Safety and Immunogenicity of Fluzone® Quadrivalent, Flublok® Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines, 2018-2019 Formulations
Phase: PHASE4
Conditions: Influenza
Sponsor: Sanofi Pasteur, a Sanofi Company

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Safety and Immunogenicity of Fluzone® Quadrivalent, Flublok® 
Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines, 
2018–2019 Formulations 
Phase IV, multi-center, open-label study to assess the safety and immunogenicity of Fluzone® 
Quadrivalent vaccine in children and adults, Flublok® Quadrivalent vaccine in adults, and 
Fluzone® High-Dose vaccine in older adults 
Clinical Study Protocol 
Health Authority File Number: 
BB-IND #: 4518 
WHO Universal Trial Number (UTN): 
U1111-1211-4864 
Study Code: 
GRC90 
Development Phase: 
Phase IV 
Sponsor: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Investigational Products: 
Fluzone® Quadrivalent, Influenza Vaccine (2018–2019 formulation) 
Flublok® Quadrivalent, Influenza Vaccine (2018–2019 formulation) 
Fluzone® High-Dose, Influenza Vaccine (2018–2019 formulation) 
Form/Route: 
Liquid/Intramuscular 
Indication For This Study: 
To evaluate the safety and immunogenicity of the 2018–2019 
formulations of Fluzone Quadrivalent vaccine in children 6 months to 
< 9 years of age and adults 18 to < 65 years of age, Flublok 
Quadrivalent vaccine in adults 18 to < 65 years of age, and Fluzone 
High-Dose vaccine in adults ≥ 65 years of age, with all study vaccines 
given by the intramuscular route 
Manufacturer: 
Same as Sponsor 
Coordinating Investigator: 
 
Tel: 
; Fax: 
 
Sponsor’s Responsible Medical 
Officers: 
, 
  
 
Sanofi Pasteur Inc. 
Tel: 
  
Fax: 
 
 
 
Sanofi Pasteur Inc. 
Tel: 
  
Fax: 
  
Pharmacovigilance Global Safety 
Expert: 
 
Sanofi Pasteur Inc. 
Tel: 
; Email: 
 
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NCT Number: NCT03617523

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Clinical Trial Manager: 
 
  
Sanofi Pasteur Inc. 
Tel: 
; Fax: 
 
Version and Date of the Protocol: 
Version 1.0 dated 18 May 2018 
 
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. 
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History of Protocol Versions 
Not applicable as this is the first version of the protocol. 
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Table of Contents 
History of Protocol Versions ........................................................................................................... 3 
List of Tables .................................................................................................................................... 9 
Synopsis .......................................................................................................................................... 10 
Tables of Study Procedures .......................................................................................................... 19 
List of Abbreviations ..................................................................................................................... 21 
1 
Introduction ..................................................................................................................... 23 
1.1 
Background ..................................................................................................................... 23 
1.1.1 
Epidemiology ................................................................................................................ 25 
1.1.2 
Prevention and Control of Infection Among Humans .................................................. 26 
1.1.3 
The Advisory Committee on Immunization Practices Recommendations ................... 27 
1.2 
Background of the Investigational Product ..................................................................... 27 
1.3 
Potential Benefits and Risks ........................................................................................... 29 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 29 
1.3.2 
Potential Risks to Subjects ........................................................................................... 29 
1.4 
Rationale for the Study ................................................................................................... 31 
2 
Study Objectives .............................................................................................................. 31 
2.1 
Observational Objectives ................................................................................................ 31 
2.1.1 
Safety ............................................................................................................................ 31 
2.1.2 
Immunogenicity ............................................................................................................ 31 
2.1.3 
Serum Collection .......................................................................................................... 32 
3 
Investigators and Study Organization ........................................................................... 32 
4 
Independent Ethics Committee/Institutional Review Board....................................... 32 
5 
Investigational Plan ......................................................................................................... 33 
5.1 
Description of the Overall Study Design and Plan ......................................................... 33 
5.1.1 
Study Design ................................................................................................................. 33 
5.1.2 
Justification of the Study Design .................................................................................. 33 
5.1.3 
Study Plan ..................................................................................................................... 33 
5.1.4 
Visit Procedures ............................................................................................................ 34 
5.1.5 
Planned Study Calendar ................................................................................................ 38 
5.1.6 
Early Safety Data Review ............................................................................................. 39 
5.2 
Enrollment and Retention of Study Population .............................................................. 39 
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5.2.1 
Recruitment Procedures ................................................................................................ 39 
5.2.2 
Informed Consent Procedures ...................................................................................... 39 
5.2.3 
Screening Criteria ......................................................................................................... 40 
5.2.4 
Inclusion Criteria .......................................................................................................... 40 
5.2.5 
Exclusion Criteria ......................................................................................................... 40 
5.2.6 
Medical History ............................................................................................................ 42 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 42 
5.2.7.1 
Temporary Contraindications ..................................................................................... 42 
5.2.7.2 
Definitive Contraindications ...................................................................................... 42 
5.2.8 
Conditions for Withdrawal ........................................................................................... 43 
5.2.9 
Lost to Follow-up Procedures ....................................................................................... 44 
5.2.10 
Classification of Subjects Who Discontinue the Study ................................................ 44 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 45 
5.2.12 
Follow-up and Reporting of Pregnancies ..................................................................... 45 
5.3 
Safety Emergency Call ................................................................................................... 46 
5.4 
Modification of the Study and Protocol .......................................................................... 46 
5.5 
Interruption of the Study ................................................................................................. 46 
6 
Vaccines Administered ................................................................................................... 46 
6.1 
Identity of the Investigational Products .......................................................................... 47 
6.1.1 
Identity of Licensed Study Product 1 ........................................................................... 47 
6.1.1.1 
Composition ............................................................................................................... 48 
6.1.1.2 
Preparation and Administration ................................................................................. 48 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 48 
6.1.2 
Identity of Licensed Study Product 2 ........................................................................... 48 
6.1.2.1 
Composition ............................................................................................................... 49 
6.1.2.2 
Preparation and Administration ................................................................................. 49 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 49 
6.1.3 
Identity of Licensed Study Product 3 ........................................................................... 49 
6.1.3.1 
Composition ............................................................................................................... 49 
6.1.3.2 
Preparation and Administration ................................................................................. 49 
6.1.3.3 
Dose Selection and Timing ........................................................................................ 50 
6.1.4 
Identity of Control Products ......................................................................................... 50 
6.2 
Identity of Other Products ............................................................................................... 50 
6.3 
Product Logistics ............................................................................................................ 50 
6.3.1 
Labeling and Packaging ................................................................................................ 50 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 50 
6.3.2.1 
Product Shipment ....................................................................................................... 50 
6.3.2.2 
Product Storage .......................................................................................................... 50 
6.3.2.3 
Product Accountability ............................................................................................... 51 
6.3.3 
Replacement Doses ....................................................................................................... 51 
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6.3.4 
Disposal of Unused Products ........................................................................................ 51 
6.3.5 
Recall of Products ......................................................................................................... 51 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 51 
6.5 
Randomization and Allocation Procedures ..................................................................... 51 
6.6 
Treatment Compliance .................................................................................................... 52 
6.7 
Concomitant Medications and Other Therapies ............................................................. 52 
7 
Management of Samples ................................................................................................. 53 
7.1 
Sample Collection ........................................................................................................... 53 
7.2 
Sample Preparation ......................................................................................................... 54 
7.3 
Sample Storage and Shipment ........................................................................................ 54 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 54 
8 
Clinical Supplies .............................................................................................................. 55 
9 
Endpoints and Assessment Methods ............................................................................. 55 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 55 
9.1.1 
Safety ............................................................................................................................ 55 
9.1.2 
Immunogenicity ............................................................................................................ 55 
9.1.3 
Efficacy ......................................................................................................................... 55 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 56 
9.2.1 
Safety ............................................................................................................................ 56 
9.2.2 
Immunogenicity ............................................................................................................ 56 
9.2.3 
Efficacy ......................................................................................................................... 56 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 56 
9.3.1 
Safety ............................................................................................................................ 56 
9.3.1.1 
Safety Definitions ....................................................................................................... 56 
9.3.1.2 
Safety Endpoints ........................................................................................................ 59 
9.3.1.3 
Safety Assessment Methods ....................................................................................... 59 
9.3.1.3.1 
Immediate Post-vaccination Observation Period ..................................................... 59 
9.3.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 Through Day 7 After Each 
Vaccination) ............................................................................................................. 60 
9.3.1.3.3 
Unsolicited Adverse Events ..................................................................................... 68 
9.3.1.3.4 
Adverse Events of Special Interest .......................................................................... 69 
9.3.1.3.5 
Assessment of Causality .......................................................................................... 70 
9.3.2 
Immunogenicity ............................................................................................................ 70 
9.3.2.1 
Immunogenicity Endpoints ........................................................................................ 70 
9.3.2.2 
Immunogenicity Assessment Methods ....................................................................... 71 
9.3.3 
Efficacy ......................................................................................................................... 71 
9.3.4 
Serum Collection .......................................................................................................... 71 
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9.3.4.1 
Serum Collection Endpoints and Assessment Methods ............................................. 71 
10 
Reporting of Serious Adverse Events ............................................................................ 71 
10.1 
Initial Reporting by the Investigator ............................................................................... 72 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 72 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 73 
10.4 
Assessment of Causality ................................................................................................. 73 
10.5 
Reporting SAEs to Health Authorities and IECs/IRBs ................................................... 73 
11 
Data Collection and Management ................................................................................. 73 
11.1 
Data Collection and CRB Completion ............................................................................ 73 
11.2 
Data Management ........................................................................................................... 74 
11.3 
Data Review .................................................................................................................... 75 
12 
Statistical Methods and Determination of Sample Size ............................................... 75 
12.1 
Statistical Methods .......................................................................................................... 75 
12.1.1 
Hypotheses and Statistical Methods for Primary Objectives ....................................... 75 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 75 
12.1.3 
Statistical Methods for Observational Objectives ........................................................ 75 
12.1.3.1 
Safety .......................................................................................................................... 76 
12.1.3.2 
Immunogenicity ......................................................................................................... 76 
12.2 
Analysis Sets ................................................................................................................... 76 
12.2.1 
Safety Analysis Set ....................................................................................................... 76 
12.2.2 
Full Analysis Set ........................................................................................................... 76 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 77 
12.2.4 
Populations Used in Analyses ...................................................................................... 77 
12.3 
Handling of Missing Data and Outliers .......................................................................... 77 
12.3.1 
Safety ............................................................................................................................ 77 
12.3.2 
Immunogenicity ............................................................................................................ 77 
12.4 
Interim/Preliminary Analysis .......................................................................................... 78 
12.5 
Determination of Sample Size and Power Calculation ................................................... 78 
13 
Ethical and Legal Issues and Investigator/Sponsor Responsibilities .......................... 78 
13.1 
Ethical Conduct of the Study/Good Clinical Practice ..................................................... 78 
13.2 
Source Data and Source Documents ............................................................................... 78 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 79 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 79 
13.4.1 
Monitoring .................................................................................................................... 79 
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13.4.2 
Audits and Inspections .................................................................................................. 80 
13.4.3 
Archiving ...................................................................................................................... 80 
13.5 
Financial Contract and Insurance Coverage ................................................................... 81 
13.6 
Stipends for Participation ................................................................................................ 81 
13.7 
Publication Policy ........................................................................................................... 81 
14 
Reference List .................................................................................................................. 82 
15 
Signature Page ................................................................................................................. 84 
 
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List of Tables 
Table 9.1: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales 
(Subjects 6 to < 36 Months of Age) ............................................................................................... 61 
Table 9.2: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales 
(Subjects 3 to < 9 Years of Age) .................................................................................................... 62 
Table 9.3: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales 
(Subjects 18 Years of Age and Older) ............................................................................................ 63 
Table 9.4: Solicited Systemic Reactions: Terminology, Definitions, and Intensity Scales 
(Subjects 6 to < 36 Months of Age) ............................................................................................... 65 
Table 9.5: Solicited Systemic Reactions: Terminology, Definitions, and Intensity Scales 
(Subjects 3 to < 9 Years of Age and 18 Years of Age  and Older) ................................................ 66 
 
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Synopsis 
Company: 
Sanofi Pasteur 
Investigational Products: 
Fluzone® Quadrivalent, Flublok® Quadrivalent, and Fluzone® High-Dose 
Influenza Vaccines (2018–2019 Formulations) 
Active Substances: 
For Fluzone Quadrivalent and Flublok Quadrivalent vaccines, influenza 
virus surface antigens and recombinant hemagglutinin antigen, respectively, 
of the following strains: 
• 
A/Michigan/45/2015 (H1N1) 
• 
A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• 
B/Maryland/15/2016 (B Victoria lineage) 
(a B/Colorado/06/2017-like virus) 
• 
B/Phuket/3073/2013 (B Yamagata lineage) 
For Fluzone High-Dose, influenza virus surface antigens of the following 
strains: 
• 
A/Michigan/45/2015 (H1N1) 
• 
A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• 
B/Maryland/15/2016 (B Victoria lineage)  
(a B/Colorado/06/2017-like virus) 
Title of the Trial: 
Safety and Immunogenicity of Fluzone® Quadrivalent, Flublok® 
Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines, 2018–2019 
Formulations 
Development Phase: 
Phase IV 
Coordinating Investigator: 
 
Study Sites: 
This will be a multi-center study conducted in 3 sites in the United States. 
Investigators and sites are listed in the “List of Investigators and Centers 
Involved in the Trial” document. 
Planned Study Period: 
First Visit, First Subject: September 2018 
Last Visit, Last Subject: December 2018 
Study Design, Schedule of Study 
Procedures, and Methodology: 
This will be a Phase IV, multi-center, open-label study of a planned 
240 subjects to describe the safety and immunogenicity of Fluzone 
Quadrivalent vaccine in children 6 months to < 9 years of age and adults 
18 to < 65 years of age, Flublok Quadrivalent vaccine in adults 18 to < 65 
years of age, and Fluzone High-Dose vaccine in adults ≥ 65 years of age. 
Using a pre-programmed interactive response technology (IRT) system, 
each subject will be assigned to a vaccine group based on the subject’s age 
at the time of enrollment. An approximately equal number of subjects from 
each group will be enrolled at each site. 
Using the IRT system, subjects 18 to < 65 years of age will be randomly 
assigned to either Group 3 or Group 4. Enrollment in Group 3 and Group 4 
will be stratified by age into 2 subgroups at each site so that approximately 
50% of subjects at each site will be 18 to < 50 years of age and 
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approximately 50% of subjects at each site will be 50 to < 65 years of age, 
and so that an equal proportion of subjects within each age subgroup receive 
either Fluzone Quadrivalent or Flublok Quadrivalent vaccine. If necessary to 
achieve 50% overall enrollment of subjects 50 to < 65 years of age and 
assignment of Fluzone Quadrivalent and Flublok Quadrivalent vaccines in a 
1:1 ratio within each age subgroup (i.e., 18 to < 50 years of age and 50 to 
< 65 years of age), individual sites may be permitted to deviate from these 
ratios. 
• 
Group 1: Children 6 to < 36 months of age assigned to receive a 
0.25-mL dose of Fluzone Quadrivalent vaccine (30 subjects planned) 
• 
Group 2: Children 3 to < 9 years of age assigned to receive a 0.5-mL 
dose of Fluzone Quadrivalent vaccine (30 subjects planned) 
• 
Group 3: Adults 18 to < 65 years of age assigned to receive a 0.5-mL 
dose of Fluzone Quadrivalent vaccine (60 subjects planned)  
• 
Group 4: Adults 18 to < 65 years of age assigned to receive a 0.5-mL 
dose of Flublok Quadrivalent vaccine (60 subjects planned)  
• 
Group 5: Adults ≥ 65 years of age assigned to receive a 0.5-mL dose of 
Fluzone High-Dose vaccine (60 subjects planned)  
 
