Safety and Immunogenicity of Recombinant Herpes Zoster Vaccine (CHO Cells) in Healthy Subjects Aged 18 Years and Above

Study Overview
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Brief Summary
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The purposes of the study are to evaluate the safety and tolerability of different dose levels of recombinant herpes zoster vaccine (CHO Cells) with 2 doses at 2-month intervals in healthy subjects aged 18 years and older, and to preliminarily explore immunogenicity.

Detailed Description
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The clinical trial will be a single-center, randomized, blind, controlled study in which two dose levels of vaccine will be tested in healthy adults aged 18 to 49 years and 50 years and older, with progression from low dose level to high dose level and younger age group to the older age group based on assessment of safety and tolerability. The younger cohort (aged 18 to 49 years) will consist of 60 subjects, 30 per dose level, and these 30 subjects will be randomized into three subgroups, including vaccine group, adjuvant group and normal saline group, with randomization ratio of 2:2:1. The older cohort (aged 50 years and older) will consist of 72 subjects, 36 per dose level, and these 36 subjects will be randomized into four subgroups, including vaccine group, adjuvant group, Shingrix® group and normal saline group, with randomization ratio of 2:2:1:1.

Official Title
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A Phase I, Single Center, Randomized, Blinded, Controlled Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Immunogenicity of Recombinant Herpes Zoster Vaccine (CHO Cells) in Healthy Subjects Aged 18 Years and Above

