Immunogenicity and Safety of Quadrivalent Recombinant Influenza Vaccine (RIV4) in Children and Adolescents Aged 9 to 17 Years and Adults Aged 18 to 49 Years.
Phase: PHASE3
Conditions: Influenza Immunization
Sponsor: Sanofi Pasteur, a Sanofi Company

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 1 of 82 
Title Page 
Protocol Title: 
Immunogenicity and Safety of Quadrivalent Recombinant Influenza Vaccine (RIV4) in Children 
and Adolescents Aged 9 to 17 Years and Adults Aged 18 to 49 Years. 
Study Code: VAP00027 
Amendment Number: Amendment 1 
Compound: Quadrivalent Recombinant Influenza Vaccine (RIV4) 
Brief Title:  
Study with Quadrivalent Recombinant Influenza Vaccine (RIV4) in Participants 9 through 49 
Years of Age. 
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 Numbers: 
BB-IND: 015784 
EudraCT: 2022-000577-11 
WHO UTN: U1111-1260-4678 
Protocol Version Number: 2.0 
Approval Date: 22 September 2022 
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. 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 2 of 82 
Table of Contents  
Document History ............................................................................................................................ 2 
List of Tables .................................................................................................................................... 7 
List of Figures .................................................................................................................................. 8 
1 
Protocol Summary ............................................................................................................. 9 
1.1 
Synopsis ............................................................................................................................ 9 
1.2 
Schema ............................................................................................................................ 13 
1.3 
Schedule of Activities (SoA) .......................................................................................... 13 
2 
Introduction ..................................................................................................................... 17 
2.1 
Study Rationale ............................................................................................................... 17 
2.2 
Background ..................................................................................................................... 17 
2.3 
Benefit/Risk Assessment ................................................................................................ 20 
2.3.1 
Risks from Study Participation ..................................................................................... 20 
2.3.2 
Benefits from Study Participation ................................................................................ 22 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 22 
3 
Objectives and Endpoints ............................................................................................... 22 
4 
Study Design .................................................................................................................... 25 
4.1 
Overall Design ................................................................................................................ 25 
4.2 
Scientific Rationale for Study Design ............................................................................. 25 
4.3 
Justification for Dose ...................................................................................................... 25 
4.4 
End of Study Definition .................................................................................................. 26 
5 
Study Population ............................................................................................................. 26 
5.1 
Inclusion Criteria ............................................................................................................ 26 
5.2 
Exclusion Criteria ........................................................................................................... 27 
5.3 
Lifestyle Considerations ................................................................................................. 29 
5.4 
Screen Failures ................................................................................................................ 29 
5.5 
Criteria for Temporarily Delaying Enrollment/Administration of Study 
Intervention ..................................................................................................................... 29 
6 
Study Intervention and Concomitant Therapy ............................................................ 29 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 3 of 82 
6.1 
Study Intervention Administered .................................................................................... 29 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 31 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 31 
6.3.1 
Randomization and Allocation Procedures .................................................................. 31 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 32 
6.4 
Study Intervention Compliance ...................................................................................... 32 
6.5 
Dose Modification .......................................................................................................... 32 
6.6 
Continued Access to Study Intervention After the End of the Study ............................. 32 
6.7 
Treatment of Overdose.................................................................................................... 33 
6.8 
Concomitant Therapy ...................................................................................................... 33 
6.8.1 
Rescue Medicine ........................................................................................................... 34 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 34 
7.1 
Discontinuation of Study Intervention ............................................................................ 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 34 
7.3 
Lost to Follow-up ............................................................................................................ 35 
8 
Study Assessments and Procedures ............................................................................... 35 
8.1 
Efficacy and Immunogenicity Assessments ................................................................... 36 
8.1.1 
Efficacy Assessments ................................................................................................... 36 
8.1.2 
Immunogenicity Assessments ...................................................................................... 36 
8.2 
Safety Assessments ......................................................................................................... 37 
8.2.1 
Medical History ............................................................................................................ 37 
8.2.2 
Influenza Vaccination History ...................................................................................... 37 
8.2.3 
Physical Examinations .................................................................................................. 37 
8.2.4 
Vital Signs .................................................................................................................... 38 
8.2.5 
Clinical Safety Laboratory Assessments ...................................................................... 38 
8.2.6 
Pregnancy Testing ........................................................................................................ 38 
8.2.7 
Viremia/Vaccinemia ..................................................................................................... 38 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting............... 38 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ......................... 38 
8.3.2 
Method of Detecting AEs and SAEs ............................................................................ 39 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................ 40 
8.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 40 
8.3.5 
Pregnancy ..................................................................................................................... 40 
8.3.6 
Adverse Events of Special Interest ............................................................................... 41 
8.3.7 
Medically Attended Adverse Events ............................................................................ 41 
8.3.8 
Early Safety Data Review ............................................................................................. 41 
8.4 
Pharmacokinetics ............................................................................................................ 42 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 4 of 82 
8.5 
Genetics ........................................................................................................................... 42 
8.6 
Biomarkers ...................................................................................................................... 42 
8.7 
Immunogenicity Assessments ......................................................................................... 42 
8.8 
Medical Resource Utilization and Health Economics .................................................... 42 
8.9 
Leftover Biological Samples and Use of Data ................................................................ 43 
9 
Statistical Considerations ............................................................................................... 44 
9.1 
Statistical Hypotheses ..................................................................................................... 45 
9.2 
Sample Size Determination ............................................................................................. 46 
9.3 
Analysis Sets ................................................................................................................... 46 
9.4 
Statistical Analyses ......................................................................................................... 47 
9.4.1 
General Considerations ................................................................................................. 48 
9.4.2 
Primary Endpoints ........................................................................................................ 48 
9.4.3 
Secondary Endpoints .................................................................................................... 49 
9.4.4 
Exploratory Endpoints .................................................................................................. 50 
9.5 
Interim Analyses ............................................................................................................. 50 
10 
Supporting Documentation and Operational Considerations .................................... 51 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations ............................ 51 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 51 
10.1.2 
Financial Disclosure ..................................................................................................... 52 
10.1.3 
Informed Consent Process ............................................................................................ 52 
10.1.4 
Data Protection ............................................................................................................. 54 
10.1.5 
Committees Structure ................................................................................................... 56 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 56 
10.1.7 
Data Quality Assurance ................................................................................................ 56 
10.1.8 
Source Documents ........................................................................................................ 57 
10.1.9 
Study and Site Start and Closure .................................................................................. 58 
10.1.10 
Publication Policy ......................................................................................................... 58 
10.2 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................... 59 
10.2.1 
Definition of AE ........................................................................................................... 59 
10.2.2 
Definition of SAE ......................................................................................................... 62 
10.2.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 63 
10.2.4 
Reporting of SAEs ........................................................................................................ 65 
10.2.5 
Assessment of Intensity ................................................................................................ 66 
10.2.5.1 
Tables for Clinical Abnormalities .............................................................................. 66 
10.2.5.1.1 
Solicited AR Intensity Grading Scale ...................................................................... 66 
10.2.5.1.2 
Unsolicited AE Intensity Grading Scale .................................................................. 73 
10.3 
Appendix: Contraceptive and Barrier Guidance ............................................................. 73 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 5 of 82 
10.3.1 
Definitions .................................................................................................................... 73 
10.3.2 
Contraception Guidance ............................................................................................... 75 
10.4 
Appendix: Contingency measures for a regional or national emergency that is 
declared by a governmental agency ................................................................................ 76 
10.5 
Appendix: Risk-based Approach .................................................................................... 76 
10.6 
Appendix: Abbreviations ................................................................................................ 77 
10.7 
References ....................................................................................................................... 80 
11 
Sponsor Signature Page .................................................................................................. 82 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 6 of 82 
Document History and Protocol Amendment Rationale  
 
