided herein. In some embodiments, the 5' cap is selected from the group consisting of (m27’3’ °)Gppp(m2'°)Ap(m2"°)GpG, (m27’3’-o)Gppp(m2’-o)Gp(m2-°)GpC, (m7)Gppp(m2-°)Ap(m2’-°)UpA, and (m7)Gppp(m2’-°)Ap(m2-°)GpG.

[0310] In some embodiments, the 5' cap is (m27’3'°)Gppp(m2’°)Ap(m2‘°)GpG, having a structure of formula (XIV):P-634738-PC(XIV)or a salt thereof.

[0311] In some embodiments, the 5' cap is (m273'°)Gppp(m2'°)Gp(m2'°)GpC, having a structure of formula (XV):P-634738-PC(XV)or a salt thereof.

[0312] In some embodiments, the 5' cap is (m7)Gppp(m2’ °)Ap(m2’ °)UpA, having a structure of formula (XVI):P-634738-PC OH OH(XVI)or a salt thereof.

[0313] In some embodiments, the 5' cap is (m7)Gppp(m2'°)Ap(m2‘°)GpG, having a structure of formula (XVII):P-634738-PC(XVII)or a salt thereof.2. Cap Proximal Sequences

[0314] In some embodiments, a 5' UTR utilized in accordance with the present disclosure comprises a cap proximal sequence, e.g., as disclosed herein. In some embodiments, a cap proximal sequence comprises a sequence adjacent to a 5' cap. In some embodiments, a cap proximal sequence comprises nucleotides in positions +1, +2, +3, +4, and / or +5 of an RNA polynucleotide.

[0315] In some embodiments, a cap structure comprises one or more polynucleotides of a cap proximal sequence. In some embodiments, a cap structure comprises an m7guanosine cap and nucleotide +1 (Ni) of an RNA polynucleotide. In some embodiments, a cap structure comprises an m7guanosine cap and nucleotide +2 (N2) of an RNA polynucleotide. In some embodiments, a cap structure comprises an m7guanosine cap and nucleotides +1 and +2 (Ni and N2) of an RNA polynucleotide. In some embodiments, a cap structure comprises an m7guanosine cap and nucleotides +1, +2, and +3 (Ni, N2, and N3) of an RNA polynucleotide.

[0316] Those skilled in the art, reading the present disclosure, will appreciate that, in some embodiments, one or more residues of a cap proximal sequence (e.g., one or more of residues +1, +2, +3, +4, and / or +5) may be included in an RNA by virtue of having been included in a cap entity (e.g.,P-634738-PC a capl or cap2 structure, etc.); alternatively, in some embodiments, at least some of the residues in a cap proximal sequence may be enzymatically added (e.g., by a polymerase such as a T7 polymerase). For example, in certain exemplified embodiments where a m27’3’°Gppp(mi2'°)ApG cap is utilized, +1 (i.e., Ni) and +2 (i.e. N2) are the (mi2'°)A and G residues of the cap, and +3, +4, and +5 are added by a polymerase (e.g., T7 polymerase).

[0317] In some embodiments, the 5” cap is a dinucleotide cap structure, wherein the cap proximal sequence comprises Ni of the 5’ cap, where Ni is any nucleotide, e.g., A, C, G or U. In some embodiments, the 5' cap is a trinucleotide cap structure (e.g., the trinucleotide cap structures provided above and herein), wherein the cap proximal sequence comprises Ni and N2 of the 5' cap, wherein Ni and N2 are independently any nucleotide, e.g., A, C, G or U. In some embodiments, the 5' cap is a tetranucleotide cap structure (e.g., the trinucleotide cap structures described above and herein), wherein the cap proximal sequence comprises Ni, N2, and N3 of the 5' cap, wherein Ni, N2, and N3 are any nucleotide, e.g., A, C, G or U.