Vaccination 
All subjects will receive either a 0.25-mL (subjects 6 to < 36 months of age 
[Group 1]) or a 0.5-mL (subjects 3 to < 9 years of age and ≥ 18 years of age 
[Groups 2, 3, 4, and 5]) intramuscular injection of study vaccine based on 
their assigned group at Visit 1. For subjects 6 months to < 9 years of age for 
whom 2 doses of influenza vaccine are recommended per Advisory 
Committee on Immunization Practices guidance, a second intramuscular 
injection of Fluzone Quadrivalent vaccine (same 0.25-mL or 0.5-mL volume 
as administered at Visit 1) will be administered at Visit 2 (28 [window, 28–
35] days after Visit 1).  
Blood Sampling Collection of Safety Data 
Study sites, at their discretion, may apply a topical analgesic to the 
venipuncture site prior to obtaining sera. However, topical analgesic agents 
must not be applied at the site of vaccine administration. 
Subjects 6 months to < 9 Years of Age (Group 1 and Group 2): 
Blood specimens (approximately 5 mL) will be obtained from all subjects 
prior to the first vaccination at Visit 1 (Day 0) and 28 (window, 28–35) days 
following the final vaccination (Visit 2, if no study vaccine is administered 
at Visit 2; or Visit 3, if a second dose of study vaccine is administered at 
Visit 2) and assayed for immunogenicity.  
Staff will observe subjects for 20 minutes following study vaccine 
administration and will record the occurrence of any immediate unsolicited 
systemic adverse events (AEs). Subjects’ parents/guardians will record 
information about solicited injection site and systemic reactions from Day 0 
through Day 7 post-vaccination, and will record information about 
unsolicited non-serious AEs and serious adverse events (SAEs) from Visit 1 
through Visit 2 for subjects receiving 1 dose of study vaccine, and from 
Visit 1 through Visit 3 for subjects receiving 2 doses of study vaccine. 
Staff will contact parents/guardians by telephone on Day 8 
(window, Days 8–10) after any study vaccine administration to remind them 
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to record any AEs experienced and any concomitant medications taken from 
the most recent visit to the next visit in the diary card and to bring the diary 
card with them to the next visit. Parents/guardians will also be reminded to 
notify the site immediately if an SAE occurs. 
Staff will review the Visit 1 through Visit 2 safety data for all vaccinated 
subjects with parents/guardians at Visit 2. Staff will also review the Visit 2 
through Visit 3 safety data with parents/guardians at Visit 3 for subjects 
receiving 2 doses of study vaccine. 
Subjects ≥ 18 years of age (Group 3, Group 4, and Group 5):  
Blood specimens (approximately 20 mL) will be obtained from all subjects 
prior to vaccination at Visit 1 and 21 (window, 21–28) days post-vaccination 
(Visit 2).  
Staff will observe subjects for 20 minutes following study vaccine 
administration and will record the occurrence of any immediate unsolicited 
systemic AEs. Subjects will record information about solicited injection site 
and systemic reactions from Day 0 through Day 7 post-vaccination, and will 
record information about unsolicited non-serious AEs and SAEs from 
Visit 1 through Visit 2. 
Staff will contact subjects by telephone on Day 8 (window, Days 8–10) after 
study vaccine administration to remind them to record any AEs experienced 
and any concomitant medications taken from the most recent visit to the 
next visit in the diary card and to bring the diary card with them to the next 
visit. Subjects will also be reminded to notify the site immediately if an SAE 
occurs. 
Staff will review the Visit 1 through Visit 2 safety data for all vaccinated 
subjects at Visit 2.  
Early Safety Data Review: 
This study will not include an early review of safety data. However, it may 
be interrupted at any time if new data about the investigational products 
become available, and/or on advice of the Sponsor, the Institutional Review 
Board(s) (IRB[s]), or the Food and Drug Administration (FDA).  
Interruption of the Study: 
The study may be discontinued if new data about the investigational 
product(s) resulting from this study or any other studies become available; 
or for administrative reasons; or on advice of the Sponsor, the Investigators, 
the IRB(s), or the governing regulatory authorities in the country where the 
study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall 
promptly inform the Investigators, the IRB(s), 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 study subjects or 
subjects’ parents/guardians, as appropriate, and should assure appropriate 
subject therapy and/or follow-up. 
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Observational Objectives: 
Safety  
To describe the safety of the 2018–2019 formulation of Fluzone 
Quadrivalent vaccine in children 6 to < 36 months of age and 3 to < 9 years 
of age, and in adults 18 to < 65 years of age, the safety of the 2018–2019 
formulation of Flublok Quadrivalent vaccine in adults 18 to < 65 years of 
age, and the safety of the 2018–2019 formulation of Fluzone High-Dose 
vaccine in adults ≥ 65 years of age.  
Immunogenicity  
To describe the immunogenicity of the 2018–2019 formulation of Fluzone 
Quadrivalent vaccine in children 6 to < 36 months of age and 3 to < 9 years 
of age, and in adults 18 to < 65 years of age, the immunogenicity of the 
2018–2019 formulation of Flublok Quadrivalent vaccine in adults 18 to 
< 65 years of age, and the immunogenicity of the 2018–2019 formulation of 
Fluzone High-Dose vaccine in adults ≥ 65 years of age.  
Serum Collection 
To provide available sera (collected from subjects before vaccination [Blood 
Sample 1] and after final vaccination [Blood Sample 2]) to the Center for 
Biologics Evaluation and Research for further analysis by the World Health 
Organization, the Centers for Disease Control and Prevention, and the FDA 
to support formulation recommendations for subsequent influenza vaccines. 
In addition, available sera from adult subjects may be further analyzed by 
the Sponsor to assess breadth of immune response induced by the study 
vaccines. 
Observational Endpoints: 
Safety 
1) 
Occurrence, nature (Medical Dictionary for Regulatory Activities 
[MedDRA] preferred term), duration, intensity, and relationship to 
vaccination of any unsolicited systemic AEs reported in the 20 minutes 
after vaccination. 
2) 
Occurrence, time to onset, number of days of occurrence, intensity, 
action taken, and whether the reaction led to early termination from the 
study, of solicited injection site reactions (prelisted in the subject’s 
diary card and case report book [CRB]) occurring from Day 0 through 
Day 7 after vaccination. 
3) 
Occurrence, time to onset, number of days of occurrence, intensity, 
action taken, and whether the reaction led to early termination from the 
study, of solicited systemic reactions (prelisted in the subject’s diary 
card and CRB) occurring from Day 0 through Day 7 after vaccination. 
4) 
Occurrence, nature (MedDRA preferred term), time to onset, duration, 
intensity, action taken, relationship to vaccination (for systemic AEs 
only), and whether the event led to early termination from the study, of 
unsolicited AEs from Visit 1 through Visit 2 for subjects receiving 
1 dose or from Visit 1 through Visit 3 for subjects receiving 2 doses. 
5) 
Occurrence, nature (MedDRA preferred term), time to onset, 
seriousness criteria, relationship to vaccination, outcome, and whether 
the SAE led to early termination from the study, of SAEs from Visit 1 
through Visit 2 for subjects receiving 1 dose or from Visit 1 through 
Visit 3 for subjects receiving 2 doses. 
Adverse events of special interest will be captured as SAEs. These include 
new onset of Guillain-Barré syndrome (GBS), encephalitis/myelitis 
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(including transverse myelitis), neuritis (including Bell’s palsy, optic 
neuritis, and brachial neuritis), thrombocytopenia, vasculitis, convulsions 
(including febrile convulsions [children only]), and anaphylaxis or other 
hypersensitivity/allergic reactions from Visit 1 through Visit 2 for subjects 
receiving 1 dose of vaccine, or from Visit 1 through Visit 3 for subjects 
receiving 2 doses of vaccine. 
Immunogenicity 
Immunogenicity will be evaluated in all subjects by analyzing sera 
collected prior to vaccination on Day 0 (Visit 1) and after final vaccination 
(28 [window, 28–35] days post-final vaccination for subjects 6 months to 
< 9 years of age [Visit 2 for subjects receiving 1 dose; Visit 3 for subjects 
receiving 2 doses]; or 21 [window, 21–28] days post-vaccination for 
subjects ≥ 18 years of age) using the hemagglutination inhibition (HAI) 
assay technique.  
For each influenza vaccine strain (i.e., 3 strains for Fluzone High-Dose 
vaccine [a trivalent vaccine] and 4 strains for Fluzone Quadrivalent vaccine 
and Flublok Quadrivalent vaccine), HAI assay titers at pre-vaccination 
(Day 0) and after the final vaccination will be determined in duplicate.  
The derived endpointsa are: 
• 
Geometric means of HAI assay titers at pre-vaccination and post-final 
vaccination  
• 
Ratios of post-final vaccination titers divided by pre-vaccination titers 
• 
Seroprotection: a titer ≥ 40 (l/dilution [dil]) at pre-vaccination and at 
post-final vaccination  
• 
Seroconversion: either a pre-vaccination titer < 10 (1/dil) and a post-
final vaccination titer ≥ 40 (1/dil), or a pre-vaccination titer ≥ 10 (1/dil) 
and a ≥ 4-fold increase in post-final vaccination titer  
a   Post-final vaccination in each of the derived endpoints is defined as 
 28 (window, 28–35) days post-final vaccination for subjects 6 months to 
 < 9 years of age, and 21 (window, 21–28) days post-vaccination for 
 subjects ≥ 18 years of age 
Serum Collection 
There are no observational endpoints for the serum collection objective. 
Planned Sample Size: 
The study will enroll approximately 240 subjects: approximately 30 subjects 
6 to < 36 months of age will be administered Fluzone Quadrivalent vaccine 
(Group 1), approximately 30 subjects 3 to < 9 years of age will be 
administered Fluzone Quadrivalent vaccine (Group 2), approximately 
60 subjects 18 to < 65 years of age will be administered Fluzone 
Quadrivalent vaccine (Group 3), approximately 60 subjects 18 to < 65 years 
of age will be administered Flublok Quadrivalent vaccine (Group 4), and 
approximately 60 subjects ≥ 65 years of age will be administered Fluzone 
High-Dose vaccine (Group 5).  
No study power assessment will be done for this study. Only descriptive 
statistical analyses will be conducted in this study. 
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Duration of Participation in the 
Study: 
Subjects 6 months to < 9 years of age: 28 (window, 28–35) days following 
the last dose of influenza vaccine, including immunogenicity and safety 
follow-up. No additional safety follow-up beyond Visit 2 (for subjects 
receiving 1 dose) or Visit 3 (for subjects receiving 2 doses) is planned. 
Subjects ≥ 18 years of age: 21 (window, 21–28) days after vaccination, 
including immunogenicity and safety follow-up. No additional safety 
follow-up beyond Visit 2 is planned. 
Licensed Study Product 1: 
Fluzone Quadrivalent vaccine, No Preservative: Pediatric Dose (0.25-mL 
dose), 2018–2019 formulation 
or 
Fluzone Quadrivalent vaccine, No Preservative (0.5-mL dose), 2018–2019 
formulation 
 Form: 
Liquid – pre-filled syringes 
 Composition: 
Each 0.25-mL dose contains 7.5 µg hemagglutinin (HA) of each antigen, 
and each 0.5-mL dose contains 15 µg HA of each antigen: 
• 
A/Michigan/45/2015 (H1N1) 
• 
A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• 
B/Maryland/15/2016 (B Victoria lineage)  
(a B/Colorado/06/2017-like virus) 
• 
B/Phuket/3073/2013 (B Yamagata lineage)  
 Route: 
Intramuscular 
 Batch Number: 
TBD 
Licensed Study Product 2: 
Flublok Quadrivalent vaccine, 2018–2019 formulation 
 Form: 
Liquid – pre-filled syringes 
 Composition: 
Each 0.5-mL dose contains 45 µg recombinant HA of each antigen: 
• 
A/Michigan/45/2015 (H1N1) 
• 
A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• 
B/Maryland/15/2016 (B Victoria lineage) 
(a B/Colorado/06/2017-like virus) 
• 
B/Phuket/3073/2013 (B Yamagata lineage)  
 Route: 
Intramuscular 
 Batch Number: 
TBD 
Licensed Study Product 3: 
Fluzone High-Dose vaccine, 2018–2019 formulation 
 Form: 
Liquid – pre-filled syringes 
 Composition: 
Each 0.5-mL dose contains 60 µg HA of each antigen:  
• 
A/Michigan/45/2015 (H1N1) 
• 
A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• 
B/Maryland/15/2016 (B Victoria lineage) 
(a B/Colorado/06/2017-like virus) 
 Route: 
Intramuscular 
 Batch Number: 
TBD 
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Inclusion Criteria: 
An individual must fulfill all of the following criteria to be eligible for study 
enrollment: 
1) Aged 6 months to < 9 years or ≥ 18 years on the day of first study 
vaccination (study product administration). 
2) For subjects 6 to < 12 months of age, born at full term of pregnancy 
(≥ 37 weeks) and with a birth weight ≥ 2.5 kg (5.5 lbs). 
3) Informed consent form (ICF) has been signed and dated by subjects 
≥ 18 years of age. 
4) Assent form has been signed and dated by subjects 7 to < 9 years of 
age, and ICF has been signed and dated by parent(s) or guardian(s) for 
subjects 6 months to < 9 years of age. 
5) Subject and parent/guardian (of subjects 6 months to < 9 years of age) 
are able to attend all scheduled visits and to comply with all study 
procedures. 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from 
study enrollment: 
1) 
Subject is pregnant, or lactating, or of childbearing potential and not 
using an effective method of contraception or abstinence from at least 
4 weeks prior to vaccination and until at least 4 weeks after 
vaccination. To be considered of non-childbearing potential, a female 
must be pre-menarche, or post-menopausal for at least 1 year, or 
surgically sterile. 
2) 
Participation at the time of study enrollment (or in the 30 days 
preceding the first study vaccination) or planned participation during 
the present study period in another clinical study investigating a 
vaccine, drug, medical device, or medical procedure.  
Note: Subjects may be considered eligible for enrollment if no 
intervention for the other study occurred within the 30 days prior to the 
first study vaccination and none are planned before the subject would 
complete safety surveillance for the present study. 
3) 
Receipt of any vaccine in the 30 days preceding the first study 
vaccination, or 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. 
4) 
Previous vaccination against influenza (in the 2018–2019 influenza 
season) with either study vaccine or another vaccine. 
5) 
Receipt of immune globulins, blood, or blood-derived products in the 
3 months preceding planned inclusion. 
6) 
Known or suspected congenital or acquired immunodeficiency; or 
receipt of immunosuppressive therapy, such as anti-cancer 
chemotherapy or radiation therapy, within the 6 months preceding 
planned inclusion; or long-term systemic corticosteroid therapy 
(prednisone or equivalent for more than 2 consecutive weeks within the 
3 months preceding planned inclusion). 
7) 
Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to study vaccine or to a vaccine 
containing any of the same substances.  
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Note: The list of vaccine components is included in the Prescribing 
Information for each study vaccine. 
8) 
Thrombocytopenia, which may be a contraindication for intramuscular 
vaccination, at the discretion of the Investigator. 
9) 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks 
preceding inclusion, contraindicating intramuscular vaccination. 
10) Deprived of freedom by an administrative or court order, or in an 
emergency setting, or hospitalized involuntarily. 
11) Current alcohol abuse or drug addiction. 
12) Chronic illness that, in the opinion of the Investigator, is at a stage 
where it might interfere with study conduct or completion.  
13) Moderate or severe acute illness/infection (according to Investigator 
judgment) on the day of planned vaccination or febrile illness 
(temperature ≥ 100.4°F [38.0°C]). A prospective subject should not be 
included in the study until the condition has resolved or the febrile 
event has subsided. 
14) Identified as an Investigator or employee of the Investigator or study 
center with direct involvement in the proposed study (subjects 
≥ 18 years of age) or identified as an immediate family member 
(i.e., parent, spouse, natural or adopted child) of the Investigator or 
employee with direct involvement in the proposed study (all subjects). 
15) History of serious adverse reaction to any influenza vaccine. 
16) Personal history of GBS. 
17) 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. 
18) Personal history of clinically significant developmental delay (at the 
discretion of the Investigator), neurologic disorder, or seizure disorder. 
19) Known seropositivity for human immunodeficiency virus, hepatitis B, 
or hepatitis C. 
Note: Subjects enrolled into this study will not be prohibited from donating 
blood for non-interventional studies or other purposes. 
Statistical Methods: 
Summaries of baseline demographic characteristics of the study subjects will 
be presented. The number of subjects enrolled and their age at enrollment 
(mean, median, and minimum and maximum), sex, race, and ethnic origin 
will be summarized, along with the number and description of protocol 
deviations. 
For the main safety and immunogenicity parameters, 95% confidence 
intervals (CIs) of point estimates of proportions will be calculated using the 
normal approximation for quantitative data and the exact binomial 
distribution (Clopper-Pearson method) for proportions. All analyses will be 
descriptive; no hypotheses will be tested. 
Safety  
The Safety Analysis Set will be used for the safety analyses. Subjects will be 
analyzed according to the vaccine they actually received. 
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Immunogenicity 
The immunogenicity analyses will be performed on both the Full Analysis 
Set and the Per-Protocol Analysis Set. Data will be summarized and 
presented for each group. 
The following immunogenicity parametersa will be calculated for each 
influenza strain with 95% CIs: 
• 
Geometric mean HAI assay titers at pre-vaccination and post-final 
vaccination  
• 
Geometric means of titer ratios (post-final vaccination divided by pre-
vaccination). 
• 
Seroprotection rates: The percentages of subjects with a titer ≥ 40 (l/dil) 
at pre-vaccination and at post-final vaccination  
• 
Seroconversion rates: The percentages of subjects with either a pre-
vaccination titer < 10 (1/dil) and a post-final vaccination titer 
≥ 40 (1/dil), or a pre-vaccination titer ≥ 10 (1/dil) and a ≥ 4-fold 
increase in post-final vaccination titer  
a  
Post-final vaccination in each of the immunogenicity parameters is 
 
defined as 28 (window, 28–35) days post-final vaccination for subjects 
 
6 months to < 9 years of age, and 21 (window, 21–28) days post-
 
vaccination for subjects ≥ 18 years of age. 
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Tables of Study Procedures 
Study Flow Chart for Subjects 6 Months to < 9 Years of Age: 2 or 3 Visits, 1 or 2 Vaccinations 
 