Previous 
Version(s) 
Date 
Comments 
1.0 
24 February 2022 
Version submitted to the IECs/IRBs 
IEC: Independent Ethics Committee; IRB: Institutional Review Board 
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: 
Change was implemented following request for clarification from the Food and Drug 
Administration (FDA) dated 13 July 2022, mainly 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. 
 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 7 of 82 
 
List of Tables  
Table 1.1: Schedule of activities ................................................................................................... 14 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 20 
Table 3.1: Objectives and endpoints ............................................................................................. 23 
Table 4.1: Overall design cc .......................................................................................................... 25 
Table 6.1: Identity of study intervention ....................................................................................... 30 
Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales – 
Children aged 2 through 11 years .................................................................................................. 67 
Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales – 
Adolescents and adults aged≥ 12 years ......................................................................................... 69 
Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales – 
Children aged 2 through 11 years, adolescents or adults aged ≥ 12 years .................................... 71 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 8 of 82 
List of Figures  
Figure 1.1 – Graphical study design .............................................................................................. 13 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 9 of 82 
1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
Immunogenicity and Safety of Quadrivalent Recombinant Influenza Vaccine (RIV4) in Children 
and Adolescents Aged 9 to 17 Years and Adults Aged 18 to 49 Years. 
Brief Title: 
Study with Quadrivalent Recombinant Influenza Vaccine (RIV4) in Participants 9 through 49 
Years of Age. 
Rationale: 
The proposed study is a Phase III, non-randomized, open-label, uncontrolled, multi-center study 
to assess the immunogenicity and safety of the RIV4 in approximately 1334 participants 9 to 49 
years of age (667 children and adolescents 9 to 17 years of age and 667 adults 18 to 49 years of 
age) in Europe and the United States (US). The goal of this study is to show that vaccination with 
RIV4 induces an immune response (as assessed by hemagglutination inhibition [HAI] geometric 
mean titers [GMTs] and seroconversion [SC] rates) in children and adolescents 9 to 17 years of 
age that is non-inferior to responses induced by RIV4 in adults 18 to 49 years of age for the 4 
virus strains at 28 days post-vaccination and to describe the HAI antibody response induced by 
RIV4 in all participants. In addition, the immunogenicity of RIV4 in terms of neutralization titer 
will be assessed in a subset of participants and the safety of RIV4 in all participants will be 
described.  

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 12 of 82 
Study intervention 
Investigational medicinal product: Quadrivalent Recombinant influenza vaccine (RIV4) 
season/2022-2023/NH 
• Form: Solution for injection 
• 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 
• Route of administration: IM 
Statistical considerations: 
The number of participants enrolled and their age at enrollment, sex, race, and ethnic origin will 
be summarized for each 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 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 the normal approximation of log-
transformed titers. 
Primary endpoints: 
The primary objective includes 8 endpoints (GMTs and seroconversion (SC) rates for each of the 
4 strains). 
For each strain, the non-inferiority (NI) 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 
the study groups. If NI of GMTs based on the 4 strains is demonstrated, then NI for SC will also 
be tested. 
Since all 8 hypotheses have to be rejected at 0.025 significance level, no formal adjustment for 
multiplicity is necessary. 
To keep the study power of 80%, the sample size was increased accordingly, to have an overall 
Type II error <20% for the 8 NI tests.  
Secondary endpoints (immunogenicity): 
Immunogenicity parameters by HAI measurement method will be described by study group with 
95% confidence intervals (CIs). 
Reverse cumulative distribution curves (RCDCs) of pre-vaccination titer at D01 and post-
vaccination titer at D29 will be generated for each study group. 
Subgroup analyses will be performed; in particular, immunogenicity will be described according 
to age subgroups, sex, race, previous influenza vaccination status, and baseline seropositivity 
status, as appropriate according to number of participants in the respective subgroups. 
Secondary endpoints (safety): 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 13 of 82 
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.  
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 an early safety data review (ESDR). 
1.2 
Schema  
The graphical design of VAP00027 study is presented in Figure 1.1. 
Figure 1.1 – Graphical study design  
 
BL: Blood sample 
VAC: vaccination 
PC: Phone Call 
1.3 
Schedule of Activities (SoA)  
Visit procedures are detailed in the Operating Guidelines. 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 14 of 82 
Table 1.1: Schedule of activities  
Phase III Study, 2 Visits, 2 Phone calls, 1 Vaccination, 2 Blood Samples, 6 Months’ Duration Per Participant 
Visit/Contact 
Collection of 
information in the case 
report form (CRF) 
Visit 1 
Phone Call 
(PC) 1* 
Visit 2 
PC2 
6-month safety follow-up†  
Study timelines (Days) 
 
D01 
D09 
D29 
D181 
Time interval (Days) 
 
 
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 
 
 
 
Urine pregnancy test (if applicable) ‡ 
 
X 
 
 
 
Collection of Medical history 
(Significant medical history)*** 
X 
X 
 
 
 
Collection of concomitant medications 
X 
Reportable concomitant 
medication 
28 days after vaccination 
 
History of seasonal influenza vaccination 
X 
X 
 
 
 
Physical examination§ 
 
X 
 
X 
 
Pre-vaccination temperature 
 
X 
 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 15 of 82 
Visit/Contact 
Collection of 
information in the case 
report form (CRF) 
Visit 1 
Phone Call 
(PC) 1* 
Visit 2 
PC2 
6-month safety follow-up†  
Study timelines (Days) 
 
