Immunogenicity and Safety of Quadrivalent Recombinant Influenza Vaccine Compared With Egg-Based Standard-Dose Quadrivalent Influenza Vaccine in Children 3 to 8 Years of Age.
Phase: PHASE3
Conditions: Influenza Immunization
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page
Protocol Title:
Immunogenicity and Safety of Quadrivalent Recombinant Influenza Vaccine Compared with 
Egg-Based Standard-Dose Quadrivalent Influenza Vaccine in Children 3 to 8 Years of Age.
Study Code: VAP00026
Amendment Number: Amendment 2
Compound: Quadrivalent Recombinant Influenza Vaccine (RIV4)
Brief Title:
Study with Quadrivalent Recombinant Influenza Vaccine (RIV4) Compared with Egg-Based 
Quadrivalent Influenza Vaccine (IIV4) in Participants Aged 3 to 8 Years
Study Phase: Phase III
Sponsor Name and Legal Registered Address:
Sanofi Pasteur Inc.
Discovery Drive, Swiftwater, PA 18370-0187, USA
Manufacturer:
Protein Sciences Corporation
Meriden, CT 06450 USA
Regulatory Agency Identifier Number(s):
BB-IND: 015784
EudraCT: 2022-000576-19
WHO UTN: U1111-1256-8841
Protocol Version Number: 3.0
Approval Date: 22 March 2023
Responsible medical officer (RMO) and pharmacovigilance (PV) representative names and 
contact information are provided in the Operating Guidelines.
The study centers, the Investigators at each center, and the Coordinating Investigator(s) are listed 
in a separate document.
1&7

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Document History and Protocol Amendment Rationale
Previous 
Version(s)
Date
Comments
1.0
24 February 2022
Version submitted to the IECs/IRBs
2.0
22 September 2022
Version submitted to the IECs/IRBs
IEC: Independent Ethics Committee; IRB: Institutional Review Board
x
Amendment 1
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment 1:
Changes were implemented following requests for clarification from the Food and Drug 
Administration (FDA) dated 13 July 2022, mainly:
x
Stratification of randomized groups by site, in addition to age group and previous influenza 
vaccination status
x
The scheduled interim analysis 
Change was also implemented following request of the pediatric investigation plan (PIP) from the 
European Medicines Agency (EMA) dated 18 March 2022, mainly the addition of subgroup 
analyses by serostatus at baseline.
Additional information regarding influenza virus neutralization assay method is provided.
x
Amendment 2
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union because 
it impacts the conduct of the study. However, nor the safety, the physical/mental integrity of 
participants or the scientific value of the study are impacted.
Overall Rationale for the Amendment 2
An interim analysis for futility is being introduced at the end of the 2022-2023 influenza season.
The End of Study will be defined as the last visit last subject or the date of last immunology 
sample analysis (whichever comes later). The immunology blood sample analysis is considered 
part of the data collection process and is key to the study primary endpoint.
Blood visit window is increased at statistical analysis level to address operational constraints 
whilst maintaining clinical relevance of the immunology read-outs.

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Table of Contents
Document History and Protocol Amendment Rationale ................................................... 2 
List of Tables.......................................................................................................................... 7 
List of Figures ........................................................................................................................ 8 
1 
Protocol Summary................................................................................................... 9 
1.1 
Synopsis .................................................................................................................. 9 
1.2 
Schema.................................................................................................................. 14 
1.3 
Schedule of Activities (SoA) ................................................................................ 16 
2 
Introduction ........................................................................................................... 22 
2.1 
Study Rationale..................................................................................................... 22 
2.2 
Background........................................................................................................... 22 
2.3 
Benefit/Risk Assessment ...................................................................................... 25 
2.3.1 
Risks from Study Participation........................................................................... 26 
2.3.2 
Benefits from Study Participation ...................................................................... 29 
2.3.3 
Overall Benefit-Risk Conclusion........................................................................ 29 
3 
Objectives and Endpoints..................................................................................... 29 
4 
Study Design .......................................................................................................... 31 
4.1 
Overall Design ...................................................................................................... 31 
4.2 
Scientific Rationale for Study Design................................................................... 32 
4.3 
Justification for Dose ............................................................................................ 32 
4.4 
End of Study Definition........................................................................................ 32 
5 
Study Population ................................................................................................... 32 
5.1 
Inclusion Criteria .................................................................................................. 32 
5.2 
Exclusion Criteria ................................................................................................. 33 
5.3 
Lifestyle Considerations ....................................................................................... 35 
5.4 
Screen Failures...................................................................................................... 35 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention................................................................................................. 35 

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6 
Study Interventions and Concomitant Therapy................................................. 35 
6.1 
Study Intervention(s) Administered...................................................................... 35 
6.2 
Preparation/Handling/Storage/Accountability...................................................... 37 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 38 
6.3.1 
Randomization and Allocation Procedures ........................................................ 38 
6.3.2 
Blinding and Code-breaking Procedures............................................................ 39 
6.4 
Study Intervention Compliance ............................................................................ 41 
6.5 
Dose Modification ................................................................................................ 41 
6.6 
Continued Access to Study Intervention After the End of the Study ................... 41 
6.7 
Treatment of Overdose.......................................................................................... 41 
6.8 
Concomitant Therapy............................................................................................ 42 
6.8.1 
Rescue Medicine................................................................................................. 42 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal................................................................................ 43 
7.1 
Discontinuation of Study Intervention.................................................................. 43 
7.1.1 
Temporary Contraindications............................................................................. 43 
7.1.2 
Definitive Contraindications............................................................................... 43 
7.2 
Participant Discontinuation/Withdrawal from the Study...................................... 43 
7.3 
Lost to Follow-up.................................................................................................. 44 
8 
Study Assessments and Procedures ..................................................................... 45 
8.1 
Efficacy and Immunogenicity Assessments ......................................................... 45 
8.1.1 
Efficacy Assessments ......................................................................................... 45 
8.1.2 
Immunogenicity Assessments ............................................................................ 46 
8.2 
Safety Assessments............................................................................................... 47 
8.2.1 
Medical History.................................................................................................. 47 
8.2.2 
Influenza Vaccination History............................................................................ 47 
8.2.3 
Physical Examinations........................................................................................ 47 
8.2.4 
Vital Signs .......................................................................................................... 47 
8.2.5 
Clinical Safety Laboratory Assessments ............................................................ 47 
8.2.6 
Pregnancy Testing .............................................................................................. 47 
8.2.7 
Viremia/Vaccinemia........................................................................................... 47 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting..... 48 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information............... 48 
8.3.2 
Method of Detecting AEs and SAEs .................................................................. 49 
8.3.3 
Follow-up of AEs and SAEs .............................................................................. 49 
8.3.4 
Regulatory Reporting Requirements for SAEs .................................................. 50 
8.3.5 
Pregnancy ........................................................................................................... 50 
8.3.6 
Adverse Events of Special Interest..................................................................... 50 

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8.3.7 
Medically Attended Adverse Events .................................................................. 50 
8.3.8 
Early Safety Data Review................................................................................... 50 
8.4 
Pharmacokinetics .................................................................................................. 51 
8.5 
Genetics................................................................................................................. 51 
8.6 
Biomarkers............................................................................................................ 51 
8.7 
Immunogenicity Assessments............................................................................... 51 
8.8 
Medical Resource Utilization and Health Economics .......................................... 51 
8.9 
Leftover Biological Samples and Use of Data...................................................... 52 
9 
Statistical Considerations ..................................................................................... 53 
9.1 
Statistical Hypotheses ........................................................................................... 53 
9.2 
Sample Size Determination................................................................................... 54 
9.3 
Analysis Sets......................................................................................................... 55 
9.4 
Statistical Analyses ............................................................................................... 56 
9.4.1 
General Considerations....................................................................................... 56 
9.4.2 
Primary Endpoint(s) ........................................................................................... 57 
9.4.3 
Secondary Endpoints .......................................................................................... 58 
9.4.4 
Exploratory Endpoint(s) ..................................................................................... 59 
9.5 
Interim Analyses ................................................................................................... 59 
10 
Supporting Documentation and Operational Considerations .......................... 60 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations.................. 60 
10.1.1 
Regulatory and Ethical Considerations .............................................................. 60 
10.1.2 
Financial Disclosure ........................................................................................... 61 
10.1.3 
Informed Consent Process.................................................................................. 61 
10.1.4 
Data Protection ................................................................................................... 63 
10.1.5 
Committees Structure ......................................................................................... 65 
10.1.6 
Dissemination of Clinical Study Data ................................................................ 65 
10.1.7 
Data Quality Assurance...................................................................................... 65 
10.1.8 
Source Documents.............................................................................................. 66 
10.1.9 
Study and Site Start and Closure ........................................................................ 67 
10.1.10 
Publication Policy............................................................................................... 67 
10.2 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ..................................................................................... 68 
10.2.1 
Definition of AE ................................................................................................. 68 
10.2.2 
Definition of SAE............................................................................................... 70 
10.2.3 
Recording and Follow-Up of AE and/or SAE.................................................... 72 
10.2.4 
Reporting of SAEs.............................................................................................. 74 
10.2.5 
Assessment of Intensity...................................................................................... 75 
10.2.5.1 
Tables for Clinical Abnormalities.................................................................... 75 

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10.2.5.1.1 
Solicited AR Intensity Grading Scale............................................................ 75 
10.2.5.1.2 
Unsolicited AE Intensity Grading Scale........................................................ 80 
10.3 
Appendix: Contingency measures for a regional or national emergency that is 
declared by a governmental agency...................................................................... 81 
10.4 
Appendix: Risk-based Approach .......................................................................... 81 
10.5 
Appendix: Abbreviations...................................................................................... 82 
11 
References .............................................................................................................. 84 
12 
Sponsor Signature Page........................................................................................ 86 

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List of Tables
Table 1.1: Schedule of activities for previously vaccinated participants 3-8 years of age............16 
Table 1.2: Schedule of activities for previously unvaccinated participants 3-8 years of age........19 
Table 2.1: Potential risks of clinical significance and risk management ......................................26 
Table 3.1: Objectives and endpoints .............................................................................................29 
Table 4.1: Overall design ..............................................................................................................31 
Table 6.1: Identity of study intervention(s)...................................................................................36 
Table 6.2: Participants disposition by group .................................................................................38 
Table 6.3: Participants disposition in the subset ...........................................................................39 
Table 9.1: Descriptive statistics produced.....................................................................................53 
Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales –
Children aged 2 through 11 years..................................................................................................76 
Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales –
Children aged 2 through 11 years, adolescents or adults aged ≥12 years ....................................78 

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List of Figures
Figure 1.1 – Graphical study design for participants previously vaccinated ................................14 
Figure 1.2 – Graphical study design for participants previously unvaccinated ............................15 