All Subjects 
Subjects Receiving 1 Dose 
of Influenza Vaccine 
Subjects Receiving 2 Doses of Influenza Vaccine 
Visit Number 
Visit 1 
Telephone Contact 
Visit 2 
Visit 2 
Telephone Contact 
Visit 3 
Study Timelines  
Day 0 
Visit 1 + 8 days 
Visit 1 + 28 days 
Visit 1 + 28 days 
Visit 2 + 8 days 
Visit 2 + 28 days 
Time Windows  
-- 
+ 8 to 10 days 
+ 28 to 35 days 
+ 28 to 35 days 
+ 8 to 10 days 
+ 28 to 35 days 
Informed consent/assenta 
X 
 
 
 
 
 
Inclusion & Exclusion Criteria 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Influenza vaccination history  
X 
 
 
 
 
 
History-directed physical examination 
X 
 
 
X 
 
 
Temperatureb 
X 
 
 
X 
 
 
Review contraindications for vaccination 
 
 
 
X 
 
 
Allocation of subject number 
X 
 
 
 
 
 
Blood sample (BL)c 
BL1 
 
BL2 
 
 
BL2 
Vaccinationd 
X 
 
 
X 
 
 
Immediate surveillance (20 minutes) 
X 
 
 
X 
 
 
Diary card (DC) provided 
DC1 
 
 
DC2 
 
 
Telephone contacte 
 
X 
 
 
X 
 
Diary card reviewed and collected  
 
 
DC1 
DC1 
 
DC2 
Interim history 
 
 
X 
X 
 
X 
Termination recordf  
 
 
X 
 
 
X 
Serious adverse events 
To be reported throughout the study period 
a 
Informed consent form will be signed and dated by parent(s) or guardian(s) for subjects 6 months to < 9 years of age and assent form will be signed and dated by subjects 7 to < 9 years of age. 
b 
The preferred route for this study is rectal for subjects 6 to < 36 months of age, and oral for subjects 3 to < 9 years of age. The axillary route may be used when a rectal or oral temperature cannot 
be obtained. 
c 
A blood sample, approximately 5 mL, will be collected from all subjects at Visit 1, prior to vaccination, and at either Visit 2 (for subjects receiving 1 influenza vaccine dose) or at Visit 3 (for 
subjects receiving 2 influenza vaccine doses). 
d 
One or 2 doses of influenza vaccine will be administered according to the Advisory Committee on Immunization Practices guidance in effect during the study. If 2 doses of influenza vaccine are 
indicated, 1 dose will be administered during Visit 1 and the second dose (same 0.25-mL or 0.5-mL volume of Fluzone Quadrivalent vaccine as administered at Visit 1) will be administered 
approximately 28 days later during Visit 2. 
e 
The subject’s parent/guardian will be contacted by telephone on Day 8 (window, Days 8–10) after vaccination as a reminder to complete the diary card and to bring it with them to the next visit. 
f 
The termination form will be completed at Visit 2 for subjects receiving 1 dose of influenza vaccine or at Visit 3 for subjects receiving 2 doses of influenza vaccine. 
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Study Flow Chart for Subjects ≥ 18 Years of Age: 2 Visits, 1 Vaccination 
 
Visit Number  
Visit 1 
Telephone Contact 
Visit 2 
Study Timelines  
Day 0 
Visit 1 + 8 days 
Visit 1 + 21 days 
Time Windows  
 
+ 8 to 10 days 
+ 21 to 28 days 
Informed consent  
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Demographic data 
X 
 
 
Medical history  
X 
 
 
Influenza vaccination history (previous season) 
X 
 
 
History-directed physical examination  
X 
 
 
Temperaturea 
X 
 
 
Urine or serum pregnancy testb 
X 
 
 
Allocation of subject number 
X 
 
 
Blood sampling (BL)c  
BL1 
 
BL2 
Vaccination  
X 
 
 
Immediate surveillance (20 minutes) 
X 
 
 
Diary card provided 
X 
 
 
Telephone contactd 
 
X 
 
Diary card reviewed and collected 
 
 
X 
Termination record 
 
 
X 
Serious adverse events 
To be reported throughout the study period 
a 
The preferred route for this study for subjects ≥ 18 years of age is oral. 
b 
Only for women of child-bearing potential. 
c 
A blood sample, approximately 20 mL, will be collected at Visit 1 and Visit 2. 
d 
Subjects will be contacted via telephone on Day 8 (window, Days 8–10) as a reminder to complete the diary card 
and to bring it with them to Visit 2. 
 
 
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List of Abbreviations 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event 
AR 
Adverse Reaction 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention 
CDM 
Clinical Data Management 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRB 
Case Report Book 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
dil 
Dilution 
DTaP 
Diphtheria-Tetanus-Acellular-Pertussis 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVFS 
First Visit, First Subject 
GBS 
Guillain-Barré Syndrome 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GPE 
Global Pharmacovigilance & Epidemiology  
HA 
Hemagglutinin 
HAI 
Hemagglutination Inhibition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IIV3 
Trivalent Inactivated Influenza Vaccine 
IME 
Important Medical Event 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  
LLT 
Lowest Level Term 
LLOQ 
Lower Limit of Quantification 
LVLS 
Last Visit, Last Subject 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Neuraminidase 
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PCV 
Pneumococcal Conjugate Vaccine 
PPAS 
Per-Protocol Analysis Set 
RBC 
Red Blood Cell 
RMO 
Responsible Medical Officer 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SD-IIV4 
Standard Dose Quadrivalent Inactivated Influenza Vaccine  
TMF 
Trial Master File 
ULOQ 
Upper Limit of Quantification 
US 
United States 
VSD 
Vaccine Safety Datalink 
WHO 
World Health Organization 
 
