Controlled Study of Immunogenicity and Safety of the Investigational vYF Candidate Vaccine in Comparison to Stamaril in Adults
Phase: PHASE2
Conditions: Yellow Fever
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
Controlled Study of Immunogenicity and Safety of the Investigational vYF Candidate Vaccine in 
Comparison to Stamaril® in Adults 
Study Code: VYF03 
Amendment Number: Amendment 1 
Compound: Yellow fever (YF) vaccine vYF 
Study Phase: Phase II 
Short Title: 
Study on an Investigational Yellow Fever Vaccine Compared with Stamaril in Adults in Europe 
and Asia 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur SA 
14 Espace Henry Vallée, 69 007 Lyon, France 
Manufacturer: Same as Sponsor 
Regulatory Agency Identifier Number(s): 
BB-IND: IND #: 019167  
EudraCT: 2020-005566-33 
WHO UTN: U1111-1260-4650 
Protocol Version Number: 4.0 
Approval Date: 01 July 2021 
Medical Monitor Name and Contact Information are provided in the Operating Guidelines. 
The study centers, the Investigators at each center, and the Coordinating Investigator(s) are listed 
in a separate document. 
NCT: NCT05011123 

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Document History  
Previous 
Version(s)* 
Date 
Comments 
1.0 
02 February 2021 
Version not submitted, internal version only. 
2.0 
15 March 2021 
Version submitted to Health Authorities (HA) and Ethics 
Committees for the initial Clinical Trial Application 
(CTA) assessment 
3.0 
30 June 2021 
Version requested by the German HA (PEI) during the 
answer to questions process of the CTA assessment 
* Versions in bold font have been approved by the Independent Ethics Committees (IEC)(s) / Institutional 
Review Boards (IRB)(s) and used in the study. 
 
Overall Rationale for the Amendment: 
Amendment to include comments received from Health Authorities / Ethics Committees during 
the assessment of the clinical trial application: 
• From the French Health Authorities, comments received on the 20 May 2021 to specify 
the methods of contraception (Appendix 10.4 ), to collect AESIs up to 6 months and for 
this country only to have 12 weeks of contraception after study intervention 
administration 
• From the Finnish Health Authorities, comments received on 20 May 2021; for this 
country, no possibility of accepting periodic abstinence as an adequate method of 
contraception 
• From the German Health Authorities, comments received on 10 Jun 2021 to address to the 
competent authority the pausing and resuming of the trial 
• From Thai CREC, comments received on 17 May 2021 to add the condition that for a 
subject who has been COVID-19 vaccinated, as per CDC recommendation, the 
investigational product (vYF / Stamaril) can be given to the subject at least 1 month later 
after COVID-19 vaccination completion 
Also, comments received from the US FDA on a similar study conducted in the USA (VYF02- Controlled 
Study of Immunogenicity and Safety of Investigational vYF Candidate Vaccine in Comparison to YF-VAX 
in Adults) was taken into consideration (to specify the duration of collection of MAAEs Appendix 10.3.1). 
 
 
 

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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 ............................................................................................................................ 13 
1.3 
Schedule of Activities (SoA) .......................................................................................... 13 
2 
Introduction ..................................................................................................................... 17 
2.1 
Study Rationale ............................................................................................................... 20 
2.2 
Background ..................................................................................................................... 21 
2.3 
Benefit/Risk Assessment ................................................................................................ 21 
2.3.1 
Risks from Study Participation ..................................................................................... 21 
2.3.2 
Benefits from Study Participation ................................................................................ 24 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 25 
3 
Objectives and Endpoints ............................................................................................... 25 
4 
Study Design .................................................................................................................... 27 
4.1 
Overall Design ................................................................................................................ 27 
4.2 
Scientific Rationale for Study Design ............................................................................. 28 
4.3 
Justification for Dose ...................................................................................................... 30 
4.4 
End of Study Definition .................................................................................................. 30 
5 
Study Population ............................................................................................................. 30 
5.1 
Inclusion Criteria ............................................................................................................ 30 
5.2 
Exclusion Criteria ........................................................................................................... 31 
5.3 
Lifestyle Considerations ................................................................................................. 33 
5.4 
Screen Failures ................................................................................................................ 33 
6 
Study Intervention ........................................................................................................... 33 
6.1 
Study Interventions Administered .................................................................................. 33 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 34 

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6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 35 
6.3.1 
Randomization and Allocation Procedures .................................................................. 35 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 36 
6.4 
Study Intervention Compliance ...................................................................................... 37 
6.5 
Concomitant Therapy ...................................................................................................... 37 
6.5.1 
Rescue Medicine ........................................................................................................... 38 
6.6 
Dose Modification .......................................................................................................... 38 
6.7 
Intervention After the End of the Study .......................................................................... 38 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 38 
7.1 
Discontinuation of Study Intervention ............................................................................ 38 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 38 
7.3 
Lost to Follow-up ............................................................................................................ 39 
8 
Study Assessments and Procedures ............................................................................... 39 
8.1 
Efficacy and Immunogenicity Assessments ................................................................... 41 
8.1.1 
Efficacy Assessments ................................................................................................... 41 
8.1.2 
Immunogenicity Assessments ...................................................................................... 41 
8.1.2.1 
Immunogenicity Endpoints ........................................................................................ 41 
8.1.2.2 
Immunogenicity Assessment Methods....................................................................... 42 
8.2 
Safety Assessments ......................................................................................................... 44 
8.2.1 
Medical History ............................................................................................................ 44 
8.2.2 
Physical Examinations .................................................................................................. 44 
8.2.3 
Vital Signs .................................................................................................................... 44 
8.2.4 
Clinical Safety Laboratory Assessments ...................................................................... 45 
8.2.5 
Viremia/Vaccinemia ..................................................................................................... 45 
8.3 
Adverse Events and Serious Adverse Events ................................................................. 45 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ......................... 45 
8.3.2 
Method of Detecting AEs and SAEs ............................................................................ 46 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................ 47 
8.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 47 
8.3.5 
Pregnancy ..................................................................................................................... 47 
8.3.6 
Adverse Events of Special Interest ............................................................................... 48 
8.3.7 
Medically Attended Adverse Events ............................................................................ 48 
8.4 
Treatment of Overdose.................................................................................................... 49 
8.5 
Pharmacokinetics ............................................................................................................ 49 
8.6 
Pharmacodynamics ......................................................................................................... 49 
8.7 
Genetics ........................................................................................................................... 49 

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8.8 
Biomarkers ...................................................................................................................... 49 
8.9 
Immunogenicity Assessments ......................................................................................... 49 
8.10 
Medical Resource Utilization and Health Economics .................................................... 49 
9 
Statistical Considerations ............................................................................................... 50 
9.1 
Statistical Hypotheses ..................................................................................................... 50 
9.2 
Sample Size Determination ............................................................................................. 50 
9.3 
Populations for Analyses ................................................................................................ 51 
9.4 
Statistical Analyses ......................................................................................................... 52 
9.4.1 
General Considerations ................................................................................................. 52 
9.4.2 
Secondary Endpoints .................................................................................................... 53 
9.4.3 
Exploratory Endpoint(s) ............................................................................................... 53 
9.5 
Interim Analyses ............................................................................................................. 54 
9.6 
Data Monitoring Committee (DMC) .............................................................................. 55 
10 
Supporting Documentation and Operational Considerations .................................... 56 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations ............................ 56 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 56 
10.1.2 
Financial Disclosure ..................................................................................................... 57 
10.1.3 
Informed Consent Process ............................................................................................ 57 
10.1.4 
Data Protection and Future Use of Stored Samples ..................................................... 58 
10.1.5 
Committees Structure ................................................................................................... 59 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 59 
10.1.7 
Data Quality Assurance ................................................................................................ 59 
10.1.8 
Source Documents ........................................................................................................ 60 
10.1.9 
Study and Site Start and Closure .................................................................................. 60 
10.1.10 
Publication Policy ......................................................................................................... 61 
10.2 
Appendix: Clinical Laboratory Tests .............................................................................. 61 
10.3 
Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................ 62 
10.3.1 
Definition of AE ........................................................................................................... 62 
10.3.2 
Definition of SAE ......................................................................................................... 65 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 66 
10.3.4 
Reporting of SAEs ........................................................................................................ 68 
10.3.5 
Assessment of Intensity ................................................................................................ 69 
10.3.5.1 
Tables for Clinical Abnormalities .............................................................................. 69 
10.3.5.1.1 
Solicited AR Intensity Grading Scale ...................................................................... 69 
10.3.5.1.2 
Unsolicited AE Intensity Grading Scale .................................................................. 74 
10.3.5.2 
Tables for Laboratory Abnormalities ......................................................................... 74 

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10.3.6 
Visit to the Center in the Event of Severe (Grade 3) Fever, or Suspicion of 
Neurotropic Disease or Acute Viscerotropic Disease Within 28 Days of 
Vaccination ................................................................................................................... 75 
10.4 
Appendix: Collection of Pregnancy Information ............................................................ 76 
10.4.1 
Definitions .................................................................................................................... 76 
10.4.2 
Contraception Guidance ............................................................................................... 78 
10.5 
Appendix: Country-specific Requirements ..................................................................... 79 
10.5.1 
Serology ........................................................................................................................ 79 
10.5.2 
Receipt of COVID-19 Vaccines During the Study ...................................................... 79 
10.5.3 
Contraception ................................................................................................................ 79 
10.6 
Appendix: Risk-based Approach .................................................................................... 80 
10.7 
Appendix: Abbreviations ................................................................................................ 81 
11 
References ........................................................................................................................ 84 
12 
Sponsor Signature Page .................................................................................................. 86 
 
 

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List of Tables  
Table 1.1: Schedule of activities ................................................................................................... 14 
Table 1.2: Blood samples collection per visit and participant ....................................................... 17 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 22 
Table 3.1: Objectives and endpoints ............................................................................................. 25 
Table 4.1: Overall design .............................................................................................................. 28 
Table 6.1: Identity of study interventions ...................................................................................... 34 
Table 8.1: Blood sampling volume (mL) per visit ........................................................................ 40 
Table 10.1 Solicited injection site reactions: terminology, definitions, and intensity scales ........ 70 
Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales ............. 72 
Table 10.3: Intensity grading scale for laboratories abnormalities ............................................... 75 
 
 
 

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List of Figures  
Figure 1.1 – Graphical study design .............................................................................................. 13 
 
 
 

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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
Controlled Study of Immunogenicity and Safety of the Investigational vYF Candidate Vaccine in 
Comparison to Stamaril in Adults 
Short Title: 
Study on an Investigational Yellow Fever Vaccine Compared with Stamaril in Adults in Europe 
and Asia 
Rationale: 
A first study, VYF01, aimed to assess the safety, viremia and immune responses of 3 dosages of 
vYF and YF-VAX, as a control vaccine, is ongoing in the USA. A second planned study, VYF02, 
aims to assess the non-inferiority of the immune response of the investigational vaccine candidate 
vYF to the licensed YF-VAX vaccine in adults in the USA. 
The proposed third study VYF03 is a Phase II, randomized, observer-blind, active-controlled 
(Stamaril) multi-center study to assess the non-inferiority of the immune response, in terms of 
seroconversion rates of the investigational vaccine candidate vYF to the licensed Stamaril, in 
adults aged 18 years up to 60 years in Europe (EU). The safety and immunogenicity profile of 
vYF in a cohort of Asian population of Chinese origin outside of China will also be presented. 
The study will also assess the immunogenicity profiles (seroprotection rates, geometric mean of 
titers [GMT] and geometric means of the individual titer ratios [GMTR]) and the safety profiles of 
vYF and Stamaril.  
Stamaril, the Sanofi Pasteur YF vaccine currently licensed and in use in more than 100 countries 
(including European and some Asian countries) will be the control vaccine. 
For the non-inferiority VYF03 study in EU, it is planned to enroll 570 participants into 2 groups 
in a 2:1 ratio: 380 participants will be administered vYF and 190 participants will be administered 
Stamaril on D01. In VYF03 in Asia, it is planned to enroll 120 participants also distributed into 2 
groups in a 2:1 ratio: 80 participants will be administered vYF and 40 participants will be 
administered Stamaril on D01. The participants in Asia (80 and 40 in the vYF and Stamaril 
groups, respectively) will be enrolled for descriptive purposes only. 
In addition, the study aims to assess the immune responses induced by the YF vaccines in terms of 
seroprotection and seroconversion rates, GMT, GMTR, depending on FV serostatus at baseline 
(eg, YF, Dengue and Zika viruses, as well as Japanese encephalitis [JE] virus in Asia), as well as 
the safety profiles. The persistence of the immune response over time, up to 5 years post-
vaccination, will be assessed yearly.  
VYF03 assessment will be based on immunogenicity and safety profiles of the vYF vaccine in 
comparison to Stamaril. 

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An Independent Data Monitoring Committee (IDMC) will be set up in the vYF program, 
including VYF03 and the non-inferiority studies of vYF compared to Stamaril or YF-VAX in 
adult and pediatric populations. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
Immunogenicity 
To demonstrate the non-inferiority of 
the antibody response in terms of 
seroconversion rates 28 days after 
vaccine administration of one dose of 
vYF (administered on D01) compared 
to the antibody response after one 
dose of the Stamaril control vaccine 
(administered on D01) in participants 
enrolled in EU in YF-naïve 
participants* 
 
 
Seroconversion rates will be assessed 28 days post-
vYF (administered on D01) and post-Stamaril 
(administered on D01) using a YF 
microneutralization (MN) assay in participants 
enrolled in EU 
Seroconversion is defined as a 4-fold increase in 
neutralizing antibody (NAb) titers as compared to the 
pre-vaccination value. 
With a nominal value of half LLOQ, ie,5 (1/dil), 
assigned to baseline YF seronegative participants, the 
seroconversion requires an increase to at least a titer 
of 20 (1/dil) on 28 day post-vaccination. 
Secondary 
 
Immunogenicity 
• 
To describe the antibody immune 
responses to YF in both vaccine 
groups in EU and in Asia before 
(D01) and after (D11 in a subset† of 
participants only, and D29, M6, and 
yearly from Y1 to Y5 in all 
participants) vYF or Stamaril 
administration 
 
 
 
Safety 
 
Seroconversion and seroprotection rates, GMT and 
GMTRs in all participants at various timepoints, 
based on YF antibody assessments using the YF MN 
assay for each group. 
 
