A recombinant herpes zoster vaccine composition and its use

Abstract

This invention discloses a recombinant herpes zoster vaccine composition and its uses. The novel vaccine composition provided by this invention, compared to other combinations of antigens and adjuvants, has more feasible production and beneficial immunizing effects.

Description

[0001] This application is a divisional application, the parent application being the invention patent application filed on June 28, 2019, with application number CN201910574549.4. Technical Field

[0002] This invention belongs to the field of biomedicine, and more specifically, this invention relates to a recombinant herpes zoster vaccine composition and its use. Background Technology

[0003] Varicella-zoster virus (VZV) is one of eight human herpesviruses, specifically human herpesvirus type 3. Varicella-zoster virus is prevalent globally and highly contagious. To date, only one serotype has been identified, and in nature, VZV only infects humans. It can cause both chickenpox and herpes zoster (HZ). Chickenpox typically occurs in childhood, while herpes zoster is more common in adults. After primary chickenpox infection, the virus can remain latent in the host's nerve ganglia. With age and weakened immune function, or due to other causes of immune impairment and immunosuppression, VZV can be reactivated and cause herpes zoster. Clinically, herpes zoster presents as a unilateral vesicular rash, characterized by its limitation to a single skin segment, usually accompanied by radicular pain. Patients experience significant pain and discomfort, with symptoms lasting for weeks or months, and even years in severe cases, leading to a decline in quality of life. In rare cases, herpes zoster may occur without a rash. Approximately 25% of shingles patients develop complications, and this percentage increases with age. The most common serious complication is postherpetic neuralgia (PHN), which is persistent pain that continues to occur after the acute phase of the herpes outbreak. It occurs in 10%-30% of shingles patients and can last for months or even years, severely impacting their quality of life. Risk factors for shingles include age, immune system deficiencies, sex, and other underlying factors.

[0004] Most primary VZV infections occur in childhood, after which VZV remains latent in ganglia and can be reactivated in adulthood. Studies show that approximately 99% of Americans aged 40 and older have serological evidence of VZV infection; 90% of Europeans aged 20-29 are serologically positive for anti-VZV; in some countries in South America, Australia, and Asia, primary VZV infection may occur later, but 90% of people over 40 years of age will have a serologically positive VZV. Therefore, globally, the vast majority of adults are at risk of developing shingles and its related complications. The global incidence of shingles is (3–5) / 1000 person-years, and in the Asia-Pacific region it is (3–10) / 1000 person-years, increasing by 2.5%–5.0% annually; the hospitalization rate is (2–25) / 100,000 person-years; the mortality rate is (0.017–0.465) / 100,000 person-years; and the recurrence rate is 1%–6%.

[0005] Since drug treatment can only relieve symptoms, vaccination is the best strategy for preventing hepatitis B (HZ) and its complications. Currently, only two HZ vaccines are available globally (the live attenuated HZ vaccine Zostavax and the HZ subunit vaccine Shingrix). Zostavax, developed by Merck, is a live attenuated vaccine containing the same VZV Oka strain used in varicella vaccines. Its minimum potency is 19,400 PFU. It was approved by the FDA in 2006 and has since been approved for marketing in more than 60 countries. A single subcutaneous dose is used for HZ prevention in people over 50 years of age. Shingrix, developed by GlaxoSmithKline, is a vaccine based on recombinant gE protein with the novel adjuvant AS01. B The subunit vaccine, Shingrix, has shown superior immunogenicity and efficacy compared to Zostavax in older adults in Phase III clinical trials. It was approved by the FDA in 2017 for use in individuals aged 50 and older, requiring two doses. While Shingrix has received conditional approval in China, currently available HZ vaccines in clinical trials in China are all live attenuated vaccines. Theoretically, their protective efficacy and duration of immunity should be lower than Shingrix's. Furthermore, Shingrix is ​​in global shortage due to production capacity issues. Therefore, China urgently needs an independently developed subunit vaccine to reduce the disease burden caused by shingles and its complications.