 
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1 
Introduction 
1.1 
Background 
This is a study using the 2018–2019 formulations of quadrivalent inactivated influenza vaccine 
(Fluzone® Quadrivalent, Influenza Vaccine), recombinant influenza vaccine (Flublok® 
Quadrivalent, Influenza Vaccine), and high-dose trivalent inactivated influenza vaccine (Fluzone® 
High-Dose, Influenza Vaccine).  
Influenza viruses types A and B belong to the genus Orthomyxoviridae and are characterized as 
enveloped, negative-strand, segmented ribonucleic acid (RNA) viruses. The viral envelope 
contains 2 virus-coded glycoprotein spikes, the hemagglutinin (HA) and neuraminidase (NA) 
proteins, which are key antigens in the host response to influenza virus in both natural 
infection and vaccination. A third protein, M2, is a minor envelope component of the A-strain 
viruses (1). 
Influenza is transmitted through inhalation of virus-containing droplets from infected individuals. 
The incubation period is usually 1 to 2 days (2). The virus multiplies in the ciliated columnar 
epithelium of the upper- and lower-respiratory tract, causing cellular necrosis and sloughing (1). 
Virus shedding typically begins just before illness onset (within 24 hours), rapidly peaks, and 
remains elevated for 1 to 2 days before rapidly declining to low levels. Usually, virus shedding 
lasts a total of 5 to 10 days (2). 
There is considerable variation in the severity of illness in different individuals, partly due to age, 
general health, and immune status relative to previous influenza infections and vaccination. The 
classic symptoms include rapid onset (12 hours or less) of malaise, fever, myalgia, headache, and 
a non-productive cough or sore throat. Most symptoms last several days, but malaise and cough 
may last for a week or more (2). Complications of influenza include primary viral pneumonia, 
secondary bacterial pneumonia, and exacerbation of underlying medical conditions such as 
chronic obstructive pulmonary disease and congestive heart failure.  
While influenza affects all age groups, the elderly, children younger than 5 years of age, and 
persons with underlying health problems are at increased risk for complications. Members of 
high-risk groups who become ill with influenza are more likely than the general population to 
require hospitalization. Among infants and younger children, estimated rates of influenza-
associated hospitalization are substantially higher than among older children and are similar to 
rates for other groups considered at higher risk for influenza-related complications, including 
persons aged ≥ 65 years due to immunosenescence and adults 50–64 years of age and older 
because they are likely to have chronic medical conditions that put them at increased risk of 
severe influenza illness (3). 
Antigenic variation is an important feature of the influenza virus. The viral HA and NA surface 
antigens are subject to continuous and sequential evolution within immune or partially immune 
populations. Antigenic drift results from mutation(s) affecting the RNA segment coding for either 
HA or NA, but more commonly HA. As a result, there is alteration in protein structure involving 
1 or a few amino acids, resulting in minor changes in antigenicity. Antigenic variants within a 
subtype (e.g., H1 or H3) emerge and through natural selection gradually become the more 
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predominant circulating virus strain, while the preceding antigenic variant is suppressed by 
specific immunity in the population. In contrast to antigenic drift, antigenic shift represents the 
emergence of completely new subtypes, typically through gene reassortment with other 
circulating strains and acquisition of antigenically different gene sequences. Antigenic shift 
occurs at irregular intervals and may lead to pandemics (1) (2). While influenza B appears to be 
more genetically stable than influenza A, the dominant circulating B strain typically varies from 
season to season. For over a decade, both Yamagata and Victoria lineages have co-circulated 
during each season with varying prevalence (4). The large antigenic divergence between the 
2 influenza B lineages limits antigenic cross-reactivity, and immunity to 1 B lineage does not 
provide adequate protection against the other. Accordingly, switching from a trivalent vaccine to a 
quadrivalent vaccine is expected to prevent additional morbidity and mortality associated with 
mismatched influenza B strains that may occur with trivalent vaccines (4). With this in mind, 
Fluzone Quadrivalent vaccine and Flublok Quadrivalent vaccine were developed. 
Vaccination with influenza vaccine is the primary method for preventing influenza and its severe 
complications. It has been shown to be effective in reducing influenza-associated morbidity and 
mortality in groups at increased risk for influenza-related complications such as infants and young 
children and persons 50 years of age and older. Of note, immune responses to the vaccine are 
lower in seniors than those in young healthy adults (3). Strategies to improve immune responses 
to the vaccine in the elderly population could provide significant additional reductions in 
influenza-associated morbidity and mortality. One approach is to increase the dose of HA in 
inactivated vaccines. Previous studies evaluating the immune responses in terms of 
hemagglutination inhibition (HAI) antibodies with higher doses of HA per strain in different 
influenza vaccines support a dose-response effect (5). 
Fluzone High-Dose vaccine contains 60 µg HA per virus strain per dose, which is 4 times the 
amount of HA per strain per dose in Fluzone vaccine. It was developed for use in the elderly to 
elicit enhanced immune responses against influenza through the use of higher antigen content. 
Flublok Quadrivalent vaccine is a recombinant HA influenza vaccine indicated for active 
immunization against disease caused by influenza A subtype viruses and type B viruses contained 
in the vaccine for adults 18 years of age and older. Use of recombinant DNA techniques to 
produce vaccine antigen expressed in cell culture is a method that avoids growing the influenza 
viruses in embryonated hen’s eggs. Recombinant technology also allows control over the 
sequence of the full-length HA produced. The recombinant proteins are highly purified and the 
vaccine contains no egg protein, preservatives or antibiotics, any of which may produce 
hypersensitivity reaction in some individuals. 
Flublok Quadrivalent vaccine contains 45 µg HA per virus strain per dose, 3 times the amount of 
HA compared to standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4). The high 
purity of a recombinant antigen enables administration of a higher concentration of HA antigen 
without a significant increase in side effects in human subjects. This higher dose of antigen may 
be a particular advantage to older adults whose immune responses to influenza vaccines can be 
suboptimal. 
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During this study, Fluzone Quadrivalent, Flublok Quadrivalent, or Fluzone-High-Dose vaccine 
will be administered according to the guidelines in the Prescribing Information and only to 
persons for whom it is indicated.  
The objectives of this study are to describe the safety and immunogenicity of Fluzone 
Quadrivalent vaccine in children 6 months to < 9 years of age and adults 18 to < 65 years of age, 
Flublok Quadrivalent vaccine in adults 18 to < 65 years of age, and Fluzone High-Dose vaccine in 
adults ≥ 65 years of age. An additional objective of the study is to provide available sera collected 
from subjects to the Center for Biologics Evaluation and Research (CBER) for further analysis by 
the World Health Organization (WHO), the Centers for Disease Control and Prevention (CDC), 
and the Food and Drug Administration (FDA) to support formulation recommendations for 
subsequent influenza vaccines. In addition, available sera from adult subjects may be further 
analyzed by the Sponsor to assess breadth of immune response induced by the study vaccines. 
1.1.1 
Epidemiology 
Influenza is noted for occurring in epidemics. Typically, localized influenza epidemics begin 
abruptly, peak in 2 to 3 weeks, and last 5 to 6 weeks. The first sign of influenza in a community is 
usually reports of increased numbers of children with febrile respiratory illness, although a 
nursing-home outbreak may be the first indication. Outbreaks in children are usually followed by 
the occurrence of influenza-like illness among adults. Following this is an increase in hospital 
admissions for pneumonia, exacerbation of chronic obstructive pulmonary disease, croup, and 
congestive heart failure. Increased absenteeism from school and the workplace occur as a late 
indicator. Finally, an increased number of deaths due to pneumonia and influenza are a highly 
specific indicator of influenza. However, due to the reporting delay and time course from 
infection to death, this indicator lags behind the others (2).  
As with other viral respiratory infections, influenza is a seasonal disease. In the Northern 
Hemisphere, influenza is most likely to occur from November to April, and in the Southern 
Hemisphere from May to October. In tropical regions, it is more endemic, with periods of 
increased activity occurring more than once a year.  
The public health impact of influenza is dramatic. During seasonal influenza epidemics from 
1979–1980 through 2000–2001, the estimated annual overall number of influenza-associated 
hospitalizations in the United States (US) ranged from approximately 55,000 to 431,000 per 
annual epidemic (mean: 226,000) (3) (6). Between the 1976–1977 season and 2006–2007 
season, estimated annual deaths attributable to influenza ranged from 3,000 to 49,000 each 
season (3) (7). Approximately 90% of the deaths attributed to pneumonia and influenza during 
these periods occurred among persons ≥ 65 years of age (3). From the 1976–1977 season through 
the 2006–2007 season, an estimated yearly average of 21,098 influenza-related deaths occurred 
among adults aged ≥ 65 years, compared with an estimated 124 deaths among persons < 19 years 
of age and 2385 deaths among persons 19 through 64 years of age (3) (7).  
In the United States, death associated with laboratory-confirmed influenza virus infection among 
children < 18 years of age has been a nationally reportable condition since 2004. Since reporting 
began, the annual number of influenza-associated pediatric deaths during regular influenza 
seasons has ranged from 37 to 171 deaths per season (3). However, between 15 April 2009 and 
02 October 2010 (the period of the 2009 H1N1 influenza pandemic), 358 deaths attributed to 
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laboratory-confirmed 2009 H1N1 influenza occurred among children < 18 years of age, the 
majority of whom had 1 or more underlying medical conditions previously associated with 
conferring a greater risk for influenza complications (3). 
Based on current understanding, the epidemiology of influenza B is characterized by major 
epidemics every 2–4 years. It causes infections in all age groups, including children, young adults, 
and the elderly. While influenza affects all age groups, young children remain at increased risk 
for complications and are more likely than the general population to require hospitalization. 
Influenza B has been associated with myalgia, myositis, pneumonia, and leukopenia in  
children (8) (9) (10). Influenza B infection in older adults leads to excess mortality in some annual 
epidemics. Across all ages, the burden of disease from influenza B is less than that from A/H3N2 
but greater than that from A/H1N1. Overall, it is a significant cause of absenteeism, clinic visits, 
hospitalizations, and deaths (4). 
1.1.2 
Prevention and Control of Infection Among Humans 
Currently, the most effective measure for reducing the impact of influenza is to vaccinate persons 
at risk each year before the onset of the influenza season, especially persons at high risk for 
influenza-related complications. The Advisory Committee on Immunization Practices (ACIP) of 
the CDC recommends that all eligible persons 6 months of age and older receive annual 
vaccination against influenza (3).  
Influenza vaccine has been effective in reducing influenza-related morbidity and mortality. The 
effectiveness of the influenza vaccine in preventing or attenuating influenza illness depends in 
part on the age and immune competence of the vaccine recipient and on the similarity between the 
virus strains present in the vaccine and those circulating in the community. Most vaccinated 
children and young adults develop high post-vaccination HAI antibody titers. These antibodies are 
protective against illness caused by strains similar to those in the vaccine or the related variants 
that may emerge during outbreak periods. Elderly persons and persons with certain chronic 
diseases may develop lower post-vaccination antibody titers than healthy young adults and thus 
may remain susceptible to influenza-related upper respiratory infections. However, even if such 
older persons develop influenza illness despite vaccination, the vaccine can be effective in 
preventing lower-respiratory tract involvement or other secondary complications, thereby 
reducing the risk of hospitalization and death (3).  
In 1 meta-analysis, influenza vaccine was shown to prevent illness in 59% (95% confidence 
interval [CI] = 51%–67%) of adults aged 18 through 65 years in 8 of 12 seasons analyzed. 
Another meta-analysis of randomized clinical trial results among healthy persons aged 16 through 
65 years suggested that when vaccine and circulating influenza viruses strains were well-matched, 
efficacy against influenza symptoms was 73% (95% CI = 54%–84%) whereas it was 
44% (95% CI = 23%–59%) when they were not well-matched. The only large randomized 
placebo-controlled trial conducted among community-dwelling persons aged ≥ 60 years reported 
a vaccine efficacy of 58% (95% CI = 26%–77%) against serologically confirmed influenza illness 
during a season when the vaccine strains were considered to be well-matched to circulating 
strains (3).  
Some observational studies that have provided estimates of vaccine effects for serious 
complications of influenza infections among community-dwelling older persons have found large 
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reductions in hospitalizations or deaths. For example, in 1 case-control study conducted during the 
1999–2000 season in persons aged < 65 years with underlying medical conditions, vaccination 
was reported to reduce deaths attributable to any cause by 78% and reduce hospitalizations 
attributable to respiratory infections or cardiopulmonary diseases by 87% (3). Recent studies 
using methods to account for unmeasured confounding factors (e.g., dementia and difficulties 
with self-care) have indicated that vaccine effectiveness among community-dwelling older 
persons for nonspecific serious outcomes such as pneumonia/influenza hospitalizations or 
all-cause mortality is < 10%, which is much more plausible than higher estimates from earlier 
studies (11). 
1.1.3 
The Advisory Committee on Immunization Practices Recommendations 
Because children 6 through 23 months of age are at substantially increased risk for influenza-
related hospitalizations, and children 24 through 59 months of age are at increased risk for 
influenza-related clinic and emergency department visits, ACIP has recommended annual 
vaccination of all eligible children in these age groups. In recent years, ACIP further expanded the 
age groups targeted for vaccination, and now recommends that all eligible persons 6 months of 
age and older receive annual influenza vaccination (3). The ACIP continues to emphasize the 
importance of vaccinating persons ≥ 6 months of age who have high-risk medical conditions (3). 
If a child 6 months through 8 years of age is receiving influenza vaccine for the first time, based 
on ACIP recommendations, 2 doses of influenza vaccine should be administered during the 
current season. This recommendation is based on studies demonstrating that vaccine effectiveness 
is lower among children who have never received influenza vaccine previously or who received 
only 1 dose in their first year of vaccination than it is among those children who received 2 doses 
in their first year of being vaccinated. Children 6 months through 8 years of age who are 
adequately primed, based on influenza vaccination history, should receive 1 dose during the 
current season as per ACIP recommendations (3).  
1.2 
Background of the Investigational Product 
Vaccine Testing and Release 
Before being released for clinical use, the 2018–2019 formulations of Fluzone Quadrivalent, 
Flublok Quadrivalent, and Fluzone High-Dose vaccines will have passed all approved release-
testing requirements.  
Previous Clinical Experience: Fluzone Vaccine 
Fluzone vaccine was licensed in the United States in 1947 as a whole-virus preparation and it has 
been available since 1980 as a split-virus preparation. Numerous clinical trials have demonstrated 
its safety, immunogenicity, and effectiveness. Clinical trials, in which Fluzone vaccine was used 
as a comparator, have also demonstrated the safety and immunogenicity, and/or effectiveness of 
Fluzone High-Dose and Fluzone Quadrivalent vaccines. 
Fluzone Quadrivalent Vaccine 
In pre-licensure studies, Fluzone Quadrivalent vaccine, which contains 4 influenza strains 
(A/H1N1, A/H3N2, and 2 B strains [1 each from the Yamagata and Victoria lineages]), induced 
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antibody responses that were comparable to those induced by trivalent Fluzone vaccine with 
respect to the strains contained in each vaccine. Pre-licensure studies also demonstrated that the 
safety profile of Fluzone Quadrivalent vaccine was similar to that of trivalent Fluzone vaccine. 
Accordingly, Fluzone Quadrivalent vaccine offers the possibility of protecting against both 
B lineages simultaneously, without compromising vaccine safety (12) (13). 
Fluzone High-Dose Vaccine 
Fluzone High-Dose vaccine, a trivalent formulation with 60 µg HA per viral strain, has been 
shown in pre-licensure studies to elicit a higher immune response in the elderly than does Fluzone 
vaccine (15 µg HA per viral strain) (14) (15) (16). Solicited injection site and systemic reactions 
were reported more frequently with Fluzone High-Dose vaccine; however, these events were 
generally mild to moderate in intensity and transient. No safety concerns were identified. 
Moreover, a large-scale efficacy trial, which was conducted during 2 influenza seasons (2011–
2012 and 2012–2013) and involved more than 30,000 persons, showed that Fluzone High-Dose 
vaccine was 24.2% more effective than Fluzone vaccine in preventing laboratory-confirmed 
symptomatic influenza in persons 65 years of age and older. The results of the study met the 
FDA-agreed criteria for demonstrating the superiority of Fluzone High-Dose vaccine compared 
with Fluzone vaccine for prevention of influenza disease in older adults (17). 
Previous Clinical Experience: Flublok Vaccine 
Flublok vaccine (trivalent formulation) was first approved in the United States on 16 January 
2013 for use in adults 18–49 years of age.  Licensure was based on results of a randomized 
controlled efficacy trial of Flublok vs placebo in 2344 subjects. The age indication was expanded 
to include all adults 18 years of age and older in 2014 based on safety and immunogenicity data 
from 2 studies; the first study was of 869 adults 65 years of age and older, and the second was of 
602 adults 50–64 years of age. 
Flublok Quadrivalent Vaccine 
On 07 October 2016, the FDA licensed Flublok Quadrivalent vaccine for adults 18 years of age 
and older. This approval was based on 2 studies conducted during the 2014–2015 influenza 
season: (1) an immunogenicity and safety study of Flublok Quadrivalent vaccine versus SD-IIV4 
in 1350 adults 18–49 years of age and (2) an efficacy, immunogenicity, and safety study of 
Flublok Quadrivalent vaccine versus SD-IIV4 in 9003 adults 50 years of age and older. In the 
former study (of adults 18–49 years of age), immunogenicity of Flublok Quadrivalent vaccine 
was non-inferior to that of the SD-IIV4 comparator for 3 of the 4 antigens; the response to the B 
Victoria lineage strain was low in both vaccine groups, making comparisons uninterpretable. In 
the latter efficacy study of adults 50 years of age and older, Flublok Quadrivalent vaccine, 
compared to the SD-IIV4 comparator, demonstrated 30% to 43% greater efficacy in preventing 
laboratory-confirmed, protocol-defined influenza-like-illness caused by any viral type or subtype. 
The most common local adverse reactions (ARs) to Flublok Quadrivalent vaccine include 
tenderness and pain at the injection site. The most common systemic reactions include headache, 
fatigue, myalgia, and arthralgia, with most events being mild to moderate in severity. Safety 
profiles of Flublok influenza vaccine and inactivated influenza vaccine (trivalent and quadrivalent 
comparisons) were demonstrated to be similar in clinical trials. 
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1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
The benefit to subjects participating in this study is potential protection from influenza disease 
following the receipt of the 2018–2019 formulation of Fluzone Quadrivalent, Flublok 
Quadrivalent, or Fluzone High-Dose vaccine. 
1.3.2 
Potential Risks to Subjects 
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 malaise, myalgia, headache, shivering, fever, and other side effects can 
occur following vaccination and most often affect persons who have had no prior exposure to the 
virus antigens in the vaccine (e.g., young children) (18). These reactions begin 6 to 12 hours after 
vaccination and usually resolve within 3 days. Placebo-controlled trials suggest that in elderly 
persons and in healthy young adults, split-virus influenza vaccine is not associated with higher 
rates of systemic symptoms when compared with placebo injection (19). 
Immediate allergic reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) 
occur rarely after influenza vaccination. These reactions probably result from hypersensitivity to 
some vaccine component (20) (21) (22).  
Guillain-Barré syndrome (GBS) is a very rare, acute, and frequently severe polyneuropathy 
characterized by ascending fulminant muscle paralysis. The 1976 swine influenza vaccine was 
associated with an increased frequency of GBS. Among persons who received the swine influenza 
vaccine in 1976, the rate of GBS that exceeded the background rate was < 10 cases/1,000,000 
persons vaccinated. Evidence for a causal relationship of GBS with subsequent vaccines prepared 
from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for such a 
possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual 
incidence of 10–20 cases per 1,000,000 adults and stretches the limits of epidemiologic 
investigation (23). 
The reasons why swine influenza vaccine triggered GBS in 1976 to 1977 have never been 
discovered. In subsequent annual influenza vaccine programs in the United States, from 1977 to 
1991, the overall relative risk estimates for GBS after influenza vaccination were slightly 
elevated but were not statistically significant in any of the studies. However, in a study of the 
1992–1993 and 1993–1994 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0–2.8; 
P = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of 
GBS for each 1,000,000 persons vaccinated. The combined number of GBS cases peaked 2 weeks 
after vaccination. A meta-analysis provided a similar risk estimate for GBS following receipt of 
2009 influenza A (H1N1) monovalent inactivated influenza vaccine (24). Thus, investigations to 
date indicate that there is no substantial increase in GBS associated with influenza vaccines (other 
than the swine influenza vaccine in 1976) and that, if influenza vaccine does pose a risk, it is 
probably slightly more than 1 additional case per 1,000,000 persons vaccinated. Even if GBS 
were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of 
approximately 1 additional case/1,000,000 persons vaccinated is substantially less than the risk 
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for severe influenza, which could be prevented by vaccination in all age groups and especially in 
persons ≥ 65 years of age and those who have medical indications for influenza vaccination. 
Neurological disorders temporally associated with influenza vaccination such as myelitis 
(including encephalomyelitis and transverse myelitis), optic neuritis/neuropathy, partial facial 
paralysis, and brachial neuritis have been reported. However, no causal relationship has been 
established. Almost all persons affected were adults, and the described clinical reactions began as 
soon as a few hours and as late as 2 weeks after vaccination. Full recovery was almost always 
reported (25). 
Analysis of reports collected by the Vaccine Adverse Events Reporting System during the 2010–
2011 influenza season suggested an increased risk of febrile seizures among children younger 
than 2 years of age who received trivalent inactivated influenza vaccine (IIV3) (26). Using data 
collected through the CDC-sponsored Vaccine Safety Datalink (VSD) project, Tse et al. (27) 
found an increased risk of fever-associated seizure occurring on the day of and 1 day after 
influenza vaccination in children 6 months through 4 years of age during the 2010–2011 influenza 
season. The risk was higher among children who received concomitant IIV3 vaccine and 
pneumococcal conjugate vaccine (PCV) 13-valent, and peaked at approximately age 16 months 
(44.9 cases per 100,000 doses). In a subsequent study that included VSD data collected over 
5 influenza seasons (2005––2011), Duffy et al. (28) reported that inactivated influenza 
vaccination in children 6–23 months of age was not an independent risk factor for febrile seizures, 
but revealed an increased risk of febrile seizure when influenza vaccine was given with either 
PCV or a diphtheria-tetanus-acellular-pertussis (DTaP)-containing vaccine. The maximum 
estimated absolute excess risk due to concomitant administration of IIV3, PCV, and DTaP-
containing vaccines compared with administration of these vaccines on separate days was 
30 cases per 100,000 vaccinees. According to CDC, the risk of febrile seizure following influenza 
vaccination is small (29). 
Cases of demyelinating disorders (e.g., incident multiple sclerosis in adults, acute disseminated 
encephalomyelitis, transverse myelitis), have been reported following influenza vaccines, 
although the Institute of Medicine concluded that the evidence is inadequate to accept or reject a 
causal relationship (25). 
Cases of vasculitis have been reported following influenza immunization. A cause-and-effect 
relationship has not been determined (25). 
A Phase III study performed in persons ≥ 65 years of age demonstrated increased rates of solicited 
injection site and systemic reactions in subjects receiving Fluzone High-Dose vaccine compared 
to persons receiving Fluzone vaccine but were typically mild and transient (16). Safety 
monitoring of Fluzone High-Dose vaccine during the first year after licensure indicated a higher 
than expected number of gastrointestinal events compared with standard-dose vaccine, but 
otherwise no new safety concerns were identified (30). 
There may be other risks not yet identified.  
Please refer to the US Prescribing Information for the vaccine administered for other adverse 
events (AEs). 
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1.4 
Rationale for the Study 
Historically, annual safety and immunogenicity studies of Fluzone vaccines have been conducted 
in the United States in support of licenses held by Sanofi Pasteur in various countries and to 
obtain serum samples for submission to CBER to aid in the influenza vaccine strain selection 
process. The aim of the GRC90 study is to evaluate the safety and immunogenicity of the 2018–
2019 formulation of Fluzone Quadrivalent vaccine in children 6 months to < 9 years of age and in 
adults 18 to < 65 years or age, the 2018–2019 formulation of Flublok Quadrivalent in adults 
18 to < 65 years of age, and of the 2018–2019 formulation of Fluzone High-Dose vaccine in 
adults ≥ 65 years of age. 
Samples of sera from subjects will be supplied to CBER after the completion of this study (i.e., 
after the last subject completes the last study visit). In turn, CBER will distribute the sera to CDC 
and other WHO-collaborating laboratories for evaluation against circulating influenza viral 
strains. It is expected that the immunologic and surveillance data will be presented at WHO 
meetings where the vaccine strain selections will be made for the Southern and Northern 
hemispheres and at the FDA Vaccines and Related Biological Products Advisory Committee 
meeting for selection of strains for influenza vaccines to be distributed in the United States.  
2 
Study Objectives 
2.1 
Observational Objectives 
2.1.1 
Safety 
To describe the safety of the 2018–2019 formulation of Fluzone Quadrivalent vaccine in children 
6 to < 36 months of age and 3 to < 9 years of age, and in adults 18 to < 65 years of age, the safety 
of the 2018–2019 formulation of Flublok Quadrivalent vaccine in adults 18 to < 65 years of age, 
and the safety of the 2018–2019 formulation of Fluzone High-Dose vaccine in adults ≥ 65 years 
of age.  
The endpoints for the observational safety objective are presented in Section 9.3.1.2. 
2.1.2 
Immunogenicity 
To describe the immunogenicity of the 2018–2019 formulation of Fluzone Quadrivalent vaccine 
in children 6 to < 36 months of age and 3 to < 9 years of age, and in adults 18 to < 65 years of 
age, the immunogenicity of the 2018–2019 formulation of Flublok Quadrivalent vaccine in adults 
18 to < 65 years of age, and the immunogenicity of the 2018–2019 formulation of Fluzone High-
Dose vaccine in adults ≥ 65 years of age.  
The endpoints for the observational immunogenicity objective are presented in Section 9.3.2.1. 
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2.1.3 
Serum Collection 
To provide available sera (collected from subjects before vaccination [Blood Sample 1] and after 
final vaccination [Blood Sample 2]) to CBER for further analysis by the WHO, the CDC, and the 
FDA to support formulation recommendations for subsequent influenza vaccines. In addition, 
available sera from adult subjects may be further analyzed by the Sponsor to assess breadth of 
immune response induced by the study vaccines. 
There are no endpoints for the serum collection objective. 
3 
Investigators and Study Organization 
This study will be conducted in 3 centers in the United States. Details of the study centers, the 
Investigators at each center, and the Coordinating Investigator(s) are provided in the “List of 
Investigators and Centers Involved in the Trial” document. 
The Sponsor’s Responsible Medical Officers (the RMOs; the persons authorized to sign this 
protocol and any amendments on behalf of the Sponsor) are 
 and 
, or such delegate(s) as may be identified in their absence. 
4 
Independent Ethics Committee/Institutional Review Board 
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent form(s) (ICF[s]), assent form(s) 
(subjects 7 to < 9 years of age must sign an assent form), 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 Institutional Review Board(s) (IRB[s]). 
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 IRB(s) (the names and qualifications of the 
members attending and voting at the meetings). 
The Investigator will submit written summaries of the status of the study to the IRB(s) annually, 
or more frequently if requested. All serious adverse events (SAEs) occurring during the study that 
are related to the product administered will be reported by the Investigator to the IRB(s), 
according to the IRB policy. 
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5 
Investigational Plan 
5.1 
Description of the Overall Study Design and Plan 
5.1.1 
Study Design 
This will be a Phase IV, multi-center, open-label study of a planned 240 subjects to describe the 
safety and immunogenicity of Fluzone Quadrivalent vaccine in children 6 months to < 9 years of 
age and adults 18 to < 65 years of age, Flublok Quadrivalent vaccine in adults 18 to < 65 years of 
age, and Fluzone High-Dose vaccine in adults ≥ 65 years of age.  
Using a pre-programmed interactive response technology (IRT) system, each subject will be 
assigned to a vaccine group based on the subject’s age at the time of enrollment. An 
approximately equal number of subjects from each group will be enrolled at each site. 
Using the IRT system, subjects 18 to < 65 years of age will be randomly assigned to either 
Group 3 or Group 4. Enrollment in Group 3 and Group 4 will be stratified by age into 2 subgroups 
at each site so that approximately 50% of subjects at each site will be 18 to < 50 years of age and 
approximately 50% of subjects at each site will be 50 to < 65 years of age, and so that an equal 
proportion of subjects within each age subgroup receive either Fluzone Quadrivalent or Flublok 
Quadrivalent vaccine. If necessary to achieve 50% overall enrollment of subjects 50 to < 65 years 
of age and assignment of Fluzone Quadrivalent and Flublok Quadrivalent vaccines in a 1:1 ratio 
within each age subgroup (i.e., 18 to < 50 years of age and 50 to < 65 years of age), individual 
sites may be permitted to deviate from these ratios. 
• Group 1: Children 6 to < 36 months of age assigned to receive a 0.25-mL dose of Fluzone 
Quadrivalent vaccine (30 subjects planned) 
• Group 2: Children 3 to < 9 years of age assigned to receive a 0.5-mL dose of Fluzone 
Quadrivalent vaccine (30 subjects planned) 
• Group 3: Adults 18 to < 65 years of age assigned to receive a 0.5-mL dose of Fluzone 
Quadrivalent vaccine (60 subjects planned)  
• Group 4: Adults 18 to < 65 years of age assigned to receive a 0.5-mL dose of Flublok 
Quadrivalent vaccine (60 subjects planned)  
• Group 5: Adults ≥ 65 years of age assigned to receive a 0.5-mL dose of Fluzone High-Dose 
vaccine (60 subjects planned)  
5.1.2 
Justification of the Study Design 
See Section 1.4 for the justification for the selection of subjects and the choice of groups. 
5.1.3 
Study Plan 
All subjects will receive either a 0.25-mL (subjects 6 to < 36 months of age [Group 1]) or a 
0.5-mL (subjects 3 to < 9 years of age and ≥ 18 years of age [Groups 2, 3, 4, and 5]) intramuscular 
injection of study vaccine based on their assigned group at Visit 1. For subjects 6 months to < 9 
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years of age for whom 2 doses of influenza vaccine are recommended per ACIP guidance, a 
second intramuscular injection of Fluzone Quadrivalent vaccine (same 0.25-mL or 0.5-mL 
volume as administered at Visit 1) will be administered at Visit 2 (28 [window, 28–35] days after 
Visit 1).  
Subjects 6 months to < 9 years of age (Group 1 and Group 2): blood specimens (approximately 
5 mL) will be obtained from all subjects prior to the first vaccination at Visit 1 (Day 0) and 28 
(window, 28–35) days following the final vaccination (Visit 2, if no study vaccine is administered 
at Visit 2; or Visit 3, if a second dose of study vaccine is administered at Visit 2) and assayed for 
immunogenicity. Staff will observe subjects for 20 minutes following study vaccine 
administration and will record the occurrence of any immediate unsolicited systemic AEs. 
Subjects’ parents/guardians will record information about solicited injection site and systemic 
reactions from Day 0 through Day 7 post-vaccination, and will record information about 
unsolicited non-serious AEs and SAEs from Visit 1 through Visit 2 for subjects receiving 1 dose 
of study vaccine, and from Visit 1 through Visit 3 for subjects receiving 2 doses of study vaccine. 
Subjects ≥ 18 years of age (Group 3, Group 4, and Group 5): blood specimens (approximately 
20 mL) will be obtained from all subjects prior to vaccination at Visit 1 and 21 (window, 21–28) 
days post-vaccination (Visit 2). Staff will observe subjects for 20 minutes following study vaccine 
administration and will record the occurrence of any immediate unsolicited systemic AEs. 
Subjects will record information about solicited injection site and systemic reactions from Day 0 
through Day 7 post-vaccination, and will record information about unsolicited non-serious AEs 
and SAEs from Visit 1 through Visit 2. 
5.1.4 
Visit Procedures 
Medical procedures (injections, examinations, etc.) must be conducted by appropriately licensed 
or credentialed study site staff working within the scope of their licenses/credentials. 
Visit 1 (Day 0): Inclusion and Vaccination 
1) Explain the study objectives and design to the subject or subject’s parent/guardian, including 
but not limited to its objectives, design, and risks and benefits, and answer any questions the 
subject or subject’s parent/guardian may have. 
2) Obtain a written informed consent from the subject or subject’s parent/guardian and assent (if 
required as per IRB regulations). The Investigator or delegate will also sign and date the ICF 
and assent form, retain the originals, and give copies of the signed and dated form(s) to the 
subject or subject’s parent/guardian. 
3) Check eligibility of the subject by reviewing applicable inclusion and exclusion criteria. 
4) Collect relevant demographic information (date of birth, sex, race, and ethnic origin). 
5) Obtain significant medical history (see Section 5.2.6 for details). 
6) For subjects 6 months to < 9 years of age, collect influenza vaccination history to determine 
vaccination schedule (1 dose versus 2 doses) per ACIP recommendations in effect during the 
study. 
7) For subjects ≥ 18 years of age, collect influenza vaccination history from previous season, 
including name of product if known. 
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8) Perform a directed physical examination, if indicated, based on medical history. 
9) Measure the temperature by the preferred route (see Section 9.3.1.3.2) and record this 
information in the source document. If the subject has a temperature ≥ 100.4°F (38.0°C) defer 
enrollment until the subject has been afebrile for at least 24 hours (see Section 5.2.7.1). 
10) When applicable, obtain a urine or serum pregnancy test. 
11) For subjects 6 months to < 9 years of age and adults ≥ 65 years of age: If subject meets all 
inclusion and no exclusion criteria, connect to the IRT system to enter required data to 
receive subject number and vaccine and dose to be administered based on subject’s age.  
For subjects 18 to < 65 years of age: If subject meets all inclusion and no exclusion criteria, 
contact the IRT system for randomization. 
12) Obtain a pre-vaccination blood sample (approximately 5 mL for subjects 6 months to 
< 9 years of age, approximately 20 mL for subjects ≥ 18 years of age; see Section 7.1 for 
detailed instructions regarding the collection of blood samples). 
13) Prepare the vaccine to be administered based on the information provided in Section 6.1.1.2, 
Section 6.1.2.2, and Section 6.1.3.2. 
14) Within 30 minutes of removing the assigned vaccine from the refrigerator, inject 1 dose of 
assigned study vaccine intramuscularly into the anterolateral muscle of the thigh or the 
deltoid muscle, as appropriate (see Section 6.1.1.2, Section 6.1.2.2, and Section 6.1.3.2).  
15) Observe subject for 20 minutes following the injection for the occurrence of allergic and 
anaphylactic reactions and immediate injection site and systemic reactions. 
16) Provide to the subject or subject’s parent/guardian an age-appropriate diary card, a digital 
thermometer, and a flexible ruler, along with instructions for their use, to record solicited 
injection site and systemic reactions from Day 0 through Day 7 post-vaccination, and 
unsolicited AEs, SAEs, as well as any concomitant medications (see Section 6.7) from Visit 1 
through Visit 2. 
17) Schedule Visit 2.  
18) Remind the subject or subject’s parent/guardian that they will be contacted by telephone on 
or about Day 8 post-vaccination to remind them to complete the diary card and to bring the 
completed diary card with them to Visit 2. 
19) Remind the subject or subject’s parent/guardian to notify the site immediately if an SAE 
occurs. 
20) Complete the relevant case report forms (CRFs) for this visit. 
Telephone Contact – Visit 1 + 8 (window, 8–10) Days 
Eight days after the study vaccination at Visit 1, a delegated staff member from the study site will 
telephone the subject or subject’s parent/guardian to perform the following: 
1) Remind the subject or subject’s parent/guardian to record on the diary card any AEs and any 
concomitant medications (see Section 6.7) from Visit 1 until Visit 2. 
2) Remind the subject or subject’s parent/guardian to notify the site immediately if an SAE 
occurs. If an SAE occurs, follow the instructions in Section 10 for reporting it. 
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3) Confirm the date of the appointment of Visit 2, instruct the subject or subject’s 
parent/guardian to return at this time, and to bring the completed diary card with them to the 
study site. 
Note: If Day 8 falls on a weekend or a holiday, the telephone call may be placed preferably on the 
following business day. If the subject or subject’s parent/guardian is not available, the study staff 
should document the attempts to make contact. 
Visit 2 (Visit 1 + 21 [window, 21–28] days) – Subjects 18 Years of Age and Older – Collection of 
Safety Information and Blood Sample  
1) 
Review the diary card with the subject and collect it as a source document. 
2) 
Review interim health history, including any AEs, medications, or therapy that occurred 
since vaccination. 
3) 
Obtain the second blood sample (approximately 20 mL; see Section 7.1 for detailed 
instructions regarding the handling of blood samples). 
4) 
Complete the relevant CRFs for this visit as well as the termination record in the case report 
book (CRB). 
Visit 2 (Visit 1 + 28 [window, 28–35] days) – Subjects 6 Months to < 9 Years of Age Receiving 
1 Dose of Influenza Vaccine – Collection of Safety Information and Blood Sample  
1) Review Diary Card 1 with the subject’s parent/guardian for accuracy and collect it as the 
source document. 
2) Review interim health history, including any AEs, medications, or therapy that occurred since 
vaccination. 
3) Obtain the second blood sample (approximately 5 mL; see Section 7.1 for detailed 
instructions regarding the collection of blood samples). 
4) Complete the relevant CRFs for this visit as well as the termination record in the CRB. 
Visit 2 (Visit 1 + 28 [window, 28–35] days) – Subjects 6 Months to < 9 Years of Age Receiving 
2 Doses of Influenza Vaccinea – Second Vaccination and Collection of Safety Information  
1) Review Diary Card 1 with the subject’s parent/guardian for accuracy and collect it as the 
source document. 
2) Review interim health history, including any AEs, medications, or therapy that occurred since 
vaccination. 
3) Perform a history-directed physical examination. 
4) Measure temperature by the preferred route (see Section 9.3.1.3.2) and record this 
information in the source document. If the subject has a temperature ≥ 100.4°F (≥ 38.0°C) 
defer vaccination until the subject has been afebrile for at least 24 hours (see Section 5.2.7.1). 
                                                 