[0318] In some embodiments, e.g., where the 5' cap is a dinucleotide cap structure, a cap proximal sequence comprises NI of a the 5' cap, and N2, N3, N4 and N5, wherein NI to N5 correspond to positions +1, +2, +3, +4, and / or +5 of an RNA polynucleotide. In some embodiments, e.g., where the 5' cap is a trinucleotide cap structure, a cap proximal sequence comprises NI and N2 of a the 5' cap, and N3, N4 and N5, wherein NI to N5 correspond to positions +1, +2, +3, +4, and / or +5 of an RNA polynucleotide. In some embodiments, e.g., where the 5' cap is a tetranucleotide cap structure, a cap proximal sequence comprises NI, N2, and N3 of a the 5’ cap, and N4 and N5, wherein NI to N5 correspond to positions +1, +2, +3, +4, and / or +5 of an RNA polynucleotide.

[0319] In some embodiments, NI is A. In some embodiments, NI is C. In some embodiments, NI is G. In some embodiments, NI is U. In some embodiments, N2 is A. In some embodiments, N2 is C. In some embodiments, N2 is G. In some embodiments, N2 is U. In some embodiments, N3 is A. In some embodiments, N3 is C. In some embodiments, N3 is G. In some embodiments, N3 is U. In some embodiments, N4 is A. In some embodiments, N4 is C. In some embodiments, N4 is G. In some embodiments, N4 is U. In some embodiments, N5 is A. In some embodiments, N5 is C. In some embodiments, N5 is G. In some embodiments, N5 is U. It will be understood that, each of the embodiments described above and herein (e.g., for NI through N5) may be taken singly or in combination and / or may be combined with other embodiments of variables described above and herein (e.g., 5' caps).P-634738-PC

[0320] In some embodiments, a cap proximal sequence comprises Ai and G2 of the Capl structure, and a sequence comprising: A3A4U5 at positions +3, +4 and +5 respectively of the nucleotide sequence.3. 5’ UTR

[0321] In some embodiments, an RNA utilized in accordance with the present disclosure comprises a 5'-UTR. In some embodiments, a 5’-UTR may comprise a plurality of distinct sequence elements; in some embodiments, such plurality may be or comprise multiple copies of one or more particular sequence elements (e.g., as may be from a particular source or otherwise known as a functional or characteristic sequence element). In some embodiments, a 5’ UTR comprises multiple different sequence elements.

[0322] The term “untranslated region” or “UTR” is commonly used in the art to refer to a region in a DNA molecule which is transcribed but is not translated into an amino acid sequence, or to the corresponding region in an RNA polynucleotide, such as an mRNA molecule. An untranslated region (UTR) can be present 5' (upstream) of an open reading frame (5'-UTR) and / or 3' (downstream) of an open reading frame (3'-UTR). As used herein, the terms “five prime untranslated region” or “5' UTR” refer to a sequence of a nucleotide sequence between the 5' end of the nucleotide sequence (e.g., a transcription start site) and a start codon of a coding region of the nucleotide sequence. In some embodiments, “5' UTR” refers to a sequence of a nucleotide sequence that begins at the 5' end of the nucleotide sequence (e.g., a transcription start site) and ends one nucleotide (nt) before a start codon (usually AUG) of a coding region of the nucleotide sequence, e.g., in its natural context. In some embodiments, a 5' UTR comprises a Kozak sequence. A 5'-UTR is downstream of the 5'-cap (if present), e.g., directly adjacent to the 5'-cap. In some embodiments, a 5' UTR disclosed herein comprises a cap proximal sequence, e.g., as defined and provided herein. In some embodiments, a cap proximal sequence comprises a sequence adjacent to a 5' cap.

[0323] In some embodiments, an RNA disclosed herein comprises a 5' UTR having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to a 5' UTR with the sequence of SEQ ID NO: 89. In some embodiments, an RNA disclosed herein comprises a 5' UTR having the sequence of SEQ ID NO: 89.P-634738-PC 4. PolyA Tail

[0324] In some embodiments, a polynucleotide (e.g., DNA, RNA) disclosed herein comprises a polyadenylate (polyA) sequence, e.g., as provided herein. In some embodiments, a polyA sequence is situated downstream of a 3'-UTR, e.g., adjacent to a 3'-UTR.

