Immunogenic compositions for the prevention of herpes zoster

Abstract

The present disclosure provides immunogenic and vaccine compositions comprising a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2 and an SLA adjuvant for use in the prevention of herpes zoster.

Description

IMMUNOGENIC COMPOSITIONS FOR THE PREVENTION OF HERPES ZOSTERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is an International PCT Application claiming priority to U.S. Provisional 63 / 557,064, filed on February 23, 2024 and U.S. Provisional 63 / 747,668, filed on January 21 , 2025, the contents each of which are incorporated herein in their entireties.REFERENCE TO THE ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (CURV_008_02WO_SeqList_ST26.xml; Size: 3,849 bytes; and Date of Creation: February 18, 2025) are herein incorporated by reference in its entirety.BACKGROUND

[0003] Shingles (herpes zoster) is a blistering rash accompanied by severe pain, lasting 2-4 weeks, which 30% of adults will get at least once. 10-18% of those with shingles get often debilitating nerve pain called Post-Herpetic Neuralgia (PHN), and 30-50% have PHN lasting >1 year(Kawai, et al. BMJOpen 2014). Contracting shingles raises stroke / major cardiovascular event risk by ~30% (Curhan, et al. J Am Heart Assoc, 2022) and has been linked to dementia / Alzheimer’s Disease (Eyting, et al. medRxiv (preprint), 2023).

[0004] Chickenpox is the highly contagious primary infection from the varicella zoster virus. Higher morbidity in infants and mortality in individuals with an impaired immune system. Chickenpox during pregnancy can cause birth defects or serious newborn infection. Virtually all adults have been exposed to the varicella virus. Among the 1 .9 billion people age 50+ worldwide, 278 million cases of shingles and 20.7 million cases of postherpetic neuralgia (PHN) will occur globally over the next decade absent vaccination (Harbecke, et al. J Infect Dis, 2021).SUMMARY

[0005] Varicella zoster virus (VZV) is the cause of varicella (also known as chickenpox and attributable to primary infection) and herpes zoster, also known as shingles and attributable to reactivation from VZV viral latency. Prior to the licensure of Varivax® (Merck) for prevention of primary VZV infection and Zostavax® (Merck) for prevention of herpes zoster, more than 90% of the North American population at least 50 years old had acquired VZV, and approximately one- third of adults would develop HZ over the course of their lifetimes. With the introduction of routine use of live-attenuated varicella vaccine in childhood, complications from VZV have dropped significantly, though notably the incidence of herpes zoster has increased markedly (CDC, 2020).

[0006] In 2017, a second herpes zoster vaccine, Shingrix® (GSK), was approved for prevention of herpes zoster in immunocompetent adults and the US Advisory Committee on Immunization Practices recommended this vaccine for adults of age >50, including those who have previously been immunized with Zostavax®. This vaccine utilizes a VZV glycoprotein E (gE) subunit adjuvanted with a combination of a toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPL) and a saponin (QS21) formulated in liposomes.

[0007] Despite the approval of Shingrix in more than 30 countries for the prevention of HZ in adults, the shingles market remains largely underserved, particularly outside the United States. Of the over 800 million adults aged 50 or over, Shingrix® has been administered to less than 3% of eligible adults in Europe (excluding Germany, with an administration rate of about 12%), Canada, Australia, and Japan. Of the 486+ million adults over age 50 in China, only 1.2% have received Shingrix®.

[0008] While immunogenicity in older adults, > 50 years of age, is superior to that observed with Zostavax®, reactogenicity to the Shingrix® vaccine is high; approximately one out of six vaccinees develop adverse reactions that interfere with daily activities (grade 3). Furthermore, even in adults who have received the initial dose of Shingrix®, 20-30% of do not go back for the required second dose due to poor tolerance of the vaccine (Patterson, et al. Hum Vaccin Immunother, 2021), increasing the incidence rate of shingles by 45% (Izurieta, et al. Clin Infect Dis, 2021).

[0009] Therefore, there remains a need in the art for shingles vaccines that are effective and well tolerated.

[0010] Amezosvatein is a novel gE subunit vaccine that is adjuvanted with a new-generation TLR4 agonist in an oil-in-water emulsion, SI.A-SE. The present disclosure provides results from a A Phase 2 trial evaluating the safety, tolerability, and immunogenicity of amezosvatein compared to Shingrix in participants 50 years of age and older. Results of the study demonstrated the noninferiority of amezosvatein versus Shingrix in anti-gE GMC at Day 84. The anti-gE GMFR and VRR for amezosvatein were similar to those for Shingrix.

[0011] Importantly, the incidence of Grade 2 solicited local and solicited system adverse events was lower for participants treated with amezosvatein than for those treated with Shingrix, indicating an increase in tolerability of amezosvatein as compared to Shingrix. In a nationwide (USA) survey of primary care physicians, patients who refused Shingrix vaccination reported fear of side effects was ‘often / always’ (15%) or ‘sometimes’ (54%) the cause (Hurley, et al. J Gen Intern Med, 2022). Furthermore, in a survey of Americans age 50+, 48% of respondents avoided Shingrix vaccination due to tolerability concerns (Wagner, et al. 2024) 39% of people whoreceived only one dose of Shingrix pointed to tolerability concerns impacting their decision to not get a second dose (Wagner, et al. 2024).

[0012] In some embodiments, the present disclosure provides an immunogenic composition comprising: at least 50 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; at least 5 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition comprises 50 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 5 pg of the SLA adjuvant. In some embodiments, the immunogenic composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 5 pg of the SLA adjuvant. In some embodiments, the immunogenic composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 10 pg of the SLA adjuvant. In some embodiments, the immunogenic composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 15 pg of the SLA adjuvant. In some embodiments, the immunogenic composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 20 pg of the SLA adjuvant.

[0013] In some embodiments, the present disclosure provides an immunogenic composition comprising: 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; 15 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier.

[0014] In some embodiments, the present disclosure provides an immunogenic composition comprising: 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; 20 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier.

[0015] In some embodiments, the present disclosure provides a vaccine composition comprising: at least 50 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; at least 5 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier. In some embodiments, the vaccine composition comprises 50 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 5 pg of the SLA adjuvant. In some embodiments, the vaccine composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 5 pg of the SLA adjuvant. In some embodiments, the vaccine composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 10 pg of the SLA adjuvant. In some embodiments, the vaccine composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 15 pg of the SLA adjuvant. In some embodiments, the vaccine composition comprises 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and 20 pg of the SLA adjuvant.

[0016] In some embodiments, the present disclosure provides a vaccine composition comprising: 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; 15 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier.

[0017] In some embodiments, the present disclosure provides a vaccine composition comprising: 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; 20 pg of an SLA adjuvant; and a pharmaceutically acceptable carrier.

