Collection of Serum Samples From Children 6 Months to < 9 Years of Age Who Received Fluzone® Quadrivalent and Adults ≥ 65 Years of Age Who Received Fluzone® High-Dose Quadrivalent, Influenza Vaccines, 2020-2021 Formulations
Phase: PHASE4
Conditions: Influenza Immunization, Healthy Volunteers
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
Collection of Serum Samples From Children 6 Months to < 9 Years of Age Who Received 
Fluzone® Quadrivalent and Adults ≥ 65 Years of Age Who Received Fluzone® High-Dose 
Quadrivalent, Influenza Vaccines, 2020–2021 Formulations 
Study Code: GRC00101 
Protocol Version Number: 1.0 
Amendment Number: Not Applicable 
Compound: Fluzone® Quadrivalent and Fluzone® High-Dose Quadrivalent Influenza Vaccines 
(2020–2021 Formulations) 
Study Phase: IV 
Short Title: 
Annual Study for Collection of Serum Samples in Children and Older Adults Receiving the 2020–
2021 Formulations of Fluzone Quadrivalent Vaccine and Fluzone High-Dose Quadrivalent 
Vaccine, Respectively 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Manufacturer: Same as Sponsor 
Regulatory Agency Identifier Numbers: 
BB-IND: 4518 
WHO UTN: U1111-1238-1821 
Approval Date: 29 June 2020 
Medical Monitor Name and Contact Information are provided in the Operating Guidelines. 
The study centers, the Investigators at each center, and the Coordinating Investigator are listed in 
a separate document. 
Document History 
Not applicable as this is the first version of the protocol. 
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Table of Contents 
List of Tables .......................................................................................................................... 6 
List of Figures ........................................................................................................................ 7 
1 
Protocol Summary ................................................................................................... 8 
1.1 
Synopsis .................................................................................................................. 8 
1.2 
Schema .................................................................................................................. 10 
1.3 
Schedule of Activities (SoA) ................................................................................ 11 
2 
Introduction ........................................................................................................... 15 
2.1 
Study Rationale ..................................................................................................... 15 
2.2 
Background ........................................................................................................... 15 
2.2.1 
Epidemiology ...................................................................................................... 17 
2.2.2 
Prevention and Control of Infection Among Humans ........................................ 18 
2.2.3 
The Advisory Committee on Immunization Practices Recommendations ......... 19 
2.2.4 
Background of the Investigational Product ........................................................ 19 
2.3 
Benefit/Risk Assessment ...................................................................................... 20 
2.3.1 
Risks from Study Participation ........................................................................... 20 
2.3.2 
Benefits from Study Participation ...................................................................... 25 
2.3.3 
Overall Benefit-Risk Conclusion ........................................................................ 25 
3 
Objectives and Endpoints ..................................................................................... 25 
4 
Study Design .......................................................................................................... 26 
4.1 
Overall Design ...................................................................................................... 26 
4.2 
Scientific Rationale for Study Design ................................................................... 27 
4.3 
Justification for Dose ............................................................................................ 28 
4.4 
End of Study Definition ........................................................................................ 28 
5 
Study Population ................................................................................................... 28 
5.1 
Inclusion Criteria .................................................................................................. 28 
5.2 
Exclusion Criteria ................................................................................................. 29 
5.3 
Lifestyle Considerations ....................................................................................... 30 
5.4 
Screen Failures ...................................................................................................... 30 
6 
Study Intervention ................................................................................................. 31 
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6.1 
Study Interventions Administered ........................................................................ 31 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 32 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 33 
6.3.1 
Randomization and Allocation Procedures ........................................................ 33 
6.3.2 
Blinding and Code-breaking Procedures ............................................................ 33 
6.4 
Study Intervention Compliance ............................................................................ 33 
6.5 
Concomitant Therapy ............................................................................................ 33 
6.5.1 
Rescue Medicine ................................................................................................. 34 
6.6 
Dose Modification ................................................................................................ 34 
6.7 
Intervention After the End of the Study ................................................................ 35 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ................................................................................ 35 
7.1 
Discontinuation of Study Intervention .................................................................. 35 
7.1.1 
Temporary Contraindications ............................................................................. 35 
7.1.2 
Definitive Contraindications ............................................................................... 35 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................................... 36 
7.3 
Lost to Follow-up .................................................................................................. 36 
8 
Study Assessments and Procedures ..................................................................... 37 
8.1 
Efficacy and Immunogenicity Assessments ......................................................... 37 
8.1.1 
Efficacy Assessments ......................................................................................... 37 
8.1.2 
Immunogenicity Assessments ............................................................................ 37 
8.2 
Safety Assessments ............................................................................................... 37 
8.2.1 
Medical History .................................................................................................. 38 
8.2.2 
Physical Examinations ........................................................................................ 38 
8.2.3 
Vital Signs .......................................................................................................... 38 
8.2.4 
Clinical Safety Laboratory Assessments ............................................................ 38 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 38 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ............... 39 
8.3.2 
Method of Detecting SAEs/AESIs ..................................................................... 39 
8.3.3 
Follow-up of SAEs and AESIs ........................................................................... 40 
8.3.4 
Regulatory Reporting Requirements for SAEs .................................................. 40 
8.3.5 
Pregnancy ........................................................................................................... 40 
8.3.6 
Adverse Events of Special Interest ..................................................................... 41 
8.4 
Treatment of Overdose ......................................................................................... 41 
8.5 
Pharmacokinetics .................................................................................................. 41 
8.6 
Pharmacodynamics ............................................................................................... 41 
8.7 
Genetics ................................................................................................................. 41 
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8.8 
Biomarkers ............................................................................................................ 41 
8.9 
Immunogenicity Assessments ............................................................................... 41 
8.10 
Health Economics or Medical Resource Utilization and Health Economics ....... 41 
9 
Statistical Considerations ..................................................................................... 42 
9.1 
Statistical Hypotheses ........................................................................................... 42 
9.2 
Sample Size Determination ................................................................................... 42 
9.3 
Populations for Analyses ...................................................................................... 42 
9.4 
Statistical Analyses ............................................................................................... 42 
9.4.1 
General Considerations ....................................................................................... 42 
9.4.2 
Primary Endpoint(s) ........................................................................................... 42 
9.4.3 
Secondary Endpoint(s) ....................................................................................... 42 
9.4.4 
Observational Endpoint(s) .................................................................................. 43 
9.4.5 
Other Safety Analyse(s) ...................................................................................... 43 
9.4.6 
Other Analyse(s) ................................................................................................. 43 
9.5 
Interim Analyses ................................................................................................... 43 
9.6 
Data Monitoring Committee (DMC) .................................................................... 43 
10 
Supporting Documentation and Operational Considerations .......................... 44 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations .................. 44 
10.1.1 
Regulatory and Ethical Considerations .............................................................. 44 
10.1.2 
Financial Disclosure ........................................................................................... 44 
10.1.3 
Informed Consent Process .................................................................................. 45 
10.1.4 
Data Protection and Future Use of Stored Samples ........................................... 45 
10.1.5 
Committees Structure ......................................................................................... 46 
10.1.6 
Dissemination of Clinical Study Data ................................................................ 46 
10.1.7 
Data Quality Assurance ...................................................................................... 47 
10.1.8 
Source Documents .............................................................................................. 48 
10.1.9 
Study and Site Start and Closure ........................................................................ 48 
10.1.10 
Publication Policy ............................................................................................... 49 
10.2 
Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .................................................................. 50 
10.2.1 
Definition of AE ................................................................................................. 50 
10.2.2 
Definition of SAE ............................................................................................... 52 
10.2.3 
Recording and Follow-Up of AE and/or SAE .................................................... 53 
10.2.4 
Reporting of SAEs .............................................................................................. 55 
10.2.5 
Assessment of Intensity ...................................................................................... 56 
10.2.5.1 
Tables for Clinical Abnormalities .................................................................... 56 
10.3 
Appendix: Risk-based Approach .......................................................................... 56 
10.4 
Appendix: Abbreviations ...................................................................................... 57 
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10.5 
References ............................................................................................................. 58 
11 
Sponsor Signature Page ........................................................................................ 61 
 
 
 
 
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List of Tables 
Table 1.1: Schedule of Activities 1 ............................................................................................... 12 
Table 1.2: Schedule of Activities 2 ............................................................................................... 14 
Table 2.1: Potential Risks of Clinical Significance and Risk Management .................................. 21 
Table 3.1: Objectives and Endpoints ............................................................................................. 26 
Table 4.1: Overall Design .............................................................................................................. 27 
Table 6.1: Identity of Study Interventions ..................................................................................... 31 
 
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List of Figures 
Figure 1.1 – Graphical Study Design for Participants 6 Months to < 9 Years of Age .................. 11 
Figure 1.2 – Graphical Study Design for Participants ≥ 65 Years of Age .................................... 11 
 
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 Protocol Summary 
1.1 
Synopsis 
Protocol Title:  
Collection of Serum Samples From Children 6 Months to < 9 Years of Age Who Received 
Fluzone® Quadrivalent and Adults ≥ 65 Years of Age Who Received Fluzone® High-Dose 
Quadrivalent, Influenza Vaccines, 2020–2021 Formulations 
Short Title: 
Annual Study for Collection of Serum Samples in Children and Older Adults Receiving the 2020–
2021 Formulations of Fluzone Quadrivalent Vaccine and Fluzone High-Dose Quadrivalent 
Vaccine, Respectively 
Rationale: 
The aim of Study GRC00101 is to obtain serum samples for submission to the Center for 
Biologics Evaluation and Research (CBER) to aid in the influenza vaccine strain selection 
process. Children 6 months to < 9 years of age will receive the 2020–2021 formulation of Fluzone 
Quadrivalent vaccine and adults ≥ 65 years of age will receive the 2020–2021 formulation of 
Fluzone High-Dose Quadrivalent vaccine. 
Serum samples from participants will be supplied to CBER after the completion of this study 
(i.e., after the last participant completes the last study visit). In turn, CBER will distribute the 
serum samples to the Centers for Disease Control and Prevention (CDC) and other World Health 
Organization (WHO)-collaborating laboratories for evaluation against circulating influenza viral 
strains. It is expected that the immunologic and surveillance data will be presented at WHO 
meetings where the vaccine strain selections will be made for the Southern and Northern 
hemispheres and at the Food and Drug Administration (FDA) Vaccines and Related Biological 
Products Advisory Committee meeting for selection of strains for influenza vaccines, including 
those to be distributed in the United States.  
No early safety data review is planned for this study. 
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Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
• 
To provide serum samples (collected from 
participants before vaccination [Blood 
Sample 1] and after final vaccination 
[Blood Sample 2]) to CBER for further 
analysis by the WHO, CDC, and FDA to 
support formulation recommendations for 
subsequent influenza vaccines. In 
addition, serum samples from adult 
participants may be further analyzed by 
the Sponsor to assess breadth of immune 
response induced by the study vaccines. 
• 
There are no endpoints for this objective. 
 
