A Phase III Randomized, Modified Double-blind, Active-controlled, Multi-center Study to Describe the Immunogenicity and Safety of the Quadrivalent Recombinant Influenza Vaccine (RIV4) Versus a Quadrivalent-inactivated Influenza Vaccine (IIV4) (Fluarix® Quadrivalent) in Participants 18 Years of Age and Older in South Korea
Phase: PHASE3
Conditions: Influenza (Healthy Volunteers)
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: A Phase III Randomized, Modified Double-blind, Active-controlled, Multi-center 
Study to Describe the Immunogenicity and Safety of the Quadrivalent Recombinant Influenza 
Vaccine (RIV4) versus a Quadrivalent-inactivated Influenza Vaccine (IIV4) (Fluarix® 
quadrivalent) in Participants 18 Years of Age and Older in South Korea 
Study Code: VAP00016  
Protocol Version Number: 5.0 
Amendment Number: 4 
Compound: Quadrivalent Recombinant Influenza Vaccine 
Study Phase: III 
Short Title: Study Describing the Immunogenicity and Safety of Quadrivalent Recombinant 
Influenza Vaccine (RIV4) versus a licensed Quadrivalent-inactivated Influenza Vaccine (IIV4) 
(Fluarix® quadrivalent) in Participants 18 Years of Age and Older in South Korea. 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur 
14 Espace Henry Vallée, 69 007 Lyon, France 
Manufacturer: Same as Sponsor 
Regulatory Agency Identifier Number(s): 
WHO UTN: U1111-1253-2122 
NCT: NCT05144945
Approval Date: 20 January 2022 
Medical Monitor Name and Contact Information Are Provided in the Operating Guidelines. 
The study centers, the Investigators at each center are listed in a separate document. 

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Document History 
Previous 
Versions 
Date 
Comments 
1.0 
10 November 2020 
Version submitted to the IEC/IRB 
2.0 
07 April 2021 
Version submitted to South Korean Health Authority 
3.0 
03 August 2021 
Version submitted to South Korean Health Authority 
4.0 
21 October 2021 
Version submitted to South Korean Health Authority 
Overall Rationale for Amendment 2: 
Changes were implemented following requests of the South Korean Health Authority (MFDS), 
mainly: 
•
Detailed Title
•
Increased participant safety follow-up from 1 to 6 months
•
Exclusion of pregnant women from participation
Overall Rationale for Amendment 3: 
Changes were implemented following requests of the South Korean Health Authority (MFDS), 
mainly: 
•
Addition of D08 phone call to participants
•
All medications from D08 to D181 will be collected
•
For the solicited safety term “Injection site induration”, the Diary Card definition was
modified to “Hardening/Firmness” from “Hardening”
•
Additional solicited safety terms were included: “tenderness” was included in solicited
injection site reactions; and “fatigue,” “nausea” and “arthralgia” were included in solicited
systemic reactions.
•
Update of Appendix 10.4 “Collection of pregnancy information” with the description of
effective contraceptive methods
•
To maintain the blind during the study period, only the independent statistician(s) will be
unblinded at the time of the interim analysis
Overall Rationale for Amendment 4: 
•
Sanofi Pasteur decision to delete the interim analysis

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Table of Contents  
Document History .................................................................................................................. 2 
List of Tables .......................................................................................................................... 7 
List of Figures ........................................................................................................................ 8 
1 
Protocol Summary ................................................................................................... 9 
1.1 
Synopsis .................................................................................................................. 9 
1.2 
Schema .................................................................................................................. 11 
1.3 
Schedule of Activities (SoA) ................................................................................ 12 
2 
Introduction ........................................................................................................... 14 
2.1 
Study Rationale ..................................................................................................... 14 
2.2 
Background ........................................................................................................... 14 
2.3 
Benefit/Risk Assessment ...................................................................................... 16 
2.3.1 
Risks from Study Participation ........................................................................... 16 
2.3.2 
Benefits from Study Participation ...................................................................... 18 
2.3.3 
Overall Benefit- Risk Conclusion ....................................................................... 19 
3 
Objectives and Endpoints ..................................................................................... 20 
4 
Study Design .......................................................................................................... 21 
4.1 
Overall Design ...................................................................................................... 21 
4.2 
Scientific Rationale for Study Design ................................................................... 23 
4.3 
Justification for Dose ............................................................................................ 23 
4.4 
End of Study Definition ........................................................................................ 23 
5 
Study Population ................................................................................................... 24 
5.1 
Inclusion Criteria .................................................................................................. 24 
5.2 
Exclusion Criteria ................................................................................................. 24 
5.3 
Lifestyle Considerations ....................................................................................... 26 
5.4 
Screen Failures ...................................................................................................... 26 
6 
Study Intervention ................................................................................................. 27 
6.1 
Study Interventions Administered ........................................................................ 27 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 28 

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6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 29 
6.3.1 
Randomization and Allocation Procedures ........................................................ 29 
6.3.2 
Blinding and Code-breaking Procedures ............................................................ 29 
6.4 
Study Intervention Compliance ............................................................................ 30 
6.5 
Concomitant Therapy ............................................................................................ 30 
6.5.1 
Rescue Medicine ................................................................................................. 30 
6.6 
Dose Modification ................................................................................................ 30 
6.7 
Intervention After the End of the Study ................................................................ 30 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ................................................................................ 31 
7.1 
Discontinuation of Study Intervention .................................................................. 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................................... 31 
7.3 
Lost to Follow-up .................................................................................................. 31 
8 
Study Assessments and Procedures ..................................................................... 33 
8.1 
Efficacy and Immunogenicity Assessments ......................................................... 33 
8.1.1 
Efficacy Assessments ......................................................................................... 33 
8.1.2 
Immunogenicity Assessments ............................................................................ 33 
8.2 
Safety Assessments ............................................................................................... 34 
8.2.1 
Medical History .................................................................................................. 34 
8.2.2 
Physical Examinations ........................................................................................ 34 
8.2.3 
Vital Signs .......................................................................................................... 34 
8.2.4 
Clinical Safety Laboratory Assessments ............................................................ 34 
8.2.5 
Viremia/Vaccinemia ........................................................................................... 34 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 34 
8.3.1 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information ............................................................................................. 35 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ................... 36 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ............................... 36 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ..................... 36 
8.3.5 
Pregnancy ........................................................................................................... 37 
8.3.6 
Adverse Events of Special Interest ..................................................................... 37 
8.4 
Treatment of Overdose.......................................................................................... 37 
8.5 
Pharmacokinetics .................................................................................................. 37 
8.6 
Pharmacodynamics ............................................................................................... 37 
8.7 
Genetics ................................................................................................................. 38 
8.8 
Biomarkers ............................................................................................................ 38 
8.9 
Immunogenicity Assessments ............................................................................... 38 

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8.10 
Medical Resource Utilization and Health Economics .......................................... 38 
9 
Statistical Considerations ..................................................................................... 39 
9.1 
Statistical Hypotheses ........................................................................................... 39 
9.2 
Sample Size Determination ................................................................................... 39 
9.3 
Populations for Analyses ...................................................................................... 40 
9.4 
Statistical Analyses ............................................................................................... 40 
9.4.1 
General Considerations ....................................................................................... 40 
9.4.2 
Immunogenicity .................................................................................................. 41 
9.4.3 
Safety .................................................................................................................. 41 
9.5 
Interim Analyses ................................................................................................... 42 
9.6 
Data Monitoring Committee ................................................................................. 42 
10 
Supporting Documentation and Operational Considerations .......................... 43 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations .................. 43 
10.1.1 
Regulatory and Ethical Considerations .............................................................. 43 
10.1.2 
Financial Disclosure ........................................................................................... 44 
10.1.3 
Informed Consent Process .................................................................................. 44 
10.1.4 
Data Protection and Future Use of Stored Samples ........................................... 45 
10.1.5 
Committees Structure ......................................................................................... 46 
10.1.6 
Dissemination of Clinical Study Data ................................................................ 46 
10.1.7 
Data Quality Assurance ...................................................................................... 46 
10.1.8 
Source Documents .............................................................................................. 47 
10.1.9 
Study and Site Start and Closure ........................................................................ 47 
10.1.10 
Publication Policy ............................................................................................... 48 
10.2 
Appendix: Clinical Laboratory Tests .................................................................... 48 
10.3 
Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .................................................................. 48 
10.3.1 
Definition of Adverse Event ............................................................................... 48 
10.3.2 
Definition of Serious Adverse Event .................................................................. 51 
10.3.3 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event .... 52 
10.3.4 
Reporting of Serious Adverse Events ................................................................. 54 
10.3.5 
Assessment of Intensity ...................................................................................... 54 
10.3.5.1 
Tables for Clinical Abnormalities .................................................................... 54 
10.3.5.1.1 
Solicited Adverse Reaction Intensity Grading Scale ..................................... 54 
10.3.5.1.2 
Unsolicited Adverse Event Intensity Grading Scale ...................................... 61 
10.4 
Appendix: Collection of Pregnancy Information .................................................. 61 
10.5 
Appendix: Risk-based Approach .......................................................................... 64 
10.6 
Appendix: Abbreviations ...................................................................................... 65 

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11 
References .............................................................................................................. 67 
12 
Sponsor Signature Page ........................................................................................ 69 
 
 
 

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List of Tables  
Table 1.1: Schedule of activities ................................................................................................... 12 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 17 
Table 3.1: Objectives and endpoints ............................................................................................. 20 
Table 4.1: Overall design .............................................................................................................. 21 
Table 6.1: Identity of study interventions ...................................................................................... 27 
Table 10.1: Solicited injection site reactions: terminology, definitions, and intensity scales ....... 55 
Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales ............. 57 
 
 
 

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List of Figures  
Figure 1.1 – Graphical study design .............................................................................................. 11 
 
 
 

