Phase II, Randomized, Observer-blind, Placebo-controlled, Multi-center Study of a Live Attenuated Respiratory Syncytial Virus Vaccine to Assess the Vaccine Virus' Transmissibility in Household or Daycare Center Settings, Shedding, and Genetic Stability, and to Describe the Immunogenicity and Safety of the Vaccine in Infants and Toddlers 6 to < 24 Months of Age in Puerto Rico (USA)
Phase: PHASE1
Conditions: Respiratory Syncytial Virus Infection
Sponsor: Sanofi Pasteur, a Sanofi Company

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 Clinical Study Protocol 
Protocol Title: 
Phase II, randomized, observer-blind, placebo-controlled, multi-center study of a live-attenuated 
Respiratory Syncytial Virus vaccine to assess the vaccine virus’ transmissibility in household or 
daycare center settings, shedding, and genetic stability, and to describe the immunogenicity and 
safety of the vaccine in infants and toddlers 6 to < 24 months of age 
Study Code: VAD00014 
Amendment Number: 2 
Compound: Live-Attenuated Respiratory Syncytial Virus (RSV) ∆NS2/∆1313/I1314L vaccine 
(RSVt vaccine) 
Brief Title: 
Study on a live-attenuated Respiratory Syncytial Virus vaccine for assessment of safety, 
transmissibility, and genetic stability of the vaccine virus among close contacts in infants and 
toddlers 6 to < 24 months of age 
Study Phase: II 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Manufacturer: Same as Sponsor 
Regulatory Agency Identifier Number: 
WHO UTN: U1111-1278-3910 
Protocol Version Number: 4.0  
Approval Date: 28 September 2023 
Responsible medical officer (RMO) and pharmacovigilance (PV) representative names and 
contact information will be provided separately. 
The study centers, the investigators at each center, and the coordinating investigator(s) are also 
listed in a separate document. 
NCT Number: NCT05687279

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Document History  
 
Previous 
Version 
Date 
Comments 
1.0 
01 August 2022 
Version not submitted 
2.0 
13 October 2022 
First version used in the study 
3.0 
26 June 2023 
Amendment 1 
IEC: Independent Ethics Committee; IRB: Institutional Review Board 
* Versions in bold font have been approved by the IEC(s) / IRB(s) and used in the study. 
Overall Rationale for the Amendment: 
The amendment of protocol version 3.0 to protocol version 4.0 (Amendment 2) included 
administrative changes and the following changes:  
• An update of the endpoint of the 3rd primary objective to clarify that the sequencing is not 
limited to the NS2 region  
• An additional exploratory objective and endpoint for infectivity, and a clarification to the 
exploratory objective for 
 
• Clarification that the first interim analysis is planned in Q4 2023 on available participant 
data irrespective of recruitment completion and the second interim analysis is planned for 
all participants 
• Addition of symptoms of RSV medically attended acute respiratory illness and the 
corresponding grading scale 
• Addition of a description of RSV B green fluorescent protein microneutralization assay 
• Addition of height and weight measurements of pediatric participants at enrollment  
  

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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 ............................................................................................................................ 12 
1.3 
Schedule of Activities (SoA) .......................................................................................... 14 
2 
Introduction ..................................................................................................................... 18 
2.1 
Study Rationale ............................................................................................................... 18 
2.2 
Background ..................................................................................................................... 18 
2.3 
Benefit/Risk Assessment ................................................................................................ 20 
2.3.1 
Risks from Study Participation ..................................................................................... 20 
2.3.2 
Benefits from Study Participation ................................................................................ 21 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 21 
3 
Objectives and Endpoints ............................................................................................... 22 
4 
Study Design .................................................................................................................... 25 
4.1 
Overall Design ................................................................................................................ 25 
4.2 
Scientific Rationale for Study Design ............................................................................. 27 
4.3 
Justification for Dose ...................................................................................................... 28 
4.4 
End of Study Definition .................................................................................................. 29 
5 
Study Population ............................................................................................................. 30 
5.1 
Inclusion Criteria ............................................................................................................ 30 
5.1.1 
Inclusion Criteria .......................................................................................................... 30 
5.2 
Exclusion Criteria ........................................................................................................... 31 
5.3 
Lifestyle Considerations ................................................................................................. 33 
5.4 
Screen Failures ................................................................................................................ 33 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Administration of 
Study Intervention ........................................................................................................... 33 

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6 
Study Interventions and Concomitant Therapy ........................................................... 34 
6.1 
Study Interventions Administered .................................................................................. 34 
6.1.1 
Medical Devices ........................................................................................................... 35 
6.2 
Preparation, Handling, Storage, and Accountability ...................................................... 37 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 37 
6.3.1 
Randomization and Allocation Procedures .................................................................. 37 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 38 
6.4 
Study Intervention Compliance ...................................................................................... 39 
6.5 
Dose Modification .......................................................................................................... 39 
6.6 
Continued Access to Study Intervention After the End of the Study ............................. 39 
6.7 
Treatment of Overdose.................................................................................................... 39 
6.8 
Concomitant Therapy ...................................................................................................... 40 
6.8.1 
Rescue Medicine ........................................................................................................... 40 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 41 
7.1 
Discontinuation of Study Intervention ............................................................................ 41 
7.1.1 
Temporary Contraindications ....................................................................................... 41 
7.1.2 
Definitive Contraindications ......................................................................................... 41 
7.1.3 
Other Reasons ............................................................................................................... 42 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 42 
7.3 
Lost to Follow-up ............................................................................................................ 42 
8 
Study Assessments and Procedures ............................................................................... 44 
8.1 
Efficacy and Immunogenicity Assessments ................................................................... 44 
8.1.1 
Efficacy Assessments ................................................................................................... 44 
8.1.2 
Transmission and Vaccine Virus Shedding Assessments ............................................ 44 
8.1.2.1 
Vaccine virus shedding .............................................................................................. 45 
8.1.2.2 
 ..................................................................................................... 45 
8.1.3 
Immunogenicity Assessments ...................................................................................... 48 
8.1.3.1 
Immunogenicity Assessment Methods....................................................................... 48 
8.1.3.1.1 
RSV A and RSV B serum neutralizing antibody titers ............................................ 48 
8.1.3.1.2 
RSV Serum Anti-F IgG ELISA ............................................................................... 49 
8.1.3.1.3 
RSV Serum Anti-F IgA ELISA ............................................................................... 49 
8.2 
Safety Assessments ......................................................................................................... 49 
8.2.1 
Medical History ............................................................................................................ 49 
8.2.2 
Physical Examinations .................................................................................................. 50 
8.2.3 
Vital Signs .................................................................................................................... 50 
8.2.4 
Clinical Safety Laboratory Tests .................................................................................. 50 

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8.2.5 
Pregnancy Testing ........................................................................................................ 50 
8.2.6 
Viremia/Vaccinemia ..................................................................................................... 50 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting............... 50 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ......................... 51 
8.3.2 
Method of Detecting AEs and SAEs ............................................................................ 52 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................ 52 
8.3.4 
Regulatory Reporting Requirements for SAEs ............................................................ 52 
8.3.5 
Pregnancy ..................................................................................................................... 53 
8.3.6 
Adverse Events of Special Interest ............................................................................... 53 
8.3.7 
Medically Attended Adverse Events ............................................................................ 53 
8.4 
Pharmacokinetics ............................................................................................................ 53 
8.5 
Genetics ........................................................................................................................... 53 
8.6 
Biomarkers ...................................................................................................................... 53 
8.7 
Immunogenicity Assessments ......................................................................................... 53 
8.8 
Medical Resource Utilization and Health Economics .................................................... 54 
8.9 
Leftover Biological Samples ........................................................................................... 54 
8.10 
Use of Biological Samples And Data For Future Research ............................................ 54 
9 
Statistical Considerations ............................................................................................... 56 
9.1 
Statistical Hypotheses ..................................................................................................... 56 
9.2 
Analysis Sets ................................................................................................................... 56 
9.3 
Statistical Analyses ......................................................................................................... 57 
9.3.1 
General Considerations ................................................................................................. 57 
9.3.2 
Primary Endpoints ........................................................................................................ 57 
9.3.3 
Secondary Endpoints .................................................................................................... 58 
9.3.4 
Exploratory Endpoints .................................................................................................. 58 
9.3.5 
Other Analysis .............................................................................................................. 59 
9.4 
Interim Analyses ............................................................................................................. 59 
9.5 
Sample Size Determination ............................................................................................. 60 
10 
Supporting Documentation and Operational Considerations .................................... 60 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations ............................ 60 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 60 
10.1.2 
Financial Disclosure ..................................................................................................... 61 
10.1.3 
Informed Consent Process ............................................................................................ 61 
10.1.4 
Data Protection ............................................................................................................. 63 
10.1.5 
Committees Structure ................................................................................................... 65 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 65 
10.1.7 
Data Quality Assurance ................................................................................................ 65 
10.1.8 
Source Documents ........................................................................................................ 66 