Overall Design: 
 
Type of design 
Parallel, multi-center 
Phase 
IV 
Control Method 
None 
Study Population 
Children 6 months to < 9 years of age 
Adults ≥ 65 years of age 
Countries 
United States 
Level and method of blinding 
None (Open label) 
Study intervention assignment method 
Participants will not be randomized. 
 
Disclosure Statement: This is a parallel group serum collection study with 3 arms and no 
blinding. 
Number of Participants: 
A total of 90 participants are expected to be enrolled. See Section 9.2. 
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Intervention Groups and Duration: 
Each participant will be assigned to a vaccine group based on the participant’s age at the time of 
enrollment. 
• Group 1: Children 6 to < 36 months of age assigned to receive a 0.5-mL dose of Fluzone 
Quadrivalent vaccine (30 participants planned) 
• Group 2: Children 3 to < 9 years of age assigned to receive a 0.5-mL dose of Fluzone 
Quadrivalent vaccine (30 participants planned) 
• Group 3: Adults ≥ 65 years of age assigned to receive a 0.7-mL dose of Fluzone High-Dose 
Quadrivalent vaccine (30 participants planned)  
An approximately equal number of participants from each group will be enrolled at each site.  
Participants will receive an intramuscular (IM) injection at Visit 1. For participants 6 months to < 
9 years of age for whom 2 doses of influenza vaccine are recommended per Advisory Committee 
on Immunization Practices (ACIP) guidance, a second IM injection of Fluzone Quadrivalent 
vaccine will be administered at Visit 2 (28 [window, 28–35] days after Visit 1). 
The duration of each subject’s participation is as follows: 
• Participants 6 months to < 9 years of age: 28 (window, 28–35) days following the last dose of 
influenza vaccine, including serious adverse event (SAE)/adverse event of special interest 
(AESI) follow-up. No additional safety follow-up beyond Visit 2 (for participants receiving 1 
dose) or Visit 3 (for participants receiving 2 doses) is planned. 
• Participants ≥ 65 years of age: 21 (window, 21–28) days after vaccination, including 
SAE/AESI follow-up. No additional safety follow-up beyond Visit 2 is planned. 
Data Monitoring Committee: No 
1.2 
Schema 
The graphical designs of GRC00101 study are presented in Figure 1.1 and Figure 1.2. 
 
 
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Figure 1.1 – Graphical Study Design for Participants 6 Months to < 9 Years of Age 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.2 – Graphical Study Design for Participants ≥ 65 Years of Age 
 
 
 
 
 
 
 
 
 
BL: blood sample 
VAC : vaccination 
1.3 
Schedule of Activities (SoA) 
Visits procedures are detailed in the Operating Guidelines. 
 
1                      21              28              49               56 
Time (days) 
VAC1 
VAC2
a 
BL1 
BL2
a 
BL2
b 
BL: blood sample 
VAC : vaccination
 
a      Participants receiving 2 doses of study vaccine, as per Advisory Committee on Immunization Practices (ACIP)  
     guidance  
b    Participants receiving 1 dose of study vaccine 
1                             14                          21   
Time (days) 
VAC1 
BL1 
BL2 
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Table 1.1: Schedule of Activities 1 
For Participants 6 Months to < 9 Years of Age: Phase IV Study, 2 or 3 Visits, 1 or 2 Vaccinations, 1 or 2 Telephone Calls, 2 Blood Samples,  
1 or 2 Months Duration Per Participant 
 
 
All Participants 
Participants 
Receiving 1 Dose of 
Influenza Vaccine 
Participants Receiving 2 Doses of Influenza 
Vaccine 
Visit/Contact 
Collection  
of information  
in the CRB 
Visit 1 
Telephone 
Contact 
Visit 2 
Visit 2 
Telephone 
Contact 
Visit 3 
Study timelines (days) 
Day 01 
Visit 1  
+ 21 days 
Visit 1 + 28 days 
Visit 1  
+ 28 days 
Visit 2  
+ 21 days 
Visit 2  
+ 28 days 
Time windows (days) 
- 
+ 19 to 23 days 
+ 28 to 35 days 
+ 28 to 35 
days 
+ 19 to 23 days 
+ 28 to 35 
days 
Visit procedures: 
 
 
 
 
 
 
 
Informed consent/assenta 
X 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
 
 
Collection of medical history 
X 
X 
 
 
 
 
 
Influenza vaccination history  
X 
X 
 
 
 
 
 
History-directed physical 
examination 
 
X 
 
 
X 
 
 
Pre-vaccination temperatureb 
X 
X 
 
 
X 
 
 
Review contraindications for 
vaccination 
X 
 
 
 
X 
 
 
Allocation of participant number 
X 
X 
 
 
 
 
 
Blood sampling (BL)c 
X 
BL1 
 
BL2 
 
 
BL2 
Vaccinationd 
X 
X 
 
 
X 
 
 
Immediate surveillance 
(20 minutes) 
X 
X 
 
 
X 
 
 
Diary card (DC) provided 
 
DC1 
 
 
DC2 
 
 
Telephone contacte 
 
 
X 
 
 
X 
 
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All Participants 
Participants 
Receiving 1 Dose of 
Influenza Vaccine 
Participants Receiving 2 Doses of Influenza 
Vaccine 
Visit/Contact 
Collection  
of information  
in the CRB 
Visit 1 
Telephone 
Contact 
Visit 2 
Visit 2 
Telephone 
Contact 
Visit 3 
Study timelines (days) 
Day 01 
Visit 1  
+ 21 days 
Visit 1 + 28 days 
Visit 1  
+ 28 days 
Visit 2  
+ 21 days 
Visit 2  
+ 28 days 
Time windows (days) 
- 
+ 19 to 23 days 
+ 28 to 35 days 
+ 28 to 35 
days 
+ 19 to 23 days 
+ 28 to 35 
days 
Diary card reviewed  
 
 
 
DC1 
DC1 
 
DC2 
Diary card collected 
 
 
 
DC1 
DC1 
 
DC2 
Interim history 
X 
 
 
X 
X 
 
X 
Reporting medical events to allow 
for the collection of SAEs and 
AESIs 
X 
To be reported throughout the study period 
Collection of reportable 
concomitant medications 
X 
X 
 
X 
X 
 
X 
End of Active Phase participation 
recordf 
X 
 
 
X 
 
 
X 
  
AESI: adverse event of special interest; CRB: case report book; SAE: serious adverse event 
a 
Informed consent form will be signed and dated by parent(s) or guardian(s) for participants 6 months to < 9 years of age and assent form will be signed and dated by participants 7 to < 9 years of age. 
b 
The preferred route for this study is rectal for participants 6 to < 36 months of age, and oral for participants 3 to < 9 years of age. The axillary route may be used when a rectal or oral temperature 
cannot be obtained. 
c 
A blood sample, approximately 5 mL, will be collected from all participants at Visit 1, prior to vaccination, and at either Visit 2 (for participants receiving 1 influenza vaccine dose) or at Visit 3 (for 
participants receiving 2 influenza vaccine doses). 
d 
One or 2 doses of influenza vaccine will be administered according to the Advisory Committee on Immunization Practices guidance in effect during the study. If 2 doses of influenza vaccine are 
indicated, 1 dose will be administered during Visit 1 and the second dose will be administered approximately 28 days later during Visit 2. 
e 
The participant’s parent/guardian will be contacted by telephone 21 (window, 19–23) days after vaccination as a reminder to notify the site immediately if a serious medical event (e.g., hospital visit) 
occurs and to complete the diary card and to bring it with them to the next visit. 
f 
The End of Active Phase participation record will be completed at Visit 2 for participants receiving 1 dose of influenza vaccine or at Visit 3 for participants receiving 2 doses of influenza vaccine. In 
case of participant discontinuation at a visit, the entire visit will be completed. 
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Table 1.2: Schedule of Activities 2 
For Participants ≥ 65 Years of Age: 2 Visits, 1 Vaccination, 1 Telephone Call, 2 Blood Samples, 
21 Days Duration Per Participant 
 
Visit/Contact 
Collection  
of 
information  
in the CRB 
Visit 1 
Telephone 
Contact 
Visit 2 
Study timelines (days) 
Day 01 
Visit 1 + 14 days 
Visit 1 + 21 
days 
Time windows (days) 
- 
+ 12 to 16 days 
+ 21 to 28 days 
Visit procedures: 
 
 
 
 
Informed consent  
X 
X 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Collection of demographic data 
X 
X 
 
 
Collection of medical history  
X 
X 
 
 
Influenza vaccination history (previous season) 
X 
X 
 
 
History-directed physical examination  
 
X 
 
 
Pre-vaccination temperaturea 
X 
X 
 
 
Allocation of participant number 
X 
X 
 
 
Blood sampling (BL)b  
X 
BL1 
 
BL2 
Vaccination  
X 
X 
 
 
Immediate surveillance (20 minutes) 
X 
X 
 
 
Diary card provided 
 
X 
 
 
Telephone contactc 
 
 
X 
 
Diary card reviewed and collected 
 
 
 
X 
Reporting of medical events to allow for the 
collection of SAEs, including AESIs 
X 
To be reported throughout the study period 
Collection of reportable concomitant 
medications 
X 
X 
 
