Immunogenicity and Safety of a Quadrivalent Influenza Vaccine in Participants Aged Above 3 Years
Phase: PHASE3
Conditions: Influenza
Sponsor: Shanghai Institute Of Biological Products

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CLINICAL TRAIL PROTOCOL 
 
 
Protocol Title: Immunogenicity and Safety of a Quadrivalent Influenza 
Vaccine: a Randomized, Blind, a Phase III Clinical Trial. 
 
 
Collaborators: Jiangsu Center for Disease Control and Prevention 
 
Sponsor: Shanghai Institute of Biological Products 
 
 
 
 
 
 
 
Document Date: October 12, 2018 
 

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BACKGROUD INFORMATION  
Influenza is an acute, highly infectious and rapid respiratory infectious disease caused by 
the influenza virus, which is one of the important causes of human death. Influenza 
viruses are classified into three subtypes A, B and C. Influenza A and influenza B viruses, 
particularly influenza A viruses, are prevalent in the population and in the form of seasonal 
influenza, while influenza C viruses are uncommon and cause only mild symptoms. 
Influenza A viruses can be divided into different subtypes according to the two surface 
antigens hemagglutinin (HA) and neuraminidase (NA) of the virus.  
 
Currently, influenza A viruses causing seasonal influenza are mainly influenza viruses of 
the H1N1 subtype and H3N2 subtype. The investigation showed that the B/Victoria 
lineage dominated the B/Yamagata strain from 1940 to 1980, while the B/Yamagata 
lineage dominated from 1987 to 1989. But since 2001, two different strains of B influenza 
virus B/Victoria/2/87-like and B/Yamagata/16/88-like have been circulating at the same 
time. 
 
In February 2012, the world health organization (who) for the first time suggested that t the 
seasonal flu vaccine should contain two kinds of B lineage strain proposal. Since 
2013-2014, flu season in the northern hemisphere, WHO began to recommend 
quadrivalent vaccine, to add another subtype B influenza virus in trivalent vaccine, in 
order to achieve better protection effect. In recent years, the development of quadrivalent 
influenza vaccine has become an important trend of influenza vaccine. 
 
STUDY OBJECT 
First objects:  
To evaluate the immunogenicity of quadrivalent influenza vaccine 30 days in healthy 
population years aged 3 years and above, according to investigate antibodies at day 30 
after one inoculation 
 
Secondary objects: 
To evaluate the safety of quadrivalent influenza vaccine 30 days in healthy population 
years aged 3 years and above, according to investigate occurrence of adverse events for 
30 days after one inoculation. 
 
To prove conversion rate and geometric mean titer (GMT) of quadrivalent influenza 
vaccine being non-inferior for shared strains to trivalent influenza vaccines. 

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STUDY DESIGN 
This will be a randomized, blind, one-center, active comparator study conducted by 
Jiangsu Center for Disease Control and Prevention. 
 
There will be three groups. Group A (quadrivalent influenza vaccine), Group B (trivalent 
influenza vaccine containing B/Victoria lineage) and Group C (trivalent influenza vaccine 
containing B/Yamagata lineage). Each group will be divided four age groups (3-8 years, 
9-17 years, 18-59 years, 60 years and older). 
 
All subjects will be inoculated with the corresponding vaccine at day 0. 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 before vaccination and day 30 after 
vaccination. All serum samples will be detected HI antibody.  
 
STUDY ENDPOINT 
Primary endpoint 
To detect the serum HI antibody at day 21 after last inoculation as secondary endpoint. 
 
Secondary endpoint 
To investigate adverse events (AE) and serious adverse events (SAE) within 30 days after 
the inoculation as primary endpoint. 
 
SAFETY OBSERVATION 
Systemic adverse reactions: fever, headache, fatigue, 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. 
 

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IMMUNOGENICITY OBSERVATION 
Seroconversion: 1:10 is the lowest serum dilution. Prevaccination HI titer < 1:10 and 
postvaccination titer ≥ 1:40 or a prevaccination titer ≥ 1:10 and at least a 4-fold increase in 
the postvaccination titer 
 
Seroprotection: Postvaccination titer ≥ 1:40 is considered to have antibody protection. 
 
