A Safety and Immunogenicity Study of a Zoster Vaccine in Healthy Adults >= 40 Years
Phase: PHASE1
Conditions: Herpes Zoster
Sponsor: Shanghai Institute Of Biological Products

                                                                                   SIBP 
Protocol ID:2017L04524-Ⅰ/Ⅱ                       1 / 9 
 
 
CLINICAL TRAIL PROTOCOL 
 
 
 
Protocol Title: A Safety and Immunogenicity Study of a Zoster Vaccine in Healthy 
Adults >= 40 Years. 
 
Collaborators: Henan Center for Disease Control and Prevention 
 
Sponsor: Shanghai Institute of Biological Products Co.,Ltd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Date: August 30, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                                                                                   SIBP 
Protocol ID:2017L04524-Ⅰ/Ⅱ                       2 / 9 
 
BACKGROUD INFORMATION 
Herpes Zoster (HZ or Shingles) is an acute inflammatory skin disease caused by reactivation of 
varicella-zoster virus (VZV) lurking in human sensory ganglia. The first infection of VZV is 
varicella, and then the virus lurks in the dorsal root ganglion for a long time. With the immune 
function weakening, the varicella-zoster virus can be reactivated, and then induce herpes zoster.  
The incidence and severity of herpes zoster increase with age, and obviously over 50 years old, 
which is related to the decrease of cellular immunity level. It is estimated that about half of the 
elderly over 85 have had at least one episode of herpes zoster. China has not carried out 
nationwide epidemiological studies on herpes zoster, which are generally carried out in local areas. 
According to epidemiological studies in Guangdong, the incidence rate of herpes zoster is about 
5‰, and the lifetime incidence rate is about 3.46%. The incidence rate of the whole population in 
Beijing is higher than 2‰ and that in Taiwan is 3.4 ~ 5.0 ‰. Thus, the incidence rate of the whole 
population in China varies from region to region. With the population aging, the incidence of 
herpes zoster will further increases. Vaccination is currently considered as an effective strategy of 
controlling herpes zoster. 
At present, vaccine produced by SIBP has received clinical approval, ready to carry out phase I/ II 
clinical trials, safety and immunogenicity of the vaccine will be evaluated by clinical trials. 
 
STUDY OBJECT 
First objects: to evaluate the safety of a dose of live attenuated zoster vaccine in healthy people 
above 40 years old; to analyse VZV specific serum conversion rate, Geometric mean titer, 
geometric mean fold increase and 95% Confidence. Serum for antibody responses 30 days 
post-vaccination were compared with control vaccine and placebo. 
 
Secondary objects: to evaluate the safety of a dose of live attenuated varicella vaccine in healthy 
people above 40 years old; to evaluate the safety of a dose of placebo in healthy people above 40 
years old; to evaluate the immunogenicity persistence of subjects on the 90th, 180th and 360th 
days after vaccination. 
 
STUDY DESIGN 
This will be a randomized, blind, one-center, placebo control study conducted by Henan Center 
for Disease Control and Prevention. There will be three groups: Zoster vaccine (>=4.3LgPFU 
VZV)、 Varicella vaccine (>=3.3LgPFU VZV)、Placebo (with no VZV).  
All subjects will be inoculated with the corresponding vaccine. Then subjects will receive 
immediate response observation for 30 minutes and systematic safety observation for 7 days after 
each dose of vaccination. After 7 days of vaccination, the adverse events will be observed by 
weekly regular follow-up and the subjects' reporting. 
All subjects will be collected serum samples at day 0 before the vaccination, day 30th and day 
90th  after the vaccination. After unmasking，subjects in Group A will be collected serum 
samples at day 180th and day 360th after the vaccination. All serum samples will be detected 
FAMA antibody. See Table below. 
 