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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
A Phase III Randomized, Modified Double-blind, Active-controlled, Multi-center Study to 
Describe the Immunogenicity and Safety of the Quadrivalent Recombinant Influenza Vaccine 
(RIV4) versus a Quadrivalent-inactivated influenza vaccine (IIV4) (Fluarix® quadrivalent) in 
Participants 18 Years of Age and Older in South Korea 
Short Title:  
Study Describing the Immunogenicity and Safety of Quadrivalent Recombinant Influenza 
Vaccine (RIV4) versus a licensed Quadrivalent-inactivated Influenza Vaccine (IIV4) (Fluarix® 
quadrivalent) in Participants 18 Years of Age and Older in South Korea. 
Rationale: 
VAP00016 study is being proposed to collect and analyze the immunogenicity and safety of the 
Quadrivalent Recombinant Influenza Vaccine (RIV4) versus a locally licensed quadrivalent-
inactivated influenza vaccine (IIV4) (Fluarix® quadrivalent) that will serve as a control.  
Clinical data generated with RIV4 support an indication in persons starting at 18 years of age and 
older. VAP00016 study will be conducted during the 2021-2022 Northern Hemisphere (NH) 
influenza season in 300 participants 18 years of age and older in South Korea. 
Objectives and Endpoints: 
Primary* Objectives 
Primary Endpoints 
Immunogenicity 
 
• 
To describe the immune response induced by 
RIV4 and IIV4 in 18-49 and ≥ 50 years of age 
participants by hemagglutination inhibition 
(HAI) measurement method 
• 
HAI antibody (Ab) titers obtained on Day 
(D) 01 and D29 
• 
Individual HAI titers ratio D29/D01 
• 
Seroconversion: titer < 10 (1/dilution [1/dil]) 
at D01 and post-injection titer ≥ 40 (1/dil) at 
D29, or titer ≥ 10 (1/dil) at D01 and a ≥ 4-fold 
increase in titer (1/dil) at D29 
• 
Titer ≥ 40 (1/dil) at D01 and D29 
• 
Detectable titer ≥ 10 (1/dil) on D01 and D29 
Safety † 
 
• 
To describe the safety profile of all 
participants in RIV4 and IIV4 groups 
• 
Presence of any unsolicited systemic adverse 
event (AE) reported in the 30 minutes after 
vaccination 
• 
Presence of solicited injection site, and 
systemic reactions occurring up to 7 days after 

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vaccination, (ie, pre-listed in the participant’s 
diary and case report form [CRF]) 
• 
Presence of unsolicited (spontaneously 
reported) AEs up to 28 days after vaccination 
• 
Presence of serious adverse events (SAEs), 
including adverse events of special interest 
(AESIs), throughout the trial period 
Other endpoints recorded or derived as described 
in the Statistical Analysis Plan (SAP). Depending 
on the item, these could include nature (Medical 
Dictionary for Regulatory Activities [MedDRA] 
preferred term [PT]), time of onset, duration, 
number of days of occurrence, grade of severity, 
relationship to the vaccine, action taken, whether 
the AE led to early termination from the study, 
seriousness, or outcome. 
*This study has no secondary or exploratory objectives 
† Details on safety endpoints (terminology, definitions, and intensity scales) are presented in Table 10.1 and 
Table 10.2. 
Overall Design 
Type of design 
Parallel, multi-center 
Phase 
III 
Control method 
Active-controlled 
(control=IIV4) 
Study population 
Participants 18 years of age and older 
(2 age groups: participants 18-49 years of age and 
participants ≥ 50 years of age) 
Country 
South Korea 
Level and method of blinding 
Modified double-blind 
Study intervention assignment method 
Randomization 
Disclosure Statement: 
This is a parallel-group prevention study with 2 arms that is participant and Investigator blinded. 
A designated unblinded administrator at each study site knows which vaccine has been 
administered. The Investigator/sub-Investigator/staff involved in the sampling and safety 
assessment are blinded. The staff in charge of the immunogenicity assays is blinded. 

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Number of Participants: 
A total of 300 participants are planned to be randomized. 
Intervention Groups and Duration: 
In each age group (18-49 years of age and ≥ 50 years of age), eligible participants will be 
randomized in a 1:1 ratio to receive a single intramuscular (IM) injection of either RIV4 or IIV4 
at D01. 
The duration of each participant’s participation will be approximately 6 months (180 days). 
Data Monitoring Committee: 
None. 
For further details regarding the safety data collection, see Section 8 (Study Assessments and 
Procedures) and Section 10 (Supporting Documentation and Operational Considerations). 
1.2 
Schema  
The graphical design of VAP00016 study is presented in Figure 1.1. 
Figure 1.1 – Graphical study design  
 
 
 
 
 
 
 
 
 
 
Abbreviations: BL, Blood sampling; V, Visit; PC, Phone call 
Visits (V) or 
Phone call (PC)
Time (days)
V01
V02
D01
D29
Vaccination
BL0001
BL0002
PC
D181
PC 
D08 

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1.3 
Schedule of Activities (SoA)  
Visit procedures are detailed in the Operating Guidelines. 
Table 1.1: Schedule of activities  
Phase III Study, 2 Visits and 2 Phone Calls, 1 Vaccination, 2 Blood Samples, 6 Months 
Duration Per Participant 
 
Visit/Contact 
Information 
to be 
collected in 
the CRF 
Visit 1 
Phone call 
1 
Visit 2‡ 
Phone call 2 
(6 Months 
Follow-up) 
Study timelines (days) 
 
D01 
D08 
D29 
D181 
Time windows (days) 
 
NA 
[+2 D] 
[+7 D] 
[+14 D] 
Visit procedures: 
 
 
 
 
 
Assent form/ Informed consent  
X 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
Collection of Medical history† 
X 
Significant  
Medical 
History 
X 
 
 
 
Urine pregnancy test (if 
applicable) § 
 
X 
 
 
 
Physical examination §§ 
 
X 
 
X 
 
Pre-vaccination temperature 
 
X 
 
 
 
Randomization/allocation of 
participant number 
X 
X 
 
 
 
Blood sampling (BL) [10 mL] 
X 
BL0001 
Pre-vac 
 
BL0002 
 
Vaccination (vac) 
X 
X 
 
 
 
Immediate surveillance (30 min) 
X 
X 
 
 
 
Diary card (DC) provided 
 
X 
 
 
 
Collection of solicited injection 
site and systemic reactions* 
X 
Up to 7 days after 
vaccination (D01 to D08) 
 
Collection of unsolicited AEs 
X 
Up to 28 days after vaccination (D01 
to D29) 
 
DC collected 
 
 
 
X 
 
Memory Aid (MA) provided 
 
 
 
X 
 
MA checked 
 
 
 
 
X 
Collection of concomitant 
medications 
X  
X 
X 
X 
X 

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Visit/Contact 
Information 
to be 
collected in 
the CRF 
Visit 1 
Phone call 
1 
Visit 2‡ 
Phone call 2 
(6 Months 
Follow-up) 
Study timelines (days) 
 
D01 
D08 
D29 
D181 
Time windows (days) 
 
NA 
[+2 D] 
[+7 D] 
[+14 D] 
Collection of SAEs, including 
AESIs 
X 
To be reported at any time during the study 
Collection of pregnancies 
X 
To be reported at any time during the study 
Check participant status, remind 
participant to collect AEs and of 
planned next visit 
 
 
X 
 
 
End of active phase participation 
record †† 
X 
 
 
X 
 
End of 6-month safety follow-up 
participation record†† 
X 
 
 
 
X 
Abbreviations: DC, diary card; mL, milliliter; NA, not applicable; Pre-vac, pre-vaccination; AE, adverse event; SAE, 
serious adverse event; AESI, adverse event of special interest; CRF, case report form; BL, blood sampling; MA, 
Memory Aid 
† Including collection of the history of seasonal influenza vaccination. 
§ Female participants of childbearing potential must have a negative urine pregnancy test prior to vaccination. Urine 
pregnancy test is applicable to childbearing potential female participant (to be considered of non-childbearing 
potential, a female must be post-menopausal for at least 1 year or surgically sterile).  
§§ Targeted physical examination based on medical history will be performed at Visit 1. Targeted physical 
examination may also be performed at Visit 2, as necessary. 
‡ The Investigator or an authorized designee will interview the participants to collect the information recorded in the 
DC and will attempt to clarify anything incomplete or unclear. 
* Solicited injection site and systemic reactions will be collected from D01 to D08 by the participant using the DC 
provided. The DC is collected at D29. 
†† Participants will be in the active phase from enrollment (D01) until completion of V02 (D29) and in the 6-Month 
safety follow-up from completion of V02 until approximately 6 months after V01. 

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2 
Introduction  
2.1 
Study Rationale  
VAP00016 study is being proposed to collect and analyze the immunogenicity and safety of the 
RIV4 versus a locally licensed IIV4 (Fluarix® quadrivalent) that will serve as a control arm.  
RIV4 is a next-generation formulation that does not contain preservatives, antibiotics, egg protein, 
or latex, any of which may produce hypersensitivity reactions in some individuals. The rationale 
for and the advantages of the recombinant platform technology for the manufacturing of influenza 
vaccine have been well described in the medical literature (1-3). Clinical data generated with 
RIV4 support an indication for active immunization in persons 18 years of age and older for the 
prevention of influenza disease.  
This Phase III, parallel, randomized, active-controlled, multi-centered, modified double-blinded, 
VAP00016 study will be conducted during the 2021-2022 Northern Hemisphere (NH) influenza 
season in 300 participants 18 years of age and older in South Korea. 
2.2 
Background  
Influenza is a highly contagious, acute viral respiratory disease caused by infection with influenza 
viruses (4). Influenza causes recurrent epidemics of acute disease in persons of all ages and is 
currently estimated to account for 290 000 to 650 000 excess deaths annually worldwide, most of 
which occur in older adults (5). 
The incubation period of influenza ranges from 1 to 4 days and peak virus shedding usually 
occurs from 1 day before the onset of symptoms to 3 days after. Typical features of influenza 
include abrupt onset of fever and respiratory symptoms such as cough (usually nonproductive), 
sore throat, and coryza, as well as systemic symptoms such as headache, muscle aches, and 
fatigue. Complications of influenza include primary viral pneumonia, secondary bacterial 
pneumonia, and exacerbation of underlying medical conditions such as chronic obstructive 
pulmonary disease and cardiovascular diseases (4). 
Annual influenza vaccination is the best means for preventing influenza illness and its 
complications. It has been shown to be effective in reducing influenza-associated morbidity and 
mortality. Health care providers should recommend vaccination for all persons ≥ 6 months of age 
who do not have contraindications to vaccination (6). 
Influenza control depends upon epidemiological data of influenza virus circulation to ensure that 
vaccination is timed ahead of peak transmission. For most countries, the World Health 
Organization (WHO) recommended timing of vaccination was appropriate for (ie, within 
4 months before) the timing of the influenza peak activity (7). 
Each year, WHO convenes technical consultations in February and September to recommend 
viruses for inclusion in influenza vaccines for the NH and the Southern Hemisphere (SH) 
influenza seasons, respectively. Generally, countries in East Asia experienced increased influenza 
activity from December 2019, with influenza A(H3N2) predominant in China and Mongolia and 
A(H1N1)pdm09 viruses predominant in Japan and South Korea (8). 

