Efficacy, Immunogenicity, and Safety of High-Dose Quadrivalent Influenza Vaccine Compared With Standard-Dose Quadrivalent Influenza Vaccine in Children 6 Months Through 35 Months of Age
Phase: PHASE3
Conditions: Influenza
Sponsor: Sanofi Pasteur, a Sanofi Company

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
Confidential/Proprietary Information 
Page 1 of 134 
Efficacy, Immunogenicity, and Safety of High-Dose Quadrivalent 
Influenza Vaccine Compared with Standard-Dose Quadrivalent 
Influenza Vaccine in Children 6 Months through 35 Months of 
Age 
Phase III, randomized, modified double-blind, active-controlled, multi-center study in children 
6 months through 35 months of age in Northern and Southern Hemisphere countries 
Clinical Study Protocol Amendment 2 
Health Authority File Number(s): 
BB-IND #: 
017556 
EudraCT #: 
2019-004721-24 
MX CTA #:     MX 203301410A0141/2021 
WHO Universal Trial Number 
(UTN): 
U1111-1243-5993 
Study Code: 
QHD00014 
Development Phase: 
Phase III 
Sponsor: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Investigational Product(s): 
Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High-Dose 
(QIV-HD) 
Form / Route: 
Suspension for injection in pre-filled syringe / Intramuscular (IM) 
Indication For This Study: 
Active immunization for prevention of influenza in children 6 months 
through 35 months of age  
Manufacturer: 
Same as Sponsor 
Coordinating Investigator: 
 MD 
Division of Pediatric Infectious Diseases, Emory University School of 
Medicine, Atlanta, GA, USA 
Tel:  
Fax: 
Email: 
This is a multi-center study with multiple investigators. Investigators and 
study sites are listed in the “List of Investigators and Centers Involved in 
the Trial” document. 
NCT Number: NCT04544267

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
Confidential/Proprietary Information 
Page 2 of 134 
Sponsor’s Responsible Medical 
Officer: 
 MD 
Global Clinical Development Strategy Expert – Vaccines 
Global Clinical Sciences Department, Sanofi Pasteur Inc. 
Tel:  
E-mail:
Global Safety Officer: 
 MD 
Global Pharmacovigilance, Sanofi Pasteur Inc. 
Tel:  
E-mail:
Coordinating Clinical Study 
Manager: 
B.Sc.
Lead Clinical Study Manager, Sanofi Pasteur Limited 
Address: 1755 Steeles Avenue West, Toronto, Ontario M2R 3T4 Canada 
Tel: 
E-mail:
Version and Date of the Protocol: 
Version 4.0 dated 01 October 2021 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
Confidential/Proprietary Information 
Page 3 of 134 
History of Protocol Versions 
Version* 
Date 
Comments 
1.0 
16 January 2020 
Version submitted to IEC/IRB 
2.0 
26 May 2020 
Version not submitted to IEC/IRB. Changes required 
based on regulatory authority feedback; Amendment 1 
3.0 
27 May 2020 
Administrative changes required immediately after 
CTL/RMO approval; Amendment 1, first version used in 
the study. 
4.0 
01 October 2021 
Amendment 2; Administrative changes required due to  
the delay in study as a result of the COVID-19 
pandemic. 
*Versions in bold font have been approved by the Independent Ethics Committee (IEC) / Institutional Review
Board (IRB) and used in the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 4 of 134 
Table of Contents  
History of Protocol Versions ........................................................................................................... 3 
List of Tables .................................................................................................................................. 10 
Synopsis .......................................................................................................................................... 11 
Table of Study Procedures 1 - Previously vaccinated subjects in the Sentinel Safety 
Cohort ............................................................................................................................... 31 
Table of Study Procedures 2 - Previously unvaccinated subjects in the Sentinel Safety 
Cohort ............................................................................................................................... 33 
Table of Study Procedures 3 (previously influenza vaccinated subjects 6 months 
through 35 months of age) .............................................................................................. 35 
Table of Study Procedures 4 (previously influenza unvaccinated subjects 6 months 
through 35 months of age) .............................................................................................. 37 
Table of Study Procedures 5 (previously influenza vaccinated subjects in the Expanded 
safety analysis set [ESafAS] with or without inclusion in the Immunogenicity 
Subset) .............................................................................................................................. 39 
Table of Study Procedures 6 (previously influenza unvaccinated subjects the 
Expanded safety analysis set [ESafAS] with or without  inclusion in the 
Immunogenicity Subset) ................................................................................................. 41 
Table of Study Procedures 7 ......................................................................................................... 43 
List of Abbreviations ..................................................................................................................... 44 
1 
Introduction ..................................................................................................................... 46 
1.1 
Background ..................................................................................................................... 46 
1.2 
Background of the Investigational Product ..................................................................... 47 
1.3 
Potential Benefits and Risks ........................................................................................... 48 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 48 
1.3.2 
Potential Risks to Subjects ........................................................................................... 48 
1.4 
Rationale for the Study ................................................................................................... 50 
2 
Study Objectives .............................................................................................................. 51 
2.1 
Primary Objective ........................................................................................................... 51 
2.2 
Secondary Objectives ...................................................................................................... 51 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 5 of 134 
2.3 
Observational Objectives ................................................................................................ 52 
3 
Investigators and Study Organization ........................................................................... 54 
4 
Independent Ethics Committee / Institutional Review Board .................................... 55 
5 
Investigational Plan ......................................................................................................... 55 
5.1 
Description of the Overall Study Design and Plan ......................................................... 55 
5.1.1 
Study Design ................................................................................................................. 55 
5.1.2 
Justification of the Study Design .................................................................................. 57 
5.1.3 
Study Plan ..................................................................................................................... 59 
5.1.4 
Visit Procedures ............................................................................................................ 61 
5.1.4.1 
Visit Procedures for subjects in the sentinel safety cohort only ................................ 61 
5.1.4.1.1 
Visit Procedures for previously influenza vaccinated subjects in the Sentinel 
Safety Cohort ........................................................................................................... 62 
5.1.4.1.2 
Visit Procedures for previously influenza unvaccinated subjects in the 
Sentinel Safety Cohort ............................................................................................. 64 
5.1.4.2 
Visit Procedures for previously influenza vaccinated subjects .................................. 66 
5.1.4.3 
Visit Procedures for previously influenza unvaccinated subjects .............................. 68 
5.1.4.4 
Visit Procedures for previously influenza vaccinated subjects who have been 
randomized into the Expanded safety analysis set (ESafAS) with or without 
Immunogenicity Subset .............................................................................................. 70 
5.1.4.5 
Visit Procedures for previously influenza unvaccinated subjects who have been 
randomized into the Expanded safety analysis set (ESafAS) with or without 
Immunogenicity Subset .............................................................................................. 72 
5.1.5 
Collection of ILI Symptoms through Passive and Active Surveillance ....................... 75 
5.1.5.1 
ILI Surveillance and Influenza Confirmation Process for all subjects (except 
Sentinel Safety Cohort subjects) ................................................................................ 75 
5.1.6 
Planned Study Calendar ................................................................................................ 77 
5.1.7 
Early Safety Data Review ............................................................................................. 77 
5.2 
Enrollment and Retention of Study Population .............................................................. 78 
5.2.1 
Recruitment Procedures ................................................................................................ 78 
5.2.2 
Informed Consent Procedures ...................................................................................... 78 
5.2.3 
Screening Criteria ......................................................................................................... 79 
5.2.4 
Inclusion Criteria .......................................................................................................... 79 
5.2.5 
Exclusion Criteria ......................................................................................................... 79 
5.2.6 
Medical History ............................................................................................................ 80 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 81 
5.2.7.1 
Temporary Contraindications ..................................................................................... 81 
5.2.7.2 
Definitive Contraindications ...................................................................................... 81 
5.2.8 
Conditions for Withdrawal ........................................................................................... 82 
5.2.9 
Lost to Follow-up Procedures ....................................................................................... 82 
5.2.10 
Classification of Subjects Who Discontinue the Study ................................................ 82 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 83 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 6 of 134 
5.3 
Safety Emergency Call ................................................................................................... 83 
5.4 
Modification of the Study and Protocol .......................................................................... 84 
5.5 
Interruption of the Study ................................................................................................. 84 
6 
Products Administered ................................................................................................... 85 
6.1 
Identity of the Investigational Product ............................................................................ 85 
6.1.1 
Identity of Study Product .............................................................................................. 85 
6.1.1.1 
Composition ............................................................................................................... 85 
6.1.1.2 
Preparation and Administration ................................................................................. 85 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 86 
6.1.2 
Identity of Control Product ........................................................................................... 86 
6.1.2.1 
Composition ............................................................................................................... 86 
6.1.2.2 
Preparation and Administration ................................................................................. 86 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 87 
6.2 
Product Logistics ............................................................................................................ 87 
6.2.1 
Labeling and Packaging ................................................................................................ 87 
6.2.2 
Product Shipment, Storage, and Accountability ........................................................... 87 
6.2.2.1 
Product Shipment ....................................................................................................... 87 
6.2.2.2 
Product Storage .......................................................................................................... 87 
6.2.2.3 
Product Accountability ............................................................................................... 88 
6.2.3 
Replacement Doses ....................................................................................................... 88 
6.2.4 
Disposal of Unused Products ........................................................................................ 88 
6.2.5 
Recall of Products ......................................................................................................... 88 
6.3 
Blinding and Code-breaking Procedures ........................................................................ 88 
6.4 
Randomization and Allocation Procedures ..................................................................... 89 
6.5 
Treatment Compliance .................................................................................................... 90 
6.6 
Concomitant Medications and Other Therapies.............................................................. 90 
7 
Management of Samples ................................................................................................. 91 
7.1 
Sample Collection ........................................................................................................... 91 
7.1.1 
Blood Samples .............................................................................................................. 91 
7.1.2 
Nasopharyngeal Samples .............................................................................................. 92 
7.2 
Sample Preparation ......................................................................................................... 92 
7.2.1 
Blood Samples .............................................................................................................. 92 
7.2.2 
Nasopharyngeal Swabs ................................................................................................. 92 
7.3 
Sample Storage and Shipment ........................................................................................ 92 
7.3.1 
Blood Samples .............................................................................................................. 92 
7.3.2 
Nasopharyngeal Samples .............................................................................................. 93 
7.4 
Future Use of Stored Biological Samples for Research .................................................. 93 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 7 of 134 
8 
Clinical Supplies .............................................................................................................. 93 
9 
Endpoints and Assessment Methods ............................................................................. 94 
9.1 
Definitions ....................................................................................................................... 94 
9.2 
Primary Endpoints and Assessment Methods ................................................................. 95 
9.2.1 
Efficacy ......................................................................................................................... 95 
9.2.1.1 
Efficacy Endpoints ..................................................................................................... 95 
9.2.1.2 
Efficacy Assessment Methods ................................................................................... 95 
9.2.2 
Immunogenicity ............................................................................................................ 96 
9.2.3 
Safety ............................................................................................................................ 96 
9.3 
Secondary Endpoints and Assessment Methods ............................................................. 96 
9.3.1 
Efficacy ......................................................................................................................... 96 
9.3.1.1 
Efficacy Endpoints ..................................................................................................... 96 
9.3.1.2 
Efficacy Assessment Methods ................................................................................... 97 
9.3.2 
Immunogenicity ............................................................................................................ 98 
9.3.2.1 
Immunogenicity Endpoints ........................................................................................ 98 
9.3.2.2 
Immunogenicity Assessment Methods....................................................................... 99 
9.3.3 
Safety .......................................................................................................................... 100 
9.3.3.1 
Safety Endpoints ...................................................................................................... 100 
9.3.3.2 
Safety Definitions ..................................................................................................... 101 
9.3.3.3 
Safety Assessment Methods ..................................................................................... 103 
9.3.3.3.1 
Immediate Post-vaccination Observation Period ................................................... 103 
9.3.3.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Each 
Vaccination) ........................................................................................................... 104 
9.3.3.3.3 
Unsolicited Adverse Events ................................................................................... 108 
9.3.3.3.4 
Adverse Events of Special Interest ........................................................................ 109 
9.3.3.3.5 
Assessment of Causality ........................................................................................ 110 
9.4 
Observational Endpoints and Assessment Methods ..................................................... 110 
9.4.1 
Efficacy ....................................................................................................................... 110 
9.4.1.1 
Efficacy Endpoints ................................................................................................... 110 
9.4.1.2 
Efficacy Assessment Methods ................................................................................. 111 
9.4.2 
Immunogenicity .......................................................................................................... 111 
9.4.2.1 
Immunogenicity Endpoints ...................................................................................... 111 
9.4.2.2 
Immunogenicity Assessment Methods..................................................................... 112 
9.4.3 
Safety .......................................................................................................................... 112 
10 
Reporting of Serious Adverse Events .......................................................................... 112 
10.1 
Initial Reporting by the Investigator ............................................................................. 112 
10.2 
Follow-up Reporting by the Investigator ...................................................................... 113 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study .................... 113 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 8 of 134 
10.4 
Assessment of Causality ............................................................................................... 113 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs ............................................... 114 
11 
Data Collection and Management ............................................................................... 114 
11.1 
Data Collection and CRB Completion .......................................................................... 114 
11.2 
Data Management ......................................................................................................... 115 
11.3 
Data Review .................................................................................................................. 116 
12 
Statistical Methods and Determination of Sample Size ............................................. 116 
12.1 
Statistical Methods ........................................................................................................ 116 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective ....................................... 117 
12.1.1.1 
Hypotheses ............................................................................................................... 117 
12.1.1.2 
Statistical Methods ................................................................................................... 117 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................. 118 
12.1.2.1 
Hypotheses ............................................................................................................... 118 
12.1.2.1.1 
Statistical Methods ................................................................................................. 118 
12.1.3 
Statistical Methods for Observational Objective(s) .................................................... 119 
12.2 
Analysis Sets ................................................................................................................. 120 
12.2.1 
Full Analysis Set for Efficacy .................................................................................... 120 
12.2.2 
Safety Analysis Set ..................................................................................................... 120 
12.2.3 
Expanded Safety Analysis Set .................................................................................... 120 
12.2.4 
Per-Protocol Analysis Set for Efficacy ....................................................................... 120 
12.2.5 
Full Analysis Set for Immunogenicity ........................................................................ 121 
12.2.6 
Per-Protocol Analysis Set for Immunogenicity .......................................................... 121 
12.2.7 
Immunogenicity Analysis Set ..................................................................................... 122 
12.2.8 
Populations Used in Analyses .................................................................................... 122 
12.3 
Handling of Missing Data and Outliers ........................................................................ 122 
12.3.1 
Efficacy ....................................................................................................................... 122 
12.3.2 
Immunogenicity .......................................................................................................... 122 
12.3.3 
Safety .......................................................................................................................... 123 
12.4 
Interim / Preliminary Analysis ...................................................................................... 123 
12.5 
Determination of Sample Size and Power Calculation ................................................. 124 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities ...................... 127 
13.1 
Ethical Conduct of the Study / Good Clinical Practice ................................................. 127 
13.2 
Source Data and Source Documents ............................................................................. 127 
13.3 
Confidentiality of Data, Data Protection, and Access to Subject Records ................... 128 
13.4 
Monitoring, Auditing, and Archiving ........................................................................... 128 
13.4.1 
Monitoring .................................................................................................................. 128 
13.4.2 
Audits and Inspections ................................................................................................ 129 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 9 of 134 
13.4.3 
Archiving .................................................................................................................... 129 
13.5 
Financial Contract and Insurance Coverage ................................................................. 130 
13.6 
Stipends for Participation .............................................................................................. 130 
13.7 
Publication Policy ......................................................................................................... 130 
14 
Reference List ................................................................................................................ 131 
15 
Signature Page ............................................................................................................... 134 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 10 of 134 
List of Tables  
Table 5.1: QHD04 study: HAI GMT ratios (QIV-HD/QIV-SD) .................................................... 57 
Table 9.1: ILI symptoms: terminology ............................................................................................ 95 
Table 9.2: Solicited injection site reactions for children 6 through 35 months of age: terminology, 
definitions, and intensity scales ..................................................................................................... 105 
Table 9.3: Solicited systemic reactions for children 6 through 35 months of age: terminology, 
definitions, and intensity scales ..................................................................................................... 107 
Table 12.1: Planned sample size by vaccine and influenza season ............................................... 125 
Table 12.2: Samples sizes for evaluation based on assessment method ....................................... 126 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
Confidential/Proprietary Information 
Page 11 of 134 
Synopsis 
Company: 
Sanofi Pasteur 
Investigational 
Product: 
Quadrivalent Influenza Vaccine (Split Virion, Inactivated) High-Dose (QIV-HD) 
Active Substances: 
Influenza virus (inactivated, split) of the following strains: A/(H1N1), A/(H3N2), B 
(Victoria Lineage), and B (Yamagata Lineage) 
Title of the Study: 
Efficacy, Immunogenicity, and Safety of High-Dose Quadrivalent Influenza Vaccine 
Compared with Standard-Dose Quadrivalent Influenza Vaccine in Children 6 Months 
through 35 Months of Age 
Development Phase: 
Phase III 
Coordinating 
Investigator: 
 MD 
Division of Pediatric Infectious Diseases, Emory University School of Medicine, 
Atlanta, GA, USA 
Study Sites: 
This will be a multi-center study conducted at approximately 200 sites in 
approximately 9 countries in the Northern Hemisphere (NH) and approximately 6 
countries in the Southern Hemisphere (SH).  
Investigators and sites are listed in the “List of Investigators and Centers Involved in 
the Trial” document. 
Planned Study Period: 
Note: The Sentinel Safety Cohort and associated study procedures were completed 
prior to Amendment 2 of this Protocol. 
The study is planned to start in September 2020 with the  Sentinel Safety Cohort. 
Following the Sentinel Safety Cohort, the main efficacy cohort in the study is planned 
to be completed during 2 NH influenza seasons (2022-2023 [Season 1] and 2023-2024 
[Season 3]) and 1 SH influenza season (2023 [Season 2]), unless the number of 
expected cases is insufficient for the primary endpoint requiring additional influenza 
seasons to be evaluated or a decision is made to stop the study earlier based on an 
interim analysis. 
Following the end of the Season 2 (2023 SH) influenza season, if the likelihood of 
achieving the expected
 influenza cases at the end of Season 3 (2023-2024 NH 
influenza season) is low, and if at least
 influenza cases meeting the primary 
endpoint have occurred, an interim analysis of the efficacy of high-dose quadrivalent 
influenza vaccine (QIV-HD) relative to a licensed standard-dose quadrivalent 
influenza vaccine (hereafter referred to as QIV-SD) for the primary efficacy endpoint 
is planned to be conducted by an independent statistician and reviewed by an 
independent data monitoring committee (IDMC) during Season 3. The IDMC may 
recommend stopping the study without adding any additional study seasons if the 
primary objective and first secondary objectives are demonstrated (ie, the stopping 
rule for superior efficacy is fulfilled), if there is a high probability to demonstrate 
these objectives at the end of the ongoing season, or for futility if the probability to 
demonstrate the primary objective at the end of the study is too low. 
Study Design, Schedule 
of Study Procedures, 
and Methodology: 
General Study Design 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 12 of 134 
QHD00014 is planned to be a Phase III, randomized, modified double-blind, active-
controlled, multi-center study to be conducted in 13,320 (100 subjects will be in an 
open-label Sentinel Safety Cohort with no comparator vaccine while 13,220 will be 
randomized and double-blinded) children 6 months through 35 months of age to 
evaluate the relative efficacy, immunogenicity, and safety of QIV-HD administered by 
intramuscular (IM) route versus a QIV-SD vaccine.  
QHD00014 is planned to start during the 2020-2021 NH influenza season with the 
Sentinel Safety Cohort. The main efficacy cohort will be conducted during the 2022-
2023 NH influenza season (Season 1), the 2023 SH influenza season (Season 2), and 
the 2023-2024 NH influenza season (Season 3). During each of these 3 study seasons, 
subjects will be randomized in a 1:1 ratio to receive either QIV-HD or QIV-SD prior to 
the start of the influenza season. Subjects will receive either 1 or 2 doses of study 
vaccine depending on whether they were previously vaccinated against influenza or 
previously unvaccinated against influenza, respectively.  
During the 2020-2021 NH influenza season, a sentinel cohort of 100 US subjects will 
be enrolled in an uncontrolled, open-label design without a comparator vaccine to 
evaluate the safety of QIV-HD prior to the enrollment of subjects in the main efficacy 
cohort. These Sentinel Safety Cohort subjects will not provide blood samples and will 
not be followed for influenza-like illness (ILI) surveillance. Enrollment in the main 
efficacy cohort will not begin until an IDMC reviews the safety of the Sentinel Safety 
Cohort. If the IDMC determines that there is no significant safety issue during their 
review of the Sentinel Safety Cohort data, then approximately
 subjects will 
subsequently be enrolled in main efficacy cohort starting with Season 1 (ie, the 2022-
2023 NH influenza season).  
The sample size in the subsequent seasons may be adjusted to maintain the likelihood 
of achieving the overall expected number of cases for the primary endpoint. The current 
estimated sample size for the efficacy cohort in Seasons 2 and 3 is
 subjects 
 and an additional
 subjects from Season 1’s 
Immunogenicity Subset will be re-enrolled in Season 3 but will not be included in 
efficacy analysis for Season 3, for a total of 13,320 subjects in the entire study. Sentinel 
Safety Cohort subjects will be excluded from reenrollment in any subsequent seasons. 
During each influenza season, a subset of subjects (hereafter referred to as the 
Immunogenicity Subset) will be randomly selected using Interactive Response 
Technology (IRT) across participating sites to provide blood samples for 
immunogenicity testing: 
Total subjects with blood draws = approximately
 subjects 
Season 1, NH = 
 subjects 
Season 2, SH =
 of randomized subjects (approximately
 subjects) 
Season 3, NH =
of randomized subjects (approximately
subjects) and 
 re-
enrolled subjects who were part of Season 1* 
An Expanded safety analysis set (ESafAS) will also be selected for collection of 
reactogenicity and unsolicited adverse events as follows:  
Total subjects in ESafAS =
subjects  
Sentinel Safety Cohort (2020-2021 NH) = 100 subjects† 
Season 1, NH =
 subjects (all subjects) † 
Season 2, SH =
 of randomized subjects (approximately
subjects) 
Season 3, NH =
 of randomized subjects (approximately 
 subjects) and
 re-
enrolled subjects from Season 1 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 13 of 134 
*A subset of approximately 
 subjects from Season 1 (2022-2023 NH) who are in the 
Immunogenicity Subset will be re-enrolled and re-randomized in Season 3 (hereafter 
referred as the Re-vaccination Cohort) and included in the ESafAS and the 
Immunogenicity Subset; these
 subjects will not be followed for ILI surveillance 
during their participation in Season 3.  
†Note: For the Sentinel Safety Cohort season and Season 1: all enrolled subjects will be 
included in the ESafAS.  
For Seasons 2 and 3: the Immunogenicity Subset and the ESafAS will include the same 
subjects. 
 
Vaccination 
For the  Sentinel Safety Cohort, eligible subjects will receive QIV-HD as follows: 
• 
Subjects enrolled in the Sentinel Safety Cohort who were previously vaccinated 
against influenza will receive 1 dose of the QIV-HD on Day (D) 0, with no 
comparator vaccine. 
• 
Subjects enrolled in the Sentinel Safety Cohort who were not previously vaccinated 
against influenza will receive 2 doses of the QIV-HD with no comparator vaccine. 
Each dose will be administered 28 days apart (at D0 and D28). 
All other eligible subjects will be randomized to receive either QIV-HD or QIV-SD: 
• 
Subjects previously vaccinated against influenza will receive 1 dose of the QIV-
HD or the comparator vaccine on D0. 
• 
Subjects who had not previously been vaccinated against influenza will receive 
2 doses of the QIV-HD or the comparator vaccine. Each dose will be administered 
28 days apart (at D0 and D28). 
Note: Previously unvaccinated subjects are defined as subjects who have not received at 
least 2 doses of seasonal influenza vaccine in a prior influenza season. These subjects 
will receive 2 doses of study vaccine at least 28 days apart after enrolling in the study. 
Subjects who have received only one dose of any influenza vaccine in the past or 
subjects whose vaccination history is unknown will also be considered as previously 
unvaccinated when enrolling and receive 2 doses of study vaccine at least 28 days 
apart. 
Previously vaccinated subjects are defined as subjects who have received at least 2 
doses of seasonal influenza vaccine in prior influenza seasons. These subjects will 
receive only 1 dose of study vaccine after enrolling in the study. 
In the Sentinel Safety Cohort, subjects will receive 1 or 2 doses of QIV-HD according 
to their influenza vaccination history as defined above. 
An unblinded administrator at each site will administer the vaccine. 
 
Definitions: 
Protocol-defined influenza-like illness (ILI): occurrence of fever ≥ 38°C (100.4°F) 
concurrently with at least one of the following symptoms: cough, wheezing, difficulty 
breathing, nasal congestion, rhinorrhea, pharyngitis (sore throat), otitis, vomiting, 
diarrhea, chills (shivering), tiredness (fatigue), headache, or myalgia (muscle aches). 
Modified Centers for Disease Control and Prevention (CDC)-defined ILI: occurrence of 
fever (defined as temperature > 38°C [>100.4°F]) with cough, pharyngitis, or sore 
throat. 
Laboratory-confirmed influenza: a positive influenza result on either polymerase chain 
reaction (PCR) or viral culture. 
Culture-confirmed influenza: a positive influenza result on viral culture. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 14 of 134 
Genetic similarity: Genetic similarity is defined when a laboratory-confirmed isolate is 
deemed similar to one of the viral strains contained in the vaccine formulations 
according to sequencing of full HA gene segments proteins. 
Antigenic similarity: Antigenic similarity is defined when a laboratory-confirmed 
isolate is deemed similar to one of the viral strains contained in the vaccine 
formulations according to Ferret Antigenicity testing (hemagglutination inhibition 
[HAI] against a panel of known standard ferret reference antisera). 
Similarity to vaccine components: For prevention of laboratory-confirmed influenza 
illness caused by viral strains similar to those contained in the vaccine in subjects 6 
months through 35 months of age, laboratory-confirmed isolate is deemed similar to 
one of the vaccine components based on antigenic similarity only. For all the other 
endpoints, similarity is based on antigenic similarity when available or based on genetic 
similarity otherwise. 
Acute lower respiratory infection (ALRI): pneumonia, bronchiolitis, bronchitis, or 
croup (laryngotracheobronchitis) based on a clinical and/or x-ray diagnosis. 
Surveillance for Influenza-like illness: 
Following randomization and vaccination(s), all subjects’ parents/guardians (except 
those subjects in the Sentinel Safety Cohort) will be instructed to contact the PI staff  
(passive surveillance) if they experience symptoms of a protocol-defined ILI during the 
annual surveillance periods, from the 1st vaccination until 30 April of the following year 
for NH seasons subjects or until 31 October of the same year for SH subjects.  
In addition, during a period from  the 1st vaccination until 30 April for NH seasons 
subjects or 31 October for SH season subjects, subjects will be contacted (active 
surveillance) once a week.  
    
Collection of nasopharyngeal (NP) swabs: 
During the period from D0 after vaccination (after the first vaccination in subjects 
receiving two doses of study vaccine) until 30 April of the following year for NH 
subjects or until 31 October of the same year for SH subjects, the site will arrange for an 
NP swab to be taken if the subject experiences a new onset of fever concomitantly with 
one or more of the above-mentioned symptoms of protocol-defined ILI (that persists for 
or reoccurs after a period of at least 12 hours).  
The NP swab will be obtained as soon as possible and no later than 7 days (between D0 
and D6) from the onset of the ILI. 
Reporting of events temporally associated with an ILI:  
In addition to obtaining an NP swab, the site will collect detailed information about the 
ILI, as well as information on occurrence of ALRI, otitis media, healthcare utilization 
events (hospitalizations, emergency room visits, and non-routine office visits [including 
urgent care visits]) and medication use (eg, antibiotics, antivirals). 
In the event that an NP swab cannot be collected, the research site will still obtain the 
above information. All subjects’ parents/guardians reporting a suspected ILI will have a 
30-day follow-up telephone call. 
Laboratory testing for the confirmation of influenza and determination of similarity 
to vaccine components: 
All NP specimens will be submitted for analysis by both culture and PCR, and a 
positive result on either test will be considered a laboratory-confirmed case of 
influenza. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 15 of 134 
Positive cultures or positive PCR samples* will undergo additional testing (typing, 
subtyping, and strain identification, utilizing genetic sequencing) to determine if the 
virus detected is similar to any of those contained in the vaccine formulation for the 
respective season. 
*Positive PCR samples that have negative culture results, or were unable to be 
expanded in culture, will not undergo additional testing. 
 
Blood sampling 
A subset of randomly selected subjects (immunogenicity subset) will provide 2 blood 
samples (5 mL each):  
• 
Previously vaccinated subjects will provide a pre-vaccination (baseline) blood 
sample at V01 (D0) and a post-vaccination blood sample at V02 (D28 [+7 days]) 
for HAI testing and potential seroneutralization (SN) and enzyme-linked lectin 
assay (ELLA) testing. 
• 
Previously unvaccinated subjects will provide a pre-vaccination (baseline) blood 
sample at V01 (D0) and a post-vaccination blood sample at V03 (28 days after V02 
[+7 days]) for HAI testing and potential SN and ELLA testing. 
 
Collection of safety data 
All subjects will be observed for 30 minutes after vaccination, and any unsolicited 
systemic adverse events (AEs) occurring during that time will be recorded as immediate 
unsolicited systemic AEs in the case report book (CRB) for subjects in the Sentinel 
Safety Cohort and ESafAS and in the source documentation for all other subjects. 
For subjects enrolled in the Sentinel Safety Cohort and in Season 1 (2022-2023 NH), 
solicited reactions will be collected through day 7 after each vaccination, and 
unsolicited AEs will be collected through day 28 after each vaccination in all subjects. 
During Season 2 (2023 SH) and Season 3 (2023-2024 NH), solicited reactions and 
unsolicited AEs will only be collected for those in the ESafAS. Serious adverse events 
(SAEs) and adverse events of special interest (AESIs) will be collected in all subjects 
throughout the study (D0 through approximately 6 to 7 months after vaccination in each 
season). AESIs will be captured as SAEs in this study. AESIs include Guillain-Barré 
syndrome (GBS), encephalitis / myelitis (including transverse myelitis), Bell’s palsy, 
convulsions, optic neuritis, and brachial neuritis. 
Parents / guardians of subjects will be asked to notify the site immediately about any 
potential SAEs (including AESIs) at any time during the study. 
Staff will review the safety data with subjects’ parents / guardians at each visit. The 
IRT system will be used to randomly assign subjects to a study product and subsets and 
to assign subject numbers in each of the groups.  
Electronic data capture (EDC) will be used for the collection of data. 
Early Safety Data 
Review: 
The safety of the investigational product will be continuously monitored by the 
Sponsor. An early safety data review (ESDR) will be performed, the goal of which is to 
allow for a cautious, step-wise approach to vaccine administration. An initial safety 
review for this study is planned when the first 100 subjects are vaccinated, and safety 
has been captured for all in a Sentinel Safety Cohort. All 100 subjects are to receive 
QIV-HD (in this open-label cohort, no comparator vaccine will be administered). After 
the Sentinel Safety Cohort vaccinations have been provided and there is safety data for 
D0-D7 post-vaccination (using the data collection methods described in the clinical 
study protocol), an IDMC will convene and review the safety data. Following a 
satisfactory safety review by the IDMC, enrollment of subjects may start in Season 1 
(2022-2023 NH). 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 16 of 134 
The safety data collected will be entered into the case report book (CRB) and will be 
summarized and reviewed by the Sponsor and the IDMC. It is understood that this 
review is based on preliminary data that have not been subject to validation and 
database lock. (The usual and ongoing process of monitoring safety signals outside of 
those specified in the protocol-defined ESDR will continue unchanged.) 
 