Data will be analyzed depending on Flavivirus (FV) 
immune status at baseline (YF-naive and immune, 
FV-naïve and immune: Dengue serotypes 1-4 naïve 
and immune, Zika-naïve and immune, as well as for 
participants enrolled in Asia, JE-naïve and immune) 
Seroprotection is defined as NAb titers ≥ threshold of 
10 (1/dil) at the corresponding timepoint.  
 
• 
To describe the safety profile of vYF 
vaccine in all participants, in EU and 
in Asia, in comparison to the safety 
profile of the control Stamaril  
• 
Presence, nature (MedDRA preferred term), 
duration, intensity and relationship to vaccination 
of any unsolicited systemic adverse events (AEs) 
reported in the 30 minutes after vaccination 

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Objectives 
Endpoints 
• 
Presence, time to onset, number of days of 
presence, and intensity of solicited injection site 
reactions up to 7 days after vaccination 
• 
Presence, time to onset, number of days of 
presence, and intensity of solicited systemic 
reactions up to 14 days after vaccination 
• 
Presence, nature (MedDRA preferred term), time 
to onset, duration, intensity, and relationship to 
vaccination of unsolicited AEs up to 28 days 
after vaccination  
• 
Presence of any serious adverse events (SAEs) 
and AESIs, up to 6-months after vaccination 
• 
Presence of related SAEs and all deaths from 
D01 up to the 5 years after vaccination 
Exploratory 
 
• 
To describe the serological status of 
FV infection (dengue and Zika in all 
participants in EU and Asia; Japanese 
encephalitis [JE] in Asia) in the study 
population at baseline 
• 
NAb levels against FV infection (dengue and 
Zika in all participants in EU and Asia; JE in 
Asia) on a blood sample taken at baseline 
D: day; FV: flavivirus; GMT: geometric mean of titers; GMTR: geometric means of titer ratio; M: month; MedDRA: 
Medical Dictionary for Regulatory Activities; Y: year  
* YF-naïve participants (or negative) at baseline correspond to participants with no detectable YF antibody (Ab) titers 
before vaccination. YF seronegative at baseline is defined as a titer < LLOQ for the assay (any participant with a 
baseline titer ≥  LLOQ will be eliminated from the primary analysis [Per protocol analysis]). 
LLOQ determined as 10 (1/dil), also defined the threshold of protection. 
†A subset of the first 90 participants (60 participants in Group 1 and 30 participants in Group 2) enrolled in EU at 
some sites will provide an additional post-vaccination blood sample on D11 to assess the immune response elicited by 
both vaccines in terms of NAb titers. A subset of the first 60 participants of Chinese origin enrolled in Asia (40 
participants in Group 1 and 20 participants in Group 2) will provide an additional post-vaccination blood sample on 
D11 to assess the immune response elicited by both vaccines in terms of NAb titers. 
‡The following AESIs have been defined for this clinical development program based upon the prior experience with 
YF vaccines: 
• Serious hypersensitivity/allergic reactions  
• Organ failure/serious viscerotropic events  
• Serious neurologic events  
 
 

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Overall Design 
Type of design 
parallel, multi-center 
Phase 
II 
Control method 
active-controlled 
(control = Stamaril); 
Ratio vYF: Stamaril of 2:1 
Study population 
healthy adults 18-60 years of age 
Countries 
EU: France, Germany, Spain, Finland 
Asia: Singapore, Thailand 
Level and method of blinding 
observer-blind (modified double-blind)  
Study intervention assignment method 
randomization 
IDMC 
Yes 
Disclosure Statement: 
This is a parallel-group prevention study with 2 arms that is observer-blinded (participant and 
Investigator blinded). 
Number of Participants: 
A total of 690 participants are expected to be randomized in EU and Asia. 
A total of 570 participants are expected to be randomized for primary objectives in EU. 
• Group 1: vYF; N=380 in EU 
• Group 2: Stamaril; N=190 in EU 
A subset of the first 90 participants (60 participants in Group 1 and 30 participants in Group 2) 
enrolled in EU at selected sites will provide an additional post-vaccination blood sample on D11 
to assess the early immune response elicited by both vaccines in terms of NAb titers. 
An additional cohort of 120 participants of Chinese origin will be randomized and enrolled in 
Asiaa (outside of People’s Republic of China [PRC]) in a ratio 2:1 into 2 groups (80 participants 
in vYF group and 40 participants in Stamaril group). A subset of the first 60 participants of 
Chinese origin enrolled in selected sites in Asia (40 participants in Group 1 and 20 participants in 
Group 2) will provide an additional post-vaccination blood sample on D11 to assess the immune 
response elicited by both vaccines in terms of NAb titers. 
Intervention Groups and Duration: 
In each group, eligible participants (18-60 years of age) will be randomized in a 2:1 ratio to 
receive a single subcutaneous (SC) injection of either the vYF vaccine (380 participants in EU and 
80 participants of Chinese origin in Asia) or Stamaril (190 participants in EU and 40 participants 
                                                 
a Chinese population in Singapore and Thailand. 

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of Chinese origin in Asia), on D01. Non-inferiority of vYF compared to Stamaril will be assessed 
using results obtained from EU participants. 
The duration of each participant’s participation will be approximately 5 years. 
Data Monitoring Committee: Yes 
1.2 
Schema  
The graphical design of VYF03 study is presented in Figure 1.1. 
Figure 1.1 – Graphical study design  
 
1.3 
Schedule of Activities (SoA)  
Visit procedures are detailed in the Operating Guidelines. 
 
Time
Days (D), 
Months (M),
Years (Y)
BL
0001
BL
0003
BL
0004
BL
0005
BL
0006
BL
0007
BL
0008
BL
0009
Y5
Follow-up for 5 years 
D1
D11
D15
D29
M6
Y1
Y2
Y3
Y4
VAC
V2
V3
V4
V1
V5
V6
V7
V8
V9
V10
vYF(Group 1) or Stamaril (Group 2)  
(2:1 participant ratio)
YEAR 2
YEAR 3
YEAR 4
YEAR 5
YEAR 1
BL
0002
Only in a 
subset of 
participants
BL: Blood sample
V: Visit
VAC: Vaccination

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Table 1.1: Schedule of activities  
Phase II Study, 9 or 10 Visits, 1 Vaccination, 8 or 9* Blood Samples, 5-year Duration Per Participant  
Visit/Contact 
Collection of 
information in 
the CRF 
Visit 1 
Visit 2† 
Visit 3‡  
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Study timelines 
(days/months/ years) 
N/A 
D01 
D11 
D15 
D29 
6 M post 
visit 1 
1 Y post 
visit 1 
2 Y post 
visit 1 
3 Y post 
visit 1 
4 Y post 
visit 1 
5 Y post 
visit 1 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
criteria 
 
 
 
 
 
 
 
 
 
 
 
Collection of 
demographic data 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(if applicable)  
 
 
 
 
 
 
 
 
 
 
 
Collection of medical 
history 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination 
 
 
 
 
 
 
 
 
 
 
 
Partial /Targeted 
 
 
 
 
 
 
 
 
 
 
 
 
 
temperature 
 
 
 
 
 
 
 
 
 
 
 
Randomization/allocat
 
number 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling (BL) 
  
 
 
  
 
  
 
   
 
    
     
     
     
     
     
     

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Visit/Contact 
Collection of 
information in 
the CRF 
Visit 1 
Visit 2† 
Visit 3‡  
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Study timelines 
(days/months/ years) 
N/A 
D01 
D11 
D15 
D29 
6 M post 
visit 1 
1 Y post 
visit 1 
2 Y post 
visit 1 
3 Y post 
visit 1 
4 Y post 
visit 1 
5 Y post 
visit 1 
Time windows (days)  
N/A 
N/A 
+2 days 
+2 day 
+3 days 
±15 days 
±15 days 
±15 days 
±30 days 
±30 days 
±30 days 
 
 
 
 
 
 
 
 
 
 
 
 
Group 1: vYF  
 
 
 
 
 
 
 
 
 
 
 
Group 2: Stamaril  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memory Aid (MA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
medically attended 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit/Contact 
Collection of 
information in 
the CRF 
Visit 1 
Visit 2† 
Visit 3‡  
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Study timelines 
(days/months/ years) 
N/A 
D01 
D11 
D15 
D29 
6 M post 
visit 1 
1 Y post 
visit 1 
2 Y post 
visit 1 
3 Y post 
visit 1 
4 Y post 
visit 1 
5 Y post 
visit 1 
Time windows (days)  
N/A 
N/A 
+2 days 
+2 day 
+3 days 
±15 days 
±15 days 
±15 days 
±30 days 
±30 days 
±30 days 
 
 
 
 
 
pregnancies 
 
 
 
 
 
 
 
 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; AESI: adverse events of special interest, BL: blood sampling; CRF: case report form; D: day; DC: diary card; M: month; MA: memory aid; Min: minutes; mL: 
milliliter; N/A: not applicable; Pre-vac: pre-vaccination; SAE: serious adverse event; Vac: vaccination 
  
† Visit 2 to be performed only for the subset of participants submitted to an additional immunogenicity test at D11 
‡ Visit 3 can be replaced by a phone call only in case the visit cannot be performed at Investigational site (in this case, the physical examination will not be performed) 
§ In case of participant discontinuation at a visit, the entire visit will be completed 
**For the entire study period, collection of vaccination with commercial YF vaccine and use of any investigational or non-registered product (drug, vaccine or medical device). Up to 
Visit 4, collection of concomitant medication. 
‡‡Only for pregnancies with estimated conception date within the 28 days before or after study vaccination 
†† HIV/Hepatitis B/Hepatitis C serology testing at baseline (Visit 1) will be optional depending on local regulatory requirements. 
 
 
 
 

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Table 1.2: Blood samples collection per visit and participant  
 
mL 
Tests 
Immunogenicity 
10.0 
NAb titers 
Sero status 
10.0 
Pre-existing FV NAb titers 
FV: flavivirus; mL: milliliter; NAb: neutralizing antibody 
2 
Introduction  
Yellow fever (YF) is a mosquito-borne hemorrhagic disease caused by a single-stranded positive 
ribonucleic acid (RNA) virus belonging to the genus flavivirus (FV). The virus causes a 
hemorrhagic fever, systemic illness characterized by high viremia, and a wide spectrum of clinical 
signs, ranging from mild symptoms to severe illness (including hepatic, renal and myocardial 
injury, and hemorrhage) with high lethality. YF is widespread in sub-Saharan Africa and tropical 
South America and continues to be a significant health problem to residents of endemic countries 
and non-vaccinated domestic and international travelers entering endemic areas. 
Approximately 200 000 YF-associated cases and 60 000 YF-associated deaths have been 
estimated to occur worldwide each year (1). The case-fatality ratio of severe YF varies widely in 
different studies but is typically 20% or higher (2). Jaundice or other gross evidence of severe 
liver disease is associated with higher mortality rates (3). The incidence rate of YF cases has not 
decreased over the last decade and resurgence continues with geographical expansion. For a two-
week stay, the estimated risks for illness and death due to YF for an unvaccinated traveler to West 
Africa is 50 cases per 100 000 and 10 cases per 100 000, respectively, and to South America is 5 
cases per 100 000 and 1 case per 100 000, respectively. From 1970 through 2013, a total of 11 
cases of YF were reported in unvaccinated travelers from the USA and EU who traveled to West 
Africa (6 cases) or South America (5 cases); 8 (73%) of these 11 travelers died (4). 
There is no specific treatment for YF; however, medicines can be used to relieve the symptoms 
and may improve the outcome for seriously ill patients. 
Outbreaks occur regularly, and the disease progresses quickly, as one infected individual can lead 
to infection of 7 other individuals. 
Recent outbreaks in Africa were reported in Angola and Democratic Republic of Congo (DRC) in 
2016. The outbreak in Angola started in December 2015, peaked in February 2016, and continued 
until June 2016 (largest outbreak since 1971), with 4 347 suspected cases and 377 deaths. 
Multiple vaccination campaigns required 20 million doses, leading to a problem of vaccine supply 
and demand. Moreover, there were outbreaks in other countries due to movement of virus-infected 
travelers, and imported cases were reported in DRC, Mauritania, Kenya, and China (infected 
Chinese workers returning from Angola) (5); it was estimated that there should be 2 800 suspected 
cases, requiring a further 9.4 million doses. 