 

                                                                                   SIBP 
Protocol ID:2017L04524-Ⅰ/Ⅱ                       3 / 9 
Subjects and Procedure Table of Phase I Clinical Trials 
Subjects and Procedure Table of Phase II Clinical Trials 
 
STUDY ENDPOINT 
Primary endpoint: 
To investigate adverse events (AE) within 30 days and serious adverse events (SAE) within 6 
months after inoculation as Primary endpoint in Phase I/ II Clinical Trials. 
Secondary endpoint: 
To detect the serum conversion rate at day 30 after inoculation;  
To detect the serum VZV specific Geometric mean titer（GMT） at day 30 after inoculation; 
To detect the serum VZV specific GMT increase fold（GMI） at day 30 after inoculation; 
To detect the serum Seroconversion、GMT、GMI at day 90/180/360 after inoculation; 
 
SAFETY OBSERVATION 
Systemic adverse reactions: fever, headache, fatigue, nausea, vomiting, diarrhea, muscle pain, 
cough, allergy (anaphylactic shock, urticaria, vascular edema, etc.). 
Local adverse reactions: pain, redness, swelling, induration, rash (injection site), itching, skin 
mucous membrane. 
The events (hospitalization, hospitalization time, disability of work ability, life or death, 
congenital malformation and so on) occur during clinical trial. 
 
IMMUNOGENICITY OBSERVATION 
Group 
Age 
Dosage and Number of 
subjects 
Inocula
tion 
Serum 
collection 
Safety 
observation 
Zoster vaccine 
>=40 
years 
 >=4.3LgPFU VZV 
24 
Day 0 
Day 0 
The local and 
Systemic AE 
and SAE will 
be observed for 
6 months after 
inoculation. 
Varicella vaccine 
 >=3.3LgPFU VZV 
24 
Placebo 
with no VZV 
24 
Total 
 
 
72 
/ 
 
/ 
Group 
Age 
osage and Number of 
subjects 
Inocula
tion 
Serum collection 
Safety 
observation 
Day 0 Day 30 
Day 90 Day 180 Day 360 
Zoster 
vaccine 
>=40 
years 
>=4.3LgPFU 
VZV 
150 Day 0 150 
150 
150 
150 
150 
The local and 
systemic AE 
and SAE will 
be observed 
for 6 months 
after 
inoculation. 
Varicella 
vaccine 
>=3.3LgPFU 
VZV 
150 Day 0 150 
150 
/ 
/ 
/ 
Placebo 
with no VZV  150 Day 0 150 
150 
/ 
/ 
/ 
Total 
/ 
 
450 
/ 
/ 

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Protocol ID:2017L04524-Ⅰ/Ⅱ                       4 / 9 
Conversion rate: pre-vaccination FAMA titer < 1:8 and post-vaccination titer ≥ 1:8 or a 
pre-vaccination titer ≥ 1:8 and at least a 4-fold increase in the post-vaccination titer 
GMT: geometric mean titer. 
GMI: GMT increase fold. 
 
EVALUATION CRITERIA OF SAFETY 
The safety evaluation of each group will be divided into three stages. All the AE from the 
inoculation to day 14 after inoculation; All the AE from day 0 after inoculation to day 30 after 
inoculation; All the SAE from day 0 to the 6 months after inoculation. 
The first stage is the basis for the Phase II Clinical Trials of the same vaccine, and will be carried  
out under blind. All the stages are the basis for evaluation of vaccine safety. If each evaluation is 
not found level 4 local and systemic adverse reactions associated with vaccine and the total 
incidence rate of level 3 of local and systemic adverse reactions and abnormal laboratory test 
which associated with the vaccination is lower than 15%, that the vaccine will be acceptable 
safety. 
 
STUDY STATUS 
Record Verification: August 2018 
Study Start: November 2018 
Primary Completion: December 2019 
Study Completion: December 2020 
 
ELIGIBILITY 
Inclusion Criteria: 
Healthy volunteers aged over 40 years (male or female). 
Able to comply with all clinical trial protocol requirements and willing to complete all the visit 
plan process during the whole clinical trial observation period. 
Able to understand the content of informed consent and willing to sign the informed consent. 
Able to complete the diary card independently. 
Patients with chronic diseases need to be in a stable period. 
Axillary temperature ≤37.0°C. 
 