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10.1.9 
Study and Site Start and Closure .................................................................................. 67 
10.1.10 
Publication Policy ......................................................................................................... 67 
10.2 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................... 68 
10.2.1 
Definition of AE ........................................................................................................... 68 
10.2.2 
Definition of SAE ......................................................................................................... 71 
10.2.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 72 
10.2.4 
Reporting of SAEs ........................................................................................................ 74 
10.2.5 
Assessment of Intensity ................................................................................................ 75 
10.2.5.1 
Tables for Clinical Abnormalities .............................................................................. 75 
10.2.5.1.1 
Solicited AR Intensity Grading Scale ...................................................................... 75 
10.2.5.1.2 
Serious and Non-serious Unsolicited AE Intensity Grading Scale .......................... 79 
10.3 
Appendix: Risk-based Approach .................................................................................... 79 
10.4 
Appendix: Protocol Amendment History ....................................................................... 80 
10.5 
Appendix: Abbreviations ................................................................................................ 81 
10.6 
References ....................................................................................................................... 83 
11 
Sponsor Signature Page .................................................................................................. 86 
 

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List of Tables  
Table 1.1: Schedule of activities for pediatric participants ........................................................... 14 
Table 1.2: Schedule of activities for ad-hoc close contact participants ........................................ 17 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 20 
Table 3.1: Objectives and endpoints ............................................................................................. 22 
Table 4.1: Overall design .............................................................................................................. 25 
Table 6.1: Study Interventions Administered ................................................................................ 34 
Table 6.2: Study Arms ................................................................................................................... 35 
Table 8.1: DAIDS severity scale for RSV MAARI ...................................................................... 46 
Table 8.2 Targets Detected by the ePlex Respiratory Pathogen Panel 2 Assay ............................ 47 
Table 10.1: 
.......................................................................... 76 
Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales – 
Infants and toddlers aged ≤ 23 months .......................................................................................... 77 
 

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List of Figures  
Figure 1:  Graphical study design for pediatric participants ......................................................... 13 
Figure 2:
............................ 36 
 

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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
Phase II, randomized, observer-blind, placebo-controlled, multi-center study of a live-attenuated 
Respiratory Syncytial Virus vaccine to assess the vaccine virus’ transmissibility in household or 
daycare center settings, shedding, and genetic stability, and to describe the immunogenicity and 
safety of the vaccine in infants and toddlers 6 to < 24 months of age  
Brief Title: 
Study on a live-attenuated Respiratory Syncytial Virus vaccine for assessment of safety, 
transmissibility, and genetic stability of the vaccine virus among close contacts in infants and 
toddlers 6 to < 24 months of age 
Rationale: 
In the context of intranasal administration of a live attenuated RSV vaccine and to demonstrate 
that a large-scale study with the RSVt vaccine can be conducted safely, both the transmission rate 
and the genetic stability of the vaccine virus will be determined. In addition, the vaccine virus 
shedding will be described in the RSVt vaccinees at regular timepoints and the clinical safety in 
their close contacts will be assessed.  
Data generated in the VAD00014 study will provide insights into the transmission of the RSVt 
vaccine virus and genetic stability, along with the safety and immunogenic profile of the RSVt 
vaccine candidate, and may support the next steps of the development, including the planned 
large-scale Phase III efficacy study. 
Objectives, Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
• 
To describe the vaccine virus transmission in 
pediatric participants receiving placebo after 
the first study intervention administration 
 
 
 
• 
To describe the vaccine virus shedding in all 
pediatric participants with detected vaccine 
virus after each administration 
 
 
• 
Presence of vaccine virus in day (D)01, D04, 
D08, D11, D15, D18, and D22 nasal swabs, 
detected by RSVt quantitative reverse 
transcription polymerase chain reaction (RSVt 
qRT-PCR) Assay in pediatric participants 
receiving placebo. 
 
• 
Titer of vaccine virus shedding in D01, D04, 
D08, D11, D15, D18, D22, D64, and D71 
nasal swabs, quantified by RSVt qRT-PCR 
Assay in all pediatric participants. 
 

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Objectives 
Endpoints 
• 
To describe the vaccine virus stability in 
pediatric participants receiving placebo and 
ad-hoc close contact participants 
• 
Difference in genetic sequence of mutated 
vaccine virus segments compared to the 
reference strain vaccine virus isolates in the 
vaccine virus positive swabs from pediatric 
participants receiving placebo and ad-hoc 
close contact participants 
Secondary  
 
Immunogenicity 
• 
To evaluate the RSV A serum neutralizing and 
RSV serum anti-F immunoglobulin G (IgG) 
antibody responses to the study intervention 
after each study intervention administration in 
all pediatric participants 
Immunogenicity 
• 
RSV A serum neutralizing antibody titers up 
to 28 days after the second administration 
(D01, D57, and D85) 
• 
RSV serum anti-F IgG enzyme-linked 
immunosorbent assay (ELISA) antibody titers 
up to 28 days after the second administration 
(D01, D57, and D85) 
Safety 
• 
To assess the safety profile of the RSVt 
vaccine after each and any study intervention 
administration in pediatric participants 
Safety 
• 
Presence of any unsolicited systemic adverse 
events (AEs) reported in the 30 minutes after 
each study intervention administration 
• 
Presence of any solicited (ie, pre-listed in the 
participant’s diary card [DC] and in the case 
report book [CRB]) administration site and 
systemic reactions within 21 days after each 
study intervention administration 
• 
Presence of any unsolicited (spontaneously 
reported) AEs within 28 days after each study 
intervention administration 
• 
Presence of any adverse events of special 
interest (AESIs) within 28 days after each 
study intervention administration 
• 
Presence of any medically attended adverse 
events (MAAEs) within 28 days after each 
study intervention administration 
• 
Presence of any serious adverse events (SAEs) 
throughout the study 
Transmission and virus shedding 
• 
To describe the vaccine virus transmission in 
pediatric participants receiving placebo after 
the second study intervention administration 
Transmission and virus shedding 
• 
Presence of vaccine virus in D64 and D71 
nasal swabs, detected by RSVt qRT-PCR 
Assay in the pediatric participants receiving 
placebo 

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Overall Design: 
 
Type of design 
Parallel, multi-center 
Phase 
II 
Control method 
Placebo-controlled 
Study population 
• 
Pediatric participants: 
Healthy infants / toddlers 6 to < 24 months of 
age in close contact with other infants / 
toddlers 6 to < 24 months of age who 
participate in the study 
• 
Ad-hoc close contact participants: 
ad-hoc close contact children and adults who 
experience acute respiratory illness (ARI) in 
the 28 days following the administration of the 
study intervention to the close contact 
pediatric participant  
Countries 
United States and Puerto Rico 
Level and method of blinding 
Observer-blind: 
• 
Blinding for vaccine group assignment: 
participants, parents or legally acceptable 
representative (LAR), outcome assessors, 
investigators, laboratory personnel, Sponsor 
study staff 
• 
No blinding for study staff who prepare and 
administer the study interventions 
Study intervention assignment method 
Pediatric participants will be screened for 
eligibility criteria at the time of inclusion and 
randomized to receive either RSVt vaccine or 
placebo in a 1:1 ratio 
Brief Summary: 
The primary purpose of the VAD00014 study is to assess the shedding, transmission, and genetic 
stability of the live-attenuated RSVt vaccine after each intranasal vaccination (56 days apart) in 
infants and toddlers 6 to < 24 months of age. Study details include: 
The study duration will be: 
• up to 8 months, including the 6 months safety follow-up phone call after the second study 
intervention administration for the pediatric participants 
The treatment administration for the pediatric participants will be on D01 and D57 (1 intranasal 
administration each). 