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x
Previously vaccinated participants are defined as participants who have received at least 
2 doses of seasonal influenza vaccine in prior influenza seasons. These participants will 
receive only 1 dose of the study vaccine after enrolling in the study.
RIV4
(N=706)
IIV4
(N=706)
Total
(N=14
12)
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 doses 28 days apart
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 dose 28 days apart
Approxim
ately 50% 
aged 3 to 
5 years
Approxim
ately 50% 
aged 6 to 
8 years
Approxim
ately 50% 
aged 3 to 
5 years
Approxim
ately 50% 
aged 6 to 
8 years
Approxim
ately 50% 
aged 3 to 
5 years
Approxim
ately 50% 
aged 6 to 
8 years
Approxim
ately 50% 
aged 3 to 
5 years
Approxim
ately 50% 
aged 6 to 
8 years
353
353
353
353
1412
The participation duration will be approximately 6 months for participants previously vaccinated 
against influenza and approximately 7 months for participants previously unvaccinated against 
influenza. 
Study interventions
Investigational medicinal product 1: Quadrivalent Recombinant influenza vaccine (RIV4) <year 
season> NH
x
Form: solution for injection
x
Composition: 45 μg of HA of each of the following strains per dose: A/H1N1 strain, A/H3N2 
strain, B/Victoria lineage strain, and B/Yamagata lineage strain
x
Route of administration: IM
Investigational medicinal product 2: Quadrivalent influenza vaccine (IIV4) season <year season> 
NH
x
Form: suspension for injection
x
Composition: 15 μg of HA of each of the following strains per dose: A/H1N1 strain, A/H3N2 
strain, B/Victoria lineage strain, and B/Yamagata lineage strain
x
Route of administration: IM

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Statistical considerations:
The number of participants enrolled and their age at enrollment, sex, race, and ethnic origin will 
be summarized for each vaccine group, as well as the number and description of protocol 
deviations. In general, categorical variables will be summarized and presented by frequency 
counts, percentages, and confidence intervals (CIs). The 95% CIs of point estimates will be 
calculated using the normal approximation for quantitative data and the exact binomial 
distribution (Clopper-Pearson method) for percentages. For GMTs, 95% CIs of point estimates 
will be calculated using normal approximation of log-transformed titers.
Primary endpoints:
The primary objective includes 8 endpoints (geometric mean titers [GMTs] and seroconversion 
[SC] rates for each of the 4 strains).
For each strain, the non-inferiority methodology will be applied to compare the post-vaccination 
GMTs and the SC rates between the groups using a 1-sided Type I error rate of 0.025 with the 
given individual hypothesis.
The primary analysis will be conducted in 2 steps starting with testing for NI of GMTs between 
RIV4 and IIV4. If NI of GMTs based on the 4 strains is demonstrated, then NI for SC will be also 
tested.
Since all 8 NI hypotheses should be rejected at 0.025 significance level, no formal adjustment for 
multiplicity is necessary.
To keep the overall study power above 80%, the sample size was increased accordingly, to have 
an overall type II error < 20% for the 8 NI tests.
It was decided to add to this study’s primary objective an interim analysis at the end of 2022-2023
season, to calculate predictive power of success (PPoS) of all NI statistical tests defined in the 
primary objective and assess safety. And thus, determining if the stopping of this study is 
warranted.
More details are given in the interim analysis section below, and complete details will be included 
in the statistical analysis plan (SAP) of this study.
Secondary endpoints (immunogenicity):
Immunogenicity parameters by HAI measurement method will be described by study group with 
95%CI.
Reverse cumulative distribution curves (RCDCs) of pre-vaccination titer at D01 and post-
vaccination titer 28 days after the last vaccination (D29 or D57) will be generated for each study 
group.
Subgroup analyses will be performed; in particular, immunogenicity will be described according 
to age subgroups, sex, race, season, previous influenza vaccination status, and baseline 
seropositivity status, as appropriate according to number of participants in the respective 
subgroups.
Secondary endpoints (Safety):

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For the main safety parameters, 95% CIs of point estimates will be calculated using exact 
binomial method (Clopper-Pearson method) for single proportions and using the normal 
approximation for quantitative data.
Analysis will be conducted for each study group, by strata of age and according to the number of 
doses received.
Data Monitoring/Other Committee: 
No independent Data Monitoring Committee (DMC) is planned.
Participant safety data will be continuously monitored by the Sponsor’s internal safety
management team (SMT), led by the Global Safety Officer, to detect any safety signals during the
study period.
In addition, this study will include ESDR.
1.2
Schema
The graphical design of VAP00026 study is presented in Figure 1.1 and Figure 1.2.
Figure 1.1 – Graphical study design for participants previously vaccinated
BL: blood sample
VAC: vaccination
PC: phone call

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Figure 1.2 – Graphical study design for participants previously unvaccinated
BL: blood sample
VAC: vaccination
PC: phone call

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1.3
Schedule of Activities (SoA)
Visit procedures are detailed in the Operating Guidelines. 
Table 1.1: Schedule of activities for previously vaccinated participants 3-8 years of age
Phase III Study, 2 Visits, 1 Vaccination, 2 Blood Samples, 6 Months’ Duration Per Participant
Visit/Contact
Collection of information 
in the CRF
Visit 1
Phone 
Call 1*
Visit 2
Phone Call 2
6-month 
follow-up†
Study timelines (Days)
D01
D09
D29
D181
Time interval (Days)
NA
V01 + 8D
V01 + 
28D
V01 + 180D
Time windows (Days)
NA
[+2 D]
[-2, +7 D]
[+14 D]
Visit procedures:
Informed consent 
X
X
Inclusion/exclusion criteria
X
X
Collection of demographic data§§
X
X
Collection of medical history***
(Significant medical history)
X
X
Collection of concomitant medications
X
Reportable concomitant 
medications
28 days after vaccination
History of Influenza vaccination
X
X
Physical examination §
X
X
Pre-vaccination temperature
X

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Visit/Contact
Collection of information 
in the CRF
Visit 1
Phone 
Call 1*
Visit 2
Phone Call 2
6-month 
follow-up†
Study timelines (Days)
D01
D09
D29
D181
Time interval (Days)
NA
V01 + 8D
V01 + 
28D
V01 + 180D
Time windows (Days)
NA
[+2 D]
[-2, +7 D]
[+14 D]
Visit procedures:
Randomization
Contact Interactive Response Technology (IRT) system for randomization, 
participant number, dose number and SN subset
X
X
Blood sampling (BL) (5 mL)
X
BL0001**
BL0002
Vaccination (vac)
X
X
Immediate surveillance (30 min)
X
X
Diary card (DC) / electronic DC [eDC] / Memory Aid (MA) provided
DC/eDC
MA
DC/eDC Reviewed and collected
DC/eDC††
MA Reviewed
MA
Collection of solicited injection site and systemic reactions
X
7 days after 
vaccination
Collection of unsolicited adverse events (AEs)
X
28 days after vaccination
Collection of medically attended AEs (MAAEs)
X
28 days after vaccination
Collection of information on SAEs, including AESIs
X
To be reported at any time during the study
End of Active Phase participation record
X
X
Six months follow-up participant record
X
X

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CRF: case report form
* The Investigator or an authorized designee will remind the participant’s parent(s) or legally acceptable representative(s) to bring back the DC/eDC at the next visit and will answer 
any questions. 
† The Investigator or an authorized designee will interview the participant’s parent(s) or legally acceptable representative(s) to collect the information recorded in the MA, and will 
attempt to clarify anything unclear
§ Complete physical examination to be performed at Visit 1 and symptom directed examination to be performed at Visit 2
** Blood sample to be drawn before vaccination
†† The Investigator or an authorized designee will interview the participant’s parent(s) or legally acceptable representative(s) to collect the information recorded in the DC/eDC, and 
will attempt to clarify anything that is incomplete or unclear.
§§ To comply with US Food and Drug Administration expectations, Sponsors are to enroll participants who reflect the demographic for clinically relevant populations with regards to
age, gender, race, and ethnicity (FDA. Collection of race and ethnicity data in clinical trials: Guidance for industry and Food and Drug Administration staff [Internet]. 2016. Available 
from: https://www.fda.gov/media/75453/download)
*** Including history of laboratory-confirmed influenza illness over the 3 previous influenza seasons

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Table 1.2: Schedule of activities for previously unvaccinated participants 3-8 years of age
Phase III Study, 3 Visits, 3 Phone Calls, 2 Vaccinations, 2 Blood Samples, 7 Months’ Duration Per Participant
Visit
Collection 
of information 
in the CRF
Visit 1
PC 1*
Visit 2
PC 2*
Visit 3
PC3
6-month safety 
follow-up†
Study timelines (Days)
D01
D09
D29
D37
D57
D209
Time interval (Days)
V01 + 
8D
V01+28D
V02 + 8D
V02 + 28D
V02 + 180D
Time windows (Days) 
NA
[+2 D]
[-2, +7 D]
[+2 D]
[-2, +7 D]
[+14 D]
Visit procedures:
Informed consent
X
X
Inclusion/exclusion criteria
X
X
Collection of demographic data††
X
X
Collection of medical history‡‡
(Significant medical history)
X
X
Collection of concomitant medications
X
Reportable concomitant 
medication
28 days after each vaccination
History of Influenza vaccination
X
X
Physical examination‡
X
X
X
Pre-vaccination temperature
X
X
Randomization
X
X

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Visit
Collection 
of information 
in the CRF
Visit 1
PC 1*
Visit 2
PC 2*
Visit 3
PC3
6-month safety 
follow-up†
Study timelines (Days)
D01
D09
D29
D37
D57
D209
Time interval (Days)
V01 + 
8D
V01+28D
V02 + 8D
V02 + 28D
V02 + 180D
Time windows (Days) 
NA
[+2 D]
[-2, +7 D]
[+2 D]
[-2, +7 D]
[+14 D]
Visit procedures:
Contact IRT system for randomization, participant 
number, dose number and SN subset
Blood sampling (BL) (5 mL)
X
BL0001§
BL0002
Definitive contraindications
X
X
Vaccination (VAC)
X
VAC1
VAC2
Immediate surveillance (30 min)
X
X
X
DC / eDC /MA provided
DC/eDC 
1
DC/eDC 2
MA
DC reviewed
DC/eDC 
1**
DC/eDC 
2**
DC collected
DC/eDC 1
DC/eDC 2
MA reviewed
MA
Collection of solicited injection site and systemic 
reactions
X
7 days after 
vaccination
7 days after vaccination
Collection of unsolicited AEs
X
28 days after each vaccination
Collection of MAAEs
X
28 days after each vaccination
Collection of information on SAEs, including AESIs
X
To be reported at any time during the study
End of Active Phase participation record
X
X