Exclusion Criteria: 
Prior history of herpes zoster. 
Prior history of vaccination with herpes zoster vaccine or chickenpox vaccine. 
History of allergic disease likely to be exacerbated by any component of the vaccine. 
Taking immunoglobulins and/or any blood products within the last 3 months or will receive these 
products during the study period. 
Taking certain pharmaceuticals to be like salicylate kind, including aspirin, and difluorosalicylic, 
or going to take these medicine during the study period. 
Participation in another research study involving receipt of an investigational product in the last 30 
days. 
Prior administration of live vaccine in last 30 days. 
Prior administration of subunit vaccine, inactivated vaccine or allergic therapy in last 14 days. 

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Protocol ID:2017L04524-Ⅰ/Ⅱ                       5 / 9 
History of serious disease and the participation in the clinical trial is likely to increase the disease 
risk and interfere with the observation of clinical trial index. 
Taking immunosuppressive therapy in last 6 months. 
Any autoimmune disease or immunodeficient state, autoimmune disease or immunodeficient 
disease. 
Active tuberculosis patient. 
Acute or chronic infections at the vaccination day (axillary temperature≥ 38.0°C). 
Coagulation disorders (coagulation factor deficiency, coagulopathy or platelet disorder) diagnosed 
by doctors, or obvious bruises or blood coagulation noticed. 
Woman who is breast-feeding. 
Previous history of mental and neurological diseases (e.g. depression, epilepsy or convulsion) 
Planned to move before the end of the study or leave the country for a long time during the 
scheduled study visit. 
(Volunteers in Phase I Clinical Trials) Abnormal Blood Routine and Biochemical Indexes before 
Inoculation (except for minor abnormalities that are not clinically significant as judged by doctors) 
Any other conditions may compromise the safety or availability of participants in the judgment of 
the investigator. 
 
DATA STATISTICS 
Statistics analysis of immunogenicity  
The pre-vaccination and post-vaccination geometric mean of antibody and its 95% confidence 
interval (confidence interval, CI) will be described. The post-vaccination serum conversion rate 
and their 95% CI will be described. Comparisons will be conducted to evaluate differences in 
response between study groups using a 
2
 test or Fisher's exact test to compare to the difference 
of serum conversion rate. Statistical significance will be considered at a level of α = 0.05 and all 
tests will be 2-sided. 
If the lower limit of 95%CI of post-vaccination serum conversion rate in the Zoster vaccine group 
is not lower than 72%, the immunogenicity will reach the design requirements. 
 
Statistics analysis of safety 
After the inoculation, the number of adverse reactions (rate), number of cases and adverse reaction 
grade were recorded. The number of adverse events after inoculation will be described. 
Comparisons will be conducted to evaluate differences in response between study groups using a 
2

 Statistical 
significance will be considered at a level of α = 0.05 and all tests will be 2-sided. 
 
 
 
 
 
 

                                                                                   SIBP 
Protocol ID:2017L04524-Ⅰ/Ⅱ                       6 / 9 
 
APPENDIX Ⅰ. GRADING STANDARDS FOR SEVERITY OF 
SAFETY INFORMATION 
 
 
The Event of clinical response and laboratory abnormalities after vaccination is judged by 
the China State Food and Drug Administration on "Guidelines for the classification of 
adverse events in vaccine clinical trials ". 
Grading of Local Adverse Events 
Local 
Adverse 
Reactions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potential Life 
Threatened 
(Grade 4) 
Pain 
Do not affect 
activity 
Influence 
activities 
or 
multiple use of 
non-narcotic 
analgesics 
Affect daily activities 
or multiple use of 
narcotic analgesics 
Emergency 
or 
hospitalization 
Induration 
<15 mm 
15-30 mm 
>30 mm 
Gangrene 
or 
exfoliative 
dermatitis 
Redness 
<15 mm 
15-30 mm 
>30 mm 
Gangrene 
or 
exfoliative 
dermatitis 
Swelling 
<15 mm and 
does 
not 
affect activity 
15-30 
mm 
or 
affect activity 
>30 mm or limit daily 
activity 
Gangrene 
Rash 
(injection 
site) 
<15 mm 
15-30 mm 
>30 mm 
 
Itching 
Injection site 
itching 
Injection 
of 
moderate itching 
Overall Itching 
 