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Influenza comprises not only a burden on the medical system but also has a huge socioeconomic 
burden in Korea. The national influenza surveillance system has played an important role in 
identifying influenza epidemic patterns and virus characteristics in Korea (9). 
The current surveillance system operated by the Korea Centers for Disease Control & Prevention 
(KCDC) provides an understanding of the characteristics of serious influenza and its disease 
burden. The hospitalization and mortality surveillance system are being operated, but the data 
collected are limited and cannot be used to fully understand the clinical course (9). 
Nevertheless, it’s known that in South Korea, approximately 7 000 patients are hospitalized and 
400 000 are treated as outpatients annually for seasonal influenza (10). 
According to data from 2003 through 2013 (10-year period), the overall all-cause excess annual 
mortality rate per 100 000 people was 5.97, whereas it was 46.98 for adults ≥ 65 years of age. In 
this same period, a total of 2 570 939 deaths were reported with an average crude mortality rate of 
around 10 deaths per 100 000 people each week, and a slightly higher mortality rate during the 
winter. During this period, South Korea experienced 2 influenza epidemics in most years, with the 
first peak in the early winter (December through January) followed by a smaller peak in the late 
spring (April through May) (11). 
To reduce the disease burden of influenza, the South Korean government has recommended 
influenza vaccination for the target groups, including children under 18, people 50 years of age 
and above, pregnant women, and those with chronic diseases (12). 
Since 2005, free trivalent influenza vaccine (TIV) has been provided in South Korea for the 
elderly above 65 years of age by the National Immunization Program (NIP). Despite the 
successful implementation of the influenza NIP, more than 2 900 deaths occur annually due to 
influenza, most of them in the elderly (11). 
Since 2000, 2 strains of influenza B have circulated concurrently. There are 2 lineages of the 
influenza B virus, namely, Victoria, and Yamagata. However, only 1 lineage is included in the 
TIV as recommended by the WHO. As both lineages circulate simultaneously, vaccine mismatch 
is the foremost problem. In South Korea, the degree of influenza B mismatch was estimated to be 
41.7% based on analysis during 4 influenza seasons (2007-2008, 2009-2010, 2011-2012, and 
2013-2014). To overcome this problem, a quadrivalent influenza vaccine (QIV) was developed, 
and since 2014, people can receive either TIV or QIV (12). 
KCDC recommends annual vaccinations for those at high risk. As part of the NIP, seasonal 
influenza vaccines are reimbursed each year during the flu season for adults ≥ 65 years of age, 
and more recently (for the 2017-2018 flu season) for children between 6 and 59 months of age 
(13). 
The estimated all-cause mortality rate associated with any influenza virus infection was highest in 
the elderly (≥ 65 years of age) and middle-aged adults 45-64 years of age, with an average of 
46.98 and 2.73 excess deaths per 100 000 people, respectively (11). 
Deaths caused by 7 major causes, including respiratory, cardiovascular, cancer, diabetes mellitus, 
renal, chronic liver, and degenerative nervous system diseases, accounted for almost 70% of the 
all-cause excess mortality attributable to influenza (11). 

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Background of the Study Intervention 
RIV4 is a recombinant hemagglutinin (rHA) influenza vaccine indicated for active immunization 
against disease caused by influenza A subtype viruses and type B viruses consisting of 4 full-
length rHA derived from the 4 influenza strains (2 A subtypes and 2 B lineages) selected by the 
WHO. These proteins are produced in a continuous insect cell line expresSF+®, derived from Sf9 
cells of the fall armyworm Spodoptera frugiperda, and grown in a serum-free medium composed 
of chemically defined lipids, vitamins, amino acids, and mineral salts. Each of the 
4 hemagglutinins (HAs) is expressed in this cell line using a baculovirus vector (Autographa 
californica nuclear polyhedrosis virus [AcNPV]) (14). 
The HA genes are cloned independently into a baculovirus expression vector plasmid. After 
confirmation of the correct sequence, the deoxyribonucleic acid (DNA) sequences are inserted 
into AcNPV by homologous recombination. Recombinant viruses containing the respective HA 
genes are then used to express the HAs in the high-yielding insect expresSF+ cell line under 
serum-free conditions. 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 or 
any cell line, thus avoiding genetic mutations that may reduce the efficacy of the vaccine. The 
recombinant proteins are highly purified, and the vaccine contains no egg protein, preservatives or 
antibiotics, any of which may produce hypersensitivity reactions in some individuals (14). 
RIV4 is a sterile liquid preparation for IM injection in a single-dose pre-filled syringe. RIV4 
contains 45 μg of rHA antigen per virus strain per 0.5 mL dose (total recombinant HA of 180 μg). 
The high purity of a recombinant antigen enables the administration of a higher concentration of 
rHA antigen without an increase in adverse reactions (ARs) (14). 
2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks, reasonably expected 
AEs, the potential risks, and uncertainties of RIV4 may be found in the current Investigator’s 
Brochure (IB), US Package Insert, patient information leaflet or Summary of Product 
Characteristics. 
2.3.1 
Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
 

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Table 2.1: Potential risks of clinical significance and risk management  
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Risk Management 
Investigated Vaccine: RIV4 
Anaphylaxis 
Anaphylaxis is an identified risk for RIV4 
(see IB (15) for more information regarding 
the data from previous experience with 
RIV4). 
No case of anaphylaxis was reported as 
related to RIV3 or RIV4 during the clinical 
development.  
Cumulatively two case of anaphylaxis of 
the level 1 definition of Brighton Case 
Collaboration (Definite Certainty of 
Diagnosis) were reported for RIV3. With a 
cumulative distribution of 10 273 172 
doses, the effective Reporting Rate for 
Anaphylaxis is approximately 0.02 per 100 
000 doses for RIV3/RIV4 combined. 
Post-marketing observational study of 
safety comparing RIV3 with licensed IIV in 
adults using adjusted logistic regression 
analyses, showed that there was no 
significant difference in acute 
hypersensitivity reactions and fever during 
post-vaccination days 0-2 in the outpatient, 
emergency department and inpatient 
settings (16). 
Background incidence rate: 
Using health care data from the Vaccine 
Safety Datalink, the rate of anaphylaxis was 
estimated to 1.31 (95% confidence interval 
(CI): 0.90-1.84) per million vaccine doses 
(17). 
Exclusion criterion E06 for 
those at increased risk.  
Addressed in IB (15) 
(administration precautions, 
potential adverse events), 
defined AESI in the trial. 
Each site must have 
measures to treat 
Anaphylaxis available at the 
time vaccination 
Guillain-Barré Syndrome 
No cases of Guillain-Barré syndrome 
(GBS) were reported as related to RIV3 or 
RIV4 during the vaccine’s clinical 
development. 
Two cases of GBS were reported during the 
post-marketing experience for RIV4. 
The incidence rate (IR) in the USA has 
been observed to range from 1.24 to 2.4 per 
Exclusion criterion E12 for 
those at increased risk. 
Addressed in IB (15) 
(administration precautions, 
potential adverse events), 
defined AESI in the trial) 

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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Risk Management 
100 000 Person Year (PY) in various 
studies (18-20); a wider range than this was 
observed in a meta-analysis of rates in the 
USA, Canada, Italy, Spain and Sweden: IR 
ranging from 0.62 to 2.66 per 100 000 PY 
(21). 
Comparator: IIV4 
Anaphylaxis 
All vaccines have the potential to cause 
allergic reactions or anaphylaxis in 
individuals who may be sensitized to 
components of the vaccine. 
Exclusion/inclusion criteria 
take in account 
contraindications, warnings 
and precautions as defined in 
product label. 
GBS 
Guillain-Barré Syndrome is considered a 
potential risk for influenza vaccines since 
the 1976 mass vaccination campaign 
against H1N1 influenza strain in the USA 
was suspended due to an excess of GBS 
cases in the vaccinated population. 
Exclusion criterion E12 for 
those at increased risk. 
Observation period after 
vaccination for early 
detection and treatment. 
Study Procedures 
Vasovagal reactions 
(syncope), or psychogenic 
reactions to needle 
(vaccine injection or 
blood sampling) 
Anxiety-related reactions can occur 
following, or even before, any vaccination 
as a psychogenic response to the needle 
injection or blood draw, and may be 
accompanied by several neurological signs 
such as transient visual disturbance, 
paresthesia or seizure-like activity, 
vasovagal syncope etc. 
Observation period after 
vaccination for early 
detection and treatment. 
Infection in rare instances 
at the injection site 
 
Early detection, observation, 
and appropriate treatment. 
Other 
Not applicable 
 
 
2.3.2 
Benefits from Study Participation  
All participants in the present study will receive an influenza vaccination with either the 
investigational RIV4 or the control vaccine IIV4 (Fluarix® quadrivalent). These participants will 
benefit from coverage against influenza and may be less likely to catch influenza or develop 
complications during the 2021-2022 NH influenza season. 
However, as with all vaccines, vaccination with the study intervention may not protect individuals 
100%. Protection generally lasts 6 to 12 months after vaccination, depending on the participant’s 
response to the study intervention. 

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2.3.3 
Overall Benefit- Risk Conclusion  
The recombinant influenza HA antigens are produced using a scalable, reproducible, and sterile 
cell culture process, resulting in a consistent protein-based vaccine with low endotoxin content 
and absolute fidelity to the HA of interest. Using this production technology, the rHA in RIV4 has 
exact fidelity to the active HA receptor site of the virus strains selected for seasonal vaccines 
without the mutations that may occur when the virus is adapted to growth in a culture matrix that 
is foreign to the wild-type strain, such as eggs or mammalian cells, assuring that the vaccine will 
provide an appropriate antigen to induce the desired immune reaction that provides protective 
efficacy against WHO-recommended strains (22, 23). Given the acceptable safety data generated 
from 5 326 participants vaccinated with RIV4 in the United States (US) (Phase III PSC12 and 
PSC16 studies) and the fact that no changes will be made to the drug substance manufacturing 
process of RIV4 and no safety signal has been detected from over 21 000 000 doses of licensed 
RIV4 sold to date of this protocol, Sanofi Pasteur considers the risk/benefit ratio appropriate for 
conducting a Phase III clinical study without an early safety data review. 
Considering the measures taken to minimize risk to participants enrolled in this study, the 
potential risks that may result from study participation are balanced by the anticipated benefits 
that may be afforded to participants. 