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A recent outbreak in Brazil was composed of 2 waves of transmission, one during the 2016-2017 
seasonal period, with 778 human cases, including 262 deaths, and another during the 2017-2018 
seasonal period, with 1 376 human cases, including 483 deaths (6). 
Human cases reported during the 2018-2019 seasonal period in 4 municipalities in Sao Paulo 
State, as well as the confirmation of epizootics in the state of Parana, mark the beginning of what 
could be a third cycle and a progression of the outbreak towards the Southeast and South regions 
of the country. The government of Brazil, with the support of the Pan American Health 
Organization/World Health Organization (WHO) is working to ensure the protection of its 
population and to prevent further spread of the YF virus. Brazil is carrying out vaccination 
campaigns for YF in several states, while strengthening surveillance and case management 
throughout the country. The number of areas with recommended vaccination has increased from 
3 526 municipalities in 2010 to 4 469 municipalities in 2018, and the entire country starting in 
2019. In line with the WHO guidelines, Brazil has adopted a single dose vaccination scheme for 
YF since April 2017 (6). From 2020, a booster dose at 4 years of age was implemented in the 
National Immunization Calendar of Brazil for infants who received their first dose at 9 months old 
(7).  
The number of cases reported during 2017-2018 in the region of the Americas exceeded the 
number reported in several decades. In South America, besides Brazil, 6 other countries reported 
confirmed cases of YF: Bolivia, Colombia, Ecuador, French Guiana, Surinam and Peru (8). In 
Peru, between epidemiological week 1 and 52 of 2018, there were 20 cases of YF reported, 
including 6 deaths. Among the 20 cases, 12 were laboratory-confirmed. This figure is higher than 
the one reported during the same period in 2017, when 10 cases of YF were confirmed (6). 
YF cases were for the first time reported in China in April 2016: 11 laboratory-confirmed cases 
had been imported into China (including 6 in Fujian Province, the area where dengue transmission 
has occurred); 6 of the cases were fatal (9). The YF cases reported in China suggest that not all 
travelers were effectively vaccinated despite Chinese public health regulations. With a large 
expatriate Chinese community (approximately 20 000) in Angola, additional undetected cases 
may likely have been imported.  
No drug has demonstrated specific benefit to treat YF disease; therefore, the management of the 
disease is supportive and based on symptoms and the organ systems affected. However, YF is a 
vaccine-preventable disease, and the occurrence of outbreaks shows that maintaining regular 
vaccine stockpiles is necessary to fight the disease. Each year, 6 million doses of YF vaccine are 
maintained by WHO and partners in a global stockpile that can be used for outbreak response at 
the request of countries with inadequate vaccine supply; in contrast, the recent outbreaks in 
Angola and DRC used approximately 30 million doses and depleted the stockpile multiple times 
during 2016 (10). 
Worldwide, there are several YF vaccines currently in use, all based on live-attenuated strains 
derived from the 17D attenuated strain and produced in embryonated eggs. Two of them, YF-
VAX (Sanofi Pasteur Inc., Swiftwater, Pennsylvania) and Stamaril® (Sanofi Pasteur, France) are 
produced by Sanofi Pasteur and indicated for individuals from 9 months of age for active 
immunization against YF disease. Moreover, Stamaril is WHO prequalified, as are some of the 
other licensed YF vaccines. 

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Both YF-VAX and Stamaril are live-attenuated vaccines derived from strain 17D-204, a higher 
passage of the 17D strain. YF-VAX is the only YF vaccine licensed in the USA by the USA Food 
and Drug Administration (FDA), and is used for military and civilian travelers. 
 
stock-out period in 2017 and Sanofi Pasteur, as an initial response, applied for a Stamaril 
FDA allowed for the importation and distribution of Stamaril in the USA to specific vaccination 
 (11). 
For most healthy individuals, a single dose of a live-attenuated YF vaccine provides long-lasting 
protection. In May 2014, the WHO World Health Assembly adopted an amendment which 
stipulated that the period of protection by YF vaccination and the term of validity of the certificate 
will change from 10 years to the duration of a person’s life. This amendment became effective in 
June 2016. On 26 February 2015, the Advisory Committee on Immunization Practices voted that a 
single primary dose of YF vaccine provides long-lasting protection and is adequate for most 
travelers. To comply with WHO International Health Regulations (IHRs) and to be officially 
recognized, YF vaccines must be administered by Health Care Providers (HCPs) certified to 
administer YF vaccine and validate the ICVP for YF vaccination.  
Despite the advances in immunization activities, challenges remain in controlling epidemics due 
to the management of global vaccine supply, including an emergency stockpile and the control of 
outbreaks. The low yields of manufacturing processes are responsible for this situation and make 
YF vaccines still an unmet public health need in case of large outbreaks. 
YF is also a viral hemorrhagic fever that perpetually threatens US military forces, Department of 
Defense (DoD) civilians and military dependents traveling or deploying to endemic regions such 
as Sub-Saharan Africa, South America, and the Caribbean. Additionally, large parts of Southeast 
Asia, the Middle East, North Africa and even North America including the southern United States 
are at risk for YF outbreaks given the widespread prevalence of the Aedes mosquito vector for the 
YF virus. 600 million people live in endemic areas and more than 2 billion are at potential risk for 
an emergent outbreak of the disease. Thus, deployed military forces, dependents and civilians are 
at risk in any area of responsibility.  
Recent epidemics coupled with manufacturing delays have caused an unprecedented global 
shortage of YF-VAX, prompting the use of Stamaril as an alternative. In addition, expected 
outbreaks might exacerbate the shortage of YF vaccine. The current study seeks to evaluate the 
next-generation vaccine developed and produced in a manner that would obviate manufacturing 
delays and, hence, improve the reliable accessibility to YF vaccine in a Public Health perspective. 
A safe and efficacious YF vaccine, produced with significantly higher yields than the current 
ones, to enable the continuation of immunization programs and to provide protection for 
populations residing in YF endemic or epidemic regions and travelers who will spend time in 
these areas, is therefore required. The development of a high-quality new YF vaccine, 
manufactured with high yields in extensively characterized Vero cells in the absence of animal 
serum, and purified and controlled in conformance with international Good Manufacturing 
Practice standards, represents an advantage over other currently available vaccines produced in 
embryonated eggs. 

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2.1 
Study Rationale  
A first study, VYF01, aiming to assess the safety, viremia and immune responses of 3 dosages of 
vYF, compared to YF-VAX, as a control vaccine, is ongoing in the USA. A second planned study, 
VYF02, aims to assess the non-inferiority of the immune response of the investigational vaccine 
candidate vYF to the licensed YF-VAX vaccine in adults in the USA. 
The proposed third study, VYF03, is a Phase II, randomized, observer-blind, active-controlled 
(Stamaril) study to assess the non-inferiority of the immune response, in terms of seroconversion 
rates, of the investigational vaccine candidate vYF to the licensed Stamaril, in adults aged 18 
years up to 60 years in EU. The safety and immunogenicity profile of vYF in a cohort of 
participants of Chinese origin living in Asia will also be presented. The study will also assess the 
immunogenicity profiles (seroprotection, GMT and GMTR) and the safety profiles of vYF and 
Stamaril.  
In EU, it is planned to enroll 570 participants into 2 groups in a 2:1 ratio: 380 participants will be 
administered vYF and 190 participants will be administered Stamaril on D01. In Asia, it is 
planned to enroll 120 participants also distributed into 2 groups in a 2:1 ratio: 80 participants will 
be administered vYF and 40 participants will be administered Stamaril on D01. 
The persistence of the immune response over time, up to 5 years post-vaccination, will be 
assessed yearly. 
VYF03 assessment will be based on immunogenicity and safety profiles of the vYF vaccine in 
comparison to Stamaril, which is the current YF vaccine licensed in more than 100 countries 
(except USA, Canada, and Japan). 
The YF neutralizing antibody titers will be determined in a microneutralization (MN) assay that 
was developed by Sanofi Pasteur and currently in use in VYF01. An interim analysis on the first 
37 randomized participants (36 of them vaccinated with either vYF 4 Log CCID50/dose, 5 Log 
CCID50/dose, 6 Log CCID50/dose, or YF-VAX) shows that GMTs well above the threshold of 
protection (10, 1/dil) were observed in all vaccine groups on D28 post vaccine administration 
(Per-Protocol analysis in YF-naïve populationa) and that 100% of YF-naïve participants 
seroconvertedb and were seroprotected on D28. The satisfactory safety profile of all vYF dosage 
groups and the measurement of quantified viremia over time from D01 to D15 completed the 
interim analysis. Therefore, the dosage of 5 Log CCID50/dose is deemed appropriate for the next 
phases of the clinical development of vYF, starting with VYF02, which is the first non-inferiority 
study in adults. 
VYF03 is designed to assess the immune response and the maintenance of the antibody titers over 
time, up to 5-years post vaccine administration as the existing YF vaccines are well known for 
inducing a long-lasting immunity. In addition, a subset of participants will be assessed on D11 to 
describe the early immune response induced in the 2 vaccine groups. 
                                                 
a YF-naïve population, or YF negative population, corresponds to participants with no pre-existing (ie, no detectable 
as below LLOQ equal to 10 (1/dil) which also defines the threshold for protection) Ab titers. Those participants 
are given a value equal to half LLOQ, ie, 5 (1/dil). 
b In VYF01, seroconversion is achieved for a 4-fold increase as compared to pre-vaccination value; and in YF-naïve 
participants seroconversion is achieved for a value equal or greater than 40 (1/dil). 

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The AESIs that are considered for the development of vYF were defined based on the knowledge 
of those associated to existing YF vaccines licensed by Sanofi Pasteur (YF-VAX and Stamaril):  
• Serious hypersensitivity/allergic reactions  
• Organ failure/serious viscerotropic events 
• Serious neurologic events 
2.2 
Background  
As with the existing licensed YF vaccines, the new vYF vaccine is a live-attenuated vaccine 
derived from the wild-type Asibi strain. It is being developed as an alternative to the egg-based 
vaccines, as it is manufactured in extensively characterized Vero cells, in the absence of animal 
serum, hence potentially also increasing vaccine safety.  
Therefore, it should facilitate the management of YF vaccine outbreaks and epidemics which is 
challenging due to limited amounts of YF vaccine stock. The development of a new attenuated 
live vYF vaccine, manufactured in extensively characterized Vero cells represents major progress. 
The safety, immunogenicity and clinical efficacy of this new vaccine is planned to be compared to 
the Sanofi Pasteur licensed Stamaril YF vaccine, and VYF03 is the first non-inferiority study in 
adult populations in EU.   
2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events (AEs), the potential risks, and uncertainties of vYF vaccine candidate vaccine may 
be found in the Investigator’s Brochure (IB).  
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: vYF 
The following AESIs have been 
defined for this clinical 
development program based 
upon the prior experience with 
YF vaccines: 
 
 
 
 
 
 
 
 
Serious hypersensitivity/allergic 
reactions (eg anaphylaxis) 
 
 
All vaccines have the potential 
to cause allergic reactions or 
anaphylaxis in individuals 
who may be sensitized to 
components of the vaccine. 
 
Exclusion criteria E07 (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)  
30-minute observation period after 
vaccination for early detection and 
treatment 
 
Organ failure/serious 
viscerotropic events (YF 
vaccine-associated viscerotropic 
disease |YEL-AVD]) 
Serious neurologic events (YF 
vaccine-associated neurotropic 
disease |YEL-AND]) 
YEL-AVD and YEL-AND are 
theoretical risks for the studied 
vaccine, according to preclinical 
tests. 
 
Serious AE related to YF 
vaccines are YEL-AVD and 
YEL-AND. They are very rare 
and thus unlikely to be seen in 
the setting of a clinical trial. 
 
Exclusion criteria E10 (personal or 
family history of thymic pathology 
[thymoma, thymectomy, or 
myasthenia]) for those at increased 
risk.  
Observation period of 28 days after 
vaccination for early detection and 
treatment. 
Addressed in the “Operating 
Guidelines for Assessing 
Viscerotropic and Neurotropic 
AEs” in studies using YF vaccines 
(standalone guidance provided to 
the Investigational sites before the 
start of the study). 
 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
Comparator: Stamaril 
Severe allergic reactions (eg, 
anaphylaxis) may occur 
following the use of Stamaril, 
even in individuals with no prior 
history of hypersensitivity to the 
vaccine components.  
 
Identified and potential risks 
observed in post-marketing 
surveillance. 
 
Exclusion criteria E07 (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)  
Stamaril is contraindicated in 
anyone with a history of acute 
hypersensitivity reaction to any 
component of the vaccine, in 
infants less than 9 months of age 
due to an increased risk of 
encephalitis, in individuals with 
severe immunosuppression 
Exclusion/inclusion criteria take in 
account contraindications, 
warnings and precautions as 
defined in product label. See 
Section 5 of this document. 
30-minute observation period after 
vaccination for early detection and 
treatment.  
 
Organ failure/serious 
viscerotropic events (YEL-
AVD) 
Serious neurologic events (YEL-
AND) 
There is an increased risk of 
severe systemic adverse 
reactions to Stamaril in 
individuals 60 years of age and 
older and in 
immunocompromised 
individuals. 
 
Serious AE related to YF 
vaccines are YEL-AVD and 
YEL-AND. They are very rare 
and thus unlikely to be seen in 
the setting of a clinical trial. 
Refer to the IB Section 6 for 
more information regarding 
the data from previous 
experience 
Exclusion criterion E10 (Personal 
or family history of thymic 
pathology (thymoma, thymectomy, 
or myasthenia]) for those at 
increased risk. 
Observation period within 28 days 
after vaccination for early detection 
and treatment. 
 
