RNA compositions encoding herpes simplex virus glycoprotein e and / or glycoprotein i antigens and uses thereof

Abstract

Disclosed herein are compositions comprising (a) a nucleoside-modified polyribonucleotide encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, (b) a nucleoside-modified polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof, or (c) a combination thereof. Further disclosed are methods for using said compositions for treating an HSV infection.

Description

P-628704-PC RNA COMPOSITIONS ENCODING HERPES SIMPLEX VIRUS GLYCOPROTEIN E AND / OR GLYCOPROTEIN I ANTIGENS AND USES THEREOF SEQUENCE LISTING STATEMENT

[0001] The instant application contains a Sequence Listing conforming to the rules of WIPO Standard ST.26 which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy, created on August 2, 2024, is named P-628704-PC-SEQLIST.xml and is 504 kilobytes in size. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with U.S. government support under AI139618 awarded by The National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD

[0003] Disclosed herein are combinations and compositions comprising (a) a polyribonucleotide encoding atruncated Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen and / or (b) a polyribonucleotide encoding atruncated HSV-2 glycoprotein I (gI) antigen. Further disclosed are methods for using said combinations and compositions for treating an HSV infection. BACKGROUND

[0004] Herpes simplex virus (HSV) type 2 is a highly prevalent sexually transmitted infection that primarilycauses genital herpes. HSV-2 belongs to the herpesviridae family and is closely related to herpes simplex virustype 1 (HSV-1), which typically causes oral herpes. HSV-2 is primarily transmitted through sexual contact with an infected individual, and once contracted, the virus remains in the body for life.

[0005] About a half-billion people worldwide are infected with HSV-2. While many of these individuals are asymptomatic, and are unaware they are infected, they are still at risk of transmitting infection to intimatepartners. 20% of infected individuals have frequent, painful and recurrent genital sores, which can significantlyimpact his / her quality of life and intimate relationships.

[0006] The virus can be particularly problematic for pregnant women, as it can be transmitted to the baby during childbirth, as neonatal herpes. This infection is uncommon (1:3,000 births in the U.S.) but devastating with high morbidity and mortality in newborns. Antiviral medications are commonly prescribed to manage outbreaks and reduce the risk of transmission to sexual partners. However, there is currently no cure for HSV-2, and efforts to develop an effective vaccine have faced challenges due to the virus's ability to evade the immune system.

[0007] Lifelong daily suppressive therapy with acyclovir or valacyclovir reduces the frequency of recurrences and lowers risk for transmission, but not all people respond or are willing to take daily therapy.

[0008] RNA (also referred to herein as “polyribonucleotide”) vaccine technology represents a groundbreaking approach to vaccination that has gained significant attention and success in recent years. Unlike traditional vaccines, which often use weakened or inactivated viruses, these vaccines work by introducing RNA into the body, which is translated in host cells as a harmless piece of the target pathogen, typically a viral protein. OnceP-628704-PC the protein is synthesized, the immune system recognizes it as foreign and mounts a defense, including the production of antibodies. These antibodies are then primed to recognize and neutralize the actual virus if the individual encounters it in the future.

[0009] There is a clear need of safe and effective vaccines for preventing and treating HSV. SUMMARY

[0010] In some embodiments, described herein is a combination comprising (a) a polyribonucleotide (also referred to as “RNA” herein) encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, and (b) a polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof. In some embodiments, a polyribonucleotide encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, and a polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof of a combination are in the same composition.

[0011] In other embodiments, described herein is a composition comprising (a) a polyribonucleotide encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, (b) a polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof, or (c) a combination thereof.

[0012] In some embodiments, described herein is a combination or composition comprising (a) a nucleoside- modified polyribonucleotide encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, and / or (b) a nucleoside-modified polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof. In some embodiments, described herein is a composition comprising a nucleoside-modified polyribonucleotide encoding a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof. In some embodiments, described herein is a composition comprising a nucleoside-modified polyribonucleotide encoding an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof.

[0013] In some embodiments, an HSV-2 gE antigen or immunogenic fragment thereof, comprises anectodomain of HSV-2 gE or an immunogenic fragment thereof. In some embodiments, an HSV-2 gI antigen or immunogenic fragment thereof, comprises an ectodomain of HSV-2 gI or an immunogenic fragment thereof. In some embodiments, an HSV-2 gE antigen or immunogenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 4 or in SEQ ID NO: 6. In some embodiments, the HSV-2 gI antigen or immunogenic fragment thereof, comprises the amino acid sequence as set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0014] In some embodiments, a polyribonucleotide encoding an HSV-2 gE antigen or immunogenic fragment thereof, comprises or consists of a ribonucleic acid sequence as set forth in SEQ ID NO: 36 or any one of SEQ ID NOs: 37-44. In some embodiments, a polyribonucleotide encoding an HSV-2 gI antigen or immunogenic fragment thereof, comprises or consists of a ribonucleic acid sequence as set forth in SEQ ID NO: 31 or any one of SEQ ID NOs: 32-35.

[0015] In some embodiments, one or more of said polyribonucleotides further encodes a secretory signal. In some embodiments, the secretory signal is located at the N-terminus of the polypeptide. In some embodiments, the secretory signal comprises or consists of an IL-2 signal peptide. In some embodiments, an IL-2 signalpeptide comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 109. In some embodiments,P-628704-PC the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the IL-2 signal peptide comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 198. In some embodiments, the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof and the IL-2 signal peptide comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 187 or SEQ ID NO: 188.

[0016] In some embodiments, one or more of said polyribonucleotides encoding the IL-2 signal peptide comprises or consists of a ribonucleic acid sequence as set forth in SEQ ID NO: 176. In some embodiments, the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the IL-2 signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 246-248. In some embodiments, the polyribonucleotide encoding the polypeptide comprising the HSV-2 gIantigen or immunogenic fragment thereof and the IL-2 signal peptide comprises or consists of a ribonucleic acidsequence as set forth in SEQ ID NO: 245.

[0017] In some embodiments, the secretory signal comprises a viral secretory signal. In some embodiments, the viral secretory signal comprises an HSV secretory signal. In some embodiments, the HSV secretory signal comprises an HSV gE signal peptide. In some embodiments, the HSV gE signal peptide comprises or consists ofan HSV-2 gE (gE2) signal peptide. In some embodiments, the HSV gE signal peptide comprises or consists of anamino acid sequence as set forth in SEQ ID NO: 97. In other embodiments, the HSV gE signal peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 98-100. In some embodiments, the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the HSV gE signal peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 202-203. In some embodiments, the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof and the HSV gE signal peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 189- 190. In some embodiments, the polyribonucleotide encoding the gE signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 143-151. In some embodiments, the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the HSV gE signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 254-258. In some embodiments, the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof and the HSV gE signal peptide comprises or consists of a ribonucleic acid sequence as set forth in SEQ ID NO: 238 or SEQ ID NO: 239.

[0018] In some embodiments, the HSV secretory signal comprises or consists of an HSV gI signal peptide. In some embodiments, a signal peptide comprises or consists of an HSV-2 gI (gI2) signal peptide. In some embodiments, a gI2 signal peptide comprises or consists of the amino acid sequence as set forth in SEQ ID NO: 106.

[0019] In some embodiments, the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the HSV gI signal peptide comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 206. In some embodiments, the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof and the HSV gI signal peptide comprises or consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 191-192. In some embodiments, the polyribonucleotide encoding the gI signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 160-175. In some embodiments, the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof and the HSV gI signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 323-326. In some embodiments, the polyribonucleotide encoding the polypeptide comprisingP-628704-PC the HSV-2 gI antigen or immunogenic fragment thereof and the HSV gI signal peptide comprises or consists of a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 240-243.

[0020] In some embodiments, the secretory signal comprises an HSV-1 secretory signal. In some embodiments, the HSV-1 secretory signal comprises an HSV-1 gB secretory signal, an HSV-1 gC secretory signal, an HSV-1 gD secretory signal, an HSV-1 gE secretory signal, an HSV-1 gI secretory signal, or a combination thereof.

[0021] In other embodiments, the secretory signal comprises an HSV-2 secretory signal. In some embodiments, the HSV-2 secretory signal comprises an HSV-2 gB secretory signal, an HSV-2 gC secretory signal, an HSV-2 gD secretory signal, an HSV-2 gE secretory signal, an HSV-2 gI secretory signal, or a combination thereof

[0022] In other embodiments, the viral secretory signal comprises an Ebola spike glycoprotein secretory signal. In other embodiments, the secretory signal comprises a human secretory signal. In some embodiments, the secretory signal comprises a human Ig heavy chain secretory signal. In other embodiments, the secretory signal comprises any secretory signal as set forth in Tables 3-4.

[0023] In some embodiments, one or more of said polyribonucleotides further comprises a 5′ untranslated region. In some embodiments, the 5′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 308-311.

[0024] In some embodiments, one or more of the polyribonucleotides further comprises a 3′ untranslated region. In some embodiments, the 3′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 312-315.

[0025] In some embodiments, one or more of said polyribonucleotides further comprises a poly-A tail. In some embodiments, the poly-A tail comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 316- 318.

[0026] In some embodiments, one or more of said polyribonucleotides further comprises a cap-independent translational enhancer. In some embodiments, one or more of said polyribonucleotides further comprises an m7GpppG cap, 3′-O-methyl-m7GpppG cap, or anti-reverse cap analog.

[0027] In some embodiments, one or more of the polyribonucleotides are nucleoside modified polyribonucleotides. In some embodiments, a nucleoside modification comprises one or more pseudouridine residues. In some embodiments, one or more pseudouridine residues comprise m1Ψ (1-methylpseudouridine). In some embodiments, one or more pseudouridine residues comprise m1acp3Ψ (1-methyl-3-(3-amino-5- carboxypropyl)pseudouridine, Ψm (2′-O-methylpseudouridine, m5D (5-methyldihydrouridine), m3Ψ (3- methylpseudouridine), or any combination thereof. In some embodiments, the one or more nucleoside modified polyribonucleotides comprise one or more m5D (5-methyldihydrouridine) residues.

[0028] In some embodiments, one or more of the polyribonucleotides are recombinantly engineeredpolyribonucleotides. In some embodiments, one or more of the polyribonucleotides are codon optimizedpolyribonucleotides.

[0029] In some embodiments, the polyribonucleotide encoding a polypeptide comprising an HSV-2 gE antigen or immunogenic fragment thereof, and the polyribonucleotide encoding a polypeptide comprising an HSV-2 gI antigen or immunogenic fragment thereof are in the same composition.P-628704-PC

[0030] In some embodiments, a combination or composition further comprises a nanoparticle, lipid, polymer, cholesterol, or cell penetrating peptide. In some embodiments, one or more of said polyribonucleotides is encapsulated in a nanoparticle, lipid, polymer, cholesterol, or cell penetrating peptide.

[0031] In some embodiments, the one or more polyribonucleotides encoding a) an HSV glycoprotein B (gB) antigen or immunogenic fragment thereof, b) an HSV glycoprotein C (gC) antigen or immunogenic fragment thereof, c) an HSV glycoprotein D (gD) antigen or immunogenic fragment thereof, d) an HSV glycoprotein H (gH) antigen or immunogenic fragment thereof, e) an HSV glycoprotein L (gL) antigen or immunogenic fragment thereof, or f) any combination thereof.

[0032] In some embodiments, the composition or combination further comprises nanoparticles, lipids, polymers, cholesterols, cell penetrating peptides, or any combination thereof. In some embodiments, one or more of the polyribonucleotides are associated with nanoparticles, lipids, polymers, cholesterols, or cell penetrating peptide. In some embodiments, one or more of the polyribonucleotides are embedded within nanoparticles, lipids, polymers, cholesterols, or cell penetrating peptide. In some embodiments, the nanoparticles are lipid nanoparticles.

[0033] In some embodiments, the composition or combination is a pharmaceutical combination composition or. In some embodiments, the pharmaceutical composition or combination further comprises a pharmaceutically acceptable excipient. In some embodiments, the composition or combination is for use in treating, preventing, inhibiting, or reducing the incidence of an HSV infection in a subject.

[0034] In other embodiments, disclosed herein is a use of a combination or composition as described herein forthe manufacture of a medicament for treating or preventing an HSV infection in a subject. In otherembodiments, disclosed herein is a use of a combination or composition as described herein for treating or preventing an HSV infection in a subject.

[0035] In some embodiments, disclosed herein is a method comprising the step of administering one or more polyribonucleotide disclosed above, or a combination or composition disclosed above to a subject. In some embodiments, disclosed herein is a method of treating a Herpes Simplex Virus (HSV) infection in a subject comprising the step of administering a combination or composition as disclosed above. In some embodiments, disclosed herein is a method of inhibiting, or reducing the incidence of a Herpes Simplex Virus (HSV) infection in a subject comprising the step of administering one or more polyribonucleotide disclosed above, or a combination or composition disclosed above.

[0036] In some embodiments, an HSV infection comprises an HSV-1 infection. In some embodiments, an HSV infection comprises an HSV-2 infection. In some embodiments, an HSV infection is a primary infection or a secondary infection. In some embodiments, an HSV infection comprises a flare, recurrence, or HSV labialis following a primary HSV infection; a reactivation of a latent HSV infection; an HSV encephalitis; an HSV neonatal infection; a genital HSV infection; or an oral HSV infection; or a combination thereof.

[0037] In some embodiments, an HSV infection is a latent HSV infection. In some embodiments, a latent HSV infection comprises a genital HSV infection or an oral HSV infection.

[0038] In some embodiments, disclosed herein is a method of inducing an immune response in a subject, comprising the step of administering one or more polyribonucleotide disclosed above, or a combination or composition as disclosed above to said subject.P-628704-PC

[0039] In some embodiments, an immune response comprises a CD4+ immune response; a CD8+ immune response; a T follicular helper cell immune response; a germinal center B cell immune response; an IgG antibody response to gE2 or gI2; or a combination thereof.

[0040] In other embodiments, disclosed herein is a method of inducing a CD4+ T-cell response to a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof comprising the step of administering one or more of the polyribonucleotides as described herein to said subject as demonstrated in Figure 3A. In other embodiments, disclosed herein is a method of inducing a CD8+ T-cell response to HSV-2 gE antigen or immunogenic fragment thereof comprising the step of administering one or more of the polyribonucleotides as described herein to said subject as demonstrated in Figures 2B and 3B.

[0041] In other embodiments, disclosed herein is a method of inducing an IgG antibody response to an HSV-2 gE antigen or immunogenic fragment thereof comprising the step of administering one or more of the polyribonucleotides as described herein to said subject, as demonstrated in Figures 4B and 5B. In other embodiments, disclosed herein is a method of inducing an IgG antibody response to an HSV-2 gI antigen or immunogenic fragment thereof comprising the step of administering one or more of the polyribonucleotides asdescribed herein to said subject, as demonstrated in Figure 5C.

[0042] In other embodiments, disclosed herein is a method of inducing an IgG antibody response to an HSV-2 gI antigen or immunogenic fragment thereof and an HSV-2 gE antigen or immunogenic fragment thereof comprising the step of administering one or more of the polyribonucleotides as described herein to said subject, as demonstrated in Figure 5A.

[0043] In some embodiments, the administration step in the methods described herein comprisesintramuscular, subcutaneous, intradermal, intranasal, intravaginal, intrarectal, or topical administration.

[0044] In some embodiments, disclosed herein is a combination or composition comprising the polypeptides encoded by the combination as disclosed herein.

[0045] In some embodiments, disclosed herein is a host cell comprising a combination or composition asdescribed herein. In other embodiments, disclosed herein is a host cell comprising one or more polypeptidesencoded by a combination or composition as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] 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 embodiments presented herein.

[0047] Figure 1A shows a scheme of the protocol of the guinea pig model experiments described in Example 2.

[0048] Figures 1B-1C show recurrent genital lesion days per group. Guinea pigs were immunized twice on days 25 and 65 post-infection with nucleoside modified RNAs encapsulated in a lipid nanoparticle and expressing an exemplary HSV-2 gE (gE2) immunogenic fragment and an exemplary HSV-2 gI (gI2) immunogenic fragment (15ug each), or PBS (control). Animals were scored daily Monday to Friday for recurrent genital lesions from 1 day after the first immunization until the end of the study on day 116. From the time of the second immunization, significant differences appeared comparing guinea pigs immunized with modified RNAs encoding exemplary gE2 immunogenic fragment and an exemplary gI2 immunogenic fragment, with the PBS group.P-628704-PC Figure 1B shows the cumulative recurrent genital lesion days per group. Figure 1C shows days with recurrent genital lesions for each animal starting 1 day after the second immunization. P values were calculated by the two-tailed Mann Whitney test and demonstrate highly significant differences comparing gE2 / gI2 with PBS (**, P<0.01; ns, P value not significant).

[0049] Figures 2A-2B show T cell responses to gE2 stimulation in mice immunized with gE2 RNA compositions in CD4+ T cells (Figure 2A) and in CD8+ T cells (Figure 2B).

[0050] Figures 3A-3D show T cell responses to gE2 stimulation in mice immunized with gE2 / gI2 bivalent RNA composition in CD4+ T cells (Figure 3A) and in CD8+ T cells (Figure 3B); and T cell responses to gI2 stimulation in mice immunized with E2 / gI2 bivalent RNA composition in CD4+ T cells (Figure 3C) and in CD8+ T cells (Figure 3D).

[0051] Figures 4A-4B show antibody responses to gE2 / gI2 (Figure 4A) and to gE2 (Figure 4B) in mice immunized with gE2 RNA composition.

[0052] Figures 5A-5C show antibody responses to gE2 / gI2 (Figure 5A), gE2 (Figure 5B), and gI2 (Figure 5C) in mice immunized with gE2 / gI2 bivalent RNA composition.

[0053] Figure 6 shows a scheme of the protocol of the mice model experiments described in Example 5.

[0054] Figures 7A-7F show survival (Figures 7A-7B), weight loss (Figures 7C-7D), and disease score (Figures 7E-7F) in a mouse model of HSV-2 in mice immunized with gE2 monovalent (Figures 7A, 7C, and 7E) or gE2 / gI2 bivalent (Figures 7B, 7D, and 7F) RNA composition.

[0055] Figures 8A-8F show HSV virus titer 2 days (Figures 8A-8B) and 4 days (Figures 8C-8D) afterinfection in mice immunized with gE2 / gI2 bivalent; as well as HSV-2 DNA copy number in DRG 28 days afterinfection (Figures 8E-8F).

[0056] Figures 9A-9B show production of antibodies blocking IgG Fc binding to gE (Figure 9A) or gE2 / gI2 (Figure 9B) protein in mice immunized with gE2 / gI2 bivalent RNA compositions.

[0057] Figure 10 depicts expression levels in HEK293T cells transfected with RNA encoding HSV-2 gE (gE2) antigens.

[0058] Figures 11A-11B depict expression levels in HEK293T cells transfected with RNA encoding HSV-2 gE (gE2) antigens.

[0059] Figures 12A-12D shows expression levels in HEK293T cells transfected with RNA encoding HSV-2 gE (gE2) antigens.

[0060] Figure 13 depicts secretion levels of HEK293T cells transfected with RNA encoding HSV-2 gE (gE2) antigens.

[0061] Figures 14A-14D show the prophylactic effect of BNT163, gB, gE2 / gI2, or a combination of them on survival (Figure 14A), disease severity (Figure 14B), genital lesions (Figure 14C), and urinary retention (Figure 14D) in guinea pigs infected with HSV-2. As used in Figures 14A-15D, “BNT163” refers to a combination of three polyribonucleotides: (i) a polyribonucleotide encoding a polypeptide that comprises a gC immunogenic fragment and has an amino acid sequence according SEQ ID NO:208; (ii) a polyribonucleotide encoding a polypeptide that comprises a gD immunogenic fragment and has an amino acid sequence accordingP-628704-PC SEQ ID NO: 231; and (iii) a polyribonucleotide encoding a polypeptide that comprises a gE immunogenic fragment and has an amino acid sequence according SEQ ID NO: 198.

[0062] Figures 15A-15B show the therapeutic effect of BNT163, gB and gE2 / gI2 on recurrent lesions in a first (Figure 15A) and the combined results of two experiments (Figure 15) experiments. As used in Figures 15A-15B, “BNT163” refers to a combination of three polyribonucleotides: (i) a polyribonucleotide encoding a polypeptide that comprises a gC immunogenic fragment and has an amino acid sequence according SEQ ID NO: 208; (ii) a polyribonucleotide encoding a polypeptide that comprises a gD immunogenic fragment and has an amino acid sequence according SEQ ID NO: 231; and (iii) a polyribonucleotide encoding a polypeptide that comprises a gE immunogenic fragment and has an amino acid sequence according SEQ ID NO: 198. CERTAIN DEFINITIONS

[0063] 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.

[0064] In order 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.

[0065] A, An, The: As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0066] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, incontext 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.

[0067] Adjuvant: “Adjuvant” refers 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 some embodiments, an immune adjuvant enhances an immune response to an antigen that is weakly immunogenic when administered alone, i.e., inducing no or weak antibody titers or cell-mediated immune response. In some embodiments, the adjuvant increases antibody titers to the antigen. In some embodiments, 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.

[0068] Administering: As used herein, the term “administering” refers to directly introducing into a subject by injection or by other means described herein and / or known in the art, a composition or combination of thepresent disclosure. In another embodiment, “administering” refers to contacting a cell of the subject’s immunesystem with a composition or combination of the present disclosure or modified polyribonucleotides encoding HSV gE and gI.

[0069] 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, anP-628704-PC 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, or 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.

[0070] 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 ofone 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 a 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.

[0071] 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 someembodiments, an antibody agent is or comprises a polypeptide whose amino acid sequence includes one or morestructural elements recognized by those skilled in the art 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 identicalP-628704-PC 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 CDRs1, 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 which 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 chainsand 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 (“SMIPsTM”); 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.)).

[0072] 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. InP-628704-PC 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 embodiments, an antigen or a processed 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 described 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 release cytotoxic factors, e.g. perforins and granzymes.

[0073] Antigenic: “Antigenic” refers 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 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.

[0074] 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, 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.P-628704-PC

[0075] 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 IC50of 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)).

[0076] C5-interfering domain: “C5-interfering domain” refers to a domain that interferes with binding of a host C3b molecule with a host C5 molecule. In another embodiment, the term refers to a domain that interferes with the interaction of a host C3b molecule with a host C5 molecule.

[0077] 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 and possesses the ability to stabilize RNA if attachedthereto, including, e.g., but not limited to anti-reverse cap analogs (ARCAs) known in the art). Those skilled inthe 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.

[0078] 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 theP-628704-PC 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.

[0079] 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) described 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) described 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 oradministered to a subject at different times. Each of these situations is contemplated as falling within themeaning of “co-administration” or “combination,” provided that a pharmaceutical composition (e.g., immunogenic composition, e.g., vaccine) described 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.

[0080] Codon-optimized: As used herein, the term “codon-optimized” refers to alteration of codons in acoding region of a nucleic acid molecule to reflect the typical codon usage of a host organism. In some embodiments, codon optimization does not alter 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 described 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 not modified compared to the amino acid sequence.

[0081] Combination: As used herein, the term “combination” refers to two or more agents (e.g., two or morepolyribonucleotides) or compositions (e.g., therapeutic compositions) that are used together. In some embodiments, two or more agents (e.g., two or more polyribonucleotides) or compositions (e.g., therapeutic compositions) are used (e.g., manufactured, formulated, sold, or administered) together. For example, in some embodiments, two or more agents or compositions may be used (e.g., manufactured, formulated, sold, or administered) as part of the same treatment or prevention regimen. In some embodiments, two or more agents or compositions may be administered simultaneously or near-simultaneously (e.g., within 24 hours or less of each other, within 12 hours or less of each other, within 6 hours or less of each other, within 3 hours or less of each other, within 2 hours or less of each other, within 1 hour or less of each other, within 30 minutes or less of each other, within 15 minutes or less of each other, within 5 minutes or less of each other, or within 1 minute orless of each other) to a subject. For clarity, a combination does not require that individual agents orcompositions be used (e.g., manufactured, formulated, sold, or administered) together in a single composition; although in some embodiments, two or more agents or compositions may be used (e.g., manufactured, formulated, sold, or administered) together in a single composition.

[0082] 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, the two or more regimens may be administered simultaneously; in someP-628704-PC 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.

[0083] 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 permitcomparison 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 conclusion 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.

[0084] Comprising: As used herein, the terms “comprise”, "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

[0085] Consisting of: As used herein, the term “consisting of” means “including and limited to.”

[0086] Consisting essentially of: The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0087] 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 / GLSEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF,Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI,P-628704-PC SWAPHI-LS, 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.

[0088] Derived: In the context of an amino acid sequence (peptide or polypeptide) “derived from” adesignated amino acid sequence (peptide or polypeptide), it refers to a structural analogue of a designatedamino 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, essentially 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.

[0089] 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.

[0090] 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 pluralityof doses each of which is separated in time from other doses. In some embodiments, individual doses areseparated 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 (i.e., is a therapeutic dosing regimen).

[0091] Effective dosage: As used herein, “effective dosage” of the modified RNA, refers, in one embodiment, to an amount sufficient to exert a therapeutic effect. In another embodiment, the term refers to an amount sufficient to elicit expression of a detectable amount of the encoded protein. Each possibility represents a separate embodiment of the present disclosure.

[0092] Encoding: As used herein, “encoding” refers to an RNA molecule that contains a gene that encodes aprotein of interest, or a fragment thereof. In another embodiment, an RNA molecule comprises or consists of aprotein coding sequence that encodes a protein of interest, or a fragment thereof. In another embodiment, oneP-628704-PC or more other proteins, or a fragment 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.

[0093] 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.

[0094] 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 orgroups are physically near to each other in space when the antigen adopts such a conformation. In someembodiments, 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.

[0095] 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 acidsequence 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.

[0096] 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.

[0097] Fragment: In one embodiment, 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 one embodiment, the fragment is an N-terminal fragment. In another embodiment, the fragment is a C-terminal fragment. In one embodiment, the fragment is a section of the protein, peptide, or nucleic acid. In one embodiment, the fragment of the HSV protein is an 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 thefull-length protein. In another embodiment, the fragment is 50-100, 100-150, 150-300, or 300-600 amino acidsshorter than the full-length protein. In another embodiment, the fragment comprises approximately 60%, 65%,P-628704-PC 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 described herein.

[0098] In some embodiments, the fragment is a section of the protein, peptide, or nucleic acid. In another embodiment, the fragment is an immunogenic section of the protein, peptide or nucleic acid. In another embodiment, the fragment is a functional section within the protein, peptide or nucleic acid. In another embodiment, the fragment is an N-terminal immunogenic fragment. In some embodiments, the fragment is a C- terminal immunogenic 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 fragmentcontains pieces of the protein linked together or pieces of multiple proteins linked together. In someembodiments, a fragment is a domain (e.g., an ectodomain).

[0099] Functional: “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 anotherembodiment, its trimerization property. In the case of functional fragments and the functional variants of thedisclosure, 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.