D01 
D09 
D29 
D181 
Time interval (Days) 
 
 
V01 + 8D 
V01 + 28D 
V01 + 180D 
Time windows (Days) 
 
NA 
[+2 D] 
[-2, +7 D] 
[+14 D] 
Visit procedures: 
 
 
 
 
 
Contact Interactive Response Technology (IRT) 
system for participant number, dose number and 
randomization to the 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 collected and reviewed  
 
 
 
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 serious adverse events 
(SAEs), including adverse events of special interest 
(AESIs) 
X 
To be reported at any time during the study 
Collection of pregnancy 
X 
To be reported at any time during the study 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 16 of 82 
Visit/Contact 
Collection of 
information in the case 
report form (CRF) 
Visit 1 
Phone Call 
(PC) 1* 
Visit 2 
PC2 
6-month safety follow-up†  
Study timelines (Days) 
 
D01 
D09 
D29 
D181 
Time interval (Days) 
 
 
V01 + 8D 
V01 + 28D 
V01 + 180D 
Time windows (Days) 
 
NA 
[+2 D] 
[-2, +7 D] 
[+14 D] 
Visit procedures: 
 
 
 
 
 
End of Active Phase participation record 
X 
 
 
X 
 
Six months follow-up participant record 
X 
 
 
 
X 
* The investigator or an authorized designee will remind the participant or participant’s parent(s)/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 or participant’s parent(s)/legally acceptable representative(s) to collect the information recorded in the MA, 
and will attempt to clarify anything that is unclear 
‡To be performed in menarche participants 
§ 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 or participant’s parent(s)/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 (FDA) 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 previous 3 influenza seasons. 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 17 of 82 
2 
Introduction  
Sanofi Pasteur’s RIV4 vaccine is a vaccine that is being developed for protection against 
influenza. 
2.1 
Study Rationale  
The proposed study is a Phase III, non-randomized, open-label, uncontrolled, multi-center study 
to assess the immunogenicity and safety of the RIV4 in approximately 1334 participants 9 to 49 
years of age (667 children and adolescents 9 to 17 years of age and 667 adults 18 to 49 years of 
age) in Europe and the US. The goal of this study is to show that vaccination with RIV4 induces 
an immune response (as assessed by HAI, GMTs and SC rates) in children and adolescents 9 to 17 
years of age that is non-inferior to responses induced by RIV4 in adults 18 to 49 years of age for 
the 4 virus strains at 28 days post-vaccination and to describe the HAI antibody response induced 
by RIV4 in all participants. In addition, the immunogenicity of RIV4 in terms of neutralization 
titer will be assessed in a subset of participants and the safety of RIV4 in all participants will be 
described. 
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 (1) (2) (3). 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 (4) 
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 (2). 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 (5) (6). 
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 9 243 to 105 690 influenza-associated respiratory deaths occur in children younger 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 18 of 82 
than 5 years each year (7). Matias et al. investigated the average seasonal burden of influenza-
attributable hospitalizations in the 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 (8). 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 (9) (10) 
should receive an annual vaccination against influenza because it has been shown to be effective 
in reducing influenza-associated morbidity and mortality (11) (12). 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 (13). 
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 hemagglutinin (rHA) 
produced from a proprietary technology that is based on the insect cell – baculovirus system 
referred to as the Baculovirus Expression Vector System. 
This RIV3 contains 135 µg of rHA derived from the 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% CI, 18.8% - 62.6%) effective in preventing 
culture-confirmed influenza in adults from 18 to 49 years of age (14). Furthermore, studies in 
adults 50 – 64 years of age (15) and in adults 65 years of age and older (16) showed HAI antibody 
responses induced by RIV3 met the pre-specified 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 participants 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 was 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 (15) (16). 
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, RIV4 containing 45 µg of each of A strains 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 19 of 82 
(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 (17) 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 seroconversion 
rates and GMTs in adults 18 to 49 years of age (18). 
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 the occurrence of unsolicited adverse events (AEs), 
serious adverse events (SAEs), adverse events of special interest (AESIs) and deaths. 
RIV4 was licensed in the US in 2016 under the trade name Flublok® Quadrivalent and in Mexico 
in March 2018 under the trade name Flublok Tetravalente. 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 (19) was conducted with RIV3 in 156 children aged 6 months – 5 years (98 
participants received RIV3 [among them 61 received the full-dose of 45 µg per antigen] and 58 
received a licensed trivalent influenza vaccine [IIV3 - Fluzone]). 
A Phase II clinical trial (20) was conducted in 219 children and adolescents 6 – 17 years of age 
who received either RIV4 or a licensed quadrivalent inactivated influenza vaccine (IIV4 - Fluarix 
Quadrivalent). 
The clinical data from pediatric studies showed 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 
immunity appears to be induced to a greater degree as the participants become older. Some of this 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 21 of 82 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
analyses, showed that there was 
no significant difference in acute 
hypersensitivity reactions and 
fever during post-vaccination 
days 0-2 in the outpatient, 
emergency department and 
inpatient settings (22). 
Background incidence rate: 
Using health care data from the 
Vaccine Safety Datalink, the rate 
of anaphylaxis was estimated to 
1.31 (95% confidence interval 
[CI]: 0.90-1.84) per million 
vaccine doses (23). 
Guillain-Barré Syndrome (GBS) 
No cases of GBS were reported 
as related to RIV3 or RIV4 
during the vaccine’s clinical 
development. 
Two cases of GBS were reported 
during the post-marketing 
experience for RIV4. 
A causal association between 
these cases of GBS and RIV4 
has not been established. 
Exclusion criterion E07 for those 
at increased risk. 
During the informed consent 
process, the participants and/or 
their parent(s)/legally acceptable 
representative(s) will be 
informed of this potential risk 
and the need to attend the clinic 
if they are unwell. GBS is an 
AESI and will be collected until 
study end. 
Addressed in IB (21) 
(administration precautions, 
potential adverse events) 
Injection site reactions and 
systemic reactions 
The most commonly reported 
solicited adverse reactions in 
adults 18 through 49 years of age 
during the clinical trial PSC16 
were tenderness (48%) and pain 
(37%) at the injection site; the 
most commonly reported 
solicited systemic adverse 
reactions were headache (20%), 
fatigue (17%), myalgia (13%) 
and arthralgia (10%).  
Most reactions were of mild 
grade, occurred within the first 3 
days following vaccination and 
resolved spontaneously within 1 
During the informed consent 
process, the participants and/or 
their parent(s)/legally acceptable 
representative(s) will be 
informed of these potential 
reactions, the need to attend the 
clinic if the participants are 
unwell, and the possibility to 
take antalgic/antipyretic drug. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 26 of 82 
4.4 
End of Study Definition  
A participant is considered to have completed the study if he/she has completed the last contact 
planned in the SoA. 
The end of the study is defined as the date of the last contact of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 
5 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
Age 
I01. 
Aged 9 to 49 years on the day of inclusionb 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I02. 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions applies: 
• Is of non-childbearing potential. To be considered of non-childbearing potential, a female 
must be pre-menarchec, post-menopausal for at least 1 year, or surgically sterile. 
OR 
• Is of childbearing potential and agrees to use an effective contraceptive method or 
abstinence from at least 4 weeks prior to the first study intervention administration until at 
least 4 weeks after the last study intervention administration.  
A female participant of childbearing potential must have a negative highly sensitive 
pregnancy test (urine or serum as required by local regulation) the day of study 
intervention 
Refer to Appendix 10.3 (Contraceptive and Barrier Guidance) for further information. 
Informed consent 
                                                 