Inclusion criteria I01 state the 
upper limit of age up 60 years on 
the day of inclusiona 
Exclusion criterion E05 (Known or 
suspected congenital or acquired 
immunodeficiency; or receipt of 
immunosuppressive therapy) 
Addressed in: 
                                                 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
-IB (administration precautions, 
potential adverse events), defined 
AESI in the trial. 
 “Operating Guidelines for 
Assessing Viscerotropic and 
Neurotropic Adverse Events in 
studies using YF vaccines” 
(standalone guidance provided to 
the Investigational sites before the 
start of the study) 
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 
30-minute observation period after 
vaccination for early detection and 
treatment 
2.3.2 
Benefits from Study Participation  
This study is experimental research and there is no guarantee that participants enrolled in VYF03 
will get any benefit. 
vYF is a next-generation live-attenuated YF vaccine produced on serum-free Vero cells without 
any component of animal origin. vYF has been developed to induce a life-long immunity against 
YF and to be at least as immunogenic as other licensed YF-17D vaccines and well-tolerated. 
Participants enrolled in VYF03 will be followed up yearly up to 5 years post vaccine 
administration to assess the maintenance over time of the immune response. 
It is expected that participants enrolled in VYF03 will be protected against YF, which means that 
both the new investigational vaccine as well as the current licensed Stamaril vaccine, elicit a safe, 
protecting, and long-lasting immune response. 
International Certificate of Vaccination or Prophylaxis for YF Vaccination 
At the end of the first interim analysis and at the end of the study, the Investigators will be 
provided with individual listings detailing for each participant the vaccine group assignment and 
the neutralizing antibody titers at the successive time points. Participants are responsible for 

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contacting the study site to obtain this information about which study group they were assigned to 
and which vaccine they received. 
Those participants enrolled in the Stamaril group can be provided by the investigational site with 
the ICVP for YF vaccination; and those participants enrolled in a vYF group would be informed 
that they need to obtain a licensed YF vaccine prior to travel to endemic areas. 
2.3.3 
Overall Benefit-Risk Conclusion  
Vaccination is the most effective preventive measure against YF infection. The important 
potential risks for vYF are those currently described for YF-VAX and Stamaril: anaphylaxis, 
YEL-AVD and YEL-AND. However, data from nonclinical studies suggest that the risk of 
occurrence of YEL-AVD and YEL-AND following vYF administration is theoretical. These 
potential and theoretical risks will be specifically monitored during the VYF03 study and 
addressed through pharmacovigilance activities. 
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. 
3 
Objectives and Endpoints  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
Immunogenicity 
• 
To demonstrate the non-inferiority of 
the antibody response in terms of 
seroconversion rates 28 days after 
vaccine administration of one dose of 
vYF (administered on D01) compared 
to the antibody response after one 
dose of the Stamaril control vaccine 
(administered on D01) in in YF-naïve 
participants enrolled in EU* 
 
Seroconversion rates will be assessed 28 days post-
vYF (administered on D01) and post-Stamaril 
(administered on D01) using a YF 
microneutralization (MN) assay in participants 
enrolled in EU 
Seroconversion is defined as a 4-fold increase in NAb 
titers as compared to the pre-vaccination value. 
 
With a nominal value of half LLOQ, ie, 5 (1/dil), 
assigned to baseline YF seronegative participants, the 
seroconversion requires an increase to at least a titer 
of 20 (1/dil) on 28 day post-vaccination. 

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Objectives 
Endpoints 
Secondary 
 
Immunogenicity 
To describe the antibody immune 
responses to YF in both vaccine groups 
before (D01) and after vYF or Stamaril 
administration, on D11 (in a subset† of 
participants only), D29, M6, and yearly 
from Y1 to Y5 in all participants  
 
YF antibody assessments will be performed using YF 
MN assay as follows for each group: 
NAb titers at D01, D11 (subset only†), D29, M6, and 
yearly from Y1 to Y5 
Derived endpoints are: 
Seroconversion rates at D11 (subset only†) and D29, 
M6, and yearly from Y1 to Y5 
Seroconversion is defined as a 4-fold increase in NAb 
titers: i) as compared to the D01 titers at each time 
point up to M6; ii) as compared to the last planned 
previous time point from Y1 onwards  
Seroprotection rates based on participants with 
antibody titers ≥ 10 (1/dil) at baseline (D01) and at 
D11 (subset only†), D29, M6, and yearly from Y1 to 
Y5 
• Geometric means of the individual titer ratios 
(GMTRs) for D11/D01 (subset only†), D29/D01, 
M6/D01 and yearly ratios.  
The corresponding parameters are seroconversion 
rate, seroprotection rate, GMT, and GMTR. 
Data will be analyzed depending on FV immune 
status at baseline (FV-naïve and immune: YF-naïve 
and immune, Dengue serotypes 1-4 naïve and 
immune, Zika-naïve and immune, and JE-naïve and 
immune in participants enrolled in Asia). 
 
Safety 
To describe the safety profile of the vYF 
vaccine in comparison to the safety 
profile of the control Stamaril 
To describe the safety of vaccination in 
all participants up to 28 days after 
vaccination 
To describe all serious adverse events 
(SAEs) up to 6-month follow-up   
To describe related SAEs and all deaths 
from D01 to 5 years after vaccination 
To describe all AESIs up to 6-month after 
vaccination‡ 
 
• 
Presence, nature (Medical Dictionary for 
Regulatory Activities [MedDRA] preferred 
term), duration, intensity and relationship to 
vaccination of any unsolicited systemic AEs 
reported in the 30 minutes after vaccination 
• 
Presence, time to onset, number of days of 
presence, and intensity of solicited (pre-listed in 
the participant’s diary and electronic case report 
form [eCRF]) injection site reactions up to 7 days 
after vaccination solicited  
• 
Presence, time to onset, number of days of 
presence, and intensity of solicited systemic 
reactions up to 14 days after vaccination 
• 
Presence, nature (MedDRA preferred term), time 
to onset, duration, intensity, and relationship to 
vaccination (for systemic AEs only) of 
unsolicited (spontaneously reported) AEs up to 
28 days after vaccination 

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Objectives 
Endpoints 
• 
Presence of any SAEs and AESIs, up to 6-month 
after vaccination 
• 
Presence of related SAEs and all deaths from 
D01 to 5 years after vaccination 
Exploratory 
 
To describe the serological status of FV 
infection (dengue and Zika in all 
participants in EU and Asia; JE in Asia) 
in the study population at baseline 
• 
NAb levels against FV infection (dengue and 
Zika in all participants in EU and Asia; JE in 
Asia) on a blood sample taken at baseline 
AESI: adverse event of special interest; D: day; eCRF: electronic case report form; FV: flavivirus; GMT: geometric 
means of titers; GMTR: geometric means of titer ratios; M: month; MN; microneutralization; NAb: neutralizing 
antibody; Y: year 
* YF-naïve participants (or negative) at baseline correspond to participants with no detectable YF antibody (Ab) titers 
before vaccination. YF seronegative at baseline is defined as a titer < LLOQ for the assay (any participant with a 
baseline titer ≥  LLOQ will be eliminated from the primary analysis [Per-protocol analysis]). 
LLOQ determined as 10 (1/dil), also defined the threshold of protection. 
‡ The following AESIs have been defined for this clinical development program based upon the prior experience with 
YF vaccines: 
• Serious hypersensitivity/allergic reactions  
• Organ failure/serious viscerotropic events 
• Serious neurologic events 
†A subset of the first 90 participants (60 participants in Group 1 and 30 participants in Group 2) enrolled in EU at 
some sites will provide an additional post-vaccination blood sample on D11 to assess the immune response elicited by 
both vaccines in terms of NAb titers. A subset of the first 60 participants enrolled at some sites in Asia (40 
participants in Group 1 and 20 participants in Group 2) will provide an additional post-vaccination blood sample on 
D11 to assess the immune response elicited by both vaccines in terms of NAb titers 
4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 

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Table 4.1: Overall design  
Type of design 
parallel, multi-center 
Phase 
II 
Control method 
active-controlled (control = Stamaril) 
ratio 2:1 
Study population 
healthy adults aged 18 to 60 years* 
Level and method of blinding 
observer-blind (modified double-blind) 
Study intervention assignment method 
randomization 
Number of participants 
570 participants in EU and 120 participants in Asia 
Intervention groups 
In each group, randomization to receive either the 
vYF vaccine candidate or the Stamaril vaccine, in a 
2:1 ratio 
Total duration of study participation 
approximately 5 years 
Countries 
EU: France, Germany, Spain, Finland 
Asia: Singapore, Thailand 
Use of an Independent Data Monitoring 
Committee 
YES (IDMC), see Section 9.6 
*“18 to 60 years” means from the day of the 18th birthday up to the day before the 60th birthday 
4.2 
Scientific Rationale for Study Design  
The proposed study VYF03 is a Phase II, randomized, observer-blind, active-controlled (Stamaril) 
study to assess the non-inferiority of the immune response, in terms of seroconversion rates, of the 
investigational vaccine candidate vYF at the selected dose of 5 Log CCID50/dose, to the licensed 
Stamaril in adults aged 18 years up to 60 years in Europe; and to describe the immune responses 
in participants enrolled in Asia. The study will also assess the immunogenicity profiles (GMTs 
and GMTRs) and the safety profiles of vYF and Stamaril. It is planned to enroll 690 participants 
in EU and Asia, distributed in 2 groups with a 2:1 ratio: 460 participants will be administered with 
vYF and 230 participants will be administered with Stamaril, on D01. 
Stamaril, used in the control arm, is the YF vaccine licensed in the over 100 countries, including 
the countries involved in this study. 
The study design is aligned with the WHO Technical Report Series recommendations (WHO 
TRS) (12) stating that the demonstration of an immune response to YF vaccination should be 
based on the measurement of neutralizing antibody titers both pre- and post-vaccination. The 
WHO TRS states in section C.2.1 that ‘Geometric mean titers (GMTs), seroconversion rates and 
reverse cumulative distributions (RCDs) should be provided. Seroconversion may be defined as 
either a fourfold increase in neutralizing antibody or the induction of measurable neutralizing 
antibody in a previously seronegative individual’. Therefore, the choice of the seroconversion 
rates for assessing the non-inferiority in studies carried out in adult and pediatric populations is 
appropriate. 

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Only adults aged 18 to 60 years will be enrolled, as those over 60 years of age are at a higher risk 
of developing YEL-AVD or YEL-AND.  
The number of participants in each group was defined based on statistical considerations for 
immunogenicity and safety (see Section 9.2). Primary analyses will be performed in YF-naïve 
population in EU (Per-Protocol Analyses Set). The objective is to demonstrate that the humoral 
response (in terms of seroconversion) of vYF (Group 1) is non-inferior to Stamaril (Group 2) 28 
days after a single dose in the YF-naïve participants in EU.  
A subset of the first 90 participants (60 participants in Group 1 and 30 participants in Group 2) 
enrolled in a selected sites in EU will provide an additional post-vaccination blood sample at D11 
to assess the immune response elicited by both vaccines in terms of NAb titers. 
As YF cases were reported in China in April 2016 in Chinese workers back from Africa, the 
immunogenicity and safety of vYF will be presented in a cohort of participants of Chinese origin 
living in Asia. A total of 120 participants of Chinese origin will be randomized and enrolled in 
Asiaa (outside of People’s Republic of China [PRC]) in a ratio 2:1, in 2 groups (80 participants in 
vYF group and 40 participants in Stamaril group). A subset of the first 60 participants enrolled in 
Asia (40 participants in Group 1 and 20 participants in Group 2) will provide an additional post-
vaccination blood sample on D11 to assess the immune response elicited by both vaccines in 
terms of NAb titers.  
Since participants will not be screened for a history of prior FV infection or vaccination, it is 
likely that some participants will have evidence of past FV infection or vaccination by the 
assessment of FV serostatus at baseline. Given the small numbers of FV-experienced individuals 
expected in EU settings, the absence of any safety concern for FV-seropositive individuals 
receiving the investigational vaccination and the infeasibility of performing virus neutralization 
tests at Investigator sites for participant recruitment, the assessment at baseline of FV serostatus 
will not be used as a criterion for study eligibility. FV- or YF-seropositive participants will 
therefore not be excluded from the study and seroconversion will be evaluated in this population 
as a secondary objective.  
In addition, for the purpose of assessing the impact on immunogenicity, neutralizing antibody 
titers against a panel of epidemiologically important and immunologically relevant FVs (such as 
Zika virus, dengue serotypes 1-4 viruses in all participants, or Japanese Encephalitis virus [JEV] 
only in Asian participants) will be measured on baseline sera, prior to vaccination, for the analysis 
of the immune response based on serostatus at baseline. 
As a secondary objective for this Phase II study, safety of the new vYF vaccine candidate will 
also be described. 
As a consequence, a total of 690 participants in EU and Asia (460 participants in Group 1 [vYF] 
and 230 participants in Group 2 [Stamaril]) will be enrolled. 
                                                 
a Chinese population in Singapore and Thailand  

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4.3 
Justification for Dose  
The vYF dose selected for this study is of 5 Log CCID50/dose, based on preclinical 
immunogenicity and toxicity study results and the safety, viremia and immunogenicity data 
generated in the first-in-human VYF01 study. 
4.4 
End of Study Definition  
A participant is considered to have completed the study if he/she has completed the last visit 
planned in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized.  
All participants enrolled in this study will be followed up for 5 years after vaccine administration. 
They will be kept in the study (and so, will not be withdrawn) even if they fail to come to one or 
more of the yearly visits during the 5-year follow-up. 
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 the following criteria are met: 
I01: 
Aged 18 years up to 60 years on the day of inclusiona 
I02: 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions applies: 
• 
Is of non-childbearing potential. To be considered of non-childbearing potential, a 
female must be postmenopausal for at least 1 year, or surgically sterile 
OR 
• 
Is of childbearing potential and agrees to use an effective contraceptive methodb 
or abstinenced from at least 4 weeks prior to study intervention administration 
until at least 4 weeksc after study intervention administration.  
                                                 
a “18 to 60 years” means from the day of the 18th birthday up to the day before the 60th birthday 
b Not applicable for Finland, see Appendix 10.4 
c Except for French participants which have to apply at least 12 weeks contraception after study intervention 
administration 
 