X 
End of Active Phase participation recordd 
X 
 
 
X 
AESI: adverse event of special interest; CRB: case report book; SAE: serious adverse event 
a 
The preferred route for this study for participants ≥ 65 years of age is oral. 
b 
A blood sample, approximately 20 mL, will be collected at Visit 1 and Visit 2. 
c 
Participants will be contacted by telephone 14 (window, 12–16) days after vaccination as a reminder to notify 
the site immediately if a serious medical event (e.g., hospital visit) occurs and to complete the diary card and to 
bring it with them to Visit 2.  
d 
In case of participant discontinuation at a visit, the entire visit will be completed. 
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2 
Introduction 
2.1 
Study Rationale 
The aim of Study GRC00101 is to obtain serum samples for submission to CBER to aid in the 
influenza vaccine strain selection process. Children 6 months to < 9 years of age will receive the 
2020–2021 formulation of Fluzone Quadrivalent vaccine and adults ≥ 65 years of age will receive 
the 2020–2021 formulation of Fluzone High-Dose Quadrivalent vaccine. 
Serum samples from participants will be supplied to CBER after the completion of this study 
(i.e., after the last participant completes the last study visit). In turn, CBER will distribute the 
serum samples to the CDC and other WHO-collaborating laboratories for evaluation against 
circulating influenza viral strains. It is expected that the immunologic and surveillance data will 
be presented at WHO meetings where the vaccine strain selections will be made for the Southern 
and Northern hemispheres and at the FDA Vaccines and Related Biological Products Advisory 
Committee meeting for selection of strains for influenza vaccines, including those to be 
distributed in the United States.  
No early safety data review is planned for this study. 
2.2 
Background 
This is a study using the 2020–2021 formulations of quadrivalent inactivated influenza vaccine 
(Fluzone Quadrivalent, Influenza Vaccine) and high-dose quadrivalent inactivated influenza 
vaccine (Fluzone High-Dose Quadrivalent, Influenza Vaccine).  
Influenza viruses types A and B belong to the genus Orthomyxoviridae and are characterized as 
enveloped, negative-strand, segmented ribonucleic acid (RNA) viruses. The viral envelope 
contains 2 virus-coded glycoprotein spikes, the hemagglutinin (HA) and neuraminidase (NA) 
proteins, which are key antigens in the host response to influenza virus in both natural 
infection and vaccination. A third protein, M2, is a minor envelope component of the A-strain 
viruses (1). 
Influenza is transmitted through inhalation of virus-containing droplets from infected individuals. 
The incubation period is usually 1 to 2 days (2). The virus multiplies in the ciliated columnar 
epithelium of the upper and lower respiratory tract, causing cellular necrosis and sloughing (1). 
Virus shedding typically begins just before illness onset (within 24 hours), rapidly peaks, and 
remains elevated for 1 to 2 days before rapidly declining to low levels. Usually, virus shedding 
lasts a total of 5 to 10 days (2). 
There is considerable variation in the severity of illness in different individuals, partly due to age, 
general health, and immune status relative to previous influenza infections and vaccination. The 
classic symptoms include rapid onset (12 hours or less) of malaise, fever, myalgia, headache, and 
a non-productive cough or sore throat. Most symptoms last several days, but malaise and cough 
may last for a week or more (2). Complications of influenza include primary viral pneumonia, 
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secondary bacterial pneumonia, and exacerbation of underlying medical conditions such as 
chronic obstructive pulmonary disease and congestive heart failure.  
While influenza affects all age groups, the elderly, children younger than 5 years of age, and 
persons with underlying health problems are amongst those at increased risk for complications. 
Members of high-risk groups who become ill with influenza are more likely than the general 
population to require hospitalization. Among infants and younger children, estimated rates of 
influenza-associated hospitalization are substantially higher than among older children and are 
similar to rates for other groups considered at higher risk for influenza-related complications, 
including persons ≥ 65 years of age who are at increased risk due to immunosenescence and 
adults 50–64 years of age and older who are at increased risk because they are likely to have 
chronic medical conditions that could lead to severe influenza illness (3). 
Antigenic variation is an important feature of the influenza virus. The viral HA and NA surface 
antigens are subject to continuous and sequential evolution within immune or partially immune 
populations. Antigenic drift results from mutation(s) affecting the RNA segment coding for either 
HA or NA, but more commonly HA. As a result, there is alteration in protein structure involving 
1 or a few amino acids, resulting in minor changes in antigenicity. Antigenic variants within a 
subtype (e.g., H1 or H3) emerge and through natural selection gradually become the more 
predominant circulating virus strain, while the preceding antigenic variant is suppressed by 
specific immunity in the population. In contrast to antigenic drift, antigenic shift represents the 
emergence of completely new subtypes, typically through gene reassortment with other 
circulating strains and acquisition of antigenically different gene sequences. Antigenic shift 
occurs at irregular intervals and may lead to pandemics (1) (2). While influenza B appears to be 
more genetically stable than influenza A, the dominant circulating B strain typically varies from 
season to season. For over a decade, both Yamagata and Victoria lineages have co-circulated 
during each season with varying prevalence (4). The large antigenic divergence between the 
2 influenza B lineages limits antigenic cross-reactivity; therefore, immunity to 1 B lineage may 
not provide adequate protection against the other. Accordingly, switching from a trivalent vaccine 
to a quadrivalent vaccine is expected to prevent additional morbidity and mortality associated 
with mismatched influenza B strains that may occur with trivalent vaccines (4). With this in mind, 
Fluzone Quadrivalent vaccine and Fluzone High-Dose Quadrivalent vaccine were developed. 
Vaccination with influenza vaccine is the primary method for preventing influenza and its severe 
complications. It has been shown to be effective in reducing influenza-associated morbidity and 
mortality in groups at increased risk for influenza-related complications such as infants and young 
children and persons 50 years of age and older. Of note, immune responses to the vaccine are 
lower in seniors than those in young healthy adults (3). Strategies to improve immune responses 
to the vaccine in the elderly population could provide substantial additional reductions in 
influenza-associated morbidity and mortality. One approach is to increase the dose of HA in 
inactivated vaccines. Previous studies evaluating the immune responses in terms of 
hemagglutination inhibition (HAI) antibodies with higher doses of HA per strain in different 
influenza vaccines support a dose-response effect (5). 
Fluzone High-Dose Quadrivalent vaccine contains 60 µg HA per virus strain per dose, which is 
4 times the amount of HA per strain per dose in Fluzone Quadrivalent vaccine. It was developed 
for use in the elderly to elicit enhanced immune responses against influenza through the use of 
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higher antigen content, with the goal of providing older adults with improved protection against 
the disease. 
During this study, Fluzone Quadrivalent or Fluzone-High-Dose Quadrivalent vaccine will be 
administered according to the guidelines in the Prescribing Information and only to persons for 
whom the respective vaccine is indicated.  
The objective of this study is to provide serum samples collected from children 6 months to 
< 9 years of age who receive Fluzone Quadrivalent vaccine and adults ≥ 65 years of age who 
receive Fluzone High-Dose Quadrivalent vaccine to CBER. The serum samples are used for 
further analysis by the WHO, CDC, and FDA to support formulation recommendations for 
subsequent influenza vaccines. In addition, serum samples from adult participants may be further 
analyzed by the Sponsor to assess breadth of immune response induced by the study vaccines. 
2.2.1 
Epidemiology 
Influenza is noted for occurring in epidemics. Typically, localized influenza epidemics begin 
abruptly, peak in 2 to 3 weeks, and last 5 to 6 weeks, although this can vary considerably by 
season (for example, the 2017–2018 season lasted 19 weeks (6)). The first sign of influenza in a 
community is usually reports of increased numbers of children with febrile respiratory illness, 
although a nursing home outbreak may be the first indication. Outbreaks in children are usually 
followed by the occurrence of influenza-like illness among adults. Following this is an increase in 
hospital admissions for pneumonia, exacerbation of chronic obstructive pulmonary disease, croup, 
and congestive heart failure. Increased absenteeism from school and the workplace occur as a late 
indicator. Finally, an increased number of deaths due to pneumonia and influenza are a highly 
specific indicator of influenza. However, due to the reporting delay and time course from 
infection to death, this indicator lags behind the others (2).  
As with other viral respiratory infections, influenza is a seasonal disease. In the Northern 
Hemisphere, influenza is most likely to occur from November to April, and in the Southern 
Hemisphere from May to October. In tropical regions, it is more endemic, with periods of 
increased activity occurring more than once a year.  
The public health impact of influenza is dramatic. Annually, from the 2010–2011 through  
2017–2018 influenza season in the United States (US), the CDC estimated that influenza resulted 
in 9.3–49.0 million illnesses, 140,000–960,000 hospitalizations, and 12,000–79,000 deaths (7). 
Estimated annual overall hospitalizations and deaths attributable to influenza during this period in 
the United States were higher compared to historical data, with annual estimated hospitalizations 
ranging from approximately 55,000 to 431,000 per season (mean: 226,000) from 1979–1980 
through 2000–2001 and deaths ranging from 3,000 to 49,000 each season from 1976–1977 
through 2006–2007 (8) (9). During the 2010–2011 through 2017–2018 influenza seasons,  
annual estimates for influenza-related hospitalizations and deaths were highest (45%–72% and 
69%–89% of overall estimates, respectively) among adults ≥ 65 years of age (10). During the 
2017–2018 season, rates of hospitalization in all age groups were the highest seasonal rates seen 
since hospital-based surveillance was expanded in 2005 to include all ages, with an estimated 
11.5 million cases of influenza in children, 30 million cases of influenza in adults 18–64 years of 
age, and more than 7.3 million cases in adults ≥ 65 years of age (11). 
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In the United States, death associated with laboratory-confirmed influenza virus infection among 
children < 18 years of age has been a nationally reportable condition since 2004. Since reporting 
began, the total number of influenza-associated deaths among children during 1 season has ranged 
from 37 (during the 2011–2012 season) to 186 (during the 2017–2018 season, as of April 19, 
2019); this excludes the 2009 pandemic, when 358 pediatric deaths from 15 April 2009 through 
2 October 2010 were reported to the CDC (12). During the 2009 pandemic, the majority of 
children who died had 1 or more underlying medical conditions previously associated with 
conferring a greater risk for influenza complications (13). During the 2017–2018 season, 
approximately 80% of the deaths occurred in children who had not received the 2017–2018 
influenza vaccine (12).  
Based on current understanding, the epidemiology of influenza B is characterized by major 
epidemics every 2–4 years. It causes infections in all age groups, including children, young adults, 
and the elderly. While influenza affects all age groups, young children remain at increased risk 
for complications and are more likely than the general population to require hospitalization. 
Influenza B has been associated with myalgia, myositis, pneumonia, and leukopenia in  
children (14) (15) (16). Influenza B infection in older adults leads to excess mortality in some 
annual epidemics. Across all ages, the burden of disease from influenza B is less than that from 
A/H3N2 but greater than that from A/H1N1. Overall, it is a significant cause of absenteeism, 
clinic visits, hospitalizations, and deaths (4). 
2.2.2 
Prevention and Control of Infection Among Humans 
Currently, the most effective measure for reducing the impact of influenza is to vaccinate persons 
at risk each year before the onset of the influenza season, especially persons at high risk for 
influenza-related complications. The ACIP of the CDC recommends that all eligible persons 
6 months of age and older receive annual vaccination against influenza (3).  
Influenza vaccine has been effective in reducing influenza-related morbidity and mortality. The 
effectiveness of the influenza vaccine in preventing or attenuating influenza illness depends in 
part on the age and immune competence of the vaccine recipient and on the similarity between the 
virus strains present in the vaccine and those circulating in the community. Most vaccinated 
children and young adults develop high post-vaccination HAI antibody titers. These antibodies are 
protective against illness caused by strains similar to those in the vaccine or the related variants 
that may emerge during outbreak periods. Elderly persons and persons with certain chronic 
diseases may develop lower post-vaccination antibody titers than healthy young adults and thus 
may remain susceptible to influenza-related upper respiratory infections. However, even if such 
older persons develop influenza illness despite vaccination, the vaccine can be effective in 
preventing lower-respiratory tract involvement or other secondary complications, thereby 
reducing the risk of hospitalization and death (3).  
Annually, from the 2011–2012 through 2018–20190Fa influenza seasons in the United States, 
overall vaccine effectiveness ranged from 19% to 52%, for children 6 months to < 9 years of age 
it ranged from 25% to 68%, and for adults ≥ 65 years of age it ranged from 17% to 50% (17). The 
                                                 