[0018] In some embodiments, the SLA adjuvant has the following structure:

[0019] In some embodiments, the present disclosure provides a method of inducing an antibody response to the VZV gE antigen in a subject in need thereof, comprising administering an immunogenic composition or a vaccine composition described herein.

[0020] In some embodiments, the present disclosure provides a method of preventing reactivation of VZV in a subject in need thereof, comprising administering an immunogenic composition or a vaccine composition described herein.

[0021] In some embodiments, the present disclosure provides a method of preventing shingles in a subject in need thereof, comprising administering a immunogenic composition or a vaccine composition described herein.

[0022] In some embodiments, the immunogenic or vaccine composition is administered at least twice. In some embodiments, the second administration of the immunogenic or vaccinecomposition is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the first administration.

[0023] In some embodiments, the subject has not previously received a dose of Shingrix®. In some embodiments, the subject has previously received one or more doses of Shingrix® or Zostavax®.

[0024] In some embodiments, the subject is 50 years old, 55 years old, 60 years old, 65 years old, 70 years old, or older. In some embodiments, the subject is between 50 and 59 years old inclusive of subjects aged 50 and 59. In some embodiments, the subject is between 60 and 69 years old inclusive of subjects aged 60 and 69. In some embodiments, the subject is 50 years old or older. In some embodiments, the subject is 70 years old or older. In some embodiments, the subject is immunocompromised. In some embodiments, the administration is subcutaneous or intramuscular.BRIEF DESCRIPTION OF DRAWINGS

[0025] FIG. 1 provides magnitude of the humoral response for amezosvatein and Shingrix® treatment groups.

[0026] FIG. 2A - FIG. 2B provide secondary immunogenicity endpoint results. FIG. 2A provides the immune response fold-increase from baseline. FIG. 2B provides the vaccine response rate.

[0027] FIG. 3 shows anti-gE GMC ELISA values (y-axis) by age (x-axis).

[0028] FIG. 4 provides a summary of incidence of solicited adverse events.

[0029] FIG. 5 provides a summary of systemic adverse events.

[0030] FIG. 6 provides a summary of local adverse events.

[0031] FIG. 7 provides a summary of selected adverse events.

[0032] FIG. 8 provides a summary of the Phase 2, Cohort C treatment regimen.DETAILED DESCRIPTION

[0033] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. Specific terminology of particular importance to the description of the present invention is defined below. In this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, “a polypeptide” refers not only to a single polypeptide but also to a combination of two or more different polypeptides that may or may not be combined, “an adjuvant” refers to a single adjuvant as well as to two or more adjuvants that may be separate or combined in a single composition, and the like.Immunogenic Compositions

[0034] In some embodiments, the present disclosure provides immunogenic compositions comprising a VZV antigen and an adjuvant. As used herein, the term “immunogenic” refers to the ability of an antigen (e.g., a polypeptide), to elicit an immune response, either a humoral or cellular immune response, and preferably both. In a preferred embodiment, the subject will display either a therapeutic or protective immunological response to administration of an “effective amount” or “immunologically effective amount” of an immunogenic composition herein such that resistance to new infection will be enhanced and / or the clinical severity of the disease will be reduced. The immunological response will normally be demonstrated by alleviation or elimination of at least one symptom associated with the infection.

[0035] As used herein, the term “vaccine” refers to an immunogenic composition which is used to induce an immune response that provides protective immunity against a pathogen (e.g., immunity that protects a subject against infection with the pathogen and / or reduces the severity of the disease or condition caused by infection with the pathogen). The protective immune response may include formation of antibodies and / or a cell-mediated response.

[0036] The immunogenic compositions may further comprise one or more excipients. The excipients are immunologically and pharmacologically inert components that are “pharmaceutically acceptable.” A “pharmaceutically acceptable” component herein is one that (1) can be included in a immunogenic composition administered to a subject without causing significant unwanted biological effects or interacting in a deleterious manner with any of the other components of the formulation; and (2) meets the criteria set out in the Inactive Ingredient prepared by the U.S. Food and Drug Administration, and, preferably, has also been designated “Generally Regarded as Safe” (“GRAS”). The type of excipient or excipients incorporated into the immunogenic compositions described herein will depend, in part, on the selected mode of administration and the particular formulation type or dosage form, e.g., injectable liquid formulations, intranasal spray formulations, or the like; modes of administration and corresponding formulations are discussed infra. In general, however, inert components that can be advantageously incorporated into the immunogenic compositions described herein include, without limitation, vehicles, solubilizers, emulsifiers, stabilizers, preservatives, isotonicity agents, buffer systems, dispersants, diluents, viscosity modifiers, absorption enhancers, and combinations thereof. A thorough discussion of pharmaceutically acceptable inert additives is available in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th Ed., ISBN: 0683306472.

[0037] In some embodiments, the immunogenic compositions described herein are provided as a sterile formulation for administration to a subject, e.g., as a suspension, solution or in lyophilized form to be rehydrated prior to use.MZM antigens

[0038] As used herein, the term “antigen” refers to a substance such as a polypeptide or peptide that is capable of eliciting an immune response.

[0039] The term “polypeptide” is intended to include any structure comprised of one or more amino acids, and thus includes dipeptides, oligopeptides, polypeptides, polypeptide fragments, and proteins. The amino acids forming all or a part of a polypeptide may be any of the twenty conventional, naturally occurring amino acids, i.e., alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y), as well as non-conventional amino acids such as isomers and modifications of the conventional amino acids, e.g., D-amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, p- amino acids, constructs or structures designed to mimic amino acids (e.g., a,a-disubstituted amino acids, N-alkyl amino acids, lactic acid, p-alanine, naphthylalanine, 3-pyridylalanine, 4- hydroxyproline, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5- hydroxylysine, and nor-leucine), and other non-conventional amino acids, as described, for example, in U.S. Pat. No. 5,679,782 to Rosenberg et al. The polypeptides described herein may include one or more non-natural amino acids bearing a functional group that enables conjugation to a secondary antigen, e.g., a polysaccharide. Polypeptides can be (a) naturally occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides, such as cell-free protein synthesis.

[0040] In some embodiments, the immunogenic compositions provided herein comprise a polynucleotide encoding the VZV antigen. In some embodiments, the polynucleotide is an mRNA polynucleotide comprising an open reading frame encoding the VZV polypeptide antigen. Naturally-occurring eukaryotic mRNA molecules can contain stabilizing elements, including, but not limited to untranslated regions (UTR) at their 5’-end (5’ UTR) and / or at their 3’-end (3’ UTR), In addition to other structural features, such as a 5’-cap structure or a 3’-poly(A) tail. Both the 5’ UTR and the 3’ UTR are typically transcribed from the genomic DNA and are elements of thepremature mRNA. Characteristic structural features of mature mRNA, such as the 5’-cap and the 3’-poly(A) tail are usually added to the transcribed (premature) mRNA during mRNA processing. In some embodiments, the aforementioned mRNAs may further comprise a 5’ cap (e.g., 7mG(5’)ppp(5’)NlmpNp), a polyA tail (e.g., ~100 nucleotides), or a 5’ cap and a polyA tail.