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The visit frequency will be twice a week after D01 (ie, first administration of study intervention) 
up to D22 for a total of 7 visits (D01, D04, D08, D11, D15, D18, and D22), and 7, 14, and 28 days 
after D57 (second administration) at D64, D71, and D85. Some of these visits may be managed as 
home visits or daycare center visits. 
Additional illness visits may occur during the study intervention phase (D01-D85) in case of acute 
respiratory symptoms. 
Number of Participants: 
A total of 100 pediatric participants are expected to be randomized (50 participants in each study 
intervention group). 
Intervention Groups and Duration: 
Eligible pediatric participants will be randomized in a 1:1 ratio to receive 2 intranasal 
administrations (56 days apart) of either the RSVt vaccine or placebo at D01 and D57. 
Eligible ad-hoc close contacts will be enrolled if they develop ARI symptoms and will not receive 
any study intervention. 
The duration of participation will be approximately 8 months for each pediatric participant. The 
duration of participation of the ad-hoc close contacts is limited to the illness Visit(s). 
Study interventions: 
Investigational medicinal product 1: RSVt vaccine 
• Form: Suspension of virus 
• Composition: Each
 dose of RSVt vaccine will contain the live-attenuated RSV with i) 
 approximately 
 to be delivered 
• Route of administration: intranasal 
Statistical considerations: 
All analysis will be descriptive. No statistical hypothesis will be tested. 
All endpoints will be summarized by study intervention group. For the main parameters, 95% 
confidence interval (CI) of point estimate will be calculated. 
Data Monitoring/Other Committee: No 
1.2 
Schema  
The graphical design of VAD00014 study for pediatric participants is presented in Figure 1. 

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Figure 1:  Graphical study design for pediatric participants  
 

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1.3 
Schedule of Activities (SoA)  
Table 1.1: Schedule of activities for pediatric participants  
Phase II Study, 11 Planned Visits, 2 Vaccinations, 3 Blood Samples, 9 Planned Nasal Swabs, One 6-Month Safety Follow-up Phone Call, 
approximately 8 Months’ Duration Per Pediatric Participant 
Visit/Contact* 
Collection 
of 
information 
in the CRF 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Safety 
follow-
up 
phone 
call 
Illness 
Visit‡‡ 
Study timelines days (D) 
 
D01 
D04 
D08 
D11 
D15 
D18 
D22 
D57 
D64 
D71 
D85 
D237 
 
Visit Interval 
 
 
V01 + 
3d 
V01 + 
7d 
V01 + 
10d 
V01 + 
14d 
V01 + 
17d 
V01 + 
21d 
V01 + 
56d 
V08 + 
7d 
V08 + 
14d 
V08 + 
28d 
V08 + 
6 
months 
 
Time windows (days) 
 
NA 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+7] 
[+1] 
[+1] 
[+7] 
[+14] 
 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of medical history 
X 
Significant  
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Vital signs† 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Rapid COVID-19 test 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 

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Visit/Contact* 
Collection 
of 
information 
in the CRF 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Safety 
follow-
up 
phone 
call 
Illness 
Visit‡‡ 
Study timelines days (D) 
 
D01 
D04 
D08 
D11 
D15 
D18 
D22 
D57 
D64 
D71 
D85 
D237 
 
Visit Interval 
 
 
V01 + 
3d 
V01 + 
7d 
V01 + 
10d 
V01 + 
14d 
V01 + 
17d 
V01 + 
21d 
V01 + 
56d 
V08 + 
7d 
V08 + 
14d 
V08 + 
28d 
V08 + 
6 
months 
 
Time windows (days) 
 
NA 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+7] 
[+1] 
[+1] 
[+7] 
[+14] 
 
Collection of reportable concomitant 
medications/vaccinations 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Randomization/allocation of participant 
number 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dose number 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Blood sampling (BL) [5  mL] 
X 
BL0001 
Pre-vac1 
 
 
 
 
 
 
BL0002 
Pre-vac2 
 
 
BL0003 
 
 
Nasal swab (NS)‡ 
X 
NS0001 
Pre-vac1 
NS0002 
NS0003 
NS0004 
NS0005 
NS0006 
NS0007 
 
NS0008 
NS0009 
 
 
UN0001 
to 
UN000X 
Vaccination (vac) 
X 
VAC1 
 
 
 
 
 
 
VAC2 
 
 
 
 
 
Immediate surveillance (30 min)§ 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
DC provided** 
 
DC1 
 
 
 
 
 
 
DC2 
 
 
 
 
 
DC reviewed†† 
 
 
DC1 
DC1 
DC1 
DC1 
DC1 
DC1 
DC1 
DC2 
DC2 
DC2 
 
 
DC collected 
 
 
 
 
 
 
 
 
DC1 
 
 
DC2 
 
 
MA provided 
 
 
 
 
 
 
 
 
 
 
 
MA 
 
 
MA reviewed 
 
 
 
 
 
 
 
 
 
 
 
 
MA 
 
Collection of solicited administration 
site and systemic reactions 
X 
From D01 to D22 
From D57 to D78 
 
 
Collection of unsolicited AEs 
X 
From D01 to D29 
From D57 to D85 
 
 

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Visit/Contact* 
Collection 
of 
information 
in the CRF 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
V11 
Safety 
follow-
up 
phone 
call 
Illness 
Visit‡‡ 
Study timelines days (D) 
 
D01 
D04 
D08 
D11 
D15 
D18 
D22 
D57 
D64 
D71 
D85 
D237 
 
Visit Interval 
 
 
V01 + 
3d 
V01 + 
7d 
V01 + 
10d 
V01 + 
14d 
V01 + 
17d 
V01 + 
21d 
V01 + 
56d 
V08 + 
7d 
V08 + 
14d 
V08 + 
28d 
V08 + 
6 
months 
 
Time windows (days) 
 
NA 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+1] 
[+7] 
[+1] 
[+1] 
[+7] 
[+14] 
 
Collection of AESIs and MAAEs 
X 
From D01 to D29 
From D57 to D85 
 
 
Collection of SAEs 
X 
Throughout the study 
 
Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Collection of End of Study Intervention 
Phase status 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Collection of 6-Month Follow-up-End 
of Study status 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; COVID-19, coronavirus disease 2019; CRF, case report form; DC: diary card; LAR, legally acceptable representatives; MA, 
memory aid; MAAE, medically-attended adverse event; NA, not applicable; SAE, serious adverse event. 
* Additional unscheduled visits may be performed for safety reasons; information will be reported in the source documents. 
† Vital signs will be collected in the eCRF. 
‡ All pediatric participants will provide a nasal swab sample for detection of vaccine virus shedding / transmission at specified visits. The same nasal swab specimen may also be tested for respiratory 
pathogens (including COVID-19), if the pediatric participant is ill at the time of the visit. If needed, home visits (including Illness Visit) may be conducted by a clinical site nurse to perform the nasal 
swabs, except for V07, which should be done at the clinical site (as a physician should review the diary card). 
§ Any unsolicited systemic adverse events occurring within the 30 minutes from study intervention administration will be recorded as immediate unsolicited systemic AE in the case report book. 
** The investigator or a designee will remind the parents / LAR to bring back the DC at the next visit and will answer any questions. 
The parent / LAR will record information in the DC about solicited reactions from D01 to D22, and unsolicited AEs and AESIs from D01 to D29 after each study intervention administration. 
†† The investigator or a designee will interview the parents / LAR to collect the information recorded in the DC and will attempt to clarify anything that is incomplete or unclear. In case of home visit(s) 
done by a clinical site nurse, the DC will be reviewed by a physician at the next clinical site visit. 
‡‡ Illness Visits: Additional nasal swab specimens for the detection of RSV and respiratory pathogens” (including COVID-19) will also be collected from pediatric participants in case of acute respiratory 
illness. All the nasal swab specimens will be collected in the recommended viral transport media tube and will be stored between -60°C and -80°C until ready to ship. 