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Visit
Collection 
of information 
in the CRF
Visit 1
PC 1*
Visit 2
PC 2*
Visit 3
PC3
6-month safety 
follow-up†
Study timelines (Days)
D01
D09
D29
D37
D57
D209
Time interval (Days)
V01 + 
8D
V01+28D
V02 + 8D
V02 + 28D
V02 + 180D
Time windows (Days) 
NA
[+2 D]
[-2, +7 D]
[+2 D]
[-2, +7 D]
[+14 D]
Visit procedures:
Six months follow-up participant record
X
X
CRF: case report form
* The Investigator or an authorized designee will remind the participant’s parent(s) or legally acceptable representative(s) to bring back the DC/eDC at the next visit and will answer 
any questions.
† The Investigator or an authorized designee will interview the participant’s parent(s) or legally acceptable representative(s) to collect the information recorded in the MA, and will 
attempt to clarify anything unclear
‡ Complete physical examination to be performed at Visit 1 and symptom directed examination to be performed at Visit 2 and Visit 3
§ Blood sample to be drawn before vaccination
** The Investigator or an authorized designee will interview the participant’s parent(s)/legally acceptable representative
†† To comply with US Food and Drug Administration expectations, Sponsors are to enroll participants who reflect the demographic for clinically relevant populations with regards to 
age, gender, race, and ethnicity (FDA. Collection of race and ethnicity data in clinical trials: Guidance for industry and Food and Drug Administration staff [Internet]. 2016. Available 
from: https://www.fda.gov/media/75453/download)
‡‡ Including history of laboratory-confirmed influenza illness over the 3 previous influenza seasons

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2
Introduction
Sanofi Pasteur’s RIV4 vaccine is a vaccine that is being developed for protection of the pediatric 
population against influenza.
2.1
Study Rationale
The proposed study is a Phase III, randomized, modified double-blind, active-controlled 
(standard-dose quadrivalent influenza vaccine, IIV4), multi-center study to assess the NI of RIV4 
compared to IIV4, the hemagglutination inhibition (HAI) antibody response induced by RIV4 
compared to the HAI antibody response induced by IIV4, the immunogenicity of RIV4 in terms 
of HAI titer, the immunogenicity of RIV4 in terms of neutralization titer and to document the 
safety of RIV4 compared to IIV4 in children. It is planned to enroll 1412 participants aged 3-8
years in USA and Europe.
IIV4 vaccine licensed in Europe and in the USA will be used in the control arm.
2.2
Background
Influenza is a contagious, acute viral respiratory disease caused by influenza type A and type B
viruses. The virus is transmitted easily from person to person via droplets and small particles 
produced when infected people cough or sneeze. Members of high-risk groups, such as infants 
and younger children as well as children with underlying medical conditions, are at increased risk 
of influenza and its complications. Complications in the pediatric population include secondary 
bacterial pneumonia, acute otitis media, bronchitis, febrile seizures, Reye’s syndrome, myositis, 
neurologic conditions, and exacerbations of underlying conditions (2) (3) (4). One study assessing 
the impact of influenza infection on young children, their family, and the health care system found 
that 28.6% of children with influenza had a secondary complication (pneumonia/chest infection, 
febrile convulsion, otitis media, croup), 40.9% were prescribed antibiotics, 65.4% of children 
missed school/day care, and 53.4% of parents missed work (5).
In adults, influenza is typically characterized by the rapid onset of fever, myalgia, sore throat, and 
non-productive cough, and can also cause severe malaise lasting for several days. The clinical 
manifestations in children, especially in young children less than 5 years of age, are less 
characteristic and may be more diverse than the clinical symptoms seen in adults (3). Besides 
symptoms of non-productive cough, nasal congestion, rhinitis, and sore throat, gastrointestinal 
symptoms such as diarrhea, vomiting, and abdominal pain can occur for 10–30% of children with 
influenza (6) (7).
The burden of influenza disease has been estimated in several modeling studies. In a 2018 study, 
Iuliano et al. estimated the number of global annual influenza-associated respiratory deaths using 
country-specific influenza-associated excess respiratory mortality estimates from 1999–2015 and 
reported that 9243 to 105 690 influenza-associated respiratory deaths occur in children younger 
than 5 years each year (8). Matias et al. investigated the average seasonal burden of influenza-

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attributable hospitalizations in the United States (US) from 1997 to 2009 and found that children 
0-4 and 5-17 years of age were estimated to have an annual mean rate of 128 and 20 per 100 000
population respectively (9). About half of the cases in children were due to influenza A infections 
and the other half were due to influenza B infections.
Vaccination currently represents the most effective medical intervention against influenza and its 
severe complications. Thus, the World Health Organization (WHO) recommends that people who 
are most at risk for severe seasonal influenza, including children less than 5 years of age (10) (11),
should receive an annual vaccination against influenza because it has been shown to be effective 
in reducing influenza-associated morbidity and mortality (12) (13). The effectiveness of the 
influenza vaccine in preventing or attenuating illness depends in part on the age and immune 
competence of the vaccine recipient. Infants and young children remain at increased risk for 
influenza because of their maturing immune system and lack of prior exposure and thus lack of 
immunity. Furthermore, during 3 recent influenza seasons in the US (US 2015-2016, 2016-2017,
2017-2018 seasons), vaccine effectiveness in children 6 months to 8 years of age was 51%, 57%, 
and 68% respectively (14).
Background of the Study Intervention
Protein Sciences Corporation (PSC), now a Sanofi Company, has initially developed a trivalent 
recombinant influenza vaccine (RIV3) consisting of purified recombinant HA (15) produced from 
a proprietary technology that is based on the insect cell – baculovirus system referred to as the 
Baculovirus Expression Vector System (BEVS).
RIV3 contains 135 μg of recombinant hemagglutinin (15) derived from 3 influenza strains (2 A 
subtypes and 1 B lineage) 45 μg of each of A strains (A/H1N1 and A/H3N2) and 45 μg of B 
strain (from Victoria or Yamagata lineages). The vaccine contains no egg proteins, preservatives, 
antibiotics, or adjuvant.
Data from multiple Phase II and Phase III studies with RIV3 showed the vaccine was well 
tolerated, immunogenic, and 44.6% (95% confidence interval [CI], 18.8% - 62.6%) effective in 
preventing culture-confirmed influenza in adults from 18 to 49 years of age (16). Furthermore, 
studies in adults 50 – 64 years (17) of age and in adults 65 years of age and older (18) showed 
HAI antibody responses induced by RIV3 met the pre-specified seroconversion (SC) criterion of 
the lower bound of the 95% CI ≥40% for adults < 65 years and ≥30% for adults ≥65 years of 
age for all three vaccine strains. The pre-specified criterion for the proportion of subjects with
post-vaccination HAI titers of ≥1:40 (“seroprotection”) with the lower bound of the 95% CI 
≥70% for adults < 65 years and ≥60% for adults ≥65 years of age were also met for both 
influenza A antigens. Responses to the B antigen were commonly less robust among recipients of 
RIV3 and the comparator trivalent influenza vaccine but were of similar magnitude in recipients 
of both vaccines (17) (18).
RIV3 was licensed under trade name Flublok® in the US for active immunization for the 
prevention of influenza disease for adults 18-49 years of age in 2013, followed by approval for 
adults 50 years of age and older in 2014.
To mitigate the risk posed by the potential widespread circulation of a strain from the alternate B 
lineage not contained in the trivalent formulation, quadrivalent recombinant influenza vaccine 

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(RIV4) containing 45 μg of each of A strains (A/H1N1 and A/H3N2) and B strains (from Victoria 
and Yamagata lineages) has been developed based on the same manufacturing process used for 
RIV3.
Clinical data generated with RIV4 in 2 subsequent Phase III studies showed RIV4 provided 30% 
to 43% better protection against influenza disease compared to a quadrivalent inactivated 
influenza vaccine (IIV4) in adults 50 years of age and older (19) during a season characterized by 
predominantly antigenically drifted strains of influenza A (H3N2) and was non-inferior to the 
same IIV4 comparator vaccine for 3 of 4 influenza vaccine strains as assessed by SC rates and 
geometric mean titers (GMT) in adults 18 to 49 years of age (20).
Vaccination with RIV4 was found to be safe and well tolerated among 5326 adults ≥ 18 years 
participating in these 2 studies, with no safety concerns identified. The safety profile of RIV4 
showed comparable reactogenicity (solicited injection site reactions and solicited systemic 
reactions) to IIV4 and no notable difference in occurrence of unsolicited adverse events (AEs), 
serious adverse events (SAEs), adverse events of special interest (AESIs) and deaths.
RIV4 was licensed in the USA in 2016 under the trade name Flublok® Quadrivalent and in 
Mexico in March 2018 under the trade name Flublok Tetravalent. In November 2020, marketing 
authorization was granted for RIV4 in the European Union (EU) under the trade name 
Supemtek®. Marketing authorization has also been approved in Brazil (May 2019, trade name 
Flublok Quadrivalent), Argentina (January 2020, trade name Virublok®), Canada (January 2021, 
trade name Supemtek), Hong-Kong (April 2021, trade name Flublok Quadrivalent), Australia 
(May 2021, trade name Flublok Quadrivalent), and Switzerland (October 2021, trade name 
Supemtek).
With approximately 21 334 843 doses of RIV4 and RIV3 distributed cumulatively and after post-
marketing surveillance data collected up to August 2021, the safety profile of the recombinant 
influenza vaccine in humans is consistent with the established clinical safety profile and has been 
confirmed to be well tolerated with no safety concerns.
After registration of RIV4 for an indication in adults aged 18 years and older, Sanofi Pasteur plans 
to extend the indication to the pediatric population.
Two randomized, active-controlled trials of recombinant influenza vaccine were conducted by 
PSC in the pediatric age group in the US. The clinical data from pediatric studies utilizing either 
RIV3 or RIV4 demonstrated very satisfactory safety and reactogenicity profiles.
A Phase I clinical trial (21) was conducted with RIV3 in 156 children aged 6 months – 5 years (98 
subjects received RIV3 [among them 61 received the full-dose of 45 μg per antigen] and 58 
received a licensed IIV3 [Fluzone]).
A Phase II clinical trial (22) was conducted in 219 children and adolescents 6 – 17 years of age 
who received either RIV4 or a licensed IIV4 (Fluarix Quadrivalent).
The clinical data from pediatric studies showed an acceptable safety and reactogenicity profiles of 
RIV3 or RIV4.
By evaluating a series of age cohorts ranging from 6 months to 17 years, it was shown that HAI 
assay immunity appears to be induced to a greater degree as the participants become older. Some 

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of this apparent diminished immune response in younger children may have been reflective of the 
relatively small sample sizes.
Therefore, Sanofi Pasteur proposes to conduct a Phase III study (VAP00026) to assess the 
immunogenicity and safety of RIV4 compared with IIV4 in large numbers of participants aged 3 
to 8 Years.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events, the potential risks, and uncertainties of RIV4 may be found in the Investigator’s 
Brochure (IB).