[0325] As used herein, the term “poly(A) sequence” or “poly-A tail” refers to an uninterrupted or interrupted sequence of adenylate residues which is typically located at the 3'-end of an RNA polynucleotide. Poly(A) sequences are known to those of skill in the art and may follow the 3’-UTR in the RNAs provided herein. An uninterrupted poly(A) sequence is characterized by consecutive adenylate residues. In nature, an uninterrupted poly(A) sequence is typical. In some embodiments, polynucleotides disclosed herein comprise an uninterrupted poly(A) sequence. In some embodiments, polynucleotides disclosed herein comprise interrupted poly(A) sequence. In some embodiments, RNAs disclosed herein can have a poly(A) sequence attached to the free 3'-end of the RNA by a template-independent RNA polymerase after transcription or a poly(A) sequence encoded by DNA and transcribed by a template-dependent RNA polymerase.

[0326] It has been demonstrated that a poly (A) sequence of about 120 A nucleotides has a beneficial influence on the levels of RNA in transfected eukaryotic cells, as well as on the levels of protein that are translated from an open reading frame that is present upstream (51) of the poly(A) sequence (Holtkamp et al., 2006, Blood, vol. 108, pp. 4009-4017, which is herein incorporated by reference).

[0327] In some embodiments, a poly(A) sequence in accordance with the present disclosure is not limited to a particular length; in some embodiments, a poly(A) sequence is any length. In some embodiments, a poly(A) sequence comprises, essentially consists of, or consists of at least 20, at least 30, at least 40, at least 80, or at least 100 and up to 500, up to 400, up to 300, up to 200, or up to 150 A nucleotides, and, in particular, about 120 A nucleotides. In this context, "essentially consists of means that most nucleotides in the poly (A) sequence, typically at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by number of nucleotides in the poly(A) sequence are A nucleotides, but permits that remaining nucleotides are nucleotides other than A nucleotides, such as U nucleotides (uridylate), G nucleotides (guanylate), or C nucleotides (cytidylate). In this context, "consists of means that all nucleotides in the poly(A) sequence, i.e., 100% by number of nucleotides in the poly(A) sequence, are A nucleotides. The term “A nucleotide” or “A” refers to adenylate.P-634738-PC

[0328] In some embodiments, a poly(A) sequence is attached during RNA transcription, e.g., during preparation of in vitro transcribed RNA, based on a DNA template comprising repeated dT nucleotides (deoxythymidylate) in the strand complementary to the coding strand. The DNA sequence encoding a poly(A) sequence (coding strand) is referred to as a poly(A) cassette.

[0329] In some embodiments, the poly(A) cassette present in the coding strand of DNA essentially consists of dA nucleotides.

[0330] , but is interrupted by a random sequence of the four nucleotides (dA, dC, dG, and dT). Such a random sequence may be 5 to 50, 10 to 30, or 10 to 20 nucleotides in length. Such a cassette is disclosed in WO 2016 / 005324 Al, hereby incorporated by reference. Any poly(A) cassette disclosed in WO 2016 / 005324 Al, which is incorporated herein by reference in its entirety, may be used in accordance with the present disclosure. A poly(A) cassette that essentially consists of dA nucleotides, but is interrupted by a random sequence having an equal distribution of the four nucleotides (dA, dC, dG, dT) and having a length of e.g., 5 to 50 nucleotides shows, at the DNA level, constant propagation of plasmid DNA in E. coli and is still associated, at the RNA level, with the beneficial properties with respect to supporting RNA stability and translational efficiency is encompassed. In some embodiments, the poly(A) sequence contained in an RNA polynucleotide provided herein essentially consists of A nucleotides but is interrupted by a random sequence of the four nucleotides (A, C, G, U). Such a random sequence may be 5 to 50, 10 to 30, or 10 to 20 nucleotides in length.

[0331] In some embodiments, no nucleotides other than A nucleotides flank a poly(A) sequence at its 3'-end, i.e., the poly(A) sequence is not masked or followed at its 3'-end by a nucleotide other than A.