The following safety parameters will be assessed as part of the ESDR review of the 
Sentinel Safety Cohort in an unblinded manner by the IDMC. They will be 
collected during a period of 7 days after the vaccination: 
• 
Immediate reactions 
• 
Solicited injection site and systemic reactions 
• 
Unsolicited AEs 
• 
SAEs (including AESIs) 
The data will be examined for the following occurrences: 
• 
An SAE (including AESIs) considered as related to the vaccination by the 
Investigator and Sponsor 
• 
> 10% of subjects experiencing Grade 3 fever within 7 days after vaccination 
If any of the above criteria are met, a recommendation will be made by the IDMC as to 
whether enrollment in the study will be allowed to resume. 
At the completion of the collection of safety data at the end of Season 1 (2022-2023 NH 
season), the IDMC will be convened to review the safety data of subjects. Enrollment 
will not be paused during this IDMC review. 
Throughout the course of the study, additional internal safety management team (SMT) 
meetings will be convened to conduct blinded analyses of safety data. Case unblinding 
may be performed if necessary. The Sponsor may also convene the IDMC for ad hoc 
review of the safety data if needed.  
If the study is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators, the IECs / IRBs, and the regulatory authorities of the reason for 
termination or suspension. If the study is prematurely terminated for any reason, the 
Investigator will promptly inform the study subjects and should assure appropriate 
therapy and follow-up. 
Interruption of the 
Study 
The study may be discontinued if new data about the investigational product resulting 
from this study or any other studies become available; or for administrative reasons; or 
on advice of the Sponsor, the Investigators, the IECs / IRBs, the IDMC, or the 
governing regulatory authorities in the countries where the study is taking place.  
The study may also be interrupted prior to accrual of all expected protocol-defined 
influenza cases upon recommendation of the IDMC after an interim unblinded analysis 
to evaluate if early efficacy or futility criteria are met. 
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 subjects’ parents/guardians and should assure appropriate subject therapy 
and/or follow-up. 
Primary Objective: 
Efficacy objective  
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months through 
35 months of age for the prevention of laboratory-confirmed influenza illness caused 
by any influenza A or B type. 
Primary Endpoint: 
Efficacy  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 17 of 134 
Occurrence of laboratory-confirmed influenza illness (≥ 14 days post-vaccination) 
caused by any influenza viral types/subtypes, in association with a protocol-defined 
ILI. 
Secondary Objectives: 
Confirmatory Efficacy Objectives 
• 
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months 
through 35 months of age for the prevention of laboratory-confirmed influenza 
illness caused by any influenza A or B type using a more stringent threshold 
• 
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months 
through 35 months of age for the prevention of laboratory-confirmed influenza 
illness caused by viral strains similar to those contained in the vaccine 
• 
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months 
through 23 months of age for the prevention of laboratory-confirmed influenza 
illness caused by any influenza A or B type 
Other Secondary Objectives are for descriptive assessment: 
Efficacy Descriptive Objectives: 
To assess the relative clinical efficacy of QIV-HD compared to QIV-SD in subjects 
for the prevention of: 
• 
laboratory-confirmed influenza illness caused by any influenza A or B type 
according to previous influenza vaccination status in prior seasons 
• 
laboratory-confirmed influenza illness caused by viral strains similar to those 
contained in the vaccine according to previous vaccination status 
• 
laboratory-confirmed influenza illness associated with acute otitis media (AOM 
based on clinical diagnosis) caused by any influenza A or B type 
• 
laboratory-confirmed influenza illness associated with AOM based on clinical 
diagnosis caused by viral strains similar to those contained in the vaccine 
• 
laboratory-confirmed influenza illness associated with ALRI based on a clinical 
and/or x-ray diagnosis caused by any influenza A or B type 
• 
laboratory-confirmed influenza illness associated with ALRI based on a clinical 
and/or x-ray diagnosis caused by viral strains similar to those contained in the 
vaccine 
• 
PCR-confirmed influenza illness caused by any influenza A or B type 
• 
PCR-confirmed influenza illness caused by viral strains similar to those contained 
in the vaccine 
• 
culture-confirmed influenza illness caused by any influenza A or B type 
• 
culture-confirmed influenza illness caused viral strains similar to those contained 
in the vaccine 
• 
laboratory-confirmed influenza illness associated with hospitalization and caused 
by any influenza A or B type 
• 
laboratory-confirmed influenza illness associated with hospitalization and caused 
by viral strains similar to those contained in the vaccine 
Immunogenicity 
• 
To compare the HAI immune response of QIV-HD to QIV-SD in subjects 6 
months through 35 months of age 
• 
To describe the HAI immune response induced by each vaccine against the 
4 vaccine strains and according to the different strain formulations used in each 
of the study influenza seasons 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 18 of 134 
• 
To describe the SN immune response induced by QIV-HD or QIV-SD against 
the 4 QIV-HD vaccine strains in a randomized subset of subjects 
• 
To describe the anti-neuraminidase (NA) immune response induced by QIV-HD 
or QIV-SD in a randomized subset of subjects   
Re-vaccination Response 
To describe the immune response (HAI method) to vaccination in Season 3 (NH) 
among subjects re-enrolled from Season 1 (NH) to Season 3 (NH), according to the 
vaccines received in both Season 1 (NH) and Season 3 (NH) 
 
Safety 
• 
To describe the safety profile (injection site reactions and systemic events) of 
each vaccine during the 28 days following each vaccination for the ESafAS (all 
subjects from Sentinel Safety Cohort, all subjects from Season 1, and a subset of 
subjects from Seasons 2 and 3) 
• 
To describe all SAEs (including AESIs) up to at least 180 days after the last 
vaccination in all subjects 
Secondary Endpoints: 
Confirmatory Efficacy Endpoints 
The following endpoints will be used for efficacy comparisons: 
• 
Occurrence of laboratory-confirmed influenza illness (≥ 14 days post-vaccination) 
caused by any influenza viral types/subtypes, in association with a protocol-
defined ILI. 
• 
Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as 
positive for viral strains similar to those contained in the vaccine  
• 
Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as 
positive in subjects 6 through 23 months of age for any influenza A or B type  
Descriptive Efficacy Endpoints 
In addition, the following endpoints will also be considered for the descriptive 
assessment of relative efficacy:  
Occurrence of an ILI starting ≥ 14 days after vaccination: 
• 
laboratory-confirmed as positive for any influenza A or B type, in subjects 
according to their previous vaccination status  
• 
laboratory-confirmed as positive for viral strains similar to those contained in the 
vaccine, in subjects according to their previous vaccination status 
• 
laboratory-confirmed as positive for any influenza A or B type, and associated 
with AOM based on clinical diagnosis occurrence  
• 
laboratory-confirmed as positive for viral strains similar to those contained in the 
vaccine, and associated with AOM based on clinical diagnosis occurrence 
• 
laboratory-confirmed as positive for any influenza A or B type, and associated 
with ALRI based on a clinical and/or x-ray diagnosis occurrence  
• 
laboratory-confirmed as positive for viral strains similar to those contained in the 
vaccine, and associated with ALRI based on a clinical and/or x-ray diagnosis 
occurrence 
• 
PCR-confirmed as positive for any influenza A or B types  
• 
PCR-confirmed as positive for viral strains similar to those contained in the 
vaccine 
• 
culture-confirmed as positive for any influenza A or B types 
• 
culture-confirmed as positive for viral strains similar to those contained in the 
vaccine 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 19 of 134 
• 
laboratory-confirmed as positive for any influenza A or B type and associated 
with hospitalization 
• 
laboratory-confirmed as positive for viral strains similar to those contained in the 
vaccine and associated with hospitalization 
Immunogenicity 
The following immunogenicity endpoints will be used for comparison in 
Immunogenicity Subset of Season 1: 
• 
Individual HAI titer on D0 and 28 days after the last vaccination 
• 
Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-
injection titer ≥ 40 (1/dil) on 28 days after the last vaccination or significant 
increase for subjects with a pre-vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase 
from pre- to post-injection titer on 28 days after the last vaccination 
In addition, the 2 above and the following endpoints will be considered in the 
Immunogenicity Subset for the descriptive assessment of immunogenicity: 
• 
Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after 
the last vaccination. 
• 
Individual titer ratio: 28 days after the last vaccination /D0. 
• 
Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination. 
Immunogenicity by SN method 
Immunogenicity will be evaluated using the SN assay in a subset of subjects. For each 
vaccine strain, antibody titers will be expressed as SN titers. The following 
immunogenicity endpoints will be described: 
• 
Individual SN antibody (Ab) titer on D0 and 28 days after the last vaccination 
• 
Individual SN Ab titer ratio (fold increase in post-vaccination titer relative to D0) 
at 28 days after the last vaccination 
• 
Subjects with SN Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at 28 days after 
the last vaccination 
• 
Fold-increase in SN Ab titer [post/pre] ≥ 2 and ≥ 4 at 28 days after the last 
vaccination 
• 
Detectable SN Ab titer (SN Ab titer ≥ 10 [1/dil]) at D0 and 28 days after the last 
vaccination 
Immunogenicity by ELLA method 
For a subset of subjects, anti-N1 and anti-N2 titers will be measured for the 
2 influenza A strains using ELLA and will be assessed based on the subject’s 
individual anti-NA titer. The following immunogenicity endpoints will be described: 
• 
Individual anti-NA Ab titer on D0 and 28 days after the last vaccination 
• 
Individual anti-NA Ab titer ratio (fold-rise in anti-NA post-vaccination titer 
relative to D0) at 28 days after the last vaccination  
• 
Subjects with anti-NA Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at 28 days 
after the last vaccination 
• 
Fold-rise in anti-NA Ab titer [post/pre] ≥ 2 and ≥ 4 at 28 days after the last 
vaccination 
• 
Detectable anti-NA titer (anti-NA Ab titer ≥ 10 [1/dil]) at D0, and 28 days after 
the last vaccination 
Re-vaccination Response 
For the approximately 
 subjects who are re-enrolled in  Season 3 (NH) and were 
part of the Immunogenicity Subset in Season 1 (NH), the HAI Ab titers against the 4 
vaccine strains used in Season 3 (NH) will be measured at D0 and D28 in Season 3 
(NH). The following endpoints will be described. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 20 of 134 
• 
HAI individual titer on D0, and 28 days after the last vaccination 
• 
Individual HAI titer ratio: D28 days after the last vaccination /D0 
• 
Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after 
the last vaccination 
• 
Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination 
• 
Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-
injection titer ≥ 40 (1/dil) on 28 days after the last vaccination or significant 
increase for subjects with a pre-vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase 
from pre- to post-injection titer on 28 days after the last vaccination. 
Safety / Reactogenicity 
Reactogenicity will be described for the ESafAS: 
• 
Occurrence of any unsolicited systemic AEs reported in the 30 minutes after each 
vaccination 
• 
Occurrence of solicited (pre-listed in the subject’s diary card and CRB) injection 
site reactions and systemic reactions occurring up to 7 days after vaccination 
• 
Occurrence of unsolicited AEs up to 28 days after vaccination 
SAEs/AESIs will be described in all subjects: 
• 
Occurrence of SAEs (including AESIs) throughout the study 
• 
Occurrence of AESIs throughout the study 
Observational 
Objectives: 
Efficacy 
The following objectives will be assessed for laboratory-confirmed influenza illness 
due to any influenza A or B type, and due to viral strains similar to those contained in 
the vaccine. To assess the relative clinical efficacy of QIV-HD compared to QIV-SD 
in subjects 6 months through 35 months of age for the prevention of: 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination caused 
by each circulating influenza virus A subtype and B lineage  
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination by age 
subgroup  
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination by 
season  
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination in 
previously unvaccinated subjects after 1st injection 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination in 
previously unvaccinated subjects between 1st and 2nd injections 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination and 
over the first 3 months after vaccination 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination 
according to other ILI definitions (modified CDC-defined ILI) 
Influenza-associated Events/Health Care Utilization 
 
• 
To describe in each vaccine group the occurrence of AOM (based on clinical 
and/or x-ray diagnosis), within 30 days after the onset of a laboratory-confirmed 
ILI 
• 
To describe in each vaccine group the occurrence of AOM (based on clinical 
and/or x-ray diagnosis), within 30 days after the onset of any ILI  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 21 of 134 
• 
To describe in each vaccine group the occurrence of ALRI (based on clinical 
and/or x-ray diagnosis), within 30 days after the onset of a laboratory-confirmed 
ILI 
• 
To describe in each vaccine group the occurrence of ALRI (based on clinical 
and/or x-ray diagnosis), within 30 days after the onset of any ILI 
• 
To describe in each vaccine group the occurrence, duration, and intensity of ILI 
symptoms occurring within 30 days after the onset of a laboratory-confirmed ILI 
• 
To describe in each vaccine group the occurrence, duration, and intensity of ILI 
symptoms occurring within 30 days after the onset of ILI 
• 
To describe in each vaccine group the use of antibiotics and antivirals that are 
associated with cases of laboratory-confirmed ILI, within 30 days after the onset 
of the ILI 
• 
To describe in each vaccine group the use of antibiotics and antivirals that are 
associated with any ILI, within 30 days after the onset of the ILI 
• 
To describe in each vaccine group hospitalizations that are associated with cases 
of laboratory-confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group hospitalizations that are associated with any 
ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group emergency room visits that are associated 
with cases of laboratory-confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group emergency room visits that are associated 
with any ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group non-routine medical office visits (including 
urgent care visits) that are associated with cases of laboratory-confirmed ILI, 
within 30 days after onset of the ILI  
• 
To describe in each vaccine group non-routine medical office visits (including 
urgent care visits) that are associated with any ILI, within 30 days after onset of 
the ILI  
• 
To describe in each vaccine group medication use that is associated with cases of 
laboratory-confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group medication use that is associated with any ILI, 
within 30 days after onset of the ILI  
• 
To describe in each vaccine group absenteeism (Parent(s) / guardian's 
absenteeism due to child sick days) that is associated with cases of laboratory-
confirmed ILI, within 30 days after onset of the ILI 
• 
To describe in each vaccine group absenteeism (Parent(s) / guardian's 
absenteeism due to child sick days) that is associated with any ILI, within 30 
days after onset of the ILI 
Correlates of Protection Objective 
To assess the association of HAI titers to the 4 vaccine strains with the occurrence of 
laboratory-confirmed ILI of any influenza A or B type, or of viral strains similar to 
those contained in the vaccine.  
Antibody persistence 
To describe the persistence of immune response 1 year after vaccination among 
subjects from Season 1 (NH) who are re-enrolled for Season 3 (NH) according to the 
vaccine received in Season 1 (NH) 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 22 of 134 
Observational 
Endpoints: 
Efficacy 
• 
Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as 
positive for each circulating influenza A subtype and B lineage: A/H1N1, 
A/H3N2, B/Victoria and B/Yamagata 
• 
Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-
confirmed as positive in each age subgroup of subjects 
• 
Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-
confirmed as positive in each season 
• 
Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-
confirmed as positive in subjects previously unvaccinated 
• 
Occurrence of an ILI starting ≥ 14 days after first vaccination and before second 
injection, laboratory-confirmed as positive in subjects previously unvaccinated 
• 
Occurrence of an ILI starting within 14-90 days after first vaccination, laboratory-
confirmed as positive  
• 
Occurrence of a modified CDC-defined ILI starting ≥ 14 days after first 
vaccination, and laboratory-confirmed as positive 
• 
For subjects enrolled in both Season 1 (NH) and Season 3 (NH), occurrence of an 
ILI starting ≥ 14 days after first vaccination in Season 3 (NH), laboratory-
confirmed as positive according to the vaccination pattern 
Influenza-associated Events/ Health care utilization 
The following events that are associated with ILI and occurring within 30 days after 
the ILI onset will be described for cases of laboratory-confirmed ILI caused by any 
viral type/subtype and for any ILI, respectively: 
• 
Occurrence of AOM based on clinical diagnosis  
• 
Occurrence of ALRI (eg, pneumonia, lower respiratory tract infection, 
bronchiolitis, bronchitis, and croup) based on clinical and/or x-ray diagnosis 
• 
Occurrence, duration, and intensity of ILI symptoms  
• 
Occurrence of medication use (eg, antibiotics, antivirals)  
• 
Occurrence of hospitalizations  
• 
Occurrence of emergency room visits  
• 
Occurrence of non-routine medical office visits (including urgent care visits)  
• 
Occurrence of absenteeism  
 
Immunogenicity for correlate of protection 
• 
HAI titer for each vaccine strain 28 days after the last vaccination, together with 
occurrence of an ILI starting ≥ 14 days after vaccination, confirmed as positive 
for any influenza A or B type 
• 
HAI titer for each vaccine strain 28 days after the last vaccination, together with 
occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed 
for viral strains similar to those contained in the vaccine 
Antibody persistence 
For the approximately 
 subjects who are re-enrolled in  Season 3 (NH) and were 
part of the Immunogenicity Subset in Season 1 (NH), the HAI Ab titers against the 4 
vaccine strains used in Season 1 (NH) will be measured at D0 before starting 
vaccination in Season 3 (NH). The following endpoints will be described. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 23 of 134 
• 
HAI individual titer on D0 and 28 days after the last vaccination of Season 1 
(NH) and on D0 of Season 3 (NH)  
• 
Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after 
the last vaccination of Season 1 (NH) and on D0 of Season 3 (NH) 
• 
Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination of 
Season 1 (NH) and on D0 of Season 3 (NH) 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 24 of 134 
Planned Sample Size: 
A total of approximately 13,320 subjects will be enrolled: 100 subjects will be 
enrolled in the open-label Sentinel Safety Cohort during the 2020-2021 NH influenza 
season and 13,220 subjects in the main cohort will be enrolled over 3 influenza 
seasons with a randomization ratio of 1:1 for QIV-HD to QIV-SD. 
 Season 1 
subjects will also be re-vaccinated in Season 3.  
Vaccine 
Number of Subjects 
QIV-HD for open-label, 
Sentinel Safety Cohort 
100 
 
Vaccine 
Season 1 (NH) 
Randomized 
Immunogenicity 
Subset  
Expanded 
safety analysis 
 
QIV-HD 
QIV-SD 
Total 
  
  
  
  
Vaccine 
Season 2 (SH) 
Randomized 
Immunogenicity 
Subset   
Expanded 
safety analysis 
) 
QIV-HD 
QIV-SD 
Total 
  
  
  
  
Vaccine 
Season 3 (NH) 
Randomized 
Immunogenicity 
Subset  
Expanded 
safety analysis 
) 
QIV-HD 
QIV-SD 
Total 
Vaccine 
Season 3 (NH) Re-vaccination Cohort† 
QIV-HD 
QIV-SD 
Total 
Overall Total 
13,320 subjects with
 tested for immunogenicity*,
 
for expanded safety, and 100 safety cohort subjects 
Abbreviations: NH, Northern Hemisphere; QIV-HD, high-dose quadrivalent influenza 
vaccine; QIV-SD, standard-dose quadrivalent influenza vaccine; SH, Southern Hemisphere 
* Number of subjects who provide blood samples in Season 1 (NH) is greater than in Season 
2 (SH) or Season 3 (NH) because unlike the Season 2 and 3 sera, which will be used for the 
descriptive immunogenicity results and correlate of protection exploratory endpoint only, 
Season 1 (NH) sera will also be used to demonstrate immunogenicity superiority.  
†Approximately
 subjects from the Immunogenicity Subset of Season 1 (NH) will re-
enroll in Season 3 (NH) to be evaluated for antibody persistence and re-vaccination 
immunogenicity endpoints. These subjects will not be part of the approximately
 
subjects in Season 3 who are being followed for ILI surveillance and efficacy. 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 25 of 134 
Samples sizes for evaluation based on assessment method are as follows:  
Assessment Method 
Number of Subjects 
hemagglutination inhibition 
(HAI) 
approximately
 subjects (all subjects in the 
Immunogenicity Subset) 
seroneutralization (SN) 
approximately
 subjects in Season 1’s 
Immunogenicity Subset 
enzyme-linked lectin assay 
(ELLA) 
Approximately
 subjects in Season 1’s 
Immunogenicity Subset 
 
However, due to the unpredictable epidemiology of influenza, the sample size and/or 
the duration of the study may be adjusted based on the blinded number of influenza 
cases in order to maintain the likelihood of achieving the expected number of 
influenza cases for the primary endpoint. 
Following the end of the Season 2 (2023 SH) influenza season, if the likelihood of 
achieving the expected 
cases at the end of the Season 3 is too low, and if at least 
 influenza cases meeting the primary endpoint have occurred, an interim analysis 
is planned to be conducted by an independent statistician and reviewed by an IDMC 
during Season 3. The study may stop after the third season if the primary objective 
and first secondary objective is demonstrated, if there is a high probability to 
demonstrate these objectives at the end of the ongoing season, or for futility if the 
probability to demonstrate the primary objective at the end of the study is too low.   
Duration of 
Participation in the 
Study: 
The duration of each subject’s participation in the respective study year will be 6 to 7 
months, depending on the time of enrollment and previous vaccination status. 
Investigational 
Product: 
Quadrivalent Influenza Vaccine (split virion, inactivated) High-Dose (QIV-HD), 
manufactured by Sanofi Pasteur.   
 Form: 
Suspension for injection in pre-filled syringe 
 Composition: 
Each 0.7 mL dose of QIV-HD will contain:  
Strains are based on WHO recommendations for the considered season. 
Active Substances: 
• 
A/(H1N1)-like strain  
 
60 µg HA 
• 
A/(H3N2)-like strain  
 
60 µg HA 
• 
B/(Victoria lineage)-like strain 
60 µg HA 
• 
B/(Yamagata lineage)-like strain 
60 µg HA 
Excipients: 
Buffered saline solution  
 
qs to appropriate volume 
Octylphenol Ethoxylate (Triton X-100)  
 not more than 350 µg 
Preservative is not used in the manufacture of QIV-HD. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Numbers: 
To be determined 
Control Product: 
Fluarix® Quadrivalent (or other commercial names), Influenza vaccine (split 
virion, inactivated) (QIV-SD) (GlaxoSmithKline Biologicals) 
 Form: 
Suspension for injection, in pre-filled syringe 
 Composition: 
Each 0.5 mL dose of QIV-SD will contain: 
Strains are based on WHO recommendations for the considered season. 
Active Substances: 
• 
A/(H1N1)-like strain  
 
15 µg HA 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 26 of 134 
• 
A/(H3N2)-like strain  
 
15 µg HA 
• 
B/(Victoria lineage)-like strain 
15 µg HA 
• 
B/(Yamagata lineage)-like strain 
15 µg HA 
Excipients: 
Buffered saline solution  
 
qs to appropriate volume  
Octylphenol-10 (Triton X-100)  
 
≤ 0.115 mg 
α-Tocopheryl hydrogen succinate   
≤ 0.135 mg 
Polysorbate 80 (Tween 80)  
 
≤ 0.550 mg  
Fluarix® Quadrivalent vaccine does not contain a preservative. 
 Route: 
IM injection into the anterolateral muscle of the thigh or the deltoid muscle of the 
upper arm, as appropriate 
 Batch Numbers: 
Commercial batches 
Inclusion Criteria: 
An individual must fulfill all of the following criteria to be eligible for study 
enrollment: 
1) Aged 6 to 35 months on the day of the first study visit* 
2) Informed consent form has been signed and dated by the parent(s) or guardian(s) 
and by an independent witness, if required by local regulations. 
3) Subject and parent / guardian are able to attend all scheduled visits and to comply 
with all study procedures. 
4) Covered by health insurance if required by local regulations 
5) For Season 3 Re-vaccination Cohort: eligible subjects must have been enrolled in 
the Season 1 (2022-2023 NH season) immunogenicity subset and must have 
completed all study procedures (ie, blood draws and vaccinations) in Season 1. 
*Note: “6 to 35 months” means from the 6th month after birth to the day before the 
36th month after birth. 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from study 
enrollment: 
1) Participation at the time of study enrollment (or in the 4 weeks preceding the first 
study vaccination) or planned participation during the present study period in 
another clinical study investigating a vaccine, drug, medical device, or medical 
procedure. 
2) For all subjects: Receipt of any vaccine in the 30 days preceding the first study 
vaccination. For subjects in immunogenicity subset: Planned receipt of any 
vaccine before Visit 2 for subjects receiving 1 dose of influenza vaccine or Visit 3 
for subjects receiving 2 doses of influenza vaccine. 
3) Previous vaccination against influenza in the preceding 6 months prior to study 
vaccination with either the study vaccine or another influenza vaccine  
4) Receipt of immune globulins, blood or blood-derived products in the 3 months 
preceding the study vaccination. 
5) 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). 
6) Known systemic hypersensitivity to any of the vaccine components, or history of 
a life-threatening reaction to the vaccines used in the study or to a vaccine 
containing any of the same substances. Exception: subjects with an egg allergy 
are allowed to enroll in the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 27 of 134 
7) Thrombocytopenia, bleeding disorder, or receipt of anticoagulants that based on 
Investigator’s judgment contraindicate intramuscular vaccination. 
8) Chronic illness that, in the opinion of the Investigator, is at a stage where it might 
interfere with study conduct or completion. 
9) Moderate or severe acute illness/infection (according to investigator judgment) on 
the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A 
prospective subject should not be included in the study until the condition has 
resolved or the febrile event has subsided. 
Note: Subjects who test positive for COVID-19 infection or have been in close 
contact with individuals who have tested positive for COVID-19 within 14 days 
preceding the first study vaccination will also be excluded from participating in 
the study until they test negative for COVID-19. 
10) Identified as natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study. 
11) Personal or family history of GBS. 
12) Any condition that in the opinion of the Investigator would pose a health risk to 
the subject if enrolled or could interfere with the evaluation of the vaccine. 
13) Personal history of clinically significant development delay (at the discretion of 
the Investigator), neurologic disorder, or seizure disorder. 
14) For Season 3 (2023-2024 NH) main cohort: subjects who were enrolled in a 
previous study season are excluded from Season 3, with the exception of the Re-
vaccination Cohort.  
Statistical Methods: 
Following the end of the Season 2 (2023 SH), an interim analysis may be conducted 
by an independent statistician and reviewed by an IDMC during Season 3 in an 
attempt to stop the study at the end of the Season 3 and avoid study extension in case 
the planned
 cases cannot be achieved in 3 seasons. Therefore, the interim analysis 
will only be conducted if the likelihood of achieving the expected
 cases at the end 
of Season 3 is low (avoiding to conduct the interim analysis if the expected 
 cases 
will be achieved) and if at least 
 evaluable influenza cases are collected (to ensure 
enough power to assess the objectives). At the interim analysis, the primary objective 
and first secondary objective will be assessed and the predictive power to demonstrate 
these objectives at the end of the ongoing season and at the end of the study will be 
calculated. The IDMC may recommend stopping the study at the end of Season 3 if 
the primary objective and first secondary objective are demonstrated, if there is a high 
probability to demonstrate these objectives at the end of Season 3, or for futility if the 
probability to demonstrate the primary objective at the end of the study is too low. In 
addition, at the time of the interim analysis, other efficacy and safety objectives may 
be assessed on the available data for information. 
The full analysis of all study objectives will be performed at the end of the study. In 
case the study is to be stopped prematurely following the results of an interim 
analysis, the full statistical report may be delivered in more than one step if deemed 
necessary. 
Primary Objective Analyses 
Efficacy 
The vaccine efficacy of the 2 groups will be compared in a step-wise manner:  
A non-inferiority testing approach will be used first, using a non-inferiority margin of 
-10%. If non-inferiority is demonstrated, a superiority test will be used using a margin 
of 5%. Both tests will use a one-sided Type I error at 2.5%, and there is no need for 
multiplicity adjustment due to the step-wise approach. 
The rVE of QIV-HD to QIV-SD will be estimated for primary endpoint as follows: 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 28 of 134 
rVE= (1- (CHD / NHD) / (CSD / NSD)) × 100% 
where: 
• 
CHD and CSD are the numbers of influenza cases meeting the considered primary 
endpoint definition in the QIV-HD and QIV-SD groups, respectively.  
• 
For analysis in per-protocol analysis set, the first episode among those occurring 
more than 14 days after the last vaccination will be considered. For analysis in 
full analysis set, the first episode among those occurring more than 14 days after 
the first vaccination will be considered. 
• 
If subject experiences multiple occurrences of the same endpoint, only the first 
episode will be considered  
• 
NHD and NSD are the numbers of subjects in the QIV-HD and QIV-SD groups, 
respectively.  
CIs for vaccine efficacy will be calculated by an exact method assuming a Binomial 
distribution of the number of cases in the vaccine group conditional on the total 
number of cases in both groups. 
The vaccine efficacy of QIV-HD will be considered as non-inferior to QIV-SD if the 
lower bound of the rVE is > -10%, and superior to QIV-SD if the lower bound of the 
CI for the rVE is > 5%. The Per-Protocol Analysis Set for Efficacy will be used as the 
primary analysis set for the non-inferiority test and the Full Analysis Set for Efficacy 
will be used as the primary analysis set for the superiority test. 
If the interim analysis is conducted, an alpha spending method quoted by Lan and 
Demets (power family, phi=2) will be used to maintain an overall Type I error (the 
‘alpha’) of 0.025 one-sided, considering that
 of information time is reached at the 
time. Consequently, a one-sided nominal alpha of
 and
 will be used at 
interim and final analysis, respectively. This corresponds to
 and 
 two-
sided CIs to be used at interim and final analysis, respectively. 
Should the interim analysis results fulfill the stopping rules, the study will be stopped 
at the end of  Season 3. In the final analysis, the rVE will be estimated using a two-
sided 95% CI if the stopping rule for superior efficacy is fulfilled at the interim 
analysis or a 
 CI will be used if otherwise. 
Secondary Objectives Analyses 
If the primary objective is demonstrated, the secondary confirmatory objectives will 
be tested. A hierarchical testing combined with graphical approach will be used to 
adjust the multiplicity of the 4 secondary confirmatory objectives, which prevents any 
inflation of the overall one-sided Type I error beyond 2.5%. 
Efficacy 
For the first secondary objective, a superiority test will be performed using a more 
stringent margin of 
 with the same nominal alpha levels being used in the interim 
analysis (ie, one-sided
) and in the final analysis (ie, one-sided
 if the 
stopping rule for superior efficacy is not fulfilled at the interim analysis or one-sided 
0.025 if otherwise) for the primary objective.  
At the time of the final analysis, if superiority is demonstrated, a graphical approach 
will be applied to control alpha within the 2 efficacy objectives. If one of them is 
claimed for efficacy using a two-sided 97.5% CI, then the other one will be tested 
using a two-sided 95% CI to assess the superiority. 
Estimation of relative efficacy for efficacy objectives will be the same as those 
described for the primary objective above except that QIV-HD will be considered as 
superior to QIV-SD if the lower bound of the CI for the corresponding rVE is > 0%. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 29 of 134 
Immunogenicity 
If all of the above efficacy objectives are demonstrated, a superiority testing approach 
will be used to compare post-vaccination geometric mean titers (GMTs) and 
seroconversion rates between QIV-HD and QIV-SD groups for each strain using a 
one-sided test with Type I error rate of 0.025 following the individual hypotheses: 
 