[0041] “Polynucleotides” comprise a polymer of nucleotides (nucleotide monomers). Polynucleotides may be or may include, for example, deoxyribonucleic acids (DNAs), ribonucleic acids (RNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a [3-D-ribo configuration, a-LNA having an a-L-ribo configuration (a diastereomer of LNA), 2’-amino-LNA having a 2’-amino functionalization, and 2’-amino-a-LNA having a 2’-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) and / or chimeras and / or combinations thereof.

[0042] Messenger RNA (mRNA) is any ribonucleic acid that encodes a (at least one) protein (a naturally-occurring, non-naturally-occurring, or modified polymer of amino acids) and can be translated to produce the encoded protein in vitro, in vivo, in situ, or ex vivo. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application may recite “T”'s in a representative DNA sequence but where the sequence represents RNA (e.g., mRNA), the “T”'s would be substituted for “U”s.

[0043] An open reading frame (ORF) is a continuous stretch of DNA or RNA beginning with a start codon (e.g., methionine (ATG or AUG)) and ending with a stop codon (e.g., TAA, TAG or TGA, or UAA, UAG or UGA). An ORF typically encodes a protein. It will be understood that the polynucleotide sequences referenced herein may further comprise additional elements, e.g., 5' and 3' UTRs, but that those elements, unlike the ORF, need not necessarily be present in an immunogenic composition of the present disclosure.

[0044] The terms “sequence identity,” “percent sequence homology,” and “sequence homology,” in the context of a polypeptide sequence, refer to two or more sequences that are the same or have a specified percentage of amino acid residues (or nucleotides) that are the same, when compared and aligned for maximum correspondence over a given length (comparison window), as measured using a sequence comparison algorithm, e.g., BLASTP or the Smith- Waterman homology search algorithm. In the present context, the percent sequence homology may be determined over the full-length of the polypeptide or just a portion. One method for calculating percent sequence homology is the BLASTP program having its defaults set at a wordlength (W) of 3, an expectation (E) of I 0, and the BLOSUM62 scoring matrix; see, e.g., Henikoff et al. (1989) Proc. Natl. Acad. Sci. USA 89:10915. Exemplary determination of sequencealignment and % sequence identity employs the BESTFIT or GAP programs in the GOG Wisconsin Software package (Accelrys, Madison Wis.), using the default parameters provided. If these preferred methods of calculating sequence identity give differing amounts, the method giving the higher sequence identity controls. The term “substantially homologous” refers to a percent sequence homology over a given length (e.g., “x” amino acids of a polypeptide) of at least about 50%, thus including, for example, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, and 100%.

[0045] In some embodiments, the present disclosure provides a purified polypeptide antigen. As used herein, when the term “purified” is used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to the concentration of the molecule in its natural environment. The term may also refer to purification of a chemically synthesized molecule from a reaction mixture in which the molecule has been generated as a reaction product. As used herein, when the term “isolated” is used in reference to a molecule, the term means that the molecule has been removed from its native environment. For example, a polynucleotide or a polypeptide naturally present in a living organism is not “isolated,” but the same polynucleotide or polypeptide separated from the coexisting materials in its natural state is “isolated.” An isolated moiety, whether separated from a native environment or from a non-natural environment (e.g., recombinant expression, cell-free expression, chemical synthesis, etc.), is preferably at least about 1 % pure, 5% pure, 10% pure, 20% pure, 30% pure, 40% pure, 50% pure, 60% pure, 70% pure, 80% pure, 90% pure, 95% pure, or 99% pure, or they may be 100% pure. As used herein, the term “% pure” indicates the percentage of a composition that is made up of the molecule of interest, by weight.

[0046] In some embodiments, the VZV antigen is a truncated form of the gE protein. In some embodiments, the truncated form of the gE protein is selected from those listed in Table 1. In particular embodiments, the immunogenic compositions described herein comprise the gE antigen of SEQ ID NO: 1 , wherein the signal peptide has been cleaved from the antigen polypeptide sequence. In particular embodiments, the immunogenic compositions described herein comprise the gE antigen of SEQ ID NO: 2. The signal peptide sequence of SEQ ID NO: 1 is shown in bold and underlined text. Additional gE antigens are described in the art. See e.g., SEQ ID NO: 3 of US 2006 / / 121052, and SEQ ID NO: 1 of WO 2006 / 094756.Table 1: Exemplary VZV gE AntigensAdjuvants

[0047] In some embodiments, the immunogenic composition further comprises one or more adjuvants. As used herein, the term “adjuvant” refers to a compound that, when used in combination with an antigen, augments the immune response to one or more antigens in the immunogenic composition. Augmentation of the immune response may include increasing the antibody titers raised against the one or more antigens, increasing the clonality of the antibody response against the one or more antigens, increasing the intensity of the cellular immune response (e.g.^ increased memory T cell formation, increased acute cytokine production), and / or diversification of the cellular immune response (e.g., increasing the number of different types of cytokines produced, increasing proliferation of one or more T cell phenotypes, etc.).