b  “9 to 49 years” means from the day of the 9th year after birth to the day before the 50th year after birth  
c  Pre-menarche females will declare by themselves that they have not yet started menstruation. If a young female 
participant reaches menarche during the study, then she is to be considered as a woman of childbearing potential 
from that time forward 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
Confidential/Proprietary Information 
Page 27 of 82 
I03. 
Assent form or informed consent form has been signed and dated by the participant 
(based on local regulations), and if applicable informed consent form has been signed and 
dated by the parent(s) or another legally acceptable representative  
Other inclusions 
I04. 
Participant or participant and parent/legally acceptable representative are able to 
attend all scheduled visits and to comply with all study procedures 
I05. 
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 (eg, HIV); 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 study intervention components, or history 
of a life-threatening reaction to the study intervention used in the study or to a product containing 
any of the same substancesd  
E03. Thrombocytopenia, or known thrombocytopenia, as reported by the participant or 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 completione 
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) 
E08. Any condition that in the opinion of the investigator would pose a health risk to the 
participant if enrolled or could interfere with the evaluation of the study intervention 
E09. Personal history of clinically significant development delay (at the discretion of the 
investigator), neurologic disorder, or seizure disorder 
d
e
The components of study intervention are listed in Section 6.1 of the protocol and in the Investigator’s Brochure. 
Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychiatric disorders or chronic infection 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 28 of 82 
E10. For participants 12 to 49 years of age: Alcohol, prescription drug, or substance abuse that, 
in the opinion of the investigator, might interfere with the study conduct or completion 
Prior/concomitant therapy 
E11. Receipt of any vaccine in the 4 weeks preceding the 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 
interventionf. 
E12. Previous vaccination against influenza (in the 6 months prior to study intervention 
administration) with an investigational or marketed vaccine 
E13. Receipt of immune globulins, blood or blood-derived products in the past 3 months 
Prior/concurrent clinical study experience 
E14. Participation at the time of study enrollment (or in the 4 weeks preceding the study 
intervention administration) or planned participation during the present study period in another 
clinical study investigating a vaccine, drug, medical device, or medical procedure  
Other exclusions 
E15. 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 
E16. Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
E17. For participants 12 to 49 years of age: Identified as an investigator or employee of the 
investigator or study center with direct involvement in the proposed study, or identified as an 
immediate family member (ie, parent, spouse, natural or adopted child) of the investigator or 
employee with direct involvement in the proposed study 
E18. For participants 9 to 11 years of age: 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 consent of the participant or of the participant’s parent(s)/legally acceptable 
representative 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. 
                                                 
f If the participant is enrolled and seeks vaccination of COVID-19 vaccine outside of the study, he/she and/or the 
parent(s)/legally acceptable representative will be encouraged to discuss this intention proactively with the study 
investigator and will be permitted to receive the authorized vaccine at the earliest 28 days after study vaccination 
and at any time thereafter. If the participant receives the authorized influenza or COVID 19 vaccine, this 
information will be collected. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 29 of 82 
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/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 10.4: Contingency measures for a regional or national emergency that is declared by a 
governmental agency should be considered for enrollment/administration of study intervention. 
6 
Study Intervention and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: Vaccines or products administered outside of study protocol are not considered as study 
interventions and are reported in the case report form (CRF) as reportable medications (see 
Section 6.8). Study procedures (eg, blood sampling) are also not considered as study 
interventions. 
6.1 
Study Intervention Administered  
Study intervention is described in Table 6.1. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 30 of 82 
Table 6.1: Identity of study intervention  
Intervention Name 
RIV4 season/2022-2023/NH 
Use 
Experimental 
IMP and NIMP 
IMP 
Type  
Vaccine 
Dose Formulation 
Solution for injection in a pre-filled syringe 
Unit Dose 
Strength(s) 
45 µg of HA of each of the following strains per dose: 
• 
A/H1N1 strain 
• 
A/H3N2 strain 
• 
B/Victoria lineage strain 
• 
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 mg* 
Dibasic sodium phosphate 0.5 mg* 
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. 
Dosage Level(s) 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
1 dose 
Route of 
Administration 
IM injection  
Site of 
Administration 
Deltoid muscle in the upper arm  
Sourcing 
Provided by the Sponsor  