Conditions
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Herpes Zoster

Intervention / Treatment
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* Biological: Low Dose Recombinant Herpes Zoster Vaccine (CHO cells)
* Biological: High Dose Recombinant Herpes Zoster Vaccine (CHO cells)
* Biological: Low dose adjuvant
* Biological: High dose adjuvant
* Biological: Positive control
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Permanent residents aged 18 years and above; Subjects voluntarily agree to participate in the study and signed an informed consent; Be able to participate in all scheduled visits and comply with the protocol requirements. Exclusion Criteria: Axillary temperature>37.0℃; History of herpes zoster within 5 years before vaccination; Prior vaccination with chickenpox vaccine or herpes zoster vaccine; Female participant who is pregnant ( urine pregnancy test was positive) or breastfeeding, or has pregnancy plans within 1 year after the last vaccination; Receipt of live vaccine within 28 days, or any other vaccine within 14 days prior to vaccination; Receipt of immunoglobulin or intravenous immunoglobulin within 3 months before vaccination; Acute diseases or acute exacerbation of chronic disease within 3 days before vaccination; A known allergy to any components of the study vaccine (especially allergic to aminoglycoside antibiotics), or history of severe allergy to any previous vaccination; History of convulsions, epilepsy, encephalopathy (such as congenital brain dysplasia, brain trauma, brain tumor, cerebral hemorrhage, cerebral infarction, brain infection disease, nerve tissue damage caused by chemical drug poisoning, etc.) or mental illness and family history; Asplenia or functional asplenia, or splenectomy caused by any condition; Primary or secondary impairment of immune function or diagnosed congenital or acquired immunodeficiency, human immunodeficiency virus (HIV) infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile rheumatoid arthritis (JRA), inflammatory bowel disease or other autoimmune diseases; Receipt of immunosuppressive therapy within 3 months before vaccination (such as long-term use of systemic glucocorticoid ≥14 days, dose ≥2mg/kg/day or ≥20mg/day prednisone or equivalent dose), but inhaled, intra-articular and topical steroids are acceptable; Severe cardiovascular disease(eg. Pulmonary heart disease, Pulmonary Edema); Severe liver or kidney disease; or diabetes with complication; History of thrombocytopenia or other coagulation disorders, which may cause intramuscular injection contraindications; Abnormal blood pressure during physical examination before vaccination (systolic pressure ≥ 140 mmHg and/or diastolic pressure ≥ 90 mmHg); Abnormal and clinically significant laboratory test results as determined by the investigator before vaccination; Current or history of alcohol and/or drug abuse; Any condition that, in the opinion the investigator, may affect the safety of the subject or the evaluation of the study results.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose vaccine group in adults aged 18 to 49 years<br>Subjects aged 18 to 49 years will be vaccinated with 2 doses of low dose recombinant herpes zoster vaccine (CHO cells) on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Low Dose Recombinant Herpes Zoster Vaccine (CHO cells)<br>* 0.5 mL per dose, containing a total of 50 µg recombinant varicella zoster virus glycoprotein E, adjuvanted with low dose MA105.<br>|
| Experimental: Low dose adjuvant group in adults aged 18 to 49 years<br>Subjects aged 18 to 49 years will be vaccinated with 2 doses of low dose adjuvant on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Low dose adjuvant<br>* 0.5 mL per dose, containing low dose MA105 adjuvant.<br>|
| Experimental: High dose vaccine group in adults aged 18 to 49 years<br>Subjects aged 18 to 49 years will be vaccinated with 2 doses of high dose recombinant herpes zoster vaccine (CHO cells) on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: High Dose Recombinant Herpes Zoster Vaccine (CHO cells)<br>* 0.5 mL per dose, containing a total of 50 µg recombinant varicella zoster virus glycoprotein E, adjuvanted with high dose MA105.<br>|
| Experimental: High dose adjuvant group in adults aged 18 to 49 years<br>Subjects aged 18 to 49 years will be vaccinated with 2 doses of high dose adjuvant on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: High dose adjuvant<br>* 0.5 mL per dose, containing high dose MA105 adjuvant.<br>|
| Placebo Comparator: Placebo group in adults aged 18 to 49 years<br>Subjects aged 18 to 49 years will be vaccinated with 2 doses of placebo on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Placebo<br>* 0.5 mL per dose, containing 4.5 mg sodium chloride.<br>* Other names: Saline for injection;|
| Experimental: Low dose vaccine group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of low dose recombinant herpes zoster vaccine (CHO cells) on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Low Dose Recombinant Herpes Zoster Vaccine (CHO cells)<br>* 0.5 mL per dose, containing a total of 50 µg recombinant varicella zoster virus glycoprotein E, adjuvanted with low dose MA105.<br>|
| Experimental: Low dose adjuvant group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of low dose adjuvant on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Low dose adjuvant<br>* 0.5 mL per dose, containing low dose MA105 adjuvant.<br>|
| Experimental: High dose vaccine group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of high dose recombinant herpes zoster vaccine (CHO cells) on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: High Dose Recombinant Herpes Zoster Vaccine (CHO cells)<br>* 0.5 mL per dose, containing a total of 50 µg recombinant varicella zoster virus glycoprotein E, adjuvanted with high dose MA105.<br>|
| Experimental: High dose adjuvant group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of high dose adjuvant on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: High dose adjuvant<br>* 0.5 mL per dose, containing high dose MA105 adjuvant.<br>|
| Active Comparator: Shingrix® group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of Shingrix® on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Positive control<br>* 0.5 mL per dose, containing a total of 50 µg recombinant varicella zoster virus glycoprotein E, adjuvanted with AS01B.<br>* Other names: Shingrix®;|
| Placebo Comparator: Placebo group in adults aged 50 years and older<br>Subjects aged 50 years and older will be vaccinated with 2 doses of placebo on a 0, 2 month schedule, administered intramuscularly (IM). | Biological: Placebo<br>* 0.5 mL per dose, containing 4.5 mg sodium chloride.<br>* Other names: Saline for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence and severity of adverse events | Incidence and severity of adverse events within 30 minutes after each vaccination. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 30 minutes after each vaccination. | 
| The incidence and severity of adverse events | Incidence and severity of adverse events within 7 days after each vaccination. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 7 days after each vaccination. | 
| The incidence and severity of adverse events | Incidence and severity of adverse events during Day 8 to 30 after each vaccination. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Day 8 to 30 after each vaccination. | 