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Age
I01: Aged 3 to 8 years on the day of inclusionc
Informed Consent
I02: Assent form has been signed and dated by the participant (according to local regulations), 
and informed consent form has been signed and dated by the parent(s) or another legally 
acceptable representative and by an independent witness, if required by local regulations
Other inclusions
I03: Participant and parent/legally acceptable representative are able to attend all scheduled visits 
and to comply with all study procedures
I04: Covered by health insurance if required by local regulations
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 past 3 months) 
E02: Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the trial or to a vaccine containing any of the same 
substancesd.
E03: Thrombocytopenia, or known thrombocytopenia, as reported by the parent(s)/legally 
acceptable representative, contraindicating intramuscular vaccination based on the Investigator's 
judgment
E04: Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination based on the Investigator's judgment
E05: Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with study conduct or completion
E06: Moderate or severe acute illness/infection (according to Investigator judgment) or febrile 
illness (temperature ≥38.0°C [≥100.4°F]) on the day of study intervention administration. A 
prospective participant should not be included in the study until the condition has resolved or the 
febrile event has subsided
E07: Personal or family history of Guillain-Barré Syndrome (GBS)
                                                
c “3 to 8 years” means from the day of the 3rd birthday to the day before the 9th birthday
d The components of study interventions are listed in Section 6.1 of the protocol and in the Investigator’s Brochure

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E08: Personal history of clinically significant development delay (at the discretion of the 
Investigator), neurologic disorder, or seizure disorder 
 
Prior/concomitant therapy 
E09: Receipt of any vaccine in the 4 weeks preceding the first study intervention administration 
or planned receipt of any vaccine in the 4 weeks following the study intervention administration 
except for COVID-19 vaccination, which may be received at least 2 weeks before study 
interventione
E10: Previous vaccination against influenza (in the previous 6 months) with an investigational or 
marketed vaccine
E11: Receipt of immune globulins, blood or blood-derived products in the past 3 months 
 
Prior/concurrent clinical study experience 
E12: Participation at the time of study enrollment (or in the 4 weeks preceding the first study 
vaccination) or planned participation during the present study period in another clinical trial 
investigating a vaccine, drug, medical device, or medical procedure 
 
Other exclusions
E13: Any condition which, in the opinion of the Investigator, might interfere with the evaluation 
of the study objectives, including planning to leave the area of the study before the end of the 
study
E14: In an emergency setting or hospitalized involuntarily
E15: Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study
If the participant has a primary physician who is not the Investigator, the site should contact this 
physician with the participant’s parent(s)/legally acceptable representative’s consent to inform 
him / her of the participant’s participation in the study. In addition, the site should ask this 
primary physician to verify exclusion criteria relating to previous therapies, such as receipt of 
blood products or previous vaccines.
                                                
e If the participant is enrolled and parent(s)/legally acceptable representative seek vaccination of COVID-19 vaccine 
outside of the study for the participant, they will be encouraged to discuss this intention proactively with the study 
investigator and the participant will be permitted to receive the authorized vaccine at the earliest 28 days after last 
study vaccination and at any time thereafter. If the participant receives the authorized influenza or COVID 19 
vaccine, this information will be collected.

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5.3
Lifestyle Considerations
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents.
Individuals who do not meet the criteria for participation in this study (screen failure) cannot be 
rescreened.
5.5
Criteria for Temporarily Delaying Enrollment/Randomization/Administration 
of Study Intervention
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 10.3: Contingency measures for a regional or national emergency that is declared by a 
governmental agency should be considered for enrollment/randomization/administration of study 
intervention.
6
Study Interventions and Concomitant Therapy
Study intervention is defined as any investigational intervention, marketed product, placebo, or 
medical device 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 CRF as reportable medications (see Section 6.8). Study 
procedures (eg, blood sampling) are also not considered as study interventions.
6.1
Study Intervention(s) Administered
Study interventions are described in Table 6.1.

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Table 6.1: Identity of study intervention(s)
Intervention Name
RIV4 <year season> NH
IIV4 <year season> NH 
Use
Experimental
Active-comparator
IMP and NIMP
IMP
IMP
Type 
Vaccine
Vaccine
Dose Form
Solution for injection in a pre-filled syringe
Suspension for injection in a pre-filled syringe
Unit Dose Strengths
45 μg of HA of each of the following strains 
per dose:
x
A/H1N1 strain
x
A/H3N2 strain
x
B/Victoria lineage strain
x
B/Yamagata lineage strain 
15 μg of HA of each of the following strains 
per dose:
x
A/H1N1 strain
x
A/H3N2 strain
x
B/Victoria lineage strain
x
B/Yamagata lineage strain
Excipients/Diluent
Each 0.5 mL dose of RIV4 will contain:
Sodium chloride 4.4 mg
Monobasic sodium phosphate 0.2 mgf
Dibasic sodium phosphate 0.5 mgg
Polysorbate 20 (Tween® 20) 27.5 μg 
Octylphenol ethoxylate (Triton X-100®)
≤100 μg
Water for injection
Preservative is not used in the manufacture or 
formulation of RIV4
Each 0.5 mL dose of IIV4 will contain:
Octylphenol-10 (Triton X-100)     ≤0.115 mg
α-Tocopheryl hydrogen succinate ≤0.135 mg
Polysorbate 80 (Tween 80)            ≤0.550 mg
Preservative is not used in the manufacture or 
formulation of IIV4
Dosage Level
0.5 mL per dose
0.5 mL per dose
                                                
f Calculated from the anhydrous form
g Calculated from the anhydrous form

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Number of Doses / 
Dosing Interval
1 or 2 doses 28 days apart
1 or 2 doses 28 days apart
Route of Administration
IM injection
IM injection
Site of Administration
Deltoid muscle in the upper arm
Deltoid muscle in the upper arm
Sourcing
Provided by the Sponsor 
Provided by the Sponsor 
Packaging and Labeling
Each study intervention will be provided in an individual box. Each study intervention (pre-filled 
syringe) will bear one fixed label and each box will bear detachable labels and one fixed label 
containing the dose number. All will be labeled as required per country requirement.
Current/Former Name(s) 
or Alias(es)
Supemtek/Flublok Quadrivalent
Fluarix Tetra (or other commercial brand 
name), Fluarix® Quadrivalent (or other 
commercial names)
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.
IMP: Investigational Medicinal Product; NIMP: Non-Investigational Medicinal Product; TBD: to be determined
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).
4)
Further guidance and information for the final disposition of unused study interventions are 
provided in the Operating Guidelines.

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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization and Allocation Procedures
On the day of enrollment, participants aged 3 to 8 years who meet all the inclusion criteria but 
none of the exclusion criteria and sign the assent form (according to local regulations) and whose 
parent(s)/legally acceptable representative sign the ICF will be randomized in a 1:1 ratio, 
stratified by season, site, age subgroup and by vaccination status for influenza, such as each study 
randomized vaccine group will have approximately 50% of participants aged 3 to 5 years and 
50% of participants aged 6 to 8 years, to receive either RIV4 or IIV4. Age subgroup will be 
stratified by vaccination status for influenza, such as each age subgroup will have approximately 
50% of participants previously vaccinated against influenza and 50% of participants previously 
unvaccinated against influenza. Participants will receive either 1 or 2 doses 28 days apart 
depending on whether they were previously vaccinated against influenza, respectively (see 
Table 6.2).
Table 6.2: Participants disposition by group
RIV4
(N=706)
IIV4
(N=706)
Total
(N=1
412)
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 doses 28 days apart
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 dose 28 days apart
Approxi
mately 
50% 
aged 3 to 
5 years
Approxi
mately 
50% 
aged 6 to 
8 years
Approxi
mately 
50% 
aged 3 to 
5 years
Approxi
mately 
50% 
aged 6 to 
8 years
Approxi
mately 
50% 
aged 3 to 
5 years
Approxi
mately 
50% 
aged 6 to 
8 years
Approxi
mately 
50% 
aged 3 to 
5 years
Approxi
mately 
50% 
aged 6 to 
8 years
353
353
353
353
1412
In addition, at least 400 participants per vaccine group will be randomized to be part of the subset 
population to assess the immunogenicity based on the SN method. Subset randomization will be 
stratified by vaccination status against influenza subgroup and age subgroups (3 to 5 years and 6 
to 8 years) in order to have approximately 25% of subset participants in each stratum (see 
Table 6.3).

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Table 6.3: Participants disposition in the subset
RIV4
(N=400)
IIV4
(N=400)
Total
(N=800)
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 doses 28 days apart
Previously vaccinated 
against influenza
1 dose
Previously 
unvaccinated against 
influenza
2 dose 28 days apart
Approxi
mately 
50% 
aged 3 to 
5 years
Approxi
mately 
50% 
aged 6 to 
8 years
Approxi
mately 
50% 
aged 3 to 
5 years
Approxima
tely 50% 
aged 6 to 8 
years
Approxima
tely 50% 
aged 3 to 5 
years
Approxi
mately 
50% 
aged 6 to 
8 years
Approxi
mately 
50% 
aged 3 to 
5 years
Approxima
tely 50% 
aged 6 to 8 
years
200
200
200
200
800
Site staff will connect to the Interactive Response Technology (IRT), enter the identification and 
security information, and confirm a minimal amount of data in response to IRT prompts. The IRT 
will then provide the group assignment and have the staff confirm it. The full detailed procedures 
for group allocation are described in the Operating Guidelines. If the participant is not eligible to 
participate in the study, then the information will only be recorded on the participant recruitment 
log.
Participant numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier). For example, 
Participant 840000100005 is the fifth participant enrolled in Center Number 1 in the US (840 
being the USA country code). In addition, the first of the 5-digit participant identifier will identify 
if the participant is part of the subset for exploratory objective (number 1) or not (number 2). For 
example, Participant 840000210003 is the third participant enrolled in Center Number 2 in the US 
and is part of the subset for exploratory objectives.
Participant numbers should not be reassigned for any reason. The randomization codes will be 
kept securely in the IRT.
6.3.2
Blinding and Code-breaking Procedures
The study will be performed in a modified double-blind fashion:
x
Participant, participant’s parent(s)/legally acceptable representative, Investigators, and study 
staff who conduct the safety assessment and immunogenicity assays will not know which 
study vaccine is administered

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x
Only the study staff who prepare and administer the study intervention and are not involved 
with the safety evaluation will know which study intervention is administered
The Investigator responsible for safety assessment will not attend the vaccination session but will 
be available in case of emergency (anaphylactic shock).
Treatment ID numbers will be used to identify each vaccine syringe for the purpose of 
randomization, vaccination and the recording of the study intervention administered. Treatment 
numbers will be randomly assigned to study interventions syringes. The IRT vendor will be 
responsible for assigning the treatment group identification and treatment number to be received 
by the enrolled participant. The participant, the participant’s parent(s)/legally acceptable 
representative, the Investigator, and the study staff members who collect the safety data and 
laboratory personnel who analyze the blood samples will all be blinded to the group assignment. 
The individual responsible for preparing / administering study intervention will not be authorized 
to collect any safety / serology data.
The code may be broken in the event of an AE only when the identification of the study 
intervention received could influence the treatment of the participant. Code-breaking should be 
limited to the participant(s) experiencing the AE.
The blind can be broken by the Investigator or a designee through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a designee must notify the Sanofi Pasteur 
responsible medical officer (RMO) if a participant’s code was broken. All contact attempts with 
the Sponsor prior to unblinding are to be documented in the source documents, and the code-
breaking case report form (CRF) is to be completed.
The Independent Ethics Committees (IEC) / Institutional Review Board (IRB) must be notified of 
the code-breaking, in accordance with local regulations. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor.
A request for the code to be broken may also be made:
x
by the Global Pharmacovigilance (GPV) Department through an internal system for 
reporting to Health Authorities in the case of an unexpected SAE considered causally 
related, as described in International Council for Harmonisation (ICH) E2Ah. In this case, 
the code will be broken only for the participant(s) in question. The information resulting 
from code-breaking (ie, the participant’s study intervention or group assignment) will not 
be communicated to either the Investigator or the immediate team working on the study, 
except for the GPV representative.
x
By the SMT if needed during the early safety data review (ESDR)
An interim analysis will be performed at the end of the 2022-2023 vaccination season. Safety 
summaries and the calculation of separate PPoS for each of the 8 NI statistical tests included in 
                                                
h All unexpected and related SAEs submitted to European Union competent authorities must be unblinded.