a  Preliminary estimates for 2018–2019. 
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CDC estimated that influenza vaccination prevented 11% of influenza-related hospitalizations 
during the 2018–20191Fb season and averted 2625 influenza-associated deaths among adults 
≥ 65 years of age. In this same period, for persons < 18 years of age, an estimated 144 influenza-
associated deaths were averted (18). 
2.2.3 
The Advisory Committee on Immunization Practices Recommendations 
Because children 6 to < 24 months of age are at substantially increased risk for influenza-related 
hospitalizations, and children 24 through 59 months of age are at increased risk for influenza-
related clinic and emergency department visits, the ACIP recommends annual vaccination of all 
eligible children in these age groups. In recent years, the ACIP further expanded the age groups 
targeted for vaccination, and now recommends that all eligible persons 6 months of age and older 
receive annual influenza vaccination (3). The ACIP continues to emphasize the importance of 
vaccinating persons ≥ 6 months of age who have high-risk medical conditions (3). 
If a child 6 months to < 9 years of age is receiving influenza vaccine for the first time, based on 
ACIP recommendations, 2 doses of influenza vaccine should be administered 4 weeks apart 
during the current season. This recommendation is based on studies demonstrating that vaccine 
effectiveness is lower among children who have never received influenza vaccine previously or 
who received only 1 dose in their first year of vaccination than it is among those children who 
received 2 doses in their first year of being vaccinated. Children 6 months to < 9 years of age who 
are adequately primed, based on influenza vaccination history, should receive 1 dose during the 
current season as per ACIP recommendations (3).  
2.2.4 
Background of the Investigational Product 
Vaccine Testing and Release 
Before being released for clinical use, the 2020–2021 formulations of Fluzone Quadrivalent and 
Fluzone High-Dose Quadrivalent vaccines will have passed all approved release-testing 
requirements.  
Previous Clinical Experience: Fluzone Vaccine 
Fluzone vaccine was licensed in the United States in 1947 as a whole-virus preparation and it has 
been available since 1980 as a split-virus preparation. Numerous clinical trials have demonstrated 
its safety, immunogenicity, and effectiveness. Clinical trials, in which Fluzone vaccine was used 
as a comparator, have also demonstrated the safety and immunogenicity, and/or effectiveness of  
Fluzone vaccines. 
Fluzone Quadrivalent Vaccine 
In pre-licensure studies, Fluzone Quadrivalent vaccine, which contains 4 influenza strains 
(A/H1N1, A/H3N2, and 2 B strains [1 each from the Yamagata and Victoria lineages]), induced 
antibody responses that were comparable to those induced by trivalent Fluzone vaccine with 
respect to the strains contained in each vaccine. Pre-licensure studies also demonstrated that the 
safety profile of Fluzone Quadrivalent vaccine was similar to that of trivalent Fluzone vaccine. 
                                                 
b  Latest data available. 
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Accordingly, Fluzone Quadrivalent vaccine offers the possibility of protecting against both 
B lineages simultaneously, without compromising vaccine safety (19) (20). 
Fluzone High-Dose Vaccine 
Fluzone High-Dose vaccine, a trivalent formulation with 60 µg HA per viral strain, has been 
shown in pre-licensure studies to elicit a higher immune response in the elderly than does Fluzone 
vaccine (15 µg HA per viral strain) (21) (22) (23). Solicited injection site and systemic reactions 
were reported more frequently with Fluzone High-Dose vaccine; however, these events were 
generally mild to moderate in intensity and transient. No safety concerns were identified. 
Moreover, a large-scale efficacy trial, which was conducted during 2 influenza seasons (2011–
2012 and 2012–2013) and involved more than 30,000 persons, showed that Fluzone High-Dose 
vaccine was 24.2% more effective than Fluzone vaccine in preventing laboratory-confirmed 
symptomatic influenza in persons 65 years of age and older. The results of the study met the 
FDA-agreed criteria for demonstrating the superiority of Fluzone High-Dose vaccine compared 
with Fluzone vaccine for prevention of influenza disease in older adults (24). 
Fluzone High-Dose Quadrivalent Vaccine 
In a pre-licensure study (25), Fluzone High-Dose Quadrivalent vaccine, which contains 
4 influenza strains (A/H1N1, A/H3N2, and 2 B strains [1 each from the Yamagata and Victoria 
lineages]), induced antibody responses that were comparable to those induced by trivalent 
Fluzone High-Dose vaccine with respect to the strains contained in each vaccine. The study also 
demonstrated that the safety profile of Fluzone High-Dose Quadrivalent vaccine was similar to 
that of Fluzone High-Dose vaccine.  
The efficacy of Fluzone High-Dose is relevant to Fluzone High-Dose Quadrivalent since both 
vaccines are manufactured according to the same process and have overlapping compositions 
(26). 
2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events (AEs), the potential risks, and uncertainties of Fluzone Quadrivalent vaccine and 
Fluzone High-Dose Quadrivalent vaccine may be found in the US Prescribing Information for the 
vaccine administered. 
2.3.1 
Risks from Study Participation 
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
 
 
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Table 2.1: Potential Risks of Clinical Significance and Risk Management 
Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Risk Management 
Investigated Vaccine: Fluzone Quadrivalent Vaccine 
Refer to the package insert for 
more information regarding 
potential risks 
Identified and potential risks 
observed in clinical trials and/or 
post-marketing surveillance. 
Exclusion/inclusion criteria take 
into account contraindications, 
warnings and precautions as 
defined in product label. 
     Injection site reactions 
Most common injection site 
reactions in children 6 to < 36 
months of age: pain or 
tenderness, erythema, and 
swelling 
Most common injection site 
reactions in children 3 to < 9 
years of age: pain, erythema, and 
swelling 
Injection site reactions are 
generally mild and usually 
resolve within 3 days 
     Systemic reactions  
Most common solicited systemic 
reactions in children 6 to < 36 
months of age: irritability, 
abnormal crying, malaise, 
drowsiness, appetite loss, 
myalgia, vomiting, and fever  
Most common solicited systemic 
reactions in children 3 to < 9 
years of age are: myalgia, 
malaise, and headache 
Systemic findings most often 
affect persons who have had no 
prior exposure to the virus 
antigens in the vaccine (e.g., 
young children) (27). These 
reactions begin 6 to 12 hours 
after vaccination and usually 
resolve within 3 days. 
    Immediate allergic reactions 
Immediate allergic reactions 
(e.g., hives, angioedema, allergic 
asthma, and systemic 
anaphylaxis) occur rarely after 
influenza vaccination. These 
reactions probably result from 
hypersensitivity to some vaccine 
component (28) (29) (30). 
These types of reactions are 
exceedingly rare and would most 
likely occur in persons with a 
severe reaction to influenza 
vaccine in the past. Vaccine 
should not be administered to 
anyone who has had a severe 
allergic reaction to any 
component of the vaccine. 
     Guillain-Barré syndrome     
     (GBS) 
Among persons who received 
the swine influenza vaccine in 
1976, the rate of GBS that 
exceeded the background rate 
was < 10 cases/1,000,000 
persons vaccinated. Evidence for 
a causal relationship of GBS 
with subsequent vaccines 
prepared from other influenza 
Even if GBS were a true side 
effect of vaccination in the years 
after 1976, the estimated risk for 
GBS of approximately 
1 additional case/1,000,000 
persons vaccinated is 
substantially less than the risk 
for severe influenza, which 
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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Risk Management 
viruses is unclear. Obtaining 
strong epidemiologic evidence 
for such a possible limited 
increase in risk is difficult for 
such a rare condition as GBS, 
which has an annual incidence of 
10–20 cases per 1,000,000 adults 
and stretches the limits of 
epidemiologic investigation (31). 
Investigations to date indicate 
that there is no substantial 
increase in GBS associated with 
influenza vaccines (other than 
the swine influenza vaccine in 
1976) and that, if influenza 
vaccine does pose a risk, it is 
probably slightly more than 
1 additional case per 1,000,000 
persons vaccinated (32). 
could be prevented by 
vaccination in all age groups. 
     Febrile Seizures 
Analysis of reports collected by 
the Vaccine Adverse Events 
Reporting System during the 
2010–2011 influenza season 
suggested an increased risk of 
febrile seizures among children 
younger than 2 years of age who 
received trivalent inactivated 
influenza vaccine (IIV3) (33). 
Using data collected through the 
CDC-sponsored Vaccine Safety 
Datalink (VSD) project, Tse et al 
(34) found an increased risk of 
fever-associated seizure 
occurring on the day of and 
1 day after influenza vaccination 
in children 6 months through 
4 years of age during the 2010–
2011 influenza season. The risk 
was higher among children who 
received concomitant IIV3 
vaccine and pneumococcal 
conjugate vaccine (PCV) 13-
valent, and peaked at 
approximately age 16 months 
(44.9 cases per 100,000 doses). 
In a subsequent study that 
included VSD data collected 
The maximum estimated 
absolute excess risk due to 
concomitant administration of 
IIV3, PCV, and DTaP-
containing vaccines compared 
with administration of these 
vaccines on separate days was 
30 cases per 100,000 vaccinees. 
According to CDC, the risk of 
febrile seizure following 
influenza vaccination is small 
(36). 
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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Risk Management 
over 5 influenza seasons (2005–
2011), Duffy et al (35) reported 
that inactivated influenza 
vaccination in children 6–23 
months of age was not an 
independent risk factor for 
febrile seizures, but revealed an 
increased risk of febrile seizure 
when influenza vaccine was 
given with either PCV or a 
diphtheria-tetanus-acellular-
pertussis (DTaP)-containing 
vaccine. 
Investigated Vaccine: Fluzone High-Dose Quadrivalent Vaccine 
Refer to the package insert for 
more information regarding 
potential risks 
Identified and potential risks 
observed in clinical trials and/or 
post-marketing surveillance. 
Exclusion/inclusion criteria take 
into account contraindications, 
warnings and precautions as 
defined in product label. 
     Injection site reactions 
Most common injection site 
reactions in adults ≥ 65 years of 
age: pain 
Injection site reactions are 
generally mild and usually 
resolve within 3 days.  
A Phase III study performed in 
persons ≥ 65 years of age 
demonstrated increased rates of 
solicited injection site reactions 
in participants receiving Fluzone 
High-Dose vaccine compared to 
persons receiving Fluzone 
vaccine but were typically mild 
and transient (23). 
    Systemic reactions 
Most common solicited systemic 
reactions in adults ≥ 65 years of 
age: malaise, myalgia, and 
headache 
A Phase III study performed in 
persons ≥ 65 years of age 
demonstrated increased rates of 
solicited systemic reactions in 
participants receiving Fluzone 
High-Dose vaccine compared to 
persons receiving Fluzone 
vaccine but were typically mild 
and transient (23). Placebo-
controlled trials suggest that in 
elderly persons and in healthy 
young adults, split-virus 
influenza vaccine is not 
associated with higher rates of 
systemic symptoms when 
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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Risk Management 
compared with placebo injection 
(37). Safety monitoring of 
Fluzone High-Dose vaccine 
during the first year after 
licensure indicated a higher than 
expected number of 
gastrointestinal events compared 
with standard-dose vaccine, but 
otherwise no new safety 
concerns were identified (38). 
    Immediate allergic reactions 
Immediate allergic reactions 
(e.g., hives, angioedema, allergic 
asthma, and systemic 
anaphylaxis) occur rarely after 
influenza vaccination. These 
reactions probably result from 
hypersensitivity to some vaccine 
component (28) (29) (30). 
These types of reactions are 
exceedingly rare and would most 
likely occur in persons with a 
severe reaction to influenza 
vaccine in the past. Vaccine 
should not be administered to 
anyone who has had a severe 
allergic reaction to any 
component of the vaccine. 
     Guillain-Barré syndrome 
Among persons who received 
the swine influenza vaccine in 
1976, the rate of GBS that 
exceeded the background rate 
was < 10 cases/1,000,000 
persons vaccinated. Evidence for 
a causal relationship of GBS 
with subsequent vaccines 
prepared from other influenza 
viruses is unclear. Obtaining 
strong epidemiologic evidence 
for such a possible limited 
increase in risk is difficult for 
such a rare condition as GBS, 
which has an annual incidence of 
10–20 cases per 1,000,000 adults 
and stretches the limits of 
epidemiologic investigation (31). 
Investigations to date indicate 
that there is no substantial 
increase in GBS associated with 
influenza vaccines (other than 
the swine influenza vaccine in 
1976) and that, if influenza 
vaccine does pose a risk, it is 
probably slightly more than 
Even if GBS were a true side 
effect of vaccination in the years 
after 1976, the estimated risk for 
GBS of approximately 
1 additional case/1,000,000 
persons vaccinated is 
substantially less than the risk 
for severe influenza, which 
could be prevented by 
vaccination in all age groups and 
especially in persons ≥ 65 years 
of age and those who have 
medical indications for influenza 
vaccination. 
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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Risk Management 
1 additional case per 1,000,000 
persons vaccinated (32). 
Study Procedures 
Vasovagal reactions (syncope), 
or psychogenic reactions to 
needle (vaccine injection or 
blood sampling) 
 