[0048] Representative major adjuvant groups suitable for use in the present immunogenic compositions are as follows:(a) Mineral salt adjuvants’, including alum-based adjuvants such as aluminum phosphate, aluminum hydroxide, aluminum sulfate, aluminum hydrophospho sulfate as well as other mineral salt adjuvants such as the phosphate, hydroxide, and sulfate salts of calcium, iron,and zirconium. Such adjuvants also include Nano Alum (Lu Y, Liu G. Nano alum: A new solution to the new challenge. Hum Vaccin Immunother. 2022 Nov 30; 18(5));(b) Saponin formulations', including the Quillaia saponin Quil A and the Quil A-derived saponin QS-21 , Matrix-M™ (Novavax), as well as immune stimulating complexes (ISCOMs) formed upon admixture of cholesterol, phospholipid, and a saponin;(c) Bacteria-derived and bacteria-related adjuvants’, including, without limitation, cell wall peptidoglycans and lipopolysaccharides derived from Gram negative bacteria such as Mycobacterium spp., Corynebacterium parvum, C. granulosum, Bordetella pertussis, and Neisseria meningitis, such as Lipid A, monophosphoryl Lipid A (MPLA, also referred to as MPL), other Lipid A derivatives and mimetics (e.g., RC529), enterobacterial lipopolysaccharide (“LPS”), TLR4 ligands, and trehalose dimycolate (“TDM”);(d) Muramyl peptides’, such as N-acetyl muramyl-L-alanyl-D-isoglutamine (“MDP”) and MDP analogs and derivatives, e.g., threonyl-MDP and nor-MDP;(e) Oil-based adjuvants’, including oil-in-water (O / W) and water-in-oil (W / O) emulsions, such as squalene-water emulsions (e.g., MF59® (also known as MF59C.1), AS03, AF03), complete Freund’s adjuvant (“CFA”) and incomplete Freund’s adjuvant (“IFA”);(f) Liposome adjuvants’. Microsphere adjuvants formed from biodegradable and nontoxic polymers such as a poly(a-hydroxy acid), a poly(hydroxy butyric) acid, a polyorthoester, a polyanhydride, a polycaprolactone, etc.;(g) Nanostructured lipid carriers (NLCs)’. Hybrid formulation between oil-in-water (o / w) emulsions and solid lipid nanoparticles (SLNs). The nanoparticle core consists of a liquid oil phase, such as squalene, with a solid phase lipid composed of a saturated triglyceride (Erasmus et al., A Nanostructured Lipid Carrierfor Delivery of a Replicating Viral RNA Provides Single, Low- Dose Protection against Zika. Mol Ther. 2018 Oct 3;26(10):2507-2522).(h) Human immunomodulators', including cytokines, such as interleukins (e.g. IL-1 , IL- 2, IL-4, IL-5, IL-6, IL-7, IL-12), interferons (e.g. interferon-y), macrophage colony stimulating factor, and tumor necrosis factor;(i) Bioadhesives and mucoadhesives'. such as chitosan and derivatives thereof and esterified hyaluronic acid and microspheres or mucoadhesives, such as cross-linked derivatives of poly(acrylic acid), polyvinyl alcohol, polyvinyl pyrrolidone, polysaccharides and carboxymethylcellulose;(j) Imidazoquinolone compounds’, including Imiquamod and homologues thereof, e.g., Resiquimod;(k) TLR-9 agonists’, such as Hsp90 and oligodeoxynucleotides containing unmethylated CpG motifs (see, e.g., Bode et al. (2011) Expert Rev. Vaccines 10(4): 499-511). Additional TLR-9 agonists include CpG 1018®, which is a 22-mer oligonucleotide sequences containing CpG motifs that are active in both human and rodents, and PF-03512676 (also known as CpG oligonucleotide 7909), which is a 24mer oligonucleotide; and(l) Carbohydrate adjuvants’, including the inulin-derived adjuvants gamma inulin and algammulin, and other carbohydrate adjuvants such as polysaccharides based on glucose andmannose, including glucans, dextrans, lentinans, glucomannans, galactomannans, levans, and xylans.(m) Synthetic derivatives:(i) GLA - a synthetic lipid A derivative and a TLR4 agonist (Coler et al. A synthetic adjuvant to enhance and expand immune responses to influenza vaccine. PLoS One. 2010;5:e13677). GLA can be provided as a squalene oil-in-water emulsion formulation, formulated in QS-21 containing liposomes (GLA-LSQ), or an aqueous formulation (GLA-AF);(ii) SLA - a second-generation lipid adjuvant (SLA) is a synthetic hexa-acylated lipid. See U.S. 10,632,191 ; U.S. 9,480,740; U.S. 9,814,772; U.S. 8,722,064; and U.S. 10,940,198, each incorporated herein by reference. The structure of SLA is provided as Formula (I) below. SLA can be provided as a squalene oil-in-water emulsion formulation (SLA-SE), formulated in QS-21 containing liposomes (SLA-LSQ), or an aqueous formulation (SLA-AF);(iii) 3M-052 - a synthetic TLR7 / 8 ligand (D. Smirnov et al., Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction, Vaccine, 29 (33) (2011), pp. 5434-5442. Can be provided in a in squalene nanoemulsion (3M-052-SE), adsorbed to aluminum (3M-052-Alum), or as an aqueous formulation (3M-052-AF)

[0049] In some embodiments, the immunogenic composition comprises a combination of one or more adjuvants. The combination of the one or more adjuvants can be of the same group (e.g. one or more TLR agonists or one or more carbohydrate antigens) or of different groups (e.g. , one or more TLR agonists and one or more carbohydrate adjuvants). In some embodiments, the immunogenic composition comprises one or more adjuvants comprising a saponin (e.g., QS-21) and a bacteria derived adjuvant (e.g., MPL).

[0050] In some embodiments, the adjuvant is an AS01 adjuvant (e.g., AS01 E or AS01 B), which is a combination of MPL and QS-21 encapsulated in a liposome. The AS01 adjuvants are composed of 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota and QS- 21 , a saponin purified from plant extract Quillaja Saponaria Molina, combined in a liposomal formulation. The liposomes are composed of dioleoyl phosphatidylcholine (DOPC) and cholesterol in a phosphate-buffered saline solution containing disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, and water for injection.

[0051] In some embodiments, the adjuvant is SLA and has the following structure:(Formula I)

[0052] or a pharmaceutically acceptable salt thereof.

[0053] The SLA adjuvant can generally be utilized as the free base or free acid. Alternatively, the SLA adjuvant can may be used in the form of an acid or base addition salt. Acid addition salts of the free amino compounds of SLA may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.

[0054] Similarly, base addition salts of the acid compounds of SLA may be prepared by methods well known in the art, and may be formed from organic and inorganic bases. Suitable organic bases include, but are not limited to, triethylamine and pyridine. Suitable inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and ammonia. Thus, the term “pharmaceutically acceptable salt” of Formula (I) is intended to encompass any and all acceptable salt forms. In some embodiments, the inorganic base addition is ammonia.

[0055] In some embodiments, the SLA adjuvant of Formula (I) is a pharmaceutically acceptable salt. In some embodiments, the SLA adjuvant of Formula (I) is an ammonium salt. In some embodiments, the SLA adjuvant of Formula (I) is a pharmaceutically acceptable salt having a representative structure:(Formula II).Exemplary compositions

[0056] In some embodiments, the immunogenic composition or vaccine comprises the VZV gE antigen of SEQ ID NO: 2, an SLA adjuvant of Formula II, and squalene. Such a composition is also referred to as amezosvatein or CRV-101. In some embodiments, the immunogenic composition or vaccine comprises 80 pg, 85 pg, 90 pg, 95 pg, 100 pg, 105 pg, 110 pg, or 115 pg of the VZV gE antigen of SEQ ID NO: 2. In some embodiments, the immunogenic composition or vaccine comprises 5 pg, 10 pg, 15 pg, or 20 pg of the SLA adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 100 pg of SEQ ID NO: 2, 15 pg of the SLA adjuvant of Formula II, and squalene. In some embodiments, the immunogenic composition or vaccine comprises 100 pg of SEQ ID NO: 2, 20 pg of the SLA adjuvant of Formula II, and squalene.

