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, 2021-2022 Formulations
Phase: PHASE4
Conditions: Influenza Immunization, Healthy Volunteers
Sponsor: Sanofi Pasteur, a Sanofi Company

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450–Fluzone® Quadrivalent, 522–Fluzone® High-Dose Quadrivalent 
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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, 2021–2022 Formulations 
Study Code: GRC00102 
Amendment Number: Not applicable 
Compound: Fluzone® Quadrivalent and Fluzone® High-Dose Quadrivalent Influenza Vaccines 
(2021–2022 Formulations)  
Brief Title: 
Annual Study for Collection of Serum Samples in Children and Older Adults Receiving the 2021–
2022 Formulations of Fluzone Quadrivalent Vaccine and Fluzone High-Dose Quadrivalent 
Vaccine, Respectively 
Study Phase: IV 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Manufacturer: Same as Sponsor 
Regulatory Agency Identifier Numbers: 
WHO UTN: U1111-1266-5255 
Protocol Version Number: 1.0 
Approval Date: 21 July 2021 
Medical Monitor Name and Contact Information are provided in the Operating Guidelines. 
The study sites, the Investigators at each site, and the Coordinating Investigator are listed in a 
separate document. 
NCT05050318

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Table of Contents  
Document History .................................................................................................................. 2 
List of Tables .......................................................................................................................... 6 
List of Figures ........................................................................................................................ 6 
1 
Protocol Summary ................................................................................................... 7 
1.1 
Synopsis .................................................................................................................. 7 
Schema 11 
1.2 
Schedule of Activities (SoA) ................................................................................ 14 
2 
Introduction ........................................................................................................... 18 
2.1 
Study Rationale ..................................................................................................... 18 
2.2 
Background ........................................................................................................... 18 
2.2.1 
Epidemiology ...................................................................................................... 20 
2.2.2 
Prevention and Control of Infection Among Humans ........................................ 21 
2.2.3 
The Advisory Committee on Immunization Practices Recommendations ......... 22 
2.2.4 
Background of the Investigational Product ........................................................ 22 
2.3 
Benefit/Risk Assessment ...................................................................................... 23 
2.3.1 
Risks from Study Participation ........................................................................... 24 
2.3.2 
Benefits from Study Participation ...................................................................... 29 
2.3.3 
Overall Benefit-Risk Conclusion ........................................................................ 29 
3 
Objectives and Endpoints ..................................................................................... 29 
4 
Study Design .......................................................................................................... 30 
4.1 
Overall Design ...................................................................................................... 30 
4.2 
Scientific Rationale for Study Design ................................................................... 31 
4.3 
Justification for Dose ............................................................................................ 31 
4.4 
End of Study Definition ........................................................................................ 31 
5 
Study Population ................................................................................................... 31 
5.1 
Inclusion Criteria .................................................................................................. 32 
5.2 
Exclusion Criteria ................................................................................................. 32 
5.3 
Lifestyle Considerations ....................................................................................... 34 
5.4 
Screen Failures ...................................................................................................... 34 

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6 
Study Interventions and Concomitant Therapy ................................................. 34 
6.1 
Study Interventions Administered ........................................................................ 35 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 36 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 37 
6.3.1 
Randomization and Allocation Procedures ........................................................ 37 
6.3.2 
Blinding and Code-breaking Procedures ............................................................ 37 
6.4 
Study Intervention Compliance ............................................................................ 37 
6.5 
Dose Modification ................................................................................................ 37 
6.6 
Continued Access to Study Intervention After the End of the Study ................... 37 
6.7 
Treatment of Overdose.......................................................................................... 37 
6.8 
Concomitant Therapy ............................................................................................ 38 
6.8.1 
Rescue Medicine ................................................................................................. 39 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ................................................................................ 39 
7.1 
Discontinuation of Study Intervention .................................................................. 39 
7.1.1 
Temporary Contraindications ............................................................................. 39 
7.1.2 
Definitive Contraindications ............................................................................... 39 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................................... 40 
7.3 
Lost to Follow-up .................................................................................................. 41 
8 
Study Assessments and Procedures ..................................................................... 41 
8.1 
Efficacy and Immunogenicity Assessments ......................................................... 42 
8.1.1 
Efficacy Assessments ......................................................................................... 42 
8.1.2 
Immunogenicity Assessments ............................................................................ 42 
8.2 
Safety Assessments ............................................................................................... 42 
8.2.1 
Medical History .................................................................................................. 42 
8.2.2 
Physical Examinations ........................................................................................ 42 
8.2.3 
Vital Signs .......................................................................................................... 42 
8.2.4 
Clinical Safety Laboratory Assessments ............................................................ 42 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting..... 43 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ............... 43 
8.3.2 
Method of Detecting SAEs/AESIs ..................................................................... 44 
8.3.3 
Follow-up of SAEs and AESIs ........................................................................... 44 
8.3.4 
Regulatory Reporting Requirements for SAEs .................................................. 44 
8.3.5 
Pregnancy ........................................................................................................... 45 
8.3.6 
Adverse Events of Special Interest ..................................................................... 45 
8.4 
Pharmacokinetics .................................................................................................. 45 
8.5 
Genetics ................................................................................................................. 45 