Anxiety-related reactions can 
occur following, or even before, 
any vaccination as a psychogenic 
response to the needle injection 
or blood draw, and may be 
accompanied by several 
neurological signs such as 
transient visual disturbance, 
paresthesia or seizure-like 
activity. 
Observation period after 
vaccination for early detection 
and treatment. 
 
DTaP: diphtheria-tetanus-acellular-pertussis; GBS: Guillain-Barré syndrome; IIV3: trivalent inactivated influenza 
vaccine; PCV: pneumococcal conjugate vaccine; VSD: Vaccine Safety Datalink 
2.3.2 
Benefits from Study Participation 
The benefit to subjects participating in this study is potential protection from influenza disease 
following the receipt of the 2020–2021 formulation of Fluzone Quadrivalent or Fluzone High-
Dose Quadrivalent vaccine. 
2.3.3 
Overall Benefit-Risk Conclusion 
Considering the measures taken to minimize risk to participants enrolled in this study, the 
potential risks that may result from study participation are balanced by the anticipated benefits 
that may be afforded to participants. 
3 
Objectives and Endpoints 
The study objectives and the corresponding endpoints are described in Table 3.1. 
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Table 3.1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To provide serum samples 
(collected from participants before 
vaccination [Blood Sample 1] and 
after final vaccination [Blood 
Sample 2]) to CBER for further 
analysis by the WHO, CDC, and 
FDA to support formulation 
recommendations for subsequent 
influenza vaccines. In addition, 
serum samples from adult 
participants may be further 
analyzed by the Sponsor to assess 
breadth of immune response 
induced by the study vaccines. 
• 
There are no endpoints for this objective. 
4 
Study Design 
4.1 
Overall Design 
The design of the study is summarized in Table 4.1. 
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Table 4.1: Overall Design 
Type of design 
Parallel, multi-center 
Phase 
IV 
Control method 
None 
Study population 
Children 6 months to < 9 years of age 
Adults ≥ 65 years of age 
Level and method of blinding 
None (Open label) 
Study intervention assignment method 
Participants will not be randomized. 
Number of participants 
90 participants (30 from 6 months to < 36 months of age, 
30 from 3 years to < 9 years of age, and 30 from 
65 years and older) 
Intervention groups 
Each participant will be assigned to a vaccine group 
based on the participant’s age at the time of enrollment 
to receive either 1 or 2 doses of Fluzone Quadrivalent 
vaccine as per ACIP guidance (participants 6 months to 
< 9 years of age) or 1 dose of Fluzone High-Dose 
Quadrivalent vaccine (participants ≥ 65 years of age). 
Total duration of study participation 
• 
Participants 6 months to < 9 years of age: 
28 (window, 28–35) days following the last dose of 
influenza vaccine (Visit 2 [for participants receiving 
1 dose] or Visit 3 [for participants receiving 
2 doses]). 
• 
Participants ≥ 65 years of age: 21 (window, 21–28) 
days after vaccination.  
Countries 
United States 
Use of an Independent Data Monitoring 
Committee, Dose Escalation 
Committee, or similar review group 
No 
4.2 
Scientific Rationale for Study Design 
Serum samples from participants will be supplied to CBER after the completion of this study 
(i.e., after the last participant completes the last study visit). In turn, CBER will distribute the 
serum samples to the CDC and other WHO-collaborating laboratories for evaluation against 
circulating influenza viral strains. It is expected that the immunologic and surveillance data will 
be presented at WHO meetings where the vaccine strain selections will be made for the Southern 
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and Northern hemispheres and at the FDA Vaccines and Related Biological Products Advisory 
Committee meeting for selection of strains for influenza vaccines, including those to be 
distributed in the United States.  
4.3 
Justification for Dose 
For participants 6 months to < 9 years of age: the vaccination schedule of 1 or 2 doses (as per 
ACIP guidance for children 6 months to < 9 years of age) for the influenza season is per standard 
practice for receipt of annual influenza vaccination. 
For participants ≥ 65 years of age: The vaccination schedule of a single dose for the influenza 
season is per standard practice for receipt of annual influenza vaccination. 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the last visit 
planned in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 
5 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible for the study only if all of the following criteria are met: 
I01: 
Aged 6 months to < 9 years or ≥ 65 years of age on the day of first study vaccination 
(study product administration) 
2Fc. 
I02: 
For participants 6 to < 12 months of age, born at full term of pregnancy (≥ 37 weeks) 
and with a birth weight ≥ 5.5 lbs (2.5 kg). 
I03: 
Informed consent form (ICF) has been signed and dated by participants ≥ 65 years of 
age. 
I04: 
Assent form has been signed and dated by participants 7 to < 9 years of age, and ICF 
has been signed and dated by parent(s) or guardian(s) for participants 6 months to 
< 9 years of age.  
                                                 
c  “6 months to < 9 years” means from the 6th month after birth to the day before the 9th year. “≥ 65 years” means 
from the day of the 65th birthday onwards. 
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I05: 
Participants and parent/guardian (of participants 6 months to < 9 years of age) are able 
to attend all scheduled visits and to comply with all study procedures. 
5.2 
Exclusion Criteria 
Participants are not eligible for the study if any of the following criteria are met: 
E01: 
Participation at the time of study enrollment (or in the 30 days preceding the first 
study vaccination) or planned participation during the present study period in another 
clinical study investigating a vaccine, drug, medical device, or medical procedure.  
Note: Participants may be considered eligible for enrollment if no intervention for the 
other study occurred within the 30 days prior to the first study vaccination and none 
are planned before the participant would complete safety surveillance for the present 
study. 
E02: 
Receipt of any vaccine in the 30 days preceding the first study vaccination, or planned 
receipt of any vaccine before Visit 2 for participants receiving 1 dose of influenza 
vaccine or Visit 3 for participants receiving 2 doses of influenza vaccine. 
E03: 
Previous vaccination against influenza (in the 2020-2021 influenza season) with either 
study vaccine or another vaccine. 
E04: 
Receipt of immune globulins, blood, or blood-derived products in the 3 months 
preceding planned inclusion. 
E05: 
Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, 
within the 6 months preceding planned inclusion; or long-term systemic corticosteroid 
therapy (prednisone or equivalent for more than 2 consecutive weeks within the 
3 months preceding planned inclusion). 
E06: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to study vaccine or to a vaccine containing any of the same 
substances.  
Note: The list of vaccine components is included in the Prescribing Information for 
each study vaccine. 
E07: 
Thrombocytopenia, which may be a contraindication for IM vaccination, at the 
discretion of the Investigator. 
E08: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating IM vaccination. 
E09: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily. 
E10: 
Current alcohol abuse or drug addiction. 
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E11: 
Chronic illness that, in the opinion of the Investigator, is at a stage where it might 
interfere with study conduct or completion.3Fd 
E12: 
Moderate or severe acute illness/infection (according to Investigator judgment) on the 
day of planned vaccination or febrile illness (temperature ≥ 100.4°F [38.0°C]). A 
prospective participant should not be included in the study until the condition has 
resolved or the febrile event has subsided. 
E13: 
Identified as an Investigator or employee of the Investigator or study center with 
direct involvement in the proposed study or identified as an immediate family member 
(i.e., parent, spouse, natural or adopted child) or in-laws of the Investigator or 
employee with direct involvement in the proposed study. 
E14: 
History of serious adverse reaction to any influenza vaccine. 
E15: 
Personal history of Guillain-Barré syndrome (GBS). 
E16: 
Any condition that in the opinion of the Investigator would pose a health risk to the 
participant if enrolled or could interfere with the evaluation of the vaccine. 
E17: 
Personal history of clinically significant developmental delay (at the discretion of the 
Investigator), neurologic disorder, or seizure disorder. 
E18: 
Known seropositivity for human immunodeficiency virus, hepatitis B, or hepatitis C. 
 