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3 
Objectives and Endpoints  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints  
Primary* Objectives 
Primary Endpoints 
Immunogenicity 
 
• 
To describe the immune response induced 
by RIV4 and IIV4 in 18-49 and ≥ 50 
years of age participants by HAI 
measurement method 
• 
HAI antibody (Ab) titers obtained on Day (D) 01 
and D29 
• 
Individual HAI titers ratio D29/D01 
• 
Seroconversion: titer < 10 (1/dilution [1/dil]) at 
D01 and post-injection titer ≥ 40 (1/dil) at D29, or 
titer ≥ 10 (1/dil) at D01 and a ≥ 4-fold increase in 
titer (1/dil) at D29 
• 
Titer ≥ 40 (1/dil) at D01 and D29 
• 
Detectable titer ≥ 10 (1/dil) on D01 and D29 
Safety † 
 
• 
To describe the safety profile of all 
participants in RIV4 and IIV4 groups 
• 
Presence of any unsolicited systemic AE reported 
in the 30 minutes after vaccination 
• 
Presence of solicited injection site, and systemic 
reactions occurring up to 7 days after vaccination, 
(ie, pre-listed in the participant’s diary and CRF) 
• 
Presence of unsolicited (spontaneously reported) 
AEs up to 28 days after vaccination 
• 
Presence of SAEs, including AESIs, throughout the 
trial period 
Other endpoints recorded or derived as described in the 
SAP. Depending on the item, these could include: 
nature (MedDRA PT), time of onset, duration, number 
of days of occurrence, grade of severity, relationship to 
the vaccine, action taken, whether the AE led to early 
termination from the study, seriousness, or outcome. 
*This study has no secondary or exploratory objectives  
† Details on safety endpoints (terminology, definitions, and intensity scales ) are presented in Table 10.1 and 
Table 10.2. 
 

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4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design  
Type of design 
Parallel, multi-center 
Phase 
III 
Control method 
Active-controlled 
(control=IIV4) 
Study population 
Participants 18 years of age and older 
(2 age groups: participants 18-49 years of age 
and participants ≥ 50 years of age) 
Level and method of blinding 
Modified double-blind  
(Participant, Investigator and staff in charge of 
the sampling, safety assessment and 
immunogenicity assays are blinded. 
Designated administrator at each study site is 
unblinded)  
Study intervention assignment method 
Randomization 
Number of participants 
300 participants 
Intervention groups 
In each age group (18-49 years of age and 
≥ 50 years of age), randomization in a 1:1 
ratio to receive a single IM injection of either 
RIV4 or IIV4 at D01 
Total duration of study participation 
Approximately 6 months 
Country 
South Korea 
Use of an Independent Data Monitoring 
Committee, Dose Escalation Committee, or 
similar review group 
No 
Disclosure Statement:  
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A designated unblinded administrator at each study site knows which vaccine has been 
administered. The Investigator/sub-investigator/staff involved in the sampling and safety 
assessment are blinded. The staff in charge of the immunogenicity assays are blinded. 
Number of Participants: 
A total of 300 participants are planned to be randomized. 
Intervention Groups and Duration: 
In each age group (18-49 years of age and ≥ 50 years of age) eligible participants will be 
randomized in a 1:1 ratio to receive a single IM injection of either RIV4 or IIV4 at D01. 
The duration of each participant’s participation will be approximately 6 months. 
Data Monitoring Committee: No 
Collection of safety data: 
Participants will be asked to notify the site immediately about any potential serious adverse events 
(SAEs) at any time during the study. 
All participants will be observed for 30 minutes after vaccination, and any unsolicited systemic 
AEs occurring during that time will be recorded as immediate unsolicited systemic AEs in the 
Case Report Form (CRF). 
Participants will use a diary card to record information about solicited reactions (D01-D08), 
unsolicited AEs (D01-D29), and SAEs and AESIs* (D01-D29). At D08, a telephone call will be 
made to check participant’s status, and to remind them to capture solicited reactions or any AEs in 
the diary card and of the planned next visit (V02). The diary card will be reviewed by study staff 
at V02. The 6-month follow-up will be done by interviewing participants over the telephone to 
capture SAEs and AESIs. A memory aid will be provided to the participants at V02 to help them 
record information on events occurring between this visit and the 6-month safety follow-up phone 
call.  
*Note: New onset of anaphylaxis, GBS, convulsion, encephalitis / myelitis (including transverse 
myelitis), neuritis (including Bell’s palsy, optic neuritis, and brachial neuritis), thrombocytopenia, 
and vasculitis will be considered as AESIs and collected as SAEs. Reporting of SAEs as well as 
all AESI will be conducted on an expedited basis by the clinical site staff and Investigators 
(within 24 hours of receipt).  
Study Interruption: The study may be discontinued if new data about the investigational product 
resulting from this study or any other studies become available; or for administrative reasons; or 
on advice of the Sponsor, the Investigators, the Independent Ethics Committees / Institutional 
Review Boards (IECs/IRBs), 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 IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 

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regulatory requirements. The Investigator shall promptly inform the study participants and should 
assure appropriate therapy and/or follow-up. 
For further details regarding the safety data collection, see Section 8 (Study Assessments and 
Procedures) and Section 10 (Supporting Documentation and Operational Considerations). 
4.2 
Scientific Rationale for Study Design  
The choice of IIV4 (Fluarix® quadrivalent) as the comparator vaccine was based on the fact that it 
is a licensed product in South Korea which was also used in the RIV4’s previous clinical studies 
PSC12 and PSC16 assessing its immunogenicity, protective efficacy, and safety.  
The study design is similar to previous clinical studies PSC12 and PSC16 in order to ease 
bridging with foreign clinical study data. 
4.3 
Justification for Dose  
The dose (45 µg of HA for each strain), and the administration schedule of RIV4 have been 
established previously (Studies PSC12 and PSC16). 
4.4 
End of Study Definition  
A participant is considered to have completed the Active Phase if he/she completed V02. 
Likewise, a participant is considered to have completed the 6-month safety follow-up if he/she 
completed the 6-month telephone contact planned in the SoA. 
The end of the study is defined as the date of the last contact of the last participant planned in the 
study SoA. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 

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5 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
I01: 
Aged ≥ 18 years on the day of inclusion. 
I02: 
Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination 
I03: 
Participants aged 18 years: Assent Form has been signed and dated by the participant 
or by an independent witness, and Informed Consent Form (ICF) has been signed and 
dated by at least one parent or another legally acceptable representative or by an 
independent witness. 
Participants aged 19 and older: ICF has been signed and dated. 
I04: 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions appliesa: 
Is of non-childbearing potential. To be considered of non-childbearing potential, a 
female must be postmenopausal for at least 1 year, or surgically sterile. 
OR 
Is of childbearing potential and agrees to use an effective contraceptive method or 
abstinence from at least 4 weeks prior to the study intervention administration until at 
least 4 weeks after study intervention administration.  
A female participant of childbearing potential must have a negative highly sensitive 
pregnancy test (urine) before the first dose of study intervention 
I05: 
Able to attend all scheduled visits and to comply with all study procedures. 
5.2 
Exclusion Criteria  
Participants are not eligible for the study if any of the following criteria are met: 
E01: 
Participation at the time of study enrollment, or in the 6 months preceding the study 
vaccination, or planned participation during the present study period in another 
clinical study investigating involving an IMP (vaccine, drug), medical device, or 
medical procedure or in any other type of medical research.  
E02: 
Receipt of any vaccine in the 4 weeks (28 days) preceding the study vaccination or 
planned receipt of any vaccine prior to Visit 2. 
E03: 
Previous vaccination against influenza (in the preceding 6 months) with either the 
study vaccine or another vaccine. 
 
a Refer to Appendix 10.4 

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E04: 
Receipt of immune globulins, blood, or blood-derived products in the past 3 months or 
planned treatment during the present study period. 
E05: 
Known or suspected abnormal immune function: immunosuppression, suspected 
congenital or acquired immunodeficiency based on medical history and physical 
examination, or receipt of immunosuppressive therapy, such as anti-cancer 
chemotherapy, or radiation therapy, within the preceding 6 months or planned 
treatment during the present study period; or long-term systemic corticosteroid 
therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 
3 months) or planned treatment during the present study period. 
E06: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to the vaccines used in the study or to a vaccine containing 
any of the same substances. 
E07: 
Thrombocytopenia or bleeding disorder, contraindicating IM vaccination based on the 
Investigator’s judgment. 
E08: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily. 
E09: 
Current alcohol abuse or drug addiction that in the opinion of the Investigator might 
interfere with the study conduct or completion. 
E10: 
Chronic illness that, in the opinion of the Investigator, is at a stage where it might 
interfere with trial conduct or completiona.  
E11: 
Moderate or severe acute illness/infection (according to Investigator judgment) on the 
day of vaccination or febrile illness (temperature ≥ 38.0°C). A prospective participant 
should not be included in the study until the condition has resolved or the febrile event 
has subsided. 
E12: 
Personal or family history of Guillain-Barré syndrome (GBS). 
E13: 
Neoplastic disease or any hematologic malignancy (except localized skin or prostate 
cancer that is stable at the time of vaccination in the absence of therapy and 
participants who have a history of neoplastic disease and have been disease-free for 
≥ 5 years). 
E14: 
Identified as an Investigator or employee of the Investigator or study center with 
direct involvement in the proposed study, or identified as an immediate family 
member (ie, parent, spouse) of the Investigator or employee with direct involvement 
in the proposed study. 
If the participant has a primary physician who is not the Investigator, the site should contact this 
physician with the participant’s consent to inform him/her of the participant’s participation in the 
 
a Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychiatric disorders, or chronic infection  
 

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study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.3 
Lifestyle Considerations  
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required. 
5.4 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents. 