[0100] Homology: The terms “homology,” “homologous,” etc., when in reference to any protein or peptide, refer, in one embodiment, 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.

[0101] In some embodiments, “homology” refers to identity of a protein sequence encoded by a modified (e.g., nucleoside-modified) polyribonucleotide 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%. 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%.

[0102] 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-628704-PC

[0103] 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 PAM120 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.

[0104] Immune evasion domain: As used herein, the term “immune evasion domain” refers to a domain that interferes with or reduces in vivo anti-HSV efficacy of anti-HSV antibodies (e.g., anti-gE antibodies). In some embodiments, the domain interferes or reduces in vivo anti-HSV efficacy of an anti-HSV immune response. In some embodiments, the domain reduces the immunogenicity of an HSV protein (e.g., gE) during subsequent infection. In some embodiments, the domain reduces the immunogenicity of an HSV protein during subsequent challenge. In some embodiments, the domain reduces the immunogenicity of HSV during subsequent challenge. In some embodiments, the domain reduces the immunogenicity of an HSV protein in the context of ongoing HSV infection. In some embodiments, the domain reduces the immunogenicity of HSV in the context of ongoing HSV infection. In some embodiments, the domain functions as an IgG Fc receptor. In some embodiments, the domain promotes antibody bipolar bridging, which in one embodiment, 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 one embodiment, gE, thereby blocking the ability of the Fc domain to activate complement.

[0105] Immunogenic fragment: As used herein, the term “immunogenic fragment” refers to a portion of a protein that is in one embodiment immunogenic and in other embodiments elicits a protective immune response when administered to a subject.

[0106] Immunogenicity and immunogenic: In one embodiment, "immunogenicity" or "immunogenic" is used herein to refer to the innate ability of a protein, peptide, nucleic acid, antigen or organism to elicit an immune response in an animal when the protein, peptide, nucleic acid, antigen or organism is administered to the animal. In one embodiment, an immunogenic polypeptide is also antigenic. Thus, “enhancing theP-628704-PC 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, 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.

[0107] Immunologically equivalent: The term “immunologically equivalent” means that an immunologicallyequivalent molecule such as the immunologically equivalent amino acid sequence exhibits the same or essentiallythe same immunological properties and / or exerts the same or essentially the same immunological effects, e.g., with respect to the type of the immunological effect. In the context of the present disclosure, in some embodiments, the term “immunologically equivalent” is used with respect to the immunological effects or properties of antigens or antigen variants used for immunization. For example, an amino acid sequence is immunologically equivalent to a reference amino acid sequence if said amino acid sequence when exposed to the immune system of a subject induces an immune reaction having a specificity of reacting with the reference amino acid sequence.

[0108] In some embodiments, an antigen receptor is an antibody or B cell receptor which binds to an epitope in an antigen. In some embodiments, an antibody or B cell receptor binds to native epitopes of an antigen.

[0109] 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 someembodiments, an assessed value achieved in a subject may be “increased” relative to that obtained in the samesubject 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 described 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 described 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 ofan assessed value by at least 5%, at least 10%, at least 20%, at least 50%, at least 75% or higher, ascompared 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.P-628704-PC

[0110] 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.

[0111] 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 isolatednucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as,for example, a host cell.

[0112] Isoform: 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 some embodiments, may arise from the same gene byalternative splicing. In some embodiments, isoforms are caused by single nucleotide polymorphisms.

[0113] 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 lipid 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 toabout 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 to about 90 nm, about80 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 described herein.

[0114] 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.

[0115] 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 µm 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, about500 nm, about 100 nm, about 50 nm, about 40 nm, about 30 nm, about 20 nm, or about 10 nm and often aboveabout 1 nm. In many embodiments, a nanoparticle may be substantially spherical so that its longest dimensionP-628704-PC 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.

[0116] 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 (including 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.

[0117] 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.

[0118] 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.

[0119] 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 someembodiments, a nucleic acid is or comprises a double-stranded nucleic acid. In some embodiments, a nucleicacid 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-deazaadenosine, 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 more 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, 110, 120, 130, 140, 150, 160, 170, 180, 190, 20,P-628704-PC 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.

[0120] 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.

[0121] 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 HSVinfection. In some embodiments, a patient is receiving or has received certain therapy to diagnose and / or totreat a disease, disorder, or condition. In some embodiments, a patient is a patient suffering from or susceptible to an HSV infection.

[0122] PEG-conjugated lipid: The term “PEG-conjugated lipid" refers to a molecule comprising a lipid portion and a polyethylene glycol portion.

[0123] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to anactive 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 a 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.

[0124] 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) described 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) described 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 effectivelyhigher doses achieved by a different, more localized route of administration) may be used.P-628704-PC

[0125] 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 described 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 template-independent RNA polymerase after transcription or a poly(A) sequence encoded by DNA and transcribed by a template-dependent RNA polymerase.

[0126] 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, apolypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide hasan 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, a 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.

[0127] 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,P-628704-PC 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.

[0128] Properdin-interfering domain: “Properdin-interfering domain” refers to a domain that blocks or inhibits binding of a host C3b molecule with a host properdin molecule. In another embodiment, the term refers to a domain that blocks or inhibits an interaction of a host C3b molecule with a host properdin molecule.

[0129] 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.

[0130] 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.

[0131] Risk: As will be understood from context, “risk” of a disease, disorder, and / or condition refers to alikelihood 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 a 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.

[0132] 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.

[0133] 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 particularP-628704-PC 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 non-specific binding moiety.

[0134] 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 ofmicrobial growth, and substantially no or no breakdown or degradation of the active biological moleculecomponent(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 stable 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.

[0135] 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 morefeatures characteristic of susceptibility to or risk of a disease, disorder, or condition (e.g., an HSV infection). Insome 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.

[0136] 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.

[0137] 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 isP-628704-PC susceptible to a disease, disorder, and / or condition will develop the disease, disorder, and / or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and / or condition will not develop the disease, disorder, and / or condition.

[0138] 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 transcriptionusing a template.

[0139] Symptoms: As used herein, the term “symptoms” in some embodiments, may be any manifestation of an HSV infection, comprising blisters, ulcerations, or lesions on the urethra, cervix, upper thigh, and / or anus in women and on the penis, urethra, scrotum, upper thigh, and anus in men, inflammation, swelling, fever, flu-like symptoms, sore mouth, sore throat, pharyngitis, pain, blisters on tongue, mouth or lips, ulcers, cold sores, neckpain, enlarged lymph nodes, reddening, bleeding, itching, dysuria, headache, muscle pain, etc., or a combinationthereof. In some embodiments, symptoms are primary, while in another embodiment, symptoms are secondary. In some embodiments, “primary” refers to a symptom that is a direct result of the subject viral infection, while in some embodiments, “secondary” refers to a symptom that is derived from or consequent to a primary cause. In some embodiments, the compositions, combinations, and strains for use in the present disclosure treat primary or secondary symptoms or secondary complications related to HSV infection.

[0140] 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 featuresof 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.

[0141] 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.

[0142] 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, avalue that is equal to or higher than the threshold level defines one subset of the population, and a value that isP-628704-PC 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.

[0143] 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 thedisease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject at a later-stage of disease, disorder, and / or condition.

[0144] Truncated: As used herein, the term “truncated” refers to a protein or polypeptide that is shorter at its N-terminal, C-terminal, or both the N-terminal and C-terminal ends as compared to the wild-type protein orpolypeptide.

[0145] 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.

[0146] Vaccine: As used herein, the term “vaccine” refers to a composition or combination or agent that induces an immune response upon administration to a subject. In some embodiments, an induced immune response provides protective immunity. In some embodiments, the vaccine stimulates antibody production or cellular immunity against a pathogen or both. In some embodiments, the vaccine is incapable of causing severe infection in a subject.

[0147] 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 moieties 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 in 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 ornucleic 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, aP-628704-PC 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 residue 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, about 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.

[0148] In some embodiments, the variant may be a sequence conservative variant. In some embodiments, 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.

[0149] 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, whereinadditional DNA segments may be ligated into the viral genome. Certain vectors are capable of autonomousreplication 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.,P-628704-PC 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.

[0150] 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. DETAILED DESCRIPTION

[0151] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the polyribonucleotides disclosed herein, and of the antigens they encode. However, it will be understood by those skilled in the art that these compositions can be useful also without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the descriptions herein. Combinations and Compositions

[0152] In some embodiments, the present disclosure provides combinations or compositions comprising one or more RNAs (also referred to herein as “polyribonucleotides.”) In some embodiments, one or more RNAs encode a polypeptide comprising Herpes Simplex Virus (HSV) glycoprotein or immunogenic fragment thereof. In some embodiments, an RNA is a modified (e.g., nucleoside-modified) RNA as described herein below.

[0153] In some embodiments, an immunogenic fragment of an HSV glycoprotein comprises or consists of an ectodomain of the glycoprotein, or a portion thereof. In another embodiment, an immunogenic fragment consists of an ectodomain of the glycoprotein, or a portion thereof.

[0154] In some embodiments, the present disclosure provides a combination or a composition comprising one or more polyribonucleotides, wherein each of said polyribonucleotides encodes a Herpes Simplex Virus (HSV) glycoprotein or immunogenic fragment thereof. In some embodiments, the RNA is modified. In some embodiments, the modified RNA comprises one or more pseudouridine or pseudouridine family residues. In some embodiments, the combination is a single composition.

[0155] In some embodiments, an HSV glycoprotein comprises or consists of glycoprotein D (gD), glycoprotein C (gC), glycoprotein E (gE), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L (gL) glycoprotein I (gI), or a combination thereof.

[0156] Thus, in some embodiments, the present disclosure provides a combination or composition comprising one or more polyribonucleotides encoding HSV gD, gC, gE, gB, gH, gL, gI, or immunogenic fragments thereof. In some embodiments, the polyribonucleotides are modified. In some embodiments, the modified polyribonucleotides comprise pseudouridine-modified polyribonucleotides.

[0157] In some embodiments, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gD or an immunogenic fragment thereof. InP-628704-PC another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gC glycoprotein or an immunogenic fragment thereof. In another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gE glycoprotein or an immunogenic fragment thereof. In another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gB glycoprotein or an immunogenic fragment thereof. In another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gH glycoprotein or an immunogenic fragment thereof. In another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gL glycoprotein or an immunogenic fragment thereof. In another embodiment, the present disclosure provides combinations or compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gI glycoprotein or an immunogenic fragment thereof.

[0158] In some embodiments, the HSV glycoproteins are HSV-2 glycoproteins or immunogenic fragments thereof. In another embodiment, the HSV glycoproteins are HSV-1 glycoproteins or immunogenic fragments thereof. In some embodiments, the HSV glycoproteins comprise both HSV-2 glycoproteins or immunogenic fragments thereof and HSV-1 glycoproteins or immunogenic fragments thereof. In other embodiments, the HSV glycoproteins comprise a mixture of HSV-2 glycoproteins or immunogenic fragments thereof and HSV-1 glycoproteins or immunogenic fragments thereof.

[0159] In some embodiments, any of the combinations or compositions as described herein consists essentially of one or more RNAs, wherein each of said RNAs encodes an HSV glycoprotein or immunogenic fragment thereof. In other embodiments, any of the combinations or compositions as described herein consists of one or more RNAs, wherein each of said RNAs encodes an HSV glycoprotein or immunogenic fragment thereof.

[0160] In some embodiments, combinations or compositions of the present disclosure and for use in themethods of the present disclosure comprise both HSV-2 glycoproteins or immunogenic glycoprotein fragmentsand HSV-1 glycoproteins or immunogenic glycoprotein fragments. In another embodiment, combinations or 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.

[0161] Disclosed herein are combinations comprising (a) a polyribonucleotide encoding a polypeptide comprising an HSV gE glycoprotein or immunogenic fragment thereof and (b) a polyribonucleotide encoding a polypeptide comprising an HSV gI glycoprotein or immunogenic fragment thereof.

[0162] In other embodiments, disclosed herein are compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gE glycoprotein or immunogenic fragment thereof. In other embodiments, disclosed herein are compositions comprising a polyribonucleotide encoding a polypeptide comprising an HSV gI glycoprotein or immunogenic fragment thereof.

[0163] In some embodiments, the polyribonucleotide is nucleoside-modified. In some embodiments, the encoded glycoprotein is truncated. In some embodiments, the encoded glycoprotein is a gE antigen, a gI antigen, or both. In some embodiments, a gE antigen, a gI antigen, or both are from HSV-2. In other embodiments, a gE antigen, a gI antigen, or both are from HSV-1. In other embodiments, the HSV-2 gE antigenP-628704-PC or immunogenic fragment thereof comprises or consists of an HSV-2 gE ectodomain. In other embodiments, the HSV-2 gI antigen or immunogenic fragment thereof comprises or consists of an HSV-2 gI ectodomain.

[0164] Also disclosed herein are combinations comprising (a) a polyribonucleotide encoding a polypeptide comprising a truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, and (b) a polyribonucleotide encoding a polypeptide comprising a truncated HSV-2 gI glycoprotein or immunogenic fragment thereof.

[0165] In some embodiments, a single polyribonucleotide encodes both the HSV gE glycoprotein or immunogenic fragment thereof, and the HSV gI glycoprotein or immunogenic fragment thereof. In other embodiments, the HSV gE glycoprotein or immunogenic fragment thereof, and the HSV gI glycoprotein or immunogenic fragment thereof are encoded by separate polyribonucleotides. In some embodiments, a single polyribonucleotide encodes both the truncated HSV gE glycoprotein or immunogenic fragment thereof, and the truncated HSV gI glycoprotein or immunogenic fragment thereof. In other embodiments, the truncated HSV gE glycoprotein or immunogenic fragment thereof, and the truncated HSV gI glycoprotein or immunogenic fragment thereof are encoded by separate polyribonucleotides.

[0166] In some embodiments, combinations or compositions disclosed herein comprise a polyribonucleotide encoding a polypeptide comprising an HSV gE glycoprotein or immunogenic fragment thereof, or a truncated HSV gE glycoprotein or immunogenic fragment thereof. In other embodiments, the combinations or compositions disclosed herein comprise a polyribonucleotide encoding a polypeptide comprising an HSV gI glycoprotein or immunogenic fragment thereof, or a truncated HSV gI glycoprotein or immunogenic fragment thereof.

[0167] In some embodiments, a combination or composition comprises or consists of one or more RNAsencoding HSV glycoproteins or immunogenic fragments thereof and lipid nanoparticles, polyplexes (PLX),lipidated polyplexes (LPLX), or liposomes. Glycoprotein E (gE)

[0168] HSV glycoprotein E (gE), or Envelope Glycoprotein E, plays an essential role in the virus's life cycle andpathogenesis. gE is one of the glycoproteins present on the viral envelope. Among others, gE promotes thefusion of the virus envelope with the host cell membrane, allowing the newly formed viral particles to be released and infect neighboring cells. Further gE has been shown to interfere with the host's immune system and help the virus evade detection and elimination by the immune system. gE forms a heterodimer with glycoprotein I (gI). HSV-2 gE

[0169] In some embodiments, a polyribonucleotide encoding a polypeptide comprising HSV gE as described herein comprises or consists of a polyribonucleotide encoding a polypeptide comprising HSV-2 gE, also termed herein gE2. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gE as described herein comprises or consists of a polyribonucleotide encoding a polypeptide comprising a fragment of an HSV-2 gE protein (e.g., an immunogenic fragment).

[0170] In some embodiments, the present disclosure provides a modified (e.g., nucleoside modified) polyribonucleotide encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, or a truncated HSV-2 gE glycoprotein or immunogenic fragment thereof. In some embodiments, the present disclosure provides a polyribonucleotide encoding the full-length or non-truncated HSV-2 gE glycoprotein.P-628704-PC

[0171] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure encodes a full-length HSV-2 gE glycoprotein comprising the following amino acid sequence: RTSWKRVTSGEDVVLLPAPAERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVVDAACMRAPEPLAIAYSPPFPAGDEGLY SELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTPTPDDYDEEDDAGVTNARRSAFPPQPPPR RPPVAPPTHPRVIPEVSHVRGVTVHMETLEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMRFDVPSSCADMRIYEACLYHPQL PECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQHAGLYLCVVYVDDHIHAWG HMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRAPHPAPSARGPLRLGAVLGAALLLAALGLSAWACMTCWRRRSWRAVKSRA SATGPTYIRVADSELYADWSSDSEGERDGSLWQDPPERPDSPSTNGSGFEILSPTAPSVYPHSEGRKSRRPLTTFGSGSPGRRHSQASYPSVLW (SEQ ID NO: 6).

[0172] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure encodes an HSV-2 gE immunogenic fragment, comprising amino acids 24-405 of HSV-2 gE (e.g., strain 2.12 or US8), as set forth in the following amino acid sequence: RTSWKRVTSGEDVVLLPAPAGPEERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVVDAACMRAPEPLAIAYSPPFPAGDE GLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTPTPDDYDEEDDAGVSERTPVSVPPPTP PRRPPVAPPTHPRVIPEVSHVRGVTVHMETPEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMRFDVPSSCAEMRIYEACLYHP QLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQHAGLYLCVVYVDDHIHA WGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRA (SEQ ID NO: 4).

[0173] In some embodiments, an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2gE glycoprotein or immunogenic fragment thereof, comprises or consists of an amino acid sequence comprising ahomology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 6 or SEQ ID NO: 4.

[0174] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure further encodes a signal peptide. In some embodiments, a signal peptide is an IL2-related signal peptide (SEQ ID NO: 109). In other embodiments, a signal peptide is an HSV-2 gE signal peptide (SEQ ID NO: 97).

[0175] In some embodiments, an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of 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,P-628704-PC 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, 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.

[0176] In some embodiments, a polyribonucleotide for use in the methods, compositions, and combinations of the present disclosure encodes, inter alia, an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gE glycoprotein or immunogenic fragment thereof (e.g., amino acids 24-405). In someembodiments, the polyribonucleotide comprises or consists of the following nucleotide sequence:CGCACCUCCUGGAAGCGCGUGACCUCCGGCGAGGACGUGGUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACCC GCGCCCACAAGCUGCUGUGGGCCGCCGAGCCCCUGGACGCCUGCGGCCCCCUGCGCCCCUCCUGGGUGGCCCUGUGGCC CCCCCGCCGCGUGCUGGAGACCGUGGUGGACGCCGCCUGCAUGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCCCCCC CCUUCCCCGCCGGCGACGAGGGCCUGUACUCCGAGCUGGCCUGGCGCGACCGCGUGGCCGUGGUGAACGAGUCCCUGGUGAUCUACGGCGCCCUGGAGACCGACUCCGGCCUGUACACCCUGUCCGUGGUGGGCCUGUCCGACGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCCCGCCCCCGUGCCCACCCCCACCCCCGACGACUACGACGAGGAGGACGACGCCG GCGUGUCCGAGCGCACCCCCGUGUCCGUGCCCCCCCCCACCCCCCCCCGCCGCCCCCCCGUGGCCCCCCCCACCCACCCCC GCGUGAUCCCCGAGGUGUCCCACGUGCGCGGCGUGACCGUGCACAUGGAGACCCCCGAGGCCAUCCUGUUCGCCCCCGG CGAGACCUUCGGCACCAACGUGUCCAUCCACGCCAUCGCCCACGACGACGGCCCCUACGCCAUGGACGUGGUGUGGAUG CGCUUCGACGUGCCCUCCUCCUGCGCCGAGAUGCGCAUCUACGAGGCCUGCCUGUACCACCCCCAGCUGCCCGAGUGCC UGUCCCCCGCCGACGCCCCCUGCGCCGUGUCCUCCUGGGCCUACCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCG CACCACCCCCCCCCCCCGCUGCUUCGCCGAGGCCCGCAUGGAGCCCGUGCCCGGCCUGGCCUGGCUGGCCUCCACCGUGA ACCUGGAGUUCCAGCACGCCUCCCCCCAGCACGCCGGCCUGUACCUGUGCGUGGUGUACGUGGACGACCACAUCCACGC CUGGGGCCACAUGACCAUCUCCACCGCCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCACCUGCCCCAGCGCCAGCCCG AGCCCGUGGAGCCCACCCGCCCCCACGUGCGCGCCUAA (SEQ ID NO: 36)

[0177] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, as described herein comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 36.

[0178] In some embodiments, a polyribonucleotide encoding a polypeptide comprising an HSV-2 gE glycoprotein or immunogenic fragment thereof, or a truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, as described herein further comprises or consists of a signal sequence that encodes a signal peptide. In other embodiments, a polyribonucleotide further comprises or consists of nucleotide sequences that are not protein-coding, for e.g., a 5’UTR, a 3’UTR, a polyA tail, etc.

[0179] In some embodiments, a polyribonucleotide for use in the methods, compositions, and combinations of the present disclosure comprises or consists of, inter alia, a nucleotide sequence encoding an immunogenic fragment of HSV-2 gE glycoprotein, a signal sequence encoding a signal peptide, and non-protein coding sequences (e.g., a 5’UTR, a 3’UTR, a polyA tail, etc.).

[0180] In some embodiments, the polyribonucleotide comprises or consists of the following nucleotide sequence: AGCAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAAP-628704-PC UCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCGCUAUGCGCAUGCAGCUGCU GCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCACUCCCGCACCUCCUGGAAGCGCGUGACCUCCGGCGAGGACG UGGUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACCCGCGCCCACAAGCUGCUGUGGGCCGCCGAGCCCCUGGACG CCUGCGGCCCCCUGCGCCCCUCCUGGGUGGCCCUGUGGCCCCCCCGCCGCGUGCUGGAGACCGUGGUGGACGCCGCCUGCA UGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCCCCCCCCUUCCCCGCCGGCGACGAGGGCCUGUACUCCGAGCUGGCCUG GCGCGACCGCGUGGCCGUGGUGAACGAGUCCCUGGUGAUCUACGGCGCCCUGGAGACCGACUCCGGCCUGUACACCCUGUC CGUGGUGGGCCUGUCCGACGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCCCGCCCCCGUGCCCACCCCCAC CCCCGACGACUACGACGAGGAGGACGACGCCGGCGUGUCCGAGCGCACCCCCGUGUCCGUGCCCCCCCCCACCCCCCCCCGC CGCCCCCCCGUGGCCCCCCCCACCCACCCCCGCGUGAUCCCCGAGGUGUCCCACGUGCGCGGCGUGACCGUGCACAUGGAGA CCCCCGAGGCCAUCCUGUUCGCCCCCGGCGAGACCUUCGGCACCAACGUGUCCAUCCACGCCAUCGCCCACGACGACGGCCC CUACGCCAUGGACGUGGUGUGGAUGCGCUUCGACGUGCCCUCCUCCUGCGCCGAGAUGCGCAUCUACGAGGCCUGCCUGUA CCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCGUGUCCUCCUGGGCCUACCGCCUGGCCGUGCGC UCCUACGCCGGCUGCUCCCGCACCACCCCCCCCCCCCGCUGCUUCGCCGAGGCCCGCAUGGAGCCCGUGCCCGGCCUGGCCU GGCUGGCCUCCACCGUGAACCUGGAGUUCCAGCACGCCUCCCCCCAGCACGCCGGCCUGUACCUGUGCGUGGUGUACGUGG ACGACCACAUCCACGCCUGGGGCCACAUGACCAUCUCCACCGCCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCACCUGCC CCAGCGCCAGCCCGAGCCCGUGGAGCCCACCCGCCCCCACGUGCGCGCCUAAACUAGUAGUGACUGACUAGGAUCUGGUUAC CACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAA AAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 79)

[0181] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 79.

[0182] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 176). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0183] In some embodiments, the polyribonucleotide comprises or consists of the following nucleotide sequence: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGC UGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCCGCACCUCCUGGAAGCGCGUGACCUCCGGCGAG GACGUGGUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACCCGCGCCCACAAGCUGCUGUGGGCCGCCGAGCCCC UGGACGCCUGCGGCCCCCUGCGCCCCUCCUGGGUGGCCCUGUGGCCCCCCCGCCGCGUGCUGGAGACCGUGGUGGACGC CGCCUGCAUGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCCCCCCCCUUCCCCGCCGGCGACGAGGGCCUGUACUCCG AGCUGGCCUGGCGCGACCGCGUGGCCGUGGUGAACGAGUCCCUGGUGAUCUACGGCGCCCUGGAGACCGACUCCGGCCU GUACACCCUGUCCGUGGUGGGCCUGUCCGACGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCCCGCCCC CGUGCCCACCCCCACCCCCGACGACUACGACGAGGAGGACGACGCCGGCGUGUCCGAGCGCACCCCCGUGUCCGUGCCCC CCCCCACCCCCCCCCGCCGCCCCCCCGUGGCCCCCCCCACCCACCCCCGCGUGAUCCCCGAGGUGUCCCACGUGCGCGGC GUGACCGUGCACAUGGAGACCCCCGAGGCCAUCCUGUUCGCCCCCGGCGAGACCUUCGGCACCAACGUGUCCAUCCACGCP-628704-PC CAUCGCCCACGACGACGGCCCCUACGCCAUGGACGUGGUGUGGAUGCGCUUCGACGUGCCCUCCUCCUGCGCCGAGAUG CGCAUCUACGAGGCCUGCCUGUACCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCGUGUCCUC CUGGGCCUACCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCACCACCCCCCCCCCCCGCUGCUUCGCCGAGGCCC GCAUGGAGCCCGUGCCCGGCCUGGCCUGGCUGGCCUCCACCGUGAACCUGGAGUUCCAGCACGCCUCCCCCCAGCACGC CGGCCUGUACCUGUGCGUGGUGUACGUGGACGACCACAUCCACGCCUGGGGCCACAUGACCAUCUCCACCGCCGCCCAG UACCGCAACGCCGUGGUGGAGCAGCACCUGCCCCAGCGCCAGCCCGAGCCCGUGGAGCCCACCCGCCCCCACGUGCGCGC CUAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAU AAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUU CACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 78).

[0184] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gE glycoprotein or immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 78.

[0185] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments,underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 176). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0186] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding an HSV-2 gE immunogenic 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: 36.

[0187] In some embodiments, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of an IgG Fc-binding domain of the HSV gE glycoprotein. In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of any other HSV gE domain known in the art to mediate binding to IgG Fc.

[0188] In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of an HSV gE domain involved in cell-to-cell spread. In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide fragment utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of an immune evasion domain. In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein orimmunogenic fragment thereof, encoded by a modified (e.g. nucleoside-modified) polyribonucleotide utilized inP-628704-PC the methods, compositions, and combinations of the present disclosure comprises or consists of a portion of an immune evasion domain.

[0189] In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is immunoprotective. A protective immune response generally involves, in some embodiments, an antibody response. In another embodiment, mutants, sequence conservative variants, and functional conservative variants of HSV gE glycoproteins or immunogenic fragments thereof, or truncated HSV gE glycoproteins or immunogenic fragments thereof, are useful in methods, compositions, and combinations of the present disclosure, providedthat all such variants retain the required immunoprotective effect.