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Table 1.2: Schedule of activities for ad-hoc close contact participants  
Phase II Study, at least 1 Unplanned Illness Visit, at least 1 Unplanned Nasal Swab, Duration is limited to the Illness Visit(s) 
Visit (V) / Contact* 
Collection of information in the CRF 
Illness Visit(s) 
Study timelines - Days(D) 
 
Not applicable 
Visit Interval 
 
ARI** symptoms during the 28 days following any 
administration of the study intervention to the close contact 
pediatric participant 
Time windows (days)  
 
Not applicable 
Informed consent†  
X 
X 
Collection of demographic data† 
X 
X 
Allocation of participant number† 
X 
X 
Nasal swab (NS)‡   
X 
UN0001 to UN000X§ 
Collection of End of Study status 
X 
At the end of the study intervention phase for the pediatric 
participant in close contact to ad-hoc participant 
Abbreviations: CRF, case report form; ARI, acute respiratory illness 
* Additional unscheduled visits may be performed for safety reasons; information will be reported in the source documents. 
† To be collected during the first illness visit. 
‡ Illness Visits: All the nasal swab specimens will be collected in the recommended viral transport media tube and will be stored between -60°C and -80°C until ready to ship. 
§ Ad-hoc close contact participants will provide a nasal swab sample for detection of vaccine virus transmission. The same nasal swab specimen may also be tested for respiratory pathogens (including 
COVID-19). 
** Acute respiratory illness includes upper and lower respiratory illness.

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2 
Introduction  
2.1 
Study Rationale  
In the context of intranasal administration of a live attenuated RSV vaccine and to demonstrate 
that a large-scale study with the RSVt vaccine can be conducted safely, both the transmission rate 
and the genetic stability of the vaccine virus will be determined. In addition, the vaccine virus 
shedding will be described in the RSVt vaccinees at regular timepoints and the clinical safety in 
their close contacts will be assessed.  
Data generated in the VAD00014 study will provide insights into the transmission of the RSVt 
vaccine virus and genetic stability, along with the safety and immunogenic profile of the RSVt 
vaccine candidate, and may support the next steps of the development, including the planned large 
scale Phase III efficacy study. 
2.2 
Background  
Respiratory syncytial virus (RSV) is the most important cause of severe acute lower respiratory 
illness (LRI) in infants and children (1) (2) and the most common cause of severe pneumonia 
requiring hospital admission in children worldwide (3). According to global estimates, RSV 
caused approximately 33 million cases of LRI and approximately 118 000 deaths in 
children < 5 years of age in 2015 (2). 
Live attenuated intranasal RSV vaccines are an attractive option for pediatric immunization 
because they mimic mild natural infections and induce durable cellular, humoral, and both local 
and systemic immunity. Several studies of live attenuated RSV vaccine candidates have indicated 
that these vaccines do not cause the vaccine-associated enhanced RSV disease observed in 
children who received formalin-inactivated RSV (4) (5) (6) (7) (8) (9) (10) (11) (12). Progress has 
been made in the understanding of the RSV gene function, and the use of reverse genetic systems 
to engineer rationally-designed attenuated RSV strains, including strains attenuated through 
deletion of the nonstructural (NS) 2 gene like the live attenuated RSV ΔNS2/Δ1313/I1314L 
vaccine candidate (13) (14). RSV NS2 is a virally-encoded type I and III interferon antagonist that 
interferes with interferon induction and signaling (15) (16) (17). The increased interferon response 
to infection may enhance the adaptive immune response, as has been demonstrated for bovine 
RSV with NS1 or NS2 deletion in calves (18). NS2 also functions as a pathogenicity factor, 
promoting epithelial cell shedding in vitro and in the hamster model, and its deletion may 
potentially reduce small airways obstruction, thus improving the safety profile of such vaccine 
candidates (19). 
Live Attenuated Respiratory Syncytial Virus (RSV) ΔNS2/Δ1313/I1314L Vaccine Candidate 
The investigational RSV ΔNS2/Δ1313/I1314L vaccine (hereafter referred to as the NIH RSV 
ΔNS2/Δ1313/I1314L vaccine), developed at the Laboratory of Infectious Diseases at the National 
Institute of Allergy and Infectious Diseases, is based on reverse genetics approaches used to create 

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deletions of the gene encoding the RSV interferon / apoptosis antagonist NS2 protein (∆NS2). 
Deletion of NS2 gene attenuates the virus and may enhance immunogenicity. RSV 
ΔNS2/Δ1313/I1314L vaccine additionally contains a genetically stabilized attenuating and 
temperature sensitivity mutation in the L protein (codon deletion ∆1313, as well as a missense 
mutation I1314L that prevents a de-attenuating mutation that otherwise can occur at position 
1314). The RSV ΔNS2/Δ1313/I1314L temperature sensitivity translates into a shut-off of virus 
replication at 38ºC-39°C. 
Prior to RSV ΔNS2/Δ1313/I1314L vaccine, three RSV vaccine viruses with the NS2 gene 
deletion (rA2cpΔNS2, rA2cp248/404ΔNS2, and rA2cp530/1009ΔNS2) had been evaluated in 
clinical studies (6). The rA2cpΔNS2 candidate was over-attenuated for adults but under-
attenuated for use in young children, whereas both rA2cp248/404ΔNS2 and rA2cp530/1009ΔNS2 
were over-attenuated and insufficiently immunogenic in seronegative children. 
Sanofi’s investigational RSV ΔNS2/Δ1313/I1314L vaccine (hereafter referred to as RSVt 
vaccine) is the same construct as the NIH RSV ΔNS2/Δ1313/I1314L vaccine. The vaccines differ 
in formulation and mode of intranasal administration. The RSVt vaccine is being developed for 
the pediatric population.  
Phase I Clinical Data (NIH RSV ΔNS2/Δ1313/I1314L) 
A Phase Ia study was conducted by the National Institutes of Health (NIH) in RSV seronegative 
children aged 6 to 24 months (n=20) who received NIH RSV ΔNS2/Δ1313/I1314L vaccine at the 
106 PFU dose level. This study showed that the 106 PFU dose level was safe, had good infectivity 
(100% of vaccinated participants infected) and immunogenicity (80% of participants with a > 4-
fold rise in neutralizing antibody titers), and primed for a strong anamnestic response to wildtype 
(WT) RSV infection in the post-RSV season surveillance (20).  
Another study aiming at describing the safety and immunogenicity of the NIH RSV 
ΔNS2/Δ1313/I1314L vaccine in RSV-seronegative children (IMPAACT 2018, NCT03227029 / 
NCT03422237) confirm the previous results such as the good safety profile, high infectivity 
(88%) and genetic stability of the candidate (21).  
This vaccine candidate is presently being evaluated in infants 4 to 6 months of age (unscreened 
for RSV antibodies at baseline) by the NIH at the Center for Immunization Research, Johns 
Hopkins University (NCT01893554) (22). In this younger age cohort, 15 participants have been 
enrolled to date and have completed the post-vaccination acute and post-acute-phase follow-up to 
date, without any safety signals. 
Based on these Phase I study data, RSVt vaccine appears to be safe and immunogenic, and it is 
currently being evaluated by Sanofi for further clinical development. 
Phase I/II Clinical Study (RSVt Vaccine) 
The ongoing Sanofi Phase I/II study (VAD00001) is a randomized, observer-blind, placebo-
controlled, multi-center, dose-finding study to evaluate the safety, immunogenicity, infectivity, 
and vaccine virus shedding after 1 or 2 administrations of the Sanofi RSVt vaccine in infants and 
toddlers 6 to 18 months of age in the United States and Latin America (Chile and Honduras). A 
total of 259 infants and toddlers 6 to18 months of age have been randomized to receive 1 or 2 

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intranasal administrations of RSVt vaccine (at either an investigational dose level of 
 
2.3 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events, the potential risks, and uncertainties of RSVt vaccine may be found in the 
Investigator’s Brochure (IB) and Investigational Directions for Use (IDFU) for a device product. 
2.3.1 Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
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: RSVt Vaccine 
Anaphylaxis 
All vaccines have the potential to 
cause allergic reactions or 
anaphylaxis in individuals who 
may be sensitized to components 
of the vaccine. 
Exclusion criterion E02 for those 
at increased risk.  
Observation period after 
vaccination for early detection 
and treatment. 
Each site must have measures to 
treat Anaphylaxis available at 
the time of vaccination 
Upper or lower respiratory tract 
illness 
If a live-attenuated RSV vaccine 
is insufficiently attenuated, 
participants could experience 
upper or lower respiratory tract 
illness 
Medical surveillance with 
qualified medical personnel to 
provide care if needed 
Study Procedures 
Vasovagal reactions (syncope), 
or psychogenic reactions to 
needle (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 
Observation period after 
vaccination for early detection 
and treatment. 