[0332] In some embodiments, the poly(A) sequence may comprise at least 20, at least 30, at least 40, at least 80, or at least 100 and up to 500, up to 400, up to 300, up to 200, or up to 150 nucleotides. In some embodiments, the poly(A) sequence may essentially consist of at least 20, at least 30, at least 40, at least 80, or at least 100 and up to 500, up to 400, up to 300, up to 200, or up to 150 nucleotides. In some embodiments, the poly(A) sequence may consist of at least 20, at least 30, at least 40, at least 80, or at least 100 and up to 500, up to 400, up to 300, up to 200, or up to 150 nucleotides. In some embodiments, the poly(A) sequence comprises at least 100 nucleotides. In some embodiments, the poly(A) sequence comprises about 150 nucleotides. In some embodiments, the poly(A) sequence comprises about 120 nucleotides.P-634738-PC

[0333] In some embodiments, a poly(A) sequence comprises a specific number of adenosines, such as about 50 or more, about 60 or more, about 70 or more, about 80 or more, about 90 or more, about 100 or more, about 120, or about 150 or about 200. In some embodiments a poly(A) sequence of an RNA may comprise 200 A residues or less. In some embodiments, a poly(A) sequence of an RNA may comprise about 200 A residues. In some embodiments, a poly(A) sequence of an RNA may comprise 180 A residues or less. In some embodiments, apoly(A) sequence 1 of an RNA may comprise about 180 A residues. In some embodiments, a poly(A) sequence may comprise 150 residues or less.5. 3' UTR

[0334] In some embodiments, an RNA utilized in accordance with the present disclosure comprises a 3'-UTR. As used herein, the terms “three prime untranslated region,” “3' untranslated region,” or “3' UTR” refer to a sequence of an mRNA molecule that begins following a stop codon of a coding region of an open reading frame sequence. In some embodiments, the 3' UTR begins immediately after a stop codon of a coding region of an open reading frame sequence, e.g., in its natural context. In other embodiments, the 3' UTR does not begin immediately after stop codon of the coding region of an open reading frame sequence, e.g., in its natural context. The term “3'-UTR” preferably does not include the poly(A) sequence. Thus, the 3'-UTR is upstream of the poly(A) sequence (if present), e.g. directly adjacent to the poly(A) sequence.

[0335] In some embodiments, an RNA disclosed herein comprises a 3'UTR comprising an F element and / or an I element. In some embodiments, a 3' UTR or a proximal sequence thereto comprises a restriction site. In some embodiments, a restriction site is a BamHI site. In some embodiments, a restriction site is an Xhol site.

[0336] In some embodiments, an RNA construct comprises an F element. In some embodiments, an F element sequence is a 3' UTR of amino-terminal enhancer of split (AES).

[0337] In some embodiments, an RNA disclosed herein comprises a 3' UTR having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to a 3’ UTR with the sequence of SEQ ID NO: 90. In some embodiments, an RNA disclosed herein comprises a 3' UTR with the sequence of SEQ ID NO: 90.Modified RNAs

[0338] In some embodiments, the present disclosure provides compositions comprising modified RNAs and methods of use thereof. In some embodiments, the modified RNA comprises one or more modified nucleoside residues. For example, in some embodiments, an RNA comprising a nucleotideP-634738-PC sequence at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence listed in Table 2, Table 4,or Table 6, comprises one or more modified nucleoside residues.

[0339] In some embodiments, an RNA as provided herein refers to a messenger RNA.

[0340] In some embodiments, all uridine residues are modified as provided herein. In some embodiments, one or more of the RNAs as provided herein are nucleoside-modified RNAs. In other embodiments, two or more of the RNAs as provided herein are nucleoside-modified RNAs. In other embodiments, three or more of the RNAs as provided herein are nucleoside-modified RNAs.

[0341] In another embodiment, the modified nucleoside of the methods and compositions of the present disclosure is m5C (5-methylcytidine). In another embodiment, the modified nucleoside is m5U (5-methyluridine). In another embodiment, the modified nucleoside is m6A (N6-methyladenosine). In another embodiment, the modified nucleoside is s2U (2 -thiouridine). In another embodiment, the modified nucleoside is T (pseudouridine). In another embodiment, the modified nucleoside is Um (2'-O-methyluridine).