[0190] In some embodiments, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, can be derived from any strain of HSV. In some embodiments, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, can be derived from sequence variants of HSV, as found in HSV-infected individuals. HSV-1 gE

[0191] In some embodiments, the HSV-1 gE fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 24-409 of gE from HSV-1 (e.g., NS strain), as set forth in the following amino acid sequence: KTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVPETVVDAACMRAPVPLAMAYAPPAPS ATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGLYTLSVGDIKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGEGED ESLAGTPASGTPRLPPSPAPPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHAIAHDDQTYTMDVVWLRFDVPTS CAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAGCSRTNPPPRCSAEAHMEPFPGLAWQAASVNLEFRDASPQH SGLYLCVVYVNDHIHAWGHITINTAAQYRNAVVEQPLPQRGADLAEPTHPHVGA (SEQ ID NO: 7).

[0192] In some embodiments, an HSV-1 gE fragment comprises or consists of 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: 7. In some embodiments, an HSV-1 gE fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 7.

[0193] In some embodiments, the gE fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 24-409 of gE from an HSV-1 strain (e.g., SEQ ID NO: 7).

[0194] In some embodiments, the HSV-1 gE fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 21-409 of gE fromHSV-1 (e.g., NS strain or US8), as set forth in the following amino acid sequence:GTPKTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVPETVVDAACMRAPVPLAMAYAPP APSATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGLYTLSVGDIKDPARQVASVVLVVQPAPVPTPPPTPADYDEDDNDEGE GEDESLAGTPASGTPRLPPSPAPPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHAIAHDDQTYTMDVVWLRFDV PTSCAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAGCSRTNPPPRCSAEAHMEPFPGLAWQAASVNLEFRDASPQHSGLYLCVVYVNDHIHAWGHITINTAAQYRNAVVEQPLPQRGADLAEPTHPHVGA (SEQ ID NO: 8).P-628704-PC

[0195] In some embodiments, an HSV-1 gE fragment comprises or consists of 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 gE fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 8.

[0196] In some embodiments, the gE fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 21-409 of gE from an HSV-1 strain (e.g., SEQ ID NO: 8).

[0197] In some embodiments, the full-length HSV-1 gE encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the following amino acid sequence: MDRGAVVGFLLGVCVVSCLAGTPKTSWRRVSVGEDVSLLPAPGPTGRGPTQKLLWAVEPLDGCGPLHPSWVSLMPPKQVPET VVDAACMRAPVPLAMAYAPPAPSATGGLRTDFVWQERAAVVNRSLVIYGVRETDSGLYTLSVGDIKDPARQVASVVLVVQPAP VPTPPPTPADYDEDDNDEGEGEDESLAGTPASGTPRLPPSPAPPRSWPSAPEVSHVRGVTVRMETPEAILFSPGEAFSTNVSIHA IAHDDQTYTMDVVWLRFDVPTSCAEMRIYESCLYHPQLPECLSPADAPCAASTWTSRLAVRSYAGCSRTNPPPRCSAEAHMEP FPGLAWQAASVNLEFRDASPQHSGLYLCVVYVNDHIHAWGHITINTAAQYRNAVVEQPLPQRGADLAEPTHPHVGAPPHAPPT HGALRLGAVMGAALLLSALGLSVWACMTCWRRRAWRAVKSRASGKGPTYIRVADSELYADWSSDSEGERDQVPWLAPPERP DSPSTNGSGFEILSPTAPSVYPRSDGHQSRRQLTTFGSGRPDRRYSQASDSSVFW (SEQ ID NO: 207).

[0198] In some embodiments, an HSV-1 gE comprises or consists of an amino acid sequence that is at least85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence SEQ ID NO: 207. In some embodiments, an HSV-1 gE has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 207.

[0199] In another embodiment, the HSV-1 gE or an immunogenic fragment thereof, encoded by RNA utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of 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, 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,P-628704-PC 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, ALO18664.1, ALO18740.1, AMB65664.1, AMB65737.1, AMB65811.1, AMB65887.1, AMB65958.1, AMN09834.1, ANN83966.1, ANN84043.1, ANN84119.1, ANN84196.1, ANN84273.1, 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, SBO07910.1, SBS69571.1, SBS69576.1, SBS69595.1, SBS69636.1, SBS69693.1, SBS69701.1, SBS69722.1, SBS69732.1, SBS69813.1, SBT69397.1, or YP_009137143.1.

[0200] In some embodiments, a polyribonucleotide encoding a polypeptide comprising HSV gE as described herein comprises or consists of a polyribonucleotide encoding a polypeptide comprising HSV-1 gE. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gE as described herein comprises or consists of a polyribonucleotide encoding a polypeptide comprising a fragment of an HSV-1 gE protein (e.g., an immunogenic fragment).

[0201] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding a polypeptide comprising an HSV-1 gE fragment comprises or consists of: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCAAGACCUCCUGGCGCCGCGUGUCCGUGGGCGAGGACGUGUCCCUGCUGCCCGCCCCCGGCCCCACCGGCCGCGGCCCCACCCAGAAGCUGCUGUGGGCCGUGGAGCCCCUGG ACGGCUGCGGCCCCCUGCACCCCUCCUGGGUGUCCCUGAUGCCCCCCAAGCAGGUGCCCGAGACCGUGGUGGACGCCGC CUGCAUGCGCGCCCCCGUGCCCCUGGCCAUGGCCUACGCCCCCCCCGCCCCCUCCGCCACCGGCGGCCUGCGCACCGACU UCGUGUGGCAGGAGCGCGCCGCCGUGGUGAACCGCUCCCUGGUGAUCUACGGCGUGCGCGAGACCGACUCCGGCCUGU ACACCCUGUCCGUGGGCGACAUCAAGGACCCCGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGCAGCCCGCCCCCGU GCCCACCCCCCCCCCCACCCCCGCCGACUACGACGAGGACGACAACGACGAGGGCGAGGGCGAGGACGAGUCCCUGGCCG GCACCCCCGCCUCCGGCACCCCCCGCCUGCCCCCCUCCCCCGCCCCCCCCCGCUCCUGGCCCUCCGCCCCCGAGGUGUCCC ACGUGCGCGGCGUGACCGUGCGCAUGGAGACCCCCGAGGCCAUCCUGUUCUCCCCCGGCGAGGCCUUCUCCACCAACGU GUCCAUCCACGCCAUCGCCCACGACGACCAGACCUACACCAUGGACGUGGUGUGGCUGCGCUUCGACGUGCCCACCUCCUGCGCCGAGAUGCGCAUCUACGAGUCCUGCCUGUACCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCGCCUCCACCUGGACCUCCCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCACCAACCCCCCCCCCCGCUGCUC CGCCGAGGCCCACAUGGAGCCCUUCCCCGGCCUGGCCUGGCAGGCCGCCUCCGUGAACCUGGAGUUCCGCGACGCCUCC CCCCAGCACUCCGGCCUGUACCUGUGCGUGGUGUACGUGAACGACCACAUCCACGCCUGGGGCCACAUCACCAUCAACAC CGCCGCCCAGUACCGCAACGCCGUGGUGGAGCAGCCCCUGCCCCAGCGCGGCGCCGACCUGGCCGAGCCCACCCACCCCC ACGUGGGCGCCUAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCU CUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAP-628704-PC GAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 77).

[0202] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 176). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0203] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding a polypeptide comprising 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: 45. Glycoprotein I (gI)

[0204] HSV glycoprotein I (gI) or Envelope Glycoprotein I, is one of the glycoproteins present on the viral envelope. Among others, gI plays a role in modulating the host immune response to HSV-2 infection by helping

[0205] In some embodiments, a polynucleotide encoding an exemplary polypeptide comprising an HSV-2 gI glycoprotein or an immunogenic fragment thereof, comprises or consists of the following nucleotide sequence:CCCCAGGCTTTACACTTTATGCTTCCGGCTCGTATGTTGTGTGGAATTGTGAGCGGATAACAATTTCACACAGGAAACAGCTATGACCATGATTACGAATTGTAATACGACTCACTATAaGcATAAAAGTCTCAACACAACATATACAAAACAAACGAATCTCAA GCAATCAAGCATTCTACTTCTATTGCAGCAATTTAAATCATTTCTTTTAAAGCAAAAGCAATTTTCTGAAAATTTTCACCATT TACGAACGATaacgccaccATGGCCATCTCCGGCGTGCCCGTGCTGGGCTTCTTCATCATCGCCGTGCTGATGTCCG CCCAGGAGTCCTGGGCCGGCCCCACCGTGTCCCTGGTGTCCGACTCCCTGGTGGACGCCGGCGCCGTGGGCCCCCAGG GCTTCGTGGAGGAGGACCTGCGCGTGTTCGGCGAGCTGCACTTCGTGGGCGCCCAGGTGCCCCACACCAACTACTACGAC GGCATCATCGAGCTGTTCCACTACCCCCTGGGCAACCACTGCCCCCGCGTGGTGCACGTGGTGACCCTGACCGCCTGCCCC CGCCGCCCCGCCGTGGCCTTCACCCTGTGCCGCTCCACCCACCACGCCCACTCCCCCGCCTACCCCACCCTGGAGCTGGGC CTGGCCCGCCAGCCCCTGCTGCGCGTGCGCACCGCCACCCGCGACTACGCCGGCCTGTACGTGCTGCGCGTGTGGGTGGG CTCCGCCACCAACGCCTCCCGCTTCGTGCTGGGCGTGGCCCTGTCCGCCAACGGCACCTTCGTGTACAACGGCTCCGACTACGGCTCCTGCGACCCCGCCCAGCTGCCCTTCTCCGCCCCCCGCCTGGGCCCCTCCTCCGTGTACACCCCCGGCGCCTCCCGCCCCACCCCCCCCCGCACCACCACCCCCCCCTCCTCCCCCCGCGACCCCACCCCCGCCCCCGGCGACACCGGCACCCCCGCC CCCGCCTCCGGCGAGATCGCCCCCCCCAACTCCACCCGCTCCGCCTCCGAGTCCCGCCACCGCtaaCUAGUAGUGACUGACU AGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACA AAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAA (SEQ ID NO: 80).

[0206] In some embodiments, the present disclosure provides a modified (e.g., nucleoside-modified) polyribonucleotide encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, or a truncated HSV-2 gI glycoprotein or immunogenic fragment thereof. In some embodiments, the present disclosure provides aP-628704-PC polyribonucleotide encoding the full-length or non-truncated HSV-2 gI glycoprotein. HSV-2 gI glycoprotein is also termed herein gI2, having all the same features and limitations.

[0207] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure encodes a full-length HSV-2 gI glycoprotein comprising the following amino acid sequence: GPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVVHVVTLTACPRRPAVAFTLCRST HHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVYNGSDYGSCDPAQLPFSAPRLGPS SVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHRLTVAQVIQIAIPASIIAFVFLGSSICFIHRCQR RYRRPRGQIYNPGGVSCAVNEAAMARLGAELRSHPNTPPKPRRRSSSSTTMPSLTSIAEESEPGPVVLLSVSPRPRSGPTAPQEV (SEQ ID NO: 1).

[0208] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure encodes an HSV-2 gI immunogenic fragment, comprising amino acids 25-230 of HSV-2 gI, as set forth in the following amino acid sequence: GPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVVHVVTLTACPRRPAVAFTLCRST HHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVYNGSDYGSCDPAQLPFSAPRLGPS SVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHR (SEQ ID NO: 2).

[0209] In some embodiments, an HSV-2 gI glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gI glycoprotein or immunogenic fragment thereof, comprises or consists of an amino acid sequence comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 1 or SEQ ID NO: 2.

[0210] In some embodiments, a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure further encodes a signal sequence encoding a signal peptide. In some embodiments, the signal peptide is an IL2 signal peptide (SEQ ID NO: 109). In other embodiments, the signal peptide is an HSV-2 gI signal peptide (SEQ ID NO: 106).

[0211] In some embodiments, an HSV-2 gI glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gI glycoprotein or immunogenic fragment thereof, encoded by modified RNA utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the amino acid sequences as set forth in any of the following GenBank Accession Numbers: ABW83313.1, ABW83327.1, ABW83385.1, ABW83397.1, AHG54731.1, AKC42829.1, AKC59306.1, AKC59377.1, AKC59519.1, AKC59590.1, AQZ56891.1,AQZ56962.2, AQZ58027.1, ATD86571.1, ATD86726.1, BAA00021.1, QAU10475.1, QAU10768.1, QBC74573.1,QBH76746.1, QBH76909.1, QBH78328.1, QBH78911.1, QBH80193.1, QBH80706.1, QBH80794.1, QBH81814.1, QBH82569.1, QBH83266.1, QBH84231.1, QBH85083.1, QBH85656.1, or SPT06174.1.

[0212] In some embodiments, a polyribonucleotide for use in the methods, compositions, and combinations of the present disclosure encodes, inter alia, an HSV-2 gI glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gI glycoprotein or immunogenic fragment thereof, (e.g., amino acids 25-230) comprising the following nucleotide sequence: GCCCAGGAGUCCUGGGCCGGCCCCACCGUGUCCCUGGUGUCCGACUCCCUGGUGGACGCCGGCGCCGUGGGCCCCCAGG GCUUCGUGGAGGAGGACCUGCGCGUGUUCGGCGAGCUGCACUUCGUGGGCGCCCAGGUGCCCCACACCAACUACUACGA CGGCAUCAUCGAGCUGUUCCACUACCCCCUGGGCAACCACUGCCCCCGCGUGGUGCACGUGGUGACCCUGACCGCCUGCP-628704-PC CCCCGCCGCCCCGCCGUGGCCUUCACCCUGUGCCGCUCCACCCACCACGCCCACUCCCCCGCCUACCCCACCCUGGAGCU GGGCCUGGCCCGCCAGCCCCUGCUGCGCGUGCGCACCGCCACCCGCGACUACGCCGGCCUGUACGUGCUGCGCGUGUGG GUGGGCUCCGCCACCAACGCCUCCCGCUUCGUGCUGGGCGUGGCCCUGUCCGCCAACGGCACCUUCGUGUACAACGGCU CCGACUACGGCUCCUGCGACCCCGCCCAGCUGCCCUUCUCCGCCCCCCGCCUGGGCCCCUCCUCCGUGUACACCCCCGGC GCCUCCCGCCCCACCCCCCCCCGCACCACCACCCCCCCCUCCUCCCCCCGCGACCCCACCCCCGCCCCCGGCGACACCGGCA CCCCCGCCCCCGCCUCCGGCGAGAUCGCCCCCCCCAACUCCACCCGCUCCGCCUCCGAGUCCCGCCACCGCUAA (SEQ ID NO: 29)

[0213] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-2 gI glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gI glycoprotein or immunogenic fragmentthereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% to SEQ ID NO: 29.

[0214] In some embodiments, a polyribonucleotide encoding a polypeptide comprising an HSV-2 gI glycoprotein or immunogenic fragment thereof, or truncated HSV-2 gI glycoprotein or immunogenic fragment thereof, as described herein further comprises a signal sequence that encodes a signal peptide. In other embodiments, apolyribonucleotide further comprises nucleotide sequences that are not protein-coding, for e.g., a 5’UTR, a3’UTR, polyA tail, etc.

[0215] In some embodiments, a polyribonucleotide for use in the methods, compositions, and combinations of the present disclosure comprises or consists of, inter alia, a nucleotide sequence encoding an immunogenic fragment of HSV-2 gI glycoprotein, a signal sequence encoding a signal peptide, and non-protein coding sequences (e.g., a 5’UTR, a 3’UTR, a polyA tail, etc.).

[0216] In some embodiments, the polyribonucleotide comprises or consists of the following nucleotide sequence: AGCAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAA UCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAACGCCACCAUGGCCAUCUCCGGC GUGCCCGUGCUGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCCGCCCAGGAGUCCUGGGCCGGCCCCACCGUGUCCC UGGUGUCCGACUCCCUGGUGGACGCCGGCGCCGUGGGCCCCCAGGGCUUCGUGGAGGAGGACCUGCGCGUGUUCGGCGAG CUGCACUUCGUGGGCGCCCAGGUGCCCCACACCAACUACUACGACGGCAUCAUCGAGCUGUUCCACUACCCCCUGGGCAACC ACUGCCCCCGCGUGGUGCACGUGGUGACCCUGACCGCCUGCCCCCGCCGCCCCGCCGUGGCCUUCACCCUGUGCCGCUCCAC CCACCACGCCCACUCCCCCGCCUACCCCACCCUGGAGCUGGGCCUGGCCCGCCAGCCCCUGCUGCGCGUGCGCACCGCCACC CGCGACUACGCCGGCCUGUACGUGCUGCGCGUGUGGGUGGGCUCCGCCACCAACGCCUCCCGCUUCGUGCUGGGCGUGGCC CUGUCCGCCAACGGCACCUUCGUGUACAACGGCUCCGACUACGGCUCCUGCGACCCCGCCCAGCUGCCCUUCUCCGCCCCCC GCCUGGGCCCCUCCUCCGUGUACACCCCCGGCGCCUCCCGCCCCACCCCCCCCCGCACCACCACCCCCCCCUCCUCCCCCCGC GACCCCACCCCCGCCCCCGGCGACACCGGCACCCCCGCCCCCGCCUCCGGCGAGAUCGCCCCCCCCAACUCCACCCGCUCCGC CUCCGAGUCCCGCCACCGCUAAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUG GAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUA AAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 335)

[0217] In some embodiments, the nucleotide sequence of the modified polyribonucleotide encoding a truncated HSV-2 gI comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 335.P-628704-PC

[0218] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 181). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 313) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0219] In some embodiments, an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide comprises or consists of an HSV-1 gI domain involved in cell-to-cell spread. In another embodiment, an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein orimmunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized inthe methods, compositions, and combinations of the present disclosure comprises or consists of an immune evasion domain. In another embodiment, an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of a portion of an immune evasion domain.

[0220] In another embodiment, an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is immunoprotective. A protective immune response generally involves, in some embodiments, an antibody response. In another embodiment, mutants, sequence conservative variants, and functional conservative variants of HSV gI glycoproteins or immunogenic fragments thereof, or truncated HSV gI glycoproteins or immunogenic fragments thereof, are useful in methods, compositions, and combinations of the present disclosure, provided that all such variants retain the required immunoprotective effect.

[0221] In some embodiments, an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gIglycoprotein or immunogenic fragment thereof, can be derived from any strain of HSV. In some embodiments,an HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, can be derived from sequence variants of HSV, as found in HSV-infected individuals.

[0222] In some embodiments, an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside- modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is a homologue of a sequence provided herein. In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is an isoform of the sequence provided herein. In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is a variant of the sequence provided herein. In another embodiment, an HSV gE glycoprotein immunogenic fragment, truncated HSV gE immunogenicP-628704-PC fragment, HSV gI glycoprotein immunogenic fragment, or truncated HSV gI glycoprotein immunogenic fragment encoded by a modified (e.g., nucleoside-modified) polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is a shortened fragment of a sequence provided herein. In some embodiments, the shortened fragment is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids shorter than an amino acid sequence provided herein.

[0223] In another embodiment, an HSV gE glycoprotein or immunogenic fragment thereof, or truncated HSV gE glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside-modified) polyribonucleotide of the methods, compositions, and combinations of the present disclosure comprises or consists of an ectodomain of HSV-2 gE. In another embodiment, an HSV gI glycoprotein or immunogenicfragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified(e.g., nucleoside-modified) polyribonucleotide of the methods, compositions, and combinations of the present disclosure comprises or consists of an ectodomain of HSV-2 gI.

[0224] In another embodiment, an HSV gE glycoprotein immunogenic fragment, truncated HSV gE immunogenic fragment, HSV gI glycoprotein immunogenic fragment, or truncated HSV gI glycoproteinimmunogenic fragment encoded by a modified (e.g., nucleoside-modified) polyribonucleotide of the methods,compositions, and combinations of the present disclosure consists of an ectodomain of an HSV gE or gI glycoprotein. In some embodiments, an HSV gE glycoprotein immunogenic fragment, truncated HSV gE immunogenic fragment, HSV gI glycoprotein immunogenic fragment, or truncated HSV gI glycoprotein immunogenic fragment encoded by a modified (e.g., nucleoside-modified) polyribonucleotide of the methods, compositions, and combinations of the present disclosure consists essentially of an ectodomain of an HSV glycoprotein E or HSV glycoprotein I (e.g., HSV-2 gI or HSV-2 gE).

[0225] In another embodiment, an HSV gE glycoprotein immunogenic fragment, truncated HSV gE immunogenic fragment, HSV gI glycoprotein immunogenic fragment, or truncated HSV gI glycoprotein immunogenic fragment encoded by a modified (e.g., nucleoside-modified) polyribonucleotide of the methods,compositions, and combinations of the present disclosure comprises or consists of a fragment of an ectodomainof an HSV E or HSV I glycoprotein. In another embodiment, an HSV gE glycoprotein immunogenic fragment, truncated HSV gE immunogenic fragment, HSV gI glycoprotein immunogenic fragment, or truncated HSV gI glycoprotein immunogenic fragment encoded by a modified (e.g., nucleoside-modified) polyribonucleotide can be derived from any gE or gI fragment known in the art.

[0226] The present disclosure also provides polyribonucleotides encoding analogs of an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment 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.

[0227] In some embodiments, an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, encoded by a modified (e.g., nucleoside- modified) polyribonucleotide of the present disclosure is homologous to a sequence set forth hereinabove, either expressly or by reference to a GenBank entry.P-628704-PC

[0228] In some embodiments, the polyribonucleotide as described herein further encodes an antigenic tag. In some embodiments, the tag is a histidine (“His”) tag. In one embodiment, the His tag comprises 5 histidine residues. In some embodiments, the His tag comprises 6 histidine residues.

[0229] In some embodiments, methods, compositions, and combinations of the present disclosure utilize a chimeric molecule, comprising a fusion of a polyribonucleotide encoding an HSV protein with a polyribonucleotide 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-2 peptide is detected, in some embodiments, using an antibody against the tag polypeptide. In some embodiments, inclusion of theepitope tag enables the recombinant HSV-2 peptide to be readily purified by affinity purification using an anti-tagantibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are known in the art.

[0230] In some embodiments, the present disclosure provides compositions or combinations comprising one or more modified (e.g., nucleoside-modified) polyribonucleotides encoding an HSV gE glycoprotein or immunogenicfragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein orimmunogenic fragment thereof or truncated HSV gI glycoprotein or immunogenic fragment thereof, and an adjuvant. In other embodiments, compositions or combinations disclosed herein do not comprise an adjuvant.

[0231] In some embodiments, a polyribonucleotide as described herein comprises an RNA molecule. In some embodiments, the RNA comprises messenger RNA (mRNA), which in one embodiment, comprises a polyA tail and a 5’ cap as described herein. In some embodiments, provided herein is a combination comprising a) an RNA encoding an HSV gE glycoprotein or immunogenic fragment thereof and (b) an RNA encoding an HSV gI glycoprotein or immunogenic fragment thereof. In some embodiments, provided herein is a combination comprising a) an mRNA encoding an HSV gE glycoprotein or immunogenic fragment thereof and (b) an mRNA encoding an HSV gI glycoprotein or immunogenic fragment thereof. In some embodiments, thepolyribonucleotide is nucleoside-modified. In some embodiments, the encoded glycoprotein is truncated. In someembodiments, the gE glycoprotein or immunogenic fragment thereof, the gI glycoprotein or immunogenic fragment thereof, or both are from HSV-2. Additional HSV Glycoproteins

[0232] In some embodiments, compositions and combinations disclosed herein comprise polyribonucleotides encoding an HSV gE glycoprotein or immunogenic fragment thereof, truncated HSV gE glycoprotein or immunogenic fragment thereof, HSV gI glycoprotein or immunogenic fragment thereof, or truncated HSV gI glycoprotein or immunogenic fragment thereof, and one or more additional polyribonucleotides encoding an additional HSV glycoprotein. In some embodiments, two or more HSV glycoproteins are encoded in a single polyribonucleotide. In some embodiments, each glycoprotein is encoded in a separate polynucleotide and a combination and / or composition comprises all of the separate polynucleotides.

[0233] In some embodiments, an additional polyribonucleotide encodes a glycoprotein selected from an HSV glycoprotein B (gB), an HSV glycoprotein C (gC), an HSV glycoprotein D (gD), an HSV glycoprotein H (gH), or an HSV glycoprotein L (gL), or any combination thereof. In some embodiments, an additional polyribonucleotide encodes an additional HSV glycoprotein I (gI) and / or an additional HSV glycoprotein E (gE). In someP-628704-PC embodiments, the additional glycoprotein comprises an HSV-2 glycoprotein. In some embodiments, the additional glycoprotein comprises an HSV-1 glycoprotein.

[0234] In some embodiments, the additional HSV glycoprotein is a full-length glycoprotein. In some embodiments, only a fragment of the additional HSV glycoprotein is encoded by the additional polyribonucleotide (e.g., an immunogenic fragment). In some embodiments, compositions or combinations disclosed herein comprise a first additional polyribonucleotide, a first and second additional polyribonucleotide, a first, second, and third additional polyribonucleotide, a first, second, third, and fourth additional polyribonucleotide, a first, second, third, fourth, and fifth additional polyribonucleotide, a first, second, third, fourth, fifth, and sixth additional polyribonucleotide, or a first, second, third, fourth, fifth, sixth, and seventh additionalpolyribonucleotide.

[0235] In some embodiments, a composition or combination as described herein comprises or consists of polyribonucleotides encoding an HSV gE glycoprotein or immunogenic fragment thereof, a truncated HSV gE glycoprotein or immunogenic fragment thereof, an HSV gI glycoprotein or immunogenic fragment thereof, or a truncated HSV gI glycoprotein or immunogenic fragment thereof, and a further polyribonucleotide encoding a gBglycoprotein or an immunogenic fragment thereof. In some embodiments, a composition or combinationdisclosed herein comprises or consists of polyribonucleotides encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, and an HSV-2 gI glycoprotein or immunogenic fragment thereof, and a further polyribonucleotide encoding a gC glycoprotein or an immunogenic fragment thereof. In some embodiments, a composition or combination disclosed herein comprises or consists of polyribonucleotides encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, and an HSV-2 gI glycoprotein or immunogenic fragment thereof, and a further polyribonucleotide encoding a gD glycoprotein or an immunogenic part thereof.