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8.6 
Biomarkers ............................................................................................................ 45 
8.7 
Immunogenicity Assessments ............................................................................... 45 
8.8 
Medical Resource Utilization and Health Economics .......................................... 45 
8.9 
Leftover Biological Samples and Use of Data ...................................................... 45 
9 
Statistical Considerations ..................................................................................... 47 
9.1 
Statistical Hypotheses ........................................................................................... 47 
9.2 
Sample Size Determination ................................................................................... 47 
9.3 
Analysis Sets ......................................................................................................... 47 
9.4 
Statistical Analyses ............................................................................................... 47 
9.4.1 
General Considerations ....................................................................................... 47 
9.4.2 
Primary Endpoint(s) ........................................................................................... 47 
9.4.3 
Secondary Endpoint(s) ....................................................................................... 48 
9.4.4 
Observational Endpoint(s) .................................................................................. 48 
9.4.5 
Other Safety Analysis ......................................................................................... 48 
9.5 
Interim Analyses ................................................................................................... 48 
10 
Supporting Documentation and Operational Considerations .......................... 49 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations .................. 49 
10.1.1 
Regulatory and Ethical Considerations .............................................................. 49 
10.1.2 
Financial Disclosure ........................................................................................... 50 
10.1.3 
Informed Consent Process .................................................................................. 50 
10.1.4 
Data Protection ................................................................................................... 51 
10.1.5 
Committees Structure ......................................................................................... 53 
10.1.6 
Dissemination of Clinical Study Data ................................................................ 53 
10.1.7 
Data Quality Assurance ...................................................................................... 54 
10.1.8 
Source Documents .............................................................................................. 54 
10.1.9 
Study and Site Start and Closure ........................................................................ 55 
10.1.10 
Publication Policy ............................................................................................... 56 
10.2 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ..................................................................................... 57 
10.2.1 
Definition of AE ................................................................................................. 57 
10.2.2 
Definition of SAE ............................................................................................... 59 
10.2.3 
Recording and Follow-Up of AE and/or SAE .................................................... 61 
10.2.4 
Reporting of SAEs .............................................................................................. 63 
10.3 
Appendix: Risk-based Approach .......................................................................... 64 
10.4 
Appendix: Abbreviations ...................................................................................... 65 
11 
References .............................................................................................................. 66 
12 
Sponsor Signature Page ........................................................................................ 69 

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Document History  
Not applicable as this is the first version of the protocol.

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List of Tables  
Table 1.1: Identity of study interventions ...................................................................................... 10 
Table 1.2: Schedule of activities 1 ................................................................................................ 15 
Table 1.3: Schedule of activities 2 ................................................................................................ 17 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 24 
Table 3.1: Objectives and endpoints ............................................................................................. 29 
Table 4.1: Overall design .............................................................................................................. 30 
Table 6.1: Identity of study interventions ...................................................................................... 35 
 
List of Figures  
Figure 1.1 – Graphical study design for participants 6 months to < 9 years of age ...................... 12 
Figure 1.2 – Graphical study design for participants ≥ 65 years of age ........................................ 13 
 
 

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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, 2021–2022 Formulations 
Brief Title: 
Annual Study for Collection of Serum Samples in Children and Older Adults Receiving the 2021–
2022 Formulations of Fluzone Quadrivalent Vaccine and Fluzone High-Dose Quadrivalent 
Vaccine, Respectively 
Rationale: 
The aim of Study GRC00102 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 2021–2022 formulation of Fluzone 
Quadrivalent vaccine and adults ≥ 65 years of age will receive the 2021–2022 formulation of 
Fluzone High-Dose Quadrivalent vaccine. 
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 
World Health Organization (WHO), 
Centers for Disease Control and 
Prevention (CDC), and Food and Drug 
Administration (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-site 
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 
 
Brief Summary: 

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This is a phase IV, multi-site, open-label study. The study will collect serum samples from 
children 6 months to < 9 years of age who received Fluzone Quadrivalent vaccine and adults 
≥ 65 years of age who received Fluzone High-Dose Quadrivalent vaccine for submission to 
CBER to aid in the influenza vaccine strain selection process.  
Study Duration:  
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. 
Visit Frequency:  
For Participants 6 Months to < 9 Years of Age: 2 or 3 visits, 1 or 2 vaccinations, 1 or 2 telephone 
calls, 2 blood samples 
For Participants ≥ 65 Years of Age: 2 visits, 1 vaccination, 1 telephone call, 2 blood samples 
Number of Participants: 
A total of 90 participants are expected to be enrolled. 
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.  
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 SAE/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. 