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the primary objective will be assessed. An unblinded independent statistician will be in charge of 
breaking the blind of the enrolled participants in the 2022-2023 season after database lock, 
conducting the interim analysis and communicating the results to a firewall Internal Committee 
(FIC) who will make the decision of recommending or not recommending the stopping of this 
study.
A final analysis will be conducted once the 6-months safety data has been collected and the final 
database lock has occurred.
The code-breaking procedures are described in the Operating Guidelines.
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:
x
All study interventions will be administered by qualified and trained study personnel
x
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
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 10.3: Contingency Measures for a regional or national emergency that is declared by a 
governmental agency. 
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.
However, in the event of an overdose, the investigator should:
1)
Contact the RMO immediately.
2)
Evaluate the participant to determine, in consultation with the RMO, whether study 
intervention should be interrupted

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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 (eg, an 
antipyretic or analgesic that could have reduced the intensity or frequency of an adverse event) or 
may interfere with the development or measurement of the immune response (eg, 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: 
x
medications impacting or that may have an impact on the evaluation of the safety (eg, 
antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], systemic 
steroids/corticosteroids)
Note: Topical analgesics should NOT be applied at the injection site of study intervention; 
however, if they are applied inadvertently, they should be recorded.
x
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)
x
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 until the end of the solicited and unsolicited 
follow-up period. 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded (except topical analgesics applied at the 
injection site of study intervention).
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 the reportable medication list. Medications will be coded.
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.

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7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
7.1.1
Temporary Contraindications
Should a participant experience one of the conditions listed below, the Investigator will postpone
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the SoA.
TCI01:
Febrile illness (temperature ≥38.0°C [≥100.4°F]) or moderate or severe acute illness 
/ infection on the day of vaccination, according to Investigator judgment
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Appendix 10.3: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency). 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 and immunogenicity. 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
In the event of a local or national immunization program with any other vaccine as needed,
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
x
A participant may be withdrawn from the study at any time at his/her parent(s)/legally 
acceptable representative 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.
x
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 Parent / 
Legally Acceptable Representative.

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x
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
x
If the participant’s parent(s)/legally acceptable representative withdraw(s) consent for 
disclosure of future information, the Sponsor may retain and continue to use any data 
collected before such a withdrawal of consent.
x
If a participant’s parent(s)/legally acceptable representative withdraw(s) consent, they 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.
x
Withdrawn participants will not be replaced.
Follow-up of Discontinuations
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document.
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for definition of “lost to follow-up”.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a parent/legally acceptable representative fails to return to 
the site for a required study visit or cannot be contacted as planned in the SoA:
x
The site must attempt to contact the parent(s)/legally acceptable representative and 
reschedule the missed visit as soon as possible and counsel the the parent(s)/legally 
acceptable representative 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. 
x
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the parent(s)/legally acceptable representative (where 
possible, 3 telephone calls and, if necessary, a certified letter to the participant’s 
parent(s)/legally acceptable representative last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical 
record.
x
Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
x
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 

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information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1.
8
Study Assessments and Procedures
x
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
x
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.
x
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
x
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.
x
Safety/Laboratory results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
Blood samples will be collected as described in the SoA table (Section 1.3).
A volume of blood of 5 mL will be collected at each visit. The maximum amount of blood 
collected for each participant over the duration of the study will not exceed 10 mL and 15 mL for 
participants previously unvaccinated and previously vaccinated against influenza, respectively.
Guidance and information for the sample collection, preparation, storage, and shipment are 
provided in the Operating Guidelines.
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10.3: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
8.1
Efficacy and Immunogenicity Assessments
Planned time points for all immunogenicity assessments are provided in the SoA.
8.1.1
Efficacy Assessments
No clinical efficacy data will be obtained in the study.

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8.1.2
Immunogenicity Assessments
HAI assay
The immunogenicity of influenza vaccines RIV4 and IIV4 will be assessed using the HAI assay 
on sera samples of blood collected at D01, D29, and D57 (for participants previously 
unvaccinated against influenza). Test serum samples and quality control sera (sheep, ferret, and/or 
human sera) will be incubated with Sigma Type III neuraminidase (NA) from Vibrio cholerae to
eliminate non-specific inhibitors. Adsorption of spontaneous anti-species agglutinins will then be 
performed by incubating the test serum samples and quality control sera with a red blood cell 
(RBC) suspension. Following this, the mixtures will be centrifugated and the supernatants 
containing the treated sera will be collected for testing. Ten 2-fold dilutions (starting at 1:10) of 
the treated test serum samples and quality control sera will be incubated with a previously titrated 
influenza antigen at a concentration of 4 hemagglutination units (HAU)/25 μL. influenza antigens 
will not be added to the serum control wells containing only serum and RBCs. The mixture will 
be then incubated and a RBC suspension added. Following incubation, the results will be read. 
The endpoint of the assay is the highest serum dilution in which complete inhibition of 
hemagglutination occurred. 
Influenza virus seroneutralization assay (SN assay)
The SN assay measures Abs directed against the viral neutralization epitopes of the influenza 
virus, which may be different from the hemagglutination epitopes; therefore, the SN titers may be 
different from the HAI titers.
To measure SN, serially diluted, heat-inactivated human serum samples are pre-incubated with a 
fixed amount of challenge virus prior to the addition of Madin-Darby canine kidney (MDCK) 
cells. After overnight incubation, the viral nucleoprotein production in infected MDCK cells is 
measured by enzyme-linked immunosorbent assay (ELISA), using monoclonal Ab specific to 
either influenza A nucleoprotein or influenza B nucleoprotein. Since serum neutralizing Abs to 
the influenza virus inhibit the viral infection of MDCK cells, the ELISA optical density results are 
inversely proportional to the titers of neutralizing Ab present in the serum. The LLOQ is set at the 
reciprocal of the lowest dilution used in the assay (ie, 10 [1/dil]). 
Assays will be performed by Sanofi Pasteur laboratory (Swiftwater, PA, USA) or an external 
testing laboratory under Sanofi Pasteur laboratory responsibility. The address is provided in the 
Operating Guidelines.

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8.2
Safety Assessments
This section presents safety assessments other than adverse events which are presented in 
Section 8.3.
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
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 or to a repetitive outpatient care will be 
collected in the CRF. Collected information will be coded.
8.2.2
Influenza Vaccination History
Participant’s parent(s)/legally acceptable representative will be questioned regarding participant’s 
prior influenza vaccination over the 3 previous influenza seasons. Information will be collected in 
the CRF.
8.2.3
Physical Examinations
At each visit, the Investigator or a designee will perform a clinical or medically-driven physical 
examination. Information will be recorded in the source document.
8.2.4
Vital Signs
Oral pre-vaccination temperature will be systematically collected by the investigator on the source 
document. Tympanic, skin, and temporal artery thermometers must not be used.
8.2.5
Clinical Safety Laboratory Assessments
Not applicable.
8.2.6
Pregnancy Testing
Not applicable.
8.2.7
Viremia/Vaccinemia
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’ 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 AE or SAE 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 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document.
Reactogenicity
Solicited injection site reactions will be collected for 7 days after each.
Solicited systemic reactions will be collected for 7 days after each vaccination.
The solicited injection site reactions and systemic reactions that are pre-listed in the diary cards 
and CRF, together with the intensity scales, are presented in Appendix 10.2.5.1.1.
Reactogenicity is to be reported only for IMPs. Refer to Table 6.1 to know which study 
intervention are considered as IMPs.
Unsolicited Non-serious Adverse Events
Unsolicited non-serious adverse events will be collected for 28 days after each.
The intensity grading scale for unsolicited non-serious adverse events is presented in 
Appendix 10.2.5.1.2.
Medically Attended Adverse Events (MAAEs)
MAAEs will be collected for 28 days after each vaccination.
Adverse Events of Special Interest (AESIs)
AESIs will be collected at any time during the study.
See Section 8.3.6 for the list of AESIs.
SAEs
Information on SAEs will be collected and assessed throughout the study, from the first dose until 
6 months after the last vaccination. However, before the first study intervention administration, 

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only SAEs related to study procedures are to be collected in the case report form (CRF) (eg, 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.
8.3.2
Method of Detecting AEs and SAEs
Individual diary card/electronic diary cards, specifically designed for this study by the Sponsor 
and provided to the study sites, will be given to study parents / legally acceptable representatives 
for the recording of daily safety information. These diary cards will include pre-listed terms and 
intensity scales as well as areas for free text to capture additional safety information or other 
relevant details. Parents / legally acceptable representatives will also be provided with rulers for 
measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
parents / legally acceptable representatives on how to correctly use these tools.
At specified intervals, the Investigator or a designee will interview the parents / legally acceptable 
representatives to collect the information recorded in the diary card/electronic 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/electronic diary card will first 
be captured in the source document and then reported electronically.
The 6-month follow-up will be done by interviewing parents / legally acceptable representatives 
either during a visit or over the telephone using a questionnaire to capture SAEs and AESIs, if 
applicable.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant’s parent(s)/legally acceptable representative is 
the preferred method to inquire about AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts, unless a participant or parents / legally acceptable representatives 
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 AEs of 
special interest (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. 