[0236] In some embodiments, a composition or combination disclosed herein comprises or consists of polyribonucleotides encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, and an HSV-2 gI glycoprotein or immunogenic fragment thereof, and a further polyribonucleotide encoding a gH glycoprotein oran immunogenic part thereof. In some embodiments, a composition or combination disclosed herein comprisesor consists of polyribonucleotides encoding an HSV-2 gE glycoprotein or immunogenic fragment thereof, and an HSV-2 gI glycoprotein or immunogenic fragment thereof, and a further polyribonucleotide encoding a gL glycoprotein or an immunogenic part thereof. Glycoprotein B (gB)

[0237] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gB glycoprotein or an immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: AGCAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAA UCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCGCUAUGCGCAUGCAGCUGCU GCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCGCCCCCGCCGCCCCCGCCGCCCCCCGCGCCUCCGGCG GCGUGGCCGCCACCGUGGCCGCCAACGGCGGCCCCGCCUCCCGCCCCCCCCCCGUGCCCUCCCCCGCCACCACCAAGGCCCGC AAGCGCAAGACCAAGAAGCCCCCCAAGCGCCCCGAGGCCACCCCCCCCCCCGACGCCAACGCCACCGUGGCCGCCGGCCACGC CACCCUGCGCGCCCACCUGCGCGAGAUCAAGGUGGAGAACGCCGACGCCCAGUUCUACGUGUGCCCCCCCCCCACCGGCGCC ACCGUGGUGCAGUUCGAGCAGCCCCGCCGCUGCCCCACCCGCCCCGAGGGCCAGAACUACACCGAGGGCAUCGCCGUGGUG UUCAAGGAGAACAUCGCCCCCUACAAGUUCAAGGCCACCAUGUACUACAAGGACGUGACCGUGUCCCAGGUGUGGUUCGGC CACCGCUACUCCCAGUUCAUGGGCAUCUUCGAGGACCGCGCCCCCGUGCCCUUCGAGGAGGUGAUCGACAAGAUCAACGCCAP-628704-PC AGGGCGUGUGCCGCUCCACCGCCAAGUACGUGCGCAACAACAUGGAGACCACCGCCUUCCACCGCGACGACCACGAGACCGA CAUGGAGCUGAAGCCCGCCAAGGUGGCCACCCGCACCUCCCGCGGCUGGCACACCACCGACCUGAAGUACAACCCCUCCCGC GUGGAGGCCUUCCACCGCUACGGCACCACCGUGAACUGCAUCGUGGAGGAGGUGGACGCCCGCUCCGUGUACCCCUACGAC GAGUUCGUGCUGGCCACCGGCGACUUCGUGUACAUGUCCCCCUUCUACGGCUACCGCGAGGGCUCCCACACCGAGCACACC UCCUACGCCGCCGACCGCUUCAAGCAGGUGGACGGCUUCUACGCCCGCGACCUGACCACCAAGGCCCGCGCCACCUCCCCCA CCACCCGCAACCUGCUGACCACCCCCAAGUUCACCGUGGCCUGGGACUGGGUGCCCAAGCGCCCCGCCGUGUGCACCAUGAC CAAGUGGCAGGAGGUGGACGAGAUGCUGCGCGCCGAGUACGGCGGCUCCUUCCGCUUCUCCUCCGACGCCAUCUCCACCAC CUUCACCACCAACCUGACCCAGUACUCCCUGUCCCGCGUGGACCUGGGCGACUGCAUCGGCCGCGACGCCCGCGAGGCCAUC GACCGCAUGUUCGCCCGCAAGUACAACGCCACCCACAUCAAGGUGGGCCAGCCCCAGUACUACCUGGCCACCGGCGGCUUCC UGAUCGCCUACCAGCCCCUGCUGUCCAACACCCUGGCCGAGCUGUACGUGCGCGAGUACAUGCGCGAGCAGGACCGCAAGCC CCGCAACGCCACCCCCGCCCCCCUGCGCGAGGCCCCCUCCGCCAACGCCUCCGUGGAGCGCAUCAAGACCACCUCCUCCAUCG AGUUCGCCCGCCUGCAGUUCACCUACAACCACAUCCAGCGCCACGUGAACGACAUGCUGGGCCGCAUCGCCGUGGCCUGGUG CGAGCUGCAGAACCACGAGCUGACCCUGUGGAACGAGGCCCGCAAGCUGAACCCCAACGCCAUCGCCUCCGCCACCGUGGGC CGCCGCGUGUCCGCCCGCAUGCUGGGCGACGUGAUGGCCGUGUCCACCUGCGUGCCCGUGGCCCCCGACAACGUGAUCGUG CAGAACUCCAUGCGCGUGUCCUCCCGCCCCGGCACCUGCUACUCCCGCCCCCUGGUGUCCUUCCGCUACGAGGACCAGGGCC CCCUGAUCGAGGGCCAGCUGGGCGAGAACAACGAGCUGCGCCUGACCCGCGACGCCCUGGAGCCCUGCACCGUGGGCCACC GCCGCUACUUCAUCUUCGGCGGCGGCUACGUGUACUUCGAGGAGUACGCCUACUCCCACCAGCUGUCCCGCGCCGACGUGA CCACCGUGUCCACCUUCAUCGACCUGAACAUCACCAUGCUGGAGGACCACGAGUUCGUGCCCCUGGAGGUGUACACCCGCCA CGAGAUCAAGGACUCCGGCCUGCUGGACUACACCGAGGUGCAGCGCCGCAACCAGCUGCACGACCUGCGCUUCGCCGACAUC GACACCGUGAUCCGCGCCGACGCCAACGCCGCCUAAUAAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCC UCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUU CGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 86).gB glycoprotein or immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: GCCCCCGCCGCCCCCGCCGCCCCCCGCGCCUCCGGCGGCGUGGCCGCCACCGUGGCCGCCAACGGCGGCCCCGCCUCCCGCC CCCCCCCCGUGCCCUCCCCCGCCACCACCAAGGCCCGCAAGCGCAAGACCAAGAAGCCCCCCAAGCGCCCCGAGGCCACCCCC CCCCCCGACGCCAACGCCACCGUGGCCGCCGGCCACGCCACCCUGCGCGCCCACCUGCGCGAGAUCAAGGUGGAGAACGCCG ACGCCCAGUUCUACGUGUGCCCCCCCCCCACCGGCGCCACCGUGGUGCAGUUCGAGCAGCCCCGCCGCUGCCCCACCCGCCCCGAGGGCCAGAACUACACCGAGGGCAUCGCCGUGGUGUUCAAGGAGAACAUCGCCCCCUACAAGUUCAAGGCCACCAUGUACUACAAGGACGUGACCGUGUCCCAGGUGUGGUUCGGCCACCGCUACUCCCAGUUCAUGGGCAUCUUCGAGGACCGCGCCCCC GUGCCCUUCGAGGAGGUGAUCGACAAGAUCAACGCCAAGGGCGUGUGCCGCUCCACCGCCAAGUACGUGCGCAACAACAUG GAGACCACCGCCUUCCACCGCGACGACCACGAGACCGACAUGGAGCUGAAGCCCGCCAAGGUGGCCACCCGCACCUCCCGCG GCUGGCACACCACCGACCUGAAGUACAACCCCUCCCGCGUGGAGGCCUUCCACCGCUACGGCACCACCGUGAACUGCAUCGU GGAGGAGGUGGACGCCCGCUCCGUGUACCCCUACGACGAGUUCGUGCUGGCCACCGGCGACUUCGUGUACAUGUCCCCCUU CUACGGCUACCGCGAGGGCUCCCACACCGAGCACACCUCCUACGCCGCCGACCGCUUCAAGCAGGUGGACGGCUUCUACGCC CGCGACCUGACCACCAAGGCCCGCGCCACCUCCCCCACCACCCGCAACCUGCUGACCACCCCCAAGUUCACCGUGGCCUGGGA CUGGGUGCCCAAGCGCCCCGCCGUGUGCACCAUGACCAAGUGGCAGGAGGUGGACGAGAUGCUGCGCGCCGAGUACGGCGG CUCCUUCCGCUUCUCCUCCGACGCCAUCUCCACCACCUUCACCACCAACCUGACCCAGUACUCCCUGUCCCGCGUGGACCUG GGCGACUGCAUCGGCCGCGACGCCCGCGAGGCCAUCGACCGCAUGUUCGCCCGCAAGUACAACGCCACCCACAUCAAGGUGG GCCAGCCCCAGUACUACCUGGCCACCGGCGGCUUCCUGAUCGCCUACCAGCCCCUGCUGUCCAACACCCUGGCCGAGCUGUA CGUGCGCGAGUACAUGCGCGAGCAGGACCGCAAGCCCCGCAACGCCACCCCCGCCCCCCUGCGCGAGGCCCCCUCCGCCAACP-628704-PC GCCUCCGUGGAGCGCAUCAAGACCACCUCCUCCAUCGAGUUCGCCCGCCUGCAGUUCACCUACAACCACAUCCAGCGCCACG UGAACGACAUGCUGGGCCGCAUCGCCGUGGCCUGGUGCGAGCUGCAGAACCACGAGCUGACCCUGUGGAACGAGGCCCGCA AGCUGAACCCCAACGCCAUCGCCUCCGCCACCGUGGGCCGCCGCGUGUCCGCCCGCAUGCUGGGCGACGUGAUGGCCGUGU CCACCUGCGUGCCCGUGGCCCCCGACAACGUGAUCGUGCAGAACUCCAUGCGCGUGUCCUCCCGCCCCGGCACCUGCUACUC CCGCCCCCUGGUGUCCUUCCGCUACGAGGACCAGGGCCCCCUGAUCGAGGGCCAGCUGGGCGAGAACAACGAGCUGCGCCU GACCCGCGACGCCCUGGAGCCCUGCACCGUGGGCCACCGCCGCUACUUCAUCUUCGGCGGCGGCUACGUGUACUUCGAGGA GUACGCCUACUCCCACCAGCUGUCCCGCGCCGACGUGACCACCGUGUCCACCUUCAUCGACCUGAACAUCACCAUGCUGGAG GACCACGAGUUCGUGCCCCUGGAGGUGUACACCCGCCACGAGAUCAAGGACUCCGGCCUGCUGGACUACACCGAGGUGCAG CGCCGCAACCAGCUGCACGACCUGCGCUUCGCCGACAUCGACACCGUGAUCCGCGCCGACGCCAACGCCGCCUAAUAA (SEQ ID NO: 76).

[0239] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising a gB glycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 86 or SEQ ID NO: 76. Glycoprotein H (gH)

[0240] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2aGcATAAAAGTCTCAACACAACATATACAAAACAAACGAATCTCAAGCAATCAAGCATTCTACTTCTATTGCAGCAATTTAAA TCATTTCTTTTAAAGCAAAAGCAATTTTCTGAAAATTTTCACCATTTACGAACGATAGCGCTATGCGCATGCAGCTGCTG CTGCTGATCGCCCTGTCCCTGGCCCTGGTGACCAACTCCCACGACACCTACTGGACCGAGCAGATCGACCCCTGGTT CCTGCACGGCCTGGGCCTGGCCCGCACCTACTGGCGCGACACCAACACCGGCCGCCTGTGGCTGCCCAACACCCCCGACGC CTCCGACCCCCAGCGCGGCCGCCTGGCCCCCCCCGGCGAGCTGAACCTGACCACCGCCTCCGTGCCCATGCTGCGCTGGTA CGCCGAGCGCTTCTGCTTCGTGCTGGTGACCACCGCCGAGTTCCCCCGCGACCCCGGCCAGCTGCTGTACATCCCCAAGAC CTACCTGCTGGGCCGCCCCCGCAACGCCTCCCTGCCCGAGCTGCCCGAGGCCGGCCCCACCTCCCGCCCCCCCGCCGAGGT GACCCAGCTGAAGGGCCTGTCCCACAACCCCGGCGCCTCCGCCCTGCTGCGCTCCCGCGCCTGGGTGACCTTCGCCGCCGC CCCCGACCGCGAGGGCCTGACCTTCCCCCGCGGCGACGACGGCGCCACCGAGCGCCACCCCGACGGCCGCCGCAACGCCC CCCCCCCCGGCCCCCCCGCCGGCACCCCCCGCCACCCCACCACCAACCTGTCCATCGCCCACCTGCACAACGCCTCCGTGAC CTGGCTGGCCGCCCGCGGCCTGCTGCGCACCCCCGGCCGCTACGTGTACCTGTCCCCCTCCGCCTCCACCTGGCCCGTGGG CGTGTGGACCACCGGCGGCCTGGCCTTCGGCTGCGACGCCGCCCTGGTGCGCGCCCGCTACGGCAAGGGCTTCATGGGCC TGGTGATCTCCATGCGCGACTCCCCCCCCGCCGAGATCATCGTGGTGCCCGCCGACAAGACCCTGGCCCGCGTGGGCAACC CCACCGACGAGAACGCCCCCGCCGTGCTGCCCGGCCCCCCCGCCGGCCCCCGCTACCGCGTGTTCGTGCTGGGCGCCCCCA CCCCCGCCGACAACGGCTCCGCCCTGGACGCCCTGCGCCGCGTGGCCGGCTACCCCGAGGAGTCCACCAACTACGCCCAGT ACATGTCCCGCGCCTACGCCGAGTTCCTGGGCGAGGACCCCGGCTCCGGCACCGACGCCCGCCCCTCCCTGTTCTGGCGCC TGGCCGGCCTGCTGGCCTCCTCCGGCTTCGCCTTCGTGAACGCCGCCCACGCCCACGACGCCATCCGCCTGTCCGACCTGC TGGGCTTCCTGGCCCACTCCCGCGTGCTGGCCGGCCTGGCCGCCCGCGGCGCCGCCGGCTGCGCCGCCGACTCCGTGTTC CTGAACGTGTCCGTGCTGGACCCCGCCGCCCGCCTGCGCCTGGAGGCCCGCCTGGGCCACCTGGTGGCCGCCATCCTGGA GCGCGAGCAGTCCCTGGCCGCCCACGCCCTGGGCTACCAGCTGGCCTTCGTGCTGGACTCCCCCGCCGCCTACGGCGCCGT GGCCCCCTCCGCCGCCCGCCTGATCGACGCCCTGTACGCCGAGTTCCTGGGCGGCCGCGCCCTGACCGCCCCCATGGTGCG CCGCGCCCTGTTCTACGCCACCGCCGTGCTGCGCGCCCCCTTCCTGGCCGGCGCCCCCTCCGCCGAGCAGCGCGAGCGCGCCCGCCGCGGCCTGCTGATCACCACCGCCCTGTGCACCTCCGACGTGGCCGCCGCCACCCACGCCGACCTGCGCGCCGCCCTGGCCCGCACCGACCACCAGAAGAACCTGTTCTGGCTGCCCGACCACTTCTCCCCCTGCGCCGCCTCCCTGCGCTTCGACCTP-628704-PC GGCCGAGGGCGGCTTCATCCTGGACGCCCTGGCCATGGCCACCCGCTCCGACATCCCCGCCGACGTGATGGCCCAGCAGAC CCGCGGCGTGGCCTCCGTGCTGACCCGCTGGGCCCACTACAACGCCCTGATCCGCGCCTTCGTGCCCGAGGCCACCCACCA GTGCTCCGGCCCCTCCCACAACGCCGAGCCCCGCATCCTGGTGCCCATCACCCACAACGCCTCCTACGTGGTGACCCACACC CCCCTGCCCCGCGGCATCGGCTACAAGCTGACCGGCGTGGACGTGCGCCGCCCCCTGTTCATCACCTACCTGACCGCCACC TGCGAGGGCCACGCCCGCGAGATCGAGCCCAAGCGCCTGGTGCGCACCGAGAACCGCCGCGACCTGGGCCTGGTGGGCGC CGTGTTCCTGCGCTACACCCCCGCCGGCGAGGTGATGTCCGTGCTGCTGGTGGACACCGACGCCACCCAGCAGCAGCTGG CCCAGGGCCCCGTGGCCGGCACCCCCAACGTGTTCTCCTCCGACGTGCCCTCCGTGGCCCTGCTGCTGTTCCCCAACGGCA CCGTGATCCACCTGCTGGCCTTCGACACCCTGCCCATCGCCACCATCGCCCCCtaataaactagtAGTGACTGACTAGGATCTG GTTACCACTAAACCAGCCTCAAGAACACCCGAATGGAGTCTCTAAGCTACATAATACCAACTTACACTTACAAAATGTTGTC CCCCAAAATGTAGCCATTCGTATCTGCTCCTAATAAAAAGAAAGTTTCTTCACATTCTAAAAAAAAAAAAAAAAAAAAAAAAA(SEQ ID NO: 319).

[0241] In other embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gH glycoprotein or immunogenic fragment thereof, comprises or consists of the following nucleotide sequence:CACGACACCTACTGGACCGAGCAGATCGACCCCTGGTTCCTGCACGGCCTGGGCCTGGCCCGCACCTACTGGCGCGACACCAACACCGGCCGCCTGTGGCTGCCCAACACCCCCGACGCCTCCGACCCCCAGCGCGGCCGCCTGGCCCCCCCCGGCGAGCTGAACC TGACCACCGCCTCCGTGCCCATGCTGCGCTGGTACGCCGAGCGCTTCTGCTTCGTGCTGGTGACCACCGCCGAGTTCCCCCGC GACCCCGGCCAGCTGCTGTACATCCCCAAGACCTACCTGCTGGGCCGCCCCCGCAACGCCTCCCTGCCCGAGCTGCCCGAGGC CGGCCCCACCTCCCGCCCCCCCGCCGAGGTGACCCAGCTGAAGGGCCTGTCCCACAACCCCGGCGCCTCCGCCCTGCTGCGCT CCCGCGCCTGGGTGACCTTCGCCGCCGCCCCCGACCGCGAGGGCCTGACCTTCCCCCGCGGCGACGACGGCGCCACCGAGCG CCACCCCGACGGCCGCCGCAACGCCCCCCCCCCCGGCCCCCCCGCCGGCACCCCCCGCCACCCCACCACCAACCTGTCCATCGC CCACCTGCACAACGCCTCCGTGACCTGGCTGGCCGCCCGCGGCCTGCTGCGCACCCCCGGCCGCTACGTGTACCTGTCCCCCT CCGCCTCCACCTGGCCCGTGGGCGTGTGGACCACCGGCGGCCTGGCCTTCGGCTGCGACGCCGCCCTGGTGCGCGCCCGCTA CGGCAAGGGCTTCATGGGCCTGGTGATCTCCATGCGCGACTCCCCCCCCGCCGAGATCATCGTGGTGCCCGCCGACAAGACCC TGGCCCGCGTGGGCAACCCCACCGACGAGAACGCCCCCGCCGTGCTGCCCGGCCCCCCCGCCGGCCCCCGCTACCGCGTGTTC GTGCTGGGCGCCCCCACCCCCGCCGACAACGGCTCCGCCCTGGACGCCCTGCGCCGCGTGGCCGGCTACCCCGAGGAGTCCAC CAACTACGCCCAGTACATGTCCCGCGCCTACGCCGAGTTCCTGGGCGAGGACCCCGGCTCCGGCACCGACGCCCGCCCCTCCC TGTTCTGGCGCCTGGCCGGCCTGCTGGCCTCCTCCGGCTTCGCCTTCGTGAACGCCGCCCACGCCCACGACGCCATCCGCCTG TCCGACCTGCTGGGCTTCCTGGCCCACTCCCGCGTGCTGGCCGGCCTGGCCGCCCGCGGCGCCGCCGGCTGCGCCGCCGACTCCGTGTTCCTGAACGTGTCCGTGCTGGACCCCGCCGCCCGCCTGCGCCTGGAGGCCCGCCTGGGCCACCTGGTGGCCGCCATCCTGGAGCGCGAGCAGTCCCTGGCCGCCCACGCCCTGGGCTACCAGCTGGCCTTCGTGCTGGACTCCCCCGCCGCCTACGGCGCC GTGGCCCCCTCCGCCGCCCGCCTGATCGACGCCCTGTACGCCGAGTTCCTGGGCGGCCGCGCCCTGACCGCCCCCATGGTGCG CCGCGCCCTGTTCTACGCCACCGCCGTGCTGCGCGCCCCCTTCCTGGCCGGCGCCCCCTCCGCCGAGCAGCGCGAGCGCGCCC GCCGCGGCCTGCTGATCACCACCGCCCTGTGCACCTCCGACGTGGCCGCCGCCACCCACGCCGACCTGCGCGCCGCCCTGGCC CGCACCGACCACCAGAAGAACCTGTTCTGGCTGCCCGACCACTTCTCCCCCTGCGCCGCCTCCCTGCGCTTCGACCTGGCCGAG GGCGGCTTCATCCTGGACGCCCTGGCCATGGCCACCCGCTCCGACATCCCCGCCGACGTGATGGCCCAGCAGACCCGCGGCGT GGCCTCCGTGCTGACCCGCTGGGCCCACTACAACGCCCTGATCCGCGCCTTCGTGCCCGAGGCCACCCACCAGTGCTCCGGCC CCTCCCACAACGCCGAGCCCCGCATCCTGGTGCCCATCACCCACAACGCCTCCTACGTGGTGACCCACACCCCCCTGCCCCGCG GCATCGGCTACAAGCTGACCGGCGTGGACGTGCGCCGCCCCCTGTTCATCACCTACCTGACCGCCACCTGCGAGGGCCACGCC CGCGAGATCGAGCCCAAGCGCCTGGTGCGCACCGAGAACCGCCGCGACCTGGGCCTGGTGGGCGCCGTGTTCCTGCGCTACA CCCCCGCCGGCGAGGTGATGTCCGTGCTGCTGGTGGACACCGACGCCACCCAGCAGCAGCTGGCCCAGGGCCCCGTGGCCGGP-628704-PC CACCCCCAACGTGTTCTCCTCCGACGTGCCCTCCGTGGCCCTGCTGCTGTTCCCCAACGGCACCGTGATCCACCTGCTGGCCTT CGACACCCTGCCCATCGCCACCATCGCCCCC (SEQ ID NO: 320).

[0242] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising a gH glycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 319 or SEQ ID NO: 320. Glycoprotein L (gL)

[0243] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gL glycoprotein or an immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: aGcATAAAAGTCTCAACACAACATATACAAAACAAACGAATCTCAAGCAATCAAGCATTCTACTTCTATTGCAGCAATTTAAA TCATTTCTTTTAAAGCAAAAGCAATTTTCTGAAAATTTTCACCATTTACGAACGATAGCGCTATGCGCATGCAGCTGCTG CTGCTGATCGCCCTGTCCCTGGCCCTGGTGACCAACTCCGGCTCCCAGGCCACCGAGTACGTGCTGCGCTCCGTGAT CGCCAAGGAGGTGGGCGACATCCTGCGCGTGCCCTGCATGCGCACCCCCGCCGACGACGTGTCCTGGCGCTACGAGGCCC CCTCCGTGATCGACTACGCCCGCATCGACGGCATCTTCCTGCGCTACCACTGCCCCGGCCTGGACACCTTCCTGTGGGACC GCCACGCCCAGCGCGCCTACCTGGTGAACCCCTTCCTGTTCGCCGCCGGCTTCCTGGAGGACCTGTCCCACTCCGTGTTCC CCGCCGACACCCAGGAGACCACCACCCGCCGCGCCCTGTACAAGGAGATCCGCGACGCCCTGGGCTCCCGCAAGCAGGCCG TGTCCCACGCCCCCGTGCGCGCCGGCTGCGTGAACTTCGACTACTCCCGCACCCGCCGCTGCGTGGGCCGCCGCGACCTGC GCCCCGCCAACACCACCTCCACCTGGGAGCCCCCCGTGTCCTCCGACGACGAGGCCTCCTCCCAGTCCAAGCCCCTGGCCA CCCAGCCCCCCGTGCTGGCCCTGTCCAACGCCCCCCCCCGCCGCGTGTCCCCCACCCGCGGCCGCCGCCGCCACACCCGCC TGCGCCGCAACtaataaactagtAGTGACTGACTAGGATCTGGTTACCACTAAACCAGCCTCAAGAACACCCGAATGGAGTCTC TAAGCTACATAATACCAACTTACACTTACAAAATGTTGTCCCCCAAAATGTAGCCATTCGTATCTGCTCCTAATAAAAAGAAA GTTTCTTCACATTCTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 321).

[0244] In other embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2gL glycoprotein or immunogenic fragment thereof, comprises or consists of the following nucleotide sequence:GGCTCCCAGGCCACCGAGTACGTGCTGCGCTCCGTGATCGCCAAGGAGGTGGGCGACATCCTGCGCGTGCCCTGCATGCGCAC CCCCGCCGACGACGTGTCCTGGCGCTACGAGGCCCCCTCCGTGATCGACTACGCCCGCATCGACGGCATCTTCCTGCGCTACC ACTGCCCCGGCCTGGACACCTTCCTGTGGGACCGCCACGCCCAGCGCGCCTACCTGGTGAACCCCTTCCTGTTCGCCGCCGGC TTCCTGGAGGACCTGTCCCACTCCGTGTTCCCCGCCGACACCCAGGAGACCACCACCCGCCGCGCCCTGTACAAGGAGATCCG CGACGCCCTGGGCTCCCGCAAGCAGGCCGTGTCCCACGCCCCCGTGCGCGCCGGCTGCGTGAACTTCGACTACTCCCGCACCC GCCGCTGCGTGGGCCGCCGCGACCTGCGCCCCGCCAACACCACCTCCACCTGGGAGCCCCCCGTGTCCTCCGACGACGAGGCC TCCTCCCAGTCCAAGCCCCTGGCCACCCAGCCCCCCGTGCTGGCCCTGTCCAACGCCCCCCCCCGCCGCGTGTCCCCCACCCGC GGCCGCCGCCGCCACACCCGCCTGCGCCGCAAC (SEQ ID NO: 322).

[0245] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising a gL glycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 321 or SEQ ID NO: 322. Glycoprotein C (gC)

[0246] In some embodiments, the present disclosure provides an RNA encoding HSV glycoprotein C (gC) or an immunogenic fragment thereof. In another embodiment, the present disclosure provides a composition orcombination comprising an RNA encoding HSV gC or an immunogenic fragment thereof.P-628704-PC HSV-1 gC

[0247] In some embodiments, a polyribonucleotide encoding a polypeptide comprising HSV gC as described herein comprises or consists of one or more polyribonucleotides encoding HSV-1 gC or an immunogenic fragment thereof. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gC as describedherein comprises or consists of one or more polyribonucleotides encoding a fragment of an HSV-1 gC protein(e.g., an immunogenic fragment).