[0057] In general, the SLA-SE adjuvant comprises the SLA adjuvant of Formula II admixed with squalene oil, other excipients, and sterile Water-for-lnjection to provide SLA-SE. SLA-SE is also referred to as AP 20-201. In some embodiments, SLA-SE adjuvant is formulated as about 10 pg / mL SLA (Formula II) in about 2% squalene oil-in-water emulsion (10 pg / mL SLA-SE). In this application, the weight of SLA-SE refers to the weight of SLA. In some embodiments, SLA-SE is formulated at about 15 pg / mL SLA in about 3.6% squalene oil-in-water emulsion (15 pg / mL SLA- SE). In some embodiments, SLA-SE is formulated at about 20 pg / mL SLA in about 4% squalene oil-in-water emulsion (20 pg / mL SLA-SE).

[0058] In some embodiments, the immunogenic composition or vaccine comprises 115 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 110 pg of the VZV gE antigen of SEQ ID NO: 1 , and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 105 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 100 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 95 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 90 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 85 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 80 pg of the VZV gE antigen of SEQ ID NO: 2, and 10 pg, 15 pg, or 20 pg of the SLA-SE adjuvant.

[0059] In some embodiments, the immunogenic composition or vaccine comprises 100 pg of the VZV gE antigen of SEQ ID NO: 2 and 15 pg of the SLA-SE adjuvant. In some embodiments, the immunogenic composition or vaccine comprises 100 pg of the VZV gE antigen of SEQ ID NO: 2 and 20 pg of the SLA-SE adjuvant.

[0060] Exemplary combinations of gE antigen and SLA amounts are provided in Table 2.Table 2: Exemplary gE and SLA amounts and ratiosAdministration and Use

[0061] In some embodiments, the present disclosure provides a method of preventing herpes zoster in a subject in need thereof comprising administration of an effective amount immunogenic composition or vaccine composition described herein. “Prevention,” as used herein, is used interchangeably with “prophylaxis” and can mean complete prevention of an infection or disease, or prevention of the development of symptoms of that infection or disease; a delay in the onset of an infection or disease or its symptoms; or a decrease in the severity of a subsequently developed infection or disease or its symptoms. In some embodiments, the present disclosure provides a method for reducing the risk of herpes zoster in a subject in need thereof comprising administering an effective amount of the immunogenic compositions described herein.

[0062] In some embodiments, the present disclosure provides methods for inducing a protective immune response against herpes zoster in a subject comprising administering to the subject an effective amount of the immunogenic or vaccine compositions described herein. In some embodiments, the protective immune response is indicated by an increase in anti-VZV gE antibody titers.

[0063] The terms “treat,” “treatment,” and “treating,” as used herein, refer to an approach for obtaining beneficial or desired results, for example, clinical results. For the purposes of this disclosure, beneficia or desired results may include inhibiting or suppressing the initiation orprogression of an infection or a disease; ameliorating, or reducing the development of, symptoms of an infection or disease; or a combination thereof.

[0064] As used herein, the term “subject” includes humans and other animals. Typically, the subject is a human. In some embodiments, the subject is 50 years aged or older. In some embodiments, the subject is 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80 years aged or older. In some embodiments, the subject is 55 years or older. In some embodiments, the subject is 60 years or older. In some embodiments, the subject is 65 years or older. In some embodiments, the subject is 70 years or older. In some embodiments, the subject is 75 years or older. In some embodiments, the subject is between 50 and 59 years old (inclusive of subjects aged 50 and 59). In some embodiments, the subject is between 50 and 69 years old (inclusive of subjects aged 50 and 69). In some embodiments, the subject is between 60 and 69 years old (inclusive of subjects aged 60 and 69). In some embodiments, the subject is 70 years old or older. In some embodiments, the subject has had a prior VZV infection. In some embodiments, the subject has received one or more doses of Shingrix®. In some embodiments, the subject has received one or more doses of Zostavax®. In other aspects, the subject is not a human; for example a non-human primate; for example, a baboon, a chimpanzee, a gorilla, or a macaque.

[0065] In some embodiments, the subject is predisposed to herpes zoster as a result of any number of risk factors, including age and / or whether or not the subject is immunocompromised. In some embodiments, the subject is immunocompromised.

[0066] The “immunologically effective amount” or “effective amount” of the immunogenic or vaccine composition is an amount that, either as a single dose or as part of a series of two or more doses, is effective for preventing herpes zoster. Herein, the term “protective immune response” encompasses eliciting an anti-VZV antibody response in the subject. Antibody titers generated after administration of the immunogenic compositions described herein can be determined by means known in the art, for example by ELISA assays of serum samples derived from immunized subjects.

[0067] Administration of the immunogenic composition can be carried out using any effective mode of systemic delivery. The composition is usually administered parenterally, such as by injection, including intravenous, intramuscular, intraperitoneal, interstitial, or subcutaneous injection; injection may also be gingival, in which case the immunogenic composition is injected directly into the gum. The composition may, in addition, be administered transmucosally, such as via the intranasal, sublingual, transbuccal, intravaginal, or intrarectal routes. Other modes ofadministration are also envisioned, however, and the invention is not limited in this regard. By way of example, other modes of administration include oral and transdermal delivery as well as administration via inhalation or using a subdermal implant.

[0068] The mode of administration largely dictates the type of formulation or dosage form that comprises the immunogenic composition. Compositions formulated for parenteral administration include sterile aqueous and nonaqueous solutions, suspensions, and emulsions. Injectable aqueous solutions contain the active agent in water-soluble form. Examples of nonaqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like. Parenteral formulations may also contain excipients such as solubilizers, emulsifiers, stabilizers, preservatives, isotonicity agents, buffer systems, dispersants, diluents, viscosity modifiers, absorption enhancers, and combinations thereof. Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium. The immunogenic composition or individual components thereof may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.

[0069] Of the transmucosal routes, intranasal administration is generally although not necessarily preferred. Intranasal formulations, including intranasally administered immunogenic compositions, are known in the art, and should be formulated with reference to the FDA’s Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products. Intranasal formulations are liquids, i.e., solutions, emulsions, suspensions, or the like, for administration as sprays, intranasal injections, or drops, and can contain adjuvants and pharmaceutically acceptable excipients as above. Because of the relatively large size of the antigens in the formulation, systemic delivery via the intranasal route requires incorporation of a transmucosal absorption enhancer in the immunogenic composition. Examples of suitable transmucosal absorption enhancers include, without limitation, alkylsaccharides, cyclodextrins, and chitosans; see Maggio (2014) J. Excip. Food Chem. 5(2): 100-12; and Merkus et al. (1999) Adv. Drug Deliv. Rev. 36: 41-57. The concentration of enhancer is selected to ensure that an immunologically effective amount of the formulation passes through the nasal membrane and into the systemic circulation at an efficient transport rate. Various anatomical and physiological considerations dictating the composition and nature of an intranasal immunogenic compositionare discussed, for example, by Aurora (October 2002) Drug Development & Delivery 2(7), incorporated by reference herein.