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 31 of 82 
Packaging and 
Labeling 
Each study intervention will be packaged in an individual box. Each pre-filled 
syringe will bear one fixed label and each box will bear detachable labels and 
one fixed label containing the sequential dose number. All will be labelled as 
required per country requirement. 
Current/Former 
Name(s) or Alias(es) 
Supemtek/Flublok Quadrivalent 
Batch Number 
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 
*: calculated from the anhydrous form. 
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. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 
Randomization and Allocation Procedures  
At least 400 participants will be randomized to be part of the subset population to assess the 
exploratory objective. The randomization of the subset will be performed to reflect the age 
distribution of the whole population. Thus, the randomization of participants will be stratified to 
include at least 30% of children aged 9 to 11 years among children and adolescents 9 to 17 years 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 32 of 82 
old; and the proportion of adults aged above 35 years will be limited to 50% in the study group 18 
to 49 years. 
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. 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). The first of the 5-
digit participant identifier will identify the participants as being part of the subset for exploratory 
objective (number 1) or not (number 2). For example, Participant 840000120005 is the fifth 
participant enrolled in Center Number 1 in the US (840 being the US country code), and is not 
part of the subset for exploratory objective. 
Participant numbers should not be reassigned for any reason. The study groups are not 
randomized; they are based on age (9 to 17 years versus 18 to 49 years) and only one vaccine 
(RIV4) will be administered in this study. Only the subset of participants for each age group to be 
tested by the seroneutralization (SN) method will be randomized within each study group.  
6.3.2 
Blinding and Code-breaking Procedures  
The study will be open-labeled. 
6.4 
Study Intervention Compliance  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose 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 10.4: 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 33 of 82 
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 
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:  
• Medications impacting or that may have an impact on the evaluation of the safety (eg, 
antipyretics, analgesics, and non-steroidal anti-inflammatory drugs, 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. 
• 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) 
• 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). 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 34 of 82 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication Form of the CRF unless the 
medication(s) received belongs to one of the pre-listed categories. Medications will 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. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Not applicable as there is only one vaccination. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: Adverse Event, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant or 
Parent / Legally Acceptable Representative. 
• 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws consent, he/she may request destruction of any biological samples 
taken (unless local law requires not to destroy them), and the investigator must document this 
in the site study records. 
• 
Withdrawn participants will not be replaced. 
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for definition of “lost to follow-up”. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 35 of 82 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or cannot be contacted as planned in the SoA: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 
• 
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 
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  
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 36 of 82 
Blood samples will be collected as described in the SoA table (Section 1.3). At Visit 1 (BL0001) 
and Visit 2 (BL0002), blood (5 mL) will be collected in tubes provided by or recommended by the 
Sponsor. 
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 10.4: 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. 
8.1.2 
Immunogenicity Assessments  
HAI assay: 
The HAI assay is the main test that detects Ab directed against the HA antigen and is commonly 
used to assess the immunogenicity of influenza vaccines. HAI Ab titers to each virus strain 
represented in the vaccine will be measured in sera obtained at baseline (D01) and 28 days after 
immunization (D29). 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 an 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 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 37 of 82 
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. 
8.2 
Safety Assessments  
This section presents safety assessments other than AEs which are presented in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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  
Participants and/or their parent(s)/legally acceptable representative will be questioned regarding 
previous influenza vaccination over the 3 previous influenza seasons. Information will be 
recorded in the source document. 
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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 38 of 82 
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  
Urine pregnancy testing will be performed in women of childbearing potential (WOCBP) before 
vaccination. 
8.2.7 
Viremia/Vaccinemia  
Not applicable. 
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 vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from the day of vaccination (D01) until 7 days 
after vaccination (D08). 
Solicited systemic reactions will be collected from the day of vaccination (D01) until 7 days after 
vaccination (D08). 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 40 of 82 
CRF. Any information that was not documented in the DC/eDC will first be captured in the source 
document and then reported electronically. 
The 6-month follow-up will be done by interviewing participants or parents/legally acceptable 
representative 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 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 AESIs (as 
defined in Section 8.3.6), will be followed during the conduct of the study until resolution, 
stabilization, or the participant is lost to follow-up (as defined in Section 7.3). For related SAEs 
ongoing at last study visit, such follow-up may need to continue after the end of the study.  
Further information on follow-up procedures is provided in Appendix 10.2. 
8.3.4 
Regulatory Reporting Requirements for SAEs  
• 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
• 
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  
Pregnant women are not eligible to participate in the study and WOCBP agree to use an effective 
contraceptive method, as defined in the inclusion criteria. However, a participant could potentially 
become pregnant during her participation.  