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A female participant of childbearing potential must have a negative highly 
sensitive pregnancy test (urine or serum as required by local regulation) before 
any dose of study intervention on Day 1 and the test will be repeated on D29 to 
confirm the participant is still not pregnant within 28 days of vaccine 
administration. 
I03: 
Informed consent form has been signed and dateda  
I04: 
Able to attend all scheduled visits and to comply with all study procedures  
I05: 
For participants enrolled in Asian countries as part of the additional cohort only: 
known Chinese origin, defined as having at least one biological parent of Chinese 
origin, and will be self-reported by the participant  
5.2 
Exclusion Criteria  
Potential participants will be recruited from a pool of volunteers who meet site-specific screening 
requirements.  
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 4 weeks preceding the study 
vaccination) or planned participation during the first 2 years of the 5-year follow-up in 
another clinical study investigating a vaccine, drug, medical device, or medical 
procedure. Enrollment in another study after the first 2 years is permitted, assuming 
that it does not exclude participation in this study. 
E02: 
Receipt of any vaccine in the 4 weeks preceding the study vaccination or planned 
receipt of any vaccine in the 4 weeks following the study vaccination (prior to visit 4), 
except for influenza vaccination, which may be received at least 2 weeks before study 
vaccinesb. This exception includes all influenza vaccines including monovalent 
pandemic influenza vaccines.  
E03: 
Previous vaccination against a FV diseasec at any time, including YF with either the 
study vaccine or another vaccine. 
E04: 
Receipt of immune globulins, blood, or blood-derived products in the past 6 months. 
E05: 
Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy, or radiation therapy, 
within the preceding 6 months; or long-term systemic corticosteroid therapy 
(prednisone or equivalent for more than 2 consecutive weeks within the past 3 
months). 
                                                 
a for participants aged less than 21 years in Singapore, an informed consent form has been signed and dated by both 
the participant and the parent(s) or another legally acceptable representative  
b Except for Thai participants, see Appendix 10.5  
c eg, Dengue vaccine, Japanese encephalitis vaccine, Tick borne encephalitis virus (TBE) vaccine, YF vaccine 
 

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E06: 
Known history of any FV infectionh. 
E07: 
Known systemic hypersensitivity to any of the vaccine components, eggs, or history 
of a life-threatening reaction to the vaccines used in the study or to a vaccine 
containing any of the same substancesa. 
E08: 
Known history or laboratory evidence of HIV infectionb 
E09: 
Known history or laboratory evidence of hepatitis B or hepatitis C infectionc 
E10: 
Personal or family history of thymic pathology (thymoma, thymectomy, or 
myasthenia). 
E11: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily. 
E12: 
Alcohol, prescription drug, or substance abuse that, in the opinion of the Investigator, 
might interfere with the study conduct or completion. 
E13: 
Chronic illness that, in the opinion of the Investigator, is at a stage where it might 
interfere with trial conduct or completiond, including malignancy, such as leukemia, or 
lymphoma. 
E14: 
Moderate or severe acute illness/infection (according to Investigator judgment) on the 
day of vaccination or febrile illness (temperature ≥ 100.4°F or 38°C). A prospective 
participant should not be included in the study until the condition has resolved or the 
febrile event has subsided. 
E15: 
Administration of any anti-viral within 2 months preceding the vaccination and 
planned administration up to the 6 weeks following the vaccination. 
E16: 
Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (ie, 
parent, spouse, natural or adopted child) of the Investigator or employee with direct 
involvement in the proposed study. 
E17: 
Planned travel in a YF endemic country within 6 months of investigational or control 
vaccine administration. 
If the participant has a primary physician who is not the Investigator, the site may contact this 
physician with the participant’s consent to inform him/her of the participant’s participation in the 
                                                 
a 
The Study Interventions are listed in Table 6.1 and the components of the study intervention in the Investigator 
Brochure 
b  HIV Serology testing will be performed on all German participants if no evidence of seronegativity in the 90 days 
preceding vaccination 
c  Hepatitis B and Hepatitis C Serology testing will be performed on all German participants if no evidence of 
seronegativity in the 90 days preceding vaccination 
d 
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. 
There is no screening period in this study. However, in case of an eligibility criterion requiring 
specific procedures before enrolment of the participant in the study, or moderate or severe acute 
illness/infection or febrile illness (temperature ≥ 100.4°F or 38.0°C) on the day of vaccination, the 
enrolment can be postponed until the additional information is available or the condition is 
resolved. 
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. 
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. 

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Table 6.1: Identity of study interventions  
Intervention 
Name 
vYF  
Stamaril 
Use 
Investigational product  
Licensed Active comparator 
IMP and 
NIMP 
IMP 
IMP 
Type  
Vaccine 
Vaccine 
Dose 
Formulation 
Powder and diluent for suspension 
for injection 
Powder and diluent for suspension 
for injection 
Unit Dose Strength 
Each single dose of 0.5 mL contains 
5 Log CCID50/dose of lyophilized 
vYF-247 attenuated strain of YF 
virus 
Each single dose of 0.5 mL contains 
at least 1000 IU of 17D-204 
attenuated strain of YF virus 
Excipients/Diluent 
Diluent for reconstitution: sterile 
0.4% sodium chloride solution 
Diluent for reconstitution: sterile 
sodium chloride solution 
Dosage Levels 
0.5 mL per dose 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
1 dose at D01 
1 dose at D01 
Route of 
Administration 
SC injection 
SC injection 
Site of 
Administration 
Deltoid area in the upper arm 
Deltoid area in the upper arm 
Sourcing 
Provided by the Sponsor  
Provided by the Sponsor  
Packaging and 
Labeling 
Each dose of the 2 vaccines (vYF and Stamaril) will be in an individual box 
that will be identified by a dose number. Each box will contain a vial with 
the powder of YF vaccine and a pre-filled syringe containing the diluent. 
Each box of vaccine dose will bear both detachable and fixed labels for 
identification 
Current/Former 
Names or Aliases 
Not applicable 
Not applicable 
Batch Number 
TBD 
TBD 
IMP: Investigational Medicinal Product; mL: milliliter; PFU: plaque-forming units; SC: subcutaneous; TBD: to be 
determined; vYF: Vero cell-based yellow fever vaccine; YF: yellow fever. 
 
6.2 
Preparation/Handling/Storage/Accountability  
Detailed guidance and information are provided in the Operating Guidelines that will be provided 
to each Investigational site before the start of the study. 

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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 
and qualified 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 disposal of unused study interventions are 
provided in the Operating Guidelines. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 
Randomization and Allocation Procedures  
If the participant is eligible for inclusion in the trial (meets the inclusion criteria and none of the 
exclusion criteria), the designated site staff will contact the Interactive Response Technology 
(IRT) to obtain the participant number and the randomized vaccine to administer to the participant 
at Visit 1.  
Randomization will be stratified by country and by age group. Two age groups will be defined: 18 
to 45 yearsa and 46 to 60 yearsb.  
Participants will be randomly assigned to the study vaccine groups 1 (vYF) or 2 (Stamaril) in a 
2:1 ratio. Site staff will connect to the IRT, enter their identification and security information, and 
confirm a minimal amount of data in response to IRT prompts. The IRT will then provide the 
group assignment and have the site staff confirm it.  
The full detailed procedures will be described in the Operating Guidelines and the IRT manual 
which will be provided to all sites prior to study start. If the participant is not eligible to 
participate in the study, then the information will only be recorded on the participant recruitment 
log. 
Participant numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier). For example, 
Participant 250000100005 is the 5th participant enrolled in Center Number 0001 in France (250 
being the France country code). The leading number in the 5-digit participant identifier will be the 
indicator of subsets. 
                                                 
a “18 to 45 years” means from the day of the 18th birthday up to the day before the 46th birthday 
b “46 to 60 years” means from the day of the 46th birthday up to the day before the 60th birthday 

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Participant numbers should not be reassigned for any reason. The randomization codes will be 
kept securely in the IRT. No replacement will be made for randomized participants who terminate 
the study early. 
6.3.2 
Blinding and Code-breaking Procedures  
The VYF03 study is a Phase II, randomized, observer-blind, active-controlled, non-inferiority 
study to the Stamaril control vaccine. 
The study will be performed in a modified double-blind fashion: Sponsor, Investigators and Study 
staff who conduct the safety assessments, and the participant will not know which vaccine is 
administered. 
Only the study staff who prepare and/or administer the vaccine and who are not involved in safety 
evaluations (“vaccinator”) will know which vaccine is administered. The “vaccinator” or 
authorized designee will have to ensure that the documents on randomization are stored in a 
secure place where only he/she has access. 
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 (RMO) if a participant’s code was broken. All contact attempts with 
the Sponsor prior to unblinding are to be documented in the source documents, and the code-
breaking case report form (CRF) is to be completed. 
The Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) 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 Harmonization (ICH) E2A. 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. 
• 
by the IDMC if needed to facilitate their assessment of safety. 
 
The code-breaking procedures are described in the Operating Guidelines. 

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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 noncompliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain accountability 
records of study intervention delivery to the study site, study intervention inventory at the site, 
dose(s) given to each participant, and unused or wasted doses 
6.5 
Concomitant Therapy  
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions / AEs during study participation. 
Documentation in the CRF of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of first vaccination. This may include 
medications of interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRF from the day of each vaccination to the end 
of the solicited and unsolicited follow-up period, except for use of any investigational or non-
registered product (drug, vaccine or medical device), or vaccination with commercial YF vaccine, 
which will be collected for the entire study period .  
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Three standard 
categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], systemic 
steroids/corticosteroids)  
• Category 2: medications impacting or that may have an impact on the immune response (eg, 
other vaccines, blood products, antibiotic classes that may interfere with bioassays used by the 
Global Clinical Immunology [GCI] department or other testing laboratories, systemic 
steroids/corticosteroids, immune-suppressors, immune-modulators with immunosuppressive 
properties, anti-proliferative drugs such as DNA synthesis inhibitors) 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, systemic steroids/corticosteroids) 
Any investigational or non-registered product (drug, vaccine or medical device), other than the 
study vaccine during the period beginning 29 days before the dose of study vaccine or during the 
study period, as well as receipt of a commercial YF vaccine, will be recorded as Category 3. 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded. Topical analgesics should not be 

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applied at the site of vaccination; however, if they are applied inadvertently to the vaccination site, 
they should be recorded as a Category 1 medication in this specific instance. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to one of the pre-listed categories. 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. 
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: Adverse Event, 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. 

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• 
Withdrawn participants will not be replaced. However, all participants enrolled in this study 
will be followed up for 5 years after vaccine administration. They will be kept in the study 
(ie, will not be withdrawn) even if they fail to come to one or more of the yearly visits during 
the 5-year follow-up.  
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for definition of “lost to follow-up”. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a 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, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods), 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 Appendix 10.1. 
8 
Study Assessments and Procedures  
• 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 

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• 
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. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the inform consent form (ICF) may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the time frame defined in the SoA. 
Urine and blood samples will be collected as described in the SoA Table (Section 1.3). 
The maximum amount of blood collected from each participant over the 5-year duration of the 
study, that may be required, will 
, see Table 8.1. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.  
In some countries or sites, an additional blood sample for HIV, and/or Hepatitis B and Hepatitis C 
testing as part of confirming eligibility criteria, may be collected per local or country regulations 
if required, and as long as the participant has consented to this additional sample being collected 
in the Participant Information Sheet and Consent Form. 
There is no screening period in this study. However, in case of an eligibility criterion requiring 
specific testing or procedures before enrolment of the participant in the study, or moderate or 
severe acute illness/infection or febrile illness (temperature ≥ 100.4°F or or 38°C) on the day of 
vaccination, the enrolment can be postponed until the additional information is available or the 
condition is resolved. 
Table 8.1: Blood sampling volume (mL) per visit  
Visit number 
(V) 
V01 
Vaccination 
V02*  
(subset of 
90 
participants 
in EU and 
60 
participants 
in Asia, 
only) 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Trial timelines 
(days, months or 
years) 
D01 
D11 
D15 
D29 
M6 
(D180) 
Y1 
(D360) 
Y2 
(D720) 
Y3 
(D1080) 
Y4 
(D1440) 
Y5 
(D1800) 
Time windows 
(days) 
N/A 
+2 
+ 2 
+ 3 
± 15 
± 15 
± 15 
± 30 
± 30 
± 30 
Immunogenicity assessments 
*only for participants in the subsets 

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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 primary objective of this study is to demonstrate the non-inferiority of the antibody response 
in terms of seroconversion rates 28 days after vaccine administration of one dose of vYF 
(administered on D01) compared to the antibody response after one dose of the Stamaril control 
vaccine (administered on D01) in a YF-naïve population in EU. YF-naïve participants (or 
negative) at baseline correspond to participants with no detectable YF Ab titers before 
vaccination. YF seronegative at baseline is defined as a titer < LLOQ for the assay (any 
participant with a baseline titer ≥ LLOQ will be eliminated from the primary analysis (Per-
protocol analysis). LLOQ determined as 10 (1/dil), also defined the threshold of protection. 
Seroconversion is defined as a 4-fold increase in NAb titers, as compared to the pre-vaccination 
value. 
The secondary objectives are to describe the immune response to YF in both vaccine groups using 
YF MN assays before (D01) and after vYF or Stamaril administration, by determining 
seroconversion and seroprotection, as well as GMT and GMTR, in all participants at several 
timepoints (D11 in subsets only, D29, M6, and yearly from Y1 to Y5). Seroprotection is defined 
as NAb titers ≥ threshold of 10 (1/dil). 
All secondary objectives will be analyzed depending the FV status at baseline (YF-naïve and – 
immune, dengue serotypes 1-4 naïve and – immune, Zika-naïve and – immune, JEV-naïve and 
immune, for Asian participants, and FV-naïve and immune). 
8.1.2.1 
Immunogenicity Endpoints  
For all objectives, YF antibody assessments will be performed using the YF MN assay. 
For the primary objective, seroconversion will be assessed 28 days post-vYF (administered on 
D01) and post-Stamaril (administered on D01) in YF-naïve participants. 
For the secondary objectives, YF antibody assessments will be performed as follows for each 
group: 
NAb titers at D01, D11 (subset only), D29, M6, and yearly from Y1 to Y5 
Derived endpoints are: 
• 
Seroconversion rates at D11 (subset only) and D29, M6, and yearly from Y1 to Y5 