[0070] Other modes of administration and corresponding formulations include, without limitation: sublingual administration with a rapidly dissolving dosage form such as a rapidly dissolving tablet; transbuccal administration using a buccal patch or other buccal delivery system; intravaginal administration using a pessary, ointment, or cream; intrarectal delivery using a rectal suppository, ointment, or cream; transdermal administration using a transdermal patch or formulation; subdermal administration with an injected implant or pellet; inhalation using a dry powder pulmonary formulation; and oral administration using an oral dosage form such as a tablet, capsule, or the like.

[0071] In some embodiments, the immunogenic composition is administered to a subject within the context of an appropriate dosage regimen. The composition may be administered once, or two or more times spaced out over an extended time period. For example, an initial, “prime” dose may be followed by at least one “boost” dose. In some embodiments, the methods provided herein comprise two or more administrations of the immunogenic compositions described herein. In some embodiments, the second administration of the immunogenic or vaccine composition is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is at least 50, at least 51 , at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, or at least 60 days after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, or 60 days after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is 55 days after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is 56 days after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is 57 days after the first administration. In some embodiments, the second administration of the immunogenic or vaccine composition is 58 days after the first administration.

[0072] Regardless of the mode of administration, e.g., intramuscular injection or subcutaneous injection, or the like, the volume of a single dose of the vaccine will generally be in the range of about 1 pL to about 500 pL. In some embodiments, the volume is in the range of about 1 pL to about 250 pL. In some embodiments, the volume is in the range of about 2.5 pL to about 200 pL. In some embodiments, the volume is in the range of about 5 pL to about 150 pL.It will be appreciated that the concentration of total antigen in the immunogenic composition corresponds to an immunologically effective dose of the composition per unit volume, working from the aforementioned dose volume guidelines.

[0073] For ease of use, the immunogenic composition of the invention can be incorporated into a packaged product, or “kit,” including instructions for self-administration or administration by a medical practitioner. The kit includes a sealed container housing a dose of the immunogenic composition, typically a “unit dose” appropriate for a single dosage event that is immunologically effective. The vaccine may be in liquid form and thus ready to administer as an injection or the like, or it may be in another form that requires the user to perform a preparation process prior to administration, e.g., hydration of a lyophilized formulation, activation of an inert component, or the like. The kit may also include two or more sealed containers with the prime dose in a first container and a boost dose in one or more additional containers.

[0074] It is to be understood that while the invention has been described in conjunction with a number of specific embodiments, the foregoing description as well as the experimental section that follows are intended to illustrate and not limit the scope of the invention. In this regard, no attempt is made to show details of the invention in more detail than is necessary for the fundamental understanding of the invention, the description taken with the drawings and / or examples making apparent to those skilled in the art how the invention may be embodied in practice. This disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the elements of the invention described herein are encompassed by the disclosure unless otherwise indicated herein or clearly contradicted by context.INCORPORATION BY REFERENCE

[0075] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.EXAMPLESExample 1: Phase 2 Study to Assess the Safety and Immunogenicity of CRV-101 Vaccine Head-to-Head with Shingrix® for the Prevention of Herpes Zoster in Adults >50 Years of Age

[0076] Amezosvatein safety, tolerability, and immunogenicity of 6 different dose combinations and antigen alone, versus placebo, was evaluated in a 90-participant Phase 1 clinical trial in a population of healthy adults, 18 to < 50 years of age. The vaccine was safe and well-tolerated in healthy adult participants at either dose level of SLA-SE (5 or 10 pg) in combination with 25, 50, or 100 pg of antigen. Amezosvatein elicited a robust humoral immune response and increased frequencies of CD4+ T cells expressing one or more cytokines among CD154, IFNy, TNFa, and IL-2 by ICS after peripheral blood mononuclear cells (PBMC) were stimulated with gE peptide in healthy adults. On the basis of the observed safety, tolerability and immunogenicity data from the Phase 1 study, a Phase 2 study was initiated by studying two different antigen dose levels of Amezosvatein. Low-Dose antigen (50pg MG1120 + 5pg SLA-SE) vs. High-Dose antigen (100pg MG 1120 + 5pg SLA-SE) were tested in a 1 :1 :1 randomization against Shingrix.

[0077] The Phase 2 Trial 1 enrolled Cohort 1 with 678 participants in a randomized, observerblind study to evaluate the safety, tolerability and immunogenicity of the Low and High dose antigen arms of Amezosvatein compared to Shingrix in participants 50 years of age and older. Participants received vaccinations on Days 0 and 56. The safety and tolerability of both antigen dose levels of Amezosvatein as well as the comparator, Shingrix, will be observed throughout the study duration. Immunogenicity is measured primarily by Day 84 anti-gE ELISA antibody GMC (geometric mean concentration) responses and VRR (vaccine response rate). Secondarily, the immunogenicity in each arm is measured by anti-VZV neutralizing antibody, CMI (cell mediated immunity) consisting of gE specific CD4+ T cell frequency and VRR, and anti-gE ELISA antibody concentration fold rise.

[0078] Safety and immunogenicity endpoints in Cohort 1 were analyzed at Day 84. The Day 84 analysis was utilized to determine the Amezosvatein vaccine dose selected for future clinical development and determine if the criteria for non-inferiority of Amezosvatein compared to Shingrix were met.

[0079] The Amezosvatein Phase 2 Cohort 1 Day 84 data for safety, tolerability, and immunogenicity demonstrated the following summary points:(a) The safety and tolerability data demonstrate a favorable safety profile when compared with Shingrix for all solicited local and systemic reactogenicity in both Low Dose and High Dose antigen cohorts and across all age subgroups.(b) At Day 84, the High Dose and Low Dose antigen arms of Amezosvatein were noninferior compared to Shingrix with regards to anti-gE antibody vaccine response rate (VRR).(c) A robust anti-gE antibody Geometric Mean Fold Rise (GMFR) >20 compared to Day 0, in both Low Dose and High Dose antigen cohorts and within each age subgroup consistent with a strong humoral response post vaccination.(d) The Day 84 anti-gE antibody GMC responses were higher in the High Dose antigen arm vs. the Low Dose antigen arm.(e) The Day 84 anti-gE antibody GMC responses were less than Shingrix in both Low Dose and High Dose antigen arms and did not achieve the non-inferiority threshold.(f) An age-related decrease was observed in the Day 84 anti-gE antibody GMC responses across the three age subgroups of 50-59; 60-69; and 70+.(g) The Day 84 anti-gE antibody GMC responses for Phase 2 Cohort 1 in both antigen dose arms were lower than what had been seen in comparable dose cohorts in the Phase 1 CRV- 101-100 Study.