 
 
 
where  
s: strain  
If superiority is demonstrated for post-vaccination GMTs and seroconversion rates for 
the 4 strains, the immunogenicity of QIV-HD will be considered as superior to QIV-
SD. 
Immunogenicity endpoints will be summarized for each vaccine strain with 95% CIs. 
The 95% CIs for the GMTs and GMT ratios (GMTRs) will be calculated using normal 
approximation of log-transformed titers. The 95% CIs for the proportions will be 
based on the Clopper-Pearson method. The ratios of GMTs will be obtained between 
groups with the 95% CIs calculated using normal approximation of log-transformed 
titers. The differences in the seroconversion rates between groups will be computed 
along with the two-sided 95% CIs by the Wilson-Score method without continuity 
correction. Additional parameters may be displayed as appropriate. 
Reverse cumulative distribution curves against each strain will be performed for 
baseline (V01) and post-vaccination immunogenicity (D28 or D56 as appropriate). 
Safety 
Safety results will be described for each vaccine group. The main parameters will be 
described with 95% CI. 
Observational Objectives Analyses 
Estimation of efficacy for the observational objectives will be as described for the 
primary objective above; for each estimate of efficacy, a 95% CI will be calculated. 
Descriptive analysis and statistical models will be used to
. As this analysis is exploratory,
 These methods will be detailed in the statistical analysis plan (SAP). 
SN and anti-NA immunogenicity results will be described for each vaccine group. The 
main parameters will be described with 95% CI. 
Calculation of Sample Size 
For efficacy assessments: 
The sample size needed for the assessment of the primary objective of the study is 
expected to be approximately
 subjects and may be adjusted based on the 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 30 of 134 
blinded number of cases in order to maintain the likelihood of achieving 
approximately
 evaluable influenza cases meeting the primary endpoint.  
These required number of evaluable influenza cases would provide at least
 power 
at final analysis to conclude on the primary objective under the following 
assumptions: 
• 
The true rVE of QIV-HD to QIV-SD is 
  
• 
An overall one-sided Type I error rate 0.025 
spent at 
interim and final analysis, respectively) 
• 
The lower bound of the CI of rVE should be > 5%  
• 
An allocation ratio of QIV-HD to QIV-SD of 1:1 
• 
An overall influenza attack rate of 
 for the occurrence of an influenza case in 
the QIV-SD group 
• 
 of enrolled subjects evaluable for the primary endpoint  
Based on the same assumptions and using a 
 threshold, the power for the first 
secondary objective at final analysis is expected at 
 approximately. 
For the assessment of the two remaining secondary confirmatory efficacy objectives, 
the assumptions will be similar to those for primary objective except 
• 
The lower bound of the CI for the corresponding rVE will be superior to 0%. 
• 
the true rVE of QIV-HD to QIV-SD is
 for each subset (ie, subjects 6 
through 35 months of age against similar strains and subjects 6 through 23 
months against any strains) 
• 
 evaluable influenza cases (
 of total cases) from each subset 
For each objective, a
 power will be achieved with a two-sided 97.5% CI and an 
 power will be achieved with a two-sided 95% CI. 
For the immunogenicity assessments: 
Approximately
 subjects will be assessed for HAI immunogenicity in Season 1. 
Based on Phase II immunogenicity results and assuming
 of non-evaluable 
subjects, this provides approximately 
 probability to obtain 95% CIs of ratios of 
GMTs and differences in seroconversion rates excluding equality for a given season 
(formulation).  
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 31 of 134 
Table of Study Procedures 1 - Previously vaccinated subjects in the 
Sentinel Safety Cohort  
Phase III Study, 2 Visits, 2 Telephone Calls, 1 Vaccination, approximately 180 Days’ Duration 
per Subject 
Visit/Contact 
V01 
Telephone Call 
01 
V02 
TC02 
Study timelines (days) 
D0 
D8 
D28 
180 days after 
V01 
Time windows (days) 
 
+2 
+7 
+14 
Informed consent form signed and dated 
X 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
Physical examination* 
X 
 
X 
 
Collection of demographic data 
X 
 
 
 
Medical history† 
X 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
Collection of concomitant medications 
At any time during the study period 
IRT Contact allocation of subject number 
and unique dose number‡ 
X 
 
 
 
Vaccination 
X 
 
 
 
Immediate surveillance (30 min) 
X 
 
 
 
DC provided§ 
X 
 
 
 
DC reviewed and collected 
 
 
X 
 
Reporting of solicited injection site and 
systemic reactions (for 7 days after 
vaccination) 
X 
 
 
Collection of unsolicited adverse events (for 
28 days after vaccination) 
X 
 
MA provided** 
 
 
X 
 
Study active phase termination record 
 
 
X 
 
Follow-up telephone call 
 
X†† 
 
X‡‡ 
Reporting of SAEs (including AESIs)§§ 
To be reported at any time during the study 
Abbreviations: AESI, adverse event of special interest; D, day; DC, diary card; MA, memory aid; SAE, serious adverse event; 
TC, telephone call; V, visit.  
* Targeted physical examination based on medical history will be performed at V01. Targeted physical examination may also be 
performed at V02, if necessary. 
† With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ Before vaccine injection. 
§ Subject’s parents / guardians will use the diary card to record information about solicited reactions, unsolicited AEs, SAEs, and 
AESIs from D0 to D7 after vaccination and will continue to record information about unsolicited AEs, SAEs, and 
AESIs from D8 to V02 
** Subject’s parents / guardians will use this MA to collect information on medications, SAEs, and AESIs from V02 to the end 
of the 6-month safety follow-up period.  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 32 of 134 
†† During this telephone call, staff will record relevant information concerning the subject’s health status, will find out whether 
the subject experienced any SAEs and AESIs not yet reported, and will remind the subjects’ parent / guardian to 
bring the completed diary card to the next visit. 
‡‡ During this telephone call, staff will review the MA to record medications and identify the occurrence of any SAEs and 
AESIs that have not yet been reported. 
§§ AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse 
myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
Note: Study procedures for the Sentinel Safety Cohort were completed prior to Amendment 2 of this protocol. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 33 of 134 
Table of Study Procedures 2 - Previously unvaccinated subjects in the 
Sentinel Safety Cohort  
Phase III Study, 3 Visits, 3 Telephone Calls, 2 Vaccinations, approximately 208 Days’ Duration 
per Subject 
Visit/Contact 
V01 
Telephone 
Call 01 
V02 
TC02 
V03 
 TC03 
Study timelines (days) 
D0 
D8 
D28 
8 days 
after 
V02 
28 days 
after 
V02 
180 days after 
V02 
Time windows (days) 
 
+2 
+7 
+2 
+7 
+14 
Informed consent form signed and dated 
X 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
Physical examination* 
X 
 
X 
 
X 
 
Collection of demographic data 
X 
 
 
 
 
 
Medical history† 
X 
 
 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
 
 
Collection of concomitant medications 
At any time during the study period 
IRT Contact -allocation of subject number 
and unique dose number‡ 
X 
 
 
 
 
 
Allocation of unique dose number  
 
 
X 
 
 
 
Temporary and definitive contraindications 
 
 
X 
 
 
 
Vaccination 
X 
 
X 
 
 
 
Immediate surveillance (30 min) 
X 
 
X 
 
 
 
DC provided§ 
DC1 
 
DC2 
 
 
 
DC reviewed and collected 
 
 
DC1 
 
DC2 
 
Recording of solicited injection site and 
systemic reactions (for 7 days after 
vaccination) 
X 
X 
 
 
Collection of unsolicited adverse events (for 
28 days after vaccination) 
X 
X 
 
MA provided** 
 
 
 
 
X 
 
Study active phase termination record 
 
 
 
 
X 
 
Follow-up telephone call 
 
X†† 
 
X†† 
 
X‡‡ 
Reporting of serious adverse events (SAEs) 
(including AESIs) §§ 
To be reported at any time during the study 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 34 of 134 
Abbreviations: AESI, adverse event of special interest; BL, blood sampling; D, day; DC, diary card; SAE, serious adverse event; 
TC, telephone call; V, visit.  
* Targeted physical examination based on medical history will be performed at V01. Targeted physical examination may also be 
performed at V02 and V03, if necessary. 
† With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ Before vaccine injection 
§ Subject’s parents / guardians will use the diary cards to record information about solicited reactions, unsolicited AEs, SAEs, 
and AESIs after each vaccination (from V01 to TC01 and from V02 to TC02) and will continue to record 
information about unsolicited AEs, SAEs, and AESIs from TC01 to V02 and D36 to V03. 
**Subject’s parents / guardians will use this MA to collect information on medications, SAEs, and AESIs from V03 to the end of 
the 6-month safety follow-up period. 
†† During this telephone call, staff will record relevant information concerning the subject’s health status, will find out whether 
the subject experienced any SAEs and AESIs not yet reported, and will remind the subjects’ parent / guardian to 
bring the completed diary card to the next visit. 
‡‡ During this telephone call, staff will review the MA to record medications and identify the occurrence of any SAEs and 
AESIs that have not yet been reported. 
§§ AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse 
myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
Note: Study procedures for the Sentinel Safety Cohort were completed prior to Amendment 2 of this protocol. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 35 of 134 
Table of Study Procedures 3 (previously influenza vaccinated subjects 
6 months through 35 months of age)  
Phase III Study, 1 Visit, 1 Telephone Call, 1 Vaccination, approximately 6 Months Duration per 
Subject per Study Year 
Visit/Contact 
V01 
Follow-up Telephone Call 
Study timelines (days) 
D0 
D180 + 14 after V01 or end of 
influenza season if later than D180 
Time windows (days) 
 
+14 
Informed consent form signed and dated 
X 
 
Inclusion / exclusion criteria 
X 
 
Physical examination* 
X 
 
Collection of demographic data 
X 
 
Medical history† 
X 
 
History of seasonal influenza vaccination 
X 
 
Collection of concomitant medications 
At any time during the study period 
Contact IRT system for randomization, 
subject number, and unique dose number 
allocation ‡ 
X 
 
Vaccination 
X 
 
Immediate surveillance (30 min) 
X 
 
Provision of Memory Aid§ 
X 
 
Review of Memory Aid 
 
X 
Study active phase termination record 
 
X 
Reporting of SAEs (including AESIs) ** 
To be reported at any time during the study 
Collection of ILI symptoms through 
passive and active surveillance  
Passive Surveillance: All subjects’ parents/guardians will be 
instructed to contact the study site if the subject experiences 
symptoms of ILI from D0 post-vaccination until 30 April of the 
following year for NH seasons subjects or until 31 October of the same 
year for SH subjects. 
Active Surveillance:  
For NH seasons subjects, during a period from D0 post-vaccination 
until approximately 30 April of the following year, subjects’ 
parents/guardians will be contacted once a week. 
For SH seasons subjects, during a period from D0 post-vaccination 
until approximately 31 October of the same year, subjects’ 
parents/guardians will be contacted once a week. 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza†† 
From D0 post-vaccination 1 until 30 April of the following year for 
NH subjects or until 31 October of the same year for SH subjects. 
Every effort has to be made to obtain the NP specimen on the same 
or the following day after confirmation of qualifying ILI symptoms 
and no later than 7 days after onset of the ILI (start date = start date 
of fever) (ie, sample is to be collected through D6 of the illness, 
considering that D0 was the day of ILI onset). 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 36 of 134 
Collection of ALRI, AOM, absenteeism, 
and health care information ‡‡ 
At any time during the study season (for NH subjects through 
30 April and for SH subjects through 31 October) in association with 
an ILI, and for 30 days (+ 7 days) following the start of ILI regardless 
of whether or not an NP swab is obtained. 
Abbreviations: AESI, adverse event of special interest; ALRI, acute lower respiratory infection; AOM, acute otitis media; D, 
day; DC, diary card; ILI, influenza-like illness; IRT, Interactive Response Technology; MA, memory aid; NP, 
nasopharyngeal; SAE, serious adverse event; TC, telephone call; V, visit.  
* Targeted physical examination will be performed at V01.  
†With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ Before vaccine injection 
§Subject’s parents / guardians will use this MA to collect information on medications, SAEs, AESIs, and ILI from V01 through 
approximately 6 to 7 months after vaccination in each season.  
** AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse 
myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
††Collected from any subject who is identified as having a protocol-defined ILI from D0 of vaccination 1 and later (start date 
after D0).  
‡‡Occurrences of any of the following in association with any protocol-defined ILI on or after D0 will be followed up for 30 
days after the illness start date: ALRI (eg, pneumonia), AOM, hospitalizations, emergency room visits, and non-
routine medical office visits (including urgent care visits), as well as the diagnoses associated with those instances. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 37 of 134 
Table of Study Procedures 4 (previously influenza unvaccinated subjects 
6 months through 35 months of age)  
Phase III Study, 2 Visits, 1 Telephone Call, 2 Vaccinations, approximately 7 months’ Duration 
per Subject per Study Year 
Visit/Contact 
V01 
V02 
Follow-up Telephone 
Call 
Study timelines (days) 
D0 
D28 
D208 (180+14 days 
after V02) or the end 
of influenza season if 
later than D208 
Time windows (days) 
 
+7 
+14 
Informed consent form signed and dated 
X 
 
 
Inclusion / exclusion criteria 
X 
 
 
Physical examination* 
X 
X 
 
Collection of demographic data 
X 
 
 
Medical history† 
X 
 
 
History of seasonal influenza vaccination 
X 
 
 
Collection of concomitant medications 
At any time during the study period 
Contact IRT system for randomization, 
subject number, and unique dose number 
allocation‡ 
X 
 
 
Temporary and definitive 
contraindications 
 
X 
 
IRT Contact for allocation of unique dose 
number  
 
X 
 
Vaccination 
X 
X 
 
Immediate surveillance (30 min) 
X 
X 
 
Provision of Memory Aid§ 
X 
 
 
Review of Memory Aid 
 
X 
X 
Study active phase termination record 
 
 
X 
Reporting of SAEs (including AESIs)** 
To be reported at any time during the study 
Collection of ILI symptoms through 
passive and active surveillance  
Passive Surveillance: All subjects’ parents/guardians will be instructed 
to contact the study site if the subject experiences symptoms of ILI 
from D0 post-vaccination until 30 April of the following year for NH 
seasons subjects or until 31 October of the same year for SH subjects. 
Active Surveillance:  
For NH seasons subjects, during a period from D0 post-vaccination 
until approximately 30 April, subjects’ parents/guardians will be 
contacted once a week. 
For SH seasons subjects, during a period from D0 post-vaccination 
until approximately 31 October, subjects’ parents/guardians will be 
contacted once a week. 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 38 of 134 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza†† 
From D0 post-vaccination 1 until 30 April of the following year for NH 
subjects and until 31 October of the same year for SH subjects. Every 
effort has to be made to obtain the NP specimen on the same or 
following day after confirmation of qualifying ILI symptoms and no 
later than 7 days after onset of the ILI (start date = start date of fever) 
(ie, sample is to be collected through D6 of the illness, considering that 
D0 was the day of ILI onset). 
Collection of ALRI, AOM, absenteeism, 
and health care information‡‡ 
At any time during the study season (for NH subjects through 30 April 
and for SH subjects through 31 October) in association with an ILI, and 
for 30 days (+ 7 d) following the start of ILI regardless of whether or 
not an NP swab is obtained. 
Abbreviations: AESI, adverse event of special interest; ALRI, acute lower respiratory infection; AOM, acute otitis media; D, 
day; DC, diary card; ILI, influenza-like illness; IRT, Interactive Response Technology; MA, memory aid; NP, 
nasopharyngeal; SAE, serious adverse event; TC, telephone call; V, visit.  
* Targeted physical examination will be performed at V01. Targeted physical examination may also be performed at V02, as 
necessary. 
†With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ IRT will also be used to randomly select subjects to participate in the immunogenicity subset 
§ Subject’s parents / guardians will use this MA to collect information on medications, ILI, SAEs and AESIs from V01 through 
approximately 6 to 7 months after vaccination in each season.  
** AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse 
myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
†† Collected from any subject who is identified as having a protocol-defined ILI from D0 of vaccination 1 and later (start date 
after D0). 
‡‡ Occurrences of any of the following in association with any protocol-defined ILI on or after Day 0 will be followed up for 
30 days after the illness start date: ALRI (eg, pneumonia), AOM, hospitalizations, emergency room visits, and non-
routine medical office visits (including urgent care visits), as well as the diagnoses associated with those instances. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 39 of 134 
Table of Study Procedures 5 (previously influenza vaccinated subjects in 
the Expanded safety analysis set [ESafAS] with or without inclusion in 
the Immunogenicity Subset)  
Phase III Study, 2 Visits, 1 Telephone Calls, 1 Vaccination, 2 blood samples, approximately 
7 months’ Duration per Subject per Study Year 
Visit/Contact 
V01 
V02 
Follow-up Telephone Call 
Study timelines (days) 
D0 
D28 
D180 (180 +14 after V01) or 
the end of influenza season 
if later than D180 
Time windows (days) 
 
+7 
+14 
Informed consent form signed and 
dated 
X 
 
 
Inclusion / exclusion criteria 
X 
 
 
Physical examination* 
X 
X 
 
Collection of demographic data 
X 
 
 
Medical history† 
X 
 
 
History of seasonal influenza 
vaccination 
X 
 
 
Collection of concomitant medications 
At any time during the study period 
Contact IRT system for randomization, 
subject number, and unique dose 
number allocation‡ 
X 
 
 
Blood sampling (BL) for 
immunogenicity subset only, 5 mL 
BL0001§ 
BL0002 
 
Vaccination 
X 
 
 
Immediate surveillance (30 min) 
X 
 
 
DC provided** 
X 
 
 
DC reviewed & collected 
 
X 
 
Reporting of solicited injection site and 
systemic reactions (for 7 days after 
vaccination) 
X 
 
 
Collection of unsolicited adverse 
events (for 28 days after vaccination)  
X 
 
Provision of Memory Aid†† 
 
X 
 
Review of Memory Aid 
 
 
X 
Study active phase termination record 
 
 
X 
Reporting of serious adverse events 
(SAEs) (including AESIs) ‡‡ 
To be reported at any time during the study 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 40 of 134 
Collection of ILI symptoms through 
passive and active surveillance§§ 
Passive Surveillance: All subjects’ parents/guardians will be instructed to 
contact the study site if the subject experiences symptoms of ILI from D0 
post-vaccination until 30 April of the following year for NH seasons 
subjects or until 31 October of the same year for SH subjects. 
Active Surveillance:  
For NH seasons subjects, during a period from D0 post-vaccination until 
approximately 30 April, subjects’ parents/guardians will be contacted once 
a week. 
For SH seasons subjects, during a period from D0 post-vaccination until 
approximately 31 October, subjects’ parents/guardians will be contacted 
once a week. 
Excluding the Season 3 Re-vaccination Cohort. 
Collection of nasopharyngeal swabs 
for laboratory confirmation of 
influenza*** 
From D0 post-vaccination until 30 April of the following year for NH 
subjects and until 31 October of the same year for SH subjects. Every 
effort has to be made to obtain the NP specimen on the same or following 
day after confirmation of qualifying ILI symptoms and no later than 7 
days after onset of the ILI (start date = start date of fever) (ie, sample is to 
be collected through D6 of the illness, considering that D0 was the day of 
ILI onset). 
Excluding the Season 3 Re-vaccination Cohort. 
Collection of ALRI, AOM, 
absenteeism, and health care 
information††† 
At any time during the study season (for NH subjects through 30 April and 
for SH subjects through 31 October) in association with an ILI, and for 30 
days (+ 7 d) following the start of ILI regardless of whether or not an NP 
swab is obtained. 
Excluding the Season 3 Re-vaccination Cohort. 
Abbreviations: AESI, adverse event of special interest; ALRI, acute lower respiratory infection; AOM, acute otitis media; BL, 
blood sampling; D, day; DC, diary card; ILI, influenza-like illness; IRT, Interactive Response Technology; MA, 
memory aid; NP, nasopharyngeal; SAE, serious adverse event; V, visit.  
* Targeted physical examination will be performed at V01. Targeted physical examination may also be performed at V02, as 
necessary. 
†With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ Before vaccine injection. IRT will also be used to randomly select subjects to participate in the immunogenicity subset 
§ Blood sampling to occur prior to vaccination. 
** Subjects / parents / guardians will use the diary cards to record information about solicited reactions, unsolicited AEs, SAEs, 
AESIs, ILI symptoms after each vaccination (from D0 to D7) and will continue to record information about 
unsolicited AEs, SAEs, and AESIs from D8 to V02. 
††Subjects / parents / guardians will use this MA to collect information on SAEs, AESIs, and ILI from V02 to the end of the 6-
month safety follow-up period.  
‡‡AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse 
myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
§§ The subset of approximately
subjects from Season 1 (2022-2023 NH) who are in the Immunogenicity Subset and who 
will be re-enrolled and re-randomized in Season 3 will not participate in collection of ILI symptoms through passive 
and active surveillance in Season 3 (NH). 
***Collected from any subject who is identified as having a protocol-defined ILI from D0 of vaccination and later (start date 
after D0). 
 †††Occurrences of any of the following in association with any protocol-defined ILI on or after Day 0 will be followed up for 
30 days after the illness start date: ALRI (eg, pneumonia), AOM, hospitalizations, emergency room visits, and non-
routine medical office visits (including urgent care visits), as well as the diagnoses associated with those instances. 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 41 of 134 
Table of Study Procedures 6 (previously influenza unvaccinated subjects 
the Expanded safety analysis set [ESafAS] with or without  inclusion in 
the Immunogenicity Subset)  
Phase III Study, 3 Visits, 1 Telephone Call, 2 Vaccinations, 2 blood samples, approximately 
7 months’ Duration per Subject per Study Year 
Visit/Contact 
V01 
V02 
V03 
Follow-up 
Telephone 
Call 
Study timelines (days) 
D0 
D28 
28 days after 
V02 
D208 (180 
+14 days after 
V02) or at the 
end of 
influenza 
season if later 
than D208 
Time windows (days) 
 
+7 
+7 
+14 
Informed consent form signed and dated 
X 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
Physical examination* 
X 
X 
 
 
Collection of demographic data 
X 
 
 
 
Medical history† 
X 
 
 
 
History of seasonal influenza vaccination 
X 
 
 
 
Collection of concomitant medications 
At any time during the study period 
Contact IRT system for randomization, 
subject number, and unique dose number 
allocation‡ 
X 
 
 
 
IRT Contact for allocation of unique dose 
number  
 
X 
 
 
Temporary and definitive contraindications 
 
X 
 
 
Blood sampling (BL) for immunogenicity 
subset only, 5 mL 
BL0001§ 
 
BL0002 
 
Vaccination 
X 
X 
 
 
Immediate surveillance (30 min) 
X 
X 
 
 
DC provided** 
DC1 
DC2 
 
 
DC reviewed & collected 
 
DC1 
DC2 
 
Reporting of solicited injection site and 
systemic reactions (for 7 days after 
vaccination) 
X 
X 
 
 
Collection of unsolicited adverse events (for 
28 days after vaccination) 
X 
 
 
Provision of Memory Aid†† 
 
 
X 
 
Review of Memory Aid 
 
 
 
X 
Study active phase termination record 
 
 
 
X 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 42 of 134 
Reporting of serious adverse events (SAEs) 
(including AESIs) ‡‡ 
To be reported at any time during the study 
Collection of ILI symptoms through passive 
and active surveillance§§ 
Passive Surveillance: All subjects’ parents/guardians will be instructed to 
contact the study site if the subject experiences symptoms of ILI from D0 
post-vaccination until 30 April of the following year for NH seasons subjects 
or until 31 October of the same year for SH subjects. 
Active Surveillance:  
For NH seasons subjects, during a period from D0 post-vaccination until 
approximately 30 April, subjects’ parents/guardians will be contacted once 
a week. 
For SH seasons subjects, during a period from D0 post-vaccination until 
approximately 31 October, subjects’ parents/guardians will be contacted 
once a week. 
Excluding the Season 3 Re-vaccination Cohort. 
Collection of nasopharyngeal swabs for 
laboratory confirmation of influenza*** 
From D0 post-vaccination until 30 April of the following year for NH 
subjects and until 31 October of the same year for SH subjects. Every effort 
has to be made to obtain the NP specimen on the same or following day 
after confirmation of qualifying ILI symptoms and no later than 7 days after 
onset of the ILI (start date = start date of fever) (ie, sample is to be collected 
through D6 of the illness, considering that D0 was the day of ILI onset). 
Excluding the Season 3 Re-vaccination Cohort. 
Collection of ALRI, AOM, absenteeism, 
and health care information††† 
At any time during the study season (for NH subjects through 30 April and 
for SH subjects through 31 October) in association with an ILI, and for 30 
days (+ 7 d) following the start of ILI regardless of whether or not an NP 
swab is obtained. 
Excluding the Season 3 Re-vaccination Cohort. 
Abbreviations: AESI, adverse event of special interest; ALRI, acute lower respiratory infection; AOM, acute otitis media; BL, 
blood sampling; D, day; DC, diary card; ILI, influenza-like illness; IRT, Interactive Response Technology; MA, 
memory aid; NP, nasopharyngeal; SAE, serious adverse event; V, visit.  
* Targeted physical examination will be performed at V01. Targeted physical examination may also be performed at V02 and V03, 
as necessary. 
†With the collection of medical history, information on breastfeeding status should be collected from subjects < 2 years old and 
information on gestational age should be collected from all subjects  
‡ IRT will also be used to randomly select subjects to participate in the immunogenicity subset 
§ Blood sampling to occur prior to vaccination. 
** Subjects / parents / guardians will use the diary cards to record information about solicited reactions, unsolicited AEs, SAEs, 
and AESIs after each vaccination (from D0 to D7) and will continue to record information about unsolicited AEs, 
SAEs, and AESIs from D8 to V02 and D36 to V03.  
††Subjects / parents / guardians will use this MA to collect information on SAEs, AESIs, and ILI from V03 to the end of the 6-
month safety follow-up period.   
‡‡AESIs will be captured as SAEs. These include Guillain-Barré syndrome, encephalitis / myelitis (including transverse myelitis), 
Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
§§ The subset of approximately 
subjects from Season 1 (2022-2023 NH) who are in the Immunogenicity Subset and who will 
be re-enrolled and re-randomized in Season 3 will not participate in collection of ILI symptoms through passive and 
active surveillance in Season 3 (NH). 
***Collected from any subject who is identified as having a protocol-defined ILI from D0 of vaccination 1 and later (start date 
after D0). 
†††Occurrences of any of the following in association with any protocol-defined ILI on or after Day 0 will be followed up for 30 
days after the illness start date: ALRI (eg, pneumonia), AOM, hospitalizations, emergency room visits, and non-routine 
medical office visits (including urgent care visits), as well as the diagnoses associated with those instances. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 43 of 134 
Table of Study Procedures 7  
Follow-up of ILI  
Days After protocol-defined ILI Onset 
D0*- D6 
D0 – D6  
D30 (+ 7 d) † 
Contact type 
Telephone Call 
Visit 
Telephone Call 
Verify information on respiratory illnesses, 
and schedule appointment for an NP swab 
within 7 days of illness start date 
X 
 