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Further information on follow-up procedures is provided in Appendix 10.2.
8.3.4
Regulatory Reporting Requirements for SAEs
x
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.
x
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.
x
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.
x
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
AESIs will be captured as SAEs. These include new onset of GBS, encephalitis/myelitis, 
including transverse myelitis, Bell’s palsy, optic neuritis, brachial neuritis, thrombocytopenia, 
vasculitis, and anaphylaxis.
8.3.7
Medically Attended Adverse Events
MAAEs will be collected using the same process as other AEs. See Appendix 10.2.1 for 
definition of MAAEs.
8.3.8
Early Safety Data Review
x
An ESDR conducted by the SMT will be performed, the goal of which is to allow for a 
cautious, stepwise approach to vaccine administration. An initial safety review for this study is 
planned when approximately 10% of participants aged 3 to 8 years are vaccinated and have 
provided safety data for 7 days after administration of the first dose.
x
The safety data collected will be entered into the CRB and will be summarized and reviewed 
by the Sponsor. It is understood that this review will be based on preliminary data that would 
not have been subject to validation and database lock.

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x
The following safety parameters collected from D01 to D08 will be assessed as part of the 
ESDR review in a blinded manner by the Sponsor:
x
Immediate reactions
x
Solicited injection site and systemic reactions
x
Unsolicited AEs reported as related by the investigator
x
SAEs (including AESIs)
x
Enrollment will not be paused during the Sponsor review. Case unblinding may occur if 
necessary.
x
If any of the following criteria are met, a decision will be made by the Sponsor as to whether 
enrollment in the study will be paused and will be allowed to resume later:
x
An SAE (including AESI) considered as related to the vaccination by the investigator 
and Sponsor
x
> 10% of participants experiencing any Grade 3 AEs within 7 days after vaccination
x
After the ESDR will be conducted, the team will continue to monitor the safety of all 
participants via SMTs and/or data review meetings during the conduct of the study. SMT 
periodicity will be detailed in the SMT charter.
8.4
Pharmacokinetics
Pharmacokinetics parameters are not evaluated in this study.
8.5
Genetics
Genetics are not evaluated in this study.
8.6
Biomarkers
No other biomarkers than those described in the immunogenicity assessments section 
(Section 8.1.2) are 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.

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8.9
Leftover Biological Samples and Use of Data
Any unused part of the biological samples collected for this study (blood samples) are being 
retained in long-term storage to support answers to regulatory questions related to the product’s 
licensure and the potential revalidation of the study results.
In addition, 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 and 
the corresponding data, 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. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 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.
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 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
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, Version 9.4 or above.
The core SAP will be written, and peer reviewed before the initiation of the study. In accordance 
with the protocol, the SAP will describe all analyses to be performed by the Sponsor and all the 
conventions to be taken.
It was decided to add to the statistical analysis initially planned, an interim analysis at the end of 
2022-2023 season, to evaluate safety and calculate separate PPoS for each of the 8 NI statistical 
tests included in the primary objective. Creating consequently the possibility of stopping this 
study if warranted.
More details are given in the interim analysis section below, and complete details will be included 
in the SAP of this study.
For descriptive purposes, the following statistics will be presented:
Table 9.1: Descriptive statistics produced
Baseline characteristics 
and follow-up description
Categorical data
Number and percentage of participants
Continuous data
Mean, standard deviation, quartiles, minimum, and maximum
Safety results
Categorical data
Solicited and biological safety: Number and percentage (95% 
CIs) of participants
Unsolicited: Number and percentage (95% CIs) of participants, 
and number of events
Continuous data
At least mean, standard deviation, minimum, and maximum
Immunogenicity results
Categorical data 
(seroprotection, 
seroconversion, cutoff)
Number and percentage (95% CIs) of participants
Continuous data 
(titer / data)
Log10: Mean and standard deviation
Anti-Log10 (work on Log10 distribution, and anti-Log10
applied): Geometric mean, 95% CI of the geometric mean, 
quartiles, minimum, and maximum
Graphical representation by reverse cumulative distribution 
curve (RCDC)
9.1
Statistical Hypotheses
Primary Objective:
Statistical Methodology for analyzing the primary 8 endpoints of GMTs and SC rates.
Non-inferiority of RIV4 as compared to IIV4 in participants 3 to 8 years of age will be conducted 
for GMTs and SC rates.
Since all 8 hypotheses have to be rejected at 0.025 significance level, no formal adjustment for 
multiplicity is necessary.

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For each strain, the non-inferiority methodology will be applied to compare the post-vaccination 
GMTs and the SC rates between the groups using a 1-sided Type I error rate of 0.025 with the 
given individual hypothesis.
The primary analysis will be conducted into 2 steps starting with testing for NI of GMTs between 
RIV4 and IIV4. If NI of GMTs based on the 4 strains is demonstrated, then NI for SC will be also 
tested.
Step1: Geometric Mean Titers
For each of the 4 strains, the hypotheses are as follows. Each of the 4 individual H0 need to be 
rejected to demonstrate NI in GMTs.
H0: GMT RIV4 /GMT IIV4 ≤ 0.667
HA: GMT RIV4 /GMT IIV4 > 0.667
or equivalently,
H0: log10 (GMT RIV4) - log10 (GMT IIV4) ≤ log10 (0.667)
HA: log10 (GMT RIV4) - log10 (GMT IIV4) > log10 (0.667)
Step 2: Seroconversion
For each of the 4 strains, the hypotheses are as follows. Each of the 4 individual H0 need to be 
rejected to demonstrate NI in SCs.
H0: P RIV4 - P IIV4 ≤ -10%
HA: P RIV4 - P IIV4 > -10%
Secondary Objectives:
There are no statistical hypotheses to be tested in the secondary objectives.
9.2
Sample Size Determination
A total of approximately 1200 evaluable participants 3 to 8 years of age will be assessed 
(approximately 50% participants enrolled in the age group 3-5 years and 50% participants 
enrolled in the age group 6-8 years) in this study. Approximately 50% of participants enrolled 
within age group will be primed, and the other 50% will be unprimed.

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Assuming similar GMTs in both groups, a one-sided alpha of 0.025 and a standard deviation of 
log10 titers of 0.6 with a NI margin of 1.5 (or 1/1.5 = 0.667); NI for GMTs would be demonstrated 
with a study power of approximately 99.6%.
Assuming in each vaccine group the same expected SC rates (0.5, 0.5, 0.7, 0.7) for each of the 4 
strains (A/H1N1, A/H3N2, B/Yamagata and B/Victoria), based on conservative estimates from 
historical data, and a NI margin of 10%, the NI for SC can be demonstrated with a study power of 
approximately 82.0% (93.7%, 93.7%, 96.7% and 96.7% for each strain, respectively).
Hence, the overall study power is estimated to be approximately 82.0% (82.0% = 99.6%[GMTs] x 
82.0%[SC]).
As shown above, to keep the study power above 80%, the sample size was increased accordingly, 
to have an overall Type II error < 20% for the 8 NI tests.
Assuming 15% attrition rate in this age group; a total of approximately 1412 participants 3 to 8 
years of age will be enrolled in this study.
9.3
Analysis Sets
For the purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Randomized
All participants randomized by study IRT to one of the study groups.
Safety Analysis Set (SafAS)
Participants who have received at least one dose of the study vaccine. All 
participants will have their safety analyzed after each dose according to the 
vaccine they actually received, and after any dose according to the vaccine 
received at the 1st dose.
Safety data recorded for a vaccine received out of the protocol design will be 
excluded from the analysis (and listed separately).
Full analysis set (FAS)
Subset of randomized participants who received at least 1 dose of the study 
vaccine and had a post-vaccination blood sample.
For the assessment of the immune response by SN assay, the analysis will be 
performed on the participants from FAS who were randomized in the 
exploratory subset (FAS-SN). 
Participants will be analyzed according to the intervention to which they were 
randomized.
Per-protocol analysis set (PPAS)
Subset of the FAS. Participants presenting with at least one of the following 
criteria will be excluded from the PPAS:
Participant did not meet all protocol-specified inclusion criteria or met at least 
one of the protocol-specified exclusion criteria
Participant did not complete the vaccination schedule
Participant received a vaccine other than the one that he / she was randomized 
to receive
Preparation and / or administration of vaccine was not done as per-protocol
Participant did not receive vaccine in the proper time window
Participant did not provide the post-dose serology sample at visit 2 or at visit 3 
in the proper time window ([D26, D39] or VAC2+[D26, D39] respectively) or 
a post-dose serology sample was not drawn at visit 2 or visit 3

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Participant received protocol-prohibited medications impacting or that may 
have an impact on the immune response as described in Section 6.8
The above criteria leading to exclusion from PPAS may be detailed and 
completed if necessary in the SAP, following the review of protocol deviations 
during the study conduct. PPAS(s) definition(s) will be finalized before the 
first database lock.
For the assessment of the immune response by SN assay, the analysis will be 
performed on the participants from PPAS who were randomized in the 
exploratory subset (PPAS-SN).
In the event of a local or national immunization program with any other 
vaccine as needed, participants who receive 1 or more doses of the vaccine 
listed above at any time during the study will not be withdrawn from the study.
9.4
Statistical Analyses
The SAP will be amended and finalized prior to any database lock (such as for interim and final 
analysis) and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
9.4.1
General Considerations
The statistical analysis will be conducted as follows:
x
At the end of the vaccination season of 2022-2023, after cleaning the database and fulfilling a 
partial database lock, the data in this study will be unblinded by an independent statistician to 
conduct an interim analysis. Safety summaries will be generated and separate PPoS of each of 
the 8 statistical tests will be calculated. The independent statistician will communicate and 
present the results to the FIC, who will make the decision of recommending or not 
recommending the stopping of the study. If the study continues the unblinded information 
from the 2022-2023 season will not be shared with the study team and the independent 
statistician will not be involved in the preparation and conduct of the study completion.
x
The final database lock will occur after the 6-month follow-up period is completed for all 
subjects randomized and vaccinated in the study, or after stopping the study to write the final 
CSR.
The number of participants enrolled and their age at enrollment, sex, race, and ethnic origin will 
be summarized for each vaccine group, as well as the number and description of protocol 
deviations. In general, categorical variables will be summarized and presented by frequency 
counts, percentages, and confidence intervals (CIs). The 95% CIs of point estimates will be 
calculated using the normal approximation for quantitative data and the exact binomial 
distribution (Clopper-Pearson method) for percentages. For GMTs, 95% CIs of point estimates 
will be calculated using normal approximation of log-transformed titers.
Details will be provided in the SAP core body.