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 41 of 82 
• 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 4 weeks after study intervention administration. 
• 
If a pregnancy is reported, the investigator should promptly inform the Sponsor and will 
record pregnancy information together with the contraceptive method on the appropriate 
form and submit it to the Sponsor within 1 month of learning of the pregnancy. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 1 month beyond the estimated delivery date, but will be in accordance 
with local regulations. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
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  
• An ESDR conducted by the Safety Management Team (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 9 to 17 years 
are vaccinated and have provided safety data for 7 days after administration of the study 
intervention. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 42 of 82 
• The safety data collected will be entered into the case report book (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. 
• The following safety parameters collected from D01 to D08 will be assessed as part of the 
ESDR review by the Sponsor: 
• Immediate reactions 
• Solicited injection site and systemic reactions 
• Unsolicited AEs reported as related by the investigator 
• SAEs (including AESIs) 
• Enrollment will not be paused during the Sponsor review. 
• 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: 
• An SAE (including AESI) considered as related to the vaccination by the investigator and 
Sponsor 
• > 10% of participants experiencing any Grade 3 AEs within 7 days after vaccination 
• After the ESDR is conducted, the team will continue to monitor the safety of all participants 
via SMT 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 43 of 82 
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, participants / parents / legally acceptable representatives will be asked to indicate in 
the ICF whether they will permit the future use of any unused stored biological samples for other 
tests 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 44 of 82 
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. 
For descriptive purposes, the following statistics will be presented: 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 45 of 82 
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 RCDC 
9.1 
Statistical Hypotheses  
Primary Objective: 
Statistical methodology for analyzing the 8 primary endpoints (GMTs and SC rates). 
Non-inferiority of the age group 9-17 years as compared to 18-49 years after vaccination of both 
age groups with RIV4, will be conducted for GMTs and SC rates. 
The primary analysis will be conducted in 2 steps starting with testing for NI of GMTs between 
the age group 9-17 years and the age group 18-49 years. If NI of GMTs based on the 4 strains is 
demonstrated, then NI of the SC rates will be also tested. 
Step1: Geometric Mean Titers 
For each virus strain, the null hypothesis and the alternative hypothesis are: 
H0: GMTRIV4(9-17y) /GMTRIV4(18-49y) ≤ 0.667 
HA: GMTRIV4(9-17y) /GMTRIV4(18-49y) > 0.667 
or equivalently, 
                    H0: log10 (GMTRIV4(9-17y)) - log10 (GMTRIV4(18-49y)) ≤ log10 (0.667) 
                    HA: log10 (GMTRIV4(9-17y)) - log10 (GMTRIV4(18-49y)) > log10 (0.667) 
For the separately considered GMT hypotheses, if the null hypothesis is rejected, then the 
alternative hypothesis of NI is supported. 
All 4 strains must show NI of GMTs to consider that GMTs have demonstrated NI. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 46 of 82 
Step 2: Seroconversion Rates 
For each virus strain, the null hypothesis and the alternative hypothesis are: 
H0: PRIV4(9-17y) – PRIV4(18-49y) ≤ -10% 
HA: PRIV4(9-17y) – PRIV4(18-49y) > -10% 
For the separately considered seroconversion hypotheses, if the null hypothesis is rejected, then 
the alternative hypothesis of NI is supported. 
All 4 strains must demonstrate NI of the SC rates to consider that SC rates have demonstrated NI. 
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 9 to 49 years of age (600 children and 
adolescents 9 to 17 years of age [approximately 30% children 9 to 11 years of age] and 600 adults 
18 to 49 years of age) will be assessed.  
Assuming the same GMT for each strain in the age groups (9 to 17 years vs. 18 to 49 years) 
compared, and a standard deviation of log10 titers of 0.6 with a NI margin of 1.5; NI for GMTs 
would be demonstrated with a power of at least 99.6%. 
Assuming in each vaccine group the same expected SC rates (0.7, 0.5, 0.6, 0.5) 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 rate can be demonstrated with a study 
power of approximately 80.10% (96.66%, 93.70%, 94.38% and 93.70% for each strain, 
respectively). 
Hence, the overall study power is estimated to be 80.0% (80.0% = 99.6%[GMTs] x 80.10%[SC 
rate]). 
As shown above, to keep the overall study power of 80%, the sample size was increased 
accordingly, to have an overall type II error <20% for the 8 NI tests. 
Assuming an attrition rate of approximately 10% in this age group, a total of approximately 
1334 participants 9 to 49 years of age will be enrolled. 
9.3 
Analysis Sets  
For the purposes of analysis, the following analysis sets are defined: 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 47 of 82 
Participant Analysis 
Set 
Description 
Enrolled 
All participants with data in the CRF. 
Note: the study groups are not randomized. The study groups are 
determined based on age. However, a subset of participants from each 
age group will be randomly selected in order for their blood to be tested 
using the SN method.  
Safety Analysis Set (SafAS) 
Participants who have received one dose of the study vaccine. All 
participants will have their safety analyzed according to the vaccine 
they actually received. 
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 participants who received one 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).  
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 receive vaccine in the proper time window 
·         Preparation and / or administration of vaccine was not done as 
per-protocol 
·         Participant did not provide the post-dose serology sample at V02 
in the proper time window or a post-dose serology sample was not 
drawn 
·         Participant received a 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). 
9.4 
Statistical Analyses  
The SAP will be finalized prior to database lock, 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 48 of 82 
9.4.1 
General Considerations  
The statistical analysis will be conducted as follows: 
• The database will be cleaned and locked to analyze primary immunogenicity data and 
safety data collected up to 28 days after vaccination.  
• The final database lock will occur after the 6-month follow-up. 
The number of participants enrolled and their age at enrollment, sex, race, and ethnic origin will 
be summarized for each 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 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 the normal approximation of log-
transformed titers. 
Details will be provided in the SAP. 
9.4.2 
Primary Endpoints  
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 and GMTs ratio.  
Statistical methodology for analyzing the 8 primary endpoints (GMTs and SC rates). 
Non-inferiority of RIV4 in participants aged 9 to 17 years vs participants aged 18 to 49 years will 
be conducted for GMTs and SC rates. 
For each strain, the NI 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 
the age group 9-17 years and the age group 18-49 years. If NI of GMTs based on the 4 strains is 
demonstrated, then NI of the SC rates 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(9-17y) 
divided by RIV4(18-49y)) at 28 days after 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. 
The 95% CI will be calculated using normal approximation of log-transformed titers. 
Step 2: Seroconversion Rates 
The statistical methodology is based on a 2-sided 95% CI of the difference in SC rates (RIV4 
[9-17years] minus RIV4 [18-49years]) at 28 days after vaccination. Non-inferiority for SC rates is 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 49 of 82 
demonstrated if the lower limit of the 2-sided 95% CI is >-10% for the 4 strains. The 95% CI of 
the rate difference is computed using the Wilson Score method without continuity correction.  
The CI of the difference in proportions PRIV4(9-17y) - PRIV4(18-49y) is computed using the Wilson 
Score method without continuity correction, quoted by Newcombe. 
All 4 strains must demonstrate NI of the SC rate in order for study seroconversion rates to 
demonstrate NI success. 
The PPAS will be used as the primary analysis set for this objective (GMTs and SC rates). 
The primary objective is successful if NI for GMTs and NI for SC rates are successful. 
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. The 95% CI of proportions difference (ie, difference 
between vaccine groups in SC) will be calculated using Wilson Score method without continuity 
correction. All analyses will be conducted by study group. The main parameters will also be 
described by age subgroup. 
The RCDCs of pre-vaccination titer (D01), and post-vaccination titer (D29) will be generated for 
each study group. The RCDCs will include the plots of the 2 study groups in the same figure. 
The analysis will be conducted for each immunogenicity variable on the PPAS and on FAS. 
In addition, subgroup analyses will be performed; in particular, immunogenicity will be described 
according to age subgroups (9-11 years, 12-17 years, 18-34 years and 35-49 years), sex, race, 
previous influenza vaccination status (received a seasonal influenza vaccine in the last past 
influenza season or not) and, baseline seropositivity status (seropositive and seronegative are 
defined as baseline antibody titer ≥ 1:10 or < 1:10), as appropriate according to number of 
participants in the respective subgroups. 
Safety 
For the main safety parameters, 95% CIs of point estimates will be calculated using the 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. 
SafAS will be the analysis population of safety data. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 50 of 82 
9.4.4 
Exploratory Endpoints  
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. All analyses will be conducted by study group. The main parameters will 
also de described by age subgroup. For some parameters (eg. GMTs, 4-fold rise) difference or 
ratio between groups may be calculated with 95%CI. The 95% CI of ratios of GMTs will be 
calculated using normal approximation of log-transformed titers and those for proportions 
difference (ie, difference between vaccine groups in SC) will be calculated using Wilson Score 
method without continuity correction. 
The RCDCs of pre-vaccination titer (D01) and post-vaccination titer (D29) 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). 
9.5 
Interim Analyses  
Not applicable.