 
Remind subject to complete Memory Aid 
or Diary Card 
X 
 
 
Collection of NP swab 
 
X 
 
Collection of ALRI, AOM, absenteeism, 
and health care information 
X 
X 
X 
Collection of information on protocol-
defined ILI symptoms ‡ 
X 
X 
X 
* Day 0 (protocol-defined ILI Start Date) refers to the first day of fever.  The end of an ILI episode is considered as the last 
day of fever ≥ 38°C. An interval of 2 days will have to have passed after the end of an ILI episode to be consider 
a new ILI episode. 
† The 7-day window allows provision to complete the telephone call. The data collected are inclusive from Day 0 through 
Day 30 of protocol-defined ILI; information > 30 days from protocol-defined ILI onset does not need to be 
collected. 
‡ During collection of information on protocol-defined ILI symptoms, the presence, or not, of concurrent ILI symptoms (ie, 
cough, wheezing, difficulty breathing, nasal congestion, rhinorrhea, sore throat, pharyngitis, otitis, vomiting, 
diarrhea, chills [shivering], tiredness [fatigue], headache, or myalgia [muscle aches]) 
Note: The subset of approximately 
subjects from Season 1 (2022-2023 NH) who are in the Immunogenicity Subset and 
who will be re-enrolled and re-randomized in Season 3 will not participate in collection of ILI symptoms through 
passive and active surveillance in Season 3 (NH). 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 44 of 134 
List of Abbreviations  
AE 
adverse event 
AESI 
adverse event of special interest 
ALRI 
acute lower respiratory infection 
AOM 
acute otitis media 
AR 
adverse reaction 
CBER 
Center for Biologics Evaluation and research 
CDC 
Centers for Disease Control and Prevention 
CDM 
Clinical Data Management 
COVID-19 
Coronavirus Disease 2019 
CQA 
Clinical Quality Assessment 
CRA 
Clinical Research Associate 
CRB 
(electronic) case report book [all the case report forms for a subject] 
CRF 
(electronic) case report form 
CTA 
clinical trial agreement 
EDC 
electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELLA 
enzyme-linked lectin assay 
EMA 
European Medicines Agency 
ESafAS 
Expanded safety analysis set 
ESDR 
Early safety data review 
FASE 
full analysis set for efficacy 
FASI 
full analysis set for immunogenicity 
FDA 
Food and Drug Administration 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GBS 
Guillain-Barré Syndrome 
GCDSE-V 
Global Clinical Development Strategy Expert – Vaccines 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titer 
GPV 
Global Pharmacovigilance 
GSK 
Glaxo Smith Kline 
HAI 
Hemagglutination inhibition 
IAS 
immunogenicity analysis set 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
ILI 
Influenza-like illness 
IME 
important medical event 
IND 
investigational new drug (application) 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 45 of 134 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LCLS 
last contact, last subject 
LLOQ 
lower limit of quantification 
LLT 
lowest level term 
MA 
Memory aid 
MDCK 
Madin-Darby canine kidney 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
NH 
Northern Hemisphere 
NP 
Nasopharyngeal 
PCR 
Polymerase chain reaction 
PPASE 
per-protocol analysis set for efficacy 
PPASI 
per-protocol analysis set for immunogenicity 
QIV 
Quadrivalent influenza vaccine 
R&D GO SML 
Research and Development Global Operations Sample Management 
and Logistics 
RBC 
Red blood cell 
RMO 
Responsible Medical Officer 
SAE 
serious adverse event 
SafAS 
safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
Standard-dose 
SH 
Southern Hemisphere 
SMT 
Safety management team 
SN 
seroneutralization 
TIV 
Trivalent influenza vaccine 
TMF 
trial master file 
ULOQ 
upper limit of quantitation 
UTM 
universal transport medium 
WHO 
World Health Organization 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 46 of 134 
1 
Introduction  
1.1 
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  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, respectively, per 
100,000 population (8). About half of the cases in children were due to influenza A infections and 
the other half 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 4 recent influenza seasons in the United States of America (US 
2015-2016, 2016-2017, 2017-2018, 2018-2019 seasons), vaccine effectiveness in children 6 
months to 8 years of age was 51%, 57%, 68%, and 48%, respectively (13). Thus, there is further 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 47 of 134 
room for improvement in increasing the vaccine efficacy against influenza in the pediatric 
population. 
Standard-dose (SD) influenza vaccines contain 15 µg hemagglutinin (HA) of each of the 4 virus 
strains recommended by the WHO for use in that hemisphere’s upcoming influenza season, for a 
total of 60 µg of HA antigen per dose. The immune response to an SD influenza vaccine is lower 
in adults 65 years of age and older than in younger healthy adults (14). Thus, Fluzone® High-Dose 
influenza vaccine (high-dose trivalent influenza vaccine [TIV-HD]), containing 60 µg HA of each 
of 3 virus strains (4 times more antigen than standard-dose trivalent influenza vaccine [TIV-SD], 
for a total of 180 µg of HA antigen per dose) was developed by Sanofi Pasteur.  
1.2 
Background of the Investigational Product  
To overcome the problem of B strain selection and further improve protection against the 
2 seasonal influenza B virus strains recommended each influenza season, Sanofi Pasteur has 
developed a QIV-HD containing 1 Victoria lineage B strain and 1 Yamagata lineage B strain in 
addition to the two influenza A strains. QIV-HD is produced using the same drug substance 
process as the licensed TIV-HD; for the drug product, the licensed TIV-HD manufacturing 
process was modified slightly to increase the fill volume in order to include the 2nd influenza B 
strain at the same HA content as the other 3 strains (60 μg HA/strain/dose).   
A Phase III immunogenicity bridging study (QHD00013) was conducted in adults 65 years of age 
and older during the 2017-2018 influenza season and demonstrated the non-inferiority of the 
hemagglutination inhibition (HAI) antibody responses between QIV-HD and TIV-HD (15). 
Furthermore, QHD00013 demonstrated that the addition of a 2nd B strain to TIV-HD did not 
interfere with the immune response to the other vaccine components or adversely affect the safety 
profile of the vaccine; in order to demonstrate the added value of the 2nd B strain in QIV-HD, 
superiority of antibody responses to each B strain in QIV-HD compared with the TIV-HD that 
does not contain the corresponding B strain was also demonstrated. Based on the comparability of 
responses to the TIV and QIV formulations, QIV-HD is expected to be more efficacious than SD 
influenza vaccines in preventing influenza disease in adults 60 years of age and older. 
In November 2019, QIV-HD was licensed in the US for adults 65 years of age and older. QIV-HD 
has since been approved in more than 30 countries. Recently QIV-HD has been approved outside 
the US in adults aged 60 years and older.   
Recognizing a similar need to improve influenza vaccine performance in infants and young 
children, the impact of increasing the antigen dose on immune responses has recently been 
evaluated with SD vaccines. Several studies have examined the safety and immunogenicity of the 
pediatric half-dose (0.25 mL) versus full-dose (0.5 mL) standard dose influenza vaccine (16) (17) 
(18), and an increase in immunogenicity has been observed, while maintaining safety and 
tolerability. Thus, QIV-HD, which contains 4 times as much HA per strain per dose as compared 
to the full-dose (0.5 mL) standard dose influenza vaccine, may demonstrate a further increase in 
immunogenicity which could lead to better protection against influenza and its complications. 
In order to assess the safety and immunogenicity of QIV-HD compared with QIV-SD, a Phase II 
study in children 6 months through 17 years of age (QHD04) was conducted in the US and 
Canada during the 2018-2019 influenza season. Three different dose formulations (30 μg, 45 μg, 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 48 of 134 
and 60 μg of HA/strain/dose) of QIV-HD were evaluated in this dose exploration study to 
determine the appropriate QIV-HD dose in children for Phase III studies. Two comparator 
vaccines were used in the study: a QIV-SD vaccine (GSK’s Fluarix® Quadrivalent) at US sites and 
an adjuvanted trivalent influenza vaccine (Seqirus’ Fluad®) at Canadian sites. The QHD04 study 
results showed that of the 3 dose formulations of QIV-HD studied, when compared to QIV-SD, 
the 60 µg HA/strain/dose QIV-HD formulation generated higher immune responses as assessed by 
HAI geometric mean titer (GMT), seroconversion rates, and seroneutralization (SN) GMT. In all 
4 age groups assessed, the highest GMT ratios were seen in children 6 through 35 months of age 
who received the QIV-HD 60 µg dose formulation versus children who received QIV-SD. No 
safety issues were observed with QIV-HD administered in children 6 months through 17 years of 
age. Slightly higher injection site reactogenicity was seen in the QIV-HD group compared with 
QIV-SD group, but systemic reactogenicity was similar between groups. Similar injection site and 
systemic reactogenicity profiles were seen between the QIV-HD and adjuvanted TIV groups. 
Reactogenicity was also similar between all 3 QIV-HD dose formulations (30 μg, 45 μg, and 60 
μg of HA/strain/dose) evaluated. In children who received 2 doses of QIV-HD 28 days apart, no 
trend towards increased reactogenicity was seen between the 1st and 2nd dose administered.  
Despite the limitations of the sample size, the safety profile of QIV-HD and the higher immune 
responses support a pediatric dose selection of 60 µg HA/strain/dose, the same dose indicated for 
adults 60 years of age and older, as the most appropriate dose to evaluate in a Phase III efficacy 
study in order to provide the highest probability of success in demonstrating superior protection 
against influenza when compared with a licensed standard dose influenza vaccine. 
Thus, the goal of this Phase III study is to demonstrate the safety, superior efficacy, and superior 
immunogenicity of QIV-HD compared with a QIV-SD (Glaxo Smith Kline’s [GSK’s] Fluarix® 
Quadrivalent or other tradenames) in children 6 through 35 months of age. 
1.3 
Potential Benefits and Risks  
1.3.1 Potential Benefits to Subjects  
All subjects enrolled in Study QHD00014 will receive an influenza vaccine which will be either 
the investigational QIV-HD, or the licensed comparator vaccine, QIV-SD. Therefore, they will be 
vaccinated against the influenza viruses recommended by the WHO for the 2020-2021 Northern 
Hemisphere (NH) season if they were in the sentinel cohort, or if in the main cohort, they will be 
vaccinated with the 2022-2023 or 2023-2024 NH influenza seasons or 2023 Southern Hemisphere 
(SH) influenza season depending on which country they are enrolled in. These children may be 
protected against those strains and may be less likely to catch influenza or develop complications 
during the respective influenza seasons. 
1.3.2 Potential Risks to Subjects  
As with any vaccine, QIV-HD may not protect all recipients against the disease it is designed to 
prevent (ie, influenza). See below for other potential risks. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 49 of 134 
Possible Reactions to Blood Draw 
Venipuncture causes transient discomfort and may cause temporary hypotension from a vasovagal 
response (eg, fainting). If pressure is not applied long enough to the venipuncture site, bruising 
due to bleeding beneath the skin may occur. Infection at the site of needle insertion could 
theoretically occur but is exceedingly rare when the standard sterile technique is utilized. 
Possible Reactions to Vaccination 
The most frequent side effect of influenza vaccination is pain or tenderness at the injection site 
that usually resolves within 3 days. Injection site reactions are generally mild. 
Systemic findings such as crying, irritability, or fever (young children); malaise or myalgia (older 
children); and other systemic symptoms can occur following vaccination and most often affect 
persons who have had no prior exposure to the vaccine antigens (eg, young children) (19). 
These reactions usually begin 6 to 12 hours after vaccination and usually resolve within 3 days.  
The following additional adverse events have been spontaneously reported during the 
postmarketing use of TIV-HD in adults, and may occur in people receiving QIV-HD 
Blood and Lymphatic System Disorders: Thrombocytopenia, lymphadenopathy 
Immune System Disorders: Anaphylaxis, other allergic/hypersensitivity reactions (including 
angioedema) 
Eye Disorders: Ocular hyperemia 
Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, 
myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), optic 
neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), paresthesia 
Vascular Disorders: Vasculitis, vasodilatation 
Gastrointestinal Disorders: Vomiting 
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, wheezing, throat tightness, 
oropharyngeal pain, and rhinorrhea 
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome 
General Disorders and Administration Site Conditions: Asthenia, chest pain  
Prior to any vaccination, all known precautions should be taken to prevent hypersensitivity 
reactions. This includes a review of the patient’s prior vaccination history with respect to possible 
hypersensitivity to the vaccine or similar vaccines. 
Epinephrine injection (1:1000) and other appropriate agents used for the control of immediate 
allergic reactions must be available to treat unexpected reactions (eg, anaphylaxis). 
 