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9.4.2
Primary Endpoint(s)
The immunogenicity parameters will be calculated in each study group with their 95% CIs using 
the exact binomial distribution (Clopper-Pearson method) for proportions and using normal 
approximation of log-transformed for GMTs.
Statistical Methodology for analyzing the primary 8 endpoints (GMTs and SC rates).
Non-inferiority of RIV4 as compared to IIV4 in participants 3 to 8 years of age will be conducted 
for GMTs and SC rates.
For each strain, the non-inferiority methodology will be applied to compare the post-vaccination 
GMTs and the SC rates between the groups using a 1-sided Type I error rate of 0.025 with the
given individual hypothesis.
The primary analysis will be conducted into 2 steps starting with testing for NI of GMTs between 
RIV4 and IIV4. If NI of GMTs based on the 4 strains is demonstrated, then NI for SC will be also 
tested.
Step 1: Geometric Mean Titers
Assuming that log10 transformation of the data follows a normal distribution, the log10 (data) 
will be used for the statistical analysis, then antilog transformations will be applied to the results 
of calculations, in order to provide the results in terms of geometric means (GMs).
The statistical methodology is based on a 2-sided 95% CI of the ratio of the GMTs (RIV4 divided 
by IIV4) at 28 days after the last vaccination. Non inferiority for GMTs is demonstrated if the 
lower limit of the 2-sided 95% CI of the GMT ratio is > 0.667 for each of the 4 virus strains. 
ANCOVA will be conducted for each strain with a model including the terms log10 of HAI titer 
at D01, priming status, age subgroup, season and the treatment represented by the vaccine 
administered as independent factors, and log10 HAI titer of each virus strain separately of the last 
vaccination as a response variable. ANCOVA will be conducted using Proc Mixed in SAS (all 
terms in the model are fixed). In Proc Mixed, the "Estimate" statement will allow to derive the 
difference (RIV4 minus IIV4) of the Least Squares-means and the 95% CI in their original log10 
values. By exponentiating the difference (RIV4 minus IIV4) and its 95% CI; the 95% CI of ratio 
(RIV4/IIV4) will be obtained and be used to derive GMTs NI final results.
Step 2: Seroconversion
The statistical methodology will be based on a 2-sided 95% CI of the difference in SC rates 
(RIV – IIV4) 28 days after the final vaccination. Non-inferiority for SC will be demonstrated if 
the lower limit of the 2-sided 95% CI is > -10% for the 4 strains. The 95% CI of the rate 
difference will be computed using the Wilson Score method without continuity correction
Non-inferiority will be assessed on PPAS as the main analysis set and will be confirmed on the 
FAS.

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As a sensitivity analysis, a generalized linear model (binomial-identity model) based on a link 
function named “identity link” will be used. The regression coefficient for the treatment (vaccines 
administered) in the binomial-identity model represent the proportions difference (difference 
between RIV4 and IIV4). The model will include priming status, age subgroup, season and the 
treatment term (represented by the vaccine administered) as independent factors. The difference 
(RIV4 – IIV4) and its 95% CI obtained will be used to derive the SC NI results.
In the sensitivity analysis, the statistical methodology will be based on a 2-sided 95% CI of the 
difference in SC rates (RIV4 – IIV4) at 28 days after last vaccination. The NI for SC rates will be 
demonstrated if the lower limit of the 2-sided 95% CI is > -10% for the 4 strains.
9.4.3
Secondary Endpoints
Immunogenicity 
The immunogenicity parameters will be calculated with their 95% CIs using the exact binomial 
distribution (Clopper-Pearson method) for proportions and using normal approximation of log-
transformed for GMTs and GMTs ratio. All analyses will be conducted by study group. The main 
parameters will also be described by age subgroup and priming status.
RCDCs of pre-vaccination titer and post-vaccination titer 28 days after the last vaccination (D29 
or D57) will be generated for each study group. The RCDCs will include the plots of the 2 study 
groups the same figure.
The analysis will be conducted for each immunogenicity variable on the PPAS, and on FAS if the 
attrition rate from FAS to PPAS is greater than 10%.
In addition, subgroup analyses will be performed; in particular, immunogenicity will be described 
according to season, sex, race, previous influenza vaccination status (received a seasonal 
influenza vaccine in the last past influenza season or not), baseline seropositivity status 
(seropositive and seronegative are defined as baseline antibody titer ≥ 1:10 or < 1:10), and age 
subgroups (3 to 5 and 6 to 8 years) as appropriate according to number of participants in the 
respective subgroups.
Subgroup analyses will be performed on PPAS.
Safety
For the main safety parameters, 95% CIs of point estimates will be calculated using exact 
binomial method (Clopper-Pearson method) for single proportions and using the normal 
approximation for quantitative data.
All analyses will be descriptive; no hypotheses will be tested.
The number of participants with documented safety will be used as denominator of the 
frequencies.
For solicited reactions, the denominator will be the total number of participants who have non-
missing data for the endpoint considered.
For unsolicited AEs, the denominator will be the total number of participants who were 
vaccinated.

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9.4.4
Exploratory Endpoint(s)
Exploratory Immunogenicity Objective:
The immunogenicity parameters will be calculated with their 95% CIs using the exact binomial 
distribution (Clopper-Pearson method) for proportions and using normal approximation of log-
transformed titers for GMTs. All analyses will be conducted by study group. The main parameters 
will also de described by age subgroup and by priming status. For some parameters (eg. GMTs, 4-
fold increase) difference or ratio between groups may be calculated with 95%CI. The 95% CI of 
ratios of GMTs will be calculated using the same method as for the primary objective.
RCDCs of pre-vaccination titer (D01) and post-vaccination titer 28 days after last vaccination 
(D29 or D57) will be generated for each study group. The RCDCs will include the plots of the 2 
groups on the same figure.
The analysis will be conducted for each immunogenicity variable on the PPAS subset (PPAS-SN) 
and on the FAS subset (FAS-SN) if the attrition rate from FAS-SN to PPAS-SN is greater than 
10%.
9.5
Interim Analyses
Following the planned recruitment period of 2022-2023 season, only approximately 25% out of 
the 1412 targeted participants aged 3 to 8 years had been enrolled and vaccinated in the study.
Thus, it was decided to conduct an interim analysis to review safety and assess the likelihood of 
the study success by the end of enrollment (1412 participants) based on the immunogenicity data 
accumulated after randomizing and vaccinating approximatively 350 younger children 
(approximately 25% of participants).
For this interim analysis: 
x
A FIC including Senior members from Clinical, Safety and Biostatistics will be set up to 
review the content of the results including the interim analysis and recommend if the 
stopping of this study is warranted  
x
An unblinded statistical team will be in charge of breaking the blind on the enrolled
participants after database lock, conducting the interim statistical analysis and 
communicating unblinded results to the FIC.
x
The recommendation for stopping the study will be based on:
o
The safety results of RIV4, and/or
o
The individual predictive power to meet NI for each strain and each parameter 
(GMT and SC rate) and/or
o
The overall PPoS of the 4 GMTs NI statistical tests based on a PPoS of less or 
equal 
.
A charter will be written to define the roles and responsibilities of every party in the conduct of
the interim analysis, the FIC functioning and the issuance of recommendation for stopping the 
study.
More details on the calculation of PPoS and the conduct of the interim analysis will be provided 
in the SAP.

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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
x
This study will be conducted in accordance with the protocol and with the following:
x
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
x
Applicable ICH Good Clinical Practice (GCP) Guidelines
x
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR])
x
The protocol, informed consent form (ICF), Investigator Brochure (IB), and other relevant 
documents (eg, 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
x
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
x
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.
x
The investigator will be responsible for the following:
x
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 (in addition to summaries required from the Sponsor)
x
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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x 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
x The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
x 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.
x 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.
x
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
x
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
x
The investigator or his/her representative will explain the nature of the study to the participant 
and their parents / legally acceptable representatives and answer all questions regarding the 
study.
x
Participants and parent(s)/legally acceptable representative must be informed that their 
participation is voluntary. Participants and/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 center.

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x
Depending on local regulations, a separate assent form (AF) may be required to be signed by 
minor participants. The assent form is in addition to, not in place of, an ICF that is signed by 
the parent(s)/legally acceptable representative.
x
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.
x
The actual Assent Form (AF) and ICF used at each center may differ, depending on local 
regulations and IEC / IRB requirements. However, all versions must contain the standard 
information found in the sample AF and ICF provided by the Sponsor. Any change to the 
content of the AF and ICF must be approved by the Sponsor and the IEC / IRB prior to the 
form being used.
x
If new information becomes available that may be relevant to the participant’s or parents’ / 
legally acceptable representatives’ willingness to continue participation in the study, this will 
be communicated to them in a timely manner. Such information will be provided via a revised 
AF and ICF or an addendum to the original AF and ICF.
x
Participants and parent(s)/legally acceptable representative must be re-consented to the most 
current version of the AF(s) and/or ICF(s) during their participation in the study.
x
A copy of the AF(s) and/or ICF(s) must be provided to the participant’s parents / legally 
acceptable representatives.
Rationale for Including Participants Unable to Give Consent:
VAP00026 study will be conducted on pediatric population aged from 3 to 8 years old. 
Depending on local regulations some participants will not be in age to give consent and 
participant’s parent(s)/legally acceptable representative consent will be collected instead.
The ICF will contain a specific section that addresses the use of remaining mandatory samples for 
optional exploratory research, unless prohibited by local laws or IRBs/IECs. The investigator or 
designee will explain to each participant the objectives of the exploratory research. Participants 
will be told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.
Recruitment Procedures
Participants will be recruited from the general population. The sites will ensure that any 
advertisements used to recruit participants (letters, pamphlets, posters, etc) are submitted to Sanofi 
Pasteur prior to submission to the IEC / IRB for approval. Detailed guidance and information are 
provided in the Operating Guidelines.
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10.3: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency.

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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 (eg, on African-American population for the Food and Drug Administration 
[FDA]).
x
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 
the unique identifier; participant names or any information which would make the participant 
identifiable will not be transferred to the Sponsor.
x
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.
x
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.
x
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 
x
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.
x
Personal data can be processed for other studies and projects. 

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x
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.
x
Personal data can be communicated to the following recipients: 
x
Personnel within Sanofi or partners or service providers involved in the study 
x
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
x
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: 
x
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers,
x
Sanofi’s Binding Corporate Rules for intra-group transfers. 
x
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.
x
Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations.
x
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. 
x
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).

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10.1.5 Committees Structure
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. The Sponsor’s 
internal safety review committee, led by the PV representative and the RMO, will be responsible 
for the blinded review, assessment, and evaluation of safety data generated from this study. This 
committee is empowered to recommend a pause in recruitment and/or further vaccination while it 
investigates any potential signal or concern.
In addition, this study will include an early safety data review (see Section 8.3.8).
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
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
x
All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF.
x
Guidance on completion of CRFs will be provided in the CRF Completion Instructions.

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x
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
x
Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact patient safety and/or reliability of study results. These predefined parameters will be 
monitored during the study, and important deviation from the QTLs and remedial actions 
taken will be summarized in the clinical study report.
x
Monitoring details describing strategy (eg, 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.
x
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
x
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract
Research Organizations).
x
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor.
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.
x
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.
x
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.
x
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
x
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.