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Study interventions 
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). 
Study interventions are described in Table 1.1. 
Table 1.1: Identity of study interventions  
Intervention Name 
Fluzone Quadrivalent vaccine, No 
Preservative (0.5-mL dose), 2021–
2022 formulation 
Fluzone High-Dose Quadrivalent 
vaccine (0.7-mL dose), 2021–2022 
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 Form 
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/Victoria/2570/2019 
(H1N1)pdm09-like virus 
• 
A/Cambodia/e0826360/2020 
(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/Victoria/2570/2019 
(H1N1)pdm09-like virus 
• 
A/Cambodia/e0826360/2020 
(H3N2)-like virus 
• 
B/Washington/02/2019 
(B/Victoria lineage)-like virus 
• 
B/Phuket/3073/2013 (B Yamagata 
lineage)-like virus 
Excipients/Diluent 
Octylphenol ethoxylate (Triton X-
100), sodium phosphate-buffered 
isotonic sodium chloride solution  
Octylphenol ethoxylate (Triton X-
100), sodium phosphate-buffered 
isotonic sodium chloride solution 

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Dosage Level 
0.5 mL per dose 
0.7 mL per dose 
Number of Doses / 
Dosing Interval 
1 or 2 doses 28 (window, 28–35) 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 
Storage Conditions 
Study interventions will be stored in a refrigerator at a temperature ranging from 
+2°C to +8°C. The study interventions must not be frozen. 
Note: Strains are based on WHO/FDA recommendations for the 2021-2022 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 
Statistical considerations: 
None 
Data Monitoring/Other Committee:  
None 
Schema  
The graphical design of GRC00102 study is 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  
 
 
 
 
 
 
 
 
 
 
BL: blood sample 
VAC: vaccination
 
a      Participants receiving 2 doses of study vaccine, as per ACIP guidance  
b    Participants receiving 1 dose of study vaccine 
 
1                      22              29              50               57 
Time (days) 
VAC1 
VAC2
a 
BL0001 
BL0002B
a 
BL0002A
b 

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Figure 1.2 – Graphical study design for participants ≥ 65 years of age. 
 
 
 
 
 
 
 
 
 
BL: blood sample 
VAC: vaccination 
 
 
1                             15                          22   
Time (days) 
VAC1 
BL0001 
BL0002 

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1.2 
Schedule of Activities (SoA)  
Visit procedures are detailed in the Operating Guidelines. 
 

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Table 1.2: 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 CRF 
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 
BL0001 
 
BL0002A 
 
 
BL0002B 
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 CRF 
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; CRF: case report form; 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 ACIP 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 1.3: 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 CRF 
Visit 1 
Telephone 
Contactc 
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 
BL0001 
 
BL0002 
Vaccination  
X 
X 
 
 
Immediate surveillance (20 minutes) 
X 
X 
 
 
Diary card provided 
 
X 
 
 
Telephone contactc 
 
 
X 
 
Reporting of medical events to allow for the 
collection of SAEs, including AESIs 
X 
To be reported throughout the study period 
Diary card reviewed and collected 
 
 
 
X 
Collection of reportable concomitant 
medications 
X 
X 
 
X 
End of Active Phase participation recordd 
X 
 
 
X 
AESI: adverse event of special interest; CRF: case report form; 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 GRC00102 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 
2021–2022 formulation of Fluzone Quadrivalent vaccine and adults ≥ 65 years of age will receive 
the 2021–2022 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 2021–2022 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 (5). 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 (6). 
Fluzone High-Dose Quadrivalent vaccine contains 60 g 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 (7)). 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 (8). 
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 (9) (10). 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 (11). 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 (12). 

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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 (13). 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 (14). During the 2017–2018 season, 
approximately 80% of the deaths occurred in children who had not received the 2017–2018 
influenza vaccine (13).  
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 (15) (16) (17). 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 (5).  
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 (5).  
Annually, from the 2011–2012 through 2018–2019a 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% (18). The 
CDC estimated that influenza vaccination prevented 11% of influenza-related hospitalizations 
                                                 
a  Preliminary estimates for 2018–2019. 