As with all injectable vaccines, appropriate medical treatment and supervision should always be 
readily available in case of an anaphylactic event following the administration of the vaccine.  
Cases of demyelinating disorders (eg, incident multiple sclerosis in adults, acute disseminated 
encephalomyelitis, transverse myelitis), have been reported following influenza vaccines, 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 50 of 134 
although the National Academy of Medicine (formerly, Institute of Medicine) concluded that the 
evidence is inadequate to accept or reject a causal relationship (20). 
In a study of the 2010–2011 influenza season, the CDC found that there was a risk of fever-
associated seizure (convulsion) occurring on the day of influenza vaccination and for 1 day after 
vaccination in children 6 months through 4 years of age. The risk was higher among children who 
received concomitant inactivated influenza vaccine and 13-valent pneumococcal conjugate 
vaccine and peaked at approximately age 16 months. The magnitude of the increased risk was less 
than 1 episode per 1000 immunized children. A similar risk was found during the 2011–2012 
season (in which the formulation of the influenza vaccine used was the same as that used during 
the 2010–2011 season); however, an increased risk for febrile seizures following influenza 
vaccination was not observed during the 2012–2013 influenza season. No increased risk was 
found for children older than 4 years of age. After taking into consideration the benefits and risks 
of vaccination, no policy change was recommended for use of inactivated influenza vaccine or 
13-valent pneumococcal conjugate vaccine (21). 
The potential risks listed here are not exhaustive; refer to the US package insert (Fluarix® 
Quadrivalent) or investigator brochure of the marketed vaccines for additional information 
regarding potential risks (22) (23). 
1.4 
Rationale for the Study  
While influenza affects all age groups, infants and young children remain at increased risk for 
influenza because of their maturing immune system, lack of prior exposure to influenza virus, and 
thus limited immunity against influenza viruses. Although standard dose influenza vaccines are 
effective, there is still room for further improvement in the currently licensed influenza vaccines’ 
ability to protect children from influenza and its complications. Therefore, following the 
successful approach taken for adults 60 years of age and older, Sanofi Pasteur is evaluating 
whether an increased antigen dose as contained in the QIV-HD vaccine can provide increased 
efficacy against influenza over the existing standard dose influenza vaccines.  
In the absence of a proven quantitative correlate of protection in the pediatric population for 
influenza vaccines, an efficacy study is recognized as the gold standard to demonstrate vaccine 
benefit (24). Based on the results of the Phase II QHD04 study, the Phase III QHD00014 study is 
designed to evaluate the relative efficacy (for the prevention of laboratory-confirmed influenza 
illness caused by any influenza A or B type), the superior immunogenicity, and the safety of 
QIV-HD 60 µg HA/strain/dose formulation versus a QIV-SD (Fluarix® Quadrivalent vaccine) in 
approximately 13,320 children 6 through 35 months of age. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 51 of 134 
2 
Study Objectives  
2.1 
Primary Objective  
Efficacy 
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months through 35 months 
of age for the prevention of laboratory-confirmed influenza illness caused by any influenza A or B 
type. 
The endpoint for the primary objective is presented in Section 9.2 
2.2 
Secondary Objectives  
Confirmatory Objectives 
• To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months through 35 
months of age for the prevention of laboratory-confirmed influenza illness caused by any 
influenza A or B type using a more stringent threshold 
• To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months through 35 
months of age for the prevention of laboratory-confirmed influenza illness caused by viral 
strains similar to those contained in the vaccine 
• 
To compare the clinical efficacy of QIV-HD to QIV-SD in subjects 6 months through 23 
months of age for the prevention of laboratory-confirmed influenza illness caused by any 
influenza A or B type 
Other Secondary Objectives are for descriptive assessment 
Efficacy 
To assess the relative clinical efficacy of QIV-HD compared to QIV-SD in subjects for the 
prevention of: 
• laboratory-confirmed influenza illness caused by any influenza A or B type according to 
previous influenza vaccination status in prior seasons 
• laboratory-confirmed influenza illness caused by viral strains similar to those contained in the 
vaccine according to previous vaccination status 
• laboratory-confirmed influenza illness associated with acute otitis media (AOM based on 
clinical diagnosis) caused by any influenza A or B type 
• laboratory-confirmed influenza illness associated with AOM based on clinical diagnosis 
caused by viral strains similar to those contained in the vaccine 
• laboratory-confirmed influenza illness associated with ALRI based on a clinical and/or x-ray 
diagnosis caused by any influenza A or B type 
• laboratory-confirmed influenza illness associated with ALRI based on a clinical and/or x-ray 
diagnosis caused by viral strains similar to those contained in the vaccine 
• PCR-confirmed influenza illness caused by any influenza A or B type 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 52 of 134 
• PCR-confirmed influenza illness caused by viral strains similar to those contained in the 
vaccine 
• culture-confirmed influenza illness caused by any influenza A or B type 
• culture-confirmed influenza illness caused viral strains similar to those contained in the 
vaccine 
• laboratory-confirmed influenza illness associated with hospitalization and caused by any 
influenza A or B type 
• laboratory-confirmed influenza illness associated with hospitalization and caused by viral 
strains similar to those contained in the vaccine 
Immunogenicity 
• 
To compare the HAI immune response of QIV-HD to QIV-SD in subjects 6 months through 
35 months of age 
• 
To describe the HAI immune response induced by each vaccine against the 4 vaccine strains 
and according to the different strain formulations used in each of the study influenza seasons 
• 
To describe the SN immune response induced by QIV-HD or QIV-SD against the 4 QIV-HD 
vaccine strains in a randomized subset of subjects 
• 
To describe the anti-neuraminidase (NA) immune response induced by QIV-HD or QIV-SD 
in a randomized subset of subjects   
Re-vaccination Response 
To describe the immune response (HAI method) to vaccination in Season 3 (NH) among subjects 
re-enrolled from Season 1 (NH) to Season 3 (NH), according to the vaccines received in both 
Season 1 (NH) and Season 3 (NH) 
Safety 
• To describe the safety profile (injection site reactions and systemic events) of each vaccine 
during the 28 days following each vaccination for the ESafAS (all subjects from Sentinel 
Safety Cohort, all subjects from Season 1, and a subset of subjects from Seasons 2 and 3) 
• To describe all SAEs (including AESIs) up to at least 180 days after the last vaccination in all 
subjects 
The endpoints for the secondary objectives are presented in Section 9.3 
2.3 
Observational Objectives  
Efficacy 
The following objectives will be assessed for laboratory-confirmed influenza illness due to any 
influenza A or B type, and due to viral strains similar to those contained in the vaccine. To assess 
the relative clinical efficacy of QIV-HD compared to QIV-SD in subjects 6 months through 35 
months of age for the prevention of: 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination caused by each 
circulating influenza virus A subtype and B lineage  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 53 of 134 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination by age subgroup  
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination by season  
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination in previously 
unvaccinated subjects after 1st injection 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination in previously 
unvaccinated subjects between 1st and 2nd injections 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination and over the first 3 
months after vaccination 
• 
laboratory-confirmed influenza illness starting ≥ 14 days after vaccination according to other 
ILI definitions (modified CDC-defined ILI)  
Influenza-associated Events/Health care utilization 
• 
To describe in each vaccine group the occurrence of AOM (based on clinical and/or x-ray 
diagnosis), within 30 days after the onset of a laboratory-confirmed ILI 
• 
To describe in each vaccine group the occurrence of AOM (based on clinical and/or x-ray 
diagnosis), within 30 days after the onset of any ILI  
• 
To describe in each vaccine group the occurrence of ALRI (based on clinical and/or x-ray 
diagnosis), within 30 days after the onset of a laboratory-confirmed ILI 
• 
To describe in each vaccine group the occurrence of ALRI (based on clinical and/or x-ray 
diagnosis), within 30 days after the onset of any ILI 
• 
To describe in each vaccine group the occurrence, duration, and intensity of ILI symptoms 
occurring within 30 days after the onset of a laboratory-confirmed ILI 
• 
To describe in each vaccine group the occurrence, duration, and intensity of ILI symptoms 
occurring within 30 days after the onset of ILI 
• 
To describe in each vaccine group the use of antibiotics and antivirals that are associated with 
cases of laboratory-confirmed ILI, within 30 days after the onset of the ILI 
• 
To describe in each vaccine group the use of antibiotics and antivirals that are associated with 
any ILI, within 30 days after the onset of the ILI 
• 
To describe in each vaccine group hospitalizations that are associated with cases of 
laboratory-confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group hospitalizations that are associated with any ILI, within 30 
days after onset of the ILI  
• 
To describe in each vaccine group emergency room visits that are associated with cases of 
laboratory-confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group emergency room visits that are associated with any ILI, 
within 30 days after onset of the ILI  
• 
To describe in each vaccine group non-routine medical office visits (including urgent care 
visits) that are associated with cases of laboratory-confirmed ILI, within 30 days after onset 
of the ILI  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 54 of 134 
• 
To describe in each vaccine group non-routine medical office visits (including urgent care 
visits) that are associated with any ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group medication use that is associated with cases of laboratory-
confirmed ILI, within 30 days after onset of the ILI  
• 
To describe in each vaccine group medication use that is associated with any ILI, within 30 
days after onset of the ILI  
• 
To describe in each vaccine group absenteeism (Parent(s) / guardian's absenteeism due to 
child sick days) that is associated with cases of laboratory-confirmed ILI, within 30 days after 
onset of the ILI 
• 
To describe in each vaccine group absenteeism (Parent(s) / guardian's absenteeism due to 
child sick days) that is associated with any ILI, within 30 days after onset of the ILI 
Correlates of Protection Objective 
To assess the association of HAI titers to the 4 vaccine strains with the occurrence of laboratory-
confirmed ILI of any influenza A or B type, or of viral strains similar to those contained in the 
vaccine.  
Antibody persistence 
To describe the persistence of immune response 1 year after vaccination among subjects from 
Season 1 (NH) who are re-enrolled for Season 3 (NH) according to the vaccine received in Season 
1 (NH). 
The endpoints for the observational objectives are presented in Section 9.4. 
3 
Investigators and Study Organization  
This study will be conducted in approximately 200 centers in approximately 9 countries in the 
Northern Hemisphere and approximately 6 countries in the Southern Hemisphere. There will be 1 
global Coordinating Investigator and Coordinating Investigators in countries where required. 
Details of the study centers, the Investigators at each center, and the Coordinating Investigators 
are provided in the “List of Investigators and Centers Involved in the Trial” document. 
An internal safety management team (SMT) will perform blinded analyses of safety data 
throughout the study at pre-specified time points as described in the SMT Charter. Ad hoc 
analysis can be performed by the SMT at any time during the conduct of the study if necessary.  
An Independent Data Monitoring Committee (IDMC), composed of members independent from 
the Sponsor, Coordinating Investigator, and Investigators, will be established to review early 
safety data, influenza cases, and efficacy. The membership composition, specific responsibilities 
of members, timing of reviews, objectives for review, and decision criteria will be documented in 
the IDMC Charter. 
The Sponsor’s Responsible Medical Officer (the RMO, the person authorized to sign this protocol 
and any amendments on behalf of the Sponsor) is 
 MD, Global Clinical 
Development Strategy Expert – Vaccines (GCDSE-V).  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 55 of 134 
4 
Independent Ethics Committee / Institutional Review Board  
Before the investigational product can be shipped to the investigational sites and before the 
inclusion of the first subject, this protocol, informed consent forms (ICFs), subject recruitment 
procedures, and any other written information to be provided to subjects must be approved by, and 
/ or receive favorable opinion from, the appropriate Independent Ethics Committees (IECs) or 
Institutional Review Boards (IRBs). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and / or 
the Sponsor are responsible for obtaining this approval and / or favorable opinion before the start 
of the study. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator to 
the Sponsor together with the composition of the IEC / IRB (the names and qualifications of the 
members attending and voting at the meetings). 
The Investigator or Sponsor will submit written summaries of the status of the study to the IEC / 
IRB annually, or more frequently if requested. All serious adverse events (SAEs) occurring during 
the study that are related to the product administered or not related to the product will be reported 
by the Investigator to the IEC / IRB, according to the IEC / IRB policy.  
5 
Investigational Plan  
5.1 
Description of the Overall Study Design and Plan  
Note: The Sentinel Safety Cohort and associated study procedures were completed prior to 
Amendment 2 of this Protocol. 
5.1.1 Study Design  
QHD00014 is planned to be a Phase III, randomized, modified double-blind, active-controlled, 
multi-center study to be conducted in 13,320 (100 subjects will be in an open-label Sentinel Safety 
Cohort with no comparator vaccine while 13,220 will be randomized and double-blinded) children 
6 months through 35 months of age to evaluate the relative efficacy, immunogenicity, and safety 
of QIV-HD administered by intramuscular (IM) route versus a QIV-SD vaccine.  
QHD00014 is planned to be conducted during the 2020-2021 NH influenza season (Sentinel 
Safety Cohort), the 2022-2023 NH influenza season (Season 1), the 2023 SH influenza season 
(Season 2), and the 2023-2024 NH influenza season (Season 3). During Seasons 1 through 3, 
subjects will be randomized in a 1:1 ratio to receive either QIV-HD or QIV-SD prior to the start 
of the influenza season. Subjects will receive either 1 or 2 doses of study vaccine depending on 
whether they were previously vaccinated against influenza or previously unvaccinated against 
influenza, respectively.  
During the 2020-2021 NH influenza season, a Sentinel Safety Cohort of 100 US subjects will be 
enrolled in an uncontrolled, open-label design without a comparator vaccine to evaluate the safety 
of QIV-HD prior to the enrollment of additional subjects. These subjects will not provide blood 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 56 of 134 
samples and will not be followed for ILI surveillance. Following the enrollment of the Sentinel 
Safety Cohort and prior to the start of Season 1 (2022-2023 NH), an IDMC will review the safety 
of this sentinel cohort. If the IDMC determines there is no significant safety issue during their 
review of the Sentinel Safety Cohort’s data, approximately
 subjects will subsequently be 
allowed to be enrolled in Season 1.  
The sample size in the subsequent seasons may be adjusted to maintain the likelihood of achieving 
the overall expected number of cases for the primary endpoint. The current estimated sample size 
for the efficacy cohort in Seasons 2 and 3 is
subjects (
 in the SH and
 in the NH) 
and an additional
 subjects from Season 1’s Immunogenicity Subset will be re-enrolled in 
Season 3 but will not be included in efficacy analysis for Season 3, for a total of 13,320 subjects 
in the entire study. Sentinel Safety Cohort subjects will be excluded from reenrollment in any 
subsequent seasons. 
During each influenza season, a subset of subjects (hereafter referred to as the Immunogenicity 
Subset) will be randomly selected using Interactive Response Technology (IRT) across 
participating sites to provide blood samples for immunogenicity testing: 
Total subjects with blood draws = approximately
 subjects 
• Season 1, NH = 
 subjects 
• Season 2, SH =
 of randomized subjects (approximately
subjects) 
• Season 3, NH =
 of randomized subjects (approximately
 subjects) and
 re-
enrolled subjects who were part of Season 1* 
An Expanded safety analysis set (ESafAS) will also be selected for collection of reactogenicity 
and unsolicited adverse events as follows:  
Total subjects in ESafAS =
 subjects  
• Sentinel Safety Cohort (2020-2021 NH) = 100 subjects† 
• Season 1, NH =
 subjects (all subjects)† 
• Season 2, SH =
 of randomized subjects (approximately
 subjects) 
• Season 3, NH =
 of randomized subjects (approximately
 subjects) and
 re-
enrolled subjects from Season 1 
*A subset of approximately
 subjects from Season 1 (2022-2023 NH) who are in the 
Immunogenicity Subset will be re-enrolled and re-randomized in Season 3 (hereafter referred as 
the Re-vaccination Cohort) and included in the ESafAS and the Immunogenicity Subset; these 
 subjects will not be followed for ILI surveillance during their participation in Season 3.  
†Note: For the Sentinel Safety Cohort season and Season 1: all enrolled subjects will be included 
in the ESafAS.  
For Seasons 2 and 3: the Immunogenicity Subset and the ESafAS will include the same subjects. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 57 of 134 
5.1.2 Justification of the Study Design  
Justification for the age range and correlate of protection evaluation 
Health authorities such as the US Food and Drug Administration and European Medicines Agency 
(EMA) have accepted non-inferior immunogenicity studies in support of licensure of new 
influenza vaccine. Non-inferior immunogenicity is demonstrated by comparing the new SD 
influenza vaccine to a licensed SD influenza vaccine, for which there are existing efficacy data, 
through HAI titers and seroconversion rates against the strains contained in the vaccines. 
However, demonstrating superior immunogenicity for QIV-HD is not sufficient evidence for 
demonstrating superior efficacy, therefore a relative efficacy study needs to be conducted to 
demonstrate superior efficacy. 
Table 5.1 shows that in the Phase II QHD04 study, children 6 through 35 months of age 
vaccinated with QIV-HD 60 µg HA/strain/dose had the highest HAI GMT ratios (post-vaccination 
GMTs of QIV-HD/QIV-SD) compared to the other 2 dose formulations evaluated (30 and 45 µg 
HA/strain/dose). Results of the seroneutralization assay also showed that the QIV-HD 60µg 
HA/strain/dose formulation generated the highest geometric mean fold rises than the other 2 QIV-
HD dose formulations evaluated. Thus, the QIV-HD dose formulation of 60 µg HA/strain/dose 
was chosen to be evaluated in the Phase III QIV-HD studies in children.  
Table 5.1: QHD04 study: HAI GMT ratios (QIV-HD/QIV-SD)  
Strain 
Children 6 months through 35 months of age 
QIV-HD 30µg 
QIV-HD 45µg 
QIV-HD 60µg 
GMT ratio 
(95% CI) 
GMT ratio 
(95% CI) 
GMT ratio 
(95% CI) 
A/H1N1 
2.13 
(0.83 ; 5.47) 
1.75 
(0.69 ; 4.38) 
4.24 
(2.05 ; 8.76) 
A/H3N2 
0.93 
(0.40 ; 2.15) 
1.49 
(0.61 ; 3.60) 
3.14 
(1.53 ; 6.44) 
B/Victoria 
1.23 
(0.58 ; 2.62) 
1.38 
(0.64 ; 2.98) 
2.04 
(1.10 ; 3.77) 
B/Yamagata 
1.10 
(0.55 ; 2.22) 
1.18 
(0.55 ; 2.54) 
1.92 
(1.08 ; 3.41) 
QHD04 also showed that children 6 through 35 months of age vaccinated with QIV-HD 60 µg 
HA/strain/dose had the highest GMT ratios (post-vaccination GMTs of QIV-HD/QIV-SD) 
compared to the other 3 age ranges evaluated (3 through 4 years, 5 through 8 years, and 9 through 
17 years of age). Thus, the relative efficacy study QHD00014 will be conducted in children 6 
through 35 months of age as this age range is the most likely age group to be able to demonstrate 
superior relative efficacy against a QIV-SD. These children are also the most vulnerable children 
to influenza and its complications given their immature immune system and naïve exposure to 
influenza. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 58 of 134 
Justification for the number of influenza seasons evaluated 
QHD00014 is planned to be conducted during the 2020-2021 NH influenza season (Sentinel 
Safety Cohort), the 2022-2023 NH influenza season, the 2023 SH influenza season, and the 2023-
2024 NH influenza season. Evaluating the relative efficacy over multiple seasons will allow for 
the assessment of the vaccine efficacy across different influenza seasons, different recommended 
strains each season, and potentially matched or mismatched influenza strains.  
Justification for the choice of comparator control vaccine 
The QHD00014 study design is a relative efficacy study which will demonstrate the superior 
efficacy of QIV-HD compared to a licensed standard dose influenza vaccine. Thus, all children 
participating in the study will receive an influenza vaccine as per the WHO recommendation that 
children less than 5 years should receive an annual vaccination against influenza because 
influenza vaccines have been shown to be effective in reducing influenza-associated morbidity 
and mortality. 
GSK’s QIV-SD (Fluarix® Quadrivalent vaccine, or other tradenames) will be the comparator in 
the QHD00014 study. Fluarix Quadrivalent vaccine was chosen because it is licensed in children 
6 months of age and older in more countries around the world compared with other standard dose 
influenza vaccines. This will allow for a single comparator QIV-SD to be used in all countries 
proposed for the study. 
Justification for modified-double blind during the entire study  
Since the QIV-HD dose volume of 0.7 mL is different than the QIV-SD comparator dose volume 
of 0.5 mL and the QIV-SD comparator will appear different, the QHD00014 study will be a 
modified double-blind study in which a designated unblinded administrator at each study site will 
know which vaccine has been administered. The Investigator/Sub-Investigator/staff involved in 
the safety assessment and influenza surveillance will be blinded in order to decrease the risk of 
potential bias in safety and efficacy assessment.   
Since the study will be conducted over multiple NH influenza seasons, a cohort of 
subjects 
who participated in Season 1 (2022-2023 NH) and were part of the Immunogenicity Subset may 
participate in Season 3 (2023-2024 NH), and the blind will be maintained throughout all seasons 
of the subject’s participation. Subjects in the Sentinel Safety Cohort (2020-2021 NH) will not be 
re-enrolled in later seasons.  
The Sentinel Safety Cohort of 100 subjects at the start of the study will not be blinded as all 
subjects in the Sentinel Safety Cohort will receive QIV-HD. 
Justification of vaccination schedule 
In order to maintain consistent vaccination schedule rules across all countries and sites for the 
classification of children considered previously influenza vaccinated and previously influenza 
unvaccinated, all global study sites will follow the US Advisory Committee on Immunization 
Practices recommendations for influenza vaccine (25). 
• Previously unvaccinated subjects are defined as subjects who have not received at least 
2 doses of seasonal influenza vaccine in prior influenza seasons. These subjects will receive 
2 doses of study vaccine at least 28 days apart after enrolling in the study. Subjects who have 
received only one dose of any influenza vaccine in the past or subjects whose vaccination 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 59 of 134 
history is unknown will also be considered as previously unvaccinated subjects when enrolling 
and receive 2 doses of study vaccine at least 28 days apart. 
• Previously vaccinated subjects are defined as subjects who have received at least 2 doses of 
seasonal influenza vaccine in prior influenza seasons. These subjects will receive only 1 dose 
of study vaccine after enrolling in the study. 
5.1.3 Study Plan  
The study plan is summarized in the Table of Study Procedures.  
The study will span several influenza seasons in different countries and recruitment will 
encompass subjects who may receive 1 or 2 vaccinations and may provide blood draws defined 
according to the pursued objectives. 
Vaccination 
For the  Sentinel Safety Cohort, eligible subjects will receive QIV-HD as follows: 
• Subjects enrolled in the Sentinel Safety Cohort who were previously vaccinated against 
influenza will receive 1 dose of the QIV-HD on Day (D) 0, with no comparator vaccine. 
• Subjects enrolled in the Sentinel Safety Cohort who were not previously been vaccinated 
against influenza will receive 2 doses of the QIV-HD with no comparator vaccine. Each dose 
will be administered 28 days apart (at D0 and D28). 
For all other eligible subjects will be randomized to receive either QIV-HD or QIV-SD: 
• Subjects previously vaccinated against influenza will receive 1 dose of the QIV-HD or the 
comparator vaccine on D0. 
• Subjects who had not previously been vaccinated against influenza will receive 2 doses of the 
QIV-HD or the comparator vaccine. Each dose will be administered 28 days apart (at D0 and 
D28). 
An unblinded administrator at each site will administer the vaccine. 
Surveillance for Influenza-like illness (not applicable for Sentinel Safety Cohort or Re-
vaccination Cohort): 
Passive Surveillance: Following randomization and vaccinations, all subjects’ parents/guardians 
(except those in the Sentinel Safety Cohort and the Re-vaccination Cohort) will be instructed to 
contact the site if the subject experiences symptoms of a protocol-defined ILI during the annual 
surveillance periods, from the 1st vaccination until 30 April of the following year for subjects in 
the NH or until 31 October of the same year for subjects in the SH.  
Active Surveillance: During a period from the first vaccination until approximately 30 April for 
NH seasons or 31 October for SH seasons, subjects’ parents and/or guardians will be contacted by 
telephone once a week.   
Collection of nasopharyngeal (NP) swabs 
During the period from D0 after vaccination (after the first vaccination in subjects receiving two 
doses of study vaccine ) until 30 April of the following year for NH subjects or until 31 October 
of the same year for SH subjects, the site will arrange for an NP swab to be taken if the subject 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 60 of 134 
experiences a new onset of fever concomitantly with one or more of the above-mentioned 
symptoms of protocol-defined ILI (that persists for or reoccurs after a period of at least 12 hours).  
The NP swab will be obtained as soon as possible and no later than 7 days (between D0 and D6) 
from the onset of the ILI. 
Reporting of events temporally associated with an ILI 
In addition to obtaining an NP swab, the site will collect detailed information about the ILI, as 
well as information on occurrence of ALRI, otitis media, healthcare utilization events 
(hospitalizations, emergency room visits, and non-routine office visits [including urgent care 
visits]) and medication use (eg, antibiotics, antivirals). 
In the event that an NP swab cannot be collected, the research site will still obtain the above 
information. All subjects’ parents/guardians reporting a suspected ILI will have a 30-day follow-
up telephone call. 
Laboratory testing for the confirmation of influenza and determination of similarity to vaccine 
components 
All NP specimens will be submitted for analysis by both culture and PCR, and a positive result on 
either test will be considered a laboratory-confirmed case of influenza. 
Positive cultures or positive PCR samples will undergo additional testing (typing, subtyping, and 
strain identification, utilizing genetic sequencing) to determine if the virus detected is similar to 
any of those contained in the vaccine formulation for the respective season. 
Note: Positive PCR samples that have negative culture results, or were unable to be expanded in 
culture, will not undergo additional testing. 
Blood sampling 
A subset of randomly selected subjects (Immunogenicity Subset) will provide 2 blood samples 
(5 mL each): 
• Previously vaccinated subjects will provide a pre-vaccination (baseline) blood sample at V01 
(D0) and a post-vaccination blood sample at V02 (D28 [+7 days]) for HAI testing and 
potential seroneutralization (SN) and enzyme-linked lectin assay (ELLA) testing. 
• Previously unvaccinated subjects will provide a pre-vaccination (baseline) blood sample at 
V01 (D0) and a post-vaccination blood sample at V03 (28 days after V02 [+7 days]) for HAI 
testing and potential SN and ELLA testing. 
Note: the Re-vaccination Cohort will automatically be part of the Immunogenicity Subset 
Collection of safety data 
All subjects will be observed for 30 minutes after vaccination, and any unsolicited systemic 
adverse events (AEs) occurring during that time will be recorded as immediate unsolicited 
systemic AEs in the case report book (CRB) for subjects in the sentinel cohort and ESafAS and in 
the source documentation for all other subjects. 
For subjects in the Sentinel Safety Cohort and Season 1 (NH), solicited reactions will be collected 
through day 7 after each vaccination, and unsolicited AEs will be collected through day 28 after 
each vaccination in all subjects. During study Seasons 2 (2023 SH) and 3 (2023-2024 NH), 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 61 of 134 
solicited reactions and unsolicited AEs will only be collected for those in the ESafAS. Serious 
adverse events (SAEs) and adverse events of special interest (AESIs) will be collected in all 
subjects throughout the study (D0 through approximately 6 to 7 months after vaccination in each 
season). AESIs will be captured as SAEs in this study. AESIs include GBS, encephalitis / myelitis 
(including transverse myelitis), Bell’s palsy, convulsions, optic neuritis, and brachial neuritis. 
Parents / guardians of subjects will be asked to notify the site immediately about any potential 
SAEs (including AESIs) at any time during the study. 
Staff will review the safety data with subjects’ parents / guardians at each visit. The IRT system 
will be used to randomly assign subjects to a study product and subsets and to assign subject 
numbers in each of the groups.  
Electronic data capture (EDC) will be used for the collection of data. 
COVID-19 Risk Assessment 
The QHD00014 study may be conducted during the ongoing outbreak of severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) in the human population considered as pandemic by the 
WHO on 11 March 2020.  
QIV-HD is an inactivated influenza vaccine and is not expected to cause immune suppression. 
Therefore, the risk that a subject in this study will contract Coronavirus Disease 2019 (COVID-
19) solely due to the administration of the study vaccine will be similar to the risk that a person 
not participating in this study will contract COVID-19. 
However, the risk of exposure to infected people cannot be completely excluded as the subjects in 
QHD00014 may be exposed to people and surfaces commuting to the study and in waiting rooms 
and exam rooms at the study sites.  
COVID-19 Risk Mitigation 
• Reevaluate the start of the study at a site or in a region as the local confinement measures 
or other safety restrictions linked to the COVID-19 pandemic are evaluated by the study 
team. 
• The number of on-site study visits has been decreased for the Sentinel Safety Cohort to 
reduce risk. 
• Continued risk assessment by the Investigator and the Sponsor prior to each study visit and 
throughout each season of the study. 
5.1.4 Visit Procedures  
The visit procedures are described per group and correspond to the Table of Study Procedures.  
Note that all Visit 1 procedures are common until the randomization.  
5.1.4.1 Visit Procedures for subjects in the Sentinel Safety Cohort only  
Note: Visit procedures for the Sentinel Safety Cohort detailed in Section 5.1.4.1 were completed 
prior to Amendment 2 of this protocol. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 62 of 134 
Subjects in the Sentinel Safety Cohort will receive open-label QIV-HD, these visit procedures 
correspond to Tables of Study Procedures 1 and 2. 
5.1.4.1.1 Visit Procedures for previously influenza vaccinated subjects in the Sentinel 
Safety Cohort  
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical history (including information on breastfeeding and 
gestational age) and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated 
8) Call the IRT for assignment of the 12-digit subject number and allocation of a dose number 
(see Section 6.4).  
9) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate 
10) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
11) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
12) Give the subject’s parent / guardian the Diary Card (DC) to record any injection site reactions 
and systemic AEs (including SAEs), and medications together with instructions for its 
completion, including explanations on the definition and use of intensity scales for collection 
of AEs. 
13) Give the subject’s parent / guardian a ruler to measure the size of any injection site reaction, a 
thermometer for temperature measurement, and instructions on how to use them. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 63 of 134 
14) Remind the subject’s parent / guardian to promptly notify the site in case of an SAE/AESI that 
may occur at any time during the study. 
15) Schedule Telephone Call 1 (to occur 8 days after Visit 1).  
16) Complete the relevant CRB forms for this visit. 
Telephone Call 1 (Day 8+2): Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Remind the subject’s parent / guardian to do the following: 
• Complete the remaining pages of the DC and bring the completed diary to V02 
• Remind the subject’s parent / guardian to promptly notify the site in case of an SAE/AESI 
that may occur at any time during the study. 
3) Schedule Visit 2 (to occur 28 days after Visit 1) if not already done. 
Visit 2 (Day 28+7): Collection of Safety Information 
The Investigator or delegate will: 
1) Review and collect the DC information with the subject’s parent / guardian and clarify with 
the subject’s parent / guardian, if required, any AEs, or SAEs that occurred since V01. If an 
SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken (see Section 6.6). 
3) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
4) Provide the subjects’ parent / guardian with a memory aid (MA) and review the directions for 
its use. 
5) Remind the subject’s parent / guardian to promptly notify the site in case of an SAE/AESI that 
may occur at any time during the study. 
6) Schedule the 6-month safety follow-up phone call 
7) Record all applicable information obtained into the CRB 
8) Complete the active phase termination record of the CRB.  
Telephone call 2 (180 [+14] days after Visit 1): Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 64 of 134 
2) Collect information on any medications taken during the study period 
3) Record all applicable information obtained into the CRB 
5.1.4.1.2 Visit Procedures for previously influenza unvaccinated subjects in the Sentinel 
Safety Cohort  
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical (including information on breastfeeding and gestational 
age) history and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated  
8) Call the IRT for assignment of the 12-digit subject number, , and allocation of a dose number 
(see Section 6.4).  
9) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate. 
10) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
11) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
12) Give the subject’s parent / guardian the Diary Card (DC1) to record any injection site 
reactions and systemic AEs (including SAEs), and medications, together with instructions for 
its completion, including explanations on the definition and use of intensity scales for 
collection of AEs. 
13) Give the subject’s parent / guardian a ruler to measure the size of any injection site reaction, a 
thermometer for temperature measurement, and instructions on how to use them. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 65 of 134 
14) Remind the subject’s parent / guardian to promptly notify the site in case of an SAE/AESI that 
may occur at any time during the study. 
15) Schedule Telephone Call 1 to occur 8 Days after Visit 1.  
16) Complete the relevant CRB forms for this visit. 
Telephone Call 1 (Day 8+2): Collection of Safety Information  
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Remind the subject’s parent / guardian to do the following: 
• Complete the remaining pages of the DC1 and bring the completed diary to V02 
• Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI that may occur at any time during the study. 
3) Schedule Visit 2 (to occur 28 days after Visit 1) if not already done. 
Visit 2 (Day 28+7): Dose Allocation, Vaccination, and Collection of Safety Information 
The Investigator or delegate will: 
1) Review and collect the DC1 information with the subject’s parent / guardian and clarify with 
the subject’s parent / guardian, if required, any AEs, or SAEs that occurred since V01. If an 
SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period. 
3) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
4) Review temporary and definitive contraindications to vaccination. 
5) Contact IRT for allocation of unique dose number. 
6) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate 
7) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
8) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
9) Provide the subjects' parent / guardian with DC2.  
10) Schedule Telephone Call 2 (to occur 8 days after Visit 2).  
11) Complete relevant CRB forms for this visit.  
Telephone Call 2 (Day 8 + 2 after Visit V02): Collection of Safety Information 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 66 of 134 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. 
1)  Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Remind the subject’s parent / guardian to do the following: 
• Complete the remaining pages of the DC2 and bring the completed diary to V03 
• Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI that may occur at any time during the study. 
3) Schedule Visit 3 (to occur 28 days after Visit 2) if not already done. 
Visit 3 (Day 28 + 7 after Visit V02): Collection of Safety Information 
1) Review and collect the DC2 information with the subject’s parent / guardian and clarify with 
the subject’s parent / guardian, if required, any AEs, or SAEs that occurred since V01. If an 
SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken (see Section 6.6). 
3) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
4) Provide the subjects’ parent / guardian with a memory aid (MA) and review the directions for 
its use.  
5) Remind the subject’s parent / guardian to promptly notify the site in case of an SAE/AESI 
symptoms that may occur at any time during the study. 
6) Schedule the 6-month safety follow-up phone call 
7) Record all applicable information obtained into the CRB 
8) Complete the active phase termination record of the CRB. 
Telephone call 3 (180 [+14] days after Visit 2): Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day.   
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period 
3) Record all applicable information obtained into the CRB 
5.1.4.2 Visit Procedures for previously influenza vaccinated subjects  
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 67 of 134 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical history (including information on breastfeeding and 
gestational age) and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated  
8) Call the IRT for assignment of the 12-digit subject number, randomization, and allocation of a 
dose number (see Section 6.4).  
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate. 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Give the subject or subject’s parent / guardian the Memory Aid to record ILI information, 
medications, and SAEs, together with instructions for its completion, including explanations 
on the definition and use of intensity scales for collection of SAEs. 
3) Give the subject or subject’s parent / guardian a thermometer for temperature measurement, 
and instructions on how to use them. 
4) Schedule the 6-month follow-up telephone call to be conducted approximately 180 days after 
V01. 
5) Remind the subject or subject’s parent / guardian to promptly notify the site in case of ILI 
symptoms or an SAE/AESI that may occur at any time during the study. 
6) Complete the relevant CRB forms for this visit. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 68 of 134 
Telephone call (180 [+14] days after Visit 1 or end of influenza season if later than D180): 
Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. Also, the telephone call must not be before the end of the influenza 
surveillance period for that season (ie. 30 April for NH and 31 October for SH subjects). 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE/AESI occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period 
3) Complete active phase termination record. 
5.1.4.3 Visit Procedures for previously influenza unvaccinated subjects  
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical history (including information on breastfeeding and 
gestational age) and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated. 
8) Call the IRT for assignment of the 12-digit subject number, randomization, and allocation of a 
dose number (see Section 6.4).  
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate. 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 69 of 134 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Give the subject or subject’s parent / guardian the Memory Aid to record any ILI information, 
medications, and SAEs, together with instructions for its completion, including explanations 
on the definition and use of intensity scales for collection of SAEs. 
3) Give the subject or subject’s parent / guardian a thermometer for temperature measurement, 
and instructions on how to use them. 
4) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 
5) Schedule Visit 2 to occur 28 Days after Visit 1.  
6) Complete the relevant CRB forms for this visit. 
Visit 2 (Day 28+7): Dose Allocation and Vaccination 
The Investigator or delegate will: 
1) Collect information on any medications taken during the study period. 
2) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
3) Review temporary and definitive contraindications to vaccination. 
4) Contact IRT for allocation of unique dose number. 
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate. 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Schedule the 6-month follow-up telephone call to be conducted approximately 180 days after 
V02. 
3) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 
4) Complete relevant CRB forms for this visit.  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 70 of 134 
Telephone call (180 [+14] days after Visit 2 or end of influenza season if later than D180): 
Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day.  Also, the telephone call must not be before the end of the influenza 
surveillance period for that season (ie. 30 April for NH and 31 October for SH subjects). 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE has occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period 
3) Complete active phase termination record.  
5.1.4.4 Visit Procedures for previously influenza vaccinated subjects who have been 
randomized into the Expanded safety analysis set (ESafAS) with or without 
Immunogenicity Subset  
Visit 1 (Day 0): Inclusion, Randomization, Vaccination, and Blood Sample (for 
Immunogenicity Subset) 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical history (including information on breastfeeding and 
gestational age) and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated 
8) Call the IRT for assignment of the 12-digit subject number, randomization, and allocation of a 
dose number (see Section 6.4). 
9) If the subject is randomized into the Immunogenicity Subset: perform the following step prior 
to vaccination 
a. Draw approximately 5 mL of blood sample (The blood sampling should be performed 
before vaccination). Process the blood sample as specified in the “Management of 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 71 of 134 
Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be 
obtained. 
Note: If the subject’s parent / guardian withdraws consent before blood sampling 
(before any invasive procedure has been performed), do not vaccinate the subject. The 
subject should be terminated from the study. 
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), then the 
subject is still to be included in the study and vaccinated. 
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate (the vaccine must be administered on 
the side opposite to that of the blood sampling, if applicable). 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Give the subject or subject’s parent / guardian the Diary Card (DC) to record any injection site 
reactions and systemic AEs, together with instructions for its completion, including 
explanations on the definition and use of intensity scales for collection of AEs. 
3) Give the subject’s parent / guardian the diary card to record ILI information, medications, and 
SAEs/AESIs, together with instructions for its completion.   
4) Give the subject or subject’s parent / guardian a ruler to measure the size of any injection site 
reaction, a thermometer for temperature measurement, and instructions on how to use them. 
5) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 
6) Schedule Visit 2 (to occur 28 days after Visit 1).  
7) Complete the relevant CRB forms for this visit. 
Visit 2 (Day 28+7): Blood Sample (for Immunogenicity Subset) and Collection of Safety 
Information 
The Investigator or delegate will: 
1) Collect information on any medications taken (see Section 6.6). 
2) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
3) Review and collect completed DC. 
4) If the subject is part of the Immunogenicity Subset: perform the following step prior to 
vaccination 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 72 of 134 
a. Draw approximately 5 mL of blood sample. Process the blood sample as specified in 
the “Management of Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be 
obtained. 
5) Give the subject’s parent / guardian the memory aid to record ILI information (except for 
subjects from Re-vaccination Cohort), medications, and SAEs/AESIs, together with 
instructions for its completion.   
6) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 
7) Schedule 6-month follow-up telephone call to be conducted approximately 180 days after 
V01.  
8) Complete the relevant CRB forms for this visit. 
Telephone call (180 [+14] days after Visit 1 or end of influenza season if later than D180): 
Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. Also, the telephone call must not be before the end of the influenza 
surveillance period for that season (ie. 30 April for NH and 31 October for SH subjects). 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period 
3) Complete active phase termination record.  
5.1.4.5 Visit Procedures for previously influenza unvaccinated subjects who have been 
randomized into the Expanded safety analysis set (ESafAS) with or without 
Immunogenicity Subset  
Visit 1 (Day 0): Inclusion, Randomization, and Vaccination 
The Investigator or delegate will: 
1) Give the subject’s parent / guardian information about the study. 
2) Obtain informed consent and answer any questions to ensure that the subject’s parent / 
guardian have been informed of all aspects of the study that are relevant to their decision to 
allow their child to participate.  
3) Date and sign the ICF after it has been signed and dated by the subject’s parent / guardian. 
Retain the original and give a signed copy to the subject’s parent / guardian. 
4) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through targeted physical examination per standard site-specific immunization practices 
(including recording temperature in source documents) and medical interview of the subject’s 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 73 of 134 
parent / guardian. If the subject is not eligible, only the specific form entitled “Recruitment 
log” will state the subject identification, no CRB will be completed. 
5) Collect relevant demographic information (eg, date of birth, sex, ethnicity, and race). 
6) Obtain verbal information on medical history (including information on breastfeeding and 
gestational age) and collect information on any medications (see Section 6.6). 
7) Obtain information on seasonal influenza vaccination history to determine if the subject is 
previously influenza vaccinated or previously influenza unvaccinated 
8) Call the IRT for assignment of the 12-digit subject number, randomization, and allocation of a 
dose number (see Section 6.4).  
9) If the subject has been randomized into the Immunogenicity Subset: draw approximately 5 mL 
of blood sample (The blood sampling should be performed before vaccination). Process the 
blood sample as specified in the “Management of Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be obtained. 
Note: If the subject’s parent / guardian withdraws consent before blood sampling (before any 
invasive procedure has been performed), do not vaccinate the subject. The subject should be 
terminated from the study. 
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), then the subject is 
still to be included in the study and vaccinated. 
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate (the vaccine must be administered on 
the side opposite to that of the blood sampling). 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Give the subject or subject’s parent / guardian the Diary Card (DC1) to record any injection 
site reactions and systemic AEs, together with instructions for its completion, including 
explanations on the definition and use of intensity scales for collection of AEs. 
3) Give the subject’s parent / guardian the diary card to record ILI information (except for 
subjects in the Re-vaccination Cohort), medications, and SAEs/AESIs, together with 
instructions for its completion.  
4) Give the subject or subject’s parent / guardian a ruler to measure the size of any injection site 
reaction, a thermometer for temperature measurement, and instructions on how to use them. 
5) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 
6) Schedule Visit 2 (to occur 28 days after Visit 1).  
7) Complete the relevant CRB forms for this visit. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 74 of 134 
Visit 2 (Day 28+7): Dose Allocation, Vaccination and Collection of Safety Information 
The Investigator or delegate will: 
1) Collect information on any medications taken during the study period. 
2) Review and collect completed DC1 
3) If deemed necessary, perform and document a targeted physical examination per standard site-
specific immunization practices and record temperature in the source documents. 
4) Review temporary and definitive contraindications to vaccination. 
5) Contact IRT for allocation of unique dose number. 
The unblinded qualified study staff member will: 
1) Administer the appropriate vaccine intramuscularly into the anterolateral muscle of the thigh 
or the deltoid muscle of the upper arm, as appropriate 
2) Record the injection site / side / route / dose number and affix the detachable corresponding 
label in the source documents. 
The Investigator or delegate will: 
1) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any SAE in the source documents. 
2) Provide the subjects' parent / guardian with DC2.  
3) Schedule Visit 3 (to occur 28 days after Visit 2).  
4) Complete relevant CRB forms for this visit.  
Visit 3 (Day 28 + 7 after Visit V02): Post-Vaccination Blood Sample (for Immunogenicity 
Subset) and Collection of Safety Information 
The Investigator or delegate will: 
1) Collect information on medication taken during the study.  
2) Review and collect DC2. 
3) If the subject is part of the Immunogenicity Subset:  
a. Draw approximately 5 mL of blood sample. Process the blood sample as specified in 
the “Management of Samples” section (see Section 7). 
Note: If 5 mL of blood sample cannot be drawn, a volume less than 5 mL can be 
obtained. 
4) Give the subject’s parent / guardian the memory aid to record ILI information (except for 
subjects in the Re-vaccination Cohort), medications, and SAEs/AESIs, together with 
instructions for its completion.   
5) Remind the subject or subject’s parent / guardian to promptly notify the site in case of an 
SAE/AESI or ILI symptoms that may occur at any time during the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 75 of 134 
6) Schedule 6-month follow-up telephone call to be conducted approximately 180 days after 
V02.  
7) Complete the relevant CRB forms for this visit. 
Telephone call (180 [+14] days after Visit 2 or end of influenza season if later than D180): 
Collection of Safety Information 
Note: If the telephone call falls on a weekend or a holiday, the telephone call may be scheduled 
on the next business day. Also, the telephone call must not be before the end of the influenza 
surveillance period for that season (ie, 30 April for NH and 31 October for SH subjects). 
The Investigator or delegate will: 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Collect information on any medications taken during the study period 
3) Complete active phase termination record.  
5.1.5 Collection of ILI Symptoms through Passive and Active Surveillance  
5.1.5.1 ILI Surveillance and Influenza Confirmation Process for all subjects (except 
Sentinel Safety Cohort subjects)  
ILI surveillance (not applicable to subjects in the Re-vaccination Cohort)  
From the first vaccination to the end of the influenza season, passive surveillance will be 
performed. Subjects’ parent(s) / guardian(s) will be instructed to contact the site as soon as 
possible (within 24 hours) if their child experiences symptoms of an ILI. 
In addition, from the first vaccination to the end of the influenza season (30 April for NH and 
31 October for SH subjects); the Investigator or delegate will contact the subjects’ parent(s) / 
guardian(s) once a week.  This contact may be done via telephone or via an optional electronic 
application.  This will be described in the Operating Guidelines and will be in accordance with 
local regulations.  
During these weekly contacts, the Investigator or delegate will: 
1) Interview the subjects’ parent(s) or guardian(s) in order to detect a possible ILI. 
2) Arrange an ILI visit at the study site or at home visit if an ILI is suspected. The ILI visit has 
to be scheduled at the earliest opportunity for laboratory confirmation of influenza (within 
7 days after the onset of the ILI considering that Day 0 is the day of fever onset). 
3) Remind subject's parent(s) / guardian(s) to record information about ILI symptoms, 
associated events, medications, and healthcare utilization in the DC or MA given.  
ILI Visit (within 7 days of ILI onset) 
Only for subjects reporting qualifying symptoms of ILI during phone calls from first vaccination 
until 30 April (NH) or 31 October (SH) of the following year etc.  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 76 of 134 
The Investigator or delegate will: 
1) Collect and review information on ILI symptoms, associated events, medications, and 
healthcare utilization and will confirm clinically the ILI diagnosis. 
2) Information on ILI symptoms, associated events, medications and healthcare utilization 
includes: 
• Information on occurrence, duration, and intensity of ILI symptoms after the onset of the 
ILI 
• Information on occurrence of AOM and ALRI after the onset of the ILI 
• Information on healthcare utilization events (inpatient hospitalization, outpatient visit, 
medications, parent(s) / guardian(s) absenteeism due to child sick days) after the onset of 
the ILI 
• Information on medications given to the subject 
3) Perform the NP swab if ILI diagnosis is clinically confirmed 
4) Schedule the ILI follow-up phone call 30 days after the ILI onset 
5) Remind the parent(s) / guardian(s) that the ILI surveillance will continue (active and passive 
surveillance) and to record information about ILI symptoms, associated events, and healthcare 
utilization in the MA 
6) Record all applicable information obtained into the CRF 
ILI follow-up Phone call(s) – 30 + 7 days after ILI onset  
For subjects who reported protocol-defined ILI symptoms.  
The Investigator or delegate will: 
1) Collect detailed information on ILI symptoms, medications, associated events, and healthcare 
utilization and their resolution 
2) Remind the parent(s) / guardian(s) that the ILI surveillance will continue (active and passive 
surveillance) and to record information about ILI, associated events, and healthcare utilization 
in the MA 
3) Record all applicable information obtained into the CRF 
Follow-up of subjects with Related AEs or with AEs That Led to Study/Vaccination 
Discontinuation: 
Unless a subject’s parent/guardian refuses further contact, each subject who experiences an AE 
(whether serious or non-serious) during the study must be followed until the condition resolves, 
becomes stable, or becomes chronic (even after the end of the subject’s participation in the study) 
if either of the following is true: 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study or from vaccination. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 77 of 134 
5.1.6 Planned Study Calendar  
The following dates are approximate. The actual dates may differ as, for example, the study will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned study period - FVFS (first visit, first subject) to LCLS (last contact, last subject): 
September 2020 to July 2024 
Planned end of study: October 2024 
Planned date of final clinical study report: Jan 2025 
5.1.7 Early Safety Data Review  
The safety of the investigational product will be continuously monitored by the Sponsor. An 
ESDR will be performed, the goal of which is to allow for a cautious, step-wise approach to 
vaccine administration. An initial safety review for this study is planned when the first 100 
subjects are enrolled in a Sentinel Safety Cohort. All 100 subjects will receive QIV-HD (in this 
open-label cohort, no comparator vaccine will be administered). After the Sentinel Safety Cohort 
has been vaccinated and has provided safety data for D0-D7 post-vaccination (using the data 
collection methods described in the clinical study protocol), an IDMC will convene and review 
the safety data. Following a satisfactory safety review by the IDMC, enrollment of subjects will 
commence in Season 1. 
The safety data collected will be entered into the CRB and will be summarized and reviewed by 
the Sponsor and the IDMC. It is understood that this review is based on preliminary data that have 
not been subject to validation and database lock. (The usual and ongoing process of monitoring 
safety signals outside of those specified in the protocol-defined ESDR will continue unchanged.) 
The following safety parameters will be assessed as part of the ESDR review of the Sentinel 
Safety Cohort in an unblinded manner by the IDMC. They will be collected during a period of 7 
days after the vaccination: 
• Immediate reactions 
• Solicited injection site and systemic reactions 
• Unsolicited AEs 
• SAEs (including AESIs) 
The data will be examined for the following occurrences: 
• An SAE (including AESIs) considered as related to the vaccination by the Investigator and 
Sponsor 
• > 10% of subjects experiencing Grade 3 fever within 7 days after vaccination 
If any of the above criteria are met, a recommendation will be made by the IDMC as to whether 
enrollment in the study will be allowed to resume. 
At the completion of the collection of safety data at the end of Season 1 (2022-2023 NH season), 
the IDMC will be convened to review the safety data of subjects. Enrollment will not be paused 
during this IDMC review.  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 78 of 134 
Throughout the course of the study, additional internal SMT meetings will be convened to 
conduct blinded analyses of safety data. Case unblinding may be performed if necessary. The 
Sponsor may also convene the IDMC for ad hoc review of the safety data if needed.  
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, IECs / IRBs, and the regulatory authorities of the reason for termination or 
suspension. If the study is prematurely terminated for any reason, the Investigator will promptly 
inform the study subjects and should assure appropriate therapy and follow-up. 
5.2 
Enrollment and Retention of Study Population  
5.2.1 Recruitment Procedures  
Subjects may be recruited from the general population. The sites will ensure that any 
advertisements used to recruit subjects (letters, pamphlets, posters, etc.) are submitted to Sanofi 
Pasteur prior to submission to the IEC / IRB for approval. 
5.2.2 Informed Consent Procedures  
Informed consent is the process by which a subject’s parent or a guardian voluntarily confirms his 
or her willingness to participate in a particular study. Informed consent must be obtained before 
any study procedures are performed. The process is documented by means of a written, signed, 
and dated ICF. 
In accordance with GCP, prior to signing and dating the consent form, the subject's parent and / or 
guardian must be informed by appropriate study personnel about all aspects of the study that are 
relevant to making the decision to allow their child to participate, and must have sufficient time 
and opportunity to ask any questions. 
If the subject’s parent or guardian is not able to read and sign the ICF, then it must be signed and 
dated by an impartial witness who is independent of the Investigator. A witness who signs and 
dates the consent form is certifying that the information in this form and any other written 
information had been accurately explained to and understood by the subject’s parent or his / her 
guardian. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s parent’s and / or 
guardian’s willingness to continue participation in the study, this will be communicated to him / 
her in a timely manner. Such information will be provided via a revised ICF or an addendum to 
the original ICF. 
Informed consent forms will be provided in duplicate, or a photocopy of the signed consent will 
be made. The original will be kept by the Investigator, and the copy will be kept by the subject's 
parent and / or guardian. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 79 of 134 
Documentation of the consent process should be recorded in the source documents. 
Rationale for Including Subjects Unable to Give Consent: 
See Section 1.4 for the rationale for conducting this study in pediatric population. 
5.2.3 Screening Criteria  
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 Inclusion Criteria  
An individual must fulfill all of the following criteria to be eligible for study enrollment: 
1) Aged 6 to 35 months on the day of the first study visita 
2) Informed consent form has been signed and dated by the parent(s) or guardian(s) and by an 
independent witness, if required by local regulations. 
3) Subject and parent / guardian are able to attend all scheduled visits and to comply with all 
study procedures. 
4) Covered by health insurance if required by local regulations 
5) For Season 3 Re-vaccination Cohort: eligible subjects must have been enrolled in the Season 1 
(2022-2023 NH season) Immunogenicity Subset and must have completed all study 
procedures (ie, blood draws and vaccinations) in Season 1. 
5.2.5 Exclusion Criteria  
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
1) Participation at the time of study enrollment (or in the 4 weeks preceding the first study 
vaccination) or planned participation during the present study period in another clinical study 
investigating a vaccine, drug, medical device, or medical procedure. 
2) For all subjects: Receipt of any vaccine in the 30 days preceding the first study vaccination. 
For subjects in Immunogenicity Subset: Planned receipt of any vaccine before Visit 2 for 
subjects receiving 1 dose of influenza vaccine or Visit 3 for subjects receiving 2 doses of 
influenza vaccine. 
3) Previous vaccination against influenza in the preceding 6 months with either the study vaccine 
or another influenza vaccine  
4) Receipt of immune globulins, blood or blood-derived products in the past 3 months. 
5) 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). 
                                                 
a “6 to 35 months” means from the 6th month after birth to the day before the 36th month after birth. 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
Confidential/Proprietary Information 
Page 80 of 134 
6) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the study or to a vaccine containing any of the
same substancesa. Exception: subjects with an egg allergy are allowed to enroll in the study.
7) Thrombocytopenia, bleeding disorder, or receipt of anticoagulants that based on Investigator’s
judgment contraindicate intramuscular vaccination
8) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere
with study conduct or completionb.
9) Moderate or severe acute illness/infection (according to investigator judgment) on the day of
vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A prospective subject should
not be included in the study until the condition has resolved or the febrile event has subsided.
Note: Subjects who test positive for COVID-19 infection or have been in close contact with
individuals who have tested positive for COVID-19 within 14 days preceding the first study
vaccination will also be excluded from participating in the study until they test negative for
COVID-19.
10) Identified as natural or adopted child of the Investigator or employee with direct involvement
in the proposed study.
11) Personal or family history of GBS.
12) Any condition that in the opinion of the Investigator would pose a health risk to the subject if
enrolled or could interfere with the evaluation of the vaccine.
13) Personal history of clinically significant development delay (at the discretion of the
Investigator), neurologic disorder, or seizure disorder.
14) For Season 3 (2023-2024 NH) main cohort: subjects who were enrolled in a previous study
season are excluded from Season 3, with the exception of the Re-vaccination Cohort.
Depending on country regulations, if the subject has a primary physician who is not the 
Investigator, the site may contact this physician with the consent of the subject’s parent(s) / 
guardian(s) to inform him / her of the subject’s participation in the study. In addition, the site 
should ask this primary physician to verify exclusion criteria relating to previous therapies, such 
as receipt of blood products or previous vaccines. 
5.2.6 Medical History 
Prior to enrollment, subjects 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 subject 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 CRB. The significant medical history section of the CRB contains a core list of body 
a
b
  The components of the QIV-HD are listed in Section 6.1 and in the Investigator’s Brochure, the components of QIV-SD 
are listed in Section 6.1 and the package insert 
of 
Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune 
disorders, diabetes, psychiatric disorders or chronic infection