a  As per ACIP guidance. 
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5) Connect to the IRT system to confirm vaccine and dose to be administered based on subject’s 
age. The second vaccine dose should be the same as the first dose (i.e., same 0.25-mL or 
0.5-mL volume of Fluzone Quadrivalent vaccine) administered at Visit 1. 
6) Prepare the vaccine to be administered based on the information provided in Section 6.1.1.2. 
7) Within 30 minutes of removing the vaccine from the refrigerator, inject subject with the 
vaccine intramuscularly into the anterolateral muscle of the thigh or the deltoid muscle, as 
appropriate (Section 6.1.1.2). 
8) Observe subject for 20 minutes following the injection for the occurrence of allergic and 
anaphylactic reactions and immediate injection site and systemic reactions. 
9) Provide age-appropriate Diary Card 2 to the subject’s parent/guardian to record solicited 
injection site and systemic reactions from Day 0 through Day 7 post-vaccination, and 
unsolicited AEs, SAEs, as well as any concomitant medications (see Section 6.7) from Visit 2 
through Visit 3. 
10) Schedule Visit 3.  
11) Remind the subject’s parent/guardian that they will be contacted by telephone on or about 
Day 8 post-vaccination to remind them to complete the diary card and to bring the completed 
diary card with them to Visit 3. 
12) Remind the subject’s parent/guardian to notify the site immediately if an SAE occurs. 
13) Complete the relevant CRFs for this visit. 
Telephone Contact – Visit 2 + 8 (window, 8–10) Days – Subjects 6 Months to < 9 Years of Age 
Receiving 2 Doses of Influenza Vaccinea 
Eight days after the study vaccination at Visit 2 (for subjects receiving a second vaccination), a 
delegated staff member from the study site will telephone the subject’s parent/guardian to perform 
the following: 
1) Remind the subject’s parent/guardian to record on the diary card any AEs and any 
concomitant medications (see Section 6.7) from Visit 2 until study termination Visit 3. 
2) Remind the subject’s parent/guardian to notify the site immediately if an SAE occurs. If an 
SAE occurs, follow the instructions in Section 10 for reporting it. 
3) Confirm the date of the appointment of Visit 3. Instruct the subject’s parent/guardian to return 
at this time and to bring the completed diary card with them to the study site. 
Note: If Day 8 falls on a weekend or a holiday, the telephone call may be placed preferably on the 
following business day. If the subject’s parent/guardian is not available, the study staff should 
document the attempts to make contact. 
                                                 
a  As per ACIP guidance. 
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Visit 3 (Visit 2 + 28 [window, 28–35] days) – Subjects 6 Months to < 9 Years of Age Receiving 
2 Doses of Influenza Vaccinea – Collection of Safety Information and Blood Sample  
1) Review Diary Card 2 with the subject’s parent/guardian for accuracy and collect it as the 
source document. 
2) Review interim health history, including any AEs, medications, or therapy that occurred since 
vaccination. 
3) Obtain blood sample (approximately 5 mL; see Section 7.1 for detailed instructions regarding 
the collection of blood samples). 
4) Complete the relevant CRFs for this visit as well as the termination record in the CRB. 
Collection of Diary Cards  
If the subject or subject’s parent/guardian does not return for Visit 2 or Visit 3, and the diary card 
is not received at the site, site personnel will contact the subject or subject’s parent/guardian by 
telephone. During the telephone call, the subject or subject’s parent/guardian will be reminded to 
return the diary card to the study site. Telephone calls will be recorded on the subject’s source 
documents. If study personnel are unable to contact the subject or subject’s parent/guardian by 
telephone with 3 attempts, study personnel will follow instructions given in Section 5.2.9. 
Follow-up of Subjects With Related AEs or With AEs That Led to Study/Vaccination 
Discontinuation: 
Unless a subject or subject’s parent/guardian refuses further contact, a 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. 
5.1.5 
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 LVLS (last visit, last subject):  
September 2018 to December 2018 
Planned end of study: December 2018 
Planned date of final clinical study report: approximately 10 months after LVLS 
                                                 
a  As per ACIP guidance 
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5.1.6 
Early Safety Data Review 
This study will not include an early review of safety data.  However, it may be interrupted at any 
time if new data about the investigational products become available, and/or on advice of the 
Sponsor, the IRB(s), or the FDA.  
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IRB(s), 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 or subjects’ parents/guardians, as appropriate, 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 site will ensure that any 
advertisements used to recruit subjects (informational brochures, parent letters, posters, and other 
advertisements) are submitted to Sanofi Pasteur prior to submission to the IRB(s) for approval. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study, or a parent/guardian confirms their willingness to allow their 
child 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 addition to the ICF that is signed by the subject or subject’s parent/guardian, subjects 
7 to < 9 years of age will be asked to review and sign a study assent form. 
In accordance with GCP, prior to signing and dating the consent form, the subject, or the 
parent(s)/guardian(s) (of subjects 6 months to < 9 years of age) must be informed by appropriate 
study personnel about all aspects of the study that are relevant to making the decision to 
participate, and must have sufficient time and opportunity to ask any questions. The same must 
also be done for subjects 7 to < 9 years of age prior to their signing and dating the assent form. 
The actual ICF used at each center may differ, depending on local regulations and 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 IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study, or the willingness of a parent/guardian (of subjects 6 months to < 9 years 
of age) to have their child continue participation in the study, this will be communicated to the 
subject or subject’s parent/guardian (as appropriate) in a timely manner. Such information will be 
provided via a revised ICF or an addendum to the original ICF (and assent form). 
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Informed consent forms and assent forms will be provided in duplicate, or a photocopy of the 
signed consent/assent  will be made. The original will be kept by the Investigator, and the copy 
will be kept by the subject or subject’s parent/guardian. 
Documentation of the consent process should be recorded in the source documents. 
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 months to < 9 years or ≥ 18 years on the day of first study vaccination (study product 
administration).a 
2) For subjects 6 to < 12 months of age, born at full term of pregnancy (≥ 37 weeks) and with a 
birth weight ≥ 2.5 kg (5.5 lbs). 
3) Informed consent form has been signed and dated by subjects ≥ 18 years of age. 
4) Assent form has been signed and dated by subjects 7 to < 9 years of age, and ICF has been 
signed and dated by parent(s) or guardian(s) for subjects 6 months to < 9 years of age. 
5) Subject and parent/guardian (of subjects 6 months to < 9 years of age) are able to attend all 
scheduled visits and to comply with all study procedures. 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential and not using an effective 
method of contraception or abstinence from at least 4 weeks prior to vaccination and until at 
least 4 weeks after vaccination. To be considered of non-childbearing potential, a female 
must be pre-menarche,b or post-menopausal for at least 1 year, or surgically sterile. 
2) Participation at the time of study enrollment (or in the 30 days preceding the first study 
vaccination) or planned participation during the present study period in another clinical study 
investigating a vaccine, drug, medical device, or medical procedure.  
 