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 51 of 82 
10 Supporting Documentation and Operational Considerations  
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. Similarly, “legally acceptable representative” is used in the protocol 
whereas “guardian” is used in the CRF. 
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, ICF, 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 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC (in addition to summaries required from the Sponsor) 
• 
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: 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 52 of 82 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, investigators should seek independent 
ethical advice before determining next steps. 
• In case the participant has decided to opt out, the investigator must record in the 
site medical files that she/he does not want to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the investigator’s contract. 
10.1.3 Informed Consent Process  
• The investigator or his/her representative will explain the nature of the study to the participant 
and/or their parents/legally acceptable representatives and answer all questions regarding the 
study. 
• Participants must be informed that their participation is voluntary. Participants or their 
parents/legally acceptable representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or study center. 
• Depending on local regulations, a separate Assent Form (AF) may be required to be signed by 
minor participants. The AF is in addition to, not in place of, an ICF that is signed by the 
parents/legally acceptable representative. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 53 of 82 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• The actual 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. 
• 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 him/her in a timely manner. Such information will be provided 
via a revised AF and ICF or an addendum to the original AF and ICF. 
• Participants and/or their parents/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. 
• A copy of the AF(s) and/or ICF(s) must be provided to the participant and/or their 
parents/legally acceptable representatives. 
Rationale for Including Participants Unable to Give Consent: 
Some participants in the VAP00027 study will be in the pediatric population. Depending on local 
regulations, some participants will not be of 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 procedures 
may be implemented for the duration of the emergency. The participant or their parent / legally 
authorized representative should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg. study visit delays/treatment extension, use of 
local labs).  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 10.4: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency.  

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 54 of 82 
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]). 
• 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. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with applicable data protection law. The level of disclosure must also 
be explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers and 
publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) or to 
Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects.  

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 55 of 82 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. The 
same rule applies in case the professionals are listed on a regulatory agencies disqualification 
list. 
• Personal data can be communicated to the following recipients:  
• Personnel within Sanofi or partners or service providers involved in the study  
• Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an adequate 
level of protection. Those transfers are safeguarded by Sanofi in accordance with the 
requirement of European law including, notably:  
• The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
• Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” or with any 
competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates in 
the Shared Investigator Platform and in the Transcelerate Investigator Registry project 
(https://transceleratebiopharmainc.com/initiatives/investigator-registry/). Therefore, personal 
data will be securely shared by Sanofi with other pharmaceutical company members of the 
Transcelerate project. This sharing allows investigators to keep their data up-to-date once for 
all across pharmaceutical companies participating in the project, with the right to object to the 
transfer of the data to the Transcelerate project.  
• Professionals have the right to object to the processing, to request for access to and the 
rectification of their personal data, as well as their erasure (where applicable) by contacting 
the Sanofi Data Protection Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to 
contact Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-
privacy-policy/contact). 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 56 of 82 
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 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 ESDR (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  
• 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. 
• Guidance on completion of CRFs will be provided in CRF Completion Instructions. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 57 of 82 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
• 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 deviations from the QTLs and remedial actions 
taken will be summarized in the clinical study report. 
• 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. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 25 years after the signature of the final 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, DCs, medical and hospital 
records, screening logs, ICFs / AFs, telephone contact logs, and worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Detailed guidance and information are provided in the Operating Guidelines. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 58 of 82 
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: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 
• 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 61 of 82 
Solicited systemic reactions are systemic AEs observed and reported under the conditions 
(nature and onset) pre-listed in the protocol and CRF. Solicited systemic reactions occurring 
during the specified collection period are always considered related to the IMP even if there is 
evidence of alternative etiology. 
Unsolicited AE/AR 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and onset window post-vaccination. For example, 
varicella or a solicited term such as headache starting after the solicited observation period (eg, 
headache starting on Day 10 post-vaccination in the case where headache occurring between the 
day of vaccination and the next 7 days is pre-listed in the protocol and CRF as a solicited 
reaction). 
An unsolicited AR is an unsolicited AE that is considered related to an IMP.  
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
All unsolicited AEs occurring at and around the IMP injection/administration site are to be 
considered by default as related to the IMP administered at that site and are therefore referred as 
unsolicited injection/administration site ARs. 
All unsolicited AEs which are not at and around the IMP injection/administration site, are 
referred as systemic unsolicited AE. For each unsolicited systemic AE, the investigator assesses 
the relationship to the IMP. Systemic AEs assessed as related to IMP are referred as systemic 
ARs. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (eg, regulators) 
might also be warranted. 
Medically Attended AE (MAAE): 
An MAAE is a new onset or a worsening of a condition that prompts the participant or 
participant’s parent/legally acceptable representative to seek unplanned medical advice at a 
physician’s office or Emergency Department. Physician contact made over the phone or by e-
mail will be considered a physician office visit for the purpose of MAAE collection. This 
includes medical advice seeking during the study visit or routine medical care. This definition 
excludes pediatric check-ups, follow-up visits of chronic conditions with an onset prior to entry 
in the study, and solicited reactions. 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 67 of 82 
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. 
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 
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 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 68 of 82 
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 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 69 of 82 
Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales – Adolescents and adults aged≥ 12 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 70 of 82 
Intensity 
scale* 
 
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. 
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: 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 1: 
≥ 25 to 
≤ 50 mm 
Grade 2: 
≥ 51 to 
≤ 100 mm 
Grade 3: 
> 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 71 of 82 
Table 10.3: 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. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 72 of 82 
  
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. 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 73 of 82 
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: 
• Grade 1 
• 
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. 
• 
DC: No interference with activity. 
• Grade 2 
• 
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. 
• 
DC: Some interference with activity. 
• Grade 3 
• 
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
DC: Significant; prevents daily activity. 
10.3 Appendix: Contraceptive and Barrier Guidance  
10.3.1 Definitions  
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 74 of 82 
Women in the following categories are not considered WOCBP 
1) Premenarchal 
2) Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 75 of 82 
10.3.2 
Contraception Guidance  
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• Intrauterine device 
• Intrauterine hormone-releasing system b 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
• Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. 
d) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception.  
e) Male condom and female condom should not be used together (due to risk of failure from friction). 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 77 of 82 
10.6 Appendix: Abbreviations  
Ab 
 
antibody 
AE 
 
Adverse Events 
AESI  
Adverse events of special interest 
AF 
 
assent form 
AR 
 
Adverse reactions 
BL 
 
blood sampling 
CI 
 
confidence interval 
CRF  
Case report form 
DC 
 
diary card 
DMC  
Data Monitoring Committee 
eDC 
 
electronic diary card 
ELISA  
enzyme-linked immunosorbent assay 
ESDR  
early safety data review 
EU 
 
European Union 
FAS 
 
Full analysis set 
FDA  
Food and Drug Administration 
FSH 
 
Follicle stimulating hormone 
GCP  
Good Clinical Practice 
GMT  
geometric mean titer 
GPV  
Global Pharmacovigilance 
HAI 
 
hemagglutination inhibition 
HAU  
hemagglutination units 
HRT  
Hormonal replacement therapy 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
IEC 
 
Independent Ethics Committees 
IIV3  
Trivalent inactivated influenza vaccine 
IIV4  
quadrivalent inactivated influenza vaccine 
IM 
 
intramuscular 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 78 of 82 
IMP 
 