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 81 of 134 
systems and disorders that could be used to prompt comprehensive reporting, as well as space for 
the reporting of specific conditions and illnesses. 
The pertinent medical history for study purposes includes conditions belonging to the following 
categories: 
1) Chronic co-morbid illnesses considered to increase the risk for influenza complications 
(including pre-specified diagnoses [eg, respiratory, cardiac, blood, endocrine, and kidney 
disorders] listed in the CRB and other significant chronic conditions, as judged by the 
Investigator) 
2) Other conditions (eg, egg allergy, eczema, febrile seizure) 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
Dates and body systems are not to be recorded, and the information collected will not be coded. 
5.2.7 Contraindications for Subsequent Vaccinations  
The contraindications apply only to previously influenza unvaccinated subjects who are going to 
receive 2 vaccine doses, 28 (+7) days apart.  
5.2.7.1 Temporary Contraindications  
Should a subject experience a condition listed below, the Investigator will postpone further 
vaccination until the condition is resolved. Postponement must still be within the timeframe for 
vaccination indicated in the Table of Study Procedures. 
• Moderate or severe acute illness/infection (according to investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A prospective subject should 
not be included in the study until the condition has resolved or the febrile event has subsided. 
5.2.7.2 Definitive Contraindications  
Should a subject experience 1 of the conditions listed below, the Investigator will discontinue 
vaccination:  
1) An anaphylactic or other significant allergic reaction to the previous dose of the vaccine 
2) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the study or to a vaccine containing any of the 
same substances 
3) Receipt of immune globulins, blood or blood-derived products since the preceding injection 
4) Known or suspected congenital or acquired immunodeficiency (eg, HIV); or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, since the 
preceding visit; or long-term systemic corticosteroid therapy (prednisone or equivalent for 
more than 2 consecutive weeks since the preceding visit) 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 82 of 134 
5) Thrombocytopenia, bleeding disorder or receipt of anticoagulants in the 3 weeks preceding 
vaccination, contraindicating intramuscular vaccination based on investigator's judgment 
6) Chronic illness that, in the opinion of the Investigator, is might interfere with subject safety, 
study conduct or completion 
7) An SAE related to the study vaccines following the previous study vaccination, based on 
investigator's judgment 
Subjects with a definitive contraindication will continue to be followed up for the study-defined 
safety, efficacy, and immunogenicity assessments, as applicable. 
In the event of a local or national immunization program with a pandemic influenza vaccine or 
other vaccine, subjects who receive pandemic influenza vaccine or other vaccine at any time 
during the study will not be withdrawn from the study. 
5.2.8 Conditions for Withdrawal  
Subject’s parents / guardians will be informed that they have the right to withdraw their child 
from the study at any time.  
• At the discretion of the Investigator or Sponsor due to safety concerns or significant non-
compliance with the protocol (based on the Investigator’s judgment), without the subject’s 
permission (withdrawal) 
• At the request of the subject’s parent / guardian (dropout) 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and in the CRB.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in which 
case, the reason for discontinuation will be noted as “Adverse Event”) or for another reason. 
Withdrawn subjects will not be replaced. 
5.2.9 Lost to Follow-up Procedures  
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (ie, documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the source documents. 
5.2.10 Classification of Subjects Who Discontinue the Study  
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the CRB. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion instructions for additional details and 
examples): 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 83 of 134 
Adverse Event 
To be used when the subject is permanently terminated from the study because of 
an AE (including an SAE), as defined in Section 9.3.3.2. 
This category also applies if the subject experiences a definitive contraindication 
that is an SAE or AE. 
Lost to Follow-up To be used when the subject cannot be found or contacted in spite of efforts to 
locate him/her before the date of his/her planned last visit, as outlined in 
Section 5.2.9. The certified letter was sent by the Investigator and returned 
unsigned, and the subject’s parent/guardian did not give any other news and did 
not come to any following visit. 
Protocol 
Deviation 
To be used: 
• 
In case of significant non-compliance with the protocol (eg, deviation of the 
Inclusion / Exclusion criteria, non-compliance with time windows, blood 
sampling or vaccination refusal, missed injection/treatment, or error in the 
vaccine/treatment administration). 
• 
If the subject experiences a definitive contraindication that is not an SAE or 
AE. 
• 
The subject’s parent/guardian signed the certified letter sent by the Investigator 
but did not give any other news and did not come to any following visit. 
Withdrawal by 
Subject’s Parent 
/ Guardian  
To be used: 
• 
When the subject’s parent/guardian indicated unwillingness to continue in the 
study 
• 
When the subject’s parent/guardian made the decision to discontinue their 
child’s participation in the study for any personal reason other than an SAE/AE 
(eg, subject is relocating, inform consent withdrawal, etc.) 
5.2.11 Follow-up of Discontinuations  
The site should complete all scheduled safety follow-ups and contact any subject’s parent / 
guardian who has prematurely terminated the study because of an AE or a protocol deviation.  
For subjects where the reason for early termination was lost to follow-up or if the subject’s parent 
/ guardian withdrew informed consent and specified that they do not want to be contacted again 
and it is documented in the source document, the site will not attempt to obtain further safety 
information. 
If the subject’s status at the end of the study is “Withdrawal by Subject’s Parent / Guardian”, the 
site will attempt to contact them for the 6-month follow-up except if they specified that they do 
not want to be contacted again and it is documented in the source document. 
5.3 
Safety Emergency Call  
If, as per the Investigator's judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor's RMO for advice on how to address any study-related medical question 
or problem. If the RMO is not available, then the Investigator may contact the Call Center—
available 24 hours a day, 7 days a week—that will forward all safety emergency calls to the 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 84 of 134 
appropriate primary or back-up Sanofi Pasteur contact, as needed. The toll-free contact 
information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department (please refer to 
Section 10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.3. 
5.4 
Modification of the Study and Protocol  
Any amendments to this study plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments (eg, those that affect the conduct of the study or the safety of subjects) 
require IEC / IRB approval, and must also be forwarded to regulatory authorities. 
An administrative amendment to a protocol is one that modifies some administrative, logistical, or 
other aspect of the study but does not affect its scientific quality or have an impact on the 
subjects’ safety. Depending on local regulations, the IECs / IRBs will either be notified of or will 
approve non-substantial amendments. 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IEC / IRB approval has already been given, are not initiated without IEC / IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.5 
Interruption of the Study  
The study may be discontinued if new data about the investigational product resulting from this or 
any other studies become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, the IECs / IRBs, or the governing regulatory authorities in the countries where the 
study is taking place.  
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 
applicable regulatory requirements. The Investigator shall promptly inform the subjects’ 
parents/guardians and should assure appropriate subject therapy and/or follow-up. 
The study may also be interrupted before the expected number of evaluable cases has been 
reached upon recommendation of the IDMC after interim analysis, if efficacy or futility criteria 
are met (See Section 12.4 for further details). In any case, the study will not stop before the 3 
influenza seasons are completed.  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 85 of 134 
6 
Products Administered  
6.1 
Identity of the Investigational Product  
6.1.1 Identity of Study Product  
The investigational QIV-HD is a quadrivalent influenza vaccine (split virion, inactivated) (60 μg 
HA/strain) containing virus strains chosen by the WHO (and recommended by Vaccines and 
Related Biological Products Advisory Committee [VRBPAC] in the US and EMA in EU) for the 
respective influenza season. The vaccine contains 2 antigens of type A (H1N1 and H3N2) and 
2 antigens of type B (one each from Yamagata and Victoria lineages). Each pre-filled syringe 
contains a total of 240 μg HA antigen per 0.7 mL dose provided in suspension for IM injection. 
QIV-HD vaccine does not contain preservative and is prepared from influenza viruses propagated 
in embryonated chicken eggs. 
6.1.1.1 Composition  
Each 0.7 mL dose of vaccine contains the following components: 
Strains are based on WHO recommendations for the considered influenza season. 
Active Substances: 
• A/H1N1-like strain 
 
 
 
60 µg HA 
• A/H3N2-like strain 
 
 
 
60 µg HA 
• B/(Victoria lineage)-like strain  
 
60 µg HA 
• B/(Yamagata lineage)-like strain  
 
60 µg HA 
Excipients: 
Buffered saline solution 
 
 
qs to appropriate volume 
Octylphenol Ethoxylate (Triton X-100)  
not more than 350 µg 
Preservative is not used in the manufacture of QIV-HD. QIV-HD may contain traces of eggs, such 
as ovalbumin, formaldehyde which are used during the manufacturing process. 
6.1.1.2 Preparation and Administration  
The vaccine is provided in a pre-filled single dose syringe and should be shaken before use. The 
vaccine is to be administered intramuscularly into the anterolateral muscle of the thigh or the 
deltoid muscle of the upper arm, as appropriate. If the vaccine is injected in the arm, it should be 
on the opposite arm from which blood was drawn before vaccination, as applicable. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.2.1), and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 86 of 134 
Subjects must be kept under observation for 30 minutes after each vaccination to ensure their 
safety, and any reactions during this period will be documented in the CRB. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic, vasovagal, or other immediate allergic reaction. 
6.1.1.3 Dose Selection and Timing  
The vaccination schedule is per standard practice for receipt of annual influenza vaccination for 
previously influenza vaccinated and influenza unvaccinated subjects and subjects 6 through 35 
months of age. 
6.1.2 Identity of Control Product  
The control product, Fluarix Quadrivalent (or other tradenames) is an influenza vaccine (split 
virion, inactivated), presented in a pre-filled syringe (QIV-SD) (GlaxoSmithKline Biologicals). 
The vaccine contains 2 antigens of type A (H1N1 and H3N2) and 2 antigens of type B (one each 
from Yamagata and Victoria lineages). Each pre-filled syringe contains a total of 60 μg HA 
antigen per 0.5  mL dose provided in suspension for IM injection. QIV-SD is registered in all 
countries where the trial will be conducted. 
6.1.2.1 Composition  
Each 0.5 mL dose contains 15 µg of HA for each of the following strains: 
Strains are based on WHO recommendations for the considered influenza season. 
Active Substances: 
• A/H1N1-like strain 
 
 
 
15 µg HA 
• A/H3N2-like strain 
 
 
 
15 µg HA 
• B/(Victoria lineage)-like strain  
 
15 µg HA 
• B/(Yamagata lineage)-like strain  
 
15 µg HA 
Excipients: 
Octylphenol-10 (Triton X-100)  
 
 
≤ 0.115 mg 
α-Tocopheryl hydrogen succinate   
 
≤ 0.135 mg 
Polysorbate 80 (Tween 80)   
 
 
≤ 0.550 mg 
 
QIV-SD does not contain a preservative. QIV-SD may contain traces of eggs (such as ovalbumin, 
chicken proteins), formaldehyde, gentamicin sulphate and sodium deoxycholate which are used 
during the manufacturing process  
6.1.2.2 Preparation and Administration  
QIV-SD will be prepared and administered according to manufacturer’s package insert. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 87 of 134 
6.1.2.3 Dose Selection and Timing  
The vaccination schedule is per standard practice for receipt of annual influenza vaccination for 
previously influenza vaccinated and influenza unvaccinated subjects and subjects 6 through 35 
months of age. 
6.2 
Product Logistics  
6.2.1 Labeling and Packaging  
The investigational and control vaccines for this study will be provided by the Sponsor and will be 
labeled in accordance with national regulations. 
The investigational QIV-HDs will be supplied in single dose syringes with investigational 
labeling and packaging. Each single dose will be identified by a unique medication number on the 
label and on the carton. The comparator vaccine, Fluarix Quadrivalent, will be supplied in single 
dose syringes with the manufacturer label on the syringes and an investigational label on the 
syringe and carton. The carton label will also have a detachable label for the sites to attach to the 
source documents. See the Operating Guidelines for additional label detail. 
6.2.2 Product Shipment, Storage, and Accountability  
6.2.2.1 Product Shipment  
The Vaccine Trial Supply Operations Manager or designee will contact the Investigator or a 
designee to determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product (comparator or investigational vaccine) to the 
site, the person in charge of product receipt will follow the instructions given in the Operating 
Guidelines, including checking that the cold chain was maintained during shipment (ie, 
verification of the temperature recorders). If there is an indication that the cold chain was broken, 
this person should immediately quarantine the product, alert the Sanofi Pasteur representative, and 
request authorization from Sanofi Pasteur to use the product. 
6.2.2.2 Product Storage  
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the study site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 88 of 134 
6.2.2.3 Product Accountability  
The person in charge of product management or vaccination study staff at the site will maintain 
records of product delivery to the study site, product inventory at the site, the dose(s) given to 
each subject, and the disposal of or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
CRB. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the study site’s product accountability records against 
the record of administered doses in the CRBs and the communication from the IRT (if applicable). 
In case of any expected or potential shortage of product during the study, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.2.3 Replacement Doses  
If a replacement dose is required (eg, because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must either contact the IRT to receive the new dose 
allocation, or follow the instructions given in the Operating Guidelines. 
6.2.4 Disposal of Unused Products  
Unused or wasted products will be returned to the Sponsor in accordance with the instructions in 
the Operating Guidelines. Product accountability will be verified throughout the study period. 
6.2.5 Recall of Products  
If the Sponsor makes a decision to launch a retrieval procedure, the Investigators will be informed 
of what needs to be done. 
6.3 
Blinding and Code-breaking Procedures  
Except for an open-label, unblinded Sentinel Safety Cohort for early safety data review, the study 
is designed as a modified double-blind study with the following measures to ensure the integrity 
of the data: 
• The unblinded qualified study staff member, independent of the safety evaluation, ILI 
surveillance, and other study evaluations, will administer the vaccine 
• The Investigators (or delegates) in charge of safety assessment and ILI surveillance, the study 
staff who collect the safety data and ILI surveillance, and the laboratory personnel who 
analyze the blood samples or NP samples will not know which product was administered 
• The subject’s parent / guardian will not know which product was administered. To maintain 
the blinding of the subject’s parent / guardian, the vaccine syringe label will be covered with 
appropriate materials prior to administration. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 89 of 134 
• Dose numbers will be used to identify each vaccine syringe for the purpose of randomization, 
vaccination, and the recording of vaccine administered. Dose numbers will be randomly 
assigned to QIV-HD and the commercial vaccines syringes. The IRT system will be 
responsible for providing the subject identification and dose number to be received by the 
enrolled subject. The subject’s parent / guardian, the Investigator, and study staff members 
who collect the safety data/ILI symptoms and laboratory personnel who analyze the blood 
samples or NP samples will all be blinded to the group assignment. The individual responsible 
for preparing / administering vaccine will not be authorized to collect any safety 
/serology/efficacy data. 
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the subject. Code-breaking should be limited to the 
subject(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur RMO if a 
subject’s code was broken. All contact attempts with the Sponsor prior to unblinding are to be 
documented in the source documents, and the code-breaking CRF is to be completed. 
A request for the code to be broken may also be made: 
• by the GPV Department through an internal system for reporting to Health authorities in the 
case of an SAE as described in ICH E2A.a In this case, the code will be broken only for the 
subject(s) in question. The information resulting from code-breaking (ie, the subject’s vaccine 
or group assignment) will not be communicated to either the Investigator or the immediate 
team working on the study, except for the GPV representative.  
• by the IDMC if needed to facilitate their assessment of safety. 
The IEC / IRB must be notified of the code-breaking. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
An interim analysis may be conducted by an independent statistician and reviewed by an IDMC 
during Season 3 if the likelihood of achieving the expected 
 cases at the end of the Season 3 is 
low and if at least
 evaluable influenza cases are collected. Unblinding is, therefore, necessary 
to the IDMC, but the information will not be communicated to either the Investigator or the 
Sponsor study team before the end of surveillance and database lock. 
6.4 
Randomization and Allocation Procedures  
The Sentinel Safety Cohort enrolled during the 2020-2021 NH influenza season, is uncontrolled 
and open-label. On the day of enrollment, subjects who fulfilled all the inclusion criteria and none 
of the exclusion criteria and complete the informed consent process will receive QIV-HD at 60 µg 
                                                 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 90 of 134 
HA/strain/dose. For all other subjects, the study will be randomized and modified double-blinded. 
On the day of enrollment, subjects who fulfilled all the inclusion criteria and none of the exclusion 
criteria and complete the informed consent process will be randomly assigned to receive either 
QIV-HD at 60 µg HA/strain/dose or Fluarix Quadrivalent in a 1:1 ratio.  
Site staff will connect to the IRT, enter the identification and security information, and confirm a 
minimal amount of data in response to IRT prompts. The IRT will then provide the subjects 
number, dose assignment and subset assignment for non-sentinel subjects. Randomization of 
subjects into vaccine groups will be performed with the permuted block method with stratification 
by site, previous influenza vaccination history, and age subgroup (< 24 months and ≥ 24 months), 
via Interactive Voice Response System (IVRS) / Interactive Web Response System (IWRS). 
Subjects that participate in Season 1 that are subsequently enrolled in the Season 3 Re-vaccination 
Cohort will be assigned a new subject number. IRT will also be used to randomize subjects into 
the immunogenicity and ESafAS subsets as defined in the protocol. 
The full detailed procedures for randomization are described in the Operating Guidelines and IRT 
specifications. If the subject is not eligible to participate in the study, then the information will 
only be recorded on the subject recruitment log. 
Subject numbers assigned in IRT will consist of a string of digits that will include information on 
the country, study site, and cohort/subset assignment.  Details are provided in the Operating 
Guidelines. 
Subject numbers should not be reassigned for any reason. The randomization codes will be kept 
securely in the IRT and an internal system until the interim or final analysis.  
6.5 
Treatment Compliance  
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified study personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site, product inventory at the site, dose(s) given to each 
subject, and the return of unused or wasted doses 
6.6 
Concomitant Medications and Other Therapies  
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions / AEs during study participation.  
All medications and vaccines will be considered reportable medications and will be coded in this 
study. 
Documentation in the CRB of all ongoing concomitant medication(s) will be collected. 
Medications will be collected in the CRB from the day of vaccination to the end of the study 
period (ie, follow-up telephone call).  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 91 of 134 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name or generic name 
• Origin of prescription: prophylaxisa Yes/No. Medication(s) prescribed for AE prophylaxis will 
be recorded in the “Action Taken” section of the AE collection tables. 
• Start and stop dates 
• Route of administration 
• Dosage 
• Dose schedule 
• Reason for treatment 
Homeopathic medication and topical treatments will not be recorded. Topical analgesics should not 
be applied at the site of vaccination; however, if they are applied inadvertently to the vaccination site, 
they should be recorded in this specific instance. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. 
7 
Management of Samples  
Blood samples for the assessment of antibody responses will be collected at Visits 1 and 2 for 
previously influenza vaccinated subjects and Visits 1 and 3 for previously influenza unvaccinated 
subjects that are randomized into the Immunogenicity Subset. See the Table of Study Procedures 
and Section 5.1.3 for details of the sampling schedule. 
7.1 
Sample Collection  
7.1.1 Blood Samples  
For subjects randomized into the Immunogenicity Subset, at Visit(s) 1 and 2 or 1 and 3 depending 
on influenza vaccination status described above, 5 mL of blood will be collected in tubes provided 
by or recommended by the Sponsor. Immediately prior to the blood draw, the staff member 
performing the procedure will verify the subject’s identity as well as the assigned subject’s 
number and sampling stage on the pre-printed label and will attach the label to the tube. When 
vaccination and blood sample collection occur at the same visit and vaccine is given only in one 
of the arms, blood is to be taken from the limb opposite to the one that will be used for 
vaccination, if possible. 
                                                 