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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
Infection in rare instances at the 
blood draw site 
 
Early detection, observation, and 
appropriate treatment. 
Use of topical anesthetic cream 
include temporary skin 
discoloration, skin irritation, 
rash, hives, and rarely dizziness 
or drowsiness 
 
Early detection, observation, and 
appropriate treatment. 
Other 
Risks occasionally associated 
with nasal swabs include pain or 
discomfort and occasionally 
epistaxis. Nasal swabs are not 
standard care in pediatric 
population. 
 
Study personnel performing 
nasal swab will receive 
appropriate training to perform 
the procedure 
2.3.2 Benefits from Study Participation  
Pediatric participants randomized in the group to receive the RSVt vaccine may benefit from 
coverage against respiratory syncytial virus and may be less likely to develop RSV associated 
pneumonia or RSV related severe illness and/or hospitalization. 
However, as with all vaccines, vaccination with the investigational vaccine may not protect 
individuals 100%. 
2.3.3 Overall Benefit-Risk Conclusion  
Considering the measures taken to minimize risk to participants enrolled in this study, the 
anticipated benefits, that may be afforded, outweigh the potential risks that may result from study 
participation. 

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3 
Objectives and Endpoints  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To describe the vaccine virus 
transmission in pediatric participants 
receiving placebo after the first study 
intervention administration 
 
 
• 
To describe the vaccine virus 
shedding in all pediatric participants 
with detected vaccine virus after each 
administration 
 
• 
To describe the vaccine virus stability 
in pediatric participants receiving 
placebo and ad-hoc close contact 
participants 
• 
Presence of vaccine virus in day (D)01, D04, D08, 
D11, D15, D18, and D22 nasal swabs, detected by 
RSVt quantitative reverse transcription polymerase 
chain reaction (qRT-PCR) Assay in pediatric 
participants receiving placebo 
 
• 
Titer of vaccine virus shedding in D01, D04, D08, 
D11, D15, D18, D22, D64, and D71 nasal swabs, 
quantified by RSVt qRT-PCR Assay in all pediatric 
participants 
 
• 
Difference in genetic sequence of mutated vaccine 
virus segments compared to the reference strain 
vaccine virus isolates in the vaccine virus positive 
swabs from pediatric participants receiving placebo 
and ad-hoc close contact participants 
Secondary 
 
Immunogenicity 
• 
To evaluate the RSV A serum 
neutralizing and RSV serum anti-F 
immunoglobulin G (IgG) antibody 
responses to the study intervention 
after each study intervention 
administration in all pediatric 
participants 
Immunogenicity 
• 
RSV A serum neutralizing antibody titers up to 
28 days after the second administration (D01, D57, and 
D85) 
• 
RSV serum anti-F IgG ELISA antibody titers up to 
28 days after the second administration (D01, D57, and 
D85) 
Safety 
• 
To assess the safety profile of the 
RSVt vaccine after each and any study 
intervention administration in 
pediatric participants. 
Safety 
• 
Presence of any unsolicited systemic AEs reported in 
the 30 minutes after each study intervention 
administration  
• 
Presence of any solicited (ie, pre-listed in the 
participant’s diary card [DC] and in the case report 
book [CRB]) administration site and systemic 
reactions within 21 days after each study intervention 
administration 

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Objectives 
Endpoints 
• 
Presence of any unsolicited (spontaneously reported) 
AEs within 28 days after each study intervention 
administration  
• 
Presence of any AESIs within 28 days after each 
study intervention administration 
• 
Presence of any MAAEs within 28 days after each 
study intervention administration  
• 
Presence of any SAEs throughout the study  
Transmission and virus shedding 
• 
To describe the vaccine virus 
transmission in pediatric participants 
receiving placebo after the second 
study intervention administration 
Transmission and virus shedding 
• 
Presence of vaccine virus in D64 and D71 nasal 
swabs, detected by RSVt qRT-PCR in the pediatric 
participants receiving placebo 
Exploratory 
 
 
 

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Objectives 
Endpoints 
 
 
 
 

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4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design  
Type of design 
Parallel, multi-center 
Phase 
II 
Control method 
Placebo-controlled 
Study population 
• 
Pediatric participants: 
Healthy infants / toddlers 6 to < 24 months of age in close contact 
with other infants / toddlers 6 to < 24 months of age who will 
participate in the study 
• 
Ad-hoc close contact participants: 
Ad-hoc close contact children and adults who experience ARI in 
the 28 days following the administration of the study intervention 
to the close contact pediatric participant  
Level and method of blinding 
Observer-blind: 
• 
Blinding for study intervention group assignment: participants, 
parents or LAR, outcome assessors, investigators, laboratory 
personnel, Sponsor study staff 
• 
No blinding for study staff who prepare and administer the study 
interventions 
Study intervention assignment method 
Pediatric participants will be screened for eligibility criteria at the time 
of inclusion and randomized to receive either RSVt vaccine or placebo 
in a 1:1 ratio.  
Randomization will be stratified by contact group (the household 
/group attended in daycare center) and by age group (< 12 months / 
≥ 12 months) 
Number of participants 
100 pediatric participants 6 to < 24 months of age  
Intervention groups 
Eligible pediatric participants will be randomized in a 1:1 ratio to 
receive 2 intranasal administrations (56 days apart) of either the RSVt 
vaccine or placebo at D01 and D57 
Total duration of study participation 
Approximately 8 months for each pediatric participant. The duration of 
the ad-hoc close contacts will be limited to the Illness Visit. 
Countries 
United States and Puerto Rico 
Use of an Independent Data Monitoring 
Committee, Dose Escalation Committee, 
or similar review group 
NO 

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VAD00014 study is planned to enroll a convenience sample of 100 children aged 6 to 
< 24 months (hereafter referred as pediatric participants) at least by pairs or larger groups of 
children, living in a context in which the probability of transmission is maximized, ie, group of 
children attending daycare centers, twins, and children living with siblings of similar age. The 
pediatric participants will be randomized to receive either the RSVt vaccine or placebo (the 
placebo group will allow to assess the transmissibility and safety of the RSVt vaccine in a blinded 
way).  
VAD00014 study will be randomized, observer-blind, placebo-controlled, and will include 
2 administrations, 56 days apart (ie, at Day (D)01 and D57). Pediatric participants will be 
randomized in 1:1 ratio and are planned to be enrolled in pairs or in small groups (ie, siblings or 
attending the same daycare center) to ensure that transmissibility from pediatric participants 
receiving the RSVt vaccine to pediatric participants receiving the placebo can be evaluated. 
Shedding, transmissibility, and genetic stability of the vaccine virus will be assessed through the 
collection of nasal swabs at regular intervals after each study intervention administration. As 
RSVt vaccine will be administered by intranasal route, vaccine virus shedding is then expected in 
the nose. Therefore, nasal swabs are commonly used for shedding assessment, especially in the 
infant population in which nasal washes are more invasive.  
In addition, pediatric participant’s close contacts who experience an ARI in the 28 days following 
the study intervention administration may be asked to provide a nasal swab. The pediatric 
participant’s close contacts are any persons who are in the same room as the pediatric participant 
for more than 4 hours a day for at least 3 days a week. These may include children attending the 
same daycare center, daycare center staff in contact with pediatric participants, or household 
members of pediatric participants. They are hereafter referred to as the ad-hoc close contact 
participants. 
Each pediatric participant will provide a blood sample at baseline, and after each study 
intervention administration, ie, 56 days after the first administration (D57, pre-administration 2) 
and 28 days after the second administration (D85). The blood sample collected at Visit 01 will be 
used to determine the pediatric participant’s RSV serostatus at baseline. The blood samples 
collected at Visit 08 and Visit 11 will be used to assess the pediatric participants’ immune 
response after each administration. The RSVt vaccine immunogenicity will be evaluated using an 
RSV A microneutralization assay and an RSV anti-F IgG ELISA. 
The safety profile of the study interventions will be assessed in all pediatric participants after each 
administration with the collection of: 
• immediate AEs occurring within 30 minutes 
• solicited administration site and systemic reactions within 21 days after each study 
intervention administration 
• unsolicited AEs, AESIs, and MAAEs within 28 days after each study intervention 
administration 
• serious AEs (SAEs) throughout the study 
For the ad-hoc close contact participants, MAAEs related to study procedures will be followed up 
to 28 days after each study procedure and collected in source documents. 