Investigational Medicinal Product 
IRB 
 
Institutional Review Boards 
IRT 
 
interactive response technology 
LLOQ  
lower limit of quantitation 
MA 
 
memory aid 
MAAE  
medically attended adverse event 
MDCK 
Madin-Darby canine kidney 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
 
neuraminidase 
NI 
 
non-inferiority 
NIMP  
Non- Investigational Medicinal Product; 
PPAS  
Per-protocol analysis set 
PSC 
 
Protein Sciences Corporation 
PV 
 
pharmacovigilance 
PY 
 
Person Year 
QTL  
quality tolerance limit 
RBC  
red blood cell 
RCDC  
reverse cumulative distribution curve 
rHA 
 
recombinant hemagglutinin 
RIV3  
Trivalent Recombinant Influenza Vaccine 
RIV4  
Quadrivalent Recombinant Influenza Vaccine 
RMO  
Responsible Medical Officer 
SAE  
Serious adverse events 
SafAS  
Safety Analysis Set 
SAP 
 
Statistical analysis plan 
SC 
 
seroconversion 
SD-IIV4 
standard-dose quadrivalent inactivated influenza vaccine 
SMT  
Safety Management Team 
SN 
 
seroneutralization 
SoA 
 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reaction 
TBD  
to be determined 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 79 of 82 
USA  
United States of America 
VAC  
vaccination 
WHO  
World Health Organization 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 80 of 82 
10.7 References  
1. Munoz FM. The impact of influenza in children. Seminars Pediatric Infect Dis. 2002;13(2):72–
8. 
2. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B Virus Infections in Children. Clin Infect 
Dis. 2003;36(3):299–305. 
3. Antonova EN, Rycroft CE, Ambrose CS, Heikkinen T, Principi N. Burden of paediatric 
influenza in Western Europe: a systematic review. Bmc Public Health. 2012;12(1):968. 
4. Willis GA, Preen DB, Richmond PC, Jacoby P, Effler PV, Smith DW, et al. The impact of 
influenza infection on young children, their family and the health care system. Influenza Other 
Resp. 2019;13(1):18–27. 
5. Kondrich J, Rosenthal M. Influenza in children. Curr Opin Pediatr. 2017;29(3):297–302. 
6. Kumar V. Influenza in Children. Indian J Pediatrics. 2017;84(2):139–43. 
7. Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of 
global seasonal influenza-associated respiratory mortality: a modelling study. Lancet. 
2018;391(10127):1285–300. 
8. Matias G, Taylor R, Haguinet F, Schuck-Paim C, Lustig R, Shinde V. Estimates of 
hospitalization attributable to influenza and RSV in the US during 1997–2009, by age and risk 
status. Bmc Public Health. 2017;17(1):271. 
9. World Health Organization. Vaccines against influenza - WHO position paper - November 
2012 - Weekly epidemiological record 2012 [461-76]. ://www.who.int/wer/2012/wer8747/en/ 
[Internet]. Weekly epidemiological record. Available from: 
https://www.who.int/wer/2012/wer8747/en/ 
10. World Health Organization. Global influenza strategy 2019-2030 [Internet]. [cited 2022 Feb 
10]. Available from: https://apps.who.int/iris/handle/10665/311184 
11. Demicheli V, Jefferson T, Ferroni E, Rivetti A, Pietrantonj CD. Vaccines for preventing 
influenza in healthy adults. Cochrane Db Syst Rev. 2018;2020(2):CD001269. 
12. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality 
Associated With Influenza and Respiratory Syncytial Virus in the United States. Jama. 
2003;289(2):179–86. 
13. Center for Disease Control and Prevention. National Center for Immunization and Respiratory 
Diseases. Past Seasons Vaccine Effectiveness Estimates 2019 [Internet]. [cited 2022 Feb 10]. 
Available from: https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html 
14. Treanor JJ, Sahly HE, King J, Graham I, Izikson R, Kohberger R, et al. Protective efficacy of 
a trivalent recombinant hemagglutinin protein vaccine (FluBlok®) against influenza in healthy 
adults: A randomized, placebo-controlled trial. Vaccine. 2011;29(44):7733–9. 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 81 of 82 
15. Baxter R, Patriarca PA, Ensor K, Izikson R, Goldenthal KL, Cox MM. Evaluation of the 
safety, reactogenicity and immunogenicity of FluBlok® trivalent recombinant baculovirus-
expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50–64 
years of age. Vaccine. 2011;29(12):2272–8. 
16. Keitel WA, Treanor JJ, Sahly HME, Gilbert A, Meyer AL, Patriarca PA, et al. Comparative 
immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine 
(TIV) among persons ≥65 years old. Vaccine. 2009;28(2):379–85. 
17. Dunkle LM, Izikson R, Patriarca P, Goldenthal KL, Muse D, Callahan J, et al. Efficacy of 
Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. New Engl J Medicine. 
2017;376(25):2427–36. 
18. Dunkle LM, Izikson R, Patriarca PA, Goldenthal KL, Muse D, Cox MMJ. Randomized 
Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated 
Influenza Vaccine in Healthy Adults 18–49 Years of Age. J Infect Dis. 2017;216(10):1219–26. 
19. King JC, Cox MM, Reisinger K, Hedrick J, Graham I, Patriarca P. Evaluation of the safety, 
reactogenicity and immunogenicity of FluBlok® trivalent recombinant baculovirus-expressed 
hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6–59 
months. Vaccine. 2009;27(47):6589–94. 
20. Dunkle LM, Izikson R, Patriarca PA, Goldenthal KL, Cox M, Treanor JJ. Safety and 
Immunogenicity of a Recombinant Influenza Vaccine: A Randomized Trial. Pediatrics. 
2018;141(5):e20173021. 
21. Quadrivalent Recombinant Influenza Vaccine. Investigator’s Brochure. Version 8.0 dated 16 
December 2021. 
22. Hansen J, Goddard K, Timbol J, Zhang L, Lewis N, Dunkle L, et al. Safety of Recombinant 
Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An Observational Study. 
Open Forum Infect Dis. 2020;7(6):ofaa179. 
23. McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, et al. Risk of 
anaphylaxis after vaccination in children and adults. J Allergy Clin Immun. 2016;137(3):868–78. 
 
 

Sanofi Pasteur 
VAP00027 
529 – Quadrivalent Recombinant Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 82 of 82 
11 Sponsor Signature Page  

Signature Page for VV-CLIN-0624738 v2.0
flublok-VAP00027-protocol
Approve & eSign
VV-CLIN-0624738 2.0