[0248] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-1 gC fragment comprises or consists of: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGGCCAUCUCCGGCG UGCCCGUGCUGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCCGCCCAGGAGUCCUGGGCCGAGACCGCCUCCA CCGGCCCCACCAUCACCGCCGGCGCCGUGACCAACGCCUCCGAGGCCCCCACCUCCGGCUCCCCCGGCUCCGCCGCCUCC CCCGAGGUGACCCCCACCUCCACCCCCAACCCCAACAACGUGACCCAGAACAAGACCACCCCCACCGAGCCCGCCUCCCCC CCCACCACCCCCAAGCCCACCUCCACCCCCAAGUCCCCCCCCACCUCCACCCCCGACCCCAAGCCCAAGAACAACACCACCC CCGCCAAGUCCGGCCGCCCCACCAAGCCCCCCGGCCCCGUGUGGUGCGACCGCCGCGACCCCCUGGCCCGCUACGGCUCC CGCGUGCAGAUCCGCUGCCGCUUCCGCAACUCCACCCGCAUGGAGUUCCGCCUGCAGAUCUGGCGCUACUCCAUGGGCC CCUCCCCCCCCAUCGCCCCCGCCCCCGACCUGGAGGAGGUGCUGACCAACAUCACCGCCCCCCCCGGCGGCCUGCUGGUG UACGACUCCGCCCCCAACCUGACCGACCCCCACGUGCUGUGGGCCGAGGGCGCCGGCCCCGGCGCCGACCCCCCCCUGUA CUCCGUGACCGGCCCCCUGCCCACCCAGCGCCUGAUCAUCGGCGAGGUGACCCCCGCCACCCAGGGCAUGUACUACCUGGCCUGGGGCCGCAUGGACUCCCCCCACGAGUACGGCACCUGGGUGCGCGUGCGCAUGUUCCGCCCCCCCUCCCUGACCCUGCAGCCCCACGCCGUGAUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCGCCUACUACCCCCGCAACCCCGUGG AGUUCGACUGGUUCGAGGACGACCGCCAGGUGUUCAACCCCGGCCAGAUCGACACCCAGACCCACGAGCACCCCGACGGC UUCACCACCGUGUCCACCGUGACCUCCGAGGCCGUGGGCGGCCAGGUGCCCCCCCGCACCUUCACCUGCCAGAUGACCU GGCACCGCGACUCCGUGACCUUCUCCCGCCGCAACGCCACCGGCCUGGCCCUGGUGCUGCCCCGCCCCACCAUCACCAUG GAGUUCGGCGUGCGCCACGUGGUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGACCUUCGCCUGGUUCCUGGGCGAC GACCCCUCCCCCGCCGCCAAGUCCGCCGUGACCGCCCAGGAGUCCUGCGACCACCCCGGCCUGGCCACCGUGCGCUCCAC CCUGCCCAUCUCCUACGACUACUCCGAGUACAUCUGCCGCCUGACCGGCUACCCCGCCGGCAUCCCCGUGCUGGAGCACC ACUAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACA UAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCU UCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 81)

[0249] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 181). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0250] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding an HSV-1 gC 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 gC fragment is as set forth in SEQ ID NO: 46.P-628704-PC

[0251] In some embodiments, the HSV-1 gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 27-457 of gC from HSV-1 (e.g., KOS strain), as set forth in the following amino acid sequence: ETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPASPPTTPKPTSTPKSPPTSTPDPKPKNNTT PAKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEFRLQIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYDSA PNLTDPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQGMYYLAWGRMDSPHEYGTWVRVRMFRPPSLTLQPHAVM EGQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTSEAVGGQVPPRTFTCQMTWHRDSVTFS RRNATGLALVLPRPTITMEFGVRHVVCTAGCVPEGVTFAWFLGDDPSPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYICRL TGYPAGIPVLEHH (SEQ ID NO: 9).

[0252] In some embodiments, an HSV-1 gC fragment comprises or consists of 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-1 gC fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 9.

[0253] In some embodiments, the gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 27-457 of gC from an HSV-1 strain.

[0254] In some embodiments, the HSV-1 gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 25-457 of gC fromHSV-1 (e.g., KOS strain), as set forth in the following amino acid sequence:GSETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPASPPTTPKPTSTPKSPPTSTPDPKPKNN TTPAKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEFRLQIWRYSMGPSPPIAPAPDLEEVLTNITAPPGGLLVYD SAPNLTDPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQGMYYLAWGRMDSPHEYGTWVRVRMFRPPSLTLQPHA VMEGQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTSEAVGGQVPPRTFTCQMTWHRDSV TFSRRNATGLALVLPRPTITMEFGVRHVVCTAGCVPEGVTFAWFLGDDPSPAAKSAVTAQESCDHPGLATVRSTLPISYDYSEYI CRLTGYPAGIPVLEHH (SEQ ID NO: 10).

[0255] In some embodiments, an HSV-1 gC fragment comprises or consists of 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-1 gC fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 10.

[0256] In some embodiments, the full-length HSV-1 gC encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the following amino acid sequence: MAPGRVGLAVVLWGLLWLGAGVAGGSETASTGPTITAGAVTNASEAPTSGSPGSAASPEVTPTSTPNPNNVTQNKTTPTEPAS PPTTPKPTSTPKSPPTSTPDPKPKNNTTPAKSGRPTKPPGPVWCDRRDPLARYGSRVQIRCRFRNSTRMEFRLQIWRYSMGPSP PIAPAPDLEEVLTNITAPPGGLLVYDSAPNLTDPHVLWAEGAGPGADPPLYSVTGPLPTQRLIIGEVTPATQGMYYLAWGRMDS PHEYGTWVRVRMFRPPSLTLQPHAVMEGQPFKATCTAAAYYPRNPVEFDWFEDDRQVFNPGQIDTQTHEHPDGFTTVSTVTS EAVGGQVPPRTFTCQMTWHRDSVTFSRRNATGLALVLPRPTITMEFGVRHVVCTAGCVPEGVTFAWFLGDDPSPAAKSAVTAP-628704-PC QESCDHPGLATVRSTLPISYDYSEYICRLTGYPAGIPVLEHHGSHQPPPRDPTERQVIEAIEWVGIGIGVLAAGVLVVTAIVYVVR TSQSRQRHRR (SEQ ID NO: 11).

[0257] In some embodiments, an HSV-1 gC comprises or consists of 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-1 gC has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 11. In another embodiment, the HSV-1 gC or an immunogenic fragment thereof, encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of 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, 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, AJE60131.1, AJE60202.1, AKE48623.1, AKE98415.1, AKE98416.1, AKE98417.1, AKE98418.1, AKE98419.1, AKE98420.1, AKE98421.1, AKE98422.1, AKE98423.1, AKE98424.1, AKE98425.1, AKE98426.1, AKE98427.1, AKE98428.1, AKE98429.1, AKE98430.1, AKE98431.1, AKE98432.1, AKE98433.1, AKE98434.1, AKE98435.1, AKG59227.1, AKG59299.1, AKG59372.1, AKG59444.1, AKG59516.1, AKG59591.1, 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, AKG60601.1, AKG60674.1, AKG60745.1, AKG60817.1, AKG60887.1, AKG60959.1, AKG61032.1, AKG61104.1, AKG61175.1, AKG61248.1, AKG61321.1, AKG61392.1, AKG61464.1, AKG61537.1, AKG61611.1, AKG61684.1, AKG61756.1, AKG61828.1, AKG61902.1, AKG61974.1, AKH80444.1, AKH80517.1, AKM76368.1, ALM22613.1, ALM22687.1, ALM22761.1, ALM22835.1, ALO18641.1, 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, ANN84861.1,ANN84938.1, ANN85014.1, ANN85091.1, 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, ARO38060.1, ARO38061.1, ARO38062.1, ARO38063.1, ARO38064.1, ARO38065.1, ARO38066.1, ASM47642.1, ASM47719.1, ASM47796.1, ASM47871.1, BAM73394.1, CAA32294.1, CAB40083.1, CAD13356.1, CAD13357.1, CAD13358.1, CAD13359.1, CAD13360.1, CAD13361.1, CAD13362.1, CAD13363.1, CAD13364.1, CAD13365.1, CAD13366.1, CAD13367.1, CAD13368.1, CAD13369.1, CAD13370.1, CAD13371.1, 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, SBO07880.1, 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_009137143.1.P-628704-PC HSV-2 gC

[0258] In some embodiments, a polyribonucleotide encoding a polypeptide comprising HSV gC as described herein comprises a polyribonucleotide encoding a polypeptide comprising HSV-2 gC. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gC as described herein comprises a polyribonucleotideencoding a polypeptide comprising a fragment of an HSV-2 gC protein (e.g., an immunogenic fragment).

[0259] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gC glycoprotein or an immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: AGCAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAA UCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCGCUAUGCGCAUGCAGCUGCU GCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCGCCUCCCCCGGCCGCACCAUCACCGUGGGCCCCCGCG GCAACGCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACGCCUCCGCCCCCCGCACCACCCCCACCCCCCCCCAGCCCCGCA AGGCCACCAAGUCCAAGGCCUCCACCGCCAAGCCCGCCCCCCCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCGAGCCCGUG CGCUGCAACCGCCACGACCCCCUGGCCCGCUACGGCUCCCGCGUGCAGAUCCGCUGCCGCUUCCCCAACUCCACCCGCACCG AGUUCCGCCUGCAGAUCUGGCGCUACGCCACCGCCACCGACGCCGAGAUCGGCACCGCCCCCUCCCUGGAGGAGGUGAUGG UGAACGUGUCCGCCCCCCCCGGCGGCCAGCUGGUGUACGACUCCGCCCCCAACCGCACCGACCCCCACGUGAUCUGGGCCGA GGGCGCCGGCCCCGGCGCCUCCCCCCGCCUGUACUCCGUGGUGGGCCCCCUGGGCCGCCAGCGCCUGAUCAUCGAGGAGCU GACCCUGGAGACCCAGGGCAUGUACUACUGGGUGUGGGGCCGCACCGACCGCCCCUCCGCCUACGGCACCUGGGUGCGCGU GCGCGUGUUCCGCCCCCCCUCCCUGACCAUCCACCCCCACGCCGUGCUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCACCUACUACCCCGGCAACCGCGCCGAGUUCGUGUGGUUCGAGGACGGCCGCCGCGUGUUCGACCCCGCCCAGAUCCACACCCAGACCCAGGAGAACCCCGACGGCUUCUCCACCGUGUCCACCGUGACCUCCGCCGCCGUGGGCGGCCAGGGCCCCCCCCG CACCUUCACCUGCCAGCUGACCUGGCACCGCGACUCCGUGUCCUUCUCCCGCCGCAACGCCUCCGGCACCGCCUCCGUGCUG CCCCGCCCCACCAUCACCAUGGAGUUCACCGGCGACCACGCCGUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGACCUUCG CCUGGUUCCUGGGCGACGACUCCUCCCCCGCCGAGAAGGUGGCCGUGGCCUCCCAGACCUCCUGCGGCCGCCCCGGCACCG CCACCAUCCGCUCCACCCUGCCCGUGUCCUACGAGCAGACCGAGUACAUCUGCCGCCUGGCCGGCUACCCCGACGGCAUCCC CGUGCUGGAGCACCACUAAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAG UCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAA AGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 268).

[0260] In other embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gC glycoprotein or immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: GCCUCCCCCGGCCGCACCAUCACCGUGGGCCCCCGCGGCAACGCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACGCC UCCGCCCCCCGCACCACCCCCACCCCCCCCCAGCCCCGCAAGGCCACCAAGUCCAAGGCCUCCACCGCCAAGCCCGCCCCC CCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCGAGCCCGUGCGCUGCAACCGCCACGACCCCCUGGCCCGCUACGGCUC CCGCGUGCAGAUCCGCUGCCGCUUCCCCAACUCCACCCGCACCGAGUUCCGCCUGCAGAUCUGGCGCUACGCCACCGCCA CCGACGCCGAGAUCGGCACCGCCCCCUCCCUGGAGGAGGUGAUGGUGAACGUGUCCGCCCCCCCCGGCGGCCAGCUGGU GUACGACUCCGCCCCCAACCGCACCGACCCCCACGUGAUCUGGGCCGAGGGCGCCGGCCCCGGCGCCUCCCCCCGCCUGU ACUCCGUGGUGGGCCCCCUGGGCCGCCAGCGCCUGAUCAUCGAGGAGCUGACCCUGGAGACCCAGGGCAUGUACUACUG GGUGUGGGGCCGCACCGACCGCCCCUCCGCCUACGGCACCUGGGUGCGCGUGCGCGUGUUCCGCCCCCCCUCCCUGACC AUCCACCCCCACGCCGUGCUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCACCUACUACCCCGGCAACCGCGC CGAGUUCGUGUGGUUCGAGGACGGCCGCCGCGUGUUCGACCCCGCCCAGAUCCACACCCAGACCCAGGAGAACCCCGACP-628704-PC GGCUUCUCCACCGUGUCCACCGUGACCUCCGCCGCCGUGGGCGGCCAGGGCCCCCCCCGCACCUUCACCUGCCAGCUGAC CUGGCACCGCGACUCCGUGUCCUUCUCCCGCCGCAACGCCUCCGGCACCGCCUCCGUGCUGCCCCGCCCCACCAUCACCA UGGAGUUCACCGGCGACCACGCCGUGUGCACCGCCGGCUGCGUGCCCGAGGGCGUGACCUUCGCCUGGUUCCUGGGCG ACGACUCCUCCCCCGCCGAGAAGGUGGCCGUGGCCUCCCAGACCUCCUGCGGCCGCCCCGGCACCGCCACCAUCCGCUCC ACCCUGCCCGUGUCCUACGAGCAGACCGAGUACAUCUGCCGCCUGGCCGGCUACCCCGACGGCAUCCCCGUGCUGGAGC ACCACUAAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGC UACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAA (SEQ ID NO: 269).

[0261] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising a gCglycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 268 or SEQ ID NO: 269.

[0262] In some embodiments, the nucleotide sequence of a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gC fragment comprises or consists of: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGC UGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCGCCUCCCCCGGCCGCACCAUCACCGUGGGCCCCC GCGGCAACGCCUCCAACGCCGCCCCCUCCGCCUCCCCCCGCAACGCCUCCGCCCCCCGCACCACCCCCACCCCCCCCCAGC CCCGCAAGGCCACCAAGUCCAAGGCCUCCACCGCCAAGCCCGCCCCCCCCCCCAAGACCGGCCCCCCCAAGACCUCCUCCG AGCCCGUGCGCUGCAACCGCCACGACCCCCUGGCCCGCUACGGCUCCCGCGUGCAGAUCCGCUGCCGCUUCCCCAACUCC ACCCGCACCGAGUUCCGCCUGCAGAUCUGGCGCUACGCCACCGCCACCGACGCCGAGAUCGGCACCGCCCCCUCCCUGGA GGAGGUGAUGGUGAACGUGUCCGCCCCCCCCGGCGGCCAGCUGGUGUACGACUCCGCCCCCAACCGCACCGACCCCCACG UGAUCUGGGCCGAGGGCGCCGGCCCCGGCGCCUCCCCCCGCCUGUACUCCGUGGUGGGCCCCCUGGGCCGCCAGCGCCU GAUCAUCGAGGAGCUGACCCUGGAGACCCAGGGCAUGUACUACUGGGUGUGGGGCCGCACCGACCGCCCCUCCGCCUAC GGCACCUGGGUGCGCGUGCGCGUGUUCCGCCCCCCCUCCCUGACCAUCCACCCCCACGCCGUGCUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCCGCCACCUACUACCCCGGCAACCGCGCCGAGUUCGUGUGGUUCGAGGACGGCCGCCGCGUGUUCGACCCCGCCCAGAUCCACACCCAGACCCAGGAGAACCCCGACGGCUUCUCCACCGUGUCCACCGUGACCUCCGCCG CCGUGGGCGGCCAGGGCCCCCCCCGCACCUUCACCUGCCAGCUGACCUGGCACCGCGACUCCGUGUCCUUCUCCCGCCGC AACGCCUCCGGCACCGCCUCCGUGCUGCCCCGCCCCACCAUCACCAUGGAGUUCACCGGCGACCACGCCGUGUGCACCGC CGGCUGCGUGCCCGAGGGCGUGACCUUCGCCUGGUUCCUGGGCGACGACUCCUCCCCCGCCGAGAAGGUGGCCGUGGCC UCCCAGACCUCCUGCGGCCGCCCCGGCACCGCCACCAUCCGCUCCACCCUGCCCGUGUCCUACGAGCAGACCGAGUACAU CUGCCGCCUGGCCGGCUACCCCGACGGCAUCCCCGUGCUGGAGCACCACUAACUAGUAGUGACUGACUAGGAUCUGGUU ACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAAUGUUGUCC CCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAA IDglycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 82.

[0264] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments,underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residuesrepresent a signal sequence (leader sequence) (SEQ ID NO: 176). In some embodiments, italicized residuesP-628704-PC represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0265] In another embodiment, the nucleotide sequence of a polyribonucleotide encoding a polypeptide comprising an HSV-2 gC 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 gC fragment is as set forth in SEQ ID NO: 47.

[0266] In some embodiments, the HSV-2 gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 27-426 of gC from HSV-2 (e.g., strain 333 or UL44), as set forth in the following amino acid sequence: ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQI RCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLG RQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRV FDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCV PEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 12).

[0267] In some embodiments, an HSV-2 gC fragment comprises or consists of 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 fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 12.

[0268] In some embodiments, an HSV-2 gC fragment comprises or consists of the following amino acid sequence: ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQI RCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLG RQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 13).

[0269] In some embodiments, an HSV-2 gC fragment comprises or consists of 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 someembodiments, an HSV-2 gC fragment has an amino acid sequence that is identical to the amino acid sequenceSEQ ID NO: 13.

[0270] In some embodiments, the HSV-2 gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 28-426 of gC from HSV-2 (e.g., strain 333 or UL44), as set forth in the following amino acid sequence:SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGR QRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVF DPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVP EGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 14).P-628704-PC

[0271] In some embodiments, an HSV-2 gC fragment comprises or consists of 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 fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 14.

[0272] In some embodiments, an HSV-2 gC fragment comprises or consists of the following amino acid sequence: SPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRVQIR CRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPLGR QRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGRRVF DPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAGCVP EGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 15).

[0273] In some embodiments, an HSV-2 gC fragment comprises or consists of 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 fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 15.

[0274] In some embodiments, the HSV-2 gC fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 26-426 of gC fromHSV-2 (e.g., strain 333 or UL44), as set forth in the following amino acid sequence:SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRV QIRCRFPNSTRTESRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPL GRQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGR RVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAG CVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 16).

[0275] In some embodiments, an HSV-2 gC fragment comprises or consists of 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-2 gC fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 16.

[0276] In some embodiments, an HSV-2 gC fragment comprises or consists of the following amino acid sequence: SASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPKTGPPKTSSEPVRCNRHDPLARYGSRV QIRCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNRTDPHVIWAEGAGPGASPRLYSVVGPL GRQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQPFKATCTAATYYPGNRAEFVWFEDGR RVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNASGTASVLPRPTITMEFTGDHAVCTAG CVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYPDGIPVLEHH (SEQ ID NO: 17).

[0277] In some embodiments, an HSV-2 gC fragment comprises or consists of 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%,P-628704-PC 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-2 gC fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 17.

[0278] In some embodiments, the full-length HSV-2 gC encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the following amino acid sequence: MALGRVGLAVGLWGLLWVGVVVVLANASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPPK TGPPKTSSEPVRCNRHDPLARYGSRVQIRCRFPNSTRTEFRLQIWRYATATDAEIGTAPSLEEVMVNVSAPPGGQLVYDSAPNR TDPHVIWAEGAGPGASPRLYSVVGPLGRQRLIIEELTLETQGMYYWVWGRTDRPSAYGTWVRVRVFRPPSLTIHPHAVLEGQP FKATCTAATYYPGNRAEFVWFEDGRRVFDPAQIHTQTQENPDGFSTVSTVTSAAVGGQGPPRTFTCQLTWHRDSVSFSRRNA SGTASVLPRPTITMEFTGDHAVCTAGCVPEGVTFAWFLGDDSSPAEKVAVASQTSCGRPGTATIRSTLPVSYEQTEYICRLAGYP DGIPVLEHHGSHQPPPRDPTERQVIRAVEGAGIGVAVLVAVVLAGTAVVYLTHASSVRYRRLR (SEQ ID NO: 18).

[0279] In some embodiments, an HSV-2 gC comprises or consists of 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 gC has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 18.

[0280] In another embodiment, the HSV-2 gC or an immunogenic fragment thereof, encoded by RNA utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the amino acidsequences 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, 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, ARO38070.1, 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.

[0281] In another embodiment, the gC protein fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises a properdin interfering domain.

[0282] In another embodiment, the gC protein fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is a C5 interfering domain. In another embodiment, the gC protein fragment is a portion of a C5 interfering domain.

[0283] In another embodiment, a gC protein fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure is an immunogenic fragment. In another embodiment,P-628704-PC a gC 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 gC are useful in methods, compositions, and combinations of the present disclosure, provided that all such variants retain the required immuno-protective effect. In another embodiment, the immunogenic fragment can comprise an immuno-protective gC antigen from any strain of HSV. In another embodiment, the immunogenic fragment can comprise sequence variants of HSV, as found in infected individuals. Glycoprotein D (gD)

[0284] In some embodiments, the present disclosure provides a polyribonucleotide encoding a polypeptide comprising HSV glycoprotein D (gD) or an immunogenic fragment thereof. In another embodiment, the present disclosure provides a composition or combination comprising a polyribonucleotide encoding a polypeptide comprising HSV gD or an immunogenic fragment thereof. HSV-1 gD

[0285] In some embodiments, a polyribonucleotide encoding a polypeptide comprising HSV gD as described herein comprises a polyribonucleotide encoding a polypeptide comprising HSV-1 gD. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gD as described herein comprises a polyribonucleotide encoding a polypeptide comprising a fragment of an HSV-1 gD protein (e.g., immunogenic fragment).

[0286] In some embodiments, a nucleotide sequence of the polyribonucleotide encoding an HSV-1 gD fragment comprises or consists of: GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGCGCAUGCAGCUGC UGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCAAGUACGCCCUGGCCGACGCCUCCCUGAAGAUG GCCGACCCCAACCGCUUCCGCGGCAAGGACCUGCCCGUGCUGGACCAGCUGACCGACCCCCCCGGCGUGCGCCGCGUGUA CCACAUCCAGGCCGGCCUGCCCGACCCCUUCCAGCCCCCCUCCCUGCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCG CCUGCCGCUCCGUGCUGCUGAACGCCCCCUCCGAGGCCCCCCAGAUCGUGCGCGGCGCCUCCGAGGACGUGCGCAAGCA GCCCUACAACCUGACCAUCGCCUGGUUCCGCAUGGGCGGCAACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAGU GCUCCUACAACAAGUCCCUGGGCGCCUGCCCCAUCCGCACCCAGCCCCGCUGGAACUACUACGACUCCUUCUCCGCCGUG UCCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCCGCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGAUCA ACGACUGGACCGAGAUCACCCAGUUCAUCCUGGAGCACCGCGCCAAGGGCUCCUGCAAGUACGCCCUGCCCCUGCGCAUCCCCCCCUCCGCCUGCCUGUCCCCCCAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUCCCCGAGAACCAGCGCACCGUGGCCGUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGGCCCCCUACACCUCCA CCCUGCUGCCCCCCGAGCUGUCCGAGACCCCCAACGCCACCCAGCCCGAGCUGGCCCCCGAGGACCCCGAGGACUCCGCC CUGCUGGAGGACCCCGUGGGCACCGUGGCCCCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGCCGCCAC CCCCUACUAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAG CUACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAG UUUCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 83)

[0287] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 176). In some embodiments, italicized residuesP-628704-PC represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0288] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding an HSV-1 gD 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 polynucleotide sequence of the HSV-1 gD fragment is as set forth in SEQ ID NO: 63.

[0289] In some embodiments, the HSV-1 gD fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 26-331 of gD (e.g., from HSV-1 Patton strain), as set forth in the following amino acid sequence: KYALADASLKMADPNRFRGKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPITVYYAVLERACRSVLLNAPSEAPQIVRGAS EDVRKQPYNLTIAWFRMGGNCAIPITVMEYTECSYNKSLGACPIRTQPRWNYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVK INDWTEITQFILEHRAKGSCKYALPLRIPPSACLSPQAYQQGVTVDSIGMLPRFIPENQRTVAVYSLKIAGWHGPKAPYTSTLLPP ELSETPNATQPELAPEDPEDSALLEDPVGTVAPQIPPNWHIPSIQDAATPY (SEQ ID NO: 19 )

[0290] In some embodiments, an HSV-1 gD fragment comprises or consists of 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-1 gD fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 19.

[0291] In some embodiments, the full-length HSV-1 gD encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the following amino acid sequence: MGGAAARLGAVILFVVIVGLHGVRGKYALADASLKLADPNRFRRKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPITVYYA VLERACRSVLLNAPSEAPQIVRGASEDVRKQPYNLTIAWFRMGGNCAIPITVMEYTECSYNKSLGACPIRTQPRWNYYDSFSAV SEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRAKGSCKYALPLRIPPSACLSPQAYQQGVTVDSIGMLPRFIPENQRTVAVYSLKIAGWHGPKAPYTSTLLPPELSETPNATQPELAPEAPEDSALLEDPVGTVAPQIPPNWHIPSIQDAATPYHPPATPNNMGLIAGAVGGSLLAALVICGIVYWMRRRTQKAPKRIRLPHIREDDQPSSHQPLFY (SEQ ID NO: 20)

[0292] In some embodiments, an HSV-1 gD comprises or consists of 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 someembodiments, an HSV-1 gD has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO:20.

[0293] In another embodiment, the HSV-1 gD or an immunogenic fragment thereof, encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of 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), AAA19630.1 (mutant strain not identified), or AAA19629.1 (strain not identified).

[0294] In another embodiment, the HSV-1 gD or an immunogenic fragment thereof, encoded by RNA utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the amino acidP-628704-PC 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, ABI63524.1, 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, AJE60151.1, 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, ALO18662.1, 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, ANN85801.1, 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, ARO37969.1, ARO37970.1, 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, SBO07908.1, 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

[0295] In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gD as described herein comprises a polyribonucleotide encoding a polypeptide comprising HSV-2 gD. In another embodiment, a polyribonucleotide encoding a polypeptide comprising HSV gD as described herein comprises polyribonucleotide encoding a fragment of an HSV-2 gD protein (e.g., immunogenic fragment). In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gD glycoprotein or an immunogenic fragment thereof, comprises or consists of the following nucleotide sequence: AGCAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUUAAA UCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCGCUAUGACCCGCCUGACCGU GCUGGCCCUGCUGGCCGGCCUGCUGGCCUCCUCCCGCGCCAAGUACGCCCUGGCCGACCCCUCCCUGAAGAUGGCCG ACCCCAACCGCUUCCGCGGCAAGAACCUGCCCGUGCUGGACCAGCUGACCGACCCCCCCGGCGUGAAGCGCGUGUACCACAU CCAGCCCUCCCUGGAGGACCCCUUCCAGCCCCCCUCCAUCCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCGCCUGCCGC UCCGUGCUGCUGCACGCCCCCUCCGAGGCCCCCCAGAUCGUGCGCGGCGCCUCCGACGAGGCCCGCAAGCACACCUACAACC UGACCAUCGCCUGGUACCGCAUGGGCGACAACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAGUGCCCCUACAACAAP-628704-PC GUCCCUGGGCGUGUGCCCCAUCCGCACCCAGCCCCGCUGGUCCUACUACGACUCCUUCUCCGCCGUGUCCGAGGACAACCUG GGCUUCCUGAUGCACGCCCCCGCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGAUCAACGACUGGACCGAGAUCA CCCAGUUCAUCCUGGAGCACCGCGCCCGCGCCUCCUGCAAGUACGCCCUGCCCCUGCGCAUCCCCCCCGCCGCCUGCCUGAC CUCCAAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUCCCCGAGAACCAGCGCACCGUG GCCCUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGCCCCCCUACACCUCCACCCUGCUGCCCCCCGAGCUGUCCG ACACCACCAACGCCACCCAGCCCGAGCUGGUGCCCGAGGACCCCGAGGACUCCGCCCUGCUGGAGGACCCCGCCGGCACCGU GUCCUCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGUGGCCCCCCACCACUAAACUAGUAGUGACUGACUA GGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCUACAUAAUACCAACUUACACUUACAAAA UGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUUUCUUCACAUUCUAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 85).