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The following AESIs will be collected: 
4.2 
Scientific Rationale for Study Design  
Rationale for enrolling pediatric participants 
It is expected that infants who already had RSV infection or who are seropositive present a lower 
virus shedding and thus a lower probability of vaccine virus transmission to their close contacts 
(23). In VAD00014 study, potential pediatric participants will not be screened based on their RSV 
baseline serostatus. Therefore, in order to maximize the probability of transmission during the 
study, enrolling a higher proportion of children aged 6 to 12 months may help to increase the 
proportion of seronegative participants and thereby increase the probability of transmission to 
pediatric participants receiving the placebo and / or to ad-hoc close contact participants. Some 
efforts will be made to enroll twins, to optimize the probability of transmission, and to limit the 
possible impact of age difference between the RSVt vaccine and placebo recipients. Stratification 
by age group could also be a way to control for the age distribution among RSVt vaccine and 
placebo recipients (eg, to ensure that for siblings, some younger and older children will receive 
RSVt vaccine).  
Evaluation of Vaccine Virus Transmission 
Transmission of the vaccine virus will be defined as presence of detected vaccine virus in the 
pediatric participants placebo-recipients and ad-hoc close contact participants, by RSVt qRT-PCR 
assay. Planned nasal swabs will be collected on all pediatric participants (ie, vaccinees and 
placebo recipients) on D01, D04, D08, D11, D15, D18, D22, D64, and D71. Nasal swabs will not 
be collected on D57 or D85 since vaccine virus shedding is not expected to last so long after the 
first administration and is expected to be lower after the second administration. 
Based on an NIH study conducted with the same vaccine construct and on the same target 
population (20), it is expected that the probability of transmission from vaccinees to other persons 
will be higher when the virus shedding in the vaccinees is the highest (between 4 and 9 days after 
vaccine administration), so that nasal swabs will be collected regularly after the first 
administration to be able to detect vaccine virus. Vaccine virus shedding is expected to be lower 
after the second administration (8), justifying the collection of fewer nasal swabs after the second 
administration, and performing the interim analysis of the primary objective of transmission after 
the first dose. 

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Illness Visit(s) 
For any pediatric participants presenting clinical symptoms of ARI during the intervention phase 
(D1 to D85), an additional nasal swab may be collected to identify potential WT RSV infection 
with Multiplex RT-PCR. Some of the regular nasal swabs from symptomatic children in which no 
vaccine virus was detected may also be tested for WT RSV strain. If ARI is diagnosed < 2 days 
before or after a scheduled nasal swab, then the planned nasal swab will be used for WT RT-PCR 
testing. The ad-hoc close contact participants with any clinical symptoms of ARI within 28 days 
after study intervention administration of the close contact pediatric participant should have an 
illness visit. 
Consideration of the RSV Season 
The VAD00014 study is planned to start during Quarter (Q)4 2022, regardless of the actual start 
of the RSV season. In the Northern Hemisphere, the RSV season usually begins in late Q3 or 
early Q4 and lasts about 5 months. However, due to the increased variability in the RSV 
epidemiology since the beginning of the SARS-CoV-2 pandemic, it is difficult to evaluate the 
extent to which the RSV season will impact the clinical study. To mitigate the impact of the RSV 
season during the study, ARI will be followed up to 28 days after the second study intervention 
administration for all pediatric participants. Baseline blood sample will be used as an indication of 
possible previous RSV exposure. 
Non-exclusion of pregnant women participants 
Ad-hoc close contact participants can include pregnant females as they will only provide nasal 
swabs and will not receive any study intervention. Thus, VAD00014 study can be considered a 
safety surveillance study for the ad-hoc close contact participants and therefore pregnant women 
are not excluded from participating in the study. 
4.3 
Justification for Dose  
Justification for 2 doses administration schedule 
There are several published studies evaluating 2 or 3 administrations of attenuated RSV 
or  parainfluenza virus type 3 (PIV3) candidate vaccines (4) (5) (8) (24) (25) (26) (27) (28) (29). 
Generally, there was a high level of restriction of the second administration, and limited serum 
immune responses. The main effect was vaccine infectivity in the individuals who did not respond 
to the first administration. Two administrations of RSV ∆NS2/∆1313/I1314L may improve the 
infectivity of either dose. 

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Justification for vaccine dose 
The vaccine dose has been selected based on benefit/risk assessment based on results obtained the 
first Phase I/II VAD00001 study conducted in infants and toddlers 6 to 18 months of age 
receiving 2 doses of RSVt vaccine at concentration of 
  
4.4 
End of Study Definition  
A participant is considered to have completed the study if he/she has completed the last visit or 
contact planned in the SoA. 
The end of the study is defined as the date of the last visit or contact of the last participant in the 
study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized. 

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5 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria  
5.1.1 Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
AGE 
I01. 
Aged 6 months to < 24 months on the day of inclusion1 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS 
I02. 
Participants who are healthy as determined by medical evaluation including medical 
history. 
I03. 
Born at full term of pregnancy (≥ 37 weeks) or born after a gestation period of 27 through 
36 weeks and medically stable as assessed by the investigator, based on the following 
definition: “Medically stable” refers to the condition of premature infants who do not 
require significant medical support or ongoing management for debilitating disease and 
who have demonstrated a clinical course of sustained recovery by the time they receive the 
first dose of study intervention 
I04. 
Attends a daycare facility at least 3 days per week and 4 hours per day at which the 
participant would be in a contact group/playroom of at least one other child 6 to 
< 24 months of age who will participate in this study or is a member of a household, which 
includes at least one other child 6 to < 24 months of age who will participate in this study 
INFORMED CONSENT 
I05. 
Informed consent form has been signed and dated by the parent(s) or other legally 
acceptable representative (and by an independent witness if required by local regulations) 
OTHER INCLUSIONS 
I06. 
Participant and parent/legally acceptable representative are able to attend all scheduled 
visits and to comply with all study procedures 
                                                 
 
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5.2 
Exclusion Criteria  
Pediatric participants are not eligible for the study if any of the following criteria are met: 
MEDICAL CONDITIONS 
E01. Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months) 
E02. Known systemic hypersensitivity to any of the study intervention components, or history 
of a life-threatening reaction to the study intervention used in the study or to a product 
containing any of the same substances2 
E03. Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere 
with study conduct or completion3 
E04. Any acute febrile illness in the past 48 hours that according to investigator judgment is 
significant enough to interfere with successful inoculation on the day of vaccination. A 
prospective participant should not be included in the study until the condition has resolved 
or the febrile event has subsided. 
E05. Probable or confirmed ongoing case of COVID-19 at the time of enrollment 
E06. Member of a household that contains an immunocompromised individual, including, but 
not limited to: 
• a person who is HIV infected 
• a person who has received chemotherapy within the 12 months prior to study 
enrollment 
• a person who has received (within the past 6 months) or is receiving (at the time of 
enrollment) immunosuppressant agents 
• a person living with a solid organ or bone marrow transplant 
E07. Member of a household that includes, or will include, an infant who is less than 6 months 
of age at the time of enrollment 
                                                 
 
2  The components of study intervention are listed in Section 6.1 of the protocol and in the Investigator’s Brochure.  
3  Chronic illness may include, but is not limited to, cardiac disorders, lung disease (including any history of reactive 
airway disease, receipt of bronchodilator or inhaled steroid therapy, or medically diagnosed wheezing), atopy, 
renal disorders, auto-immune disorders, diabetes, psychomotor diseases, and known congenital or genetic diseases 