Note: Participants enrolled into this study will not be prohibited from donating blood for non-
interventional studies or other purposes. 
If the participant has a primary physician who is not the Investigator, the site should contact this 
physician with the participant’s consent to inform him/her of the participant’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.3 
Lifestyle Considerations 
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents. 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened. 
                                                 
d  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, autoimmune disorders, 
diabetes, psychomotor diseases, and known congenital or genetic diseases. 
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6 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Study Interventions Administered 
Study interventions are described in Table 6.1. 
Table 6.1: Identity of Study Interventions 
Intervention Name 
Fluzone Quadrivalent vaccine, No 
Preservative (0.5-mL dose), 2020–
2021 formulation 
Fluzone High-Dose Quadrivalent 
vaccine (0.7-mL dose), 2020–2021 
formulation 
Use 
Other (as indicated in the prescribing 
material) 
Other (as indicated in the prescribing 
material) 
IMP and NIMP 
IMP 
IMP 
Type  
Vaccine 
Vaccine 
Dose Formulation 
Suspension for injection in a pre-filled 
syringe 
Suspension for injection in a pre-filled 
syringe 
Unit Dose 
Strength(s) 
15 µg of HA of each of the following 
strains per dose: 
• 
A/Guangdong-
Maonan/SWL1536/2019 
(H1N1)pdm09-like virus 
• 
A/Hong Kong/2671/2019 (H3N2)-
like virus 
• 
B/Washington/02/2019 (B/Victoria 
lineage)-like virus 
• 
B/Phuket/3073/2013 (B Yamagata 
lineage)-like virus 
60 µg of HA of each of the following 
strains per dose: 
• 
A/Guangdong-
Maonan/SWL1536/2019 
(H1N1)pdm09-like virus 
• 
A/Hong Kong/2671/2019 (H3N2)-
like virus 
• 
B/Washington/02/2019 (B/Victoria 
lineage)-like virus 
• 
B/Phuket/3073/2013 (B Yamagata 
lineage)-like virus 
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Excipients/Diluent 
Formaldehyde, egg protein, 
octylphenol ethoxylate (Triton X-
100), sodium phosphate-buffered 
isotonic sodium chloride solution  
Formaldehyde, egg protein, 
octylphenol ethoxylate (Triton X-
100), sodium phosphate-buffered 
isotonic sodium chloride solution 
Dosage Level 
0.5 mL per dose 
0.7 mL per dose 
Number of Doses / 
Dosing Interval 
1 or 2 doses 28 days apart for children 
aged 6 months to < 9 years (as per 
ACIP guidance) 
1 dose 
Route of 
Administration 
IM injection 
IM injection 
Site of 
Administration 
Anterolateral muscle of the thigh or 
the deltoid muscle 
Deltoid muscle  
Sourcing 
Provided by the Sponsor  
Provided by the Sponsor  
Packaging and 
Labeling 
Fluzone Quadrivalent and Fluzone High-Dose Quadrivalent vaccines will be 
supplied with their manufacturer’s commercial labeling and packaging. 
Current/Former 
Name(s) or Alias(es) 
Not applicable 
Not applicable 
Batch Number 
TBD 
TBD 
Note: Strains are based on WHO/FDA recommendations for the 2020-2021 NH influenza season 
ACIP: Advisory Committee on Immunization Practices; FDA: Food and Drug Administration; HA: hemagglutinin;  
IM: intramuscular; IMP: Investigational Medicinal Product; NH: Northern Hemisphere;  
NIMP: Non Investigational Medicinal Product; TBD: to be determined; WHO: World Health Organization 
6.2 
Preparation/Handling/Storage/Accountability 
Detailed guidance and information are provided in the Operating Guidelines. 
1) The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
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3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions are 
provided in the Operating Guidelines. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization and Allocation Procedures 
Participants will not be randomized. Each participant will be assigned to a vaccine group based on 
the participant’s age at the time of enrollment. 
Participant numbers will be 12 digits long, with a 3-digit country identifier, a 4-digit study center 
identifier, and a 5-digit participant identifier. The 5-digit participant identifier will correspond to 
the chronological order of enrollment in the center. For example, Participant 840000100001 is the 
first participant enrolled in Center Number 1 (in the United States) and Participant 840000200002 
is the second participant enrolled in Center Number 2 (in the Unites States). 
Participant numbers should not be reassigned for any reason. 
6.3.2 
Blinding and Code-breaking Procedures 
This is an open-label study. 
6.4 
Study Intervention Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any noncompliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose(s) given to each participant, and unused or wasted doses 
6.5 
Concomitant Therapy 
At the time of enrollment, ongoing medications and other therapies (e.g., blood products) should 
be recorded in the source document as well as new medications prescribed for new medical 
conditions/AEs during study participation. 
Documentation in the case report book (CRB) of ongoing concomitant medication(s) will be 
limited to specific categories of medication(s) of interest beginning on the day of first vaccination. 
This may include medications of interest that were started prior to the day of vaccination. 
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Reportable medications will be collected in the CRB from the day of each vaccination to the end 
of the follow-up period (i.e., from Visit 1 through Visit 2 for participants receiving 1 dose of 
study vaccine or from Visit 1 through Visit 3 for participants receiving 2 doses of study vaccine). 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. As Category 1 
medications are NOT reportable for this study, there are 2 standard categories of reportable 
medications, defined as follows: 
• Category 2: medications impacting or that may have an impact on the immune response 
(e.g., other vaccines, blood products, antibiotic classes that may interfere with bioassays 
used by the Global Clinical Immunology [GCI] department or other testing laboratories, 
systemic steroids/corticosteroids, immune-suppressors, immune-modulators with 
immunosuppressive properties, anti-proliferative drugs such as DNA synthesis inhibitors) 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (e.g., systemic steroids/corticosteroids) 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name 
• Origin of prescription: prophylaxis Yes/No. Medication(s) prescribed for AE prophylaxis will 
be recorded in the Action Taken of the AE collection tables. 
• Medication category (2 or 3) 
• Start and stop dates 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded.  
Topical analgesics should not be applied at the site of vaccination; however, if they are applied 
inadvertently to the vaccination site, they should be recorded as a Category 3 medication. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
case report form (CRF) only. No details will be recorded in the concomitant medication CRF unless 
the medication(s) received belongs to one of the pre-listed categories. Medications will not be 
coded. 
6.5.1 
Rescue Medicine 
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available on site in the event of an anaphylactic, vasovagal, or other immediate allergic 
reaction. 
6.6 
Dose Modification 
Not applicable. 
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6.7 
Intervention After the End of the Study 
Not applicable. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
7.1.1 
Temporary Contraindications 
Should a participant experience one of the conditions listed below, the Investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the SoA. 
TCI01: 
Febrile illness (temperature ≥ 100.4°F [≥ 38.0°C]) or moderate or severe acute 
illness /infection on the day of vaccination, according to Investigator judgment 
7.1.2 
Definitive Contraindications 
Participants will permanently discontinue (definitive discontinuation) study intervention for the 
reasons listed below. These participants must not receive any additional dose of study intervention 
but should continue to be followed for safety. Additional unscheduled visits may be performed for 
safety reasons and information will be reported in the source documents. 
Should a participant experience 1 of the conditions listed below, the Investigator will discontinue 
vaccination: 
DCI01: 
An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
DCI02: 
Receipt of any non-study vaccine (including a non-study dose of 2020–2021 influenza 
vaccine), immune globulins, blood, or blood-derived products between Visit 1 and 
Visit 2. 
DCI03: 
Bleeding disorder, receipt of anticoagulants, or thrombocytopenia, which may be a 
contraindication for IM vaccination, at the discretion of the Investigator. 
DCI04: 
Development of any condition that in the opinion of the Investigator would pose a 
health risk to the participant or could interfere with the evaluation of the study vaccine 
(including GBS, clinically significant developmental delay, neurologic disorder, 
seizure disorder, human immunodeficiency virus infection, hepatitis B, or hepatitis C). 
DCI05: 
Development of immunodeficiency; or receipt of immunosuppressive therapy such as 
anti-cancer chemotherapy or radiation therapy; or receipt of long-term systemic 
corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks). 
DCI06: 
Adverse events that are considered a contraindication for further participation in the 
study. 
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7.2 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in 
the CRB: Adverse Event, Lost to Follow-up, Protocol Deviation, or Withdrawal by 
Participant or Parent/Guardian/Legally Acceptable Representative. 
• 
The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws consent, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
• 
Withdrawn participants will not be replaced. 
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. For participants where the 
reason for early termination is lost to follow-up, the site will not attempt to obtain further safety 
information. See Section 7.3 for definition of “lost to follow-up”. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or cannot be contacted as planned in the SoA: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods), or at least to determine his/her health status while fully respecting 
his/her rights. These contact attempts should be documented in the participant’s medical 
record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1. 
8 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. There are no screening criteria other than the inclusion 
and exclusion criteria. 
Blood samples will be collected as described in the SoA tables (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 10 mL for participants 
6 months to < 9 years of age or 40 mL for participants ≥ 65 years of age. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples. 
Guidance and information for the sample collection, preparation, storage, and shipment are 
provided in the Operating Guidelines. 
8.1 
Efficacy and Immunogenicity Assessments 
8.1.1 
Efficacy Assessments 
No clinical efficacy data will be obtained in the study. 
8.1.2 
Immunogenicity Assessments 
No immunogenicity data will be obtained in the study. 
8.2 
Safety Assessments 
This section presents safety assessments other than AEs, which are presented in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA tables (Section 1.3). 
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8.2.1 
Medical History 
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE/AESI or to a repetitive outpatient care 
will be collected in the CRB. 
8.2.2 
Physical Examinations 
At Visit 01, the Investigator or a delegate will perform a history-directed physical examination. 
Information will be recorded in the source document. 
8.2.3 
Vital Signs 
Oral (participants 3 years to < 9 years and participants ≥ 65 years of age) or rectal (participants 
6 months to < 36 months) pre-vaccination temperature will be systematically collected by the 
investigator on the source document. Tympanic, skin, and temporal artery thermometers must not 
be used. 
8.2.4 
Clinical Safety Laboratory Assessments 
Not applicable. 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.2. 
Participants or parents/guardians (of participants 6 months to < 9 years of age) will be instructed 
to record information about any medical events that might represent SAEs or AESIs that may 
occur from Visit 1 through Visit 2 (Diary Card 1) for all participants and from Visit 2 through 
Visit 3 (Diary Card 2) for participants receiving 2 doses of study vaccine. Space will be provided 
in the diary card for this purpose.  
AEs will be reported by the participants/participants’ parents/guardians to the investigator, then 
by the investigator to the Sponsor. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an SAE/AESI and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
 