[0342] In other embodiments, the modified nucleoside is m¹A (1-methyladenosine), m2A (2-methyladenosine), m6A (N6-methyladenosine), Am (2'-O-methyladenosine), ms2m6A (2-methylthio-N6-methyladenosine), i6A...

Claims

P-634738-PC CLAIMSWhat is claimed is:

1. A method of treating, suppressing, inhibiting, or preventing a Herpes Simplex Virus (HSV) infection in a subject comprising administering to the subject a combination comprising:(a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof,(b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and(c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof to a subject,wherein administration of the combination induces an anti-HSV immune response, wherein the anti-HSV immune response comprises a B-cell response, wherein the B-cell response comprises (a) production of antibodies directed against HSV-2 gC, HSV-gE, or a combination thereof (b) a memory B-cell response, or (c) a combination thereof.

2. The method of claim 1, wherein the first ribonucleotide sequence, second ribonucleotide sequence and / or third ribonucleotide sequence are in separate compositions.

3. The method of claim 1, wherein the first ribonucleotide sequence, second ribonucleotide sequence and / or third ribonucleotide sequence are in a single composition.

4. The method of any one of claims 1-3, wherein the B-cell response comprises production of antibodies directed against HSV-2 gC.

5. The method of claim 4, wherein the antibodies directed against HSV-2 gC bind one or more gC epitopes.

6. The method of claim 5, wherein the one or more gC epitopes comprises the epitope target of Hl 196, MP5, LH50a, 2010, LH1, or a combination thereof.P-634738-PC 7. The method of claim 6, wherein the epitope target comprises amino acids 97-111 of SEQ ID NO: 15 (Hl 196); amino acids 81-95 of SEQ ID NO: 15 (LH1); nucleotides 129-143 of SEQ ID NO: 15 (LH50a); amino acids 193-207 of SEQ ID NO: 15 (LH50a); or a combination thereof.

8. The method of any one of claims 1-7, wherein the B-cell response further comprises production of antibodies directed against HSV-2 gD.

9. The method of claim 8, wherein the antibodies directed against HSV-2 gD bind one or more gD epitopes.

10. The method of claim 9, wherein the one or more gD epitopes comprises the epitope target of MC5, MC2, LP2, E317, 1D3, MC14, or a combination thereof.

11. The method of claim 10, wherein the epitope target comprises amino acids 54 and 75-79 of SEQ ID NO: 21 (MC5); amino acids 67, 243, 245, 246, and 248 of SEQ ID NO: 21 (MC2); amino acid 216 of SEQ ID NO: 21 (LP2); amino acids 38, 215, 222, and 223 of SEQ ID NO: 21 (E317); amino acids 10-20 of SEQ ID NO: 21 (1D3); amino acids 262-272 of SEQ ID NO: 21 (MC14); or a combination thereof.

12. The method of any one of claims 1-11, wherein the memory B-cell response comprises a response against HSV-2 gC, HSV-2 gD, HSV-2 gE, or a combination thereof.

13. The method of any one of claims 1-12, wherein the B-cell response comprises an HSV-2 gC specific memory B-cell response.

14. The method of any one of claims 1-13, wherein the B-cell response comprises an HSV-2 gD specific memory B-cell response.

15. The method of any one of claims 13-14, wherein the gC and / or gD specific memory B-cell response is an early onset B-cell response.

16. The method of claim 15, wherein the early onset B-cell response is about 1 to 39 days post administration of the combination.P-634738-PC 17. The method of claim 15, wherein the early onset B-cell response is about 5 to 15 days after administration of the combination.

18. The method any one of claims 1-17, wherein the B-cell response comprises an HSV-2 gE specific memory B-cell response.

19. The method of claim 18, wherein the gE specific memory B-cell response is a late onset B- cell response.

20. The method of claim 19, wherein the late onset B-cell response is at least 40 days after administration of the combination.

21. The method of claim 23, wherein the late onset response is at least 6 months after administration of the combination.