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6 
Study Intervention  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: routine vaccines administered outside of study protocol are not considered as study 
interventions.  
6.1 
Study Interventions Administered  
Study interventions are described in Table 6.1. 
Table 6.1: Identity of study interventions  
Intervention 
Name 
RIV4 
IIV4 
Use 
Experimental 
Active comparator  
IMP and NIMP 
IMP 
IMP 
Type  
Vaccine 
Vaccine 
Dose Formulation 
Solution for injection 
Suspension for injection 
Unit Dose 
Strengths 
45 µg of HA of each of the following 
strains* per dose: 
• 
A/Wisconsin/588/2019 (H1N1) 
• 
A/Tasmania/503/2020 (an 
A/Cambodia/e0826360/2020-like 
virus) (H3N2) 
• 
B/Washington/02/2019 
• 
B/Phuket/3073/2013 
Inactivated viral preparations 
containing 15 µg of HA of each of the 
following strains* per dose: 
• 
 A/Victoria/2570/2019 (H1N1) 
IVR-215 
• 
A/Tasmania/503/2020 (H3N2) 
IVR-221 [an 
A/Cambodia/e0826360/2020 
(H3N2)-like virus]) 
• 
B/Washington/02/2019 
• 
B/Phuket/3073/2013 
Excipients/Diluent Each 0.5 mL dose of RIV4 will contain: 
Sodium chloride 
 
  4.4 mg 
Monobasic sodium phosphate  0.195 mg  
Dibasic sodium phosphate 
  1.3 mg 
Polysorbate 20 (Tween® 20) 
  27.5 µg  
Octylphenol ethoxylate  
(Triton X-100®) 
 
≤ 100 µg 
Each 0.5 mL dose of IIV4 will contain: 
Octylphenol-10  
(Triton X-100)  
     ≤ 0.115 mg 
α-Tocopheryl hydrogen  
succinate  
 
     ≤ 0.135 mg 
Polysorbate 80  
(Tween 80) 
 
     ≤ 0.550 mg 

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Preservative is not used in the 
manufacture or formulation of RIV4 
Preservative is not used in the 
manufacture or formulation of IIV4 
Dosage Level 
0.5 mL per dose 
0.5 mL per dose 
Number of Doses/ 
Dosing Interval 
1 dose per participant 
1 dose per participant 
Route of 
Administration 
IM injection  
IM injection  
Site of 
Administration 
Deltoid muscle in the upper arm 
Deltoid muscle in the upper arm 
Sourcing 
Provided by the Sponsor  
Provided by the Sponsor  
Packaging and 
Labeling 
Each study intervention will be provided in an individual box. Each study 
intervention (pre-filled syringe) will bear 1 fixed label and each box will bear 
detachable labels and 1 fixed label containing the dose number. All will be labeled 
as required per country requirement. 
Current/Former 
Name(s) or 
Alias(es) 
NA 
NA 
Batch Number 
TBD 
TBD 
Storage 
Conditions 
2-8°C 
2-8°C 
Abbreviations: IMP, Investigational Medicinal Product; NIMP, Non-Investigational Medicinal Product; TBD, to be determined; 
NA, not applicable; HA, hemagglutinin; IM, intramuscular 
* Strains based on WHO recommendations for the 2021-2022 NH influenza season 
6.2 
Preparation/Handling/Storage/Accountability  
Detailed guidance and information are provided in the Operating Guidelines. 
1) The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3) The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions are 
provided in the Operating Guidelines. 

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6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 
Randomization and Allocation Procedures  
In each age group (18-49 years of age and ≥ 50 years of age), eligible participants will be 
randomized in a 1:1 ratio through the Interactive Response Technology (IRT) to receive a single 
IM injection of either RIV4 or IIV4 at D01. 
Site staff will connect to the IRT, enter the identification, security information, and confirm a 
minimal amount of data in response to IRT prompts. The IRT will then provide the dose number 
assignment and the site staff confirm it. The full detailed procedures for dose number allocation 
are described in the Operating Guidelines. If the participant is not eligible to participate in the 
study, then the information will only be recorded on the participant recruitment log. 
Participant numbers that are assigned by the IRT consisting of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier). 
Participant numbers should not be reassigned for any reason. The randomization codes will be 
kept securely in the IRT system. 
6.3.2 
Blinding and Code-breaking Procedures  
The study will be performed in a modified double-blind fashion: 
• Participant, Investigators/sub-investigator/staff involved in the sampling, the immunogenicity 
assays and safety assessment will not know which vaccine is administered. 
• Only the study site staff who prepare and administer the vaccine and are not involved with the 
safety evaluation will know which vaccine is administered 
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the participant. Code-breaking should be limited to the 
participant(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur 
Responsible Medical Officer if a participant’s code was broken. All contact attempts with the 
Sponsor prior to unblinding are to be documented in the source documents, and the code-breaking 
CRF is to be completed. 
The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) must be notified of 
the code-breaking, in accordance with local regulations. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
A request for the code to be broken may also be made by the Global Pharmacovigilance (GPV) 
Department through an internal system for reporting to Health Authorities in the case of an 
unexpected SAE considered causally related, as described in International Council for 

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Harmonization (ICH) E2Aa. In this case, the code will be broken only for the participant(s) in 
question. The information resulting from code-breaking (ie, the participant’s vaccine or group 
assignment) will not be communicated to either the Investigator or the immediate team working 
on the study, except for the GPV representative. 
The code-breaking procedures are described in the Operating Guidelines. 
6.4 
Study Intervention Compliance  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1) and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• All vaccinations will be administered by qualified and trained study personnel. 
• The person in charge of study intervention management at the site will maintain accountability 
records of study intervention delivery to the study site, study intervention inventory at the site, 
dose(s) given to each participant, and unused or wasted doses. 
6.5 
Concomitant Therapy  
At the time of enrollment, all ongoing medications, and other therapies (eg, blood products) 
should be recorded in the CRF as well as new medications prescribed for new medical 
conditions/AEs during study participation.  
All medications will be reportable and will be collected in the CRF until last contact date of the 
participant. 
Dosage, administration route and indication will be collected in the e-CRF. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF. Medications will not be coded. 
6.5.1 
Rescue Medicine  
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. 
6.6 
Dose Modification  
Not applicable. 
6.7 
Intervention After the End of the Study  
Not applicable. 
 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 

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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Not applicable as there is only one vaccination. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
• The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: AE, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant.  
• The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws consent, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
• Withdrawn participants may be replaced. 
 
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for the definition of “lost to follow-
up”. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or cannot be contacted as planned in the SoA: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 

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schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods), or at least to determine his/her health status while fully respecting his/her rights. 
These contact attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of the 
Appendix 10.1. 

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8 
Study Assessments and Procedures  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Blood samples will be collected as described in the SoA table (Section 1.3). At Visit 1 (BL0001) 
and Visit 2 (BL0002), 10 mL of blood will be collected in tubes provided by or recommended by 
the Sponsor. 
Guidance and information for the sample collection, preparation, storage, and shipment are 
provided in the Operating Guidelines. 
8.1 
Efficacy and Immunogenicity Assessments  
8.1.1 
Efficacy Assessments  
No clinical efficacy data will be obtained in the study. 
8.1.2 
Immunogenicity Assessments  
The HAI assay is the main test that detects Ab directed against the HA antigen and is commonly 
used to assess the immunogenicity of influenza vaccines. HAI Ab titers to each virus strain 
represented in the vaccine will be measured in sera obtained at baseline (D01) and 28 days after 
immunization (D29). 
All methods will be performed at a Sanofi Pasteur laboratory or at a qualified contract laboratory 
under Sanofi Pasteur’s responsibility, as described below. Test serum samples and quality control 
sera (sheep, ferret, and / or human sera) are incubated with Sigma Type III neuraminidase (NA) 
from Vibrio cholerae to eliminate non-specific inhibitors. Adsorption of spontaneous anti-species 
agglutinins are then performed by incubating the test serum samples and quality control sera with 
a red blood cell (RBC) suspension. Following this, the mixtures are centrifuged and the 
supernatants containing the treated sera are collected for testing. Ten 2-fold dilutions (starting at 
1:10) of the treated test serum samples and quality control sera are incubated with a previously 
titrated influenza antigen at a concentration of 4 hemagglutination units (HAU) / 25 µL. Influenza 
antigen is not added to the serum control wells containing only serum and RBCs. The mixture is 
then incubated and a RBC suspension is added. Following incubation, the results are read. The 

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endpoint of the assay is the highest serum dilution in which complete inhibition of 
hemagglutination occurred. Each serum sample can either be tested in singleton (ie, one assay 
run) or in 2 independent assay runs (duplicate) which will include 2 independent samplings of the 
original serum and 2 independent preparations of influenza virus antigen. The lower limit of 
quantitation (LLOQ) is set at the lowest dilution used in the assay, 1:10. Titers below this level 
are reported as < 10 (1/dilution [dil]). If the highest / last serum dilution used in the assay 
exhibited complete inhibition of hemagglutination, the serum Ab titer is reported as ≥ 10 240 
(1/dil). 
8.2 
Safety Assessments  
This section presents safety assessments other than AEs which are presented in Section 8.2.5. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 
Medical History  
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE or to a repetitive outpatient care will be 
collected in the CRF. The history of seasonal influenza vaccination will be collected in the CRF. 
8.2.2 
Physical Examinations  
Targeted physical examination based on medical history will be performed at Visit 1. Targeted 
physical examination may also be performed at Visit 2, as necessary. Information will be recorded 
in the source document. 
8.2.3 
Vital Signs  
Pre-vaccination temperature (axillary) will be systematically collected by the Investigator on the 
source document. Tympanic, skin and temporal artery thermometers must not be used. 
8.2.4 
Clinical Safety Laboratory Assessments  
Not applicable. 
8.2.5 
Viremia/Vaccinemia  
Not applicable. 
8.3 
Adverse Events and Serious Adverse Events  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.3. 