[0006] VZV-specific immune responses are crucial for reducing the incidence of shingles and postherpetic neuralgia. Shingrix, developed by GlaxoSmithKline, is a novel adjuvant based on AS01. BThe subunit vaccine has been proven effective in preventing shingles and its associated neuralgia, and this novel adjuvant plays a crucial role in this vaccine. Therefore, selecting appropriate adjuvants to develop a vaccine that enhances cellular and humoral immune responses in the target population can effectively prevent shingles. GlaxoSmithKline's AS01 B Adjuvant systems, including liposomes, MPL, and QS-21, can induce strong cellular immune responses. However, the production scale of MPL and QS-21 is currently limited due to sourcing constraints, and large-scale production conditions in China are still immature, failing to meet the needs of large-scale commercial production. Other chemically synthesizable adjuvants that can also effectively induce cellular immune responses, including CpG ODN, can be produced on a large scale, facilitating quality and sourcing control. Toll-like receptor 9 (TLR9) CpG ODN is an immune agonist that can stimulate cells expressing TLR9 and activate downstream innate immune pathways. On the one hand, it induces the expression of type I interferon and inflammatory factors; on the other hand, it promotes the maturation of plasmacytoid dendritic cells, thereby enhancing humoral and cellular immune responses. Aluminum adjuvants are the most widely used human vaccine adjuvants to date, and they are also widely used in combination with other adjuvants. In many completed clinical trials of vaccines, including hepatitis B and malaria prophylaxis vaccines, the combination of aluminum adjuvants and CpG has relatively complete safety data and data showing that it greatly promotes immune response.

[0007] Although existing technologies have been used in the development of vaccines against varicella-zoster virus (VZV), problems remain, such as low VZV antigen protein expression efficiency, weak activity, and unsatisfactory immunization effects. Therefore, there is an urgent need in the field to develop improved VZV vaccines. Developing new compositions or vaccines through adjuvants or formulation combinations to improve and enhance the immune response is currently a good but very challenging strategy. Summary of the Invention

[0008] The present invention focuses on providing a new generation of recombinant herpes zoster prophylactic vaccine, which contains varicella-zoster virus (VZV) antigen. More specifically, the antigen may be VZV virus glycoprotein E (gE protein).

[0009] The VZV described in this invention is a double-stranded DNA virus with only one serotype. Its genome is approximately 125,000 bp in length, encoding 71 genes and ultimately expressing 67 different proteins, including seven glycoproteins (gpI–gpVI), named gE, gB, gH, gI, gC, gK, and gL. Among these, gE protein is the main surface structural protein of VZV and the most important neutralizing antigen, exhibiting high conservation. Specifically, the VZV-gE glycoprotein is encoded by ORF68, consists of 623 amino acids, and is a type I transmembrane glycoprotein. gE glycoprotein is most abundantly expressed on the surface of the virus and infected cells, and also contains T and B cell epitopes. Therefore, research on VZV-gE is the most extensive, and it can serve as a candidate antigen for a new generation of subunit varicella or shingles vaccines.

[0010] Existing research on VZV gE proteins indicates that the wild-type VZV gE protein molecule comprises four regions: a signal peptide, an extracellular region, a transmembrane region, and an intracellular region. All three antigenic determinants of VZV gE are located in the extracellular region (see, for example, Grose C. Glycoproteins encoded by varicella-zoster virus: biosynthesis, phosphorylation, and intracellular trafficking. Annu Rev Microbil. 1990, 44:59-80.). Several gE protein sequences (e.g., amino acid sequences with Sequence IDs Q9J3M8.1, AQT34120.1, AGY33616.1, and AEW88548.1) are available for use by those skilled in the art in the NCBI database. The inventors of this invention retrieved 25 full-length sequences of VZV gE protein from NCBI, originating from different viral strains. Amino acid sequence analysis and alignment results showed that the amino acid sequences of 7 viral strains were completely identical (AAK19946.1, AHB80298.1, Q9J3M8.1, ABE67176.1, AGL51024.1, AFO85645.1, ABF22079.1), and each site showed the highest conservation, making them ideal choices for gE antigen protein sequences.

[0011] Meanwhile, considering the impact of hydrophobic transmembrane regions on the expression of exogenous proteins, protein expression levels can be improved by removing the transmembrane region (hydrophobic region) and intracellular region (e.g., patent CN102517302A). Furthermore, when mutant protein precursors are expressed using the host cell's translational apparatus and transferred to the cell membrane for secretion, the signal peptide region is typically cleaved by signal peptidases (e.g., patents CN102548578A, CN102711812B). The transmembrane region, intracellular region, and signal peptide of this protein can all be predicted using relevant application software. For example, SignalP (http: / / www.cbs.dtu.dk / services / SignalP / ) can be used to predict whether a protein has a signal peptide, TMHMM Server V.2.0 software can be used to predict the transmembrane region of the protein, and PSORT software can be used to determine the accuracy of secreted signal peptides and whether the signal peptide cleavage site can be identified and cleaved.