22. The method of any one of claims 1-21, wherein the anti-HSV immune response further comprises a T-cell response.

23. The method of claim 22, wherein the T-cell response comprises a response against HSV-2 gC, HSV-2 gD, HSV-2 gE, or a combination thereof.

24. The method of claim 23, wherein the T-cell response comprises an HSV-2 gE specific T-cell response.

25. The method of any one of claims 22-24, wherein the T-cell response comprises a CD8+ T- cell response.

26. The method of claim 25, wherein the CD8+ T-cell response comprises a specific response against HSV-2 gC, HSV-2 gD, HSV-2 gE, or a combination thereof.

27. The method of claim 25 or 26, wherein the CD8+ T-cell response comprises an HSV-2 gE specific CD8+ T-cell response.P-634738-PC 28. The method of any one of claims 1-27, wherein the anti-HSV immune response comprises an HSV-2 gC and HSV-2 gD specific memory B-cell response, and an HSV-2 gE specific CD8+ T-cell response.

29. The method of any one of claims 1-28, wherein one or more of said polypeptides comprises a secretory signal.

30. The method of claim 29, wherein the secretory signal comprises or consists of an HSV secretory signal.

31. The method of claim 30, wherein the HSV secretory signal comprises or consists of an HSV- 2 secretory signal.

32. The method of claim 31, wherein the HSV-2 secretory signal comprises or consists of an HSV-2 glycoprotein D (gD) secretory signal.

33. The method of claim 32, wherein the HSV-2 gD secretory signal comprises an amino acid sequence as set forth in SEQ ID NO: 54 (MGRLTSGVGTAALLVVAVGLRVVCA).

34. The method of claim 33, wherein the ribonucleotide encoding the polypeptide comprising a secretory signal comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 69 (AUGGGCCGCCUGACCUCCGGCGUGGGCACCGCCGCCCUGCUGGUGGUGGCCG UGGGCCUGCGCGUGGUGUGCGCC).

35. The method of claim 29, wherein the secretory signal comprises or consists of an IL2 secretory signal.

36. The method of claim 35, wherein the IL2 secretory signal comprises an amino acid sequence as set forth in SEQ ID NO: 88 (MRMQLLLLIALSLALVTNS).

37. The method of claim 36, wherein the ribonucleotide comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 70 (AUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACC AACUCC).P-634738-PC 38. The method of any one of claims 1-37, wherein the first ribonucleotide sequence encodes an HSV-2 gC antigen or antigenic fragment thereof comprising the amino acid sequence as set forth in SEQ ID NO: 9.

39. The method of claim 38, wherein the ribonucleotide comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 36.

40. The method of any one of claims 1-37, wherein the first ribonucleotide sequence encodes an HSV-2 gC antigen or antigenic fragment thereof comprising the amino acid sequence as set forth in SEQ ID NO: 12.

41. The method of any one of claims 1-40, wherein the second ribonucleotide sequence encodes an HSV-2 gD antigen or antigenic fragment thereof comprising the amino acid sequence as set forth in SEQ ID NO: 18.

42. The method of claim 41, wherein the ribonucleotide comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 39.

43. The method of claim 1-40, wherein the second ribonucleotide sequence encodes an HSV-2 gD antigen or antigenic fragment thereof comprising the amino acid sequence as set forth in SEQ ID NO: 82 or having at least 95% sequence identity to SEQ ID NO: 82.

44. The method of any one of claims 1-43, wherein the third ribonucleotide sequence encodes an HSV-2 gE antigen or antigenic fragment thereof comprising the amino acid sequence as set forth in SEQ ID NO: 4.

45. The method of claim 44, wherein the ribonucleotide comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 34.

46. The method of any one of claims 1-45, wherein the composition further comprises lipid nanoparticles, polyplexes (PLX), lipidated polyplexes (LPLX), or liposomes.

47. The method of claim 46, wherein one or more of the ribonucleotides are fully or partially encapsulated within the lipid nanoparticle, polyplexes (PLX), lipidated polyplex (LPLX), or liposome.P-634738-PC 48. The method of claim 47, wherein one or more of the ribonucleotides are encapsulated within the lipid nanoparticle.