 
 
 

                                                                                   SIBP 
Protocol ID:2017L04524-Ⅰ/Ⅱ                       7 / 9 
Grading of Systemic Adverse Events 
Systemic 
Adverse 
Reactions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potential Life 
Threatened 
(Grade 4) 
Fever 
37.1-37.5℃ 
37.6-39.0℃ 
>39.0℃ 
 
Headache 
No activity, no 
treatment 
Transient, slightly 
affected activity 
requiring 
treatment 
(multiple use of 
non-narcotic 
analgesics) 
Severe effects on 
daily activities, 
initial anesthetic 
response 
Refractory, 
repeated 
anesthetic 
treatment. 
Emergency or 
hospitalization 
Fatigue and 
fatigue 
The normal 
activity is less 
than 48 hours, 
and it did not 
affect the activity 
Normal activity 
decreased from 
20% to 50% > 48 
hours, slightly 
affecting activities 
Normal activity 
decreased by 
more than 50%, 
seriously affecting 
daily activities, 
unable to work 
Unable to take 
care of oneself, 
emergency or 
hospitalization 
Nausea and 
vomiting 
1~2 times per 24 
hours, intake is 
normal and does 
not affect the 
activity 
2 ~ 5 times per24 
hours, intake is 
significantly 
reduced, or 
limited activity 
> 6 times within 24 
hours, no obvious 
intake, the need for 
intravenous infusion
requires 
hospitalization or 
other nutrition 
because of 
hypotension, 
shock 
Diarrhea 
Mild or transient, 
2 ~ 3 stools per 
day or mild 
diarrhea lasting 
for less than 1 
weeks 
Moderate or 
persistent, 4~5 
times per day, or 
more than 1 week 
diarrhea 
> 6 times of water 
stool per day, or 
blood diarrhea, 
orthostatic 
hypotension 
Hypotension 
shock requiring 
hospitalization 
Myalgia 
Not affecting daily 
activities 
Muscle 
tenderness at the 
non injection site 
slightly affects 
daily activity 
Severe muscle 
tenderness 
seriously affects 
daily activities  
The symptoms 
are obvious, 
muscle necrosis, 
emergency or 
hospitalization 

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Protocol ID:2017L04524-Ⅰ/Ⅱ                       8 / 9 
Cough 
Transient, without 
treatment 
Persistent cough, 
effective 
treatment 
Paroxysmal 
cough, treatment 
can not control 
Emergency or 
hospitalization 
Allergy 
Pruritus without 
skin rash 
Local urticaria 
Extensive urticaria, 
vascular edema 
Severe allergy 
Other 
adverse or 
clinical 
adverse 
reactions 
(based on 
the 
correspondi
ng criteria) 
Do not affect 
activities 
Slightly affects 
activities without 
drug treatment 
Serious impact on 
daily activities 
requires drug 
treatment 
 
 
 

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Protocol ID:2017L04524-Ⅰ/Ⅱ                       9 / 9 
APPENDIX Ⅱ. THE RELATIONSHIP BETWEEN ADVERSE 
EVENTS AND TRIAL VACCINES 
 
Absolutely unrelated: Because of other factors lead to adverse events, there 
is evidence that adverse events are caused by other causes, not related to 
vaccination. 
 
Possible unrelated: Adverse events probable be caused by other factors, 
such as the clinical status of the subjects, other treatment or concomitant 
medication, inconsistent with the known adverse reactions of vaccination. 
 
Quite possible related: Adverse events are consistent with known 
information of vaccine, and there is a causal relationship with the vaccine, not 
by other factors, such as the clinical status of the subjects, or other treatment 
with medication. 
 
Possible related: Adverse events are consistent with known information of 
vaccine, and there is a causal relationship with the vaccine, not by other 
factors, such as the clinical status of the subjects, or other treatment with 
medication. 
 
Related: Adverse events are consistent with known information of vaccine, 
and there is a causal relationship with the vaccine, not by other factors, such 
as the clinical status of the subjects, or other treatment with medication. In 
addition, adverse events will be repeated when subjects are tested with the 
vaccine.