[0296] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments, underlined residues represent 5’ untranslated sequences (SEQ ID NO: 309). In some embodiments, bold residues represent a signal sequence (leader sequence) (SEQ ID NO: 180). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 313) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0297] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding an HSV-2 gD 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 polynucleotide sequence of the HSV-2 gD fragment is as set forth in SEQ ID NO: 65.

[0298] In other embodiments, the polyribonucleotide encoding an HSV-2 gD glycoprotein comprises or consists of the following nucleotide sequence:

[0299] AUGACCCGCCUGACCGUGCUGGCCCUGCUGGCCGGCCUGCUGGCCUCCUCCCGCGCCAAGUACGCCCUGGCCGAC CCCUCCCUGAAGAUGGCCGACCCCAACCGCUUCCGCGGCAAGAACCUGCCCGUGCUGGACCAGCUGACCGACCCCCCCGGCG UGAAGCGCGUGUACCACAUCCAGCCCUCCCUGGAGGACCCCUUCCAGCCCCCCUCCAUCCCCAUCACCGUGUACUACGCCGU GCUGGAGCGCGCCUGCCGCUCCGUGCUGCUGCACGCCCCCUCCGAGGCCCCCCAGAUCGUGCGCGGCGCCUCCGACGAGGC CCGCAAGCACACCUACAACCUGACCAUCGCCUGGUACCGCAUGGGCGACAACUGCGCCAUCCCCAUCACCGUGAUGGAGUAC ACCGAGUGCCCCUACAACAAGUCCCUGGGCGUGUGCCCCAUCCGCACCCAGCCCCGCUGGUCCUACUACGACUCCUUCUCCG CCGUGUCCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCCGCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGA UCAACGACUGGACCGAGAUCACCCAGUUCAUCCUGGAGCACCGCGCCCGCGCCUCCUGCAAGUACGCCCUGCCCCUGCGCAU CCCCCCCGCCGCCUGCCUGACCUCCAAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUC CCCGAGAACCAGCGCACCGUGGCCCUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGCCCCCCUACACCUCCACCC UGCUGCCCCCCGAGCUGUCCGACACCACCAACGCCACCCAGCCCGAGCUGGUGCCCGAGGACCCCGAGGACUCCGCCCUGCU GGAGGACCCCGCCGGCACCGUGUCCUCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGUGGCCCCCCACCACU AA (SEQ ID NO: 307). In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising a gD glycoprotein or an immunogenic fragment thereof, comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 85 or SEQ ID NO: 307.

[0300] In some embodiments, the nucleotide sequence of a polyribonucleotide encoding an exemplary polypeptide comprising an HSV-2 gD fragment comprises or consists of:P-628704-PC GGAAUAAAAGUCUCAACACAACAUAUACAAAACAAACGAAUCUCAAGCAAUCAAGCAUUCUACUUCUAUUGCAGCAAUUU AAAUCAUUUCUUUUAAAGCAAAAGCAAUUUUCUGAAAAUUUUCACCAUUUACGAACGAUAGCAUGACCCGCCUGACCG UGCUGGCCCUGCUGGCCGGCCUGCUGGCCUCCUCCCGCGCCAAGUACGCCCUGGCCGACCCCUCCCUGAAGAUG GCCGACCCCAACCGCUUCCGCGGCAAGAACCUGCCCGUGCUGGACCAGCUGACCGACCCCCCCGGCGUGAAGCGCGUGUA CCACAUCCAGCCCUCCCUGGAGGACCCCUUCCAGCCCCCCUCCAUCCCCAUCACCGUGUACUACGCCGUGCUGGAGCGCG CCUGCCGCUCCGUGCUGCUGCACGCCCCCUCCGAGGCCCCCCAGAUCGUGCGCGGCGCCUCCGACGAGGCCCGCAAGCAC ACCUACAACCUGACCAUCGCCUGGUACCGCAUGGGCGACAACUGCGCCAUCCCCAUCACCGUGAUGGAGUACACCGAGUG CCCCUACAACAAGUCCCUGGGCGUGUGCCCCAUCCGCACCCAGCCCCGCUGGUCCUACUACGACUCCUUCUCCGCCGUGU CCGAGGACAACCUGGGCUUCCUGAUGCACGCCCCCGCCUUCGAGACCGCCGGCACCUACCUGCGCCUGGUGAAGAUCAAC GACUGGACCGAGAUCACCCAGUUCAUCCUGGAGCACCGCGCCCGCGCCUCCUGCAAGUACGCCCUGCCCCUGCGCAUCCC CCCCGCCGCCUGCCUGACCUCCAAGGCCUACCAGCAGGGCGUGACCGUGGACUCCAUCGGCAUGCUGCCCCGCUUCAUCC CCGAGAACCAGCGCACCGUGGCCCUGUACUCCCUGAAGAUCGCCGGCUGGCACGGCCCCAAGCCCCCCUACACCUCCACC CUGCUGCCCCCCGAGCUGUCCGACACCACCAACGCCACCCAGCCCGAGCUGGUGCCCGAGGACCCCGAGGACUCCGCCCU GCUGGAGGACCCCGCCGGCACCGUGUCCUCCCAGAUCCCCCCCAACUGGCACAUCCCCUCCAUCCAGGACGUGGCCCCCC ACCACUAACUAGUAGUGACUGACUAGGAUCUGGUUACCACUAAACCAGCCUCAAGAACACCCGAAUGGAGUCUCUAAGCU ACAUAAUACCAACUUACACUUACAAAAUGUUGUCCCCCAAAAUGUAGCCAUUCGUAUCUGCUCCUAAUAAAAAGAAAGUU UCUUCACAUUCUAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 84)

[0301] In some embodiments, all uridine residues are 1-methyl-pseudouridine. In some embodiments,underlined residues represent 5’ untranslated sequences (SEQ ID NO: 308). In some embodiments, bold residuesrepresent a signal sequence (leader sequence) (SEQ ID NO: 180). In some embodiments, italicized residues represent 3’ untranslated sequences (SEQ ID NO: 312) after which follows the poly adenylation tail (SEQ ID NO: 316).

[0302] In another embodiment, the nucleotide sequence of the polyribonucleotide encoding an HSV-2 gD 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 gD fragment is as set forth in SEQ ID NO: 65.

[0303] In some embodiments, the HSV-2 gD fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 26-331 of gD (e.g., from HSV-2 strain 333 or US6), as set forth in the following amino acid sequence: KYALADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASD EARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKI NDWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPE LSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 21).

[0304] In some embodiments, an HSV-2 gD 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: 21. In some embodiments, an HSV-2 gD fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 21.P-628704-PC

[0305] In some embodiments, an HSV-2 gD fragment encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 30-331 of gD from HSV-2 (e.g., strain 333 or US6), as set forth in the following amino acid sequence: ADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEAR KHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKIND WTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELS DTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 22).

[0306] In some embodiments, an HSV-2 gD 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: 22. In some embodiments, an HSV-2 gD fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 22.

[0307] In some embodiments, an HSV-2 gD fragment encoded by RNA utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of amino acids 31-331 of gD from HSV-2 (e.g., strain 333 or US6), as set forth in the following amino acid sequence: DPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEARK HTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDW TEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDT TNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHH (SEQ ID NO: 23).

[0308] In some embodiments, an HSV-2 gD 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: 23. In some embodiments, an HSV-2 gD fragment has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 23.

[0309] In some embodiments, the full-length HSV-2 gD encoded by a polyribonucleotide utilized in themethods, compositions, and combinations of the present disclosure comprises or consists of the following amino acid sequence: MGRLTSGVGTAALLVVAVGLRVVCAKYALADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYA VLERACRSVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHHAPAAPSNP GLIIGALAGSTLAVLVIGGIAFWVRRRAQMAPKRLRLPHIRDDDAPPSHQPLFY (SEQ ID NO: 24).

[0310] In some embodiments, an HSV-2 gD 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: 24. In some embodiments, an HSV-2 gD has an amino acid sequence that is identical to the amino acid sequence SEQ ID NO: 24.

[0311] In another embodiment, the HSV-2 gD or an immunogenic fragment thereof, encoded by a polyribonucleotide utilized in the methods, compositions, and combinations of the present disclosure comprises or consists of the amino acid sequences as set forth in GenBank Accession Numbers: 1003204A, AAA45841.1,P-628704-PC 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, 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, ARO38000.1, ARO38001.1, ARO38002.1, ARO38003.1, ARO38004.1, ARO38005.1, ARO38006.1, ARO38007.1, ARO38008.1, ARO38009.1, ARO38010.1, 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, ARO38030.1, 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.

[0312] In another embodiment, the gD protein or fragment (e.g., immunogenic fragment) includes Y63. In another embodiment, the gD protein or fragment (e.g., immunogenic fragment) includes R159. In another embodiment, the gD protein or fragment (e.g., immunogenic fragment) includes D240. In another embodiment, the gD protein or fragment (e.g., immunogenic fragment) includes P246. In another embodiment, the gD protein or fragment (e.g., immunogenic fragment) includes a residue selected from Y63, R159, D240, and P246. In another embodiment, inclusion of one of these residues elicits antibodies that inhibit binding to nectin-1.

[0313] The nomenclature used herein for gD amino acid residues includes the residues of the signal peptideencoded by the signal sequence. Thus, residue one of the mature protein is referred to as “26.”

[0314] .

[0315] In some embodiments, a polyribonucleotide 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.

[0316] 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.P-628704-PC

[0317] 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.

[0318] 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.

[0319] In some embodiments, a polyribonucleotide 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.

[0320] 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. TABLE 1: Exemplary amino acid sequences of HSV immunogens Sequence Amino acid sequence SEQ ID NO: NameP-628704-PC Sequence Amino acid sequence SEQ ID NO: Name CLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLP-628704-PC Sequence Amino acid sequence SEQ ID NO: Name HSV-2 gC ASPGRTITVGPRGNASNAAPSASPRNASAPRTTPTPPQPRKATKSKASTAKPAPPP 12P-628704-PC Sequence Amino acid sequence SEQ ID NO: Name HSV-1 gD KYALADASLKMADPNRFRGKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPIT 19P-628704-PC Sequence Amino acid sequence SEQ ID NO: Name RDDHETDMELKPAKVATRTSRGWHTTDLKYNPSRVEAFHRYGTTVNCIVEEVDAR [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.

[0322] In some embodiments, methods of the present disclosure comprise administering to a subject a polyribonucleotide 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 immunogens Sequence Nucleic acid sequence SEQ ID NO: NameP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name GGGCCCCUCCUCCGUGUACACCCCCGGCGCCUCCCGCCCCACCCCCCCCCGCACP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AGAACAACAACCCCUCCUAGCAGCCCCAGAGAUCCCACACCAGCUCCAGGCGAUP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name UGAACCUCUGGCCAUUGCCUACUCUCCACCAUUUCCAGCCGGCGACGAGGGCCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name CAGCACAGCUGCCCAGUACCGCAAUGCCGUCGUGGAGCAGCACCUCCCCCAACP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name GCGCCGAAAUGAGAAUCUACGAAGCCUGCCUGUACCACCCCCAGCUGCCCGAAP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name GCCCCCGUGCCCACCCCCCCCCCCACCCCCGCCGACUACGACGAGGACGACAACP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name HSV-1 gC GAGACCGCCUCCACCGGCCCCACCAUCACCGCCGGCGCCGUGACCAACGCCUC 46P-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AUCCACCCCCACGCCGUGCUGGAGGGCCAGCCCUUCAAGGCCACCUGCACCGCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name Version 1.1 ACCUAAGACAGGCCCUCCAAAGACAAGCUCUGAGCCCGUGCGGUGCAACAGACP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AGCUUCAGCCGUAGAAACGCCUCUGGAACCGCCAGUGUGUUGCCGAGGCCGACP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name GAUCCCCACGUGAUCUGGGCAGAAGGAGCCGGUCCUGGGGCCUCUCCACGGCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AUUCGCAGCACUCUGCCCGUGUCCUACGAGCAGACGGAGUACAUCUGCAGGCUP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name UCCACCCCCACGCCGUGCUGGAAGGCCAGCCCUUCAAAGCCACCUGCACCGCCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AUCCCCACGUGAUUUGGGCCGAGGGUGCUGGACCUGGGGCUUCACCCAGGCUP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name AUGAUCCCCUUGCCAGAUACGGGAGCAGAGUGCAGAUUAGGUGCCGGUUUCCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name UCACCAUGGAGUUCACCGGCGAUCACGCAGUGUGCACUGCUGGGUGUGUACCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name HSV-2 gD AAAUAUGCUCUCGCUGAUCCGAGCCUCAAGAUGGCAGAUCCCAACCGAUUUCG 73P-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name ACCCGCCCCGAGGGCCAGAACUACACCGAGGGCAUCGCCGUGGUGUUCAAGGAP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name CUUCGUGCUGGACUCCCCCGCCGCCUACGGCGCCGUGGCCCCCUCCGCCGCCCP-628704-PC Sequence Nucleic acid sequence SEQ ID NO: Name CUGGUAGUCCAGGACGACGGCAUAGCCAGGCCUCCUACAGCUCAGUCCUGUG Atona mmunogens

[0323] In some embodiments, compositions or combinations disclosed herein comprise polyribonucleotides encoding an HSV gE glycoprotein or immunogenic fragment thereof, and an HSV gI glycoprotein or immunogenic fragment thereof, and one or more additional polyribonucleotides encoding one or more additional HSV immunogens. In some embodiments, two or more immunogens are encoded in a single polyribonucleotide. In some embodiments, each immunogen is encoded in a separate polynucleotide and the composition or combination comprises all of the separate polynucleotides.

[0324] In some embodiments, the additional immunogen has a strong CD4+ response. In some embodiments, the additional immunogen has a strong CD8+ response.

[0325] In some embodiments, the immunogen comprises an immediate early gene, which, in some embodiments, comprises ICP4, Ribonucleotide reductase subunit 1, ICP10 (HSV-2), ICP6 (HSV-1), ICP27, or a combination thereof.

[0326] In some embodiments, the immunogen comprises a Tegument protein, which, in some embodiments, comprises VP11 / 12, VP13 / 14, VP16, VP22, or a combination thereof. Signal elements

[0327] In some embodiments, the polyribonucleotides disclosed herein comprise a 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.

[0328] In some embodiments, a utilized signal sequence is a heterologous signal sequence. In some embodiments, a heterologous signal sequence comprises or consists of a non-human signal sequence. In some embodiments, a heterologous signal sequence comprises or consists of a viral signal sequence. In some embodiments, a viral signal sequence comprises or consists of an HSV signal sequence (e.g., an HSV-1 or HSV-2 signal sequence). In some embodiments, a signal sequence comprises or consists of an HSV-1 signal sequence. In some embodiments, a signal sequence comprises or consists of an HSV-2 signal sequence. In some embodiments, a signal sequence encodes a signal peptide characterized by a length of about 15 to 30 amino acids. In some embodiments, a signal sequence encodes a signal peptide that in some embodiments allows transport of an HSV-1 glycoprotein or immunogenic fragment thereof, an HSV-2 glycoprotein or immunogenic fragment thereof, or both, with which it is associated into a defined cellular compartment. In some embodiments, the cellular compartment comprises a cell surface, endoplasmic reticulum (ER) or endosomal- lysosomal compartment.

[0329] In some embodiments, a signal sequence is the native signal sequence of the encoded glycoprotein.P-628704-PC

[0330] 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: 97). In some embodiments, an HSV-2 gE signal peptide comprises RTS at the C terminus of the signal peptide (SEQ ID NO: 98). In some embodiments, an HSV-2 gE signal peptide comprises A20V, A21V, and A22V substitutions (SEQ ID NO: 99). In some embodiments, a signal peptide is or comprises an HSV-1 gE signal peptide (SEQ ID NO: 100).

[0331] In some embodiments, a signal sequence is or comprises an HSV gI signal sequence (e.g., an HSV-1 or HSV-2 gI signal sequence). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gI signal peptide (SEQ ID NO: 104). In some embodiments, an HSV-2 gI signal peptidecomprises an additional leucine residue at the C terminus of the signal peptide (SEQ ID NO: 105). In someembodiments, an HSV-2 gI signal peptide comprises amino acid residues 1-18 of the wild-type peptide (SEQ ID NO: 107). In some embodiments, an HSV-2 gI signal peptide comprises amino acid residues 1-24 of the wild- type peptide (SEQ ID NO: 106). In some embodiments, a signal peptide is or comprises an HSV-1 gI signal peptide (SEQ ID NO: 108).

[0332] 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). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-2 gD signal peptide (SEQ ID NO: 87). In another embodiment, an HSV-2 gD signal peptide comprises KY (SEQ ID NO: 88), KYA (SEQ ID NO: 89), KYAL (SEQ ID NO: 90), or KYALA (SEQ ID NO: 91) at the C terminus of the signal peptide. In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-1 gD signal peptide (SEQ ID NO: 92). In some embodiments, an HSV-1 gD signal peptide comprises KY at the C terminus of the signal peptide (SEQ ID NO: 93).

[0333] 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: 94). In another embodiment, a signal peptideencoded by a signal sequence is or comprises an HSV-1 gC signal peptide (SEQ ID NO: 95).

[0334] 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: 101). In some embodiments, a signal peptide encoded by a signal sequence is or comprises an HSV-1 gB signal peptide (SEQ ID NO: 102). In some embodiments, an HSV-1 gB signal peptide comprises AP at the C terminus of the signal peptide (SEQ ID NO: 103).

[0335] 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. In other embodiments, the heterologous signal sequence comprises an IL-2-like signal peptide, as described herein (SEQ ID NO: 109). In some embodiments, the IL-2 signal peptide comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 109. In some embodiments, the IL-2 signal peptide is encoded by a signal sequence comprising the nucleotide sequence of SEQ ID NO: 176. In some embodiments, the IL-2 signal sequence comprises a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 176.

[0336] In some embodiments, a heterologous signal peptide encoded by a heterologous signal sequence comprises or consists of an azurocidin signal peptide (SEQ ID NO: 110). In some embodiments, a heterologousP-628704-PC signal peptide encoded by a heterologous signal sequence comprises or consists of an MHC Class II signal peptide (SEQ ID NO: 111). In some embodiments, a heterologous signal a heterologous signal peptide encodedconsists of an Ebola virus spike glycoprotein (SGP) signal peptide (SEQ ID NO: 113). In other embodiments, an RNA encoding a glycoprotein as described herein does not comprise a signal sequence. In some embodiments, an RNA as described herein only encodes an ectodomain without a signal peptide.

[0338] In some embodiments, a modified (e.g., nucleoside-modified) polyribonucleotide encoding an HSV gE glycoprotein or immunogenic fragment thereof, comprises a signal sequence encoding a signal peptide. In some embodiments, a modified (e.g., nucleoside-modified) polyribonucleotide encoding an HSV gI glycoprotein or immunogenic fragment thereof, comprises a signal sequence encoding a signal peptide. In some embodiments, each of the modified (e.g., nucleoside-modified) polyribonucleotides encoding HSV gE and HSV gI glycoproteinsor immunogenic fragments thereof, comprises a signal sequence encoding a signal peptide.

[0339] A skilled artisan would appreciate that a signal peptide encoded by a signal sequence, is a short stretch of amino acids located at the N-terminus of a polypeptide (e.g., the N-terminus of an HSV gE and / or HSV gI glycoprotein or immunogenic fragment thereof). In some embodiments, the signal peptide serves as a recognition site for the cellular machinery that facilitates its transport to the appropriate organelle and secretion. In some embodiments, the signal peptide directs the immunogenic fragment or polypeptide to an organelle within the cell, as the plasma membrane, where the HSV gE or HSV gI glycoproteins or immunogenic fragments thereof, can be either translocated across or inserted into the membrane.

[0340] 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. TABLE 3: Exemplary signal peptides Sequence Name Amino Acid Sequence SEQ ID NO:P-628704-PC Sequence Name Amino Acid Sequence SEQ ID NO: HSV-2 gE Signal Sequence MARGAGLVFFVGVWVVSCLAAAP 97 [ 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 sequences Sequence Name Version Nucleic Acid Sequence SEQ ID NO:P-628704-PC Sequence Name Version Nucleic Acid Sequence SEQ ID NO: HSV-2 gD KYA Version 3 AUGGGCAGACUGACCUCCGGCGUGGGCACCGCCGCCCUGC 121 UGGUGGUGGCCGUGGGCCUGAGAGUGGUGUGCGCCAAAUP-628704-PC Sequence Name Version Nucleic Acid Sequence SEQ ID NO: HSV-2 gC Version 2 AUGGCCUUGGGGAGAGUGGGCCUUGCAGUGGGUCUGUGG 139 GGACUGCUCUGGGUUGGCGUAGUCGUCGUGCUGGCUAACP-628704-PC Sequence Name Version Nucleic Acid Sequence SEQ ID NO: HSV-1 gB AP Version 3 AUGCACCAGGGAGCACCUUCUUGGGGAAGAAGAUGGUUU 158 GUGGUGUGGGCUCUGCUGGGACUGACCCUGGGAGUGCUGP-628704-PC Sequence Name Version Nucleic Acid Sequence SEQ ID NO: Azurocidin-like Version 1 AUGACCCGCCUGACCGUGCUGGCCCUGCUGGCCGGCCUGC 180 UGGCCUCCUCCCGCGCCExemplary signal peptide and HSV immunogen combinations

[0342] The present disclosure also provides polyribonucleotides comprising a nucleotide sequence encoding a protein, wherein the protein comprises an HSV (e.g., HSV-1, HSV-2, or both) glycoprotein or immunogenic fragment thereof, and a signal peptide. In some embodiments, a nucleotide sequence encodes a protein, wherein the protein comprises an HSV-2 glycoprotein or immunogenic fragment thereof, and a signal peptide.

[0343] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an HSV gE glycoprotein and an IL-2 signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MRMQLLLLIALSLALVTNSRTSWKRVTSGEDVVLLPAPAERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVVDAACM RAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTPTPDDYDEE DDAGVTNARRSAFPPQPPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETLEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMRFD VPSSCADMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQ HAGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRAPHPAPSARGPLRLGAVLGAALLLAALGLSA WACMTCWRRRSWRAVKSRASATGPTYIRVADSELYADWSSDSEGERDGSLWQDPPERPDSPSTNGSGFEILSPTAPSVYPHSEG RKSRRPLTTFGSGSPGRRHSQASYPSVLW (SEQ ID NO: 197).

[0344] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gE glycoprotein and an IL-2 signal peptide. In some embodiments, theexemplary polypeptide comprises the following amino acid sequence:MRMQLLLLIALSLALVTNSRTSWKRVTSGEDVVLLPAPAGPEERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVVDA ACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTPTPDDY DEEDDAGVSERTPVSVPPPTPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETPEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMP-628704-PC RFDVPSSCAEMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHAS PQHAGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRA (SEQ ID NO: 198).

[0345] In some embodiments, a modified (e.g., nucleoside-modified) polyribonucleotide encodes an exemplary polypeptide comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 197, or SEQ ID NO: 198.

[0346] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gE glycoprotein and an IL-2 signal peptide, comprises the following nucleotide sequence: AUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCCGCACCUCCUGGAAGCG CGUGACCUCCGGCGAGGACGUGGUGCUGCUGCCCGCCCCCGCCGGCCCCGAGGAGCGCACCCGCGCCCACAAGCUGCUGUG GGCCGCCGAGCCCCUGGACGCCUGCGGCCCCCUGCGCCCCUCCUGGGUGGCCCUGUGGCCCCCCCGCCGCGUGCUGGAGAC CGUGGUGGACGCCGCCUGCAUGCGCGCCCCCGAGCCCCUGGCCAUCGCCUACUCCCCCCCCUUCCCCGCCGGCGACGAGGGC CUGUACUCCGAGCUGGCCUGGCGCGACCGCGUGGCCGUGGUGAACGAGUCCCUGGUGAUCUACGGCGCCCUGGAGACCGAC UCCGGCCUGUACACCCUGUCCGUGGUGGGCCUGUCCGACGAGGCCCGCCAGGUGGCCUCCGUGGUGCUGGUGGUGGAGCC CGCCCCCGUGCCCACCCCCACCCCCGACGACUACGACGAGGAGGACGACGCCGGCGUGUCCGAGCGCACCCCCGUGUCCGUG CCCCCCCCCACCCCCCCCCGCCGCCCCCCCGUGGCCCCCCCCACCCACCCCCGCGUGAUCCCCGAGGUGUCCCACGUGCGCGG CGUGACCGUGCACAUGGAGACCCCCGAGGCCAUCCUGUUCGCCCCCGGCGAGACCUUCGGCACCAACGUGUCCAUCCACGCC AUCGCCCACGACGACGGCCCCUACGCCAUGGACGUGGUGUGGAUGCGCUUCGACGUGCCCUCCUCCUGCGCCGAGAUGCGC AUCUACGAGGCCUGCCUGUACCACCCCCAGCUGCCCGAGUGCCUGUCCCCCGCCGACGCCCCCUGCGCCGUGUCCUCCUGGG CCUACCGCCUGGCCGUGCGCUCCUACGCCGGCUGCUCCCGCACCACCCCCCCCCCCCGCUGCUUCGCCGAGGCCCGCAUGGA GCCCGUGCCCGGCCUGGCCUGGCUGGCCUCCACCGUGAACCUGGAGUUCCAGCACGCCUCCCCCCAGCACGCCGGCCUGUAC CUGUGCGUGGUGUACGUGGACGACCACAUCCACGCCUGGGGCCACAUGACCAUCUCCACCGCCGCCCAGUACCGCAACGCCG UGGUGGAGCAGCACCUGCCCCAGCGCCAGCCCGAGCCCGUGGAGCCCACCCGCCCCCACGUGCGCGCCUAA (SEQ ID NO: 245).

[0347] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gE glycoprotein and an IL-2 signal peptide, comprises a nucleotide sequence comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 245.