49. The method of any one of claims 46-48, wherein the lipid nanoparticle comprises (a) a polymer-conjugated lipid; (b) a cationic lipid; and (c) one or more neutral lipids.

50. The method of claim 49, wherein the polymer-conjugated lipid comprises a PEG-conjugated lipid.

51. The method of any one of claims 49-50, wherein the one or more neutral lipids comprises cholesterol.

52. The method of any one of claim 1-51, wherein the composition further comprises one or more ribonucleotides encoding:(a) HSV glycoprotein B (gB) antigen or antigenic fragment thereof;(b) HSV glycoprotein H (gH) antigen or antigenic fragment thereof;(c) HSV glycoprotein L (gL) antigen or antigenic fragment thereof;(d) HSV glycoprotein I (gl) antigen or antigenic fragment thereof; or(e) any combination thereof.

53. The method of claim 52, wherein the HSV gB antigen or antigenic fragment thereof comprises one or more mutations that stabilize the HSV gB antigen or antigenic fragment thereof relative to a comparable HSV gB antigen or antigenic fragment thereof that does not comprise the one or more mutations.

54. The method of claim 53, wherein the one or more mutations are one or more amino acid substitutions.

55. The method of claim 54, wherein the one or more amino acid substitutions comprise 251C, 718C, or a combination thereof, wherein the numbering is with reference to SEQ ID NO: 25.P-634738-PC 56. The method of any one of claims 52-55, wherein the ribonucleotide sequence encodes an HSV gB antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gB antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in any one of SEQ ID NOs: 22-32 and 92.

57. The method of any one of claims 52-56, wherein the ribonucleotide sequence encodes an HSV gH antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gH antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 49.

58. The method of any one of claim 1-57, wherein the composition further comprises one or more ribonucleotides encoding HSV glycoprotein L (gL) or antigenic fragment thereof.

59. The method of claim 58, wherein the ribonucleotide sequence encodes an HSV gL antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gL antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 48.

60. The method of any one of claim 1-59, wherein the composition further comprises one or more ribonucleotides encoding HSV glycoprotein I (gl) or antigenic fragment thereof.

61. The method of claim 60, wherein the ribonucleotide sequence encodes an HSV gl antigen or antigenic fragment thereof and wherein the amino acid sequence of said HSV gl antigen or antigenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 47.

62. A combination comprising:(a) a first ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein C (gC) antigen or antigenic fragment thereof,(b) a second ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein D (gD) antigen or antigenic fragment thereof, and(c) a third ribonucleotide sequence that encodes a polypeptide comprising an HSV glycoprotein E (gE) antigen or antigenic fragment thereof,P-634738-PC wherein the first ribonucleotide sequence, the second ribonucleotide sequence, the third ribonucleotide sequence, or any combination thereof is formulated at a dose of 3, 30, or 60 pg or at a dose of 1, 5, or 50 pg per administration.

63. The combination of claim 62, wherein the first ribonucleotide sequence, second ribonucleotide sequence and / or third ribonucleotide sequence are in a single composition.

64. A method of treating, suppressing, inhibiting, or preventing a Herpes Simplex Virus (HSV) infection in a subject or inducing an anti-HSV immune response in a subject comprising administering to the subject a combination of any one of claims 62-63.

65. A composition comprising the combination of any one of claims 62-63.

66. A method of inducing an HSV glycoprotein C (gC)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gC antigen or antigenic fragment thereof.

67. The method of claim 66, wherein said HSV gC specific B-cell response comprises an HSV- 2 gC-specific B-cell response.

68. The method of claim 66 or 67, wherein the B-cell response comprises production of antibodies directed against HSV-2 gC.

69. The method of claim 68, wherein the antibodies directed against HSV-2 gC bind one or more gC epitopes.

70. The method of claim 69, wherein the one or more gC epitopes comprises the epitope target of Hl 196, MP5, LH50a, 2010, LH1, or a combination thereof.