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during the 2018–2019a 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 (19). 
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 (5). The ACIP continues to emphasize the importance of 
vaccinating persons ≥ 6 months of age who have high-risk medical conditions (5). 
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 (5).  
2.2.4 
Background of the Investigational Product  
Vaccine Testing and Release 
Before being released for clinical use, the 2021–2022 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. 
                                                 
a  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 (20) (21). 
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) (22) (23) (24). 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 (25). 
Fluzone High-Dose Quadrivalent Vaccine 
In a pre-licensure study (26), 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 
(27). 
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. 
 

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2.3.1 
Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
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) (28). 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 
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 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
hypersensitivity to some vaccine 
component (29) (30) (31). 
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 
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 (32). 
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 (33). 
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. 
     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) (34). 
Using data collected through the 
The maximum estimated 
absolute excess risk due to 
concomitant administration of 
IIV3, PCV, and diphtheria-
tetanus-acellular-pertussis 
(DTaP)-containing vaccines 
compared with administration of 
these vaccines on separate days 
was 30 cases per 100,000 
vaccinees. According to CDC, 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
CDC-sponsored Vaccine Safety 
Datalink (VSD) project, Tse et al 
(35) 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 
over 5 influenza seasons (2005–
2011), Duffy et al (36) 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 
DTaP-containing vaccine. 
the risk of febrile seizure 
following influenza vaccination 
is small (37). 
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 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
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 (24). 
    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 (24). 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 
compared with placebo injection 
(38). 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 (39). 
    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 (29) (30) (31). 
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 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
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 (32). 
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 (33). 
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. 
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, 
Observation period after 
vaccination for early detection 
and treatment. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
paresthesia or seizure-like 
activity. 
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 2021–2022 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. 
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 
• 
There are no endpoints for this objective. 

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Objectives 
Endpoints 
analyzed by the Sponsor to assess 
breadth of immune response 
induced by the study vaccines. 
4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design  
Type of design 
Parallel, multi-site 
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) 
 
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. 

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Countries 
United States 
Use of 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 
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 synoptic 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. 

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5.1 
Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
Age 
I01: 
Aged 6 months to < 9 years or ≥ 65 years of age on the day of inclusion a. 
Type of participant and disease characteristics 
I02: 
Participants who are healthy as determined by medical evaluation, including medical 
history and physical examination. 
I03:  
For infants and toddlers, born at full term of pregnancy (≥ 37 weeks) or born after a 
gestation period of 27 through 36 weeks and medically stable as assessed by the 
investigator, based on the following definition: “Medically stable” refers to the condition 
of premature infants who do not require significant medical support or ongoing 
management for debilitating disease and who have demonstrated a clinical course of 
sustained recovery by the time they receive the first dose of study intervention. 
Weight 
I04: 
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). 
Informed Consent 
I05: 
Informed consent form (ICF) has been signed and dated by participants ≥ 65 years of age. 
I06: 
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 another legally acceptable representative for 
participants 6 months to < 9 years of age.  
Other Inclusions 
I07: 
Participants or participant and parent/legally acceptable representative (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: 
Medical conditions 
E01: 
Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the 3 months preceding planned 
inclusion). 
                                                 
a  “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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E02: 
Known systemic hypersensitivity to any of the study intervention components, or history 
of a life-threatening reaction to the study interventions used in the study or to a product 
containing any of the same substancesb.  
E03: 
Thrombocytopenia, contraindicating IM injection, at the discretion of the Investigator. 
E04: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating IM vaccination. 
E05: 
Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with study conduct or completion.c 
E06: 
Moderate or severe acute illness/infection (according to Investigator judgment) on the day 
of study intervention administration 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. 
E07: 
Alcohol, prescription drug, or substance abuse that, in the opinion of the Investigator, 
might interfere with the study conduct or completion. 
E08: 
History of serious adverse reaction to any influenza vaccine. 
E09: 
Personal history of Guillain-Barré syndrome (GBS). 
E10: 
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. 
E11: 
Personal history of clinically significant developmental delay (at the discretion of the 
Investigator), neurologic disorder, or seizure disorder. 
E12: 
Known seropositivity for human immunodeficiency virus, hepatitis B, or hepatitis C. 
Prior/concomitant therapy 
E13: 
Receipt of any vaccine in the 30 days preceding the first study intervention administration, 
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. 
E14: 
Previous vaccination against influenza (in the 2021-2022 influenza season) with an 
investigational or marketed vaccine.  
E15: 
Receipt of blood-derived immune globulins, blood, or blood-derived products in the past 3 
months. 
Prior/concurrent clinical study experience 
E16: 
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 
                                                 