| The incidence and severity of adverse events | Incidence and severity of adverse events within 30 days after each vaccination. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 30 days after each vaccination. | 
| Incidence of abnormal and clinically significant laboratory test results | Laboratory test includes hematology, blood biochemistry and urine analysis. | Day 4 after each vaccination . | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Serious Adverse Event | Incidence of Serious Adverse Event (SAE) from the first vaccination to 12 months after full vaccination. | From the first vaccination to 12 months after full vaccination (From Day 0 to Day 420). | 
| Potential Immune Mediated Disorder | Incidence of Potential Immune Mediated Disorder (pIMD) from the first vaccination to 12 months after full vaccination. | From the first vaccination to 12 months after full vaccination (From Day 0 to Day 420). | 
| Geometric mean concentration (GMC) of anti-gE antibody and anti-VZV antibody | Measured by ELISA. | Prior to each vaccination (Day 0, Day 60). | 
| Geometric mean concentration (GMC) of anti-gE antibody and anti-VZV antibody | Measured by ELISA. | Day 14 after each vaccination (Day 14, Day 74). | 
| Geometric mean concentration (GMC) of anti-gE antibody and anti-VZV antibody | Measured by ELISA. | Month 1 after each vaccination (Day 30, Day 90). | 
| Geometric mean concentration (GMC) of anti-gE antibody and anti-VZV antibody | Measured by ELISA. | Month 6 and 12 after the second vaccination (Day 240, Day 420). | 
| Seroconversion rate of anti-gE antibody and anti-VZV antibody | Seroconversion is defined as a ≥4 fold rise in antibody concentration compared with baseline for those antibody concentration was ≥Cut-off value at baseline; or a ≥4 fold Cut-off value in antibody concentration compared with baseline for those antibody concentration was <Cut-off value at baseline. | Prior to the second vaccination (Day 60). | 
| Seroconversion rate of anti-gE antibody and anti-VZV antibody | Seroconversion is defined as a ≥4 fold rise in antibody concentration compared with baseline for those antibody concentration was ≥Cut-off value at baseline; or a ≥4 fold Cut-off value in antibody concentration compared with baseline for those antibody concentration was <Cut-off value at baseline. | Day 14 after each vaccination (Day 14, Day 74). | 
| Seroconversion rate of anti-gE antibody and anti-VZV antibody | Seroconversion is defined as a ≥4 fold rise in antibody concentration compared with baseline for those antibody concentration was ≥Cut-off value at baseline; or a ≥4 fold Cut-off value in antibody concentration compared with baseline for those antibody concentration was <Cut-off value at baseline. | Month 1 after each vaccination (Day 30, Day 90). | 
| Positive rate of anti-gE antibody and anti-VZV antibody | Positive rate is defined as percentage of subjects with antibody concentration ≥Cut-off value. | Prior to each vaccination (Day 0, Day 60). | 
| Positive rate of anti-gE antibody and anti-VZV antibody | Positive rate is defined as percentage of subjects with antibody concentration ≥Cut-off value. | Day 14 after each vaccination (Day 14, Day 74). | 
| Positive rate of anti-gE antibody and anti-VZV antibody | Positive rate is defined as percentage of subjects with antibody concentration ≥Cut-off value. | Month 1 after each vaccination (Day 30, Day 90). | 
| Positive rate of anti-gE antibody and anti-VZV antibody | Positive rate is defined as percentage of subjects with antibody concentration ≥Cut-off value. | Month 6 and 12 after the second vaccination (Day 240, Day 420). | 
| Geometric mean increase(GMI) of anti-gE antibody and anti-VZV antibody concentration | The antibody concentration prior to the second vaccination compared with that at baseline (Day 0). | Prior to the second vaccination (Day 60). | 
| Geometric mean increase(GMI) of anti-gE antibody and anti-VZV antibody concentration | The antibody concentration at Day 14 after each vaccination compared with that at baseline (Day 0). | Day 14 after each vaccination (Day 14, Day 74). | 
| Geometric mean increase(GMI) of anti-gE antibody and anti-VZV antibody concentration | The antibody concentration at 1 month after each vaccination compared with that at baseline (Day 0). | Month 1 after each vaccination (Day 30, Day 90) | 
| Four-fold increase rate of the anti-gE antibody and anti-VZV antibody concentration | The antibody concentration prior to the second vaccination compared with that at baseline (Day 0). | Prior to the second vaccination (Day 60). | 
| Four-fold increase rate of the anti-gE antibody and anti-VZV antibody concentration | The antibody concentration at Day 14 after each vaccination compared with that at baseline (Day 0). | Day 14 after each vaccination (Day 14, Day 74). | 
| Four-fold increase rate of the anti-gE antibody and anti-VZV antibody concentration | The antibody concentration at month 1 after each vaccination compared with that at baseline (Day 0). | Month 1 after each vaccination (Day 30, Day 90). | 
| Frequency of gE-specific CD4+ T-cells expressing at least 1 Immunological activation marker | The analysis focused on CD4+ T-cells expressing at least 1 immunological activation marker among Interferon gamma (IFN-γ), Interleukin 2 (IL-2), Tumour Necrosis Factor alpha (TNF-α) and CD40 Ligand (CD40L). | Prior to the first vaccination (Day 0). | 
| Frequency of gE-specific CD4+ T-cells expressing at least 1 Immunological activation marker | The analysis focused on CD4+ T-cells expressing at least 1 immunological activation marker among Interferon gamma (IFN-γ), Interleukin 2 (IL-2), Tumour Necrosis Factor alpha (TNF-α) and CD40 Ligand (CD40L). | Month 1 after the second vaccination (Day 90). | 
| Frequency of gE-specific CD4+ T-cells expressing at least 1 Immunological activation marker | The analysis focused on CD4+ T-cells expressing at least 1 immunological activation marker among Interferon gamma (IFN-γ), Interleukin 2 (IL-2), Tumour Necrosis Factor alpha (TNF-α) and CD40 Ligand (CD40L). | Month 6, 12 after the second vaccination (Day 240, Day 420). | 
| Cellular immune response | Cellular immune response is defined as the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥2 fold increase compared with baseline for those the frequency of gE-specific CD4+ T-cells ≥Cut-off value at baseline; or the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥Cut-off value for those the frequency of gE-specific CD4+ T-cells <Cut-off value at baseline. | Prior to the first vaccination (Day 0). | 
| Cellular immune response | Cellular immune response is defined as the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥2 fold increase compared with baseline for those the frequency of gE-specific CD4+ T-cells ≥Cut-off value at baseline; or the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥Cut-off value for those the frequency of gE-specific CD4+ T-cells <Cut-off value at baseline. | Month 1 after the second vaccination (Day 90). | 
| Cellular immune response | Cellular immune response is defined as the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥2 fold increase compared with baseline for those the frequency of gE-specific CD4+ T-cells ≥Cut-off value at baseline; or the frequency of gE-specific CD4+ T-cells (expressing at least 1 Immunological activation marker) ≥Cut-off value for those the frequency of gE-specific CD4+ T-cells <Cut-off value at baseline. | Month 6, 12 after the second vaccination (Day 240, Day 420) |