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E08. Attends a daycare facility and shares a daycare room with infants less than 6 months of 
age, and parent/legally acceptable representative is unable or unwilling to suspend 
attendance at the daycare facility for 28 days following study intervention administration 
E09. Any need of supplemental oxygen therapy in a home or hospital setting at the time of 
enrollment. 
PRIOR/CONCOMITANT THERAPY 
E10. Participant’s mother previous receipt or planned administration of an investigational RSV 
vaccine or any monoclonal antibody (such as Infliximab) during pregnancy and/or 
breastfeeding. 
E11. Receipt or planned receipt of any of the following vaccines prior to or after the first study 
intervention administration: 
• any influenza vaccine within 7 days prior to and after, or 
• any COVID-19 or inactivated vaccine or live-attenuated rotavirus vaccine within 14 
days prior to and after, or 
• any live vaccine, other than rotavirus vaccine, within 28 days prior to and after 
E12. Previous receipt of an investigational RSV vaccine or receiving any anti-RSV product 
(such as ribavirin or RSV IG or RSV monoclonal antibody) at the time of enrollment. 
E13. Receipt of immune globulins, blood or blood-derived products in the past 3 months 
E14. Receipt of intranasal and intra-ocular medications within 3 days prior to study enrollment 
E15. Receipt at the time of enrollment or previous receipt of salicylate (aspirin) or salicylate-
containing products 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
E16. Participation at the time of study enrollment (or in the 6 weeks preceding the first study 
intervention administration) or planned participation during the present study period in 
another clinical study investigating a vaccine, drug, medical device, or medical procedure 
OTHER EXCLUSIONS 
E17. Deprived of freedom in an emergency setting, or hospitalized involuntarily 
E18. Identified as a natural or adopted child of the Investigator or employee with direct 
involvement in the proposed study 
If the participant has a primary physician who is not the investigator, the site should contact this 
physician with the participant’s consent to inform him / her of the participant’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 

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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  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. Screening information is recorded in the 
source documents. 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened. 
5.5 
Criteria for Temporarily Delaying Enrollment/Randomization/Administration 
of Study Intervention  
The Sponsor may decide to temporarily delay the enrollment/randomization/administration of 
study intervention in case of occurrence of an event requiring further investigation and until the 
Sponsor’s governance decision on further steps. 
Temporary intervention discontinuation may be considered by the investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency. For all temporary intervention discontinuations, duration should be 
recorded by the investigator in the source documents. 

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6 
Study Interventions and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: Vaccines or products administered outside of study protocol are not considered as study 
interventions and are reported in the CRF as reportable medications (see Section 6.8). Study 
procedures (eg, blood sampling) are also not considered as study interventions. 
6.1 
Study Interventions Administered  
Study interventions are described in Table 6.1. 
Table 6.1: Study Interventions Administered  
Intervention 
Name 
RSVt Vaccine 
  
Placebo 
Use 
Experimental 
Placebo  
IMP and NIMP 
IMP 
IMP 
Type  
Vaccine 
Vaccine 
Dose Form 
Nasal spray suspension 
Nasal spray 
suspension 
Unit Dose 
Strength 
Each
 dose of RSVt vaccine will contain the live-
attenuated RSV with 
 
 
dose. 
Same formulation 
buffer as RSVt 
vaccine 
Excipients/Diluent 
 
Same formulation 
buffer as RSVt 
vaccine 
Dosage Level(s) 
 
Number of Doses / 
Dosing Interval 
2 doses 56 days apart for pediatric participants 
2 doses 56 days 
apart for pediatric 
participants 
Route of 
Administration 
Intranasal 
Intranasal 

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Site of 
Administration 
Each nostril 
Each nostril 
Sourcing 
Provided by the Sponsor  
Provided by the 
Sponsor  
Packaging and 
Labeling 
The investigational and placebo products in single-dose vials will be supplied with 
investigational labeling and packaging according to national regulations. Each 
single dose of investigational or placebo product will be identified by a unique 
number on the primary label and on the outer carton label. The carton label will 
also have a detachable label for the sites to attach to the source documents. 
Current/Former 
Name(s) or 
Alias(es) 
Not applicable 
Not applicable 
Batch Number 
TBD 
TBD 
Storage 
Conditions 
Study interventions will be stored in a freezer at ≤ -60°C (≤ -76°F) and will be 
protected from the light. 
IMP: Investigational Medicinal Product; NIMP: Non-Investigational Medicinal Product; TBD: to be determined 
Table 6.2 summarizes the study interventions per arm. 
Table 6.2: Study Arms  
Arm title 
Group 1 
RSVt 
Group 2 
Control 
Arm type 
Experimental 
Placebo 
Associated study interventions 
RSVt vaccine 
Placebo 
6.1.1 Medical Devices  
Medical device (not manufactured by the Sponsor) provided for use in this study is the 
Instructions for medical device use are provided in the product insert. 

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In vitro device performance characterization: 
 
6.2 
Preparation, Handling, Storage, and Accountability  
1) The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
3) The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions will 
be provided to the study personnel. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
6.3.1 Randomization and Allocation Procedures  
Site staff will connect to the Interactive Response Technology (IRT), enter the identification and 
security information, and confirm a minimal amount of data in response to IRT prompts. For all 
participants, the IRT will assign a participant number. For pediatric participants, the IRT will then 
provide the group assignment and have the site staff confirm it. If the participant is not eligible to 
participate in the study, then the information will only be recorded on the participant recruitment 
log. 
Participant numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier).  
The first digit of the 5-digit participant identifier will correspond to the participant group (ie, 0 for 
pediatric participants and 1 for ad-hoc close contact participants). For the pediatric participants 
only, the 2nd and 3rd digits of the participant identifier will correspond to the group of contact 
identifier. For example, Participant 630000101235 is the 35th participant enrolled in Center 
Number 1 (630 being Puerto Rico country code) and is part of Contact Group Number 12; 

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Participant 630000110024 is the 24th ad-hoc close contact participant enrolled in Center 
Number 1. 
Participant numbers should not be reassigned for any reason. The randomization codes will be 
kept securely in the IRT and an internal system. 
6.3.2 Blinding and Code-breaking Procedures  
The study will be performed in a modified double-blind fashion: 
• Participants, participants’ parents or legally acceptable representative, Investigators and study 
staff who conduct the safety and immunogenicity assessments will not know which study 
intervention is administered 
• Only the study staff who prepare and administer the study intervention and are not involved 
with the safety evaluation will know which study intervention is administered 
The Investigator responsible for safety assessment will not attend the vaccination session but will 
be available in case of emergency (anaphylactic shock). 
Treatment ID numbers will be used to identify each vaccine dose for the purpose of 
randomization, vaccination, and the recording of the study intervention administered. Treatment 
numbers will be randomly assigned to study interventions. The IRT vendor will be responsible for 
assigning the treatment group identification and treatment number to be received by the enrolled 
pediatric participant. The participant, the participant’s parent(s)/legally acceptable representative, 
the Investigator, and the study staff members who collect the safety data and laboratory personnel 
who analyze the blood samples will all be blinded to the group assignment. The individual 
responsible for preparing / administering study intervention will not be authorized to collect any 
safety / serology data. 
The code may be broken in the event of an AE only when the identification of the study 
intervention received could influence the treatment of the participant. Code-breaking should be 
limited to the pediatric participant(s) experiencing the AE. 
The blind can be broken by the investigator or a designee through the IRT system. Once the 
emergency has been addressed by the site, the investigator or a designee must notify the Sponsor’s 
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 Independent Ethics Committees (IEC) / Institutional Review Boards (IRB) must be notified 
of the code-breaking, in accordance with local regulations. All documentation pertaining to the 
event must be retained in the site’s study records and in the Sponsor’s 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 Harmonisation (ICH) E2A. In this case, 

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the code will be broken only for the participant(s) in question. The information resulting 
from code-breaking (ie, the participant’s study intervention or group assignment) will not 
be communicated to either the investigator or the immediate team working on the study, 
except for the GPV representative. 
An unblinded interim analysis will be performed in Q4, 2023 on available data collected from 
D01 (V01) to D22 (V07), irrespective of study enrollment status. An additional unblinded interim 
analysis will be performed once all data collected from D01 (V01) to D22 (V07) from all 
participants is available. The interim analyses will include baseline immunogenicity, safety, and 
shedding / transmission up to 21 days after the first administration, in order to share preliminary 
data to Health Authorities.  
Randomization code will be broken for the Sponsor but blinding will be maintained at sites and 
participants/parents levels. 
6.4 
Study Intervention Compliance  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose(s) given to each participant, and unused or wasted doses 
6.5 
Dose Modification  
Not applicable. 
6.6 
Continued Access to Study Intervention After the End of the Study  
Not applicable. 
6.7 
Treatment of Overdose  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the investigator should: 
1) Contact the RMO immediately. 
2) Evaluate the participant to determine, in consultation with the RMO, whether study 
intervention should be interrupted 
3) Closely monitor the participant for any AE/SAE. 
4) Document the quantity of the excess of the overdose in the source documents. 