Note: Subjects may be considered eligible for enrollment if no intervention for the other 
study occurred within the 30 days prior to the first study vaccination and none are planned 
before the subject would complete safety surveillance for the present study. 
                                                 
a  “6 months to < 9 years” means from the 6 month after birth to the day before the 9th year. “≥ 18 years” means 
from the day of the 18th birthday onwards. 
b  Pre-menarche females will declare by themselves that they have not yet started menstruation. If a young female 
subject reaches menarche during the study, then she is to be considered as a woman of childbearing potential from 
that time forward. 
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3) Receipt of any vaccine in the 30 days preceding the first study vaccination, or 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. 
4) Previous vaccination against influenza (in the 2018–2019 influenza season) with either study 
vaccine or another vaccine. 
5) Receipt of immune globulins, blood, or blood-derived products in the 3 months preceding 
planned inclusion. 
6) Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the 6 months preceding planned inclusion; or long-term systemic corticosteroid therapy 
(prednisone or equivalent for more than 2 consecutive weeks within the 3 months preceding 
planned inclusion). 
7) Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to study vaccine or to a vaccine containing any of the same substances.  
 
Note: The list of vaccine components is included in the Prescribing Information for each 
study vaccine. 
8) Thrombocytopenia, which may be a contraindication for intramuscular vaccination, at the 
discretion of the Investigator. 
9) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination. 
10) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily. 
11) Current alcohol abuse or drug addiction. 
12) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with study conduct or completion.a 
13) Moderate or severe acute illness/infection (according to Investigator judgment) on the day of 
planned vaccination or febrile illness (temperature ≥ 100.4°F [38.0°C]). A prospective subject 
should not be included in the study until the condition has resolved or the febrile event has 
subsided. 
14) Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study (subjects ≥ 18 years of age) or identified as an immediate 
family member (i.e., parent, spouse, natural or adopted child) of the Investigator or employee 
with direct involvement in the proposed study (all subjects). 
15) History of serious AR to any influenza vaccine. 
                                                 
a  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, autoimmune disorders, 
diabetes, psychomotor diseases, and known congenital or genetic diseases 
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16) Personal history of GBS. 
17) 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. 
18) Personal history of clinically significant developmental delay (at the discretion of the 
Investigator), neurologic disorder, or seizure disorder. 
19) Known seropositivity for human immunodeficiency virus, hepatitis B, or hepatitis C. 
Note: Subjects enrolled into this study will not be prohibited from donating blood for non-
interventional studies or other purposes. 
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 
systems and disorders that could be used to prompt comprehensive reporting, as well as space for 
the reporting of specific conditions and illnesses. 
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, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. 
5.2.7 
Contraindications for Subsequent Vaccinations 
5.2.7.1 
Temporary Contraindications 
Should a subject experience 1 of the conditions listed below, the Investigator will postpone further 
vaccination until the condition is resolved. Postponement must still be within the timeframe for 
vaccination indicated in the Table of Study Procedures. 
• Febrile illness (temperature ≥ 100.4°F [≥ 38.0°C]) or moderate or severe acute 
illness/infection on the day of vaccination, according to Investigator judgment  
5.2.7.2 
Definitive Contraindications 
Should a subject experience 1 or more of the conditions listed below, after the first dose of study 
vaccine, the Investigator will not administer the second dose of vaccine that has been allocated for 
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use in the study (i.e., study vaccine); however, the Investigator may administer a second dose of 
licensed, non-study influenza vaccine in accordance with standard clinical care. 
Definitive contraindications include but are not limited to: 
1) An anaphylactic or other significant allergic reaction to the previous dose of vaccine. 
2) Receipt of any non-study vaccine (including a non-study dose of 2018–2019 influenza 
vaccine), immune globulins, blood, or blood-derived products between Visit 1 and Visit 2. 
3) Bleeding disorder, receipt of anticoagulants, or thrombocytopenia, which may be a 
contraindication for intramuscular vaccination, at the discretion of the Investigator. 
4) Development of any condition that in the opinion of the Investigator would pose a health 
risk to the subject or could interfere with the evaluation of the study vaccine (including 
GBS, clinically significant developmental delay, neurologic disorder, seizure disorder, 
human immunodeficiency virus infection, hepatitis B, or hepatitis C). 
5) Development of an immunodeficiency; or receipt of immunosuppressive therapy such as 
anti-cancer chemotherapy or radiation therapy; or receipt of long-term systemic 
corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks). 
6) Adverse events that are considered a contraindication for further participation in the study. 
Subjects with a definitive contraindication will continue to be followed up for the study-defined 
safety and immunogenicity assessments, as applicable. Therefore, in this study subjects with a 
definitive contraindication will be discontinued from the study (and, accordingly, will not have a 
post-vaccination blood sample collected), but will continue to be followed for study-defined 
safety assessments. 
5.2.8 
Conditions for Withdrawal  
Subjects or subjects’ parents/guardians will be informed that they have the right to withdraw or 
withdraw their child from the study at any time.  
A subject may be withdrawn from the study: 
• At the discretion of the Investigator or Sponsor due to safety concerns (withdrawal) without 
the subject’s or parent’s/guardian’s permission. 
• At the request of the subject or parent/guardian (dropout).  
The following will result in automatic withdrawal or exclusion of a subject from the study: 
• Significant non-compliance with the protocol, based on the Investigator’s judgment 
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. 
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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 (i.e., 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 CRB and 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 CRB completion instructions for additional details and 
examples): 
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 9.3.1.1. 
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 or 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 noncompliance with the protocol 
(e.g., 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 a 
protocol deviation. 
• 
The subject or the 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 or 
Parent/Guardian/Legally 
Acceptable Representative 
To be used: 
• 
When the subject or parent/guardian indicated unwillingness to 
continue in the study 
• 
When the subject or parent/guardian made the decision to 
discontinue participation in the study for any personal reason other 
than an SAE/AE (e.g., subject is relocating, inform consent 
withdrawal) 
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5.2.11 Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the study because of an AE, a protocol deviation, or loss of eligibility, 
including definitive contraindications.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
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 or 
Parent/Guardian/Legally Acceptable Representative”, the site will attempt to contact them except 
if they specified that they do not want to be contacted again and it is documented in the source 
document. 
5.2.12 Follow-up and Reporting of Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy and if at least 1 dose of the study 
vaccine(s) has been administered, the subject will not be discontinued from the study, but no 
further vaccination will be administered until after delivery (if applicable and still within the study 
vaccination window). However, the subject will be followed for safety assessment (and may be 
followed for immunogenicity assessment, if applicable). 
All pregnancy cases should be reported if they occurred during the study. To report the pregnancy 
case, the Investigator must fill out Pregnancy Reporting forms in the electronic data capture 
(EDC) system and inform the Sponsor within 1 month of identifying a pregnancy case.  
If the EDC system is not available, the Investigator must fill out a paper Pregnancy Reporting 
Form (provided by the Sponsor at the start of the study) and inform the Sponsor within 1 month of 
identifying a pregnancy case. 
Study staff must then maintain contact with the subject to obtain information about the outcome 
(i.e., details about the delivery and the newborn, or about pregnancy termination) and must update 
the Pregnancy Reporting forms even after the end of the study. This information should be 
provided to the Sponsor within 1 month of delivery. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, blighted 
ovum, fetal death, stillbirth, and congenital anomalies reported in the baby are always considered 
as SAEs, and the information should be provided to the Global Pharmacovigilance & 
Epidemiology (GPE) Department regardless of when the SAE occurs (e.g., even after the end of 
the study). 
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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 RMOs for advice on study-related medical question or problem. The 
RMOs will be available 24 hours a day, 7 days a week, as needed. Contact information for each of 
the RMOs is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPE Department (Please refer to 
Section 10). 
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 (e.g., those that affect the conduct of the study or the safety of 
subjects) require 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. Regulatory authorities need only be notified about administrative changes. 
Administrative changes do not require IRB approval; however, the IRB(s) must be notified 
whenever such a change is made. 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IRB approval has already been given, are not initiated without 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 IRB(s), or the governing regulatory authorities in the country where the study is 
taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRB(s), 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 study subjects or subjects’ 
parents/guardians, as appropriate, and should assure appropriate subject therapy and/or follow-up. 
6 
Vaccines Administered 
Subjects 6 to < 36 months of age and subjects 3 to < 9 years of age will be administered Fluzone 
Quadrivalent vaccine, subjects 18 to < 65 years of age will be administered either Fluzone 
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Quadrivalent vaccine or Flublok Quadrivalent vaccine, and subjects ≥ 65 years of age will be 
administered Fluzone High-Dose vaccine. 
• Fluzone Quadrivalent vaccine, pediatric dose (subjects 6 to < 36 months of age):  
7.5 µg/HA of each antigen per 0.25-mL dose (total HA content per dose: 30 µg) 
• Fluzone Quadrivalent vaccine (subjects 3 to < 9 years of age and 18 to < 65 years of age):  
15 µg/HA of each antigen per 0.5-mL dose (total HA content per dose: 60 µg) 
• Flublok Quadrivalent vaccine (subjects 18 to < 65 years of age): 
45 µg/HA of each antigen per 0.5-mL dose (total HA content per dose: 180 µg) 
• Fluzone High-Dose vaccine (subjects ≥ 65 years of age): 
60 µg/HA of each antigen per 0.5-mL dose (total HA content per dose: 180 µg) 
Subjects will receive an intramuscular injection of the product that they are assigned to receive. 
For subjects 6 months to < 9 years of age, 1 or 2 doses of influenza vaccine will be administered 
according to ACIP guidance in effect during the study. If 2 doses of influenza vaccine are 
indicated, 1 dose will be administered during Visit 1 and the second dose (same 0.25-mL or 
0.5-mL volume of Fluzone Quadrivalent vaccine as administered at Visit 1) will be administered 
approximately 28 days later, during Visit 2. 
6.1 
Identity of the Investigational Products  
The 2018–2019 formulations of Fluzone Quadrivalent (0.25-mL and 0.5-mL pre-filled syringe 
presentations) and Fluzone High-Dose vaccines are sterile suspensions prepared from influenza 
viruses propagated in embryonated chicken eggs. The virus-containing fluid is harvested and the 
virus inactivated with formaldehyde. The influenza virus is concentrated and purified in a linear 
sucrose density gradient solution using a continuous flow centrifuge. The virus is then chemically 
disrupted producing a split antigen. The split antigen is then suspended in sodium phosphate-
buffered isotonic sodium chloride solution. Neither antibiotics nor preservatives are used in the 
manufacture of the vaccine formulations used in this study. Fluzone Quadrivalent and Fluzone 
High-Dose vaccines are clear and slightly opalescent in color. 
The 2018–2019 formulation of Flublok Quadrivalent vaccine is a sterile, clear, colorless solution 
of recombinant HA proteins from 4 influenza viruses for intramuscular injection. It contains 
purified HA proteins produced in a continuous insect cell line (expresSF+®) that is derived from 
Sf9 cells of the fall armyworm, Spodoptera frugiperda (which is related to moths, caterpillars, and 
butterflies), and grown in serum-free medium composed of chemically-defined lipids, vitamins, 
amino acids, and mineral salts. Each of the 4 HAs is expressed in this cell line using a baculovirus 
vector (Autographa californica nuclear polyhedrosis virus), extracted from the cells with Triton 
X-100 and further purified by column chromatography. The purified HAs are then blended and 
filled into single-dose syringes.  
6.1.1 
Identity of Licensed Study Product 1 
Fluzone Quadrivalent vaccine, No Preservative: Pediatric Dose (0.25-mL dose),  
2018–2019 formulation  
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or 
Fluzone Quadrivalent vaccine, No Preservative (0.5-mL dose), 2018–2019 formulation 
6.1.1.1 
Composition 
Each 0.25-mL dose contains 7.5 µg HA of each antigen, and each 0.5-mL dose contains 
15 µg HA of each antigen: 
• A/Michigan/45/2015 (H1N1) 
• A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• B/Maryland/15/2016 (B Victoria lineage) (a B/Colorado/06/2017-like virus) 
• B/Phuket/3073/2013 (B Yamagata lineage) 
6.1.1.2 
Preparation and Administration 
Fluzone Quadrivalent vaccine is a liquid preparation; as such, no diluent is required. This product 
is provided in 0.25-mL and 0.5-mL, pre-filled, single-dose syringes. The vaccine will be 
administered intramuscularly into the anterolateral muscle of the thigh or the deltoid muscle, as 
appropriate. The vaccine must be administered within 30 minutes of removing the vaccine from 
the refrigerator. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and/or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered; another dose is to be used, and the event is to be reported to the Sponsor.  
Subjects must be kept under observation for 20 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 
Fluzone Quadrivalent vaccine will be administered at Visit 1 (Day 0) as a single 0.25-mL dose to 
subjects 6 to < 36 months of age (Group 1), and as a 0.5-mL dose to subjects 3 to < 9 years of age 
(Group 2) and subjects 18 to < 65 years of age (Group 3) assigned to receive this vaccine. For 
subjects 6 months to < 9 years of age for whom 2 doses of influenza vaccine are recommended 
per ACIP guidance, a second dose of the same volume of Fluzone Quadrivalent vaccine as the 
first dose will be administered at Visit 2 (28 [window, 28–35] days after Visit 1). 
6.1.2 
Identity of Licensed Study Product 2  
Flublok Quadrivalent vaccine, 2018–2019 formulation 
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6.1.2.1 
Composition 
Each 0.5-mL dose contains 45 µg recombinant HA of each antigen: 
• A/Michigan/45/2015 (H1N1) 
• A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• B/Maryland/15/2016 (B Victoria lineage) (a B/Colorado/06/2017-like virus) 
• B/Phuket/3073/2013 (B Yamagata lineage)  
6.1.2.2 
Preparation and Administration 
Flublok Quadrivalent vaccine is a liquid preparation; as such, no diluent is required. This product 
is provided in 0.5-mL, pre-filled, single-dose syringes. The vaccine will be administered 
intramuscularly into the deltoid of choice using a needle of appropriate length. To ensure 
intramuscular vaccination, the subject will be instructed to relax the arm; the needle will be 
inserted straight into the deltoid muscle, centered between the shoulder and the axilla and midway 
between the posterior and anterior aspects of the arm. The vaccine must be administered within 
30 minutes of its removal from the refrigerator. 
Additional procedures for preparing and administering Flublok Quadrivalent vaccine are the same 
as those described for the study product in Section 6.1.1.2. 
6.1.2.3 
Dose Selection and Timing 
Flublok Quadrivalent vaccine will be administered as a single 0.5-mL dose given at Visit 1 
(Day 0) to subjects 18 to < 65 years of age who are assigned to receive this vaccine (Group 4).  
6.1.3 
Identity of Licensed Study Product 3  
Fluzone High-Dose vaccine, 2018–2019 formulation 
6.1.3.1 
Composition 
Each 0.5 mL dose contains 60 µg HA of each antigen: 
• A/Michigan/45/2015 (H1N1) 
• A/Singapore/INFIMH-16-0019/2016 (H3N2)  
• B/Maryland/15/2016 (B Victoria lineage) (a B/Colorado/06/2017-like virus) 
6.1.3.2 
Preparation and Administration 
Fluzone High-Dose vaccine is a liquid preparation; as such, no diluent is required. This product is 
provided in 0.5-mL, pre-filled, single-dose syringes. The vaccine will be administered 
intramuscularly into the deltoid of choice using a needle of appropriate length. To ensure 
intramuscular vaccination, the subject will be instructed to relax the arm; the needle will be 
inserted straight into the deltoid muscle, centered between the shoulder and the axilla and midway 
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between the posterior and anterior aspects of the arm. The vaccine must be administered within 
30 minutes of its removal from the refrigerator. 
Additional procedures for preparing and administering Fluzone High-Dose vaccine are the same 
as those described for the study product in Section 6.1.1.2. 
6.1.3.3 
Dose Selection and Timing 
Fluzone High-Dose vaccine will be administered as a single 0.5-mL dose given at Visit 1 (Day 0) 
to subjects ≥ 65 years of age assigned to receive this vaccine (Group 5).  
6.1.4 
Identity of Control Products  
Not applicable. 
6.2 
Identity of Other Products 
Not applicable. 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
All study vaccines will be supplied by the Sponsor. Fluzone Quadrivalent, Flublok Quadrivalent, 
and Fluzone High-Dose vaccines will be supplied with their manufacturer’s commercial labeling 
and packaging. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator 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 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 (i.e., 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. 
6.3.2.2 
Product Storage 
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
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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. 
6.3.2.3 
Product Accountability 
The person in charge of product management 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 system. 
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. 
6.3.3 
Replacement Doses 
If a replacement dose is required (e.g., 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. 
6.3.4 
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. 
6.3.5 
Recall of Products 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
This is an open-label study. 
6.5 
Randomization and Allocation Procedures 
On the day of enrollment, subjects who meet all inclusion criteria and no exclusion criteria will be 
assigned to 1 of 5 vaccine groups (6 to < 36 months of age, Fluzone Quadrivalent vaccine 
[Group 1], 3 to < 9 years of age, Fluzone Quadrivalent vaccine [Group 2], 18 to < 65 years of age, 
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Fluzone Quadrivalent vaccine [Group 3], 18 to < 65 years of age, Flublok Quadrivalent vaccine 
[Group 4], or ≥ 65 years of age, Fluzone High-Dose vaccine [Group 5]); see Section 6 for details 
regarding the vaccine to be administered to each group. Site staff will connect to the IRT system, 
enter the identification and security information, and confirm a minimal amount of data (including 
the number of doses) in response to IRT system prompts. The IRT system will then provide the 
subject number and vaccine and dose to be administered based on subject’s age and have the site 
staff confirm it. Subjects 18 to < 65 years of age will be randomly assigned to either Group 3 or 
Group 4. The full detailed procedures for using the IRT system are described in the Operating 
Guidelines. If the subject is not eligible to participate in the study, information will only be 
recorded on the subject recruitment log. 
Subject numbers that are assigned by the IRT system will consist of a 12-digit string (a 3-digit 
country code, 4 digit study center identifier and a 5-digit subject identifier connected by “-”). For 
example, Subject 8400001-00001 is the first subject enrolled in center number 1 in the United 
States (840 being the US country code). Subject numbers should not be reassigned for any reason. 
The randomization codes will be kept securely in the IRT.  
6.6 
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 disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications and other therapies (e.g., blood products) should 
be recorded in the source document as well as new medications prescribed for new medical 
conditions/AEs during study participation.  
Documentation in the CRB of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of first vaccination. This may include 
medications of interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRB from the day of each vaccination to the end 
of the solicited and unsolicited follow-up period (i.e., from Visit 1 through Visit 2 for subjects 
receiving 1 dose of study vaccine or from Visit 1 through Visit 3 for subjects receiving 2 doses of 
study vaccine).  
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Three 
standard categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of safety 
(e.g., antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs]). Topical 
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analgesics should NOT be applied at the site of vaccination; however, if they are applied 
inadvertently to the vaccination site, they should be recorded as a Category 1 medication in 
this specific instance, not as a Category 2 medication. 
• Category 2: medications impacting or that may have an impact on the immune response 
(e.g., other vaccines, blood products and immune globulins, antibiotic classes that may 
interfere with bioassays used by the Global Clinical Immunology [GCI] department, immune-
suppressors, immune-modulators with immunosuppressive properties, anti-proliferative drugs 
such as DNA synthesis inhibitors).  
• Category 3: medications impacting or that may have an impact on both safety and immune 
response (e.g., steroids/corticosteroids). 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name 
• Origin of prescription: prophylaxis (Yes/No). Medication(s) prescribed for AE prophylaxis 
will be recorded in the Action Taken of the AE collection tables. 
• Medication category (1, 2, or 3) 
• Start and stop dates 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to 1 of the prelisted categories. Medications will not be coded. 
7 
Management of Samples 
Blood samples for the assessment of antibody responses will be collected at Visit 1 and at Visit 2 
for subjects receiving 1 dose of study vaccine or at Visit 1 and Visit 3 for subjects receiving 
2 doses of study vaccine. See the Table of Study Procedures and Section 5.1.3 for details of the 
sampling schedule. 
7.1 
Sample Collection 
A total of 2 blood samples (each approximately 5 mL for subjects 6 months to < 9 years of age or 
approximately 20 mL for subjects ≥ 18 years of age) will be collected from all subjects. The first 
blood sample will be collected at Visit 1 prior to vaccination. The second blood sample will be 
collected at Visit 2, if no study vaccine is administered at Visit 2; or at Visit 3, if study vaccine is 
administered at Visit 2. 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; will verify the assigned subject’s number on the pre-printed label that 
contains that subject’s number and the sampling stage; and will attach the label to the tube. Blood 
is to be taken from the limb opposite to the one that will be used for vaccination, if possible. 
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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. 
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 up to a maximum of 24 hours. The samples are then centrifuged, 
and the serum is transferred to the appropriate number of aliquoting tubes. These tubes should be 
pre-labeled with adhesive labels that identify the study code, the subject’s number, and the 
sampling stage (see Section 7.1).  
The subject’s number and the date of sampling, the number of aliquots obtained, and the subject 
or subject’s parent’s/guardian’s consent for future use of his/her samples are to be specified on a 
sample identification list. All these items, as well as the date and time of preparation, are to be 
recorded in the source document. Space is provided on the sample identification list for comments 
on the quality of samples. 
7.3 
Sample Storage and Shipment 
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 
during the entire study. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines.  
Shipments to the laboratory (GCI) will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. 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 Class 6.2 
specifications and the International Air Transport Association 602 packaging instructions. 
7.4 
Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) for at least 5 years after the last license approval in the relevant market areas has 
been obtained for the vaccine being tested. 
Subjects or subjects’ parents/guardians 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 
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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, and other study documents, as well as with the following study materials: all study 
vaccines, blood collection tubes, cryotubes, cryotube storage boxes, cryotube labels, temperature 
recorders, shipping containers, rulers, pregnancy tests, 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. 
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 
Primary Endpoints and Assessment Methods 
9.1.1 
Safety 
There are no primary objectives for safety. 
9.1.2 
Immunogenicity 
There are no primary objectives for immunogenicity. 
9.1.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
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9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Safety 
There are no secondary objectives for safety. 
9.2.2 
Immunogenicity 
There are no secondary objectives for immunogenicity. 
9.2.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
9.3 
Observational Endpoints and Assessment Methods 
The observational safety objective is presented in Section 2.1.1. 
9.3.1 
Safety 
9.3.1.1 
Safety Definitions 
The following definitions are taken from the International Conference on Harmonisation (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 
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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 (e.g., 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 
• 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 ARs. 
(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) 
                                                 