71. The method of claim 70, wherein the epitope target comprises 97-111 of SEQ ID NO: 15 (Hl 196); 81-95 of SEQ ID NO: 15 (LH1); 129-143 of SEQ ID NO: 15 (LH50a); 193-207 of SEQ ID NO: 15 (LH50a); or a combination thereof.

72. The method of any one of claims 66-71, wherein said gC antigen or antigenic fragment comprises an HSV-2 gC antigen or antigenic fragment.P-634738-PC 73. The method of any one of claims 66-72, wherein the B-cell response comprises a memory B-cell response.

74. The method of any one of claims 66-72, wherein the B-cell response is an early onset B-cell response.

75. The method of claim 74, wherein the early onset B-cell response is about 1 to 39 days post administration of the combination.

76. The method of claim 74, wherein the early onset B-cell response is about 5 to 15 days after administration of the combination.

77. The method of any one of claims 66-72, wherein the B-cell response is a late onset B-cell response.

78. The method of claim 77, wherein the late onset B-cell response is at least 40 days after administration of the combination.

79. The method of claim 77, wherein the late onset response is at least 6 months after administration of the combination.

80. A method of inducing an HSV glycoprotein D (gD)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gD antigen or antigenic fragment thereof.

81. The method of claim 80, wherein the HSV gD specific B-cell response comprises an HSV-2 gD-specific B-cell response.

82. The method of claim 81, wherein the B-cell response comprises production of antibodies directed against HSV-2 gD.

83. The method of claim 82, wherein the antibodies directed against HSV-2 gD bind one or more gD epitopes.P-634738-PC 84. The method of claim 83, wherein the one or more gD epitopes comprises the epitope target of MC5, MC2, LP2, E317, 1D3, MC14, ora combination thereof.

85. The method of claim 84, wherein the epitope target comprises 54 and, 75-79 of SEQ ID NO:21 (MC5); 67, 243, 245, 246, and 248 of SEQ ID NO: 21 (MC2); 216 of SEQ ID NO: 21 (LP2); 38, 215, 222, and 223 of SEQ ID NO: 21 (E317); 10-20 of SEQ ID NO: 21 (1D3); 262-272 of SEQ ID NO: 21 (MCI 4); or a combination thereof.

86. The method of any one of claims 80-85, wherein said gD antigen or antigenic fragment comprises an HSV-2 gD antigen or antigenic fragment.

87. The method of any one of claims 80-86, wherein the B-cell response comprises a memory B-cell response.

88. The method of any one of claims 80-87, wherein the B-cell response is an early onset B-cell response.

89. The method of claim 88, wherein the early onset B-cell response is about 1 to 39 days post administration of the combination.

90. The method of claim 88, wherein the early onset B-cell response is about 5 to 15 days after administration of the combination.

91. The method of any one of claims 80-87, wherein the B-cell response is a late onset B-cell response.

92. The method of claim 91, wherein the late onset B-cell response is at least 40 days after administration of the combination.

93. The method of claim 91, wherein the late onset response is at least 6 months after administration of the combination.

94. A method of inducing an HSV glycoprotein E (gE)-specific B-cell response in a subject comprising administering to the subject a composition comprising: a ribonucleotide sequence that encodes a polypeptide comprising an HSV gE antigen or antigenic fragment thereof.P-634738-PC 95. The method of claim 94, wherein said HSV gE specific B-cell response comprises an HSV- 2 gE-specific B-cell response.

96. The method of claim 94 or 95, wherein said gE antigen or antigenic fragment comprises an HSV-2 gE antigen or antigenic fragment.

97. The method of any one of claims 94-96, wherein the B-cell response comprises a memory B-cell response.

98. The method of any one of claims 94-97, wherein the B-cell response is an early onset B-cell response.

99. The method of claim 98, wherein the early onset B-cell response is about 1 to 39 days post administration of the combination.

100. The method of claim 98, wherein the early onset B-cell response is about 5 to 15 days after administration of the combination.

101. The method of any one of claims 94-97, wherein the B-cell response is a late onset B-cell response.

102. The method of claim 101, wherein the late onset B-cell response is at least 40 days after administration of the combination.

103. The method of claim 101, wherein the late onset response is at least 6 months after administration of the combination.

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