[0348] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an HSV-2 gE glycoprotein and an HSV-2 gE signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MARGAGLVFFVGVWVVSCLAAAPRTSWKRVTSGEDVVLLPAPAERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLETVV DAACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPVPTP TPDDYDEEDDAGVTNARRSAFPPQPPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETLEAILFAPGETFGTNVSIHAIAHDDGPYAMDVVWMRFDVPSSCADMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAWLASTVNLEFQHASPQHAGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRAPHPAPSARGPLRLGA VLGAALLLAALGLSAWACMTCWRRRSWRAVKSRASATGPTYIRVADSELYADWSSDSEGERDGSLWQDPPERPDSPSTNGSG FEILSPTAPSVYPHSEGRKSRRPLTTFGSGSPGRRHSQASYPSVLW (SEQ ID NO: 5).P-628704-PC

[0349] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gE glycoprotein and an HSV-2 gE signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MARGAGLVFFVGVWVVSCLAAAPRTSWKRVTSGEDVVLLPAPAGPEERTRAHKLLWAAEPLDACGPLRPSWVALWPPRRVLE TVVDAACMRAPEPLAIAYSPPFPAGDEGLYSELAWRDRVAVVNESLVIYGALETDSGLYTLSVVGLSDEARQVASVVLVVEPAPV PTPTPDDYDEEDDAGVSERTPVSVPPPTPPRRPPVAPPTHPRVIPEVSHVRGVTVHMETPEAILFAPGETFGTNVSIHAIAHDDG PYAMDVVWMRFDVPSSCAEMRIYEACLYHPQLPECLSPADAPCAVSSWAYRLAVRSYAGCSRTTPPPRCFAEARMEPVPGLAW LASTVNLEFQHASPQHAGLYLCVVYVDDHIHAWGHMTISTAAQYRNAVVEQHLPQRQPEPVEPTRPHVRA (SEQ ID NO: 202).

[0350] In some embodiments, a modified (e.g., nucleoside-modified) polyribonucleotide encodes an exemplary polypeptide comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 5, or SEQ ID NO: 202.

[0351] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an HSV-2 gI glycoprotein and an IL-2 signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MRMQLLLLIALSLALVTNSGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVV HVVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVYN GSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHRLTVAQVIQI AIPASIIAFVFLGSSICFIHRCQRRYRRPRGQIYNPGGVSCAVNEAAMARLGAELRSHPNTPPKPRRRSSSSTTMPSLTSIAEESEPGPVVLLSVSPRPRSGPTAPQEV (SEQ ID NO: 187).

[0352] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an IL-2 signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MRMQLLLLIALSLALVTNSGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVVHVVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVYNGSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHR (SEQ ID NO: 188).

[0353] In some embodiments, the present disclosure provides modified (e.g., nucleoside-modified) polyribonucleotides encoding an exemplary polypeptide comprising a homology greater than 70%, 75%, 80%,85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 187, or SEQ ID NO: 188.

[0354] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an IL-2 signal peptide, comprises the following nucleotide sequence: AUGCGCAUGCAGCUGCUGCUGCUGAUCGCCCUGUCCCUGGCCCUGGUGACCAACUCCGCCCAGGAGUCCUGGGCCGGCCCCACCGUGUCCCUGGUGUCCGACUCCCUGGUGGACGCCGGCGCCGUGGGCCCCCAGGGCUUCGUGGAGGAGGACCUGCGCGUGUUCGGCGAGCUGCACUUCGUGGGCGCCCAGGUGCCCCACACCAACUACUACGACGGCAUCAUCGAGC UGUUCCACUACCCCCUGGGCAACCACUGCCCCCGCGUGGUGCACGUGGUGACCCUGACCGCCUGCCCCCGCCGCCCCGCC GUGGCCUUCACCCUGUGCCGCUCCACCCACCACGCCCACUCCCCCGCCUACCCCACCCUGGAGCUGGGCCUGGCCCGCCA GCCCCUGCUGCGCGUGCGCACCGCCACCCGCGACUACGCCGGCCUGUACGUGCUGCGCGUGUGGGUGGGCUCCGCCACCP-628704-PC AACGCCUCCCGCUUCGUGCUGGGCGUGGCCCUGUCCGCCAACGGCACCUUCGUGUACAACGGCUCCGACUACGGCUCCU GCGACCCCGCCCAGCUGCCCUUCUCCGCCCCCCGCCUGGGCCCCUCCUCCGUGUACACCCCCGGCGCCUCCCGCCCCACC CCCCCCCGCACCACCACCCCCCCCUCCUCCCCCCGCGACCCCACCCCCGCCCCCGGCGACACCGGCACCCCCGCCCCCGCCU CCGGCGAGAUCGCCCCCCCCAACUCCACCCGCUCCGCCUCCGAGUCCCGCCACCGCUAA (SEQ ID NO: 234).

[0355] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an IL-2 signal peptide, comprises a nucleotide sequence comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 234.

[0356] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an HSV-2 gI glycoprotein and an HSV-2 gI signal peptide. In some embodiments, an exemplary polypeptide comprises the following amino acid sequence: MPGRSLQGLAILGLWVCATGLVVRGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNH CPRVVHVVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSA NGTFVYNGSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRH RLTVAQVIQIAIPASIIAFVFLGSSICFIHRCQRRYRRPRGQIYNPGGVSCAVNEAAMARLGAELRSHPNTPPKPRRRSSSSTTMP SLTSIAEESEPGPVVLLSVSPRPRSGPTAPQEV (SEQ ID NO: 191).

[0357] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an HSV-2 gI signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence: MPGRSLQGLAILGLWVCATGLVVRGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNH CPRVVHVVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSA NGTFVYNGSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRH RGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVVHVVTLTACPRRPAVAFTL CRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVYNGSDYGSCDPAQLPFSA PRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHR (SEQ ID NO: 194).

[0358] In some embodiments, the present disclosure provides modified (e.g., nucleoside-modified) polyribonucleotides encoding an exemplary polypeptide comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 191, or SEQ ID NO: 194.

[0359] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an HSV-2 gIglycoprotein and an MHC II / HLA-2 signal peptide. In some embodiments, the exemplary polypeptide comprisesthe following amino acid sequence: MAISGVPVLGFFIIAVLMSGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGNHCPRVVH VVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALSANGTFVY NGSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESRHRLTVAQ VIQIAIPASIIAFVFLGSSICFIHRCQRRYRRPRGQIYNPGGVSCAVNEAAMARLGAELRSHPNTPPKPRRRSSSSTTMPSLTSIAE ESEPGPVVLLSVSPRPRSGPTAPQEV (SEQ ID NO: 195).

[0360] In some embodiments, a polyribonucleotide encodes an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an MHC II / HLA-2 signal peptide. In some embodiments, the exemplary polypeptide comprises the following amino acid sequence:P-628704-PC MAISGVPVLGFFIIAVLMSAQESWAGPTVSLVSDSLVDAGAVGPQGFVEEDLRVFGELHFVGAQVPHTNYYDGIIELFHYPLGN HCPRVVHVVTLTACPRRPAVAFTLCRSTHHAHSPAYPTLELGLARQPLLRVRTATRDYAGLYVLRVWVGSATNASRFVLGVALS ANGTFVYNGSDYGSCDPAQLPFSAPRLGPSSVYTPGASRPTPPRTTTPPSSPRDPTPAPGDTGTPAPASGEIAPPNSTRSASESR HR (SEQ ID NO: 196).

[0361] In some embodiments, the present disclosure provides modified (e.g., nucleoside-modified) polyribonucleotides encoding an exemplary polypeptide comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 195, or SEQ ID NO: 196.

[0362] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an MHC II / HLA-2 signal peptide, comprises the following nucleotide sequence: AUGGCCAUCUCCGGCGUGCCCGUGCUGGGCUUCUUCAUCAUCGCCGUGCUGAUGUCCGCCCAGGAGUCCUGGGCCGGCC CCACCGUGUCCCUGGUGUCCGACUCCCUGGUGGACGCCGGCGCCGUGGGCCCCCAGGGCUUCGUGGAGGAGGACCUGC GCGUGUUCGGCGAGCUGCACUUCGUGGGCGCCCAGGUGCCCCACACCAACUACUACGACGGCAUCAUCGAGCUGUUCCA CUACCCCCUGGGCAACCACUGCCCCCGCGUGGUGCACGUGGUGACCCUGACCGCCUGCCCCCGCCGCCCCGCCGUGGCCU UCACCCUGUGCCGCUCCACCCACCACGCCCACUCCCCCGCCUACCCCACCCUGGAGCUGGGCCUGGCCCGCCAGCCCCUG CUGCGCGUGCGCACCGCCACCCGCGACUACGCCGGCCUGUACGUGCUGCGCGUGUGGGUGGGCUCCGCCACCAACGCCU CCCGCUUCGUGCUGGGCGUGGCCCUGUCCGCCAACGGCACCUUCGUGUACAACGGCUCCGACUACGGCUCCUGCGACCC CGCCCAGCUGCCCUUCUCCGCCCCCCGCCUGGGCCCCUCCUCCGUGUACACCCCCGGCGCCUCCCGCCCCACCCCCCCCC GCACCACCACCCCCCCCUCCUCCCCCCGCGACCCCACCCCCGCCCCCGGCGACACCGGCACCCCCGCCCCCGCCUCCGGCG AGAUCGCCCCCCCCAACUCCACCCGCUCCGCCUCCGAGUCCCGCCACCGCUAA (SEQ ID NO: 244)

[0363] In some embodiments, a polyribonucleotide encoding an exemplary polypeptide comprising an immunogenic fragment of an HSV-2 gI glycoprotein and an MHC II / HLA-2 signal peptide, comprises a nucleotide sequence comprising a homology greater than 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% to SEQ ID NO: 244.

[0364] Additional 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 5. TABLE 5: Exemplary signal peptide / HSV-2 immunogen combinations SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein F FT A TP I L PT F FT AP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein TP E RR V P R NE PR E RR V P R VE RR V P R NE PR VE RR V P R Q TA R V S VE RR V P R EL AR DY T F FT A TP I LP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein PT VE RR V P R W G VV VI MR SR HI P A H K F V H VV A V PE LA S PP P RL LY A P A SV PP H S PQ R LP M TL PT IA S SPP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein PT E AI D PV Y L LY A E AI D PV Y L LY A V V Y TP C PV R A P VV PR D W H P EE AI D PV Y L LY A RG A D P AH T P T RP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein TN P SR LV YY P R EG G R RV VY Y P R EG G S DP SA TL TC V C Q P PL AP LE CT G TA E A N MV II P VT D V P R V II PP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein VT D V A C V R G S FT TL N R EV R G S FT TL P R V II P VT D V A N MV II P VT D V SA D VS LT AT A V E PS H NVP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein EL KA A A Y N E SL G AV S M IR G S PS LG AV S M IR S G G G AT G CV CR A Y G Q AA Q GC IC A D VS LT AT A V EP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein S H NV EL KA A A Y A P LE R VL T E RS N E SL G AV S M IR V E Y K H W D G R AR A IP D Q RT EH SL S LP E C QP-628704-PC SEQ ID Signal HSV Amino Acid Sequence NO: Peptide Glycoprotein TV A V A PI IL L T D G R AR A IP E LA S PP P RL LY A SA S RA P RQ T DV Y Y RA P RQ T DV Y Y

[0365] Additional exemplary polyribonucleotides 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, a polyribonucleotide 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.P-628704-PC TABLE 6: Exemplary signal sequence / HSV-2 glycoprotein sequence combinations SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C G G G C C U C U A C C CA G C CC A CC G G G G G C C U C U A C C CA G C CC A CC G C G G G C C U C U A C C CAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G C CC A CC G C G GG C A C CC C G A G GU C G C U CC AC G G UC G A C U CC C G C U UG G C C C CC CC G U U G G U GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U A C UA C C CA A G G CG C AC A G G C A UC A A G G AG U C GC A CU GA G A A A A U U G UU U C UA C C C C A CC GA UP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G G G G A C U CU A A CC A C CU GG U C C G C C CG C C A G U CC C A C CC G C CA C A GC C G C C C CU A C C C G G G CG CCP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G AU C G G A C C G CU C C G C C C C G G C A T G T C G A G C C G C TC GT G CC CT G C C CG AC CG C G A G C GC A G GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G A U G A CU G C AG G C G A U G U G C A C C G U A GG CC C G G G G A UC U G U A C GC U U U CC UG G C U CU G AG C CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G A GG C U G GC C G CG G G AU U C C A C G C C C AC G U C U G C CG GC U A GC G UG CC C U U AC G G G C C AC C G AU UC C C CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G AA G CU A G G A G A U U C C UG A CU G C U U A G C G U U C C C G U A A U A G GU U G G UG U C A G A CU G CC G CC CCP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G GC A C G G A U C C C C CC G A GU U G G UG U C A G A CU G CC G CC CC G GC A C G G A U C C C C CC G A GC U A A G UG CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C C C U CA U U C AC GA C C G AA G G CA U UG C G G C G G CG C A G C U AC C UA A U C UC AU A CC U G G G C GU A A C U G CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GC G U U A C CG C C G C CG G C C A U U CA G G G CC G C C G C G C A G U U A C CG C C G C CG G C C A U U CA G G G CCP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G C C G C G C A C U U A C CG C C G C CG G C C A U U CA G G G CC G C C G C G C A A UU C A C GC A G G G GU U A CG GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U G AU A A C CC G C G G U G C G C U U A C CG C C G C CG G C C A U U CA G G G CC G C C G C G C A C G T AA C G CA GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G CT CC T T C G A G G AT C CA TG CT GA A A TA AG CA C CT C C A C G CA G G CT CC T T C G A G G AT C CA TG CT GA A A TA AG CA CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C G T AA C G CA G G CT CC T T C G A G G AT C CA TG CT GA A A TA AG CA C T A C AG G C TG TT G T CC G CC G C C G G GC C GT C AG GTP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C AT C AC G CA C A GA G C U AC C UA A U C UC AU A CC U G G G C GU A A C U G C C G G U A G U G C A G UG A A G CC A CG CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U GU A A G G C C G A A A G G G U CA GA G C C C C U CA U U A C G C CC G G G U U C G U UA A G G G A G AC AU G U C CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C U C G A CA A U A A U A A C G A C G A A A G G G U CA GA G C C C C U CA U U A C G C CC G G G U U C G U UA A G GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C C G CC A CC A C C G CC A G C GG G U G A GA C A G G C A C AG G A C G A G U A CA C AG U G CC G C U AA UA U U C G C C GAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U U C C A UG A A U A UC C A C C UC AU CC A A CC U G C C C C A CA A C U G UC A G C A CC G A C A C A C AU G C UC C C CAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence A C G A U GG C A U C A U CC G G C C U A U U A C CC A G C C U C G C C CC GC GU A CC U A U C G A C A C U CC C U G UU UP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C A AA AA A CC A CC U C A C G G U UA UC G U AU C G C GC CG G C G U A C C U C AA U G GC U G CA C G G G C C G CU G CC A UAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GC GA A C C GA G A C C CU G A C C CA GU U G GG CC C G A G C G AC A C G G A U C G G A G G U GA AC U U C U G GU U G GG CCP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C G A G C G AC A C G G A U C G G A G G U GA AC U U C U G GU U G GG CC C G A G C G AC A C G G A U C G G A G G U GA ACP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U U C U G G A C C AC A C A AA AC C G CC G A GC CG C A C A G C CC CA C U G U A A C GU U C G C AA A G AC U U G C C A GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C C C C G G U AC C GC G G C CU G C G AA C C U AA U C A U G G C C A G U C G C U C AC UC A AG C U G AG C U GC U C CA GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C G A C A A A C CA C A AC C U AC G CC C C A C G G C A U GA G C A C GA C A G A G GA G A C A UA G U U A U C CA C A UC CGP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G U G C G G C A C GA C A G A G GA G A C A UA G U U A U C CA C A UC CG G U G C G G AC A C GA C A G A G GA G A C A UAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G U U A U C CA C A UC CG G U G C G G A G G GG CC A G A G GA G A C A UA G U U A U C CA C A UC CG G U G C G G G A C AAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C C A G CC G G U U U C CA A A A C GA UU A C C AU G A C C C G G A C GA C A G A G GA UG A C A UA G U U A U C CA C A UC CGP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G U G C G G A A C AA U GU CA A C G G U U A G C C A G G A U G UG C G G C A U G C AG AA C GA C G C A C A G A C A UAP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G U C A U C C AA GA U CU G UU G A G C G G C AC C GA U UC A C CU C C C C C A A C C A U CC CU C C C A A C G C G G GC UP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence A A A C CU GC CC A GG G A C U G A A A G AC C GC C U A G G UG U G AG C C C A U U G C C AC G G C A C G A A AG G AC CU G GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U A G A U C C G CG C CA G U U G U A CA G G AC GA U G A A G G AC G U G U A G A AU AC A C A G CU G G G AA GC AC C U G CGP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence G U C CG C C UA U U C A G CC C U GC A CC C G C U U CA G C C G C U C G C G UU A G CC C U C C U U U UA AC A C C C C AP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GC A C C AC A U G GA U G A G AC C AA U U U G U A U C C A AC CA GC A G U A G C CA G CC U C G C CG U CA G C C C G C U UC CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence AU G U G C GG CA C G C G AU A G U U G G U C G C GC A U G G U C A C G CC A CA C U C U C AG U U G CU G A UC G U C G CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GA C U A C CG C G U A G A U U G C G U A G A G U A G C U G U A C U AU G G C C C A A C U G A C C G G GG CU A C ACP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence C G G U UA UC G AU AU CA G C G G G G A U G CA CC A C A G A C A G CU G G G AA GC AC C U G CG G U C CG C C UA U U C A G CC CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence U G G A CC C G C U U CA G C C G C U C G C G UU A G CC C U C C U U U UA AU U U U C A CC U CA U A U CA C C GA AC G C CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence A CC A A U U U G U A U C G CU U C C CC CC U U A AC C AU GC C GA A U G UA G C A A U UU C A GA CC CG GA GC U A G C U CC C UP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence UC A G C G A C U A G GC CC G C C G A A C CA C AA U C A A A CA GC CC A C UG C G U C G G A GU U A UG C U C C C AU C U A GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence AC C AG U AU AU C AC G G A GU U A UG C U C C C AU C U A G AC C G U AU AU C AC G G A GC U A G C U CC A U C A G C G A C U A GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GC CU G C C GC C C A U G CU C C U C C CG U G C A CC U A CA A C G TC AT CC T C CT C TC G GC CC C CC C CT C G CC A C T GT T GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GT C G CC G G T CC GC CT G C G A C C TC G G C TG C AC A C G C CT CC T G A C T T G GT GA C CA T AA T AA AA T AA AC C C C C C CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence GC C CG AG T AC C C CA CG GC A A CA T AA AA T A C AC T C G C CC CA TC T CC A CA AT G TT TG T CC T G CA CT TG AC AG CC CT CC C T G C A CP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence AC C GA TA T G AG T G CT A A G G TC G C G TA CA G TC G CC TT G G A T C AT G CA C T G AG T G CT A A G G TC G C G TA CA G TC GP-628704-PC SEQ ID Signal Immunogen Version Nucleotide Sequence NO: Sequence CC TT G G A T C AT G CA CExemplary Nucleotide Sequence Features

[0366] In some embodiments, nucleotide sequences described herein can comprise a nucleotide sequence that encodes a 5’UTR and / or a 3’ UTR. In some embodiments, polynucleotides described herein can comprise a nucleotide sequence that encodes a polyA tail. In some embodiments, nucleotide sequences described herein may comprise a 5’ cap, which may be incorporated during transcription, or joined to a nucleotide sequence post- transcription.

[0367] In some embodiments, polyribonucleotides disclosed herein comprise a 5’ untranslated region (“5’ UTR”). In some embodiments, polyribonucleotides disclosed herein do not comprise a 5’ UTR. As a skilled artisan would appreciate, the 5’ UTR is directly upstream from the initiation codon. In some embodiments, the 5’ untranslated region is not translated. In some embodiments, the 5’ UTR is translated, but not as a part of the truncated gE or gI antigen polypeptides. In some embodiments, the 5’ UTR regulates the translation of the main coding sequence of the truncated HSV glycoproteins or immunogenic fragments thereof. In some embodiments, the 5’ UTR comprises the 5’ UTR of the tobacco etch virus.

[0368] In other embodiments, polyribonucleotides of the methods, compositions, and combinations of the present disclosure further comprise an internal ribosome entry site (IRES). In some embodiments, the IRES comprises a 5'Leader IRES and intercistronic IRES in the 1.8-kb family of immediate early transcripts (IRES)1; Aphthovirus IRES; Cripavirus IRES; Hepatitis A IRES; Hepatitis C IRES; Kaposi's sarcoma-associated herpesvirusIRES; Pestivirus IRES; Picornavirus IRES; Rhopalosiphum padi virus IRES; or a combination thereof.

[0369] In other embodiments, polyribonucleotides of the methods, compositions, and combinations of the present disclosure further comprise a cap-independent translational enhancer (CITE). In another embodiment, modified (e.g., nucleoside-modified) polyribonucleotides of the methods, compositions, and combinations of the present disclosure do not comprise a CITE. In some embodiments, the CITE is a tobacco etch virus (TEV) cap- independent translational enhancer. In other embodiments, the CITE comprises TED (translation enhancer domain); BTE (BYDV-like translation element); PTE (PMV-like translation element); TSS (T-shaped structure); Y- shaped; I-shaped; or a combination thereof. In other embodiments, the cap-independent translational enhancer is any other cap-independent translational enhancer known in the art. Each possibility represents a separate embodiment of the present disclosure.P-628704-PC

[0370] In some embodiments, polyribonucleotides disclosed herein comprise a 3’ untranslated region (“3’ UTR”). In some embodiments, polyribonucleotides disclosed herein do not comprise a 3’ UTR. As a skilled artisan would appreciate, the 3’ UTR is directly downstream from the termination codon. In some embodiments, the 3’ UTR is not translated. In some embodiments, the 3’ UTR is translated, but not as a part of the truncated gE or gI antigen polypeptides. In some embodiments, the 3’ UTR regulates the translation of the main coding sequence of the truncated gE or gI antigens. In some embodiments, the 3’ UTR comprises the 3’ UTR from Xenopus beta globin gene.

[0371] In another embodiment, polyribonucleotides of the methods, compositions, and combinations of the present disclosure further comprises a poly-A tail. In another embodiment, polyribonucleotides of the methods,compositions, and combinations of the present disclosure does not comprise a poly-A tail. Each possibilityrepresents a separate embodiment of the present disclosure.

[0372] In another embodiment, polyribonucleotides of the methods, compositions, and combinations of the present disclosure comprises an m7GpppG cap. In another embodiment, polyribonucleotides of the methods, compositions, and combinations of the present disclosure do not comprise an m7GpppG cap. In anotherembodiment, modified (e.g., nucleoside-modified) polyribonucleotides of the methods, compositions, andcombinations of the present disclosure comprises a 3′-O-methyl-m7GpppG. In another embodiment, polyribonucleotides of the methods, compositions, and combinations of the present disclosure comprise a non- reversible cap analog, which, in some embodiments, is added during transcription of the polyribonucleotides. In another embodiment, polyribonucleotides of the methods, compositions, and combinations of the present disclosure comprise an anti-reverse cap analog. Each possibility represents a separate embodiment of the present disclosure.

[0373] In some embodiments, a nucleotide sequence provided herein encodes one or more glycoproteins (e.g., gE, gI, or a combination thereof) or an immunogenic fragment thereof. In some embodiments, a polyribonucleotide comprises a 5’ cap, a 5’UTR, a nucleotide sequence that encodes one or more glycoproteins(e.g., gE, gI, or a combination thereof) or immunogenic fragments thereof, a 3’ UTR, and a polyA tail.1. 5' Cap

[0374] In some embodiments, a polyribonucleotide can include a cap structure at the five-prime end (5'). For example, natural eukaryotic mRNA comprises a 7-methylguanosine cap linked to the mRNA via a 5´ to 5´- triphosphate bridge resulting in a cap0 structure (m7GpppN). 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 “cap1” 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 cap0- mRNA cannot be translated as efficiently as cap1-mRNA in which the role of 2'-O-Me in the penultimate position at the mRNA 5’ end is determinant. Lack of the 2'-O-Me has been shown to trigger innate immunity and activate an interferon (IFN) response. Daffis, et al. (2010) Nature, 468:452-456; and Züst et al. (2011) Nature Immunology, 12:137-143, each of which is incorporated herein by reference in its entirety.

[0375] 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 cap0 (methylation of the first nucleobase, e.g.,P-628704-PC m7GpppN), cap1 (additional methylation of the ribose 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.

[0376] 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 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 bemodified, 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’O methylation at a ribose (3’OMeG). 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 described herein.

[0377] 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.

[0378] In some embodiments, a utilized 5' cap is a cap0, a cap1, or cap2 structure. See, e.g., Fig. 1 ofRamanathan 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 described herein comprises a cap1 structure. In some embodiments, an RNA described herein comprises a cap2 structure.

[0379] In some embodiments, an RNA described herein comprises a cap0 structure. In some embodiments, a cap0 structure comprises a guanosine nucleoside methylated at the 7-position of guanine ((m7)G). In some embodiments, such a cap0 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 cap0 structure comprises a guanosine nucleoside methylated at the 2'-position of the ribose of guanosine. In some embodiments, a cap0 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).

[0380] In some embodiments, a cap1 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'O methylated firstnucleotide in an RNA ((m2'-O)N1). In some embodiments, a cap1 structure comprises a guanosine nucleosidemethylated at the 7-position of guanine ((m7)G) and the 3' position of the ribose, and a 2'O methylated firstP-628704-PC nucleotide in an RNA ((m2'-O)N1). In some embodiments, a cap1 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)N1) or (m27,3’-O)Gppp(2'-O)N1), wherein N1 is as defined and described herein. In some embodiments, a cap1 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)N1pN2 or (m27,3’- O)Gppp(2'-O)N1pN2 , wherein each of N1 and N2 is as defined and described herein.

[0381] 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'O methylated first and second nucleotides in an RNA ((m2’-O)N1p(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'Omethylated first and second nucleotides in an RNA. In some embodiments, a cap2 structure is connected to anRNA via a 5'- to 5'-triphosphate linkage and is also referred to herein as, e.g., ((m7)Gppp(2'-O)N1p(2'-O)N2) or (m27,3’-O)Gppp(2'-O)N1p(2'-O)N2), wherein each of N1 and N2 is as defined and described herein.

[0382] In some embodiments, the 5' cap is a dinucleotide cap structure. In some embodiments, the 5' cap is a dinucleotide cap structure comprising N1, wherein N1 is as defined and described herein. In some embodiments,the 5' cap is a dinucleotide cap G*N1, wherein N1 is as defined above and herein, and G* comprises a structureof formula (I): or a salt thereof,wherein each R2 and R3 is -OH or -OCH3; and X is O or S.

[0383] 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.

[0384] In some embodiments, X is O. In some embodiments, X is S.