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. 
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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 20 minutes after vaccination. 
Solicited Reaction: 
A solicited reaction is an “expected” AR (sign or symptom) observed and reported under the 
conditions (nature and onset) prelisted in the protocol and CRB (e.g., injection site pain from 
Day 0 through Day 7 post-vaccination, or headache from Day 0 through Day 7 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. 
The assessment of these reactions by the Investigator is mandatory. 
Unsolicited AE/AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between 
Day 0 and Day 7 is a solicited reaction (i.e., prelisted in the protocol and CRB), then a headache 
starting on Day 7 is a solicited reaction, whereas headache starting on Day 8 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 (e.g., erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An AESI is one of scientific and medical concerns 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 (e.g., regulators) might also be warranted. 
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9.3.1.2 
Safety Endpoints 
The observational endpoints for the evaluation of safety are: 
1) Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred 
term), duration, intensity, and relationship to vaccination of any unsolicited systemic AEs 
reported in the 20 minutes after vaccination. 
2) Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited injection site reactions 
(prelisted in the subject’s diary card and CRB) occurring from Day 0 through Day 7 after 
vaccination. 
3) Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited systemic reactions (prelisted 
in the subject’s diary card and CRB) occurring from Day 0 through Day 7 after vaccination. 
4) Occurrence, nature (MedDRA preferred term), time to onset, duration, intensity, action taken, 
relationship to vaccination (for systemic AEs only), and whether the event led to early 
termination from the study, of unsolicited AEs from Visit 1 through Visit 2 for subjects 
receiving 1 dose or from Visit 1 through Visit 3 for subjects receiving 2 doses. 
5) Occurrence, nature (MedDRA preferred term), time to onset, seriousness criteria, relationship 
to vaccination, outcome, and whether the SAE led to early termination from the study, of 
SAEs from Visit 1 through Visit 2 for subjects receiving 1 dose or from Visit 1 through 
Visit 3 for subjects receiving 2 doses. 
Adverse events of special interest will be captured as SAEs. These include new onset of GBS, 
encephalitis/myelitis (including transverse myelitis), neuritis (including Bell’s palsy, optic 
neuritis, and brachial neuritis), thrombocytopenia, vasculitis, convulsions (including febrile 
convulsions [children only]), and anaphylaxis or other hypersensitivity/allergic reactions from 
Visit 1 through Visit 2 for subjects receiving 1 dose of vaccine, or from Visit 1 through Visit 3 for 
subjects receiving 2 doses of vaccine. 
9.3.1.3 
Safety Assessment Methods 
At each visit, the Investigator or a delegate will perform a directed physical examination, if 
indicated, based on interim history and will ask the subject or subject’s 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. 
9.3.1.3.1 
Immediate Post-vaccination Observation Period 
Subjects will be kept under observation for 20 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. Any AE 
that occurs during this period will be noted on the source document and recorded in the CRB, as 
follows: 
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• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected). 
• 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.  
• 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. 
9.3.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 Through Day 7 After Each 
Vaccination) 
After each vaccination, the subject or the subject’s parent/guardian 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 subject or the subject’s parent/guardian in the diary card 
on the day of vaccination and for the next 7 days (i.e., 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 (e.g., medication) 
The action(s) taken by the subject or subject’s parent/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  
 
The subject or subject’s parent/guardian will be contacted by telephone 8 days after each 
vaccination to remind them to record all safety information in the diary card. 
If the timing of the telephone call should fall on a weekend or a holiday, the call should be made 
on the next business day. If contact is not made on the designated day, study staff will continue 
calling until contact is made. Every telephone attempt and its outcome will be documented in the 
source document. 
Table 9.1, Table 9.2, Table 9.3, Table 9.4, and Table 9.5 present the injection site reactions and 
systemic reactions that are prelisted in the diary cards and CRB, together with the intensity scales. 
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Table 9.1: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales (Subjects 6 to < 36 Months of Age) 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Injection site tenderness 
Injection site erythema 
Injection site swelling 
Data analysis term 
(MedDRA preferred 
term [PT]) 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Tenderness 
Redness 
Swelling 
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 
Intensity scalea 
 
Grade 1: Minor reaction when injection site is 
touched 
Grade 2: Cries or protests when injection site 
is touched 
Grade 3: Cries when injected limb is 
mobilized, 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 
a  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. 
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Table 9.2: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales (Subjects 3 to < 9 Years of Age) 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
Data analysis term 
(MedDRA preferred 
term [PT]) 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when 
the injection site is touched or injected limb 
is mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scalea 
 
Grade 1: Easily tolerated 
Grade 2: Sufficiently discomforting to 
interfere with normal behavior or activities 
Grade 3: Incapacitating, unable to perform 
usual activities 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
a  For the subjective reaction of pain, subjects or subjects’ 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. 
 
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Table 9.3: Solicited Injection Site Reactions: Terminology, Definitions, and Intensity Scales (Subjects 18 Years of Age and Older) 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
Data analysis term 
(MedDRA preferred 
term [PT]) 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when 
the injection site is touched or injected limb 
is mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
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Intensity scalea 
 
Grade 1: A type of adverse event that is 
usually transient and may require only 
minimal treatment or therapeutic 
intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2: A type of adverse event that is 
usually alleviated with additional therapeutic 
intervention. The event interferes with usual 
activities of daily living, causing discomfort 
but poses no significant or permanent risk of 
harm to the research participant. 
Grade 3: A type of adverse event that 
interrupts usual activities of daily living, or 
significantly affects clinical status, or may 
require intensive therapeutic intervention. 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
a 
For the subjective reaction of pain, subjects 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 
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Table 9.4: Solicited Systemic Reactions: Terminology, Definitions, and Intensity Scales (Subjects 6 to < 36 Months of Age) 
CRB term (MedDRA 
lowest level term 
[LLT]) 
Fever 
 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
Data analysis term 
(MedDRA preferred 
term [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 scalea 
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 
a  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. 
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Table 9.5: Solicited Systemic Reactions: Terminology, Definitions, and Intensity Scales (Subjects 3 to < 9 Years of Age and 18 Years of Age  
and Older) 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Fever 
 
Headache 
Malaise 
Myalgia 
Data analysis term 
(MedDRA preferred 
term [PT]) 
Pyrexia 
Headache 
Malaise 
Myalgia 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Definition 
Elevation of temperature to  
≥ 38.0°C (≥ 100.4°F) 
Pain or discomfort in the head or 
scalp. Does not include migraine. 
General ill feeling. 
Malaise is a generalized feeling of 
discomfort, illness, or lack of well-
being that can be associated with a 
disease state. It can be accompanied 
by a sensation of exhaustion or 
inadequate energy to accomplish 
usual activities. 
Muscle aches and pains are common 
and can involve more than one 
muscle at the same time. Muscle 
pain can also involve the soft tissues 
that surround muscles. These 
structures, which are often referred 
to as connective tissues, include 
ligaments, tendons, and fascia (thick 
bands of tendons). 
Does not apply to muscle pain at the 
injection site which should be 
reported as injection site pain. 
Intensity scalea 
Grade 1: ≥ 38.0°C to ≤ 38.4°C, 
or ≥ 100.4°F to ≤ 101.1°F 
Grade 1: A type of adverse event 
that is usually transient and may 
require only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 
Grade 1: A type of adverse event 
that is usually transient and may 
require only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 
Grade 1: A type of adverse event 
that is usually transient and may 
require only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 
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Grade 2: ≥ 38.5°C to ≤ 38.9°C, 
or ≥ 101.2°F to ≤ 102.0°F 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
a  For all reactions but fever, subjects or subjects’ 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. 
 
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Important notes for the accurate assessment of temperature: 
Subjects or subjects’ parents/guardians 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, 
and the highest temperature will be recorded by the site in the CRB. The preferred route for this 
study is rectal for subjects 6 to < 36 months of age, and oral for subjects 3 to < 9 years of age and 
≥ 18 years of age. The axillary route may be used when a rectal or oral temperature cannot be 
obtained. Pre-vaccination temperature is also to be systematically collected by the Investigator on 
the source document. Tympanic thermometers must not be used. 
9.3.1.3.3 
Unsolicited Adverse Events 
In addition to recording solicited reactions, subjects or subjects’ parents/guardians will be 
instructed to record any other medical events that may occur from Visit 1 through Visit 2 (Diary 
Card 1) for all subjects and from Visit 2 through Visit 3 (Diary Card 2) for subjects receiving 
2 doses of study vaccine. Space will be provided in the diary card for this purpose.  
Information on SAEs will be collected and assessed throughout the study, from Visit 1 through 
Visit 2 for subjects receiving 1 dose of study vaccine, and from Visit 1 through Visit 3 for 
subjects receiving 2 doses of study vaccine.  
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 Death/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 
(e.g., outcome, medical history, results of investigations, copy of hospitalization reports). 
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 9.1, Table 9.2, Table 9.3, Table 
9.4, and Table 9.5). 
                                                 
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. 
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All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Grade 2: A type of AE that is usually alleviated with additional therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.  
• Grade 3: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• 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 9.3.1.3.5. 
• Action taken for each AE (e.g., medication) 
The action(s) taken by the subject or subject’s parent(s)/guardian(s) 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 
9.3.1.3.4 
Adverse Events of Special Interest 
Adverse events of special interest will be captured as SAEs. These include new onset of GBS, 
encephalitis/myelitis (including transverse myelitis), neuritis (including Bell’s palsy, optic 
neuritis, and brachial neuritis), thrombocytopenia, vasculitis, convulsions (including febrile 
convulsions [children only]), and anaphylaxis or other hypersensitivity/allergic reactions from 
Visit 1 through Visit 2 for subjects receiving 1 dose of vaccine, or from Visit 1 through Visit 3 for 
subjects receiving 2 doses of vaccine. 
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9.3.1.3.5 
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. 
9.3.2 
Immunogenicity 
The observational immunogenicity objective is presented in Section 2.1.2. 
9.3.2.1 
Immunogenicity Endpoints 
Immunogenicity will be evaluated in all subjects by analyzing sera collected prior to vaccination 
on Day 0 (Visit 1) and after final vaccination (28 [window, 28–35] days post-final vaccination for 
subjects 6 months to < 9 years of age [Visit 2 for subjects receiving 1 dose; Visit 3 for subjects 
receiving 2 doses]; or 21 [window, 21–28] days post-vaccination for subjects ≥ 18 years of age) 
using the HAI assay technique.  
For each influenza vaccine strain (i.e., 3 strains for Fluzone High-Dose vaccine [a trivalent 
vaccine] and 4 strains for Fluzone Quadrivalent vaccine and Flublok Quadrivalent vaccine), HAI 
assay titers at pre-vaccination (Day 0) and after the final vaccination will be determined in 
duplicate.  
The derived endpointsa are: 
• Geometric means of HAI assay titers at pre-vaccination and post-final vaccination  
• Ratios of post-final vaccination titers divided by pre-vaccination titers 
• Seroprotection: a titer ≥ 40 (l/dilution [dil]) at pre-vaccination and at post-final vaccination  
• Seroconversion: either a pre-vaccination titer < 10 (1/dil) and a post-final vaccination titer 
≥ 40 (1/dil), or a pre-vaccination titer ≥ 10 (1/dil) and a ≥ 4-fold increase in post-final 
vaccination titer  
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a    Post-final vaccination in each of the derived endpoints is defined as 28 (window, 28–35) days post-final  
  vaccination for subjects 6 months to < 9 years of age, and 21 (window, 21–28) days post-vaccination for subjects 
  ≥ 18 years of age 
9.3.2.2 
Immunogenicity Assessment Methods  
Anti-influenza antibodies will be measured by HAI assay performed by Sanofi Pasteur’s GCI 
department or an external testing laboratory under GCI’s supervision. Serum samples and quality 
control sera (sheep and/or human sera) will be incubated with Sigma Type III NA to eliminate 
non-specific inhibitors. Adsorption of spontaneous anti-species agglutinins will be performed by 
incubating the serum samples and quality control sera with a red blood cell (RBC) suspension. 
Following this, the mixtures will be centrifuged and the supernatants containing the treated sera 
will be collected for testing. Ten 2-fold dilutions (starting at 1/10) of the treated serum samples 
and quality control sera will be incubated with a previously titrated influenza virus at a 
concentration of 4 hemagglutination unit/25 μL. Influenza virus will not be added to the serum 
control wells containing only serum and RBCs. The mixture will be incubated and a RBC 
suspension will be added. Following incubation, the results will be read. The endpoint of the 
assay is the highest serum dilution in which complete inhibition of hemagglutination occurred. 
Each serum sample will be titrated in independent duplicates, and the 2 values, which do not 
differ by more than one 2-fold dilution, will be reported. The geometric mean titer between the 
2 values will be calculated after the release of the data to the Clinical Data Management (CDM) 
platform. The lower limit of quantification (LLOQ) for HAI is set at 10, the lowest serum dilution 
used in the assay (i.e., 1/10). Titers below this level are reported as < 10. If the highest/last serum 
dilution used in the assay exhibits complete inhibition of hemagglutination, the serum antibody 
titer will be reported as ≥ 10240 (1/dil). 
9.3.3 
Efficacy 
No clinical efficacy will be obtained in the study. 
9.3.4 
Serum Collection 
The observational objective for serum collection is presented in Section 2.1.3. 
9.3.4.1 
Serum Collection Endpoints and Assessment Methods 
There are no observational endpoints for the serum collection objective. 
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 (e.g., medical 
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records, discharge summary, autopsy report) in order to provide comprehensive safety 
information. All relevant information must then be transcribed onto the AE CRF and the 
appropriate Death/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 GPE 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 [MD or DO]) 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 Death/Safety Complementary 
Information CRFs. An e-mail alert will automatically be sent by the EDC system to the GPE 
mailbox, the CRA, and the RMOs with relevant SAE information details. 
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 
Death/Safety Complementary Information CRFs and send them to the Sponsor by 1 of the 
following means: 
• By fax, to the following number:
 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: 
 