[0080] An analysis of the Phase 2 Cohort 1 data identified two primary explanations for the anti- gE antibody GMC data findings:(a) The observed age-related decrease in Day 84 anti-gE antibody GMC values suggests a significant contribution by immune-senescence.(b) The Phase 2 Cohort 1 the Amezosvatein Investigational Product contained an adjuvant formulation that had comparable levels of SLA to the Phase 1 study but a significant reduction in the squalene content.

[0081] These findings supported the Study Amendment to add three additional CRV-101 subject cohorts (Cohorts 2, 3, & 4), each receiving Amezosvatein containing High Antigen Dose (100 pg MG1120) plus one of three adjuvant SLA-SE doses of 5 pg, 10 pg, and 15 pg respectively. The squalene amount in the formulation for 5pg and 10pg SLA-SE was comparable to the Phase 1 formulation. Subjects in the 50-59 and 60-69 year old age subgroups were enrolled in the Amendment #3 (Cohorts 2, 3, and 4). Subjects in the 70+ year-old age subgroup were not enrolled in the Amendment #3 cohorts. Safety and tolerability would be monitored in the same manner as cohort 1. All subjects enrolled under Amendment #3 will be followed to Day 421 and may continue in the same Long Term Follow-up Extension as Cohort 1.

[0082] The results of this amendment are intended to facilitate insight into the following:(a) The effect of higher adjuvant SLA doses to overcome immune-senescence(b) The effect of higher adjuvant SLA doses on safety and reactogenicity(c) The contribution of squalene to immunogenicity

[0083] A summary of the cohorts and study arms is provided in Table 3 below.Table 3: Study Arms

[0084] Cohort 1 comprised of fixed adjuvant dose (5pg SLA) with two antigen doses (50pg (1 B) and 100pg (1A) of MG1120 gE antigen) and Cohort 2 / 3 / 4 comprised fixed antigen dose (100pg MG1120) with three adjuvant doses (5pg (4A), 10pg (2A), and 15pg (3A) of SLA).

[0085] In Cohort 1 , the immunogenicity objective was to demonstrate Amezosvatein Vaccine noninferiority to Shingrix based on humoral immune responses and to evaluate safety and reactogenicity of two antigen dose levels of Amezosvatein compared to Shingrix in healthy adult participants >50 years of age. Non-inferiority was based on the co-primary endpoints of Month 3 anti-gE ELISA antibody concentration and vaccine response defined as a 4-fold or greater increase in anti-gE ELISA antibody concentrations from baseline to Month 3. The study is designed to rule out a 33% or greater relative decrease in the Month 3 anti-gE ELISA geometric mean concentration and to rule out a 10% or greater absolute decrease in the vaccine response rate. Anti-VZV neutralizing antibody and cell-mediated immunity responses will be evaluated as a secondary endpoint.

[0086] In Cohorts 2, 3, and 4 the immunogenicity objective is to identify an adjuvant dose that is more immunogenic than the 100 pg MG1120 + 5 pg SLA-SE formulation from Cohort 1 and has an immune response that is non-inferior to the Shingrix vaccine pooled from Cohort 1 through 4 in subjects 50 - 69 years of age. A given adjuvant dose was considered superior to the high antigen dose Cohort 1 formulation if the lower bound of the two-sided 80% confidence interval for the ratio of Day 84 anti-gE antibody GMC of new to old vaccine (Cohort 1 , High Antigen Dose) was greater than 1.0. A given adjuvant dose was considered non-inferior to pooled Cohort 1-4 Shingrix, in the 50-69 age group, if the lower bound of the two-sided 80% confidence interval for the ratio of Day 84 anti-gE antibody GMC of the adjuvant dose to pooled Cohort 1 -4 Shingrix was greater than 0.67. Anti-VZV neutralizing antibody and cell-mediated immune responses may beevaluated in one or more doses from cohorts 2, 3 or 4 to support the evaluation of the appropriate dose for further clinical development after anti-gE antibody results are evaluated.

[0087] Cohort 1 participants are randomized 1 :1 :1 to CRV-101 Vaccine high antigen dose (100pg MG1120 + 5pg SLA-SE), CRV-101 Vaccine low antigen dose (50pg MG1120 + 5pg SLA-SE), or Shingrix. Both study vaccines, CRV-101 Vaccine and Shingrix, were administered by intramuscular injection on Day 0 and Day 56. Safety, reactogenicity, and immunogenicity analysis is ongoing and performed overall and by age group of 50 to <60, 60 to <70, and >70 years of age.

[0088] Cohort 2, 3, and 4 were designed to evaluate the safety, tolerability, and immunogenicity of the High Antigen (100pg MG1120) dose component with three adjuvant dose levels (SLA 10pg, 15pg, and 5pg with increased SE component (containing 20 pL, 30 pL, and 20 pL squalene respectively). Participants were healthy adults aged >50 to <70 years of age, randomized 5:1 to arms within each cohort, CRV-101 Vaccine to Shingrix, and dosed with intramuscular injections on Day 0 and 56. Approximately 50% of each Cohort were >50 to <60, and >60 to <70.

[0089] Safety, reactogenicity and immunogenicity analysis were performed overall, by cohort, and grouped by 50 to <60, 60 to <70 years of age.

[0090] In Cohorts 1-4, participants were followed for safety, immunogenicity, and herpes zoster cases, from Day 0 to Day 421 [Month 14], and up to 5 additional years in the long term follow up (LTFU) extension period (LTFU year 2, 3, 4, 5, 6). Safety in the extension years consists of collection of SAEs and PIMMCs, and herpes zoster cases.Results

[0091] Results for the high dose antigen arm (100 pg gE + 5 pg SLA - Cohort 3A) compared to Shingrix are shown in FIG. 1 - FIG. 7. As shown, Cohort 3A demonstrated a non-inferior immune response to Shingrix.

[0092] FIG. 1 shows that the primary immunogenicity endpoint of the magnitude of the humoral immune response was met and Amezosvatein demonstrated a non-inferior immune response to Shingrix. Similar results were achieved for the immune response increase from baseline (Geometric Mean Fold Rise - FIG. 2A) and Vaccine response rate (FIG. 2B - threshold of success defined as >4-fold rise in Geometric Mean Fold Rise (GMFR) in antibody response compared to pre-vaccination). Furthermore, plotting the anti-gE GMC ELISA values by age shows that there was no decline in the antibody response by age (FIG. 3).