b  The components of study interventions are listed in the Prescribing Information for each study vaccine. 
c  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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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. 
Other exclusions 
E17: 
Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily. 
E18: 
Identified as an Investigator or employee of the Investigator or study site with direct 
involvement in the proposed study or identified as an immediate family member (i.e., 
parent, spouse, natural or adopted child) or in-law of the Investigator or employee with 
direct involvement in the proposed study. 
Note: Participants enrolled into this study will not be prohibited from donating blood for non-
interventional studies or other purposes. 
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 enrolled in the study. 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. 
6 
Study Interventions and Concomitant Therapy  
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. 
Note: Vaccines or products administered outside of study protocol are not considered as study 
interventions and are reported in the case report form (CRF) as reportable medications (see 
Section 6.8). Study procedures (e.g., blood sampling) are also not considered as study 
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6.1 
Study Interventions Administered  
Table 6.1: Identity of study interventions  
Study interventions are described in Table 6.1. 
 
Intervention Name 
Fluzone Quadrivalent vaccine, No 
Preservative (0.5-mL dose), 2021–
2022 formulation 
Fluzone High-Dose Quadrivalent 
vaccine (0.7-mL dose), 2021–2022 
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 Form 
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/Victoria/2570/2019 
(H1N1)pdm09-like virus 
• 
A/Cambodia/e0826360/2020 
(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/Victoria/2570/2019 
(H1N1)pdm09-like virus 
• 
A/Cambodia/e0826360/2020 
(H3N2)-like virus 
• 
B/Washington/02/2019 
(B/Victoria lineage)-like virus 
• 
B/Phuket/3073/2013 (B Yamagata 
lineage)-like virus 
Excipients/Diluent 
Octylphenol ethoxylate (Triton X-100), 
sodium phosphate-buffered isotonic 
sodium chloride solution  
Octylphenol ethoxylate (Triton X-
100), sodium phosphate-buffered 
isotonic sodium chloride solution 
Dosage Level 
0.5 mL per dose 
0.7 mL per dose 

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Number of Doses / 
Dosing Interval 
1 or 2 doses 28 (window, 28–35) 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 
Storage Conditions 
Study interventions will be stored in a refrigerator at a temperature ranging from 
+2°C to +8°C. The study interventions must not be frozen. 
Note: Strains are based on WHO/FDA recommendations for the 2021-2022 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. 
3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 

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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 site 
identifier, and a 5-digit participant identifier. The 5-digit participant identifier will correspond to 
the chronological order of enrollment in the site. For example, participant 840000100001 is the 
first participant enrolled in Site Number 1 (in the United States) and participant 840000200002 is 
the second participant enrolled in Site Number 2 (in the Unites States). 
Participant number 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 study intervention is administered as planned (see 
Table 6.1), and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions 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 
Dose Modification  
Not applicable. 
6.6 
Continued Access to Study Intervention After the End of the Study  
Not applicable. 
6.7 
Treatment of Overdose  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 

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However, in the event of an overdose, the investigator should: 
1) Contact the Medical Monitor immediately. 
2) Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted 
3) Closely monitor the participant for any AE/SAE. 
4) Document the quantity of the excess of the overdose in the source documents. 
6.8 
Concomitant Therapy  
Reportable medications include medications that may affect the interpretation of safety data or may 
interfere with the development or measurement of the immune response (e.g., the use of immune-
suppressors, immune-modulators, or some antibiotics that can affect certain bioassays). Some 
medications such as steroids can affect both the evaluation of the safety and the immune response 
to a vaccine. 
This may include medications of interest that were started prior to the day of vaccination, and 
even stopped prior to enrollment if there is a reasonable possibility that they may have an impact 
on safety and / or immune assessment during study participation. 
The following reportable medications are defined:  
• Category 2: medications impacting or that may have an impact on the immune response 
(eg, other vaccines, blood products, antibiotic classes that may interfere with bioassays 
used by Sanofi Pasteur laboratory 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 (eg, systemic steroids/corticosteroids) 
Reportable medications will be collected in the CRF 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). 
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 
CRF only. No details will be recorded in the concomitant medication Form of the CRF unless the 
medication(s) received belongs to one of the pre-listed categories. Medications will not be coded.  