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8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 20 minutes after each vaccination to ensure their 
safety. Any SAEs/AESIs during this post-vaccination observation should be documented in the 
source document. 
AESIs 
Adverse events of special interest will be collected from Visit 1 to Visit 2 for participants 
receiving 1 dose of study vaccine, and from Visit 1 to Visit 3 for participants receiving 2 doses of 
study vaccine. 
See Section 8.3.6 for the list of AESIs. 
SAEs 
Information on SAEs will be collected and assessed throughout the study, from Visit 1 to Visit 2 
for participants receiving 1 dose of study vaccine, and from Visit 1 to Visit 3 for participants 
receiving 2 doses of study vaccine. However, before the first study intervention administration, 
only SAEs related to study procedures are to be collected. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will not be recorded on the AE section of the CRB. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.2. The investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
Sponsor. 
8.3.2 
Method of Detecting SAEs/AESIs 
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study participants for the recording of safety information. These diary 
cards will include free text to capture additional safety information or other relevant details.  
At specified intervals, the Investigator or an authorized designee will interview the participants or 
participants’ parents/guardians to collect the information recorded in the diary card, and will 
attempt to clarify anything that is incomplete or unclear. All clinical study information gathered 
by the study site will be reported electronically by the Investigator or authorized designee using a 
web-based CRB. Any information that was not documented in the diary card will first be captured 
in the source document and then reported electronically. 
Care will be taken not to introduce bias when detecting SAEs/AESIs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
SAE occurrences. 
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8.3.3 
Follow-up of SAEs and AESIs 
Unless a participant/participant’s parent guardian refuses further contact, each participant who 
experiences an SAE4Fe/AESI during the study must be followed until the condition resolves, 
becomes stable, or becomes chronic (even after the end of the participant’s participation in the 
study) if either of the following is true: 
• The SAE/AESI is considered by the Investigator to be related to the study intervention 
administered 
• The SAE/AESI caused the discontinuation of the participant from the study or from 
vaccination 
The Investigator will inform the Sponsor of the date of final disappearance of the event or the date 
of “chronicity” establishment. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
For all studies except those investigating medical devices investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according to 
local regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy 
Not applicable as the study does not include women of childbearing potential. 
                                                 
e  The classification of an SAE is determined by the GPV Department and RMO(s) at Sanofi Pasteur. 
GPV: Global Pharmacovigilance; RMO: Responsible Medical Officer 
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8.3.6 
Adverse Events of Special Interest 
Adverse events of special interest will be captured as SAEs. These include new onset of GBS, 
encephalitis/myelitis (including transverse myelitis), neuritis (including Bell’s palsy, optic 
neuritis, and brachial neuritis), thrombocytopenia, vasculitis, convulsions (including febrile 
convulsions [children only]), and anaphylaxis or other hypersensitivity/allergic reactions from 
Visit 1 through Visit 2 for participants receiving 1 dose of vaccine, or from Visit 1 through Visit 3 
for participants receiving 2 doses of vaccine. 
8.4 
Treatment of Overdose 
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the investigator should: 
1) Contact the Medical Monitor immediately. 
2) Closely monitor the participant for any AE/SAE. 
3) Document the quantity of the excess of the overdose in the source documents. 
8.5 
Pharmacokinetics 
Pharmacokinetics parameters are not evaluated in this study. 
8.6 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Immunogenicity Assessments 
See Section 8.1.2. 
8.10 Health Economics or Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
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9 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No hypotheses will be tested. Only descriptive statistical analyses will be conducted in this study. 
9.2 
Sample Size Determination 
The study will enroll approximately 90 participants: approximately 30 participants 6 to 
< 36 months of age will be administered Fluzone Quadrivalent vaccine (Group 1), approximately 
30 participants 3 to < 9 years of age will be administered Fluzone Quadrivalent vaccine 
(Group 2), and approximately 30 participants ≥ 65 years of age will be administered Fluzone 
High-Dose Quadrivalent vaccine (Group 3).  
No study power calculation will be conducted for this study. 
9.3 
Populations for Analyses 
The following population is defined: 
Population 
Description 
All Vaccinated Participants 
Population 
Participants who have received at least 1 dose of the study vaccine.  
9.4 
Statistical Analyses 
No statistical analysis plan (SAP) will be written for this study. This section of the protocol will 
be followed to provide descriptive tables and listings of data. 
9.4.1 
General Considerations 
Summaries of baseline demographic characteristics of the study participants will be presented. 
The number of participants enrolled and their age at enrollment (mean, median, and minimum and 
maximum), sex, race, and ethnic origin will be summarized, along with the number and 
description of protocol deviations. Listings of participants by age group, sex, vaccine received, 
and history of vaccination in the previous season will be provided. 
9.4.2 
Primary Endpoint(s) 
There are no primary endpoints for this study. 
9.4.3 
Secondary Endpoint(s) 
There are no secondary endpoints for this study. 
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9.4.4 
Observational Endpoint(s) 
There are no observational endpoints for this study. 
9.4.5 
Other Safety Analyse(s) 
Listings or tables of SAEs and AESIs will be provided. 
9.4.6 
Other Analyse(s) 
Not applicable. 
9.5 
Interim Analyses 
This study will not include an early safety data review. However, participant safety will be 
continuously monitored by the Sponsor’s internal safety review committee which includes safety 
signal detection at any time during the study. 
No analyses are planned to be performed prior to the formal completion of the study. 
9.6 
Data Monitoring Committee (DMC) 
Not applicable. 
 
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10 Supporting Documentation and Operational Considerations 
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations 
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRB in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. 
10.1.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure (IB), and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator or the 
Sponsor (according to local regulations) and reviewed and approved by the IRB/IEC before 
the study is initiated 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants 
• The investigator or the Sponsor (according to local regulations) will be responsible for the 
following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 Financial Disclosure 
Information related to financial disclosure is described in the Investigator’s contract. 
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10.1.3 Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
parents/guardians will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 
• In addition to the ICF that is signed by the participant or participant’s parent/guardian, 
participants 7 to < 9 years of age will be asked to review and sign a study assent form. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• The actual ICF used at each center may differ, depending on local regulations and IEC/IRB 
requirements. However, all versions must contain the standard information found in the 
sample ICF provided by the Sponsor. Any change to the content of the ICF must be approved 
by the Sponsor and the IEC/IRB prior to the form being used. 
• If new information becomes available that may be relevant to the participant’s or 
parents’/guardians’ willingness to continue participation in the study, this will be 
communicated to him/her in a timely manner. Such information will be provided via a revised 
ICF or an addendum to the original ICF (and assent form). 
• Participants must be re-consented to the most current version of the ICF(s) and assent during 
their participation in the study. 
• A copy of the ICF(s)/assent must be provided to the participant or the participant’s legally 
authorized representative. 
Recruitment Procedures 
Participants may be recruited from the general population. The site will ensure that any advertisements 
used to recruit participants (informational brochures, parent letters, posters, and other advertisements) are 
submitted to Sanofi Pasteur prior to submission to the IRB(s) for approval. 
10.1.4 Data Protection and Future Use of Stored Samples 
• All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with 
all applicable laws and regulations including the Global Data Protection Regulation (GDPR). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for 
which they are collected. Each category of data must be properly justified and in line with the 
study objective. 
• Participants race and ethnicity will be collected in this study because these data are required 
by regulatory agencies (e.g., on African-American population for the FDA in the United 
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States or on Japanese population for the Pharmaceuticals and Medical Devices Agency in 
Japan). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred to the 
Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
• Participant data will be used for this study and in support of the whole drug development 
program for the Investigational Product, including negotiations with payers and publication of 
results. 
• Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) up to 25 years after the end of the study. These samples are being retained in 
long-term storage to support answers to regulatory questions related to the product’s licensure 
and the potential revalidation of the study results. 
In addition, participants/parents/guardians (of participants 6 months to < 9 years of age) will 
be asked to indicate in the ICF whether they will permit the future use of any unused stored 
serum samples for other tests. If they refuse permission, the samples will not be used for any 
testing other than that directly related to this study. If they agree to this use, they will not be 
paid for giving permission. Anonymity of samples will be ensured. The aim of any possible 
future research is unknown today, and may not be related to this particular study. It may be to 
improve the knowledge of vaccines or infectious diseases, or to improve existing tests or 
develop new tests to assess vaccines. Human genetic tests will never be performed on these 
samples without specific individual informed consent. 
10.1.5 Committees Structure 
This study will not include an early safety data review. However, participant safety will be 
continuously monitored by the Sponsor’s internal safety review committee which includes safety 
signal detection at any time during the study. 
10.1.6 Dissemination of Clinical Study Data 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
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websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data Quality Assurance 
• All participant data relating to the study will be recorded on electronic CRB unless transmitted 
to the Sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRB. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRB. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRB by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
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10.1.8 Source Documents 
 “Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent/assent forms, telephone contact logs, and 
worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the CRB that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Detailed guidance and information are provided in the Operating Guidelines. 
10.1.9 Study and Site Start and Closure 
Details on which clinical supplies are provided by the Sponsor or the site are described in the 
Operating Guidelines. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study-site has all the documents necessary for archiving and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
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10.1.10 Publication Policy 
Information related to publication policy is described in the Investigator’s contract. 
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10.2 Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.2.1 Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
Other Definitions 
Adverse Reaction: 
All noxious and unintended responses to a study intervention related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a study intervention” means that a causal relationship between a 
study intervention and an AE is at least a reasonable possibility) 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs 
(including those related to the study intervention administered) that occur within the first 
30 minutes after vaccination. 
Injection Site Reaction/Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration 
site. Injection/administration site reactions are commonly inflammatory reactions. They are 
considered to be related to the study intervention administered. 
Systemic AE/AR: 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (e.g., erythema 
that is localized but that is not occurring at the injection site). 
Systemic AEs assessed as related to study intervention are referred as systemic ARs. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (e.g., regulators) 
might also be warranted. 
Reactogenicity / Solicited Reactions 
A solicited reaction is an “expected” AR ion (sign or symptom) observed and reported under 
the conditions (nature and onset) pre-listed in the protocol and CRB. 
By definition, solicited reactions are considered as being related to the study intervention 
administered. 
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For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions. 
Unsolicited AE/AR 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
i.e., pre-listed in the CRB in terms of diagnosis and/or onset window post-vaccination. For 
example, varicella or a solicited term such as headache starting after the solicited observation 
period (headache starting on Day 10 post-vaccination in the case where headache occurring 
between the day of vaccination and the next 7 days is pre-listed in the protocol and CRB as a 
solicited reaction). 
An unsolicited AR is an unsolicited AE that is considered related to study intervention. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
10.2.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
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accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other important medical event 
• Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
health of the participant or may require intervention to prevent one of the other outcomes 
listed in the above definition. These important medical events should also usually be 
considered serious. 
• 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse, new-onset diabetes or autoimmune 
disease. 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant / event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 
10.2.3 Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRB. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the CRB pages. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
 
 
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Assessment of Causality 
By convention, all SAEs reported at the injection site are considered to be related to the study 
intervention and therefore are referred to as reactions and do not require the Investigator’s 
opinion on relatedness. 
• Causality of SAEs will be recorded as follows: 
• 
For SAEs/AESIs, relationship to study intervention will be assessed by both the 
Investigator and the Sponsor. Sponsor assessment is entered in the GPV database only.   
• 
For SAEs only, the causal relationship to study procedures (related/not related to study 
procedures) will be assessed by both the Investigator and the Sponsor. Sponsor 
assessment is entered in the GPV database only. 
• The Investigator will assess the causal relationship between each SAE/AESI and the study 
intervention administered5F6 as either not related or related, based on the following 
definitions: 
• 
Not related – The SAE/AESI is clearly/most probably caused by other etiologies such 
as an underlying condition, therapeutic intervention, or concomitant therapy; or the 
delay between vaccination and the onset of the SAE is incompatible with a causal 
relationship; or the SAE/AESI started before the first vaccination (screening phase, if 
applicable) 
• 
Related – There is a “reasonable possibility” that the SAE/AESI was caused by the 
study intervention administered, meaning that there is evidence or arguments to 
suggest a causal relationship 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• The investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• For each SAE/AESI, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE/AESI has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE/AESI data to the Sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE/AESI follow-up report with the updated causality assessment. 
                                                 
6 Study intervention administered can correspond to either the investigational product or other products when no 
investigational product is administered at the visit 
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• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the SAE/AESI as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, when available the investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRB. 
• The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
• Serious adverse events/AESIs likely to be related to the study intervention, that persist at 
the end of the study will be followed up by the Investigator until their complete 
disappearance or the stabilization of the participant’s condition. The Investigator will 
inform the Sponsor of the date of final disappearance of the event or the date of 
“chronicity” establishment. 
10.2.4 Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. The site will enter the 
SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section). 
• Details regarding SAE reporting can be found in the Operating Guidelines. 
 