[0012] To serve the purposes of this invention, in the embodiments of this invention, the protein sequence ID=Q9J3M8.1 on NCBI is used as the basis, and the C-terminal 77 amino acids are truncated (removing the transmembrane region and intracellular region) as the model antigen (the N-terminal 1-30 amino acids are the signal peptide).

[0013] The above-mentioned antigens can be easily obtained using conventional techniques in modern molecular biology. A typical method includes expressing the above-mentioned gE protein in CHO cells, which includes the following steps:

[0014] (1) The gE gene of the present invention is cloned into the expression vector;

[0015] (2) Transfect the expression vector obtained in step (1) into CHO cells;

[0016] (3) By screening mixed clonal cell populations and single clonal cells, engineered cell lines that stably express gE protein were obtained;

[0017] (4) Use the cell line described in step (3) to express and obtain VZV gE protein.

[0018] The proteins obtained above can be processed using conventional methods, such as hydrophobic chromatography, anion exchange chromatography, hydroxyapatite chromatography, ultrafiltration, and nanofiltration, to obtain antigen proteins with a purity of over 95%.

[0019] It should be noted that the method of stably expressing the VZV gE recombinant protein using CHO cell lines is a well-known method in the art, and can be found in Molecular Cloning: A Laboratory Manual and other literature, such as Haumont M et al., Virus Research 40 (1996), 199-204, Purification, characterization and immunogenicity of recombinant varicella-zoster virus glycoprotein gE secreted by Chinesehamster ovary cells. Those skilled in the art can also choose other expression systems, such as Escherichia coli and Pichia pastoris, to obtain the gE protein (for example, refer to the relevant descriptions of gE protein preparation in patents CN108315344A or CN107022559A).

[0020] In a preferred embodiment, the vaccine composition further comprises a pharmaceutically acceptable carrier. In one preferred embodiment, the pharmaceutically acceptable carrier is an aluminum adjuvant combined with a CpG ODN adjuvant. An important discovery by the inventors of this invention also includes that the combination of the above two adjuvants and the gE protein exhibits unexpectedly high immunogenicity. This makes the vaccine composition of this invention a leading candidate vaccine for the next generation of varicella-zoster virus.

[0021] The aluminum adjuvant described in this invention is currently the most widely used adjuvant in vaccines, with over 80 years of application history. Systematic studies can be found in, for example, Chapter 8, "Adjuvant Properties of Aluminum and Calcium Compounds," and Chapter 9, "Structure and Properties of Aluminum Adjuvants," of the book *Vaccine Design: The Subunit and Adjuvant Approach* (ISBN: 0-306-44867-X), or Chapter 4, "Use of Aluminum Compounds as Vaccine Adjuvants," of the book *Vaccine Adjuvants: Preparation Methods and Research Protocols* (ISBN: 1-59259-083-7). Several commercially available aluminum adjuvants are currently available for use in vaccines, including but not limited to... (aluminum hydroxide) and (Aluminum phosphate). The aluminum adjuvant required for preparation was prepared using the self-preparation method for aluminum adjuvants as described in the aforementioned studies.

[0022] CpG ODN adjuvants are a class of immunostimulatory oligonucleotides known to possess adjuvant properties. They can activate B cells, NK cells, dendritic cells, and other cells, inducing the release of IL-12 and IFN-γ, thereby inducing a strong Th1 response and cellular immunity. Mature artificial production technologies for these adjuvants already exist, as described in international applications such as WO 96 / 02555 and WO 99 / 33488. Several commercially available CpG ODN adjuvants are currently available, such as CpG 7909 (Coley) or CpG 1018 (Dynavax). However, those skilled in the art can also design CPG sequences to achieve artificial synthesis according to their needs, but the ideal CPGs used in this invention are CPG7909 and CPG1018.