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Seroconversion is defined as a 4-fold increase in NAb titers: i) as compared to the D01 titers 
at each time point up to M6; ii) as compared to the last planned previous time point from Y1 
onwards 
• 
Seroprotection rates based on participants with antibody titers ≥ 10 (1/dil) at baseline (D01) 
and at D11 (subset only), D29, M6, and yearly from Y1 to Y5 
• 
GMTRs for D11/D01 (subset only), D29/D01, M6/D01 and yearly ratios.  
The corresponding parameters are seroconversion rate, seroprotection rate, GMT, and GMTR 
Data will be analyzed depending on FV immune status at baseline (FV-naïve and immune: YF-
naïve and immune, Dengue serotypes 1-4 naïve and immune, Zika-naïve and immune, and JE-
naïve and immune in participants enrolled in Asia) 
8.1.2.2 
Immunogenicity Assessment Methods  
YF MN Method Description (all participants, visits V1 and V4 to V10 for the main cohort, and 
visits V1, V2, and V4 to V10 for the subset of participants) 
YF NAb titers will be measured using a MN assay. Serial, 2-fold dilutions of serum to be tested 
(previously heat-inactivated) are mixed with a constant concentration of the YF vaccinal strain 
17D. The mixtures are inoculated into wells of a 96-well microplate with permissive Vero cells 
and incubated for 2 days. A reduction in virus infectivity (viral antigen production) due to 
neutralization by antibody present in serum samples is detected by enzyme linked immunosorbent 
assay (ELISA). After washing and fixation, YF viral antigen production in cells is detected by 
successive incubations with a flavivirus-specific mAb, horse radish peroxidase anti-mouse 
immunoglobulin G (IgG) conjugate, and a chromogenic substrate. The resulting optical density is 
measured using a microplate reader. The reduction in YF virus infectivity as compared to that in 
the virus control wells constitutes a positive neutralization reaction indicating the presence of 
NAbs in the serum sample. The method was qualified by assessing precision, specificity, LLOQ, 
and dilutability. To verify the LLOQ of 10, a panel of 17 additional human serum samples diluted 
in a negative serum targeting a titer of ½ of the LLOQ to exactly the LLOQ was tested 11 times 
by 2 qualified analysts in 2 independent assay runs. This data supports that the LLOQ of 10 was 
verified for the YFV MN assay and LOD can be considered as equivalent to LLOQ (LOD = 
LLOQ):  
• LLOQ determined as 10 (1/dil) with the MN assay defines the threshold of protection; a 
participant presenting with detectable Ab (≥ LLOQ) is considered as protected against YF 
virus 
• As LOD = LLOQ, YF-naïve population, or YF negative population, corresponds to 
participants with no pre-existing Ab titers ie, no detectable as below LLOQ equal to 
1:10.  Those subjects are given a value equal to half LLOQ, ie, 5 (1/dil) 
• Seroconversion is defined as having at least a 4-fold increase of Ab titers as compared to 
baseline (pre-vaccination value); Sanofi Pasteur would like to consider this 4-fold increase in 
Ab titers for both participants with or without pre-existing Ab titers.   

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o 
For participants assigned with a value at baseline of 10 (LLOQ) or more, 1/dil, 
seroconversion means values of 40, 1/dil, or more post-vaccination.  
o 
For participants with a nominal value of 5 (half LLOQ) 1/dil assigned to baseline YF 
seronegative subjects, this means that seroconversion requires an increase to at least 
a titer of 20, 1/dil on day 28 post-vaccination.  
The assay was deemed suitable for its intended use to quantitate YF NAb in human serum. 
Laboratory technicians conducting the immunogenicity assays will be blinded to the group to 
which each participant was assigned. 
The YF MN assay will be performed at Sanofi Pasteur GCI, Swiftwater, Pennsylvania, or at a 
qualified contract laboratory for GCI.  
Zika MN method description (all participants, samples from V1) 
Zika NAbs will be measured using a MN assay. Serial, 2-fold dilutions of serum to be tested 
(previously heat-inactivated) are mixed with a constant concentration of Zika virus. The mixtures 
are inoculated in duplicate into wells of a 96-well microplate with permissive Vero cells. After 
adsorption, cells are incubated for 4 days. A reduction in virus infectivity (viral antigen 
production) due to neutralization by antibody present in serum samples is detected by ELISA. 
After washing and fixation, Zika viral antigen production in cells is detected by successive 
incubations with flavivirus-specific mAb, horseradish peroxidase goat anti-mouse IgG conjugate, 
and a chromogenic substrate. The resulting optical density is measured using a microplate reader. 
The reduction in Zika virus infectivity as compared to that in the virus control wells constitutes a 
positive neutralization reaction indicating the presence of NAbs in the serum sample (13). The 
Zika microneutralization assay will be performed at Sanofi Pasteur GCI, Swiftwater, 
Pennsylvania, or at a qualified contract laboratory for GCI. The LLOQ of the assay is 10 (1/dil). 
Dengue PRNT method description (all participants, samples from V01) 
Dengue neutralizing Ab levels will be measured by plaque reduction neutralization test (PRNT) 
(using parental dengue virus strains of CYD dengue vaccine constructs) by Sanofi Pasteur GCI, 
Swiftwater, USA (or outsourced with a GCI selected external laboratory). Serial, 2-fold dilutions 
of serum to be tested (previously heat-inactivated) are mixed with a constant challenge-dose of 
each dengue serotype 1, 2, 3 or 4 (expressed as PFU/mL). The mixtures are inoculated into wells 
of a microplate with confluent Vero cell monolayers. After adsorption, cell monolayers are 
incubated for a few days. A reduction in virus infectivity due to neutralization by Ab present in 
serum samples is detected. The reported value (end point neutralization titer) represents the 
highest dilution of serum at which ≥ 50% of dengue challenge virus (in plaque counts) is 
neutralized when compared to the negative control wells which represents the 100% virus load. 
The end point neutralization titers are presented as continuous values. The LLOQ of the assay is 
10 (1/dil). The PRNT assay data will be used for the baseline serostatus analyses. The dengue 
PRNT assay will be performed at Sanofi Pasteur GCI, Swiftwater, Pennsylvania, or at a qualified 
contract laboratory for GCI. 
JEV PRNT method description (all Asian participants, samples from V01) 
JE virus neutralizing Ab measurement will be assessed by PRNT. Serial 10-fold dilutions of 
serum to be tested (previously heat-inactivated) are mixed with a constant concentration 
(expressed as PFU/mL) of the JE Beijing strain (genotype III). The mixtures are inoculated into 

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wells of a plate of confluent LLC-MK2 cells. After adsorption, cell monolayers are overlaid and 
incubated for several days. The reported value (end point neutralization titer) represents the 
highest dilution of serum at which ≥ 50% of JE challenge virus is neutralized when compared to 
the negative control wells, which represents the 100% virus load. The LLOQ for this study will be 
10 (1/dil). The threshold for protection defining JE-naïve or JE immune subjects is 10 (1/dil) (14). 
The JE PRNT assay will be performed at Sanofi Pasteur GCI, Swiftwater, Pennsylvania, or at a 
qualified contract laboratory for GCI. 
Other FV 
NAbs against other flaviviruses from participant may be assessed during the course of study 
analysis if deemed appropriate. The same methodology will be used for other viruses.  
8.2 
Safety Assessments  
This section presents safety assessments other than AEs which are presented in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
At each visit, the Investigator or a delegate will perform a physical examination and will ask the 
participant about any solicited reactions (D01 to D15) and unsolicited AEs (D01 to D29) recorded 
in the DC or MA, as well as about any other AEs that may have occurred since the previous visit. 
All relevant data will be transcribed into the CRF according to the instructions provided by the 
Sponsor. 
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. 
8.2.2 
Physical Examinations  
At each visit, the Investigator or a delegate will perform a medically driven physical examinationa. 
Information will be recorded in the source document and in the CRF. 
8.2.3 
Vital Signs  
Oral pre-vaccination temperature will be systematically collected by the Investigator on the source 
document. Tympanic, skin, and temporal artery thermometers must not be used (see 
Section 10.3.5.1 for more details). 
No other vital signs (eg, blood pressure, pulse rate) will be collected in the CRF. 
                                                 
a In case the D15 visit is replaced by a phone call, the physical examination will not be performed. 

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8.2.4 
Clinical Safety Laboratory Assessments  
Urine pregnancy testing will be performed in women of childbearing potential before vaccination 
(D01) and repeated on D29. 
8.2.5 
Viremia/Vaccinemia  
Viremia will not be evaluated in this study. 
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. 
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 AE and SAE Information  
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from the day of vaccination (D01) until 7 days 
after vaccination (D08). 
Solicited systemic reactions will be collected from the day of vaccination (D01) until 14 days after 
vaccination (D15). 
The solicited injection site reactions and systemic reactions that are pre-listed in the diary cards 
and CRF, together with the intensity scales, are presented in Appendix 10.3.5.1.1. 
Unsolicited Non-serious Adverse Events 
Unsolicited non-serious adverse events will be collected from the day of vaccination (D01) until 
28 days after vaccination (D29). 
The intensity grading scale for unsolicited non-serious adverse events is presented in 
Appendix 10.3.5.1.2. 
Medically Attended Adverse Events (MAAEs) 
MAAEs will be collected up to D29 as part of the unsolicited AEs; up to M6 post-vaccination as 
part of the SAE (Serious MAAE) and at any time during the study as part of SAEs that are related 
or fatal (serious related or fatal MAAE).  

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Adverse Events of Special Interest (AESIs) 
AESIs will be collected from D01 to Month 6 (D180).  
See Section 8.3.6 for the list of AESIs. 
SAEs 
Information on SAEs will be collected and assessed throughout the study, from inclusion at D01 
until 6 months after vaccination, and related SAEs and fatal SAEs throughout the study, up to 5 
years after vaccination. However, before the study intervention administration, only SAEs related 
to study procedures are to be collected. 
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 case report book (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. 
8.3.2 
Method of Detecting AEs and SAEs  
Individual diary cards (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 diary cards will include pre-listed terms and intensity scales as well as areas for free text to 
capture additional safety information or other relevant details. 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 diary card or memory aid 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 diary card will first be captured in the source 
document and then reported electronically. 
The 6-month follow-up will be done by interviewing participants using a questionnaire to capture 
SAEs and AESIs, if applicable. 
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. 

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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs  
Unless a participant or parents / guardians / legally acceptable representatives (if applicable) 
refuse(s) 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 SAEs  
• 
Prompt notification by the Investigator to the Sponsor of a 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. 
• 
For all studies except those investigating medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy  
Pregnancy is an exclusion criterion for enrollment in this study, but a participant could potentially 
become pregnant during her participation.  
Details of all pregnancies in female participants which started within the minimal period of 
requested contraception (from 4 weeks before to 4 weeksa after study intervention administration) 
will be collected by the Investigator and recorded in the Pregnancy CRF. The participant will be 
                                                 
a 12 weeks for France 

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followed to determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, and the information will be forwarded to the 
Sponsor. 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  
The following AESIs have been defined for this clinical development program based upon the 
prior experience with YF vaccines: 
• 
Serious hypersensitivity/allergic reactions  
• 
Organ failure/serious viscerotropica events (YEL-AVD) 
• 
Serious neurologicb events (YEL-AND) 
The scope of AESIs is larger than the scope of corresponding potential risks, and eligible events 
are considered AESI even if they are considered unrelated to the vaccination. AESIs will be 
assessed as per appropriate Brighton Collaboration and/or Advisory Committee on Immunization 
Practices (ACIP) definitions. Specific guidelines are provided to the Investigator to help in the 
detection and evaluation of AEs that may raise suspicion of potential vaccine viscerotropism or 
neurotropism (see “Operating Guidelines for Assessing Viscerotropic and Neurotropic Adverse 
Events in studies using YF vaccines”). 
8.3.7 
Medically Attended Adverse Events  
MAAEs will be collected using the same process as other AEs. See Appendix 10.3.1 for definition 
of MAAEs: up to D29 as any other unsolicited AEs, up to M6 post-vaccination as any SAE in 
case of a serious MAAE, and at any time during the study in case of a serious related or fatal 
MAAE. 
                                                 
a As defined in Brighton collaboration criteria for viscerotropic disease, including but not limited to: liver dysfunction 
(AST and ALT ≥ 3xULN or total bilirubin ≥ 1.5xULN); renal impairment (blood urea nitrogen or creatinine ≥ 1.5 
x ULN if no history of renal disease, or ≥1.5 x patient's baseline if history of renal disease); thrombocytopenia 
< 100 000/µl; CPK ≥ 5xULN; respiratory failure; requirement for vasopressor drugs to maintain systolic blood 
pressure etc. 
b As defined in ACIP criteria for neurologic and neurotropic disease, including but not limited to: focal neurologic 
dysfunction (ataxia, aphasia, paresis etc.), new onset of seizure, aseptic meningitis, encephalopathy, encephalitis, 
autoimmune disease with central (ADEM) or peripheral (GBS) nervous system involvement. 
 