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AEs will be reported by the participants to the Investigator, then by the Investigator to the 
Sponsor. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information  
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from D01 to D08 after vaccination. 
Solicited systemic reactions will be collected from D01 to D08 after vaccination. 
The solicited injection site reactions and systemic reactions that are pre-listed in the diary cards 
(DCs) and CRF, together with the intensity scales, are presented in Appendix 10.3.5.1.1. 
Unsolicited Non-serious Adverse Events 
Unsolicited non-serious AEs will be collected from D01 to D29 after vaccination. 
The intensity grading scale for unsolicited non-serious AEs is presented in Appendix 10.3.5.1.2. 
Adverse Events of Special Interest  
AESIs are considered as serious and will be collected from D01 to D181 (6 months).  
See Section 8.3.6 for the list of AESIs. 
Serious Adverse Events 
Information on SAEs will be collected and assessed throughout the study, from D01 until D181 (6 
month after vaccination). However, before the study intervention administration, only SAEs 
related to study procedures are to be collected (eg, SAEs related to blood sampling). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will not be recorded on the AE section of the CRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 

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8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events  
Individual DCs, specifically designed for this study by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information. These DCs 
will include pre-listed terms and intensity scales as well as areas for free text to capture additional 
safety information or other relevant details. Participants 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 
participants on how to correctly use these tools. 
At specified intervals, the Investigator or an authorized designee will interview the participants to 
collect the information recorded in the DC 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 CRF. Any information that was not 
documented in the DC will first be captured in the source document and then reported 
electronically. 
The 6-month follow-up will be done by interviewing participants over the telephone. During this 
call the staff will review the MA with the participant and determine whether the participant 
experienced any SAE or AESI not yet reported. 
The method of recording, evaluating, and assessing causal relationship of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events  
Unless a participant refuses further contact, each participant 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 participant’s participation in the study) if 
either of the following is true: 
• The AE is considered by the Investigator to be related to the study intervention administered 
• The AE caused the discontinuation of the participant from the study or from vaccination 
The Investigator will inform the Sponsor of the date of final disappearance of the event or the date 
of “chronicity” establishment. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and Investigators. 

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• For all studies except those investigating medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious ARs according to local regulatory requirements and 
Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy  
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until delivery by the Investigator and recorded in the Pregnancy CRF. Any 
data collected after CRF lock will be transmitted to the pharmacovigilance department on the 
paper form. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 1 month of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.4. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse Events of Special Interest  
AESI 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, and anaphylaxis. 
8.4 
Treatment of Overdose  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the Investigator should: 
1) Contact the Medical Monitor immediately. 
2) Closely monitor the participant for any AE/SAE. 
3) Document the quantity of the excess of the overdose in the source documents. 
8.5 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study. 
8.6 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 

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8.7 
Genetics  
Genetics are not evaluated in this study. 
8.8 
Biomarkers  
No other biomarkers than those described in the immunogenicity assessments section 
(Section 8.1.2) are evaluated in this study. 
8.9 
Immunogenicity Assessments  
See Section 8.1.2. 
8.10 Medical Resource Utilization and Health Economics  
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 

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9 
Statistical Considerations  
9.1 
Statistical Hypotheses  
No hypotheses will be tested. The analyses will be descriptive. 
9.2 
Sample Size Determination  
A total of approximately 300 participants will be enrolled as follows: 
• 75 participants from 18 to 49 years of age in RIV4 group 
• 75 participants ≥ 50 years of age in RIV4 group 
• 75 participants 18 to 49 years of age in IIV4 group 
• 75 participants ≥ 50 years of age in IIV4 group 
Assuming a drop-out rate of 5%, a total of 71 evaluable participants per group of age and vaccine 
is anticipated. 
No formal power calculation has been performed but based on the planned sample size the 
estimation precision is provided as follows. For proportions, the expected precision of estimation 
(using PASS14) is: 71 participants per treatment group provide a maximum width of 95% 
confidence interval (CI) of 24.2% for single proportions and a maximum width of 95% CI of 
32.0% for differences between proportions (when the group proportions are 50%). For 
quantitative data, the distance from the mean to the limits of 95% CI is equal to 0.154 for single 
mean and 0.216 for difference in means (when the estimated standard deviation is 0.65). 
 
In case of any unexpected situations where this planned number is not reached (due to an 
unexpected high number of withdrawals or unevaluable data) then additional participants might 
be recruited before database lock to achieve that planned sample size. Such assessment and 
decision will be performed in a blind manner during the course of the trial before database lock or 
any statistical analysis.  

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9.3 
Populations for Analyses  
The following populations are defined: 
Population 
Description 
Safety Analysis Set (SafAS) 
Participants who have received a dose of the study vaccine. All 
participants will have their safety analyzed according to the vaccine 
they actually received. 
Safety data recorded for a vaccine received out of the protocol design 
will be excluded from the analysis (and listed separately). 
Full analysis set (FAS) 
Subset of randomized participants who received a dose of the study 
vaccine and had a post-vaccination blood sample. Participants will be 
analyzed according to the intervention to which they were randomized. 
Per-protocol analysis set 
(PPAS) 
Subset of the FAS. Participants presenting with at least one of the 
following conditions will be excluded from the PPAS: 
• 
Participant did not meet all protocol-specified inclusion criteria or 
met at least one of the protocol-specified exclusion criteria 
• 
Participant did not receive vaccine  
• 
Participant received a vaccine other than the one that he/she was 
randomized to receive 
• 
Preparation and/or administration of vaccine was not done as per-
protocol 
• 
Participant did not receive vaccine in the proper time window 
• 
Participant did not provide the post-dose serology sample at Visit 2 
in the proper time window or a post-dose serology sample was not 
drawn 
• 
Participant received a protocol-prohibited 
therapy/medication/vaccine  
9.4 
Statistical Analyses  
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints.  
The endpoints for immunogenicity and safety are shown in Table 3.1. 
9.4.1 
General Considerations  
All analyses will be descriptive and be provided by age groups and overall. No replacement will 
be done for safety and immunogenicity missing data and outliers. Analysis will be done using the 
collected values. Nevertheless, for unsolicited systemic AEs, missing relationship will be 

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considered as related to study vaccine(s) at the time of analysis. Details will be provided in the 
SAP. 
9.4.2 
Immunogenicity  
Descriptive analyses on HAI Ab response measured at D01 and D29 will be performed in each 
age, intervention group and pooled age group, including but will not be limited to: 
• Geometric mean of HAI Ab titer (GMT) and 95% CI at D01 and D29 
• Geometric mean fold-rise (GMFR) of HAI Ab titer and 95%CI. Fold-rise is computed as 
individual titer ratio of post-vaccination value divided by baseline value.  
• Number and percentage of participants with seroconversion (seroconversion rate): titer < 
10 (1/dilution [1/dil]) at D01 and post-injection titer ≥ 40 (1/dil) at D29, or titer ≥ 10 
(1/dil) at D01 and a ≥ 4-fold increase in titer (1/dil) at D29 
• Number and percentage of participants with titer ≥ 40 (1/dil) at D01 and D29 
• Number and percentage of participants with detectable titer ≥ 10 (1/dil) at D01 and D29 
The 95% CIs for the GMTs and GMT ratios (GMTRs) will be calculated using a normal 
approximation of log-transformed titers. The 95% CIs for the proportions will be based on the 
Clopper-Pearson method. The ratios of GMTs (RIV4/IIV4) in each age group will be obtained 
between groups with the 95% CIs calculated using a normal approximation of log-transformed 
titers. The differences in the seroconversion rates between groups in each age group will be 
computed along with the 2-sided 95% CIs by the Wilson-Score method without continuity 
correction. Additional parameters may be displayed as appropriate. 
In addition, as a complementary analysis to support bridging discussion, Bayesian method will be 
used to evaluate the probability of non-inferiority in GMTs. The posterior probability of the true 
ratio of GMTs (RIV4/IIV4) to be higher than the commonly accepted non-inferiority margin 
(0.667) will be calculated using the Bayesian approach to support bridging with previous non-
inferiority trials. Further details about the statistical methodology will be provided in the SAP.  
Reverse cumulative distribution curves in each age group against each strain will be performed 
for baseline (D01) and post-vaccination immunogenicity (D29). 
The Full Analysis Set (FAS) and Per-Protocol Analysis Set (PPAS) will be used for the main 
immunogenicity analyses. Details of both analyses’ sets are described in Section 9.3. 
9.4.3 
Safety  
Safety endpoints will be analyzed descriptively for participants in the safety analysis set (SafAS). 
The following safety parameters will be described by the 95% CI based on the Clopper-Pearson 
method in each age, intervention group and pooled age group. Additional parameters may be 
displayed as appropriate. The current MedDRA version will be used for the coding of all 
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Solicited Reactions  
Number and percentage of participants with: 
• Presence of solicited injection site reactions and systemic reactions occurring up to 7 days 
after injection 
• Each solicited reaction according to time of onset, maximum intensity, and number of days of 
occurrence and action taken 
Unsolicited Events and Reactions  
Number and percentage of participants with: 
• Any unsolicited immediate systemic event in the 30 minutes after injection according to 
System Organ Classes (SOC) and Preferred Terms (PT) 
• Any unsolicited event and reaction 28 days after injection according to SOC and PT 
• Any unsolicited event/reaction according to time of onset, maximum intensity, and duration 
SAEs 
Number and percentage of participants with:  
• Any SAE within 28 days after injection and throughout the entire study according to SOC and 
PT, seriousness and outcome 
AESIs 
• Number and percentage of participants with: 
• Any AESI within 28 days after injection and throughout the entire study according to SOC 
and PT, seriousness and outcome 
9.5 
Interim Analyses  
This study will not include an early safety data review. However, participant safety will be 
continuously monitored by the Sponsor’s internal safety review committee which includes safety 
signal detection at any time during the study. 
9.6 
Data Monitoring Committee  
Not applicable. 

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10 Supporting Documentation and Operational Considerations  
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
requirements. 
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines. 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]). 
• The protocol, protocol amendments, Assent Form, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator or the Sponsor 
(according to local regulations) and reviewed and approved by the IRB/IEC before the study 
is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC (in addition to summaries required from the Sponsor). 
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity 

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• 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
• 
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the Investigator’s contract. 
10.1.3 Informed Consent Process  
• The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the Assent Form and/or 
ICF. 
• The actual Assent Form and ICF used at each center may differ, depending on local 
regulations and IRB/IEC requirements. However, all versions must contain the standard 
information found in the sample Assent Form and ICF provided by the Sponsor. Any change 
to the content of the Assent Form and/or ICF must be approved by the Sponsor and the 
IRB/IEC prior to the form being used. 
• If new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study, this will be communicated to him/her in a timely manner. 
Such information will be provided via a revised Assent Form and/or ICF or an addendum to 
the original Assent Form and ICF. 
• Participants must be re-consented to the most current version of the Assent Form(s) and/or 
ICF(s) during their participation in the study. 
• A copy of the Assent Form(s) and/or ICF(s) must be provided to the participant or the 
participant’s legally authorized representative. 
 