[0023] The vaccine formulation provided by this invention can be prepared with reference to the methods described in, for example, the book *Vaccine Design: The Subunit and Adjuvant Approach* (ISBN: 0-306-44867-X). The preparation method provided by this invention is more suitable for mixing the aforementioned antigen protein of this invention with the aforementioned pharmaceutically acceptable carrier. As a more specific example, in a preferred embodiment, the gE protein should preferably be adsorbed onto the aluminum adjuvant; simultaneously, the selected CpG ODN adjuvant should also preferably be adsorbed onto the aluminum adjuvant.

[0024] The fundamental principle of vaccine formulation development is that each dose of vaccine should be sufficient to induce a protective immune response in the recipient without significant toxic side effects. Generally, the dosage varies slightly for different antigen proteins, and the optimal dosage for a specific vaccine can be determined by observing antibody titers and other responses in the subject. The vaccine formulation provided by this invention contains an antigen protein content of approximately 10-100 μg, more preferably 50-100 μg, an aluminum adjuvant content of approximately 100-600 μg, more preferably 225-600 μg, and a CpG ODN adjuvant content of approximately 50-1200 μg, and more preferably 300-900 μg.

[0025] A second aspect of the invention is to provide the use of the aforementioned vaccine composition for the prevention or treatment of diseases or conditions related to shingles virus infection.

[0026] A third aspect of the invention is to provide a vaccine administration device, including, but not limited to, a needle device and a liquid injection device. The choice of device is primarily based on different routes of administration, common routes of administration including intramuscular injection, intraperitoneal injection, intradermal injection, or subcutaneous injection, or administration via the oral / gastrointestinal tract, respiratory tract, and genitourinary tract mucosa. The vaccine of the present invention can be administered via intramuscular injection, and the administration device is a syringe and an injection needle device.

[0027] The inventors of this invention made a key discovery: the combined use of the two adjuvants and gE protein exhibited unexpectedly high immunogenicity. This makes the vaccine composition of this invention a next-generation candidate vaccine for varicella-zoster virus.

[0028] Other aspects of the invention will be apparent to those skilled in the art from the disclosure herein. Detailed Implementation

[0029] Example 1: Preparation of a vaccine composition containing VZV gE antigen protein

[0030] To investigate the technical effects of the vaccine compositions provided by this invention, the inventors of this invention prepared several vaccine composition formulations (0.5 ml / dose), each containing VZV gE protein, aluminum adjuvant, and CpG ODN adjuvant. The specific preparation method is as follows: first, the gE antigen stock solution is adsorbed onto the aluminum adjuvant (aluminum phosphate adjuvant) to prepare adsorption samples with different ratios of gE antigen / aluminum adjuvant (w / w) (the aluminum adjuvant content here actually refers to the aluminum element content); then, different concentrations of CpG ODN sample (CpG 7909) are added to the gE antigen / aluminum adjuvant sample. After thorough mixing, if not administered immediately, the above formulations can be stored at 2-8°C, with the specific proportions as follows:

[0031] serial number gE(μg) Aluminum adjuvant (μg) CpG ODN 7909 adjuvant (μg) Volume (μl) 1 10 600 300 500 2 10 600 600 500 3 10 600 900 500 4 10 600 1200 500 5 50 600 300 500 6 50 600 600 500 7 50 600 900 500 8 50 600 1200 500 9 100 600 300 500 10 100 600 600 500 11 100 600 900 500 12 100 600 1200 500 13 0 600 1200 500 14 10 225 600 500 15 50 225 600 500 16 100 225 600 500

[0032] Example 2:

[0033] Regarding the recombinant herpes zoster vaccine composition to be evaluated in Example 1, the inventors conducted immunogenicity studies using C57BL / 6 mice as an animal model. The immunogenicity of the vaccine composition provided by this invention was studied using gE protein as the antigen and aluminum adjuvant and CpG ODN as adjuvants. Six- to eight-week-old C57BL / 6 mice were randomly divided into groups of 10 mice each. The vaccine, prepared with gE protein and adjuvant, was administered intramuscularly. Vaccination was performed at weeks 0 and 3, and spleen samples were collected at week 5. The titer of anti-VZV gE protein binding antibodies (total IgG) in serum was detected using ELISA, and the level of cellular immunity in spleen cells, primarily IFN-γ expression, was detected using ELISPOT. It should be noted that, in addition to the above 16 experiments, parallel experiments with the same formulation were also conducted to verify the effectiveness of the vaccine composition composed of CpG ODN 1018, VZV gE protein, and aluminum adjuvant, with all other parameters and experimental procedures remaining unchanged. The final data showed that its IgG (GMT) value was essentially the same as when using other CpGs.