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6.8.1 
Rescue Medicine  
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available at the study site in the event of an anaphylactic, vasovagal, or other immediate 
allergic reaction. 
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: 
Moderate or severe acute illness/infection (according to Investigator judgment) on the 
day of study intervention administration or febrile illness (temperature ≥ 100.4°F 
[38.0°C]). 
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by 
the Investigator in the source documents.  
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 at least one 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 2021–2022 influenza 
vaccine), blood-derived 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 

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(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. 
In the event of a local or national immunization program with a COVID-19 Vaccine, participants 
who receive the vaccine mentioned above at any time during the study will not be withdrawn from 
the study. 
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, or 
compliance reasons. This is expected to be uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: Adverse Event, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant or 
Parent / 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 biological samples 
taken (unless local law requires not to destroy them), 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”. 

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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). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 
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. 
Blood samples will be collected as described in the SoA table (Section 1.2). 
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. 

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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 (Section 1.2). 
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 CRF. Collected information will not be coded.  
8.2.2 
Physical Examinations  
At Visit 01, the Investigator or a designee 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 assessed by the investigator prior to 
immunization. Tympanic, skin, and temporal artery thermometers must not be used. 
8.2.4 
Clinical Safety Laboratory Assessments  
Not applicable. 

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8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.2. 
AEs will be reported by the participants or participants’ parents/legally acceptable representatives 
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). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.2. 
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. The post-vaccination observation should be documented in the source document. 
Adverse Events of Special Interest 
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. 
AESIs will be captured as SAEs. 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 2 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 in the CRF (e.g., SAEs related to blood 
sampling). 
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 information on AEs or SAEs 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. 

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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 daily safety information. These 
diary cards will include areas for free text to capture additional safety information or other 
relevant details.  
At specified intervals, the Investigator or a designee will interview the participants or participants’ 
parents/legally acceptable representatives 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 designee using a 
web-based CRF. 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. 
8.3.3 
Follow-up of SAEs and AESIs  
After the initial SAE/AESI report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts, unless a participant or participant’s parents/legally 
acceptable representative(s) refuses further contact. All AEs that are considered by the 
Investigator as serious, or related to the study intervention administered, or that led to study or 
vaccination discontinuation, or AESIs (as defined in Section 8.3.6)], will be followed during the 
conduct of the study until resolution, stabilization, or the participant is lost to follow-up (as 
defined in Section 7.3). For related SAEs ongoing at last study visit, such follow-up may need to 
continue after the end of the study.  
Further information on follow-up procedures is provided in Appendix 10.2. 
8.3.4 
Regulatory Reporting Requirements for SAEs  
• 
Prompt notification by the investigator to the Sponsor of an 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. 
• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, 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. 

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• 
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. 
8.3.5 
Pregnancy  
Not applicable as the study does not include women of childbearing potential. 
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 
Pharmacokinetics  
Pharmacokinetic parameters are not evaluated in this study. 
8.5 
Genetics  
Genetics are not evaluated in this study. 
8.6 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.7 
Immunogenicity Assessments  
See Section 8.1.2. 
8.8 
Medical Resource Utilization and Health Economics  
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.9 
Leftover Biological Samples and Use of Data  
Any unused part of the biological samples collected for this study (serum 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. 

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In addition, participants or participants’ parents/legally acceptable representatives will be asked to 
indicate in the ICF whether they will permit the future use of any unused stored biological 
samples for other tests, unless prohibited by local laws or IRBs/IECs (in such case, consent for 
future use of any unused biological samples will not be included in the site-specific ICF). If they 
refuse permission, the biological samples will not be used for any testing other than that directly 
related to this study. If they agree to this future use, they will not be paid for giving permission. 
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 and their mechanism of action, 
the knowledge of infectious diseases, or to improve existing tests or develop new tests to assess 
vaccines, or to help identify new vaccine targets or biomarkers that predict participant response to 
the vaccine. Such research may also include, but is not limited to, performing assessments on 
DNA, RNA, proteins or metabolites. If future research on genetic material is performed, a specific 
individual consent will be obtained. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). In the event future research is conducted for other purposes, the study 
participants will be informed of those purposes and will be given means to object to the use of 
their biological samples or data for those research projects. 
All study participant data and biological samples will be coded such that no direct identifiers will 
be linked to participants. Coded data and biological samples may be transferred to a Sponsor site 
(or a subcontractor site), which may be located outside of the country where the study is 
conducted. The Sponsor adopts safeguards for protecting participant confidentiality and personal 
data (see Section 10.1.4). 
The biological samples will be securely stored at the Sanofi Pasteur laboratory and/or other 
laboratories for up to 25 years after the end of the study. Any samples remaining at the end of 
retention period will be destroyed. If a participant requests destruction of his/her samples before 
the end of the retention period, the Investigator must notify the Sponsor (or its contract 
organization) in writing. In such case, samples will be destroyed and sample related coded data 
will be anonymized unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
Note: The other biological samples collected to qualify the participant for inclusion in the study or 
to monitor his/her health during the study are dedicated for immediate use. If any of these 
biological samples are not completely used up, they will be destroyed at the latest at the end of the 
study or after the time requested by local law. 