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Recruitment Procedures 
Participants will be recruited from the general population. The sites will ensure that any 
advertisements used to recruit participants (letters, pamphlets, posters, etc.) are submitted to 
Sanofi Pasteur prior to submission to the IEC / IRB for approval. Detailed guidance and 
information are provided in the Operating Guidelines. 
10.1.4 Data Protection and Future Use of Stored Samples  
• All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with 
all applicable laws and regulations including the GDPR. Data collected must be adequate, 
relevant and not excessive, in relation to the purposes for which they are collected. Each 
category of data must be properly justified and in line with the study objective. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred to the 
Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
• Participant data will be used for this study and in support of the whole drug development 
program for the Investigational Product, including negotiations with payers and publication of 
results. 
• Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) up to 25 years after the end of the study. These samples are being retained in 
long-term storage to support answers to regulatory questions related to the product’s licensure 
and the potential revalidation of the study results. 
The other biological samples collected to qualify the participant for inclusion in the study or to 
monitor his/her health are dedicated for immediate use. In case they are not completely used 
up, they will be destroyed at the latest at the end of the study or after the time requested by 
local law. 
In addition, participants will be asked to indicate in the Assent Form and/or ICF whether they 
will permit the future use of any unused stored serum samples for other tests. If they refuse 
permission, the samples will not be used for any testing other than that directly related to this 
study. If they agree to this use, they will not be paid for giving permission. Anonymity of 
samples will be ensured. The aim of any possible future research is unknown today, and may 
not be related to this particular study. It may be to improve the knowledge of vaccines or 
infectious diseases, or to improve existing tests or develop new tests to assess vaccines. 
Human genetic tests will never be performed on these samples without specific individual 
informed consent 

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10.1.5 Committees Structure  
There will be no Data Monitoring Committee.  
10.1.6 Dissemination of Clinical Study Data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data Quality Assurance  
• All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations [CROs]). 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 

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• Records and documents, including signed Assent Forms and ICFs, pertaining to the conduct of 
this study must be retained by the Investigator for 25 years after the signature of the final 
study report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, screening logs, Assent Forms, ICFs, telephone contact logs, and worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Detailed guidance and information are provided in the Operating Guidelines. 
10.1.9 Study and Site Start and Closure  
Details on which clinical supplies are provided by the Sponsor or the site are described in the 
Operating Guidelines. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study site has all the documents necessary for archiving and a study site 
closure visit has been performed along with a Site Close Out Form submitted to the IRB, as 
required. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the Investigator. 
• Discontinuation of further study intervention development. 

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If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.10 Publication Policy  
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: Clinical Laboratory Tests  
Not applicable. 
10.3 Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
10.3.1 Definition of Adverse Event  
Adverse Event Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to 
the study intervention 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study intervention 
 
Events Meeting the Adverse Event Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease) 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae 
 

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Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the participant’s condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
 
Other Definitions 
Adverse Reaction: 
All noxious and unintended responses to a study intervention related to any dose should be 
considered ARs. 
(The phrase “responses to a study intervention” means that a causal relationship between a study 
intervention and an AE is at least a reasonable possibility) 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the study intervention administered) that occur within the first 30 minutes after 
vaccination. 
Injection Site Reaction/Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration site. 
Injection/administration site reactions are commonly inflammatory reactions. They are considered to 
be related to the study intervention administered. 
Systemic Adverse Event/Adverse Reaction: 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (eg, erythema that is 
localized but that is not occurring at the injection site). 
Systemic AEs assessed as related to study intervention are referred as systemic ARs. 
Adverse Event of Special Interest: 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the Sponsor’s 
study intervention or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. Such an event might warrant further investigation in 
order to characterize and understand it. Depending on the nature of the event, rapid communication 
by the study Sponsor to other parties (eg, regulators) might also be warranted. 
Reactogenicity/Solicited Reactions: 
A solicited reaction is an “expected” AR (sign or symptom) observed and reported under the 
conditions (nature and onset) pre-listed in the protocol and CRF. 
By definition, solicited reactions are considered as being related to the study intervention 
administered. 

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For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions. 
Unsolicited Adverse Event/Adverse Reaction: 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, ie, 
pre-listed in the CRF in terms of diagnosis and/or onset window post-vaccination. For example, 
varicella or a solicited term such as headache starting after the solicited observation period (headache 
starting on D10 post-vaccination in the case where headache occurring between the day of 
vaccination and the next 7 days is pre-listed in the protocol and CRF as a solicited reaction). 
An unsolicited AR is an unsolicited AE that is considered related to study intervention. Unsolicited 
AEs includes both serious (SAEs) and non-serious unsolicited AEs. 

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10.3.2 Definition of Serious Adverse Event  
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious”' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption 
e. 
Is a congenital anomaly/birth defect 
f. 
Other important medical event 
• 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the health of the 
participant or may require intervention to prevent one of the other outcomes listed in the above 
definition. These important medical events should also usually be considered serious 
• 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse, new onset diabetes or autoimmune disease 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant/event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 

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10.3.3 Recording and Follow-Up of Adverse Event and/or Serious Adverse Event  
Adverse Event and Serious Adverse Event Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event 
• The Investigator will then record all relevant AE/SAE information in the CRF 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the CRF pages 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE 
 
Assessment of Causal Relationship 
By convention, all AEs reported at the injection site (whether solicited or unsolicited) and all 
solicited systemic AEs are considered to be related to the study intervention (see definition in 
Section 6) and therefore are referred to as reactions and do not require the Investigator’s 
opinion on relatedness. 
• Causal relationship of unsolicited systemic AEs and SAEs will be recorded as follows: 
• 
For non-serious unsolicited systemic AEs (except for non-serious AESIs), relationship 
to study intervention will usually be assessed by the Investigator only 
• 
For SAEs and non-serious AESIs, relationship to study intervention will be assessed 
by both the Investigator and the Sponsor. Sponsor assessment is entered in the GPV 
database only 
• 
For SAEs only, the causal relationship to study procedures (related/not related to study 
procedures) will be assessed by both the Investigator and the Sponsor. Sponsor 
assessment is entered in the GPV database only 
• The Investigator will assess the causal relationship between each unsolicited systemic AE 
and the study intervention administereda 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 vaccination (screening phase, if applicable) 
• 
Related – There is a “reasonable possibility” that the AE was caused by the study 
intervention administered, meaning that there is evidence or arguments to suggest a 
causal relationship 
• The Investigator will use clinical judgment to determine the relationship 
 
a Study intervention administered can correspond to either the investigational product or other products when no 
investigational product is administered at the visit 

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• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated 
• The Investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causal relationship 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the Investigator always make an assessment of causal relationship for every event before the 
initial transmission of the SAE data to the Sponsor 
• The Investigator may change his/her opinion of causal relationship in light of follow-up 
information and send an SAE follow-up report with the updated causal relationship 
assessment 
• The causal relationship assessment is one of the criteria used when determining regulatory 
reporting requirements 
 
Follow-up of Adverse Events and Serious Adverse Events 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causal relationship of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals 
• If a participant dies during participation in the study or during a recognized follow-up 
period, when available the Investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology 
• New or updated information will be recorded in the originally completed CRF 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information 
• AEs likely to be related to the study intervention, 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 participant’s condition. The Investigator will inform the Sponsor 
of the date of final disappearance of the event or the date of “chronicity” establishment 

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10.3.4 Reporting of Serious Adverse Events  
Serious Adverse Event Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. The site will enter the 
SAE data into the electronic system as soon as it becomes available 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data 
• If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) 
• Details regarding SAE reporting can be found in the Operating Guidelines 
 
Serious Adverse Event Reporting to the Sponsor via Paper Case Report Form 
• The SAE paper CRF can be sent to the Sponsor by one of the following means: 
• 
By fax, to the following number: 570-957-2782 
• 
In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.com 
• 
By express mail, to the following address: Global Pharmacovigilance and 
Epidemiology, Sanofi Pasteur Inc. 1 Discovery Drive, Swiftwater, PA, 18370-0187, 
US 
 
Using a Verbal Autopsy Questionnaire to Aid in Determining the Cause of Death 
• In case of the absence or inadequacy of health information that would allow a thorough 
evaluation of the causes of the death of a study participant, the verbal autopsy procedure 
may be triggered by either the Investigator or the Sponsor. Detailed instructions on the use 
of the verbal autopsy questionnaire, as well as the questionnaire itself, are provided in the 
Operating Guidelines 
 
10.3.5 Assessment of Intensity  
The Investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 
10.3.5.1 Tables for Clinical Abnormalities  
10.3.5.1.1 Solicited Adverse Reaction Intensity Grading Scale  
 

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

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CRB term 
(MedDRA 
lowest level 
term 
[LLT]) 
Injection site pain 
Injection site 
erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Injection site tenderness 
Intensity 
scale* 
 
Grade 1: A type of 
adverse event (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. 
Grade 1: ≥ 25 to ≤ 50 
mm 
Grade 2: ≥ 51 to ≤ 100 
mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 
mm 
Grade 2: ≥ 51 to ≤ 100 
mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 
mm 
Grade 2: ≥ 51 to ≤ 100 
mm 
Grade 3: > 100 mm 
Grade 1: 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. 
* 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 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales  
 
CRB term 
(MedDRA 
lowest 
level term 
[LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
Fatigue 
Nausea 
Arthralgia 
MedDRA 
preferred 
term 
[PT] 
Pyrexia 
Headache 
Malaise 
Myalgia 
Chills 
Fatigue 
Nausea 
Arthralgia 
Diary card 
term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Chills 
Fatigue 
Nausea 
Joint Pain 
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 are 
common and can involve 
more than one muscle at 
the same time. Muscle 
pain can also involve the 
soft tissues that surround 
muscles. These 
structures, which are 
often referred to as 
connective tissues, 
include ligaments, 
tendons, and fascia (thick 
bands of tendons). 
Does not apply to muscle 
pain at the injection site 
which should be reported 
as injection site pain. 
Cold feeling 
Overall 
tiredness and 
lack of energy 
Upper abdominal 
discomfort 
associated with 
an urge to vomit 
Pain in a joint or 
joints 
 

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CRB term 
(MedDRA 
lowest 
level term 
[LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
Fatigue 
Nausea 
Arthralgia 
Intensity 
scale* 
Grade 1: 
≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to 
≤ 101.1°F 
Grade 1: A type 
of adverse event 
(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 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 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 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 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 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 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. 
 