[0034] The specific procedures for evaluating immunogenicity are as follows:

[0035] 1. Animal experiments on recombinant herpes zoster vaccine

[0036] Six- to eight-week-old C57BL / 6 mice were randomly divided into groups of 10 each. Different doses of vaccine (Table 1) were administered intraperitoneally, with an injection volume of 0.5 ml. Immunization was performed at weeks 0 and 3. Blood was collected at week 5 to obtain spleens. Serum was separated for ELISA to detect antibody titers, and splenic lymphocytes were separated for ELISPOT analysis.

[0037] 2. Combined with antibody titer detection

[0038] Two weeks after the second immunization of mice, serum was collected to detect the titer of antibodies binding to the anti-gE protein.

[0039] (1) Dilute the antigen gE stock solution with PBS to 1 μg / ml, and add 100 μl of the diluted stock solution to each well of the ELISA plate. Incubate overnight at 4°C. Wash with a plate washer.

[0040] (2) Prepare 5% skim milk with PBS, and add 100 μl of skim milk to each well of the ELISA plate. Incubate at 37°C for 2 hours. Wash with a plate washer.

[0041] (3) Prepare 2% skim milk with PBS, serially dilute the serum to be tested, add 100 μl of diluted serum to each well of the ELISA plate, and incubate at 37°C for 1 hour. Wash with a plate washer.

[0042] (4) Dilute the goat anti-mouse IgG secondary antibody with 2% skim milk prepared in PBS at a ratio of 1:10000. Add 100 μl of the skim milk-diluted secondary antibody to each well of the ELISA plate. Incubate at 37°C for 1 hour. Wash with a plate washer.

[0043] (5) Prepare the chromogenic solution according to the ratio of 9 ml chromogenic buffer, 1 ml TMB, and 10 μl 3% H2O2. Add 100 μl of chromogenic solution to each well of the ELISA plate. Incubate at 37°C for 10 min. Add 50 μl of stop solution to each well of the ELISA plate.

[0044] (6) 450nm / 620nm readings.

[0045] 3. Cellular immune detection

[0046] Two weeks after the second immunization of mice, spleens were harvested from each group of mice, and lymphocytes were isolated. The expression level of IFN-γ in mouse spleen lymphocytes (n=2) was measured by ELISPOT.

[0047] (1) Coating with ELISPOT plates (aseptic procedure, performed the day before spleen harvesting)

[0048] Wet the ELISPOT plate with 35% ethanol and add 15 μl / well to each 96-well ELISPOT plate, retaining for no more than 1 minute. Wash the plate 5 times with 200 μl / well of sterile water. Add 150 μl of IFN-γ coated antibody to 10 ml of PBS, mix well, and filter through a 0.2 μm filter membrane. Add 100 μl / well of the antibody dilution buffer to each 96-well ELISPOT plate and incubate overnight at 4°C.

[0049] (2) ELISPOT plate sealing (aseptic operation)

[0050] Discard the coating antibody and wash the plate 5 times with 200 μl / well of sterile PBS. Add 200 μl / well of 1640 complete culture medium (containing 10% FBS) to each 96-well ELISPOT plate and block at room temperature for at least 30 minutes. Discard the liquid and gently blot dry the plate with sterile gauze to prevent air bubbles from forming when adding the next culture medium.

[0051] (3) Lymphocyte preparation (aseptic technique)

[0052] Mice were euthanized and immersed in 75% ethanol. The spleens were removed in a laminar flow hood. A piece of burnt 200-mesh copper mesh was placed in a 35mm culture dish, and 1ml of lymphocyte separation medium was added. The mesh was ground using the plunger of a 1ml syringe. The separation medium containing the suspended spleen cells was filtered through a 200-mesh copper mesh and transferred to a 15ml centrifuge tube. Lymphocyte separation medium was added to a final volume of 4ml, and 0.5ml of RPMI 1640 basal medium was placed on top. The tube was centrifuged at 800g at room temperature for 30 minutes using a variable speed (V / V) setting. The lymphocyte layer was aspirated, and 10ml of RPMI 1640 basal medium was added. The cells were washed and centrifuged at 250g at room temperature for 10 minutes. The supernatant was discarded, and the cells were resuspended in 2ml of RPMI 1640 complete medium and counted.