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8.4 
Treatment of Overdose  
Since the study intervention is administered by a health care professional and it is in a single dose 
vaccine administration at the first visit, 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. 
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  
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS software at least Version 9.4 (SAS Institute, Cary, NC, USA). 
A detailed Statistical Analysis Plan (SAP) will be written before the database lock. Based on the 
protocol, the SAP will describe all analyses to be performed as well as statistical tables, and 
listings. 
9.1 
Statistical Hypotheses  
Primary objective: 
A non-inferiority approach will be used to compare the post-vaccination seroconversion rates of 
vYF and Stamaril groups in EU YF-naïve participants. Details on statistical methods are provided 
in Section 9.4. 
Secondary and observational objectives: 
No hypotheses will be tested. The analyses will be descriptive. 
9.2 
Sample Size Determination  
The sample size is based on the primary objective and on the safety secondary objectives. 
A total of 690 participants are expected to be enrolled in the study, using a 2:1 repartition (460 
participants in the vYF group, with 380 in EU and 80 in Asia, and 230 participants in the Stamaril 
group, 190 in EU and 40 in Asia).  
In EU, considering a potential attrition rate 
 such sample size would provide 456 evaluable 
participants, with 304 participants enrolled in Group 1 (vYF) and 152 in Group 2 (Stamaril). This 
will give 
 power (Farrington and Manning formula) to declare the non-inferiority of Group 
1 (vYF) versus Group 2 (Stamaril) based on seroconversion rates of 
 at D29 after a single 
dose of the investigational or control vaccine, assuming: 
• 
A one-sided alpha level 
 
• 
A non-inferiority margin δ
  
The subset sample sizes have been arbitrarily set to 90 participants in EU and 60 participants in 
Asia, in which 60 and 40 participants will be enrolled in Group 1 in EU and Asia, respectively, 
and 30 and 20 participants will be enrolled in Group 2, in EU and Asia, respectively. 

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9.3 
Populations for Analyses  
The following populations are defined: 
Population 
Description 
Randomized 
All participants with data in the CRF. 
Full analysis set (FAS) 
Subset of randomized participants who received at least 1 dose of the 
study vaccine or control vaccine and had a valid post-vaccination blood 
sample result.  
Participants will be analyzed according to the intervention to which they 
were randomized. 
Safety Analysis Set (SafAS) 
Participants who have received at least 1 dose of the study vaccines. 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). 
Per-protocol analysis set 
(PPAS) 
Subset of the FAS. Participants presenting with at least one of the 
following relevant protocol deviations will be excluded from the PPAS: 
Participant is not YF-naïve 
Participant did not meet all protocol-specified inclusion criteria or met 
at least one of the protocol-specified exclusion criteria  
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 
Non-availability of other critical measurements for the primary analysis: 
• Baseline serology sample was not collected in the protocol-specified 
time window or the serology sample was not drawn 
• Participant did not provide the post-dose serology sample on Day 29 
visit (D28 after vaccination) in the proper time window or the blood 
sample was not drawn  
• Participant received any therapy / medication / vaccine which could 
inhibit the immune response until the time point considered for the 
analysis (Day 29, Visit 4)  
• In addition to the reasons listed above, participants will also be 
excluded from the PPAS if their baseline or post-vaccination 
serology sample at D29 (Visit 4) did not produce a valid test result 
(ie, results for all antigens are missing or out-of-range) 

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This list may not be exhaustive. The above protocol deviations leading 
to exclusion from the PPAS may be detailed and completed if 
necessary, in the SAP following a data review. The PPAS definition 
will be finalized before the database lock (and code-breaking if 
applicable). 
In the event of a local or national immunization program with a eg, 
pandemic influenza vaccine, any other vaccine as needed, participants 
who receive 1 or more doses of eg, a pandemic influenza vaccine, or the 
vaccine listed above at any time during the study will not be withdrawn 
from the study. 
9.4 
Statistical Analyses  
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
9.4.1 
General Considerations  
Primary analyses will be performed on the Per-Protocol Analyses Set in YF-naïve subjects.  
The objective is to demonstrate that the humoral response (in terms of seroconversion of vYF 
(Group 1) is non-inferior to the humoral response of Stamaril (Group 2) 28 days after a single 
dose in YF-naïve participants. 
Primary Objective: 
The percentages of participants with seroconversion 28 days after vaccination will be used to 
compare responses between Group 1 and Group 2 with the following hypotheses: 
• H0 (Null hypothesis): p(vYF)-p(Stamaril) ≤ - δ 
• H1 (Alternative hypothesis): p(vYF)-p(Stamaril) > - δ 
Where δ the non-inferiority margin is set to 5%. 
Where p(vYF) and p(Stamaril) are the proportion of participants with seroconversion. 
Seroconversion is defined as a fourfold increase in NAb titers as compared to pre-vaccination 
value.  
The non-inferiority will be demonstrated if the lower limit of the 2-sided 95% confidence interval 
(CI) of the difference between the 2 percentages is > -5%. 
The CI of the difference in percentages will be computed using the Wilson score method without 
continuity correction as quoted by Newcombe (15) for seroconversion rates. 
The non-inferiority of the primary objective will be demonstrated if the null hypothesis is rejected. 

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9.4.2 
Secondary Endpoints  
The statistical analysis for secondary objectives will be descriptive.  
Immunogenicity: 
Analyses will be performed per vaccine group on the Full Analyses Set. 
The immunogenicity parameters will be described per vaccine group. Immunogenicity analyses 
will be provided on participants by YF serostatus and by FV serostatus. 
The following parameters will be analyzed: 
• GMTs for each vaccine group  
• Seroconversion rates: number and percentage of participants in each vaccine group converted 
with neutralizing antibody titer 4-fold increased compared to D01 up to M6: D11 (subset only) 
compared to D01, D29 compared to D01, M6 compared to D01; and yearly from Y1 to Y5 
compared with the latest planned timepoint: Y1 compared to M6, Y2 compared to Y1, Y3 
compared to Y2, Y4 compared to Y3, Y5 compared to Y4  
• Within-group GMTRs for each vaccine group post-vaccination injection, compared to D01 
(D11/D01 [subset only], D29/D01, M6/D01 and yearly ratios: Y1/M6, Y2/Y1, Y3/Y2, Y4/Y3, 
Y5/Y4 [see Section 8.1.2.1])  
• Number and percentage of participants (seroprotection rates) in each vaccine group with 
antibody titers ≥ 1:10 (1/dil) at baseline (D01) and at D11 (subset only), D29, M6, and yearly 
from Y1 to Y5 
The 95% CIs will be calculated using: 
• The normal approximate method for GMTs and GMTRs 
• The exact binomial distribution for percentages (Clopper-Pearson’s method, quoted by 
Newcombe) 
Assuming that log10 transformation of the titers/ratios follows a normal distribution, first, the 
mean and 95% CI will be calculated on log10 (titers/ratios) using the usual calculation for normal 
distribution, then antilog transformations will be applied to the results of calculations, to compute 
GMTs/GMTRs and their 95% CIs. 
Safety: 
Safety results will be described per vaccine groups on the SafAS. The main parameters for the 
safety endpoints will be described by 95% CIs of point estimates, calculated using the exact 
binomial distribution from Clopper-Pearson’s method quoted by Newcombe (16) for proportions. 
9.4.3 
Exploratory Endpoint(s)  
Exploratory endpoints are NAb levels against FV infection (dengue, Zika, and JEV) in blood 
samples taken at baseline. 

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9.5 
Interim Analyses  
Interim Analyses 
Six statistical analyses will be performed on data obtained from all participants.  
The first interim analysis will be performed on the immunogenicity results obtained up to the D29 
visit and safety data obtained up to the 6-month follow-up visit, then the successive interim 
analyses will be performed on data connected up to Y1 visit and not yet analyzed, then every year 
on the data gathered at each yearly visit up to 4 years after YF vaccine administration; these 
results will be presented in an interim clinical study report (CSR) (immunogenicity data up to D29 
and safety data up to M6) or CSR addendum (up to Y4). In addition, the first interim analysis will 
be performed on immunogenicity and safety data gathered on all EU participants enrolled and 
followed up, even in case the submission/approval in Asian countries and/or the recruitment of 
participants of Chinese origin is delayed as compared to that in EU. As a consequence, an interim 
CSR might be produced to present the analysis on participants enrolled in EU only. 
Final Analysis 
The final analysis will be performed at the end of the follow-up (5 years after YF vaccine 
injection). 
The SAP will describe the planned interim analyses in greater detail. 
Ongoing safety surveillance 
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: Safety Management 
Team (SMT) which includes safety signal detection at any time during the study.  
This SMT led by the Global Safety Officer (GSO) includes core representatives from the Global 
Pharmacovigilance (GPV) Department and from the Clinical Department. The SMT is 
empowered to recommend a pause in recruitment while it investigates any potential signal or 
concern. 
The enrollment will be paused if one of the following pausing/halting criteria that could 
potentially constitute an unreasonable and significant risk for study participants occurs: 
• 
 
  
 
 
  
 
  
Pausing of a trial needs to be addressed to the competent authority. After pausing of the trial an 
amendment for resuming the trial needs to be submitted to the authority. 
The study can be resumed if investigations conclude that there is no unreasonable and significant 
risk for study participants. 

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9.6 
Data Monitoring Committee (DMC)  
An independent DMC (IDMC) will be utilized throughout this study, composed of external 
independent experts in relevant clinical specialties and at least one biostatistician knowledgeable 
about statistical methods for clinical trials and sequential analysis of study data. 
The committee will periodically assess the progress of the clinical study, all safety data, and will 
recommend to Sanofi Pasteur whether to continue, modify, or stop the study. The IDMC will 
make recommendations to the Sponsor on a medical and ethical basis. 
In case of safety concern raised by the IDMC, the Sponsor will decide whether further vaccine 
administration should be temporarily halted as a precautionary measure while investigating the 
potential safety signal. 
Pausing of a trial needs to be addressed to the competent authority. After pausing of the trial an 
amendment for resuming the trial needs to be submitted to the authority. 
For details on IDMC, refer to Appendix 10.1.5. 

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10 Supporting Documentation and Operational Considerations  
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. 
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and the applicable amendments 
and Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines 
o 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
o 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, protocol amendments, 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: 
o 
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). 
o 
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 
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The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity.  
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), 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 
and/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 (HIPAA) 
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 ICF. 
• The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
• If new information becomes available that may be relevant to the 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 ICF or an addendum to the original ICF.  
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative. 

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Recruitment Procedures 
Potential participants will be recruited from a pool of volunteers who meet site-specific screening 
requirements. 
Prior to enrollment, the Investigator, or a designee will complete the informed consent procedures 
with potentially eligible participants. After the participant (and his/her legally acceptable 
representative, if applicable) has signed the ICF, and following confirmation by the Investigator 
that the participant has satisfied all inclusion / exclusion criteria, eligible participants will be 
included in the study and randomized by IRT. They will provide their initial blood sample and 
will be vaccinated according to their IRT assigned study groups. 
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 race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA). 
• 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 

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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 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.  
10.1.5 Committees Structure  
This study will not include an early safety data review. However, participant safety will be 
continuously monitored by the Sponsor.  
Moreover, an IDMC will be set up for VYF03. 
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. 

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• 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 noncompliance issues and 
monitoring techniques (central, remote, or on site monitoring) are provided in the Monitoring 
Plan. 
• The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
• 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. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after the signature of the final study report unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
10.1.8 Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. 
• 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 that will be provided 
to the Investigational site before the start of the study. 
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. 

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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 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 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication Policy  
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: Clinical Laboratory Tests  
A urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) will be performed before vaccination at D01 (Visit 1) and at D29 (Visit 4). 
Pregnancy Testing is compulsory at V01 since pregnant women cannot be included in this study.  
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study will not be reported to Investigational sites until 
the study has been unblinded for the first interim analysis, in order to allow the Investigators to 
provide the ICVP for YF vaccination to the participants randomized in the Stamaril group. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
 

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10.3 Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
10.3.1 Definition of AE  
AE Definition 
• An AE is any untoward medical occurrence in a 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 AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, 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 intervention-intervention 
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. 
 
Events NOT Meeting the AE 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. 