[0093] Furthermore, amezosvatein demonstrated an increase in tolerability, as indicated by a decrease in the reported adverse events. A summary of solicited systemic adverse events is provided in Table 4 and local adverse events in Table 5.Table 4: Solicited Systemic Adverse Events by GradeTable 5: Solicited Local Adverse Events by Grade

[0094] As shown in FIG. 4-FIG. 7, Amezosvatein has reduced adverse events vs. Shingrix within 7 days of either dose. FIG. 4 shows the difference in all solicited adverse event, with a specific comparison of grade 2 / 3 adverse events between the two groups. FIG. 5 shows the comparisons for systemic adverse events. FIG. 6 shows the comparisons for local adverse events. FIG. 7 shows comparisons between specific types of adverse events. In each comparison, Amezosvatein demonstrated reduced adverse events compared to those reported with Shingrix.

[0095] An additional Part C cohort of the Phase 2 trial was added to assess increasing concentrations of the SLA-SE adjuvant. Part C cohorts are summarized below. See also FIG. 8.

[0096] Part C cohorts will be evaluated on the same metrics as the Part A and B cohorts described above including anti-gE antibody and anti-VZV neutralizing antibody responses and Anti-gE CD4 T-cell responses.Example 2: A Study to Evaluate Amezosvatein Compared with Shingrix® in Adults >50 Years of Age

[0097] A randomized, observer-blind, parallel group, active comparator, multi-center, Phase 3 study is planned to determine the immunogenicity and safety of amezosvatein compared to Shingrix. Participants >50 years of age will be enrolled. Participants >65 years of age will represent a minimum of 25% and a maximum of 30% of the total population enrolled, and participants >70 years of age will represent 10% of the total population enrolled.

[0098] Participants will be randomized in a 1 :1 ratio to receive amezosvatein or Shingrix. Randomization will be stratified by age and country. Each participant will receive 2 doses of vaccine: the first on Day 1 , and the second on Day 57.

[0099] The total duration of the study for each participant is up to 226 days, including Screening on Day -1 and / or Day 1 , vaccine administration on Day 1 and Day 57, and follow-up visits through Month 8 (Day 225). The study includes the following visits for each participant: clinic visits on Day -1 (if screening begins on Day -1), Day 1 , Day 57, Day 85, and Day 225, and telephone contacts on Day 8, Day 29, Day 64, Day 113, and Day 169.

[0100] Serum will be collected at Day 1 and Day 85 from all participants for immunology assessments. Peripheral blood mononuclear cells will be collected at Day 1 and Day 85 from a subset of approximately 50% study participants and will be stored for potential exploratory analysis.

[0101] An eDiary will be used to solicit local and systemic reactogenicity AEs for 7 days after each study vaccine injection; unsolicited symptoms will be assessed for 28 days after each study vaccine injection. SAEs and PIMMCs will be recorded and monitored from the time of signing theinformed consent through the end-of-study (EOS) or early discontinuation. MAAEs will be monitored from Day 1 post vaccination through the EOS or early discontinuation.

[0102] Between approximately 550 and 750 participants will be enrolled. This represents a planned overall power of 90% or greater to confirm non-inferiority in anti-gE ELISA antibody GMO ratio of amezosvatein vs. Shingrix.

[0103] Study arms of the Phase 3 trial are summarized in Table 6.Table 6: Study summary

Claims

CLAIMS1 . An immunogenic composition comprising: a. at least 50 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. at least 5 pg of an SLA adjuvant; and c. a pharmaceutically acceptable carrier.

2. The immunogenic composition of claim 1 , comprising a. 50 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 5 pg of the SLA adjuvant3. The immunogenic composition of claim 1 , comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 5 pg of the SLA adjuvant4. The immunogenic composition of claim 1 , comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 10 pg of the SLA adjuvant5. The immunogenic composition of claim 1 , comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 15 pg of the SLA adjuvant.

6. The immunogenic composition of claim 1 , comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 20 pg of the SLA adjuvant.

7. An immunogenic composition comprising: a. 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. 15 pg of an SLA adjuvant; and c. a pharmaceutically acceptable carrier.

8. An immunogenic composition comprising: a. 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. 20 pg of an SLA adjuvant; andc. a pharmaceutically acceptable carrier.

9. A vaccine composition comprising: a. at least 50 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. at least 5 pg of an SLA adjuvant; and c. a pharmaceutically acceptable carrier.

10. A vaccine composition of claim 9, comprising a. 50 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 5 pg of the SLA adjuvant11. A vaccine composition of claim 9, comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 5 pg of the SLA adjuvant12. A vaccine composition of claim 9, comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 10 pg of the SLA adjuvant13. A vaccine composition of claim 9, comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 15 pg of the SLA adjuvant.

14. A vaccine composition of claim 9, comprising a. 100 pg of the VZV gE antigen comprising SEQ ID NO: 2; and b. 20 pg of the SLA adjuvant.

15. A vaccine composition comprising: a. 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. 15 pg of an SLA adjuvant; and c. a pharmaceutically acceptable carrier.

16. A vaccine composition comprising: a. 100 pg of a Varicella Zoster Virus (VZV) glycoprotein E (gE) antigen comprising SEQ ID NO: 2; b. 20 pg of an SLA adjuvant; andc. a pharmaceutically acceptable carrier.

17. The immunogenic composition of any one of claims 1-8 or the vaccine composition of any one of claims 9-16, wherein the SLA adjuvant has the following structure:

18. A method of inducing an antibody response to the VZV gE antigen in a subject in need thereof, comprising administering the immunogenic composition of any one of claims 1-8 or the vaccine composition of any one of claims 9-15.

19. A method of preventing reactivation of VZV in a subject in need thereof, comprising administering the immunogenic composition of any one of claims 1-8 or the vaccine composition of any one of claims 9-15.

20. A method of preventing shingles in a subject in need thereof, comprising administering the immunogenic composition of any one of claims 1-8 or the vaccine composition of any one of claims 9-17.

21. The method of any one of claims 18-20, comprising administering the immunogenic or vaccine composition at least twice.

22. The method of claim 21 , wherein the second administration of the immunogenic or vaccine composition is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after the first administration.

23. The method of any one of claims 18-22, wherein the subject has not previously received a dose of Shingrix®.

24. The method of any one of claims 18-22, wherein the subject has previously received one or more doses of Shingrix® or Zostavax®.

25. The method of any one of claims 18-24, wherein the subject is 50 years old, 55 years old, 60 years old, 65 years old, 70 years old, or older.

26. The method of claim 25, wherein the subject is between 50 and 59 years old inclusive of subjects aged 50 and 59.

27. The method of claim 25, wherein the subject is between 60 and 69 years old inclusive of subjects aged 60 and 69.

28. The method of claim 25, wherein the subject is 50 years old or older.

29. The method of claim 25, wherein the subject is 70 years old or older30. The method of any one of claims 18-29, wherein the subject is immunocompromised.

31. The method of any one of claims 18-30, wherein the administration is subcutaneous or intramuscular.

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