• By express mail, to the following address:  
Reception & Triage – Case Management 
Global Pharmacovigilance Department, Sanofi Pasteur, Inc. 
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 1 of the RMOs 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 (e.g., outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Death/Safety Complementary Information 
CRFs. An e-mail alert will be sent automatically to the GPE Department and to the CRA. Copies 
of documents (e.g., medical records, discharge summary, autopsy) may be requested by the GPE 
Department. 
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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 (e.g., 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 9.3.1.3.5. 
Following this, the Sponsor’s Pharmacovigilance Global Safety Expert will also assess the causal 
relationship to the product, based on the available information and current medical knowledge. 
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 RMOs will notify the Investigators in writing of the occurrence of any reportable 
SAEs. The Investigators/Sponsor will be responsible for informing the IRB(s) that reviewed the 
study protocol. 
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 participants for the recording of daily safety information as 
described in Section 9.3.1.3. These diary cards will include prelisted terms and intensity scales 
(see Table 9.1, Table 9.2, Table 9.3, Table 9.4, and Table 9.5) as well as areas for free text to 
capture additional safety information or other relevant details. Subjects or subjects’ 
parents/guardians 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 or subjects’ parents/guardians on 
how to correctly use these tools.  
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At specified intervals, the Investigator or an authorized designee will interview the subjects or 
subjects’ parents/guardians to collect the information recorded in the diary card, and will attempt 
to clarify anything that is incomplete or unclear. All clinical study information gathered by the 
study site will be reported electronically by the Investigator or authorized designee using a web-
based CRB. (Any information that was not documented in the diary card will first be captured in 
the source document and then reported electronically.) The CRB has been designed specifically 
for 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 and Pregnancy Data 
During the study, SAE data (reported on the AE, Death, and Safety Complementary Information 
CRFs) and pregnancy data (reported by the Investigator on ePregnancy Forms) will be integrated 
into the Sponsor’s centralized GPE 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 
Pharmacovigilance Global Safety Expert and the RMO(s). Follow-up information concerning a 
completed case will be entered into the GPE database, and a new version of the case will be 
created. 
The information from the GPE 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 CDM platform or authorized representative. 
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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. 
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 data warehouse. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPE Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review 
A 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 
Summaries of baseline demographic characteristics of the study subjects will be presented. The 
number of subjects enrolled and their age at enrollment (mean, median, and minimum and 
maximum), sex, race, and ethnic origin will be summarized, along with the number and 
description of protocol deviations. 
12.1.1 Hypotheses and Statistical Methods for Primary Objectives 
There are no primary objectives for this study. 
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives 
There are no secondary objectives for this study. 
12.1.3 Statistical Methods for Observational Objectives 
For the main safety and immunogenicity parameters, 95% CIs of point estimates of proportions 
will be calculated using the normal approximation for quantitative data and the exact binomial 
distribution (Clopper-Pearson method) for proportions.  
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12.1.3.1 Safety  
All analyses will be descriptive; no hypotheses will be tested. 
12.1.3.2 Immunogenicity 
All analyses will be descriptive; no hypotheses will be tested. Data will be summarized and 
presented for each age group.  
The following immunogenicity parametersa will be calculated for each influenza strain with 
95% CIs: 
• Geometric mean HAI assay titers at pre-vaccination and post-final vaccination  
• Geometric means of titer ratios (post-final vaccination divided by pre-vaccination). 
• Seroprotection rates: The percentages of subjects with a titer ≥ 40 (l/dil) at pre-vaccination and 
at post-final vaccination  
• Seroconversion rates: The percentages of subjects with either a pre-vaccination titer 
< 10 (1/dil) and a post-final vaccination titer ≥ 40 (1/dil), or a pre-vaccination titer ≥ 10 (1/dil) 
and a ≥ 4-fold increase in post-final vaccination titer  
a  
Post-final vaccination in each of the immunogenicity parameters is defined as 28 (window, 28–35) days post-final 
vaccination for subjects 6 months to < 9 years of age, and 21 (window, 21–28) days post-vaccination for subjects 
≥ 18 years of age. 
12.2 Analysis Sets 
Three main analysis sets will be used: the Safety Analysis Set, the Full Analysis Set (FAS), and 
the Per-Protocol Analysis Set (PPAS). 
12.2.1 Safety Analysis Set 
The Safety Analysis Set is defined as those subjects who have received at least 1 dose of the study 
vaccinea. All subjects will have their safety analyzed after “any dose” according to the vaccine 
they actually received as the first dose. Safety analysis after each dose will be assessed in the 
subset of the Safety Analysis Set having received that dose. All subjects will have their safety data 
analyzed after each vaccination according to the vaccine they actually received for that dose. 
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
12.2.2 Full Analysis Set 
The FAS is defined as the subset of subjects who received at least 1 dose of the study vaccine and 
have a valid post-vaccination blood sample result for at least 1 strain.  
                                                 
a  for which safety data are scheduled to be collected 
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12.2.3 Per-Protocol Analysis Set 
The PPAS is a subset of the FAS. The subjects presenting with at least 1 of the following relevant 
protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least 1 of the protocol-
specified exclusion criteria 
• Subject did not complete the vaccination schedule 
• Subject received a vaccine or dose other than the one that he/she was assigned to receive 
• Preparation and/or administration of vaccine was not done as per-protocol  
• Subject did not receive vaccine in the proper time window  
• Subject did not provide a post-dose serology sample in the proper time window or a post-dose 
serology sample was not drawn 
• Subject received a protocol-prohibited therapy/medication/vaccine that might impact antibody 
response to the study vaccine 
• Any other deviation identified during conduct of the study and judged by the clinical team 
during data review as having a potential impact on the assessment of immunogenicity 
In addition to the reasons listed above, subjects will also be excluded from the PPAS if their 
post-vaccination serology sample did not produce a valid test result for any antigen. 
12.2.4 Populations Used in Analyses 
Baseline and demographic analyses will be performed on all enrolled subjects. 
The safety analyses will be performed on the Safety Analysis Set.  
The immunogenicity analyses will be performed on both the FAS and PPAS. 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No imputation of missing data will be conducted. All subjects with safety data and all safety data 
recorded in the CRFs will be included in the safety analyses. No search for outliers will be 
performed. 
12.3.2 Immunogenicity 
For the computations, LLOQ and upper limit of quantification (ULOQ) will be managed as 
follows:  
• If a titer is < LLOQ, then LLOQ/2 will be used 
• If a titer is ≥ LLOQ and < ULOQ, then the titer itself will be used 
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• If a titer is ≥ ULOQ, then ULOQ will be used 
Missing data will not be imputed. No search for outliers will be performed. 
12.4 Interim/Preliminary Analysis 
No interim analyses are planned.  
12.5 Determination of Sample Size and Power Calculation 
The study will enroll approximately 240 subjects: approximately 30 subjects 6 to < 36 months of 
age will be administered Fluzone Quadrivalent vaccine (Group 1), approximately 30 subjects 
3 to < 9 years of age will be administered Fluzone Quadrivalent vaccine (Group 2), approximately 
60 subjects 18 to < 65 years of age will be administered Fluzone Quadrivalent vaccine (Group 3), 
approximately 60 subjects 18 to < 65 years of age will be administered Flublok Quadrivalent 
vaccine (Group 4), and approximately 60 subjects ≥ 65 years of age will be administered Fluzone 
High-Dose vaccine (Group 5).  
No study power assessment will be done for this study. Only descriptive statistical analyses will 
be conducted in this study. 
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. 
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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. 
13.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality 
agreement with Sanofi Pasteur. 
Sanofi Pasteur personnel (or designates), the IRB(s), and regulatory agencies, including the FDA, 
require direct access to all study records, and will treat these documents in a confidential manner. 
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. 
13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring  
Before the start of the study (i.e., 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 CRB 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. 
                                                 
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. 
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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 (e.g., 
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 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 must keep all study documents after the completion or discontinuation of the 
study, whatever the nature of the investigational center (private practice, hospital, or institution), 
for as long as required by applicable laws and regulations. In the absence of any applicable laws 
or regulations, study documents will be kept at a minimum for the duration indicated on the 
Clinical Trial Agreement (CTA). In no event, should study personnel destroy or permit the 
destruction of any study documents upon less than 90 days advance written notification to the 
Sponsor. In addition, study documents should continue to be stored, at Sponsor’s sole expense, in 
the event that the Sponsor requests in writing that such storage continues for a period of time that 
exceeds that required by any applicable law or regulation or the CTA. The Investigator will 
inform Sanofi Pasteur of any address change or if they will no longer be able to house the study 
documents. 
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 
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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 CTA 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 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. 
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14 Reference List 
 
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Orenstein WA, Offit PA, eds. Vaccines. 6th ed. Edinburgh, UK: Elsevier/Saunders; 
2012;257-93. 
2 
Treanor JT. Influenza viruses, including avian influenza and swine influenza. In: Mandell 
GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of 
Infectious Diseases. 7th ed. New York, NY: Churchill Livingstone; 2010:2265-88. 
3 
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal 
Influenza with Vaccines. Recommendations of the Advisory Committee on Immunization 
Practices - United States, 2016-17 Influenza Season. MMWR Recomm Rep. 2016;65(No. 
RR-5):1-54. 
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Belshe RB. The need for quadrivalent vaccine against seasonal influenza. Vaccine. 
2010;28(suppl 4):D45-53. 
5 
Monto AS, Ansaldi F, Aspinall R, et al. Influenza control in the 21st century: optimizing 
protection of older adults. Vaccine. 2009;27(37):5043-53. 
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Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the 
United States. JAMA. 2004;292(11):1333-40. 
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Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal 
influenza-United States, 1976-2007. MMWR. 2010;59(33):1057-62. 
8 
Hu JJ, Kao CL, Lee PI, et al. Clinical features of influenza A and B in children and 
association with myositis. J Microbiol Immunol Infect. 2004;37(2):95-8. 
9 
Hite LK, Glezen WP, Demmler GJ, Munoz FM. Medically attended pediatric influenza 
during the resurgence of the Victoria lineage of influenza B virus. Int J Infect Dis. 
2007;11(1):40-7. 
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Glezen WP, Couch RB, Taber LH, et al. Epidemiologic observations of influenza B virus 
infections in Houston, Texas, 1976-1977. Am J Epidemiol. 1980;111(1):13-22. 
11 
Centers for Disease Control and Prevention. Prevention and control of seasonal influenza 
with vaccines: Recommendations of the Advisory Committee on Immunization Practices-
United States, 2013-14. MMWR. 2013;62(RR07):1-43. 
12 
Greenberg DP, Robertson CA, Landolfi VA, Bhaumik A, Senders SD, Decker MD. Safety 
and immunogenicity of an inactivated quadrivalent influenza vaccine in children 6 months 
through 8 years of age. Pediatr Infect Dis J. 2014;33(6):630-6. 
13 
Greenberg DP, Robertson CA, Noss MJ, Blatter MM, Biedenbender R, Decker MD. Safety 
and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed 
trivalent inactivated influenza vaccines in adults. Vaccine. 2013;31(5):770-6. 
14 
Keitel WA, Atmar RL, Cate TR, et al. Safety of high doses of influenza vaccine and effect 
on antibody responses in elderly persons. Arch Intern Med. 2006;166(10):1121-7. 
15 
Couch RB, Winokur P, Brady R, et al. Safety and immunogenicity of a high dosage 
trivalent influenza vaccine among elderly subjects. Vaccine. 2007;25(44):7656-63. 
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16 
Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind 
controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose 
influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172-80. 
17 
DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-
dose influenza vaccine in older adults. N Engl J Med. 2014;371(7):635-45. 
18 
Centers for Disease Control and Prevention. Prevention and control of influenza: 
recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. 
MMWR. 2007;56(RR-6):1-54. 
19 
Mitchell DK, Ruben FL, Gravenstein S. Immunogenicity and safety of inactivated influenza 
virus vaccine in young children in 2003-2004. Pediatr Infect Dis J. 2005;24(10):925-7. 
20 
Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-
Preventable Diseases. Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. Washington D.C. 
Public Health Foundation, 2015. 
21 
Woo EJ. Allergic reactions after egg-free recombinant influenza vaccine: reports to the US 
Vaccine Adverse Event Reporting System. Clin Infect Dis. 2015;60(5):777-80. 
22 
Woo EJ, Moro PL, Cano M, Jankosky C. Postmarketing safety surveillance of trivalent 
recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. 
Vaccine. 2017;35(42):5618-21. 
23 
Seneviratne U. Guillain-Barré syndrome. Postgrad Med J. 2000;76(902):774-82. 
24 
Salmon DA, Proschan M, Forshee R, et al. Association between Guillain-Barré syndrome 
and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. 
Lancet. 2013;381(9876):1461-8. 
25 
Stratton K, Ford A, Rush E, et al. Committee to Review Adverse Effects of Vaccines Board 
on Population Health and Public Health Practice: adverse effects of vaccines evidence of 
causality. Washington, D.C.: The National Academies Press; 2012. Available at: 
https://www.nap.edu/read/13164/chapter/1. Accessed May 7, 2018. 
26 
Leroy Z, Broder K, Menschik D, Shimabukuro T, Martin D. Febrile seizures after 2010-
2011 influenza vaccine in young children, United States: a vaccine safety signal from the 
Vaccine Adverse Event Reporting System. Vaccine. 2012;30(11):2020-3. 
27 
Tse A, Tseng HF, Greene SK, Vellozzi C, Lee GM; VSD Rapid Cycle Analysis Influenza 
Working Group. Signal identification and evaluation for risk of febrile seizures in children 
following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 
2010-2011. Vaccine. 2012;30(11):2024-31. 
28 
Duffy J, Weintraub E, Hambidge SJ, et al. Febrile seizure risk after vaccination in children 
6 to 23 months. Pediatrics. 2016;138(1):e20160320. 
29 
Center for Disease Control and Prevention Website. Childhood Vaccines and Febrile 
Seizures. Available at: https://www.cdc.gov/vaccinesafety/concerns/febrile-seizures.html. 
Accessed May 7, 2018. 
30 
Moro PL, Arana J, Cano M, et al. Postlicensure safety surveillance for high-dose trivalent 
inactivated influenza vaccine in the Vaccine Adverse Event Reporting System, 1 July 2010-
31 December 2010. Clin Infect Dis. 2012;54(11):1608-14. 
 
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15 Signature Page 
 
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Document Number
CLI_00008801
Version Number
1.0
Project Code
Flu seasonal
Arficact Name
Protocol Body
-
-
-
Approver Name
Date
(Universal Time)
Reason for Signature
Approval
24 May 2018
02:51:03
I am approving this document
-
-
 
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