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Other Definitions 
Adverse Reaction: 
An adverse reaction (AR) is any noxious and unintended response to a study intervention 
related to any dose. 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs which 
occur within the first 30 minutes after vaccination. 
Reactogenicity / Solicited Reactions 
The reactogenicity of a vaccine refers to the property of such vaccine to be able to produce 
common "expected" adverse reactions (either systemic or at the injection site) and its associated 
signs and symptoms. 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) pre-listed in the protocol and CRF (eg, injection site 
pain or headache occurring between the day of vaccination and the next 7 days).  
By definition, solicited reactions are considered as being related to the corresponding IMP 
administered. 
For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions. 
Injection / Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration site 
of the IMP. Injection/administration site reactions are commonly inflammatory reactions. 
Solicited injection / administration site reactions are reactions at and around the 
injection / administration site of the IMP observed and reported under the conditions (nature 
and onset) pre-listed in the protocol and CRF. It is considered by default as being related to the 
IMP administered at that site. 
Note: « Administration site reaction » term is only to be used for vaccines that are not intended 
to be administered by injection. 
Systemic AR: 
Systemic ARs are all ARs 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 injection or administration site (eg, erythema that 
is localized but that is not occurring at the injection site).  
Solicited systemic reactions are systemic AEs observed and reported under the conditions 
(nature and onset) pre-listed in the protocol and CRF. Solicited systemic reactions occurring 

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

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MAAEs, being a subset of AEs/SAEs for which specific actions are taken, are collected within 
solicited/unsolicited/SAE and fatal or related SAE collection periods, as applicable. 
They are collected up to D29 as part of the unsolicited AEs, up to M6 post-vaccination as part 
of the SAE (Serious MAAE) and at any time during the study as part of SAEs that are related or 
fatal (serious related or fatal MAAE). 
10.3.2 Definition of SAE  
 
An SAE is defined as any adverse event 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 admitted (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• 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. 
Is other medically important event 
• The term "Other medically important events" refers to events which do not meet any of the 
above seriousness criteria, but which are considered as serious based on investigator medical 
judgment  

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• Medical or scientific judgment should be exercised by the Investigator in deciding whether 
expedited reporting is appropriate in other situations such as significant medical events that 
may 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  include invasive or malignant cancers,  intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions or 
development of intervention dependency or intervention abuse, new onset diabetes or 
autoimmune disease or suspected transmission of any infectious agent via an authorised 
medicinal product. 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant / event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 
10.3.3 Recording and Follow-Up of AE and/or SAE  
AE and SAE 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. 
• 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 (either solicited or unsolicited) and all 
solicited systemic AEs are considered to be related to the IMP (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: 

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• 
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 (except for injection site reactions which will 
be related by default). 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 administered as either not related or related, based on the 
following definitions: 
• 
Not related – The AE is clearly / most probably caused by other etiologies such as 
participant’s 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 vaccination (screening phase, if applicable) 
• 
Related – There is a “reasonable possibility” that the AE was caused by the study 
intervention administered, meaning that there are facts (evidence) or arguments to 
suggest a causal relationship 
• The Investigator will use clinical judgment to determine the relationship. 
• 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 makes 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. 
 

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Follow-up of AEs and SAEs 
• 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 submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
Serious adverse events likely to be related to the study intervention, 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. 
10.3.4 Reporting of SAEs  
SAE 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) 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. 
 

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SAE Reporting to the Sponsor via Paper CRF 
• The SAE paper CRF can be sent to the Sponsor by one of the following means: 
• 
By fax, to the following number: 
 
• 
In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: 
 
• 
By express mail, to the following address: Global Pharmacovigilance, Sanofi Pasteur 
SA, 14 Espace Henry Vallée, F-69367 Lyon cedex 07, France 
 
Safety Emergency Call 
If, as per the Investigator's judgment, a participant experiences a medical emergency, the 
Investigator may contact the Sponsor's RMO for advice on how to address any study-related 
medical question or problem. If the RMO is not available, then the Investigator may contact the 
Call Center—available 24 hours a day, 7 days a week—that will forward all safety emergency 
calls to the appropriate primary or back-up Sanofi Pasteur contact, as needed. The toll-free 
contact information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department. 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.3.2. 
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 AR 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  
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when 
the injection site is touched or injected limb 
is mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, 
depending on the space available for the 
fluid to disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 

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Intensity scale* 
 
CRB: 
Grade 1: A type of adverse event that is 
usually transient and may require only 
minimal treatment or therapeutic 
intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2: A type of adverse event that is 
usually alleviated with additional 
therapeutic intervention. The event 
interferes with usual activities of daily 
living, causing discomfort but poses no 
significant or permanent risk of harm to the 
research participant. 
Grade 3: A type of adverse event that 
interrupts usual activities of daily living, or 
significantly affects clinical status, or may 
require intensive therapeutic intervention. 
Diary card: 
Grade 1: No interference with usual 
activities 
Grade 2: Some interference with usual 
activities 
Grade 3: Significant; prevents usual 
activities 
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 
MedDRA: Medical Dictionary for Regulatory Activities 
* For the scale will be provided in the CRF and the intensity will be transcribed from in the diary card. For other injection site reactions (erythema and swelling), the classification as 
Grades 1, 2, or 3 will be applied at the time of statistical analysis; the scale is provided for information purposes only. The actual size of the reaction will be reported in the CRF. 

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

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

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Important notes for the accurate assessment of temperature: 
Participants 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 eDC and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this study is oral.  
10.3.5.1.2 Unsolicited AE Intensity Grading Scale  
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.3.5.1.1). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
CRF: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• 
Diary card: No interference with usual activities. 
• Grade 2 
• 
CRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• 
Diary card: Some interference with usual activities. 
• Grade 3 
• 
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
Diary card: Significant; prevents usual activities. 
10.3.5.2 Tables for Laboratory Abnormalities  
The pre-defined intensity thresholds for laboratories abnormalities are shown in Table 10.3. 

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Table 10.3: Intensity grading scale for laboratories abnormalities  
Laboratory Endpoint 
Unit 
Grade 1 
Grade 2 
Grade 3 
Decrease in WBC 
cells / 
mm3 
< LLN to ≥ 3 000 
< 3 000 to ≥ 2 000 
< 2 000 
Decrease in 
Lymphocytes 
cells / 
mm3 
< LLN to ≥ 700 
< 700 to ≥ 500 
< 500 
Decrease in Neutrophils 
cells / 
mm3 
< LLN to ≥1 500 
< 1 500 to ≥ 1 000 
< 1 000 
Decrease in Platelets 
cells / 
mm3 
<LLN to ≥ 100 000 
< 100 000 to ≥ 75 000 
< 75 000 
ALT (increase by 
factor) 
 
> ULN to < 2.5 x 
ULN 
 2.5 to < 4.0 x ULN 
≥ 4.0 x ULN 
AST (increase by 
factor) 
 
> ULN to < 2.5 x 
ULN 
 2.5 to < 4.0 x ULN 
≥ 4.0 x ULN 
ULN:  Upper Limit of Normal 
LLN:  Lower Limit of Normal 
WBC: white blood cell 
ALT: alanine aminotransferase 
AST: aspartate transaminase 
10.3.6 Visit to the Center in the Event of Severe (Grade 3) Fever, or Suspicion of 
Neurotropic Disease or Acute Viscerotropic Disease Within 28 Days of Vaccination  
Participants will be instructed to inform (or to visit) the study site if participants develop severe 
(Grade 3) fever (≥ 39.0°C, 102 °F). 
In the event of specific clinical symptoms (severe [Grade 3] fever, or suspicion of neurotropic 
diseases or acute viscerotropic diseases) within 28 days of vaccination, specimen (blood, body 
fluid or tissue samples) might be collected to support the diagnosis according to the local practice. 
The Investigator or authorized designee will: 
• Perform a physical examination (including body temperature) and collect information in the 
source document 
• Collect blood by venipuncture for assessment of biological safetya and detection of YF 
viremia 
• Collect cerebrospinal fluid (CSF) for cultures and virological/bacterial research, when 
required 
• Collect suspected diagnosis 
• Treatment will be given according to local practices and standards by local HCPs 
Information collected at this visit will be recorded in the eCRF 
                                                 
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In case a neurotropic disease or acute viscerotropic disease is suspected, it is strongly 
recommended that the Investigator follows the guidelines for the assessment of viscerotropic and 
neurotropic AEs. On the basis of the severity of the symptoms reported, the Investigator will 
decide whether body fluid or tissue samples may need to be collected to support the differential 
diagnosis or vaccine causality. YEL-AVD and YEL-AND will be reported as SAEs. Events 
suggestive of YEL-AND and YEL-AVD will be assessed as per ACIP case definition criteria.  
10.4 Appendix: Collection of Pregnancy Information  
10.4.1 Definitions  
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1) Premenarchal 
2) Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 

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COLLECTION OF PREGNANCY INFORMATION 
Female Participants who become pregnant 
The Investigator will only collect pregnancy information on any female participant who becomes 
pregnant while participating in this study with an estimated conception date within the 28 days 
before or after study vaccination. 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. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the participant and the neonate, and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 4 weeks 
beyond the estimated delivery date but will be in accordance with local regulations. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
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. 
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. 

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10.4.2 
Contraception Guidance  
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• Intrauterine device (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. 
• 
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 (not applicable in Finland) 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
• Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) 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.  
d) Male condom and female condom should not be used together (due to risk of failure from friction). 

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10.5 Appendix: Country-specific Requirements  
10.5.1 Serology  
HIV, Hepatitis B, and Hepatitis C Serology testing will be performed on German participants. 
HIV serology testing may be performed (but is not mandatory) as part of the screening procedures 
in Thailand, and as long as a separate IRB/IEC approved HIV Consent Form has been signed by 
the participant beforehand. 
10.5.2 Receipt of COVID-19 Vaccines During the Study  
The highest priority is for a study participant or potential participant to receive their COVID-19 
immunization(s) as soon as possible following their country recommendations.  
Pre-enrollment (applicable for all countries): The timing between the first and second COVID-
19 doses depends on which vaccine the participant received and as per local recommendation. 
If a participant must complete the COVID-19 immunization regimen as part of their country/local 
regulations, the participant must have completed the full COVID-19 immunization regimen at least 
4 weeks before enrolment in the study.  
• If the first dose of a COVID-19 vaccination is received before the participant is enrolled in 
the study, it is recommended to postpone enrollment until at least 4 weeks after the second 
(last) COVID-19 dose.  
• If the interval between doses of COVID-19 vaccine available locally is longer than 4 weeks 
as prescribed by the manufacturer and/or by local health authority, subject can receive the 
study vaccine following the rule of 4 weeks preceding OR 4 weeks following any 
vaccination  
Applicable in Thailand: For a subject who has been COVID-19 vaccinated, as per CDC 
recommendation, the investigational product (vYF / Stamaril) can be given to the subject at least 1 
month later after COVID-19 vaccination completion 
Post-enrollment (applicable for all countries): In case a COVID-19 vaccination is decided during 
the study, it is preferable to wait until the D01-D29 period is completed to avoid any interference 
in the immune responses (assessed on D01 and D29, and in the subset group, additionally on D11).   
Information will be recorded in the eCRF under the specific form to be completed for COVID-
19.  Any COVID-19 vaccine received during the reporting period must be recorded as Category 2 
reportable concomitant therapy, specifying the tradename and the date/time of its administration. 
Wherever possible the site of injection of the IMP should be in the limb separate from the limb in 
which COVID vaccine is administered (if it has already been administered).  
Where it is not possible to have the IMP and COVID vaccine administered in separate limbs, a 
distance of at least 1.5 to 2 inches should be maintained between the two administration sites. 
10.5.3 Contraception  
• French participants have 12 weeks of contraception after study intervention administration 

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• For Finland participants, periodic abstinence is not considered as an adequate method of 
contraception 
10.6 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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10.7 Appendix: Abbreviations  
ACIP   
Advisory Committee on Immunization Practices  
AE 
 
adverse events 
AESI  
adverse events of special interest 
AR 
 
adverse reactions 
BL 
 
blood sampling 
CDISC 
Clinical Data Interchange Standards Consortium 
CDP  
clinical development plan 
CI 
 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF  
case report form 
CSR  
clinical study report 
D 
 
day 
DC 
 
diary card 
DENV  
Dengue virus 
DMC  
Data Monitoring Committee 
DoD  
Department of Defense 
DRC  
Democratic Republic of Congo 
eDC 
 
electronic diary card 
ELISA  
enzyme linked immunosorbent assay 
FAS 
 
full analysis set 
FDA  
Food and Drug Administration 
FSH 
 
follicle stimulating hormone 
FV 
 
flavivirus 
GCI 
 
Global Clinical Immunology 
GCP  
Good Clinical Practice 
GDPR  
General Data Protection Regulation 
GMT  
geometric mean titer 
GMTR 
geometric means of the individual titer ratios 
GPV  
Global Pharmacovigilance 
HCP  
Health Care Provider 

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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
 
human immunodeficiency virus 
HRT  
hormonal replacement therapy 
IB 
 
Investigator’s brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonization 
ICVP  
International Certificate of Vaccination or Prophylaxis 
IDMC  
Independent Data Monitoring Committee 
IEC 
 
Independent Ethics Committees 
IgG 
 
immunoglobulin G 
IHR 
 
International Health Regulations 
IMP 
 
investigational medicinal product 
IRB 
 
Institutional Review Boards 
IRT 
 
Interactive Response Technology 
LLN  
lower limit of normal 
LLOQ  
lower limit of quantitation 
M 
 
month 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
 
milliliter 
MN 
 
microneutralization 
NAb  
neutralizing antibody 
NIMP  
non- investigational medicinal product 
PPAS  
per-protocol analysis set 
RMO  
Responsible Medical Officer 
RNA  
Ribonucleic acid 
SAE  
serious adverse events 
SafAS  
safety analysis safety analysis  
SAP 
 
statistical analysis plan 
SC 
 
subcutaneous 
SmPC  
Summary of Product Characteristics 
SoA 
 
schedule of activities 

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ULN  
upper limit of normal 
V 
 
visit 
VAC  
vaccination 
WHO  
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
Y 
 
year 
YEL-AND 
YF vaccine-associated neurotropic disease 
YEL-AVD 
YF vaccine-associated viscerotropic disease 
YF 
 
yellow fever 
 
 

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11 References  
1. 
Vaccines and vaccination against yellow fever. WHO position paper -- June 2013. Wkly 
Epidemiol Rec. 2013;88(27):269-83. 
2. 
Staples JE, Bocchini JAJ, Rubin L, Fischer M. Yellow Fever Vaccine Booster Doses: 
Recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb 
Mortal Wkly Rep. 2015;64(23):647-50. 
3. 
WHO. World Health Organization. Yellow Fever Fact Sheet. Accessed on August 2020. 
Available from: http://www.who.int/mediacentre/factsheets/fs100/en/. 
4. 
Gershman MD, Staples JE. Centers for Disease Control and Prevention (CDC) - Yellow 
Fever. Infectious Diseases Related to Travel - Viral Hemorragic Fevers [Internet]. 2016. Accessed 
on July 2020. Available from: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-
related-to-travel/yellow-fever. 
5. 
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