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SAE Reporting to the Sponsor via Paper CRF 
• 
The SAE paper CRF can be sent to the Sponsor by 1 of the following means: 
• 
By fax, to the following number: 1-570-957-2782 
• 
In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.com 
• 
By express mail, to the following address:  
• 
Sanofi Pasteur, Inc. 
Reception & Triage – Case Management 
Global Pharmacovigilance Department  
Discovery Drive, Swiftwater, PA 18370 
 
Safety Emergency Call 
If, as per the Investigator’s judgment, a participant experiences a medical emergency, the 
Investigator may contact the Sponsor’s responsible medical officers (RMOs) for advice on how 
to address any study related medical question or problem. The RMOs will be available 24 hours 
a day, 7 days a week, as needed. Contact information for each of the RMOs is provided in the 
Operating Guidelines. 
This process does not replace the need to report an SAE/AESI. The Investigator is still required 
to follow the protocol-defined process for reporting SAEs/AESIs to the Global 
Pharmacovigilance Department (please refer to Section 10.2.4). 
10.2.5 Assessment of Intensity 
Not applicable. 
10.2.5.1 Tables for Clinical Abnormalities 
Not applicable. 
10.3 Appendix: Risk-based Approach 
ICH E6-R2 guideline for GCP is introducing the « risk-based approach » concept which permits 
to focus efforts on what is critical for a study and most specifically on Critical Data and Critical 
Processes. Critical data and processes are defined for the study with associated risks in the Study 
Risk Management Plan. 
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10.4 Appendix: Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AR 
Adverse Reaction 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention 
CRB 
Case Report Book 
CRF 
Case Report Form 
DTaP 
Diphtheria-Tetanus-Acellular-Pertussis 
FDA 
Food and Drug Administration 
GBS 
Guillain-Barré Syndrome 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance Department 
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IIV3 
Trivalent Inactivated Influenza vaccine 
NA 
Neuraminidase 
RMO 
Responsible Medical Officer 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SoA 
Schedule of Activities 
US 
United States 
VSD 
Vaccine Safety Datalink 
WHO 
World Health Organization 
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10.5 References 
1. 
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Orenstein WA, Offit PA, editors. Vaccines. 6th ed. Edinburgh, UK: Elsevier/Saunders; 2012. p. 
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2. 
Treanor JT. Influenza viruses, including avian influenza and swine influenza. In: Mandell 
GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett's Principles and Practice of 
Infectious Diseases. 7th ed. New York, NY: Churchill Livingstone; 2010. p. 2265-88. 
3. 
Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Bresee JS, Fry AM, et al. Prevention 
and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee 
on Immunization Practices - United States, 2017-18 Influenza Season. MMWR Recomm Rep. 
2017;66(2):1-20. 
4. 
Belshe RB. The need for quadrivalent vaccine against seasonal influenza. Vaccine. 
2010;28 Suppl 4:D45-53. 
5. 
Monto AS, Ansaldi F, Aspinall R, McElhaney JE, Montaño LF, Nichol KL, et al. 
Influenza control in the 21st century: Optimizing protection of older adults. Vaccine. 
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6. 
Centers for Disease Control and Prevention Website. Influenza (Flu) 2017-2018 2019 
[cited 2020 June 02]. Available from: https://www.cdc.gov/flu/about/season/flu-season-2017-
2018.htm#anchor_1534865788578. 
7. 
Centers for Disease Control and Prevention Website. Burden of influenza. 2020 [cited 
2020 June 02]. Available from: https://www.cdc.gov/flu/about/burden/index.html. 
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Thompson WW, Shay DK, Weintraub E, Brammer L, Bridges CB, Cox NJ, et al. 
Influenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333-40. 
9. 
Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal 
influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-62. 
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Centers for Disease Control and Prevention Website. Past seasons estimated influenza 
disease burden. 2020 [cited 2020 June 02]. Available from: 
https://www.cdc.gov/flu/about/burden/past-seasons.html. 
11. 
Centers for Disease Control and Prevention Website. Estimated influenza illnesses, 
medical visits, hospitalizations, and deaths in the United States - 2017-2018 influenza season. 
2019 [cited 2020 June 02]. Available from: https://www.cdc.gov/flu/about/burden/2017-
2018.htm. 
12. 
Centers for Disease Control and Prevention Website. Summary of the 2017-2018 influenza 
season. 2019 [cited 2020 June 02]. Available from: https://www.cdc.gov/flu/about/season/flu-
season-2017-2018.htm. 
13. 
Centers for Disease Control and Prevention. Prevention and control of seasonal influenza 
with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United 
States, 2013-2014. MMWR Recomm Rep. 2013;62(RR-07):1-43. 
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14. 
Hu JJ, Kao CL, Lee PI, Chen CM, Lee CY, Lu CY, et al. Clinical features of influenza A 
and B in children and association with myositis. J Microbiol Immunol Infect. 2004;37(2):95-8. 
15. 
Hite LK, Glezen WP, Demmler GJ, Munoz FM. Medically attended pediatric influenza 
during the resurgence of the Victoria lineage of influenza B virus. Int J Infect Dis. 2007;11(1):40-
7. 
16. 
Glezen WP, Couch RB, Taber LH, Paredes A, Allison JE, Frank AL, et al. Epidemiologic 
observations of influenza B virus infections in Houston, Texas, 1976-1977. American journal of 
epidemiology. 1980;111(1):13-22. 
17. 
Centers for Disease Control and Prevention Website. Past seasons vaccine effectiveness. 
2020 [cited 2020 June 02]. Available from: https://www.cdc.gov/flu/vaccines-work/past-seasons-
estimates.html. 
18. 
Chung J, Rolfes M, Flannery B, Prasad P, O’Halloran A, Garg S, et al. Effects of Influenza 
Vaccination in the United States During the 2018–2019 Influenza Season. Clin Infect Dis. 2020. 
19. 
Greenberg DP, Robertson CA, Landolfi VA, Bhaumik A, Senders SD, Decker MD. Safety 
and immunogenicity of an inactivated quadrivalent influenza vaccine in children 6 months 
through 8 years of age. Pediatr Infect Dis J. 2014;33(6):630-6. 
20. 
Greenberg DP, Robertson CA, Noss MJ, Blatter MM, Biedenbender R, Decker MD. 
Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed 
trivalent inactivated influenza vaccines in adults. Vaccine. 2013;31(5):770-6. 
21. 
Keitel WA, Atmar RL, Cate TR, Petersen NJ, Greenberg SB, Ruben F, et al. Safety of 
high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern 
Med. 2006;166(10):1121-7. 
22. 
Couch RB, Winokur P, Brady R, Belshe R, Chen WH, Cate TR, et al. Safety and 
immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine. 
2007;25(44):7656-63. 
23. 
Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind 
controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza 
vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172-80. 
24. 
DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy 
of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 
2014;371(7):635-45. 
25. 
Chang LJ, Meng Y, Janosczyk H, Landolfi V, Talbot HK. Safety and immunogenicity of 
high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized 
clinical trial. Vaccine. 2019;37(39):5825-34. 
26. 
Fluzone High-Dose Quadrivant [Package Insert]. Swiftwater, PA: Sanofi Pasteur Inc.; 
2019. 
27. 
Fiore AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and 
control of influenza. Recommendations of the Advisory Committee on Immunization Practices 
(ACIP), 2007. MMWR Recomm Rep. 2007;56(RR-6):1-54. 
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28. 
Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-
Preventable Diseases. 13 ed. Hamborsky J, Kroger A, Wolfe S, editors: Washington D.C. Public 
Health Foundation; 2015. 
29. 
Woo EJ. Allergic reactions after egg-free recombinant influenza vaccine: reports to the US 
Vaccine Adverse Event Reporting System. Clin Infect Dis. 2015;60(5):777-80. 
30. 
Woo EJ, Moro PL, Cano M, Jankosky C. Postmarketing safety surveillance of trivalent 
recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. 
Vaccine. 2017;35(42):5618-21. 
31. 
Seneviratne U. Guillain-Barré syndrome. Postgrad Med J. 2000;76(902):774-82. 
32. 
Salmon DA, Proschan M, Forshee R, Gargiullo P, Bleser W, Burwen DR, et al. 
Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent 
inactivated vaccines in the USA: a meta-analysis. Lancet (London, England). 
2013;381(9876):1461-8. 
33. 
Leroy Z, Broder K, Menschik D, Shimabukuro T, Martin D. Febrile seizures after 2010-
2011 influenza vaccine in young children, United States: a vaccine safety signal from the vaccine 
adverse event reporting system. Vaccine. 2012;30(11):2020-3. 
34. 
Tse A, Tseng HF, Greene SK, Vellozzi C, Lee GM. Signal identification and evaluation 
for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the 
Vaccine Safety Datalink Project, 2010-2011. Vaccine. 2012;30(11):2024-31. 
35. 
Duffy J, Weintraub E, Hambidge SJ, Jackson LA, Kharbanda EO, Klein NP, et al. Febrile 
Seizure Risk After Vaccination in Children 6 to 23 Months. Pediatrics. 2016;138(1). 
36. 
Centers for Disease Control and Prevention Website. Childhood Vaccines and Febrile 
Seizures 2020 [cited 2020 June 02]. Available from: 
https://www.cdc.gov/vaccinesafety/concerns/febrile-seizures.html. 
37. 
Mitchell DK, Ruben FL, Gravenstein S. Immunogenicity and safety of inactivated 
influenza virus vaccine in young children in 2003-2004. Pediatr Infect Dis J. 2005;24(10):925-7. 
38. 
Moro PL, Arana J, Cano M, Menschik D, Yue X, Lewis P, et al. Postlicensure safety 
surveillance for high-dose trivalent inactivated influenza vaccine in the Vaccine Adverse Event 
Reporting System, 1 July 2010-31 December 2010. Clin Infect Dis. 2012;54(11):1608-14. 
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11 Sponsor Signature Page 
 
 
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Document Number
CLI_00310135
Version Number
1.0
Project Code
Flu seasonal
Arficact Name
Protocol Body
-
-
-
Approver Name
Date
(Universal Time)
Reason for Signature
Approval
-
-
 
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