a Prophylactic medication in this study is defined as a medication taken to prevent any AEs that may occur following the 
administration of the study vaccine(s) (vaccines listed in the trial product section of the protocol) during the solicited follow-up 
period. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 92 of 134 
7.1.2 Nasopharyngeal Samples  
For assessment of influenza virus by cell culture and PCR, an NP swab sample will be collected 
from both nasal passages using the same swab applicator and placed in a tube of universal 
transport medium (UTM) provided by the Sponsor. Immediately prior to taking the sample, the 
person performing the procedure will verify the subject’s identity and will confirm that the 8-digit 
subject number and any other required information are those of the subject. Each tube of UTM 
will be clearly labeled with a self-adhesive bar-coded label that will be applied to the tube 
immediately before collection of the NP swab. 
7.2 
Sample Preparation  
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
7.2.1 Blood Samples  
Following the blood draw, the tubes are to be left undisturbed, positioned vertically and not 
shaken, for a minimum of 1 hour and a maximum of 24 hours to allow the blood to clot. Samples 
can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be refrigerated at a 
temperature of +2°C to +8°C after the period of clotting at room temperature and must be 
centrifuged within a maximum of 24 hours. 
After centrifugation, the serum is transferred to the appropriate number of aliquoting tubes. These 
tubes are pre-labeled with adhesive labels that identify the study code, the subject’s number and 
the sampling stage or visit number. 
The subject’s number and the date of sampling, the number of aliquots obtained, the date and time 
of preparation, and the parent’s / guardian’s consent for future use of his / her child’s samples are 
to be specified on a sample identification list and recorded in the source document. Space is 
provided on this list for comments on the quality of samples. 
7.2.2 Nasopharyngeal Swabs  
Detailed instructions for the preparation of NP samples are described in the Operating Guidelines 
provided to the site. 
The subject’s identification number and any other required information, the date of sampling, and 
the date and time of preparation will be clearly documented. 
7.3 
Sample Storage and Shipment  
7.3.1 Blood Samples  
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 93 of 134 
during the entire study. If it rises above -10°C for any period of time, the Cold Chain Break Group 
must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratories will be made only after appropriate monitoring and following 
notification of the Monitoring Team. Sera will be shipped frozen, using dry ice to maintain them 
in a frozen state, in the packaging container provided by the carrier. Again, temperatures will be 
monitored. Shipments must be compliant with the United Nations (UN) Class 6.2 specifications 
and the International Air Transport Association (IATA) 602 packaging instructions. 
Samples will be shipped to Global Clinical Immunology (GCI) under the oversight of Research 
and Development Global Operations Sample Management and Logistics (R&D GO SML) at 
Sanofi Pasteur. The address is provided in the Operating Guidelines.  
7.3.2 Nasopharyngeal Samples  
Detailed instructions for the storage of NP swabs at study site and shipment of NP swab samples 
to testing laboratory (a laboratory under the guidance of GCI, USA) are described in the 
Operating Guidelines provided to the site. 
7.4 
Future Use of Stored Biological Samples for Research  
Any unused part of the serum samples and NP swab-derived products will be securely stored at 
the Sanofi Pasteur serology laboratory (GCI under the oversight of R&D GO SML), Swiftwater, 
Pennsylvania, USA) for up to 25 years after the end of the study (or more if required by local 
regulations). These samples are being retained in long-term storage to support answers to 
regulatory questions related to the product’s licensure and the potential revalidation of the study 
results. 
In addition if permitted by local regulations, Subjects’ parent(s) / guardian(s) will be asked to 
indicate in the ICF whether they will permit the future use of any unused stored serum samples for 
other tests. If they refuse permission, the samples will not be used for any testing other than that 
directly related to this study. If they agree to this use, they will not be paid for giving permission. 
Anonymity of samples will be ensured. The aim of any possible future research is unknown today 
and may not be related to this particular study. It may be to improve the knowledge of vaccines or 
infectious diseases, or to improve existing tests or develop new tests to assess vaccines. Human 
genetic tests will never be performed on these samples without specific individual informed 
consent.  
8 
Clinical Supplies  
Sanofi Pasteur will supply the study sites with protocols, ICFs, CRBs, SAE reporting forms, diary 
cards, memory aids, and other study documents, as well as with the following study materials: all 
study vaccines, blood collection tubes, cryotubes, cryotube storage boxes, cryotube labels, NP 
swab kit, temperature recorders, shipping containers, rulers, and digital thermometers. 
The means for performing EDC will be defined by Sanofi Pasteur. If a computer is provided by 
Sanofi Pasteur, it will be retrieved at the end of the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 94 of 134 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines.  
9 
Endpoints and Assessment Methods  
9.1 
Definitions  
Protocol-defined ILI: occurrence of fever ≥ 38°C (100.4°F) concurrently with at least one of the 
following symptoms: cough, wheezing, difficulty breathing, nasal congestion, rhinorrhea, 
pharyngitis (sore throat), otitis, vomiting, diarrhea, shivering (chills), fatigue (tiredness), 
headache, or myalgia (muscle aches). 
Modified CDC-defined ILI: occurrence of fever (defined as temperature > 38°C [> 100.4°F]) 
with cough, pharyngitis, or sore throat 
Laboratory-confirmed influenza: a positive influenza result on either polymerase chain reaction 
(PCR) or viral culture. 
Culture-confirmed influenza: a positive influenza result on viral culture. 
Genetic similarity: Genetic similarity is defined when a laboratory-confirmed isolate is deemed 
similar to one of the viral strains contained in the vaccine formulations according to sequencing of 
full HA gene segments proteins. 
Antigenic similarity: Antigenic similarity is defined when a laboratory-confirmed isolate is 
deemed similar to one of the viral strains contained in the vaccine formulations according to 
Ferret Antigenicity testing (hemagglutination inhibition [HAI] against a panel of known standard 
ferret reference antisera). 
Similarity to vaccine components: For prevention of laboratory-confirmed influenza illness 
caused by viral strains similar to those contained in the vaccine in subjects 6 months through 35 
months of age, laboratory-confirmed isolate is deemed similar to one of the vaccine components 
based on antigenic similarity only. For all the other endpoints, similarity is based on antigenic 
similarity when available or based on genetic similarity otherwise. 
ALRI: pneumonia, bronchiolitis, bronchitis, or laryngotracheobronchitis (croup) based on a 
clinical and/or x-ray diagnosis 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 95 of 134 
9.2 
Primary Endpoints and Assessment Methods  
9.2.1 Efficacy  
9.2.1.1 Efficacy Endpoints  
The primary endpoint for the evaluation of efficacy is the occurrence of laboratory-confirmed 
influenza illness (≥ 14 days post-vaccination) caused by any influenza viral types/subtypes, in 
association with a protocol-defined ILI.  
9.2.1.2 Efficacy Assessment Methods  
ILI Assessment 
ILI assessment will be based on information captured in the CRF reflecting information reported 
by the subject’s parent / guardian in the diary card or memory aid.  
Table 9.1 present the terminology used for ILI symptoms: the terms used in the CRF after 
investigator’s diagnosis and the corresponding ones used in the diary card / memory aid for the 
parent(s) / guardian to help them detecting an ILI. 
Table 9.1: ILI symptoms: terminology  
CRF term 
Diary card / memory 
aid term 
Fever 
Temperature 
Cough 
Cough 
Nasal congestion 
Stuffy nose 
Rhinorrhea 
Runny nose 
Otitis 
Earache 
Vomiting 
Vomiting 
Diarrhea 
Diarrhea 
Wheezing 
Wheezing 
Difficulty Breathing 
Difficulty Breathing 
Pharyngitis (sore 
throat) 
Sore Throat 
Shivering 
Chills 
Fatigue 
Tiredness 
Headache 
Headache 
Myalgia 
Muscle Aches 
Influenza Culture and Virus Isolation: 
NP swab samples from subjects with ILI will be used to inoculate and infect influenza virus 
susceptible tissue culture cell lines. Influenza positive cultures will be confirmed by using 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 96 of 134 
immunofluorescence techniques with influenza type–specific (eg, for influenza A and influenza 
B) antibodies. 
Molecular Detection (PCR): 
Clinical samples collected during the study period will undergo an extraction procedure to isolate 
the viral RNA from the NP swab prior to testing. 
The initial molecular test will be a real-time Reverse Transcriptase mediated Polymerase Chain 
Reaction (RT-PCR) based assay to determine if either Influenza A and/or Influenza B virus are 
present in the clinical sample.  
Note: All assays will be under the supervision of Sanofi Pasteur GCI, Swiftwater, PA. 
9.2.2 Immunogenicity  
There are no primary objectives for immunogenicity.  
9.2.3 Safety  
There are no primary objectives for safety.  
9.3 
Secondary Endpoints and Assessment Methods  
9.3.1 Efficacy  
9.3.1.1 Efficacy Endpoints  
The following endpoints will be used for efficacy comparisons: 
• Occurrence of laboratory-confirmed influenza illness (≥ 14 days post-vaccination) caused by 
any influenza viral types/subtypes, in association with a protocol-defined ILI. 
• Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as positive for 
viral strains similar to those contained in the vaccine  
• Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as positive in 
subjects 6 through 23 months of age for any influenza A or B type  
Descriptive Efficacy Endpoints 
In addition, the following endpoints will also be considered for the descriptive assessment of 
relative efficacy:  
Occurrence of an ILI starting ≥ 14 days after vaccination: 
• laboratory-confirmed as positive for any influenza A or B type, in subjects according to their 
previous vaccination status  
• laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, in 
subjects according to their previous vaccination status 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 97 of 134 
• laboratory-confirmed as positive for any influenza A or B type, and associated with AOM 
based on clinical diagnosis occurrence  
• laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, and 
associated with AOM based on clinical diagnosis occurrence 
• laboratory-confirmed as positive for any influenza A or B type, and associated with ALRI 
based on a clinical and/or x-ray diagnosis occurrence  
• laboratory-confirmed as positive for viral strains similar to those contained in the vaccine, and 
associated with ALRI based on a clinical and/or x-ray diagnosis occurrence 
• PCR-confirmed as positive for any influenza A or B types  
• PCR-confirmed as positive for viral strains similar to those contained in the vaccine 
• culture-confirmed as positive for any influenza A or B types 
• culture-confirmed as positive for viral strains similar to those contained in the vaccine 
• laboratory-confirmed as positive for any influenza A or B type and associated with 
hospitalization 
• laboratory-confirmed as positive for viral strains similar to those contained in the vaccine and 
associated with hospitalization 
9.3.1.2 Efficacy Assessment Methods  
Influenza Culture (Virus Isolation) and Molecular Detection (PCR): 
The assessment methods for the secondary efficacy objectives are the same as those listed for the 
primary efficacy assessment methods above in Section 9.2.1.2. 
Sequencing Methodology: 
For samples that exhibit as positive for influenza in viral culture and/or in the real-time RT-PCR 
detection assay, further testing by Sanger sequencing of the HA and NA full gene segments will 
be instituted to identify the specific subtype of the influenza strain. 
Note: Positive PCR samples that have negative culture results, or were unable to be expanded in 
culture, will not undergo additional testing.  
Ferret Antigenicity Testing: 
Influenza virus culture-positive samples will be typed using the HAI assay method against a panel 
of known standard ferret reference antisera to different influenza virus strains. The reference ferret 
antisera are pretreated enzymatically to remove non-specific inhibitors and incubated with test virus 
antigen and/or reference virus antigen. Turkey Red Blood Cells (RBCs) are prepared for use in the 
assay by washing and then added to the virus/antisera mixture. Following incubation, the reading is 
done by observing hemagglutination or inhibition of hemagglutination in the wells. The endpoint 
titer of the antisera against a specific virus antigen is the highest serum dilution in which complete 
inhibition of hemagglutination occurs. 
Antibodies directed against the viral HA prevent the binding of HA to its receptors, sialic acid 
containing glycoprotein present on the surface of RBCs, thereby preventing agglutination of RBCs 
by the virus. Antigenic variations in the hemagglutinin are reflected in differences in the ability of 
specific antisera to inhibit hemagglutination. The influenza virus antigen in the sample will be 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 98 of 134 
considered to be antigenically similar to the vaccine strain (matching) if there is a ≤ 4-fold 
difference in the titer of the clinical isolate and the vaccine strain against a reference antiserum 
homologous to the vaccine. 
9.3.2 Immunogenicity  
9.3.2.1 Immunogenicity Endpoints  
The following immunogenicity endpoints will be used for comparison in Immunogenicity Subset 
of Season 1: 
• Individual HAI titer on D0 and 28 days after the last vaccination 
• Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-injection titer ≥ 40 
(1/dil) on 28 days after the last vaccination or significant increase for subjects with a pre-
vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase from pre- to post-injection titer on 28 days after 
the last vaccination 
In addition, the 2 above and the following endpoints will be considered in the Immunogenicity 
Subset for the descriptive assessment of immunogenicity: 
• Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after the last 
vaccination 
• Individual titer ratio: 28 days after the last vaccination /D0 
• Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination 
Immunogenicity by SN method 
Immunogenicity will be evaluated using the SN assay in a subset of subjects from the 
Immunogenicity Subset. For each vaccine strain, antibody titers will be expressed as SN titers. 
The following immunogenicity endpoints will be described: 
• Individual SN antibody (Ab) titer on D0 and 28 days after the last vaccination 
• Individual SN Ab titer ratio (fold increase in post-vaccination titer relative to D0) at 28 days 
after the last vaccination 
• Subjects with SN Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D0 and 28 days after the 
last vaccination 
• Fold-increase in SN Ab titer [post/pre] ≥ 2 and ≥ 4 at 28 days after the last vaccination 
• Detectable SN Ab titer (SN Ab titer ≥ 10 [1/dil]) at D0 and 28 days after the last vaccination 
Immunogenicity by ELLA method 
For a subset of subjects, anti-N1 and anti-N2 titers will be measured for the 2 influenza A strains 
using ELLA and will be assessed based on the subject’s individual anti-NA titer. The following 
immunogenicity endpoints will be described: 
• Individual anti-NA Ab titer on D0 and 28 days after the last vaccination 
• Individual anti-NA Ab titer ratio (fold-rise in anti-NA post-vaccination titer relative to D0) at 
28 days after the last vaccination  
• Subjects with anti-NA Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D0 and 28 days after 
the last vaccination 
• Fold-rise in anti-NA Ab titer [post/pre] ≥ 2 and ≥ 4 at 28 days after the last vaccination 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 99 of 134 
• Detectable anti-NA titer (anti-NA Ab titer ≥ 10 [1/dil]) at D0, and 28 days after the last 
vaccination 
Re-vaccination Response 
For subjects enrolled in both Season 1 (NH) and Season 3 (NH), HAI Ab titers against the 4 
vaccine strains used in Season 3 (NH) will be measured at D0 and D28 in Season 3 (NH). The 
following endpoints will be described. 
• HAI individual titer on D0, and 28 days after the last vaccination 
• Individual HAI titer ratio: D28 days after the last vaccination /D0 
• Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after the last 
vaccination 
• Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination 
• Seroconversion for subjects with a pre-vaccination titer < 10 (1/dil): post-injection titer ≥ 40 
(1/dil) on 28 days after the last vaccination or significant increase for subjects with a pre-
vaccination titer ≥ 10 (1/dil): ≥ 4-fold increase from pre- to post-injection titer on 28 days after 
the last vaccination. 
9.3.2.2 Immunogenicity Assessment Methods  
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI supervision. The address is provided in the Operating 
Guidelines. 
Anti-Influenza Virus Ab Titration by Inhibition of Hemagglutination 
Test serum samples and quality control sera (sheep, ferret, and/or human sera) are incubated with 
Sigma Type III neuraminidase from Vibrio cholerae to eliminate non-specific inhibitors. 
Adsorption of spontaneous anti-species agglutinins is then performed by incubating the test serum 
samples and quality control sera with an RBC suspension. Following this, the mixtures are 
centrifuged and the supernatants containing the treated sera are collected for testing. Ten twofold 
dilutions (starting at 1:10) of the treated test serum samples and quality control sera are incubated 
with a previously titrated influenza antigen at a concentration of 4 hemagglutination unit 
(HAU)/25 µL. Influenza antigen is not added to the serum control wells containing only serum 
and RBCs. The mixture is then incubated and an RBC suspension is added. Following incubation, 
the results are read. The endpoint of the assay is the highest serum dilution in which complete 
inhibition of hemagglutination occurred. Each serum sample can either be tested in singleton (ie, 
one assay run) or in 2 independent assay runs (duplicate) which will include 2 independent 
samplings of the original serum and 2 independent preparations of influenza virus antigen. The 
decision to test the study samples, either in singleton or duplicate HAI, will be taken by the study 
team prior to the execution of clinical testing by the laboratory. The lower limit of quantitation 
(LLOQ) is set at the lowest dilution used in the assay, 1:10. Titers below this level are reported as 
< 10 (1/dil). If the lowest / first serum dilution used in the assay exhibits hemagglutination, the 
serum Ab titer will be reported as < 10 (1/dil). If the highest / last serum dilution used in the assay 
exhibits complete inhibition of hemagglutination, the serum Ab titer will be reported as ≥ 10240 
(1/dil).  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 100 of 134 
Influenza Virus Neutralization Test (also called serum neutralization (SN) assay in this 
protocol) 
NT measures Abs directed against the viral neutralization epitopes of the influenza virus, which 
may be different from the hemagglutination epitopes, therefore, the NT titers may be different 
from the HAI titers. 
To measure NT, serially diluted, heat-inactivated human serum samples will be 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 inhibits 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). Titers below this level are 
reported as < 10 (1/dil). Titers > 10240 (1/dil) will be pre-diluted, retested, and end point titers 
will be reported.  
Influenza Virus Antibody Titration by Enzyme-linked Lectin Assay 
The ELLA measures neuraminidase inhibiting Ab by quantifying enzymatic activity using 
peanutagglutinin (PNA) to bind to terminal galactose moieties that are exposed after enzymatic 
cleavage. Serum samples, quality control sera, and a determined amount of virus will be added 
into duplicate wells of a fetuin-coated 96-well plate and incubated overnight. The following day, 
peroxidase-conjugated PNA will be added to the washed plate and incubated, followed by 
washing and color development with o-Phenylenediamine dihydrochloride (OPD) substrate. The 
absence of color indicates inhibition of NA activity due to the presence of NA-specific inhibiting 
Abs. The titer of each determination will be the reciprocal of the last dilution with an optical 
density (OD) equal to or less than the midpoint between the mean OD of the virus only control 
wells and the mean OD of the background wells on each plate. The LLOQ is set at the reciprocal 
of the lowest dilution used in the assay, ie, 10 (1/dil). Titers below this level will be reported as 
< 10 (1/dil). There is no defined upper limit of quantification (ULOQ) for the NA1 and NA2 
ELLAs. There are assay ranges which have upper bounds that are established during method 
qualification. Samples which result in titers greater than these upper bounds would be retested 
using an additional 1:8 pre-dilution to bring the titer into the assay range and then back calculated 
to account for the pre-dilution factor of 1:8. 
9.3.3 Safety  
9.3.3.1 Safety Endpoints  
Reactogenicity will be described for the ESafAS: 
• Occurrence of any unsolicited systemic AEs reported in the 30 minutes after each vaccination 
• Occurrence of solicited (pre-listed in the subject’s diary card and CRB) injection site reactions 
and systemic reactions occurring up to 7 days after vaccination 
• Occurrence of unsolicited AEs up to 28 days after vaccination 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 101 of 134 
SAEs/AESIs will be described in all subjects: 
• Occurrence of SAEs (including AESIs) throughout the study 
• Occurrence of AESIs throughout the study 
9.3.3.2 Safety Definitions  
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Therefore an AE may be: 
• A new illness 
• The worsening of a pre-existing condition 
• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the actions taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the study period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing medical 
condition worsens following study interventions in frequency or intensity, or if according to the 
Investigator there is a change in its clinical significance, this change should be reported as an AE 
(exacerbation). This applies equally to recurring episodes of pre-existing conditions (eg, asthma) 
if the frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious, which is based on 
subject / event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose  
• Results in death 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 102 of 134 
• Is life-threateninga 
Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability / incapacityc 
• Is a congenital anomaly / birth defect 
• Is an important medical event (IME) 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as IMEs that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the health of the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These IMEs 
should also usually be considered serious. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse, new onset diabetes, or autoimmune disease. 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
The following additional definitions are used by Sanofi Pasteur: 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the product administered) that occur within the first 30 minutes after vaccination. 
Solicited Reaction: 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) pre-listed in the protocol and CRB (eg, injection site pain 
or headache occurring between D0 and D7 post-vaccination). 
By definition, solicited reactions are to be considered as being related to the product administered. 
For injectable vaccines, solicited reactions can either be solicited injection site reactions or 
solicited systemic reactions. 
Unsolicited AE / AR: 
                                                 
a  The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or outpatient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 103 of 134 
An unsolicited AE is an observed AE that does not fulfill the conditions pre-listed in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between D0 
and D7 is a solicited reaction (ie, pre-listed in the protocol and CRB), then a headache starting on 
D7 is a solicited reaction, whereas headache starting on D8 post-vaccination is an unsolicited AE. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
Injection Site Reaction: 
An injection site reaction is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions. They are considered to be related to the product administered. 
Systemic AE 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (eg, erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest is one of scientific and medical concern specific to the 
Sponsor’s product 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. 
9.3.3.3 Safety Assessment Methods  
At Visit 1, the Investigator or a clinical delegate will perform a clinical or medically-driven 
physical examination.  
At subsequent visits for subjects that are randomized to be included in the immunogenicity or 
Expanded safety analysis sets, the Investigator or delegate may perform a clinical or medically-
driven physical examination as necessary and will ask the subjects' parent / guardian about any 
solicited reactions and unsolicited AEs recorded in the diary card, as well as about any other AEs 
that may have occurred since the previous visit. All relevant data will be transcribed into the CRB 
according to the instructions provided by the Sponsor. 
9.3.3.3.1 Immediate Post-vaccination Observation Period  
Subjects will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. Any AE 
that occurs during this period will be noted on the source document for all subjects and recorded 
in the CRB for subjects in the expanded safety analysis set, as follows: 
• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected) for subjects in the expanded safety analysis set. 
• Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded in the CRB in the same way as any reactions starting on the day of vaccination for 
subjects in the expanded safety analysis set. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 104 of 134 
• For all subjects SAEs will be recorded in the CRB and reported to the Sponsor in the same 
way as any other SAEs, according to the procedures described in Section 10. 
9.3.3.3.2 Reactogenicity (Solicited Reactions from Day 0 to Day 7 After Each Vaccination)  
After each vaccination for subjects randomized into the Expanded safety analysis set, subjects' 
parent(s) / guardian(s) will be provided with a diary card, a digital thermometer, and a flexible 
ruler, and will be instructed how to use them. The following items will be recorded by the subjects 
in the diary card on the day of vaccination and for the next 7 days (ie, Day 0 through Day 7) until 
resolution: 
• Daily temperature, with the route by which it was taken 
• Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
• Action taken for each event (eg, medication) 
The action(s) taken by the subjects' parent or guardian to treat and/or manage any solicited 
reactions will be classified in the CRB using the following list (all applicable items should be 
checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination 
Table 9.2 and Table 9.3 present, respectively, the injection site reactions and systemic reactions 
that are pre-listed in the diary cards and CRB, together with the intensity scales. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 105 of 134 
Table 9.2: Solicited injection site reactions for children 6 through 35 months of age: terminology, definitions, and intensity scales  
CRB term 
(MedDRA 
LLT) 
Injection site tenderness 
Injection site 
erythema 
Injection site swelling 
Injection site 
induration 
Injection site 
bruising 
MedDRA PT 
Injection site pain 
Injection site 
erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Diary card 
term 
Tenderness 
Redness 
Swelling 
Hardening 
Bruising 
Definition 
Pain when the injection site is 
touched or injected limb 
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 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 106 of 134 
CRB term 
(MedDRA 
LLT) 
Injection site tenderness 
Injection site 
erythema 
Injection site swelling 
Injection site 
induration 
Injection site 
bruising 
Intensity scale* 
 
Grade 1: Minor reaction when 
injection site is touched 
Grade 2: Cries or protests 
when injection site is touched 
Grade 3 (CRB): Cries when 
injected limb is mobilized, or 
the movement of the injected 
limb is reduced 
Grade 3 (diary card): Cries 
when injected limb is moved or 
the movement of the injected 
limb is reduced 
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 
*  For the subjective reaction of tenderness, parents /guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and swelling, 
they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 107 of 134 
Table 9.3: Solicited systemic reactions for children 6 through 35 months of age: terminology, definitions, and intensity scales  
CRB term 
(MedDRA LLT) 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
MedDRA PT 
Pyrexia 
Vomiting  
Crying 
Somnolence 
Decreased appetite 
Irritability 
Diary card term 
Temperature 
Vomiting 
Abnormal crying 
Drowsiness 
Loss of appetite 
Irritability 
Definition 
Elevation of 
temperature to 
≥°38.0°C (≥ 100.4°F) 
Vomiting does not 
include spitting up 
Inconsolable crying 
without a determined 
reason 
Reduced interest in 
surroundings, or 
increased sleeping 
See intensity scale 
An excessive response 
to stimuli: increased 
fussiness, whining, and 
fretfulness despite 
attempts to comfort the 
infant and despite 
caregiver responses that 
would normally be 
soothing 
Intensity scale* 
Grade 1:  
≥ 38.0°C to ≤ 38.5°C 
or ≥ 100.4°F to ≤ 101.3°F 
Grade 1: 1 episode per 
24 hours 
Grade 1: < 1 hour 
Grade 1: Sleepier than 
usual or less interested 
in surroundings 
Grade 1: Eating less 
than normal 
Grade 1: Easily 
consolable 
 
Grade 2: 
> 38.5°C to ≤ 39.5°C 
or > 101.3°F to ≤ 103.1°F 
Grade 2: 2–5 episodes 
per 24 hours 
Grade 2: 1–3 hours  
Grade 2: Not interested 
in surroundings or did 
not wake up for a feed / 
meal 
Grade 2: Missed 1 or 2 
feeds / meals 
completely 
Grade 2: Requiring 
increased attention 
 
Grade 3: > 39.5°C 
or > 103.1°F 
Grade 3: ≥ 6 episodes 
per 24 hours or 
requiring parenteral 
hydration 
Grade 3: > 3 hours 
Grade 3: Sleeping most 
of the time or difficult 
to wake up 
Grade 3: Refuses ≥ 3 
feeds / meals or refuses 
most feeds / meals 
Grade 3: Inconsolable 
*  For all reactions but fever, parents / guardians will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, 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 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 108 of 134 
Important notes for the accurate assessment of temperature: 
Subjects' parent(s) / guardian(s) 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 diary card / memory aid, and 
the highest temperature will be recorded by the site in the CRB. The preferred route for this study 
is rectal for subjects enrolled in this study, however axillary is also acceptable if subjects' 
parent(s) / guardian(s) are unable to obtain the preferred route of measurement. Pre-vaccination 
temperature is also systematically collected by the Investigator on the source document. Tympanic 
thermometers must not be used. 
9.3.3.3.3 Unsolicited Adverse Events  
In addition to recording solicited reactions, subjects' parent(s) / guardian(s) of subjects 
randomized into the Expanded safety analysis set will be instructed to record any other medical 
events that may occur during the 28-day period after each vaccination to be taken as per the study 
design. Space will be provided in the diary card for this purpose.  
Information on SAEs will be collected and assessed throughout the study, from Day 0 until the 6-
month follow-up phone call or end of influenza season surveillance. Any SAE occurring at any 
time during the study will be reported by the Investigator in the CRB according to the completion 
instructions provided by the Sponsor; this includes checking the “Serious” box on the AE CRF 
and completing the appropriate Safety Complementary Information CRFs. All information 
concerning the SAE is to be reported either as part of the initial reporting or during follow-up 
reporting if relevant information became available later (eg, outcome, medical history, results of 
investigations, copy of hospitalization reports). In case a subject experiences febrile convulsion 
(neurological event associating fever and seizure), the assessment will be performed according to 
the “Guideline for definition and collection of cases of febrile convulsion”, and this event will be 
considered an SAE. See Section 10 for further details on SAE reporting. 
For each unsolicited AE (whether serious or non-serious), the following information is to be 
recorded: 
• Start and stop datesa  
• Intensity of the event: 
For measurable unsolicited AEs that are part of the list of solicited reactions, the size of the 
AE as well as the temperature for fever will be collected and analyzed based on the 
corresponding scale used for solicited reactions (see Table 9.2 and Table 9.3). 
All other unsolicited AEs will be classified according to the following intensity scale: 
                                                 
a  The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the study will be 
considered as ongoing at the end of the study. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 109 of 134 
• 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 
Diary card: No interference with usual activities. 
• 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 
Diary card: Some interference with usual activities.  
• 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 
Diary card: Significant; prevents usual activities. 
• Whether the AE was related to the investigational product (for unsolicited systemic AEs) 
The Investigator will assess the causal relationship between the AE and the investigational 
product as either “Not related” or “Related”, as described in Section 9.3.3.3.5. 
• Action taken for each AE (eg, medication) 
The action(s) taken by the subjects' parent or guardian to treat and/or manage any unsolicited 
AEs will be classified in the CRB using the following list (all applicable items should be 
checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination  
• Whether the AE was serious 
For each SAE, the Investigator will complete all seriousness criteria that apply (outcome, 
elapsed time, and relationship to study procedures) 
• Whether the AE caused study discontinuation 
9.3.3.3.4 Adverse Events of Special Interest  
AESIs will be captured as SAEs and will be collected throughout the study. These include new 
onset of GBS, encephalitis / myelitis (including transverse myelitis), Bell’s palsy, convulsions, 
optic neuritis, and brachial neuritis (26) (27) (28). 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 110 of 134 
9.3.3.3.5 Assessment of Causality  
The Investigator will assess the causal relationship between each unsolicited systemic AE and the 
product administered as either not related or related, based on the following definitions: 
Not related – The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before the first vaccination (screening phase, if applicable) 
Related – There is a “reasonable possibility” that the AE was caused by the product 
administered, meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all AEs reported at the injection site (whether solicited or unsolicited) and 
all solicited systemic AEs are considered to be related to the administered product and therefore 
are referred to as reactions and do not require the Investigator’s opinion on relatedness. 
Adverse events likely to be related to the product, whether serious or not, that persist at the end of 
the study will be followed up by the Investigator until their complete disappearance or the 
stabilization of the subject’s condition. The Investigator will inform the Sponsor of the date of 
final disappearance of the event or the date of “chronicity” establishment. 
9.4 
Observational Endpoints and Assessment Methods  
9.4.1 Efficacy  
9.4.1.1 Efficacy Endpoints  
• Occurrence of an ILI starting ≥ 14 days after vaccination, laboratory-confirmed as positive for 
each circulating influenza A subtype and B lineage: A/H1N1, A/H3N2, B/Victoria and 
B/Yamagata 
• Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-confirmed as 
positive in each age subgroup of subjects 
• Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-confirmed as 
positive in each season 
• Occurrence of an ILI starting ≥ 14 days after first vaccination, laboratory-confirmed as 
positive in subjects previously unvaccinated 
• Occurrence of an ILI starting ≥ 14 days after first vaccination and before second injection, 
laboratory-confirmed as positive in subjects previously unvaccinated 
• Occurrence of an ILI starting within 14-90 days after first vaccination, laboratory-confirmed 
as positive  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 111 of 134 
• Occurrence of a modified CDC-defined ILI starting ≥ 14 days after first vaccination, and 
laboratory-confirmed as positive 
• For subjects enrolled in both Season 1 (NH) and Season 3 (NH), occurrence of an ILI starting 
≥ 14 days after first vaccination in Season 3 (NH), laboratory-confirmed as positive according 
to the vaccination pattern 
Influenza-associated Events/ Health care utilization 
The following events that are associated with ILI and occurring within 30 days after the ILI onset 
will be described for cases of laboratory-confirmed ILI caused by any viral type/subtype and for 
any ILI, respectively: 
• Occurrence of AOM based on clinical diagnosis  
• Occurrence of ALRI (eg, pneumonia, lower respiratory tract infection, bronchiolitis, 
bronchitis, and croup) based on clinical and/or x-ray diagnosis 
• Occurrence, duration, and intensity of ILI symptoms  
• Occurrence of medication use (eg, antibiotics, antivirals)  
• Occurrence of hospitalizations  
• Occurrence of emergency room visits  
• Occurrence of non-routine medical office visits (including urgent care visits)  
• Occurrence of absenteeism 
9.4.1.2 Efficacy Assessment Methods  
9.4.2 Immunogenicity  
9.4.2.1 Immunogenicity Endpoints  
Immunogenicity for correlate of protection 
• HAI titer for each vaccine strain 28 days after the last vaccination, together with occurrence of 
an ILI starting ≥ 14 days after vaccination, confirmed as positive for any influenza A or B type 
• HAI titer for each vaccine strain 28 days after the last vaccination, together with occurrence of 
an ILI starting ≥ 14 days after vaccination, laboratory-confirmed for viral strains similar to 
those contained in the vaccine 
Antibody persistence 
For subjects enrolled in both Season 1 (NH) and Season 3 (NH) and who are randomized to the 
Immunogenicity Subset, the HAI Ab titers against the 4 vaccine strains used in Season 1 (NH) 
will be measured at D0 before starting vaccination in Season 3 (NH). The following endpoints 
will be described. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 112 of 134 
• HAI individual titer on D0 and 28 days after the last vaccination of Season 1 (NH) and on D0 
of Season 3 (NH)  
• Detectable HAI titer, ie, with a titer ≥ 10 (1/dilution [dil]) at D0 and 28 days after the last 
vaccination of Season 1 (NH) and on D0 of Season 3 (NH) 
• Subjects with titer ≥ 40 (1/dil) on D0 and 28 days after the last vaccination of Season 1 (NH) 
and on D0 of Season 3 (NH) 
9.4.2.2 Immunogenicity Assessment Methods  
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI supervision. The address is provided in the Operating 
Guidelines. 
A description of the anti-influenza antibody titration by inhibition of hemagglutination is found in 
Section 9.3.2.2. 
9.4.3 Safety  
There are no observational safety objectives.  
10 
Reporting of Serious Adverse Events  
To comply with current regulations on SAE reporting to health authorities, the Investigator must 
document all SAEs regardless of causal relationship and notify the Sponsor and the Clinical 
Research Associate (CRA) within the notification timelines stated in the following sections. The 
Investigator will give access and provide the Sponsor and the CRA with all necessary information 
to allow the Sponsor to conduct a detailed analysis of the safety of the investigational product(s). 
It is the responsibility of the Investigator to request all necessary documentation (eg, medical 
records, discharge summary, autopsy) in order to provide comprehensive safety information. All 
relevant information must then be transcribed onto the AE CRF and the appropriate Safety 
Complementary Information CRFs. 
10.1 Initial Reporting by the Investigator  
Serious adverse events occurring during a subject’s participation in the study or experiment must 
be reported within 24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must 
be reported, even if the Investigator considers that it is not related to the vaccine. The Investigator 
(licensed physician [M.D. or D.O.]) must validate the information entered on the AE CRF by 
completing the investigator validation form. 
The Investigator must indicate on the AE CRF that the event was serious and must complete the 
relevant SAE section of this form as well as the appropriate Safety Complementary Information 
CRFs. An e-mail alert will automatically be sent by the EDC system to the GPV mailbox, the 
CRA and the GCDSE-V with relevant SAE information details. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 113 of 134 
If the EDC system is unavailable, the site must notify the Sponsor, using the paper version of the 
CRB, as described in the operating guidelines. 
The Investigator must complete the paper copies of the AE CRF and of the appropriate Safety 
Complementary Information CRFs and send them to the Sponsor by one of the following means: 
• By fax, to the following number: +1 570-957-2782  
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.com 
• By express mail, to the following address: 
Global PharmacoVigilance, Sanofi Pasteur 
Discovery Drive 
Swiftwater, PA 18370 
When the EDC system becomes available, the Investigator must transcribe the information from 
the paper forms into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact the RMO. If the RMO cannot 
be reached, the Investigator may contact the Call Center as described in Section 5.3.  
10.2 Follow-up Reporting by the Investigator  
The AE CRF completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (eg, outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Safety Complementary Information CRFs. 
An e-mail alert will be sent automatically to the GPV Department and to the CRA. Copies of 
documents (eg, medical records, discharge summary, autopsy) may be requested by the GPV 
Department. 
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study  
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
investigational product(s), other products (eg, a benefit vaccine), or to the experiment must also be 
reported as soon as possible. In such a case, the reporting procedure to be followed is identical to 
that described in Section 10.1. 
10.4 Assessment of Causality  
The causal relationship between the SAE and the product administered will be evaluated by the 
Investigator as described in Section 9.3.3.3.5. 
Following this, the Sponsor’s Global Safety Officer will also assess the causal relationship to the 
product, based on the available information and current medical knowledge. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 114 of 134 
The causal relationship to study procedures will be also assessed in the CRB. 
The decision to modify or discontinue the study may be made after mutual agreement between the 
Sponsor and the Investigator(s).  
10.5 Reporting SAEs to Health Authorities and IECs / IRBs  
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO (
 MD, GCDSE-V) will notify the Investigators in writing of 
the occurrence of any reportable SAEs. The Investigators / Sponsor will be responsible for 
informing the IECs or IRBs that reviewed the study protocol according to local regulations. 
11 
Data Collection and Management  
11.1 Data Collection and CRB Completion  
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study subjects in the ESafAS for the recording of daily safety, ILI 
symptoms and associated events, and healthcare utilization described in Section 9.3.3.3. These 
diary cards will include pre-listed terms and intensity scales (see Table 9.2 and Table 9.3) as well 
as areas for free text to capture additional safety information or other relevant details. Subject's 
parent(s) / guardian(s) in the ESafAS will also be provided with rulers for measuring the size of 
injection site reactions, and with standard digital thermometers for measuring daily temperatures. 
To ensure consistency of reporting, the study sites will instruct subjects' parent(s) / guardian(s) on 
how to correctly use these tools.  
The 6-month follow-up will be done by interviewing subjects either during a visit or over the 
telephone using a questionnaire to capture ILI symptoms, associated events, and healthcare 
utilization, SAEs, AESIs, and medications if applicable. A memory aid will be provided to the 
subjects at the preceding study visit to help them record information on events occurring between 
this visit and the 6-month follow-up. 
Relevant information will be transcribed into the AE CRF. Any SAEs captured during this 6-
month follow-up period will be reported and followed up as per the normal process for reporting 
SAEs. 
At specified intervals, the Investigator or an authorized designee will interview the subjects' 
parent(s) / guardian(s) to collect the information recorded in the diary card, and will attempt to 
clarify anything that is incomplete or unclear. All clinical study information gathered by the study 
site will be reported electronically by the Investigator or authorized designee using a web-based 
CRB. (Any information that was not documented in the diary card will first be captured in the 
source document and then reported electronically.) The CRB has been designed specifically for 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 115 of 134 
this study under the responsibility of the Sponsor, using a validated Electronic Records / 
Electronic Signature-compliant platform (21 CFR Part 11). 
To ensure the correct and consistent completion of the CRBs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion instructions will be provided to assist with data entry during the course of the study. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in study personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any study personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry to track all modifications 
and ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRBs; must provide explanations for all missing information; and must sign the CRB using 
an e-signature. 
11.2 Data Management  
Management of SAE Data 
During the study, SAE data (reported on the AE, Death, and Safety Complementary Information 
CRFs) will be integrated into the Sponsor’s centralized GPV database upon receipt of these forms 
and after a duplicate check. Each case will be assigned a case identification number. Each case 
will be assessed by the case management platform or its delegate before being reported to the 
relevant authorities as necessary. The assessment of related cases will be done in collaboration 
with the Global Safety Officer and the RMO. Follow-up information concerning a completed case 
will be entered into the GPV database, and a new version of the case will be created. 
The information from the GPV database cases will be reconciled with that in the clinical database. 
Management of Clinical and Laboratory Data 
Clinical data, defined as all data reported in the CRB, and laboratory data will be handled by the 
Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
During the study, clinical data reported in the CRBs will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and / or consistency checks will be 
systematically applied to detect errors or omissions. In addition, data reviews may be performed 
several times by the Sponsor’s staff in the course of the study. Any questions pertaining to the 
reported clinical data will be submitted to the Investigator for resolution using the EDC system. 
Each step of this process will be monitored through the implementation of individual passwords to 
maintain appropriate database access and to ensure database integrity. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 116 of 134 
The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical Datawarehouse. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review  
A blind review of the data is anticipated through the data review process led by Data Management 
before database lock.  
12 
Statistical Methods and Determination of Sample Size  
12.1 Statistical Methods  
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, Version 9.4 or above (SAS Institute, Cary, North Carolina, 
USA). 
A statistical analysis plan (SAP) will be written and peer reviewed before any analyses. In 
accordance with the protocol, the SAP will describe all analyses to be performed by the Sponsor 
and all the conventions to be taken. 
Following the end of the Season 2, an interim analysis may be conducted by an independent 
statistician and reviewed by an IDMC during Season 3 in an attempt to stop the study at the end of 
Season 3 and avoid study extension in case the planned
 cases cannot be achieved in 3 
seasons. So the interim analysis will only be conducted if the likelihood of achieving the expected 
 cases at the end of Season 3 is low (avoiding to conduct the interim analysis if the expected 
 cases will be achieved) and if at least
 evaluable influenza cases are collected (to ensure 
enough power to assess the objectives). At the interim analysis, the primary objective and first 
secondary objective will be assessed and the predictive power to demonstrate these objectives at 
the end of the ongoing season and at the end of the study will be calculated. The IDMC may 
recommend stopping the study at the end of Season 3 if the primary objective and first secondary 
objective are demonstrated (ie, the stopping rule for superior efficacy), if there is a high 
probability to demonstrate these objectives at the end of Season 3, or for futility if the probability 
to demonstrate the primary objective at the end of the study is too low. In addition, at the time of 
the interim analysis, other efficacy and safety objectives may be assessed on the available data for 
information. 
The full analysis of all study objectives will be performed at the end of the study. In case the study 
is to be stopped prematurely following the results of an interim analysis, the full statistical report 
may be delivered in more than one step if deemed necessary. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 117 of 134 
12.1.1 Hypotheses and Statistical Methods for Primary Objective  
12.1.1.1 Hypotheses  
12.1.1.2 Statistical Methods  
Efficacy 
The vaccine efficacy of the 2 groups will be compared in a step-wise manner:  
A non-inferiority testing approach will be used first, using a non-inferiority margin of -10%. If 
non-inferiority is demonstrated, a superiority test will be used using a margin of 5%. Both tests 
will use a one-sided Type I error at 2.5%, and there is no need for multiplicity adjustment due to 
the step-wise approach. 
The rVE of QIV-HD to QIV-SD will be estimated for primary endpoint as follows: 
rVE= (1- (CHD / NHD) / (CSD / NSD)) × 100% 
where: 
• CHD and CSD are the numbers of influenza cases meeting the considered primary endpoint 
definition in the QIV-HD and QIV-SD groups, respectively.  
• For analysis in per-protocol analysis set, the first episode among those occurring more than 14 
days after the last vaccination will be considered. For analysis in full analysis set, the first 
episode among those occurring more than 14 days after the first vaccination will be 
considered. 
• If subject experiences multiple occurrences of the same endpoint, only the first episode will be 
considered  
• NHD and NSD are the numbers of subjects in the QIV-HD and QIV-SD groups, respectively.  
CIs for vaccine efficacy will be calculated by an exact method assuming a Binomial distribution 
of the number of cases in the QIV-HD group conditional on the total number of cases in both 
groups. 
The vaccine efficacy of QIV-HD will be considered as non-inferior to QIV-SD if the lower bound 
of the rVE is > -10%, and superior to QIV-SD if the lower bound of the CI for the rVE is > 5%. 
The Per-Protocol Analysis Set for Efficacy (PPASE) will be used as the primary analysis set for 
the non-inferiority test and the Full Analysis Set for Efficacy (FASE) will be used as the primary 
analysis set for the superiority test. 
If the interim analysis is conducted, an alpha spending method quoted by Lan and Demets (power 
family, phi=2) will be used to maintain an overall Type I error (the ‘alpha’) of 0.025 one-sided, 
considering that
 of information time is reached at the time. Consequently, a one-sided 
nominal alpha of 
and
 will be used at interim and final analysis, respectively. 
This corresponds to 
 and
 two-sided CIs to be used at interim and final analysis, 
respectively. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 118 of 134 
Should the interim analysis results fulfill the stopping rules as defined in Section 12.4, the study 
will be stopped at the end of Season 3 and the rVE will be estimated in the final analysis using a 
two-sided 95% CI if the superior efficacy stopping rule is fulfilled at the interim analysis or 
 CI if otherwise. 
A sensitivity analysis of the primary objective excluding all siblings participating in the study will 
also be provided to eliminate potential bias due to within-siblings flu contamination.  
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives  
12.1.2.1 Hypotheses  
12.1.2.1.1 Statistical Methods  
If the primary objective is demonstrated, the secondary confirmatory objectives will be tested. A 
hierarchical testing combined with graphical approach will be used to adjust the multiplicity of the 
4 secondary confirmatory objectives, which prevents any inflation of the overall one-sided Type I 
error beyond 2.5%. 
Efficacy 
For the first secondary objective, a superiority test will be used using a more stringent margin of 
 with the same nominal alpha levels being used in the interim 
analysis (ie, one-sided
) and in the final analysis (ie, one-sided
 if the stopping 
rule for superior efficacy is not fulfilled at the interim analysis or one-sided
 if otherwise) for 
the primary objective.  
At the time of the final analysis, if superiority is demonstrated, a graphical approach will be 
applied to control alpha within the 2 efficacy objectives. If one of them is claimed for efficacy 
using a two-sided 97.5% CI, then the other one will be tested using a two-sided 95% CI to assess 
superiority. 
Estimation of rVE for efficacy objectives will be the same as those described for the primary 
objective above in Section 12.1.1.2 except that QIV-HD will be considered as superior to QIV-SD 
if the lower bound of the CI for the corresponding rVE is > 0%. The FASE will be used as the 
mains analysis set. 
A complementary analysis of comparing Kaplan-Meier curves between QIV-HD and QIV-SD 
groups for the above secondary efficacy objectives will be performed.  
For the prevention of laboratory-confirmed influenza illness caused by viral strains similar to 
those contained in the vaccine in subjects 6 months through 35 months of age, a secondary 
analysis using similarity based on genetic sequencing and an exploratory analysis using similarity 
based on antigenic similarity when available or genetic similarity otherwise will be performed.  
A sensitivity analysis considering the first episode occurring from the first dose will be performed 
for the primary endpoint on the PPASE and FASE.  
Estimation of efficacy for other secondary objectives will be as described for the primary 
objective above; for each estimate of efficacy, a 95% CI will be calculated. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 119 of 134 
Immunogenicity 
If all of the above confirmatory efficacy objectives are demonstrated, a superiority testing 
approach will be used to compare post-vaccination GMTs and seroconversion rates between QIV-
HD and QIV-SD groups for each strain using a one-sided test with Type I error rate of 0.025 
following the individual hypotheses: 
 