GMT: geometric mean titer. 
 
GMI: GMT increase fold. 
 
EVALUATION CRITERIA OF SAFETY 
The safety evaluation of each group will be divided into three stages. From the first dose 
inoculation to day 7 after inoculation; From the first dose inoculation to day 21 after 
inoculation; From the second dose inoculation to day 30 after the second dose inoculation. 
The first stage is the basis for the follow-up group of the same vaccine, and will be carried 
out under blind. The latter two stages are the basis for evaluation of vaccine safety, and 
will be carried out under unblind. 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. 
 
EVALUATION CRITERIA OF IMMUNOGENICITY 
If seroconversion rate is higher than 40%, the antibody protection rate higher than 70%, 
GMI more than 2.5 times, the vaccine will be acceptable immunogenicity. 
 
STUDY STATUS 
Record Verification: October 2018 
Study Start: November 2018 
Primary Completion: March 2019 
Study Completion: June 2019 
 
ELIGIBILITY 
Inclusion Criteria: 
Over the age of three years,healthy population 
Subjects/ (and the guardian) informed consent, voluntarily participated and signed the 

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informed consent form, with the ability to use thermometers, scales and to fill in diary 
cards as required 
To comply with the requirements of clinical trial program 
Temperature≤37.0℃ on day of enrollment 
 
Exclusion Criteria: 
A history of influenza virus infection or suspected infection Abnormal blood routine, blood 
biochemistry and urine routine examination indexes in last three months 
Any prior administration of influenza vaccine in last six months 
Allergy to any component in the vaccine, especially for egg allergy 
Allergy history of any previous vaccination or drug 
Acute episodes of chronic illness or acute illness on the day of vaccination 
Received a live vaccine within fourteen days prior to receiving the vaccine, or received a 
subunit or inactivated vaccine within seven days 
Congenital or acquired immune deficiencies, or treatment with immunosuppressive 
agents, such as long-term treatment with systemic corticosteroids 
Suffering from severe chronic diseases (such as Down's syndrome, diabetes, sicklemia or 
neurological disorders, Green's Barre syndrome) 
Asthma, required urgent treatment in last two years 
The blood products were received prior to the acceptance of the vaccine 
Known or suspected of respiratory disease, acute infection or chronic disease active 
period, HIV infection, cardiovascular disease, severe hypertension, malignant tumor 
during treatment, skin diseases 
History of epilepsy, convulsions, or a family history of psychosis 
Abnormal coagulation function (such as coagulation factor deficiency, coagulation 
disorders, platelet abnormalities), or obvious bruising or coagulopathy 
Plan to move or leave the area for an extended period of time before the end of the study 
Under anti-tb treatment 
Any prior administration of other research medicine/vaccine in last one month 
Women are pregnant or in the near future planned pregnancy or pregnancy test positive 
 
DATA STATISTICS 
Statistics analysis of immunogenicity  
The prevaccination and postvaccination geometric mean of antibody and its 95% 
confidence interval (confidence interval, CI) will be described. The postvaccination serum 
conversion rate and protection rate of antibody and their 95% CI will be described. 

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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 and protection rate. Statistical significance will be considered at a level of α = 0.05 
and all tests will be 2-sided. 
 
If serum HI antibody conversion rate is more than 40%; protection rate more than 70%; 
GMI more than 2.5 folds, the immunogenicity will reach the design requirements.  
 
Statistics analysis of safety 
After the first dose inoculation and the second dose 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
 test or Fisher's exact test to compare to the difference of adverse events rate. 
Statistical significance will be considered at a level of α = 0.05 and all tests will be 
2-sided. 
 
Comparison of compliance 
The rate of expulsion and the rate of drug combination 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 the rate of 
expulsion and the rate of drug combination. Statistical significance will be considered at a 
level of α = 0.05 and all tests will be 2-sided. 
 
 

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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 
 
 
 
 

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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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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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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.