[0385] In some embodiments, the 5' cap is a dinucleotide cap0 structure (e.g., (m7)GpppN1, (m27,2’- O)GpppN1, (m27,3’-O)GpppN1, (m7)GppSpN1, (m27,2’-O)GppSpN1, or (m27,3’-O)GppSpN1), wherein N1 is as defined and described herein. In some embodiments, the 5' cap is a dinucleotide cap0 structure (e.g., (m7)GpppN1, (m27,2’-O)GpppN1, (m27,3’-O)GpppN1, (m7)GppSpN1, (m27,2’-O)GppSpN1, or (m27,3’-O)GppSpN1), wherein N1 is G. In some embodiments, the 5' cap is a dinucleotide cap0 structure (e.g.,(m7)GpppN1, (m27,2’-O)GpppN1, (m27,3’-O)GpppN1, (m7)GppSpN1, (m27,2’-O)GppSpN1, or (m27,3’- O)GppSpN1), wherein N1 is A, U, or C. In some embodiments, the 5' cap is a dinucleotide cap1 structure (e.g., (m7)Gppp(m2’-O)N1, (m27,2’-O)Gppp(m2’-O)N1, (m27,3’-O)Gppp(m2’-O)N1, (m7)GppSp(m2’-O)N1, (m27,2’-P-628704-PC O)GppSp(m2’-O)N1, or (m27,3’-O)GppSp(m2’-O)N1), wherein N1 is as defined and described herein. In some embodiments, the 5' cap is selected from the group consisting of (m7)GpppG (“Ecap0”), (m7)Gppp(m2’-O)G (“Ecap1”), (m27,3’-O)GpppG (“ARCA” or “D1”), and (m27,2’-O)GppSpG (“beta-S-ARCA”). In some embodiments, the 5' cap is (m7)GpppG (“Ecap0”), having a structure of formula (II): or a salt

[0386] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)G (“Ecap1”), having a structure of formula (III): or a salt

[0387] In some embodiments, the 5' cap is (m27,3’-O)GpppG (“ARCA” or “D1”), having a structure of formula (IV): or a saltP-628704-PC

[0388] In some embodiments, the 5' cap is (m27,2’-O)GppSpG (“beta-S-ARCA”), having a structure of formula (V): or a salt

[0389] In some embodiments, the 5' cap is a trinucleotide cap structure. In some embodiments, the 5' cap is a trinucleotide cap structure comprising N1pN2, wherein N1 and N2 are as defined and described herein. In some embodiments, the 5' cap is a dinucleotide cap G*N1pN2, wherein N1 and N2 are as defined above and herein, and G* comprises a structure of formula (VI): or a salt thereof, wherein

[0390] In some embodiments, the 5' cap is a trinucleotide cap0 structure (e.g., (m7)GpppN1pN2, (m27,2’- O)GpppN1pN2, or (m27,3’-O)GpppN1pN2), wherein N1 and N2 are as defined and described herein). In some embodiments, the 5' cap is a trinucleotide cap1 structure (e.g., (m7)Gppp(m2’-O)N1pN2, (m27,2’-O)Gppp(m2’- O)N1pN2, (m27,3’-O)Gppp(m2’-O)N1pN2), wherein N1 and N2 are as defined and described herein. In some embodiments, the 5' cap is a trinucleotide cap2 structure (e.g., (m7)Gppp(m2’-O)N1p(m2’-O)N2, (m27,2’- O)Gppp(m2’-O)N1p(m2’-O)N2, (m27,3’-O)Gppp(m2’-O)N1p(m2’-O)N2), wherein N1 and N2 are as defined and described 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”), (m7)Gppp(m2’- O)ApG, (m7)Gppp(m2’-O)GpG, (m27,3’-O)Gppp(m26,2’-O)ApG, and (m7)Gppp(m2’-O)ApU.

[0391] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m2’-O)ApG (“CleanCap AG”, “CC413”), having a structure of formula (VII):P-628704-PC or a salt

[0392] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m2’-O)GpG (“CleanCap GG”), having a structure offormula (VIII):or a salt

[0393] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)ApG, having a structure of formula (IX):P-628704-PC or a salt

[0394] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)GpG, having a structure of formula (X): or a salt

[0395] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m26,2’-O)ApG, having a structure of formula (XI):P-628704-PC or a salt

[0396] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)ApU, having a structure of formula (XII): or a salt thereof.

[0397] In some embodiments, the 5' cap is a tetranucleotide cap structure. In some embodiments, the 5' cap is a tetranucleotide cap structure comprising N1pN2pN3, wherein N1, N2, and N3 are as defined and described herein. In some embodiments, the 5' cap is a tetranucleotide cap G*N1pN2pN3, wherein N1, N2, and N3 are as defined above and herein, and G* comprises a structure of formula (XIII):P-628704-PC or a salt thereof, wherein

[0398] In some embodiments, the 5' cap is a tetranucleotide cap0 structure (e.g. (m7)GpppN1pN2pN3, (m27,2’-O)GpppN1pN2pN3, or (m27,3’-O)GpppN1N2pN3), wherein N1, N2, and N3 are as defined and described herein). In are(XIV): or a salt

[0400] In some embodiments, the 5' cap is (m27,3’-O)Gppp(m2’-O)Gp(m2’-O)GpC, having a structure of formula (XV):P-628704-PC or a salt

[0401] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)Ap(m2’-O)UpA, having a structure of formula (XVI): or a salt

[0402] In some embodiments, the 5' cap is (m7)Gppp(m2’-O)Ap(m2’-O)GpG, having a structure of formula (XVII):P-628704-PC or a salt2. Cap Proximal Sequences

[0403] 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.

[0404] In some embodiments, a cap structure comprises one or more polynucleotides of a cap proximalsequence. In some embodiments, a cap structure comprises an m7 guanosine cap and nucleotide +1 (N1) of anRNA 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 (N1and N2) of an RNA polynucleotide. In some embodiments, a cap structure comprises an m7guanosine cap and nucleotides +1, +2, and +3 (N1, N2, and N3) of an RNA polynucleotide.

[0405] 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., a cap1 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’-OGppp(m12’-O)ApG cap is utilized, +1 (i.e., N1) and +2 (i.e. N2) are the (m12’-O)A and G residues of the cap, and +3, +4, and +5 are added by a polymerase (e.g., T7 polymerase).

[0406] In some embodiments, the 5'’ cap is a dinucleotide cap structure, wherein the cap proximal sequence comprises N1 of the 5’ cap, where N1 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 described above and herein), wherein the capP-628704-PC proximal sequence comprises N1 and N2 of the 5' cap, wherein N1 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 N1, N2, and N3of the 5' cap, wherein N1, N2, and N3 are any nucleotide, e.g., A, C, G or U.

[0407] In some embodiments, e.g., where the 5' cap is a dinucleotide cap structure, a cap proximal sequence comprises N1 of a 5' cap, and N2, N3, N4 and N5, wherein N1 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 N1 and N2 of a 5' cap, and N3, N4 and N5, wherein N1 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 N1, N2, and N3 of a 5’cap, and N4 and N5, wherein N1 to N5 correspond to positions +1, +2, +3, +4, and / or +5 of an RNA polynucleotide.

[0408] In some embodiments, N1 is A. In some embodiments, N1 is C. In some embodiments, N1 is G. In some embodiments, N1 is U. In some embodiments, N2 is A. In some embodiments, N2 is C. In someembodiments, 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 N1 through N5) may be taken singly or in combination and / or may be combined with other ...

Claims

P-628704-PC CLAIMS What is claimed is:

1. A combination comprising: (a) a polyribonucleotide encoding a polypeptide comprising Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof and (b) a polyribonucleotide encoding a polypeptide comprising an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof.

2. The combination of claim 1, wherein said HSV-2 gE antigen or immunogenic fragment thereof comprises an HSV-2 gE ectodomain.

3. The combination of claim 1 or 2, wherein said HSV-2 gI antigen or immunogenic fragment thereof comprises an HSV-2 gI ectodomain.

4. The combination of any one of claims 1-3, wherein said HSV-2 gE antigen or immunogenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 4 or SEQ ID NO:

6.

5. The combination of any one of claims 1-4, wherein said HSV-2 gI antigen or immunogenic fragment thereof comprises the amino acid sequence as set forth in any one of SEQ ID NOs: 1-3.

6. The combination of any one of claims 1-5, wherein said polyribonucleotide encoding said HSV-2 gE antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

36.

7. The combination of any one of claims 1-5, wherein said polyribonucleotide encoding said HSV-2 gE antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 37-44.

8. The combination of any one of claims 1-7, wherein said polyribonucleotide encoding said HSV-2 gI antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

31.

9. The combination of any one of claims 1-7, wherein said polyribonucleotide encoding said HSV-2 gI antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 32-35.

10. The combination of any one of claims 1-9, wherein one or more of said polyribonucleotides further encode a secretory signal.

11. The combination of claim 10, wherein the secretory signal is located at the N-terminus of the polypeptide.

12. The combination of claim 10, wherein the secretory signal comprises an IL-2 signal peptide.

13. The combination of claim 12, wherein said IL-2 signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

109.

14. The combination of any one of claims 10-13, wherein the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:

198.

15. The combination of any one of claims 10-14, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 187 or SEQ ID NO:

188.

16. The combination of any one of claims 12-15, wherein one or more of said polyribonucleotides encoding the IL-2 signal peptide comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

176.

17. The combination of any one of claims 10-16, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 246-248.P-628704-PC 18. The combination of any one of claims 10-17, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

245.

19. The combination of claim 10 or 11, wherein the secretory signal comprises a viral secretory signal.

20. The combination of claim 19, wherein the viral secretory signal comprises an HSV secretory signal.

21. The combination of claim 20, wherein the HSV secretory signal comprises an HSV gE signal peptide.

22. The combination of claim 21, wherein said HSV gE signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

97.

23. The combination of claim 21, wherein said HSV gE signal peptide comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 98-100.

24. The combination of any one of claims 21-23, wherein the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 202-203.

25. The combination of any one of claims 21-24, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 189-190.

26. The combination of any one of claims 21-25, wherein one or more of said polyribonucleotides encoding the gE signal peptide comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 143-151.

27. The combination of any one of claims 21-26, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 254-258.

28. The combination of any one of claims 21-27, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 238 or SEQ ID NO:

239.

29. The combination of claim 20, wherein the HSV secretory signal comprises an HSV gI signal peptide.

30. The combination of claim 29, wherein said HSV gI signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

106.

31. The combination of any one of claims 29-30, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 191 or SEQ ID NO:

192.

32. The combination of any one of claims 29-31, wherein one or more of said polyribonucleotides encoding the gI signal peptide comprises a ribonucleic acid sequence as set forth in in any one of SEQ ID NOs: 160-175.

33. The combination of any one of claims 29-32, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 240-243.

34. The combination of claim 20, wherein said secretory signal comprises an HSV-1 secretory signal.

35. The combination of claim 34, wherein said HSV-1 secretory signal comprises an HSV-1 gB secretory signal, an HSV-1 gC secretory signal, an HSV-1 gD secretory signal, an HSV-1 gE secretory signal, an HSV-1 gI secretory signal, or a combination thereof.

36. The combination of claim 20, wherein said secretory signal comprises an HSV-2 secretory signal.

37. The combination of claim 36, wherein said HSV-2 secretory signal comprises an HSV-2 gB secretory signal, an HSV-2 gC secretory signal, an HSV-2 gD secretory signal, an HSV-2 gE secretory signal, an HSV-2 gI secretory signal, or a combination thereof.P-628704-PC 38. The combination of claim 19, wherein the viral secretory signal comprises an Ebola spike glycoprotein secretory signal.

39. The combination of claim 10 or 11, wherein the secretory signal comprises a human secretory signal.

40. The combination of claim 39, wherein the secretory signal comprises a human Ig heavy chain secretory signal.

41. The combination of claim 10 or 11, wherein the secretory signal comprises any secretory signal as set forth in Tables 3-4.

42. The combination of any one of claims 1-41, wherein one or more of said polyribonucleotides further comprise a 5′ untranslated region.

43. The combination of claim 42, wherein the 5′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 308-311.

44. The combination of any one of claims 1-43, wherein one or more of said polyribonucleotides further comprise a 3′ untranslated region.

45. The combination of claim 44, wherein the 3′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 312-315.

46. The combination of any one of claims 1-45, wherein one or more of said polyribonucleotides further comprise a poly-A tail.

47. The combination of claim 46, wherein the poly-A tail comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 316-318.

48. The combination of any one of claims 1-47, wherein one or more of said polyribonucleotides further comprise a cap-independent translational enhancer.

49. The combination of any one of claims 1-48, wherein one or more of said polyribonucleotides further comprise an m7GpppG cap, 3′-O-methyl-m7GpppG cap, or anti-reverse cap analog.

50. The combination of any one of claims 42-49, wherein one or more of said polyribonucleotides is an RNA construct comprising in 5' to 3' order: (i) a 5' UTR; (ii) said polyribonucleotide(s); (iii) a 3' UTR; and (iv) a polyA tail sequence.

51. The combination of claim 50, wherein (i) the 5' UTR comprises a modified human alpha-globin 5'-UTR or a tobacco etch virus 5'-UTR; and (ii) the 3' UTR comprises a first sequence from the amino terminal enhancer of split (AES) messenger RNA and a second sequence from the mitochondrial encoded 12S ribosomal RNA or a Xenopus beta globin 3'-UTR.

52. The combination of any one of claims 1-51, wherein one or more of the polyribonucleotides are nucleoside modified polyribonucleotides.

53. The combination of claim 52, wherein the one or more nucleoside modified polyribonucleotides comprise one or more m5D (5-methyldihydrouridine) residues.

54. The combination of claim 52 or 53, wherein the one or more nucleoside modified polyribonucleotides comprise one or more pseudouridine residues.

55. The combination of claim 54, wherein said one or more pseudouridine residues comprise one or more m1Ψ (1-methylpseudouridine) residues.P-628704-PC 56. The combination of claim 54, wherein said one or more pseudouridine residues comprise m1acp3Ψ (1- methyl-3-(3-amino-5-carboxypropyl)pseudouridine, Ψm (2′-O-methylpseudouridine, m3Ψ (3- methylpseudouridine), or any combination thereof.

57. The combination of any one of claims 1-56, wherein one or more of the polyribonucleotides are recombinantly engineered polyribonucleotides.

58. The combination of any one of claims 1-57, wherein one or more of the polyribonucleotides are codon optimized polyribonucleotides.

59. The combination of any one of claims 1-58, wherein the polyribonucleotide encoding a polypeptide comprising an HSV-2 gE antigen or immunogenic fragment thereof, and the polyribonucleotide encoding a polypeptide comprising an HSV-2 gI antigen or immunogenic fragment thereof are in the same composition.

60. The combination of any one of claims 1-59, further comprising one or more polyribonucleotides encoding a) an HSV glycoprotein B (gB) antigen or immunogenic fragment thereof, b) an HSV glycoprotein C (gC) antigen or immunogenic fragment thereof, c) an HSV glycoprotein D (gD) antigen or immunogenic fragment thereof d) an HSV glycoprotein H (gH) antigen or immunogenic fragment thereof, e) an HSV glycoprotein L (gL) antigen or immunogenic fragment thereof, or f) any combination thereof.

61. The combination of any one of claims 1-60, further comprising nanoparticles, lipids, polymers, cholesterols, cell penetrating peptides, or any combination thereof.

62. The combination of claim 61, wherein one or more of the polyribonucleotides are associated with nanoparticles, lipids, polymers, cholesterols, or cell penetrating peptide.

63. The combination of claim 61 or 62, wherein said nanoparticles are lipid nanoparticles.

64. The combination of any one of claims 1-63, wherein the combination is a pharmaceutical combination.

65. The combination of claim 64, further comprising a pharmaceutically acceptable excipient.

66. The combination of any one of claims 1-65 for use in treating, preventing, inhibiting, or reducing the incidence of an HSV infection in a subject.

67. A composition comprising: (a) a polyribonucleotide encoding a polypeptide comprising a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, (b) a polyribonucleotide encoding a polypeptide comprising an HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof, or (c) a combination thereof.

68. The composition of claim 67, wherein said HSV-2 gE antigen or immunogenic fragment thereof comprises an HSV-2 gE ectodomain.

69. The composition of claim 67 or 68, wherein said HSV-2 gI antigen or immunogenic fragment thereof comprises an HSV-2 gI ectodomain.

70. The composition of any one of claims 67-69, wherein said HSV-2 gE antigen or immunogenic fragment thereof comprises the amino acid sequence as set forth in SEQ ID NO: 4 or SEQ ID NO:

6.

71. The composition of any one of claims 67-70, wherein said HSV-2 gI antigen or immunogenic fragment thereof comprises the amino acid sequence as set forth in any one of SEQ ID NOs: 1-3.

72. The composition of any one of claims 67-71, wherein said polyribonucleotide encoding said HSV-2 gE antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 36.P-628704-PC 73. The composition of any one of claims 67-72, wherein said polyribonucleotide encoding said HSV-2 gE antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 37-44.

74. The composition of any one of claims 67-73, wherein said polyribonucleotide encoding said HSV-2 gI antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

31.

75. The combination of any one of claims 67-73, wherein said polyribonucleotide encoding said HSV-2 gI antigen or immunogenic fragment thereof, comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 32-35.

76. The composition of any one of claims 67-75, wherein one or more of said polyribonucleotides further encode a secretory signal.

77. The composition of claim 76, wherein the secretory signal is located at the N-terminus of the polypeptide.

78. The composition of claim 76 or 77, wherein the secretory signal comprises an IL-2 signal peptide.

79. The composition of claim 78, wherein said IL-2 signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

109.

80. The composition of any one of claims 76-79, wherein the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:

198.

81. The composition of any one of claims 76-80, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 187 or SEQ ID NO:

188.

82. The composition of any one of claims 78-81, wherein one or more of said polyribonucleotides encoding the IL-2 signal peptide comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

176.

83. The composition of any one of claims 76-82, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 246-248.

84. The composition of any one of claims 76-83, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in SEQ ID NO:

245.

85. The composition of any of claims 76-84, wherein the secretory signal comprises a viral secretory signal.

86. The composition of claim 85, wherein the viral secretory signal comprises an HSV secretory signal.

87. The composition of claim 86, wherein said HSV secretory signal comprises an HSV gE signal peptide.

88. The composition of claim 87, wherein said HSV gE signal peptide comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 98-100.

89. The composition of claim 87, wherein said HSV gE signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

97.

90. The composition of any one of claims 87-89, wherein the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 202-203.

91. The composition of any one of claims 87-90, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 189-190.

92. The composition of any one of claims 87-91, wherein one or more of said polyribonucleotides encoding the gE signal peptide comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 143-151.P-628704-PC 93. The composition of any one of claims 87-92, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gE antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 254-258.

94. The composition of any one of claims 87-93, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in SEQ ID NO: 238 or SEQ ID NO:

239.

95. The composition of claim 86, wherein said HSV secretory signal comprises an HSV gI signal peptide.

96. The composition of claim 95, wherein said HSV gI signal peptide comprises an amino acid sequence as set forth in SEQ ID NO:

106.

97. The composition of any one of claims 95-96, wherein the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO: 191 or SEQ ID NO:

192.

98. The composition of any one of claims 95-97, wherein one or more of said polyribonucleotides encoding the gI signal peptide comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 160-175.

99. The composition of any one of claims 95-98, wherein the polyribonucleotide encoding the polypeptide comprising the HSV-2 gI antigen or immunogenic fragment thereof comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 240-243.

100. The composition of claim 86, wherein said secretory signal comprises an HSV-1 secretory signal.

101. The composition of claim 100, wherein said HSV-1 secretory signal comprises an HSV-1 gB secretory signal, an HSV-1 gC secretory signal, an HSV-1 gD secretory signal, an HSV-1 gE secretory signal, an HSV-1 gI secretory signal, or a composition thereof.

102. The composition of claim 86, wherein said secretory signal comprises an HSV-2 secretory signal.

103. The composition of claim 102, wherein said HSV-2 secretory signal comprises an HSV-2 gB secretory signal, an HSV-2 gC secretory signal, an HSV-2 gD secretory signal, an HSV-2 gE secretory signal, an HSV-2 gI secretory signal, or a composition thereof.

104. The composition of claim 85, wherein the viral secretory signal comprises an Ebola spike glycoprotein secretory signal.

105. The composition of claim 76 or 77, wherein the secretory signal comprises a human secretory signal.

106. The composition of claim 105, wherein the secretory signal comprises a human Ig heavy chain secretory signal.

107. The composition of claim 76 or 77, wherein the secretory signal comprises any secretory signal as set forth in Tables 3-4.

108. The composition of any one of claims 67-107, wherein one or more of said polyribonucleotides further comprise a 5′ untranslated region.

109. The composition of claim 108, wherein the 5′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 308-311.

110. The composition of any one of claims 67-109, wherein one or more of said polyribonucleotides further comprise a 3′ untranslated region.

111. The composition of claim 110, wherein the 3′ untranslated region comprises a ribonucleic acid sequence as set forth in any one of SEQ ID NOs: 312-315.

112. The composition of any one of claims 67-111, wherein one or more of said polyribonucleotides further comprise a poly-A tail.P-628704-PC 113. The composition of claim 112, wherein the poly-A tail comprises a ribonucleic acid sequence an amino acid sequence as set forth in any one of SEQ ID NOs: 316-318.

114. The composition of any one of claims 67-113, wherein one or more of said polyribonucleotides further comprise a cap-independent translational enhancer.

115. The composition of any one of claims 67-114, wherein one or more of said polyribonucleotides further comprise an m7GpppG cap, 3′-O-methyl-m7GpppG cap, or anti-reverse cap analog.

116. The composition of any one of claims 108-115, wherein one or more of said polyribonucleotides is an RNA construct comprising in 5' to 3' order: (i) a 5' UTR; (ii) said polyribonucleotide; (iii) a 3' UTR; and (iv) a polyA tail sequence.

117. The composition of claim 116, wherein (i) the 5' UTR comprises a modified human alpha-globin 5'-UTR or a tobacco etch virus 5'-UTR; and (ii) the 3' UTR comprises a first sequence from the amino terminal enhancer of split (AES) messenger RNA and a second sequence from the mitochondrial encoded 12S ribosomal RNA or a Xenopus beta globin 3'-UTR.

118. The composition of any one of claims 67-117, wherein one or more of the polyribonucleotides are nucleoside modified polyribonucleotides.

119. The composition of claim 118, wherein the one or more nucleoside modified polyribonucleotides comprise one or more m5D (5-methyldihydrouridine) residues.

120. The composition of claim 118 or claim 119, wherein the one or more nucleoside modified polyribonucleotides comprise one or more pseudouridine residues.

121. The composition of claim 120, wherein said one or more pseudouridine residues comprise one or more m1Ψ (1-methylpseudouridine) residues.

122. The composition of claim 120, wherein said one or more pseudouridine residues comprise m1acp3Ψ (1- methyl-3-(3-amino-5-carboxypropyl)pseudouridine, Ψm (2′-O-methylpseudouridine, m3Ψ (3- methylpseudouridine), or any composition thereof.

123. The composition of any one of claims 67-122, wherein one or more of the polyribonucleotides are recombinantly engineered polyribonucleotides.

124. The composition of any one of claims 67-123, wherein one or more of the polyribonucleotides are codon optimized polyribonucleotides.

125. The composition of any one of claims 67-124, further comprising one or more polyribonucleotides encoding: a) an HSV glycoprotein B (gB) antigen or immunogenic fragment thereof, b) an HSV glycoprotein C (gC) antigen or immunogenic fragment thereof, c) an HSV glycoprotein D (gD) antigen or immunogenic fragment thereof d) an HSV glycoprotein H (gH) antigen or immunogenic fragment thereof, e) an HSV glycoprotein L (gL) antigen or immunogenic fragment thereof, or f) any composition thereof.

126. The composition of any one of claims 67-125, further comprising nanoparticles, lipids, polymers, cholesterols, cell penetrating peptides, or any composition thereof.P-628704-PC 127. The composition of claim 126, wherein one or more of the polyribonucleotides are associated with nanoparticles, lipids, polymers, cholesterols, or cell penetrating peptide.

128. The composition of claim 126 or 127, wherein said nanoparticles are lipid nanoparticles.

129. The composition of any one of claims 67-128, wherein the composition is a pharmaceutical composition.

130. The composition of claim 129, further comprising a pharmaceutically acceptable excipient.

131. The composition of any one of claims 67-130 for use in treating, preventing, inhibiting, or reducing the incidence of an HSV infection in a subject.

132. Use of a combination of any one of claims 1-66 or a composition of any one of claims 67-131 for the manufacture of a medicament for treating or preventing an HSV infection in a subject.

133. Use of a combination of any one of claims 1-66 or a composition of any one of claims 67-131 for treating or preventing an HSV infection in a subject.

134. A method of treating a Herpes Simplex Virus (HSV) infection in a subject comprising the step of administering the combination of any one of claims 1-66 or a composition of any one of claims 67-131 to said subject.

135. A method of preventing, inhibiting, or reducing the incidence of a Herpes Simplex Virus (HSV) infection in a subject comprising the step of administering the combination of any one of claims 1-66 or a composition of any one of claims 67-131 to said subject.

136. The method of claim 134 or 135, wherein said HSV infection comprises an HSV-1 infection.

137. The method of claim 134 or 135, wherein said HSV infection comprises an HSV-2 infection.

138. The method of any one of claims 134-137, wherein said infection is a primary infection or a secondary infection.

139. The method of any one of claims 134-138, wherein said HSV infection comprises a flare, recurrence, or HSV labialis following a primary HSV infection; a reactivation of a latent HSV infection; an HSV encephalitis; an HSV neonatal infection; a genital HSV infection; an oral HSV infection; or any combination thereof.

140. The method of any one of claims 134-139, wherein said HSV infection is a latent HSV infection.

141. The method of claim 140, wherein said latent HSV infection comprises a genital HSV infection or an oral HSV infection.

142. A method of inducing an immune response in a subject, comprising a step of administering a combination of any one of claims 1-66 or a composition of any one of claims 67-131 to said subject.

143. The method of claim 142, wherein said immune response comprises a CD4+ immune response; a CD8+ immune response; a T follicular helper cell immune response; a germinal center B cell immune response; an IgG antibody response to gE2 or gI2; or any combination thereof.

144. A method of inducing a CD4+ T-cell response to a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, a CD8+ T-cell response to HSV-2 gI antigen or immunogenic fragment thereof, or any combination thereof comprising the step of administering a combination of any one of claims 1-66 or a composition of any one of claims 67-131 to said subject.

145. A method of inducing an antibody response to a Herpes Simplex Virus-2 (HSV-2) glycoprotein E (gE) antigen or immunogenic fragment thereof, HSV-2 glycoprotein I (gI) antigen or immunogenic fragment thereof, or any combination thereof comprising the step of administering a combination of any one of claims 1-66 or a composition of any one of claims 67-131 to said subject.

146. The method of claim any one of claims 134-145, wherein the administration step comprises intramuscular, subcutaneous, intradermal, intranasal, intravaginal, intrarectal, or topical administration.

147. A combination comprising the polypeptides encoded by the combination of any one of claims 1-66.P-628704-PC 148. A composition comprising one or more polypeptides encoded by the composition of any one of claims 67- 131.

149. A host cell comprising a combination of any one of claims 1-66 or a composition of any one of claims 67- 131.

150. A host cell comprising one or more polypeptides encoded by a combination of any one of claims 1-66 or a composition of any one of claims 67-131.

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