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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 done for this study. 
9.3 
Analysis Sets  
For the purposes of analysis, the following analysis set is defined: 
 
Participant Analysis Set 
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 seasons will be provided. 
9.4.2 
Primary Endpoint(s)  
There are no primary endpoints for this study. 

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9.4.3 
Secondary Endpoint(s)  
There are no secondary endpoints for this study. 
9.4.4 
Observational Endpoint(s)  
There are no observational endpoints for this study. 
9.4.5 
Other Safety Analysis  
Listings or tables of SAEs and AESIs will be provided. 
9.5 
Interim Analyses  
No analyses are planned to be performed prior to the formal completion of the study. 
 

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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 CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. Similarly, “legally acceptable representative” is used in the protocol 
whereas “guardian” is used in the CRF. 
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 ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, 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 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The investigator 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 
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 

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• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
• In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
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), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the Investigator’s contract. 
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 acceptable representative and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
parents/legally acceptable representative 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 site. 
• In addition to the ICF that is signed by the participant or participant’s parent/guardian, 
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• 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 site 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 participants’ 
parents/legally acceptable representatives 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. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s)/assent must be provided to the participant or their parents/legally 
acceptable representatives. 
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  
All personal data collected and/or processed in relation to this study will be handled in compliance 
with all applicable Privacy & Data Protection laws and regulations, including the GDPR (General 
Data Protection Regulation). The study Sponsor is the Sanofi company responsible for ensuring 
compliance with this matter, when processing data from any individual who may be included in 
the Sanofi databases, including Investigators, nurses, experts, service providers, Ethics Committee 
members, etc.  
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. 
Protection of participant data 
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 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 or its service providers will be identifiable only by 

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the unique identifier; 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 applicable 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. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers and 
publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) or to 
Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects.  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. The 
same rule applies in case the professionals are listed on a regulatory agencies disqualification 
list. 
• Personal data can be communicated to the following recipients:  
• Personnel within Sanofi or partners or service providers involved in the study  
• Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an adequate 
level of protection. Those transfers are safeguarded by Sanofi in accordance with the 
requirement of European law including, notably:  
• The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
• Sanofi’s Binding Corporate Rules for intra-group transfers.  

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• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with any 
competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates in 
the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry (IR) 
project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). Therefore, 
personal data will be securely shared by Sanofi with other pharmaceutical company members 
of the Transcelerate project. This sharing allows Investigators to keep their data up-to-date 
once for all across pharmaceutical companies participating in the project, with the right to 
object to the transfer of the data to the Transcelerate project.  
• Professionals have the right to object to the processing, to request for access to and the 
rectification of their personal data, as well as their erasure (where applicable) by contacting 
the Sanofi Data Protection Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to 
contact Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-
privacy-policy/contact). 
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  
Study participants 
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 
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. 
Professionals involved in the study or in the drug development program 

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Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
 
10.1.7 Data Quality Assurance  
• All participant data relating to the study will be recorded on electronic CRF 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 CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion Instructions. 
• 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 (eg, Contract 
Research Organizations). 
• 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 synoptic 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. 
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. 

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• Data entered in the CRF 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. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF 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. 
 
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 or 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 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: 
For study termination: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
For site termination: 
• 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 or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 

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• Total number of participants included earlier than expected 
 
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. 
10.1.10 Publication Policy  
Information related to publication policy is described in the Investigator’s contract. 

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10.2 Appendix: AEs and SAEs: 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 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 (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, 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 intervention-intervention 
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. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 

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• 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: 
An adverse reaction (AR) is any noxious and unintended response to a study intervention 
related to any dose. 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs which 
occur within the first 30 minutes after vaccination. 
Reactogenicity / Solicited Reactions 
The reactogenicity of a vaccine refers to the property of such vaccine to be able to produce 
common "expected" ARs (either systemic or at the injection site) and its associated signs and 
symptoms. 
A solicited reaction is an “expected” AR (sign or symptom) observed and reported under the 
conditions (nature and onset) pre-listed in the protocol and CRF. 
By definition, solicited reactions are considered as being related to the corresponding IMP 
administered. 
For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions  
Injection / Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration site 
of the IMP. Injection/administration site reactions are commonly inflammatory reactions. 
Solicited injection / administration site reactions are reactions at and around the 
injection / administration site of the IMP observed and reported under the conditions (nature 
and onset) pre-listed in the protocol and CRF. It is considered by default as being related to the 
IMP administered at that site. 
Note: « Administration site reaction » term is only to be used for vaccines that are not intended 
to be administered by injection. 
Systemic AR: 
Systemic ARs are all ARs 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 injection or administration site (eg, erythema that 
is localized but that is not occurring at the injection site).  