[0053] (4) Sample addition (aseptic technique)

[0054] Add cells: Dilute cells to 6 × 10⁶ using complete culture medium based on cell count results. 6 / ml, while adding mAb CD28-A diluted 1000-fold to the cell suspension. Add 100μl / well to each ELISPOT plate. Positive control: Add 1μl of ConA stimulant, stimulating concentration of 5μg / ml. Test sample: Add gE protein peptide library diluted with serum-free medium, final concentration 2μg / ml; Negative control: No ConA stimulant or short peptide stimulant added. Incubate at 37℃, 5% CO2 for 24 hours. Do not move the culture plate during this time to avoid cell displacement and blurring of the ELISPOT spots.

[0055] (5) Spot detection

[0056] Discard the cell suspension and wash the plate 5 times with 200 μl / well of sterile PBS. Add 50 μl of biotin-labeled detection antibody to 10 ml of dilution buffer (PBS + 0.1% BSA), mix well, and filter through a 0.2 μm filter. Add 100 μl to each well and incubate at 37°C for 2 hours. Discard the biotin-labeled detection antibody dilution buffer and wash the plate 5 times with 200 μl / well of sterile PBS. Dilute the antibody with dilution buffer (PBS + 0.1% BSA), add 50 μl to 10 ml of dilution buffer, mix well, and filter through a 0.2 μm filter. Add 100 μl to each well and incubate at 37°C for 1 hour. From this step onwards, protect the plate from light. Discard the antibody dilution buffer and wash the plate 5 times with 200 μl / well of sterile PBS. Add 50 μl of Fluorescence Enhancer-II to each well of a 96-well ELISPOT plate and incubate at 37°C for 15 minutes. Discard the liquid inside the plate, invert the plate onto absorbent paper, and pat dry any small water droplets. Remove the protective layer and place the plate in a thermostatic incubator at 37°C in the dark to dry the membrane. Place the ELISPOT plate in... Inside the S5 VersC CnClyzer ELISA dot image automatic analyzer, after adjusting the appropriate parameters, dot counting is performed.

[0057] The specific results are shown in Table 2 below:

[0058] Table 2 Summary of the results of the study on the ratio of antigen, aluminum adjuvant, and CpG ODN7909 adjuvant

[0059]

[0060]

[0061] Table 3 Summary of the results of the study on the ratio of antigen, aluminum adjuvant, and CpG1018

[0062]

[0063] As can be seen from Tables 2-3, the vaccine composition prepared according to the specific components and proportions provided by the present invention has good immunomodulatory activity. In particular, when the content of gE protein is between 50-100 μg, the content of aluminum adjuvant is between 225-600 μg, and the content of CpG ODN adjuvant is between 300-900 μg, it has excellent cellular immunomodulatory effects and can be used as a new generation of vaccine composition.

[0064] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A recombinant varicella vaccine composition, characterized in that, The recombinant herpes zoster vaccine composition contains the gE protein of VZV virus, and the vaccine composition further contains a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is an aluminum adjuvant combined with a CpG adjuvant, the content of the gE protein is between 10-100 μg, the content of the aluminum adjuvant is between 225-600 μg, and the content of the CpG adjuvant is between 300-1200 μg; The CpG adjuvant is CpG7909 or CpG1018; the volume of the composition is 500 μL; The method for preparing the recombinant herpes zoster vaccine composition includes: first adsorbing gE protein onto aluminum adjuvant, and then adding CpG adjuvant to the gE antigen / aluminum adsorbed sample.

2. The vaccine composition of claim 1, wherein The content of the gE protein is between 50-100 μg.

3. The vaccine composition of claim 1, wherein The content of the CpG adjuvant is between 300 and 900 μg.

4. The vaccine composition according to any one of claims 1 to 3, wherein The content of the gE protein is 100 μg, the content of the aluminum adjuvant is 600 μg, and the content of the CpG adjuvant is between 600-900 μg.

5. The vaccine composition of claim 1, wherein The aluminum adjuvant is aluminum phosphate and / or aluminum hydroxide.

6. Use of the vaccine composition according to any one of claims 1-5 in the preparation of a medicament for the prevention of diseases related to herpes zoster virus infection.

7. A kit comprising the vaccine composition of any one of claims 1-5, characterized in that, The kit includes a vaccine administration device, which includes a needle device and a liquid injection device.

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