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CRB term 
(MedDRA 
lowest 
level term 
[LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
Fatigue 
Nausea 
Arthralgia 
 
Grade 2: 
≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to 
≤ 102.0°F 
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 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 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 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 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 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 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. 
 

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CRB term 
(MedDRA 
lowest 
level term 
[LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
Fatigue 
Nausea 
Arthralgia 
 
Grade 3: 
≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type 
of AE that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention. 
Grade 3: A type 
of AE that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention. 
Grade 3: A type of AE 
that interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Grade 3: A 
type of AE that 
interrupts 
usual activities 
of daily living, 
or significantly 
affects clinical 
status, or may 
require 
intensive 
therapeutic 
intervention 
Grade 3: A 
type of AE that 
interrupts 
usual activities 
of daily living, 
or significantly 
affects clinical 
status, or may 
require 
intensive 
therapeutic 
intervention. 
Grade 3: A type 
of AE that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention. 
Grade 3: A type 
of AE that 
interrupts usual 
activities of daily 
living, or 
significantly 
affects clinical 
status, or may 
require intensive 
therapeutic 
intervention. 
 
*  For all reactions but fever, subjects 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: 
Participants are to measure body temperature once per day, preferably always at the same time. 
The optimal time for measurement is the evening, when body temperature is the highest. 
Temperature is also to be measured at the time of any apparent fever. The observed daily 
temperature and the route of measurement are to be recorded in the DC, and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this study is axillary. 
10.3.5.1.2 Unsolicited Adverse Event Intensity Grading Scale  
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.3.5.1.1). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
CRF: 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 
• 
DC: No interference with usual activities 
• Grade 2 
• 
CRF: 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 
• 
DC: Some interference with usual activities 
• Grade 3 
• 
CRF: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention 
• 
DC: Significant; prevents usual activities 
10.4 Appendix: Collection of Pregnancy Information  
DEFINITIONS: 
Women of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the Following Categories are not Considered Women of Childbearing Potential 
1) Premenarchal 
2) Premenopausal female with one of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 

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For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than 1 FSH measurement is 
required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
COLLECTION OF PREGNANCY INFORMATION 
Female Participants who Become Pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information together with the 
contraceptive method if any will be recorded on the appropriate form and submitted to the 
Sponsor within 1 month of learning of a participant's pregnancy. If the Electronic DC (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. 
• The participant will be followed to determine the outcome of the pregnancy. Study staff must 
maintain contact with the participant to obtain information about the outcome (ie, 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 by Investigator.  
• For live births, an additional follow-up will be conducted 6 months after the delivery date to 
determine if any congenital anomalies in the infant not detected at birth have been diagnosed. 
An Infant Data Collection Form will be used for this purpose. Up to 3 follow-up attempts will 
be conducted with the child’s physician or hospital (in cases of adverse outcome involving 
hospitalization). Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 

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• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring 
at > 22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
CONTRACEPTION GUIDANCE 
 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) b 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 

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• Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. 
d) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  
e) Male condom and female condom should not be used together (due to risk of failure from friction). 
10.5 Appendix: Risk-based Approach  
ICH E6-R2 guideline for GCP is introducing the “risk-based approach” concept which permits to 
focus efforts on what is critical for a study and most specifically on Critical Data and Critical 
Processes. Critical data and processes are defined for the study with associated risks in the Study 
Risk Management Plan. 

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10.6 Appendix: Abbreviations  
1/dil 
 
1/dilution  
Ab 
 
Antibody 
AcNPV 
Autographa californica nuclear polyhedrosis virus 
AE 
 
Adverse event 
AESI  
Adverse event of special interest 
AR 
 
Adverse reaction 
BL 
 
Blood sampling 
CI 
 
Confidence interval 
CRF  
Case report form 
CRO  
Contract Research Organization 
D 
 
Day 
DC 
 
Diary card 
DNA  
Deoxyribonucleic acid 
FAS 
 
Full analysis set 
FSH 
 
Follicle stimulating hormone 
GBS  
Guillain-Barré syndrome  
GCI 
 
Global Clinical Immunology 
GCP  
Good Clinical Practice 
GDPR  
General Data Protection Regulation 
GMT  
Geometric mean titer 
GMTR 
Geometric mean titer ratio 
GPV  
Global Pharmacovigilance 
HA 
 
Hemagglutinin 
HAI 
 
Hemagglutination inhibition 
HRT  
Hormonal replacement therapy 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed consent form 
ICH 
 
International Council for Harmonization 
IEC 
 
Independent Ethics Committee 
IIV4  
Quadrivalent-inactivated influenza vaccine 
IM 
 
Intramuscular 
IMP 
 
Investigational Medicinal Product 

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IRB 
 
Institutional Review Board 
IRT 
 
Interactive response technology  
KCDC  
Korea Centers for Disease Control & Prevention  
LLT 
 
Lowest level term 
MA  
 
Memory aid 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
 
Not applicable 
NH 
 
Northern Hemisphere 
NIMP  
Non- Investigational Medicinal Product 
NIP 
 
National Immunization Program  
PC  
 
Phone call 
PPAS  
Per-protocol analysis set 
PT 
 
Preferred term 
PY 
 
Person Year 
QIV 
 
Quadrivalent influenza vaccine 
rHA 
 
Recombinant hemagglutinin 
RIV4  
Recombinant Influenza Vaccine, Quadrivalent 
SAE  
Serious adverse events 
SafAS  
Safety Analysis Set 
SAP 
 
Statistical Analysis Plan 
SH 
 
Southern Hemisphere 
SoA 
 
Schedule of Activities 
SOC   
System Organ Classes  
TBD  
To be determined 
TIV 
 
Trivalent influenza vaccine  
US 
 
United States 
USPI  
US Prescribing Information 
V 
 
Visit 
WHO  
World Health Organization 

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11 References  
1. 
Cox MM, Hashimoto Y. A fast track influenza virus vaccine produced in insect cells. 
Journal of invertebrate pathology. 2011;107 Suppl:S31-41. 
2. 
Holtz KM, Anderson DK, Cox MMJ. Production of a Recombinant Influenza Vaccine 
Using the Baculovirus Expression Vector System. BioProcess J. 2003;2(5):65-73. 
3. 
Wang K, Holtz KM, Anderson K, Chubet R, Mahmoud W, Cox MM. Expression and 
purification of an influenza hemagglutinin--one step closer to a recombinant protein-based 
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4. 
Blanton L, Brammer L, Finelli L, Grohskopf LA, Bresee J, Klimov A. 2011.  VPD 
Surveillance Manual, 5th Edition Influenza. 
5. 
Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. 
Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. 
Lancet. 2018;391(10127):1285-300. 
6. 
Epperson S, Davis CT, Brammer L, Abd Elal AI, Ajayi N, Barnes J, et al. Update: 
Influenza Activity - United States and Worldwide, May 19-September 28, 2019, and Composition 
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report. 2019;68(40):880-4. 
7. 
El Guerche-Séblain C, Caini S, Paget J, Vanhems P, Schellevis F. Epidemiology and 
timing of seasonal influenza epidemics in the Asia-Pacific region, 2010-2017: implications for 
influenza vaccination programs. BMC public health. 2019;19(1):331. 
8. 
WHO. Recommended composition of influenza virus vaccines for use in the 2020-2021 
northern hemisphere influenza season2020 Accessed on February 2020. Available from: 
https://www.who.int/influenza/vaccines/virus/recommendations/202002_recommendation.pdf?ua
=1. 
9. 
Choi WS. The National Influenza Surveillance System of Korea. Infection & 
chemotherapy. 2019;51(2):98-106. 
10. 
Suh M, Kang DR, Lee DH, Choi YJ, Tchoe B, Nam CM, et al. Socioeconomic burden of 
influenza in the Republic of Korea, 2007-2010. PLoS One. 2013;8(12):e84121. 
11. 
Park M, Wu P, Goldstein E, Joo Kim W, Cowling BJ. Influenza-Associated Excess 
Mortality in South Korea. Am J Prev Med. 2016;50(4):e111-e9. 
12. 
Yun JW, Choi MJ, Shin GS, Lim JO, Noh JY, Kim YK, et al. Cost-effectiveness of 
influenza vaccine strategies for the elderly in South Korea. PLoS One. 2019;14(1):e0209643. 
13. 
Kim YK, Song JY, Jang H, Kim TH, Koo H, Varghese L, et al. Cost Effectiveness of 
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and Older Adults in Korea. PharmacoEconomics. 2018;36(12):1475-90. 
14. 
Flublok Quadrivalent Influenza Vaccine [package insert on the internet]. Meridien (CT): 
Protein Science Corporation. Updated November 2019Accessed on October 2020. Available 
from: https://www.fda.gov/media/123144/download. 

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15. 
Quadrivalent Recombinant Influenza Vaccine. Investigator's Brochure. Version 6.0 dated 
21 January 2020  
16. 
Hansen J, Goddard K, Timbol J, Zhang L, Lewis N, Dunkle L, et al. Safety of 
Recombinant Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An 
Observational Study. Open forum infectious diseases. 2020;7(6). 
17. 
McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, et al. Risk of 
anaphylaxis after vaccination in children and adults. The Journal of allergy and clinical 
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18. 
Klein NP, Ray P, Carpenter D, Hansen J, Lewis E, Fireman B, et al. Rates of autoimmune 
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Lee CD, Jones TF. Hospital discharge database optimization in Guillain-Barré syndrome 
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Walling AD, Dickson G. Guillain-Barré syndrome. American family physician. 
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Yoshikawa H. [Epidemiology of Guillain-Barré Syndrome]. Brain Nerve. 
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Gouma S, Zost SJ, Parkhouse K, Branche A, Topham DJ, Cobey S, et al. Comparison of 
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Nachbagauer R, Choi A, Izikson R, Cox MM, Palese P, Krammer F. Age Dependence and 
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12 Sponsor Signature Page