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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 center study-site has all the documents necessary for archiving and a study-site 
closure visit has been performed along with a termination report.
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:
x
Discontinuation of further study intervention development
x
Information on the study intervention leads to doubt as to the benefit/risk ratio
For site termination:
x
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
x
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator
x
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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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
x
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.
x
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
x
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
x
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
x
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 
x
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.
x
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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10.2.5 Assessment of Intensity
The investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”.
10.2.5.1 Tables for Clinical Abnormalities
10.2.5.1.1 Solicited AR Intensity Grading Scale

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Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales –
Children aged 2 through 11 years
CRF term 
(MedDRA 
lowest 
level term 
[LLT])
Injection site 
pain
Injection 
site 
erythema
Injection site 
swelling 
Injection site 
induration
Injection site 
bruising
Diary 
card term
Pain
Redness
Swelling
Hardening
Bruising
Definition
Pain either 
present 
spontaneously 
or when the 
injection site 
is touched or 
injected limb 
is mobilized
Presence of 
a redness 
including 
the 
approximate 
point of 
needle entry
Swelling at or 
near the 
injection site
Swelling or 
edema is caused 
by a fluid 
infiltration in 
tissue or cavity 
and, depending 
on the space 
available for the 
fluid to disperse, 
swelling may be 
either soft 
(typically) or 
firm (less 
typical) to touch 
and thus can be 
best described 
by looking at the 
size of the 
swelling
Hardening at or 
near the injection 
site. Hardening is 
caused by a slow 
diffusion of the 
product in the 
tissue leading to a 
thick or hard area 
to touch at or near 
the injection site 
and thus can be
best described by 
looking at the size 
of the hardening.
Bruising is the 
result of the 
diffusion of blood 
in the skin from 
ruptured blood 
vessels that forms 
a purple or black 
and blue spot on 
the skin. It can be 
best described by 
looking at its size.

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Intensity 
scale*
CRF:
Grade 1: 
Easily 
tolerated
Grade 2: 
Sufficiently 
discomforting 
to interfere 
with normal 
behavior or 
activities
Grade 3: 
Incapacitating, 
unable to 
perform usual 
activities
Diary card:
Grade 1: No 
interference 
with activity
Grade 2: 
Some
interference 
with activity
Grade 3: 
Significant; 
prevents daily 
activity
Grade 1: 
> 0 to 
< 25 mm
Grade 2: 
≥25 to 
< 50 mm
Grade 3: 
≥50 mm
Grade 1: > 0 to 
< 25 mm
Grade 2: ≥25 to 
< 50 mm
Grade 3: 
≥50 mm
Grade 1: > 0 to 
< 25 mm
Grade 2: ≥25 to 
< 50 mm
Grade 3: ≥50 mm
Grade 1: > 0 to 
< 25 mm
Grade 2: ≥25 to 
< 50 mm
Grade 3: ≥50 mm
MedDRA: Medical Dictionary for Regulatory Activities
* For pain, the scale will be provided in the CRF and the intensity will be transcribed from the diary card. For other 
injection site reactions (erythema and swelling), the classification as Grades 1, 2, or 3 will be applied at the time of 
statistical analysis; the scale is provided for information purposes only. The actual size of the reaction will be reported in
the CRF.

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Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales –
Children aged 2 through 11 years, adolescents or adults aged ≥12 years
CRF term 
(MedDRA 
lowest 
level term 
[LLT])
Fever
Headache
Malaise
Myalgia
Chills
Diary card 
term
Temperature
Headache
Feeling unwell
Muscle aches and 
pains
Chills
Definition
Elevation of 
temperature 
to ≥°38.0°C 
(≥100.4°F)
Pain or discomfort 
in the head or 
scalp. Does not 
include migraine.
General ill feeling.
Malaise is a 
generalized feeling 
of discomfort, 
illness, or lack of 
well-being that 
can be associated 
with a disease 
state. It can be 
accompanied by a 
sensation of 
exhaustion or 
inadequate energy 
to accomplish 
usual activities.
Muscle aches and 
pains are common 
and can involve 
more than one 
muscle at the same 
time. Muscle pain 
can also involve 
the soft tissues that 
surround muscles. 
These structures, 
which are often 
referred to as 
connective tissues, 
include ligaments, 
tendons, and fascia 
(thick bands of 
tendons).
Does not apply to 
muscle pain at the 
injection site which 
should be reported 
as injection site 
pain.
Cold feeling
Intensity 
scale*
Grade 1: 
≥38.0°C to 
≤38.4°C,
or ≥100.4°F 
to ≤101.1°F
CRF:
Grade 1: A type 
of adverse event 
that is usually 
transient and may 
require only 
minimal treatment 
or therapeutic 
intervention. The 
event does not 
generally interfere 
with usual 
activities of daily 
living.
CRF:
Grade 1: A type of 
adverse event that 
is usually transient 
and may require 
only minimal 
treatment or 
therapeutic 
intervention. The 
event does not 
generally interfere 
with usual 
activities of daily 
living.
CRF:
Grade 1: A type of 
adverse event that 
is usually transient 
and may require 
only minimal 
treatment or 
therapeutic 
intervention. The 
event does not 
generally interfere 
with usual 
activities of daily 
living.
CRF:
Grade 1: A type 
of adverse event 
that is usually 
transient and may 
require only 
minimal treatment 
or therapeutic 
intervention. The 
event does not 
generally interfere 
with usual 
activities of daily 
living.

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Grade 2: 
≥38.5°C to 
≤38.9°C,
or ≥101.2°F 
to ≤102.0°F
Grade 2: A type 
of adverse event 
that is usually 
alleviated with 
additional 
therapeutic 
intervention. The 
event interferes 
with usual 
activities of daily 
living, causing 
discomfort but 
poses no 
significant or 
permanent risk of 
harm to the 
research 
participant.
Grade 2: A type of 
adverse event that
is usually 
alleviated with 
additional 
therapeutic 
intervention. The 
event interferes 
with usual 
activities of daily 
living, causing 
discomfort but 
poses no 
significant or 
permanent risk of 
harm to the 
research 
participant.
Grade 2: A type of 
adverse event that 
is usually 
alleviated with 
additional 
therapeutic 
intervention. The 
event interferes 
with usual 
activities of daily 
living, causing 
discomfort but 
poses no 
significant or 
permanent risk of 
harm to the 
research 
participant.
Grade 2: A type 
of adverse event 
that is usually 
alleviated with 
additional 
therapeutic 
intervention. The 
event interferes 
with usual 
activities of daily 
living, causing 
discomfort but 
poses no 
significant or 
permanent risk of 
harm to the 
research 
participant.
Grade 3: 
≥39.0°C
or ≥102.1°F
Grade 3: A type 
of adverse event 
that interrupts 
usual activities of 
daily living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention.
Diary card:
Grade 1: No 
interference with 
activity
Grade 2: Some 
interference with 
activity
Grade 3: 
Significant; 
prevents daily 
activity
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention.
Diary card:
Grade 1: No 
interference with 
activity
Grade 2: Some 
interference with 
activity
Grade 3: 
Significant; 
prevents daily 
activity
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention.
Diary card:
Grade 1: No 
interference with 
activity
Grade 2: Some 
interference with 
activity
Grade 3: 
Significant; 
prevents daily 
activity
Grade 3: A type 
of adverse event 
that interrupts 
usual activities of 
daily living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention.
Diary card:
Grade 1: No 
interference with 
activity
Grade 2: Some 
interference with 
activity
Grade 3: 
Significant; 
prevents daily 
activity
MedDRA: Medical Dictionary for Regulatory Activities
* For all reactions (except fever), the scale will be provided in the CRF and the intensity will be transcribed from the 
diary card. For fever, the body temperature will be recorded, and the classification as Grade 1, 2, or 3 will be assigned 
at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale.

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Important notes for the accurate assessment of temperature:
Participants or parents / legally acceptable representatives are to measure body temperature once 
per day, preferably always at the same time. The optimal time for measurement is the evening, 
when body temperature is the highest. Temperature is also to be measured at the time of any 
apparent fever. The observed daily temperature and the route of measurement are to be recorded 
in the DC / eDC / MA, and the highest temperature will be recorded by the site in the CRF. The 
preferred route for this study is oral.
10.2.5.1.2 Unsolicited AE Intensity Grading Scale
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.2.5.1.1).
All other unsolicited AEs will be classified according to the following intensity scale:
x
Grade 1
x
CRF: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
x
Diary card: No interference with activity.
x
Grade 2
x
CRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant.
x
Diary card: Some interference with activity.
x
Grade 3
x
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention.
x
Diary card: Significant; prevents daily activity.

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10.3
Appendix: Contingency measures for a regional or national emergency that is 
declared by a governmental agency
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency:
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site.
Contingency procedures are suggested below and in Section 5.5, Section 6.4, Section 7.1.1,
Section 8, and Section 10.1.3 for an emergency that prevents access to the study site, to ensure the 
safety of the participants, to consider continuity of the clinical study conduct, protect trial 
integrity, and assist in maintaining compliance with Good Clinical Practice in Conduct of Clinical 
Trials Guidance. Sponsor agreement MUST be obtained prior to the implementation of these 
procedures for the duration of the emergency.
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
[screening/enrollment/randomization/administration of study intervention] may be [temporarily 
delayed/halted] (see also Section 5.5).
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  In case this is not possible due to a temporary disruption caused by an
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.  
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency:
•
If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data
•
If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely 
•
Use of local clinic or laboratory locations may be allowed
Contingencies implemented due to emergency will be documented. 
10.4
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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10.5
Appendix: Abbreviations
AE
Adverse Events
AESI
Adverse events of special interest
AF
assent form
AR
Adverse reactions
CI
confidence interval
CRB
case report book
CRF
Case report form
D
day
DC
diary card
eDC
electronic diary card
ELISA
enzyme-linked immunosorbent assay
ESDR
early safety data review
FAS
Full analysis set
FDA
Food and Drug Administration
FIC
firewalled Internal Committee
GBS
Guillain-Barré Syndrome
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GMT
geometric mean titer
GPV
Global Pharmacovigilance
HAI
hemagglutination inhibition
HIPAA
Health Insurance Portability and Accountability
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committees
IM
intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional Review Boards
IRT
Interactive Response Technology

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IIV3
Egg-Based Trivalent Influenza Vaccine
IIV4
Egg-Based Quadrivalent Influenza Vaccine
LLOQ
lower limit of quantitation
MAAE
medically attended adverse event
MDCK
Madin-Darby canine kidney
MedDRA
Medical Dictionary for Regulatory Activities
NI
non-inferior
NIMP
Non- Investigational Medicinal Product;
PPAS
Per-protocol analysis set
PPoS
predictive power of success
PSC
Protein Sciences Corporation
PV
pharmacovigilance
QTL
quality tolerance limit
RCDC
reverse cumulative distribution curve
RIV4
quadrivalent inactivated influenza vaccine
RMO
Responsible Medical Officer
SAE
Serious adverse events
SafAS
Safety Analysis Set
SAP
Statistical analysis plan
SC
seroconversion
SMT
safety management team
SN
seroneutralization
SoA
Schedule of Activities
TBD
to be determined
WHO
World Health Organization

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Sponsor Signature Page

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