 
 
where s: strain  
If superiority is demonstrated for post-vaccination GMTs and seroconversion rates for the 
4 strains, the immunogenicity of QIV-HD will be considered as superior to QIV-SD. The Full 
analysis set for immunogenicity (FASI) will be used as the main analysis set. 
Immunogenicity endpoints will be summarized for each vaccine strain with 95% CIs. The 95% 
CIs for the GMTs and GMT ratios (GMTRs) will be calculated using normal approximation of 
log-transformed titers. The 95% CIs for the proportions will be based on the Clopper-Pearson 
method. The ratios of GMTs will be obtained between groups with the 95% CIs calculated using 
normal approximation of log-transformed titers. The differences in the seroconversion rates 
between groups will be computed along with the two-sided 95% CIs by the Wilson-Score method 
without continuity correction. Additional parameters may be displayed as appropriate. 
Reverse cumulative distribution curves against each strain will be performed for baseline (V01) 
and post-vaccination immunogenicity (D28 or D56 as appropriate). 
Safety 
Safety results will be described for each vaccine group. The main parameters will be described 
with 95% CI. 
12.1.3 Statistical Methods for Observational Objective(s)  
Estimation of efficacy for the observational objectives will be as described for the primary 
objective; for each estimate of efficacy, a 95% CI will be calculated. 
Descriptive analysis and statistical models will be used to investigate
 As this analysis is exploratory, several statistical approaches 
such as
. These methods will be detailed 
in the SAP. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 120 of 134 
12.2 Analysis Sets  
Seven main analysis sets will be used: the FASE, the PPASE, the full analysis set for 
Immunogenicity (FASI), the per-protocol analysis set for Immunogenicity (PPASI), the 
Immunogenicity Analysis Set (IAS), the safety analysis set (SafAS), and the expanded safety 
analysis set (ESafAS).  
12.2.1 Full Analysis Set for Efficacy  
The FASE will be used for the analysis of all efficacy objectives and is defined as the subset of 
randomized subjects who received at least 1 dose of the study vaccine. Subjects will be analyzed 
as randomized.  
12.2.2 Safety Analysis Set  
The SafAS will be used for SAEs/AESIs analyses and is defined as those subjects who have 
received at least one dose of the study vaccine(s). In particular, sentinel subjects and the Re-
vaccination Cohort will be included in SafAS.  
12.2.3 Expanded Safety Analysis Set  
The ESafAS will be used for the analysis of solicited and unsolicited AEs and is defined as the 
sentinel subjects, subjects in the main cohort randomized in ESafAS and the Re-vaccination 
Cohort in Season 3 who received at least 1 dose of the study vaccine.  
All subjects will have their safety analyzed after each dose according to the vaccine they actually 
received, and after any dose according to the vaccine received at the 1st dose.  
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
12.2.4 Per-Protocol Analysis Set for Efficacy  
The PPASE is a subset of the FASE and will be used for primary and secondary efficacy 
objectives. The subjects presenting with at least one of the following conditions will be excluded 
from the PPASE: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria  
• Subject did not complete the vaccination schedule according to their previous vaccination 
history 
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• For previously unvaccinated subjects, subject did not receive 2nd injection in the proper time 
window (28 days to 38 days after first injection) 
• Subject received non-study influenza vaccine  

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 121 of 134 
• Subject did not have at least one contact point more than 14 days after vaccination and before 
the end of the surveillance period  
For note, any cases between dose 1 and dose 2 for subjects receiving two doses will not be 
considered in the PPASE analysis.  
The above conditions leading to exclusion from the PPASE may be detailed and completed if 
necessary in the SAP, following the review of protocol deviations during the study conduct. In 
any case, the PPASE definition will be finalized before the first database lock.  
In the event of a local or national immunization program with a pandemic influenza vaccine or 
other vaccine, subjects who receive 1 or more doses of pandemic influenza vaccine or other 
vaccine at any time during the study will not be withdrawn from the study. 
Subjects will be analyzed as treated. 
12.2.5 Full Analysis Set for Immunogenicity  
The FASI will be used as the main analysis set for secondary superior immunogenicity objective 
and is defined as the subjects randomized in Immunogenicity Subset in Season 1 who received at 
least 1 dose of the study vaccine and had one post-vaccination blood sample. Subjects will be 
analyzed as randomized. 
12.2.6 Per-Protocol Analysis Set for Immunogenicity  
The PPASI is a subset of the FASI and will be used for secondary superior immunogenicity 
objective as a sensitivity analysis. The subjects presenting with at least one of the following 
conditions will be excluded from the PPASI: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria  
• Subject did not complete the vaccination schedule according to their previous vaccination 
history  
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• For previously unvaccinated subjects, subject did not receive 2nd injection in the proper time 
window (28 days to 38 days after first injection) 
• Subject did not provide post-dose serology samples in the proper time window or a post-dose 
serology sample was not drawn 
• Subject received concomitant treatment that may affect the immunogenicitya or a non-study 
influenza vaccine, prior to the post-vaccination blood sample 
                                                 
a other vaccines, blood products, immune-suppressors, immune-modulators with immunosuppressive properties, anti-proliferative 
drugs such as DNA synthesis inhibitors 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 122 of 134 
In the event of a local or national immunization program with a pandemic influenza vaccine or 
other vaccine, subjects who receive 1 or more doses of pandemic influenza vaccine or other 
vaccine at any time during the study will not be withdrawn from the study. 
The above conditions leading to exclusion from the PPASI may be detailed and completed if 
necessary in the SAP, following the review of protocol deviations during the study conduct. In 
any case, the PPASI definition will be finalized before the first database lock.  
Subjects will be analyzed as treated. 
12.2.7 Immunogenicity Analysis Set  
The IAS will be used for all descriptive immunogenicity objectives and is defined as the subjects 
in the main cohort randomized in Immunogenicity Subset and the subjects in the Re-vaccination 
Cohort in Season 3 who received at least 1 dose of the study vaccine and had one post-vaccination 
blood sample. Subjects will be analyzed as treated. 
For analysis of immunogenicity by NT and ELLA methods, the subset of IAS with available 
results on the considered serological method will be used. 
For correlate of protection assessment, subjects part of both IAS and FASE will be considered. 
12.2.8 Populations Used in Analyses  
In addition to the ones above, all randomized subjects with data in the CRB will be taken into 
account in the description of the population (eg, the disposition, the demographic, or baseline 
characteristics).  
12.3 Handling of Missing Data and Outliers  
12.3.1 Efficacy  
For primary objective, a time-to-event analysis will be conducted to address the possible 
imbalance in the drop-out rates between vaccine groups. Further details will be described in SAP. 
12.3.2 Immunogenicity  
For HAI and ELLA tests, in order to appropriately manage replicate values for analysis purposes, 
the individual geometric mean of all values will be computed for each blood sample after 
managing extreme values as described. The computed value is then considered the titer for that 
particular blood sample. 
• If a titer is < LLOQ, then the computed value, LLOQ/2, will be used. 
• If a titer is ≥ LLOQ and < upper limit of quantitation (ULOQ) , then the titer itself will be 
used. 
• If a titer is ≥ ULOQ (or ˃ ULOQ), then computed value, ULOQ, will be used. 
Any other replacement to be applied to specific endpoints will be described in the SAP. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 123 of 134 
No test or search for outliers will be performed.  
For the secondary confirmatory immunogenicity objective, if the degree of missing 
immunogenicity data in FASI is unexpectedly high (more than
) on HAI data for at least one 
strain, a sensitivity analysis with multiple imputation methods will be performed.  
12.3.3 Safety  
No replacement will be done. Nevertheless, missing relationship will be considered as related at 
the time of the statistical analysis. No search for outliers will be performed. In all subject listings, 
partial and missing data will be clearly indicated as missing. 
12.4 Interim / Preliminary Analysis  
Due to the unpredictable epidemiology of influenza, the sample size and/or the duration of the 
study may be adjusted based on the blinded number of influenza cases in order to maintain the 
likelihood of achieving the expected number of influenza cases for the primary endpoint. 
In any case, the study will not stop before the 3 influenza seasons are completed. However, 
following the end of the second influenza season, if the likelihood of achieving the expected
cases at the end of the Season 3 is too low, and if at least
 influenza cases meeting the primary 
endpoint have occurred, an interim analysis is planned to be conducted by an independent 
statistician and reviewed by an IDMC during Season 3.  The study may stop if the primary 
objective and first secondary objectives are demonstrated, if there is a high probability to 
demonstrate these objectives at the end of the ongoing season, or for futility if the probability to 
demonstrate the primary objective at the end of the study is too low.  
The stopping rules are: 
     
Detailed statistical methods for the calculation of predicted total number of evaluable cases and 
the predictive power will be provided in the SAP. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 124 of 134 
12.5 Determination of Sample Size and Power Calculation  
A total of approximately 13,320 subjects will be enrolled: 100 subjects will be enrolled in the 
2020-2021 NH influenza season in the open-label Sentinel Safety Cohort and 13,220 subjects in 
the  main cohort will be enrolled over 3 subsequent influenza seasons with a randomization ratio 
of 1:1 for QIV-HD to QIV-SD. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 125 of 134 
Table 12.1: Planned sample size by vaccine and influenza season  
Vaccine 
Number of Subjects 
QIV-HD for open-label, 
Sentinel Safety Cohort 
100 
 
Vaccine 
Season 1 (NH) 
Randomized 
Immunogenicity 
Subset  
Expanded safety 
analysis set 
 
QIV-HD 
QIV-SD 
Total 
  
  
  
  
Vaccine 
Season 2 (SH) 
Randomized 
Immunogenicity 
Subset   
Expanded safety 
analysis set 
(ESafAS) 
QIV-HD 
QIV-SD 
Total 
  
  
  
  
Vaccine 
Season 3 (NH) 
Randomized 
Immunogenicity 
Subset  
Expanded safety 
analysis set 
(ESafAS) 
QIV-HD 
QIV-SD 
Total 
Vaccine 
Season 3 (NH) Re-vaccination Cohort† 
QIV-HD 
QIV-SD 
Total 
Overall Total 
13,320 subjects with
 tested for immunogenicity*, 
 for 
expanded safety, and 100 Sentinel Safety Cohort subjects 
Abbreviations: NH, Northern Hemisphere; QIV-HD, high-dose quadrivalent influenza vaccine; QIV-SD, standard-dose 
quadrivalent influenza vaccine; SH, Southern Hemisphere 
* Number of subjects who provide blood samples in Season 1 (NH) is greater than in Season 2 (SH) or Season 3 (NH) because 
unlike the Season 2 and 3 sera, which will be used for the descriptive immunogenicity results and 
 Season 1 (NH) sera will also be used to demonstrate immunogenicity superiority.  
†Approximately 
 subjects from the Immunogenicity Subset of Season 1 (NH) will re-enroll in Season 3 (NH) to be 
evaluated for antibody persistence and re-vaccination immunogenicity endpoints. These subjects will not be part of the 
approximately
 subjects in Season 3 who are being followed for ILI surveillance and efficacy. 
 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 126 of 134 
Table 12.2: Samples sizes for evaluation based on assessment method  
Assessment Method 
Number of Subjects 
hemagglutination inhibition 
(HAI) 
approximately
 subjects (all subjects in the 
Immunogenicity Subset) 
seroneutralization (SN) 
approximately
 subjects in Season 1’s 
Immunogenicity Subset 
enzyme-linked lectin assay 
(ELLA) 
Approximately
 subjects in Season 1’s 
Immunogenicity Subset 
 
Calculation of Sample Size 
For efficacy assessments: 
The sample size needed for the assessment of the primary objective of the study is expected to be 
approximately
subjects and may be adjusted based on the blinded number of cases in order 
to maintain the likelihood of achieving approximately 
 evaluable influenza cases from the 
PPASE meeting the primary endpoint.  
These required numbers of evaluable influenza cases would provide at least 
 power at final 
analysis to conclude on the primary objective under the following assumptions: 
• The true rVE of QIV-HD to QIV-SD is 
  
• An overall one-sided Type I error rate 0.025 (
 spent at interim and final 
analysis, respectively) 
• The lower bound of the CI of rVE should be > 5%  
• An allocation ratio of QIV-HD to QIV-SD of 1:1 
• An overall influenza attack rate of 
 for the occurrence of an influenza case in the QIV-SD 
group 
• 
 of enrolled subjects evaluable for the primary endpoint  
Based on the same assumptions and using a 
 threshold, the power for the first secondary 
objective at final analysis is expected at 
 approximately. 
For the assessment of the two other secondary confirmatory efficacy objectives, the assumptions 
will be similar to those for primary objective except 
• The lower bound of the CI for the corresponding rVE will be superior to 0 %. 
• The true rVE of QIV-HD to QIV-SD is 
for each subset (ie, subjects 6 through 35 months 
of age against similar strains and subjects 6 through 24 months of age against any strains) 
• 
 evaluable influenza cases (
 of total cases) from each subset 
For each objective, a 
 power will be achieved with a two-sided 97.5% CI and an 
 power 
will be achieved with a two-sided 95% CI. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 127 of 134 
For the immunogenicity assessments: 
Approximately 
subjects will be assessed for HAI immunogenicity in Season 1. Based on 
Phase II immunogenicity results and assuming
 of non-evaluable subjects, this provides 
approximately
 probability to obtain 95% CIs of ratios of GMTs and differences in 
seroconversion rates excluding equality for a given season (formulation).  
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities  
13.1 Ethical Conduct of the Study / Good Clinical Practice  
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
13.2 Source Data and Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. The purpose of study source documents is to document the existence of subjects and 
to substantiate the integrity of the study data collected. Investigators must maintain source 
documents so that they are accurate, complete, legible, and up to date. 
For missing or discrepant data on a diary card, the study coordinator will obtain verbal clarification 
from the subject, enter the response into the “investigator’s comment” page of the diary card, and 
transfer the information to the CRB. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the study, regardless of the outcome. 
The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
by the Sponsor or an inspector against the electronic records. Any subsequent changes of an 
electronic record require the record to be re-printed, dated (with an indication of the date of 
change), and signed. Such records must also be kept together with the original printed copy. 
Good Documentation Practice should be followed by the Investigator and the site staff managing 
source documents. 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 128 of 134 
13.3 Confidentiality of Data, Data Protection, and Access to Subject Records  
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality agreement 
with Sanofi Pasteur. In the event a subject’s medical records are not at the investigational site, it is 
the responsibility of the Investigator, to obtain those records if needed. 
All personal data collected related to subjects, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations, including the GDPR (General Data Protection Regulation). 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. 
Subjects’ race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (30). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
that would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the subjects, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party.  
13.4 Monitoring, Auditing, and Archiving  
13.4.1 Monitoring  
Before the start of the study (ie, before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the study protocol and the detailed study procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRB completion, and the handling of samples and products. The Sponsor’s 
staff or a representative will ensure and document that all material to be used during the study has 
been received at the site; and that the study investigator team and local Sponsor/delegate staff 
have been properly informed about the study, GCP and regulatory requirements, and the 
Sponsor’s procedures. Specific training sessions for the study investigator team and the CRAs on 
these topics may be performed as necessary and should be documented. 
The following instruction manuals will be provided: the CRF Completion Instructions for entering 
data into the CRB, and the Operating Guidelines for detailed study procedures such as the product 
management and sample-handling procedures. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 129 of 134 
After the start of the study, the Sponsor’s staff or a representative will be in regular contact with 
the investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits and must allow the Sponsor/delegate staff direct access 
to subject medical files and CRBs. During these visits, the Sponsor/delegate staff will: 
• Evaluate the quality of the study progress (adherence to protocol and any study-specific 
guidelines, quality of data collection and document completion, signature of consent forms, 
occurrence of SAEs, sample and product management, cold-chain monitoring, archiving) 
• Source-verify completed CRBs and any corresponding answered queries 
• Determine the number of complete or ongoing issues identified at monitoring visits (eg, 
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator, 
and corrective or preventive actions will be determined, as appropriate. 
• After all protocol procedures have been completed and the data have been entered into the 
CRB, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the study, a close-out visit will be performed to ensure that: 
• The center has all the documents necessary for archiving 
• All samples have been shipped to the appropriate laboratories 
• All unused materials and products have been either destroyed or returned to the Sponsor 
13.4.2 Audits and Inspections  
A quality assurance audit may be performed at any time by the Sponsor’s Clinical Quality 
Assessment department (CQA) or by independent auditors to verify that the study has been 
conducted according to the protocol, GCP and ICH requirements, and other applicable 
regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to study documents during these inspections and audits. 
13.4.3 Archiving  
The Investigator and the study site shall retain and preserve 1 copy of the Study File containing 
the essential documents related to the study and records generated during the study (“Study File”) 
for the longer of the 2 following periods (“Retention Period”): 
• 25 years after the signature of the final study report or  
• such longer period as required by applicable regulatory requirements 
If during the Retention Period, the study site is no longer able to retain the Study File due to 
exceptional circumstances (such as bankruptcy), the study site shall contact the Sponsor to 
organize the transfer of the Study File to the Sponsor’s designee at the Sponsor’s expense. 
Following the Retention Period, the Investigator and/or the study site are responsible to dispose of 
the Study File according to the applicable regulations. Patient medical records shall be retained in 
compliance with local regulations. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 130 of 134 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other documents 
related to the study will be kept by the Sponsor in the Trial Master File (TMF). Data on AEs are 
included in the TMF. All data and documents will be made available if requested by relevant 
authorities. 
13.5 Financial Contract and Insurance Coverage  
A Clinical Trial Agreement will be signed by all the parties involved in the study’s performance, 
if relevant. The Sponsor has an insurance policy to cover any liabilities that may arise from use of 
the product and / or the study protocol. 
13.6 Stipends for Participation  
Subjects’ parent / guardian may be provided with a stipend, according to local practice, to 
compensate for the time and travel required for study visits and procedures. 
13.7 Publication Policy  
Data derived from this study are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the study must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the study, any participating center may 
publish or otherwise use its own data provided that any publication of data from the study gives 
recognition to the study group. In addition, Sanofi Pasteur shall be offered an association with all 
such publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study at least 90 days prior to submission for publication / 
presentation. Any information identified by Sanofi Pasteur as confidential must be deleted prior to 
submission, it being understood that the results of this study are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 131 of 134 
14 Reference List  
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 Viruses. 2019 01;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. (2012). Vaccines against influenza WHO position paper – 
November 2012. Wkly Epidemiol Rec. 2012 Nov 23;87(47):461–76. 
10.  
World Health Organization. (2019). Global influenza strategy 2019-2030. World Health 
Organization. https://apps.who.int/iris/handle/10665/311184. 
11.  
Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in 
healthy children. Cochrane Database Syst Rev. 2018;(2):CD004879. 
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.  
Centers for Disease Control and Prevention, National Center for Immunization and 
Respiratory Diseases (NCIRD). Past Seasons Vaccine Effectiveness Estimates [homepage 
on the Internet]. Centers for Disease Control and Prevention; c2019 [updated 2020 
January 29; cited 2021 Aug 18]. Available from: https://www.cdc.gov/flu/vaccines-
work/past-seasons-estimates.html 
14.  
Centers for Disease Control and Prevention. Flu vaccination coverage, United States, 
2015-16 influenza season [homepage on the Internet]. Centers for Disease Control and 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 132 of 134 
Prevention; [cited 2019 Oct 26]. Available from: 
https://www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm 
15.  
Chang L-J, Meng Y, Janosczyk H, Landolfi V, Talbot HK, QHD00013 Study Group. 
Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults 
≥65 years of age: A phase 3 randomized clinical trial. Vaccine. 2019;37(39):5825–34. 
16. 
Halasa NB, Gerber MA, Berry AA, Anderson EL, Winokur P, Keyserling H, et al. Safety 
and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) 
Compared With Half-Dose TIV Administered to Children 6 Through 35 Months of Age. J 
Pediatric Infect Dis Soc. 2015;4(3):214–24. 
17.  
Safety and Immunogenicity of Fluzone® Quadrivalent Vaccine Administered to Healthy 
Children [homepage on the Internet]. U.S. National Library of Medicine; [updated 2018 
April 03; cited 2019 October 26].Available from: 
https://clinicaltrials.gov/ct2/show/NCT02915302 
18.  
An Efficacy Study of GlaxoSmithKline (GSK) Biologicals’ Candidate Influenza Vaccine 
GSK2321138A in Children [homepage on the Internet]. U.S. National Library of 
Medicine; [updated 2018 September 26; cited 2019 October 26]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01439360 
19.  
Fiore AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and 
control of influenza. Recommendations of the Advisory Committee on Immunization 
Practices (ACIP), 2007. MMWR. 2007;56(RR-6):1–54. 
20.  
Institute of Medicine. 2012. Adverse Effects of Vaccines: Evidence and Causality. 
Washington, DC: The National Academies Press. Doi: 10.17226/13164. 
21.  
Centers for Disease Control and Prevention. Prevention and control of seasonal influenza 
with vaccines. Recommendations of the Advisory Committee on Immunization Practices -
United States, 2013-2014. MMWR. 2013;62(RR-07):1–43. 
22.  
Fluarix® Quadrivalent [package insert]. GlaxoSmithKline Biologicals (Dresden, 
Germany). 
23.  
Fluzone® High-Dose Quadrivalent [package insert]. Sanofi Pasteur (Swiftwater, PA, 
USA). 
24.  
Granström M, Voordouw AC. Registration of influenza vaccines for children in Europe. 
Vaccine. 2011;29(43):7572–5. 
25.  
Grohskopf LA, Alyanak E, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and 
Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory 
Committee on Immunization Practices — United States, 2019–20 Influenza Season. 
MMWR Recomm Rep. 2019;68(3):1–21. 
26.  
Sejvar JJ, Kohl KS, Gidudu J, Amato A, Bakshi N, Baxter R, et al. and Brighton 
Collaboration GBS Working Group. Guillain-Barré syndrome and Fisher syndrome: Case 

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 133 of 134 
definitions and guidelines for collection, analysis, and presentation of immunization safety 
data. Vaccine. 2011;29(3):599–612. 
27.  
Bonhoeffer J, Menkes J, Gold MS, de Souza-Brito G, Fisher MC, Halsey N, et al; and 
Brighton Collaboration Seizure Working Group. Generalized convulsive seizure as an 
adverse event following immunization: case definition and guidelines for data collection, 
analysis, and presentation. Vaccine. 2004;22(5–6):557–62. 
28.  
Sejvar JJ, Kohl KS, Bilynsky R, Blumberg D, Cvetkovich T, Galama J, et al; and Brighton 
Collaboration Encephalitis Working Group. Encephalitis, myelitis, and acute disseminated 
encephalomyelitis (ADEM): Case definitions and guidelines for collection, analysis, and 
presentation of immunization safety data. Vaccine. 2007;25(31):5771–92. 
29.  
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials. 
Chapman and Hall/CRC. 2000. 
30.  
Guidance for Industry and Food and Drug Administration Staff. Collection of race and 
ethnicity data in clinical trials [homepage on the Internet]. Available from: 
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126396.pdf 
                                                                                                                                          

Sanofi Pasteur 
QHD00014 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 4.0 
 
Confidential/Proprietary Information 
Page 134 of 134 
15 Signature Page  
 
 
 
 

Signature Page for VV-CLIN-0563179 v4.0
flu-qiv-hd-qhd00014-protocol
Approve & eSign
Clinical
VV-CLIN-0563179 4.0