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Solicited systemic reactions are systemic AEs observed and reported under the conditions 
(nature and onset) pre-listed in the protocol and CRF. Solicited systemic reactions occurring 
during the specified collection period are always considered related to the IMP even if there is 
evidence of alternative etiology. 
Unsolicited AE/AR 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and onset window post-vaccination. For example, 
varicella or a solicited term such as headache starting after the solicited observation period (eg, 
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 CRF as a solicited 
reaction). 
An unsolicited AR is an unsolicited AE that is considered related to an IMP.  
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
All unsolicited AEs occurring at and around the IMP injection/administration site are to be 
considered by default as related to the IMP administered at that site and are therefore referred as 
unsolicited injection/administration site ARs. 
All unsolicited AEs which are not at and around the IMP injection/administration site, are 
referred as systemic unsolicited AE. For each unsolicited systemic AE, the investigator assesses 
the relationship to the IMP. Systemic AEs assessed as related to IMP are referred as systemic 
ARs. 
Adverse Event of Special Interest (AESI): 
An AESI (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 (eg, regulators) might 
also be warranted. 
10.2.2 Definition of SAE  
An SAE is defined as any adverse event 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 

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•
In general, hospitalization signifies that the participant has been admitted (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 or significant 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
accidental trauma (eg, 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.
Is other medically important event
•
The term "Other medically important events" refers to events which do not meet any of the
above seriousness criteria, but which are considered as serious based on investigator
medical judgment
•
Medical or scientific judgment should be exercised by the investigator in deciding whether
expedited reporting is appropriate in other situations such as significant medical events that
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 include invasive or malignant cancers, intensive treatment in an
emergency room or at home for allergic bronchospasm, blood dyscrasias, convulsions, or
development of intervention dependency or intervention abuse, new-onset diabetes or
autoimmune disease, or suspected transmission of any infectious agent via an authorised
medicinal product.
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. 

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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 (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• 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 CRF 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. 
 
Assessment of Causal Relationship 
By convention, all AEs reported at the injection site are considered to be related to the IMP (see 
definition in Section 6) and therefore are referred to as reactions and do not require the 
Investigator’s opinion on relatedness. 
• Causal relationship of SAEs will be recorded as follows: 
• 
For SAEs/AESIs, relationship to study intervention will be assessed by both the 
Investigator and the Sponsor (except for injection site reactions which will be related 
by default). Sponsor assessment is entered in the Global Pharmacovigilance 
Department (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 administered 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 participants’ underlying condition, therapeutic intervention, or concomitant therapy; 
or the delay between vaccination and the onset of the SAE/AESI is incompatible with 
a causal relationship; or the SAE/AESI started before the first vaccination (screening 
phase, if applicable) 

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• 
Related – There is a “reasonable possibility” that the SAE/AESI was caused by the 
study intervention administered, meaning that there are facts (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 SAE/AESI and has provided an assessment of causal relationship. 
• 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 makes an assessment of causal relationship for every 
event before the initial transmission of the SAE/AESI data to the Sponsor. 
• The investigator may change his/her opinion of causal relationship in light of follow-up 
information and send an SAE follow-up report with the updated causal relationship 
assessment. 
• The causal relationship assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of SAEs/AESIs 
• 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 causal relationship 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 submitted documents. 
• The investigator will submit any updated SAE/AESIs 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. 

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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) 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. 
 
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). 

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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 
CRF 
Case Report Form 
DTaP 
Diphtheria-Tetanus-Acellular-Pertussis 
FDA 
Food and Drug Administration 
GBS 
Guillain-Barré Syndrome 
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 
IMP 
Investigational Medicinal Product;   
IRB 
Institutional Review Board 
IIV3 
Trivalent Inactivated Influenza vaccine 
NA 
Neuraminidase 
NIMP 
Non Investigational Medicinal Product 
PCV 
Pneumococcal Conjugate Vaccine 
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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12 Sponsor Signature Page