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6.8 
Concomitant Therapy  
Reportable medications include medications that may affect the interpretation of safety data (eg, an 
antipyretic or analgesic that could have reduced the intensity or frequency of an adverse event) or 
may interfere with the development or measurement of the immune response (eg, the use of 
immune-suppressors, immune-modulators, or some antibiotics that can affect certain bioassays 
and intranasal and ophthalmic medications in the context of this intranasal vaccine). Some 
medications such as steroids can affect both the evaluation of the safety and the immune response 
to a vaccine. 
This may include medications of interest that were started prior to the day of vaccination, and 
even stopped prior to enrollment if there is a reasonable possibility that they may have an impact 
on safety and / or immune assessment during study participation. 
The following reportable medications are defined:  
• Medications impacting or that may have an impact on the evaluation of the safety (eg, 
antipyretics, analgesics, intranasal/intraocular medications, and non-steroidal 
anti-inflammatory drugs [NSAIDs], systemic steroids/corticosteroids) 
• 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 
Sponsor’s laboratory or other testing laboratories, systemic steroids/corticosteroids, 
immune-suppressors, immune-modulators with immunosuppressive properties, anti-
proliferative drugs such as deoxyribonucleic acid [DNA] synthesis inhibitors) 
• Medications impacting or that may have an impact on both the safety and the immune 
response (eg, systemic steroids/corticosteroids) 
Reportable medications will be collected in the CRF until the end of the unsolicited follow-up 
period.  
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical (other than intranasal and intraocular) and ear treatments will not be recorded. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication Form of the CRF unless the 
medication(s) received belong(s) to the reportable medications list. Medications will be coded 
using the WHODrug dictionary.  
The following medications will be prohibited during the study period for pediatric participants: 
intranasal and intraocular medications, and salicylate or salicylate-containing products. 
6.8.1 Rescue Medicine  
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available at the study site in the event of an anaphylactic, vasovagal, or other immediate 
allergic reaction. 

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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 10.1. 
7.1 
Discontinuation of Study Intervention  
7.1.1 Temporary Contraindications  
Should a participant experience one of the conditions listed below, the investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the SoA.  
If the postponement occurs out of the timeframe for vaccination, the participant will be 
permanently discontinued from study intervention but will continue to be followed for safety  
TCI01: 
Any acute febrile illness in the past 48 hours that according to investigator judgment is 
significant enough to interfere with successful inoculation on the day of vaccination. 
A prospective participant should not be included in the study until the condition has 
resolved or the febrile event has subsided 
TCI02: 
Receipt or planned receipt of any of the following vaccines prior to or after the first 
study intervention administration: 
• any influenza vaccine within 7 days prior to and after, or 
• any COVID-19 or inactivated vaccine or live-attenuated rotavirus vaccine 
within 14 days prior to and after, or 
• any live vaccine, other than rotavirus vaccine, within 28 days prior to and after 
Temporary intervention discontinuation may be considered by the investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by 
the investigator in the source documents.  
7.1.2 Definitive Contraindications  
Participants will permanently discontinue (definitive discontinuation) study intervention for the 
reasons listed below. These participants must not receive any additional dose of study intervention 
but should continue to be followed for safety and immunogenicity.  
Should a participant experience at least one of the conditions listed below, the investigator will 
discontinue vaccination: 
DCI01: 
An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
DCI02: 
Probable or confirmed ongoing case of COVID-19 at the time of enrollment 
DCI03: 
Serious AE assessed as related to the study vaccine following the previous dose of 
vaccine, based on Investigator’s judgment 

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In the event of a local or national immunization program with a pandemic influenza vaccine or 
any other vaccine as needed, participants who receive pandemic influenza vaccine or any other 
vaccine as needed at any time during the study will not be withdrawn from the study. 
7.1.3 Other Reasons  
A participant may discontinue from study intervention at any time at his/her own parent/LAR 
request, or at the discretion of the investigator for safety, behavioral, or compliance reasons. 
Participants should continue to be followed for safety. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at his/her own parent/LAR request, or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• 
The reason for withdrawal should be clearly documented in the source documents and in the 
CRF.  
• 
The participant will be permanently discontinued from the study intervention and the study at 
that time. However, 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. 
• 
If the participant withdraws consent for disclosure of future information, the Sponsor will 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws consent, he/she may request destruction of any biological samples 
taken (unless local law requires not to destroy them), and the investigator must document this 
in the site study records. 
• 
Withdrawn participants will not be replaced. However, in specific situations, if judged 
necessary and according to the number of withdrawn participants, the sample size may be 
increased to maintain the number of evaluable participants of the study. Participants’ numbers 
will not be reassigned. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he/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 

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schedule, and ascertain whether the participant wishes to and/or should continue in the 
study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 

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8 
Study Assessments and Procedures  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Safety/laboratory results that could unblind the study will not be reported to sites or other 
blinded personnel until the study has been unblinded at the site level. 
Blood and nasal samples will be collected as described in the SoA tables (Section 1.3). 
The maximum amount of blood collected from each pediatric participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 15 mL 
(approximately 5 mL for each blood sampling). Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
The volume for each pediatric participant nasal swab must be 4 mL of nasal swab specimen 
collected in viral transport media (
).  
Guidance and information for the sample collection, preparation, storage, and shipment will be 
provided to the study personnel. 
8.1 
Efficacy and Immunogenicity Assessments  
Planned timepoints for all immunogenicity assessments are provided in the SoA. 
8.1.1 Efficacy Assessments  
No clinical efficacy data will be obtained in the study. 
8.1.2 Transmission and Vaccine Virus Shedding Assessments  
Assays will be performed by the Sponsor’s laboratory (Sanofi, USA) or by an external testing 
laboratory under the Sponsor’s laboratory responsibility.  

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8.1.2.1 Vaccine virus shedding  
Shedding of the attenuated RSV vaccine strain in nasal swab samples will be evaluated by RSVt 
qRT-PCR assay in all the nasal swabs collected, from planned and unplanned visits, in pediatric 
and ad-hoc close contact participants. 
 
8.1.2.2 

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The above ARI episodes will be graded following the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017;  
(30) except for 
and fever. 
Table 8.1: DAIDS severity scale for RSV MAARI  
Grade 1 Mild 
Grade 2 
Moderate 
Grade 3 Severe 
 
Grade 4 Potentially 
Life-Threatening 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated  
Moderate 
symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated  
Severe symptoms 
causing inability 
to perform usual 
social & 
functional 
activities with 
intervention or 
hospitalization 
indicated  
 
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
All deaths related to an RSV MAARI are to be classified as Grade 5. 

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Table 8.2 Targets Detected by the ePlex Respiratory Pathogen Panel 2 Assay  

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8.1.3 Immunogenicity Assessments  
8.1.3.1 Immunogenicity Assessment Methods  
Assays will be performed by the Sponsor’s laboratory (Sanofi, USA) or an external testing 
laboratory under the Sponsor’s laboratory responsibility.  
8.1.3.1.1 RSV A and RSV B serum neutralizing antibody titers  
RSV A and RSV B serum neutralizing antibody titers will be evaluated by Microneutralization 
(MN) assay. 
 

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8.1.3.1.2 RSV Serum Anti-F IgG ELISA  
Assays will be performed by the Sponsor’s laboratory (Sanofi, USA) or an external testing 
laboratory under the Sponsor’s laboratory responsibility.  
The ELISA method to be used is summarized below. The method is currently in development and 
a detailed procedure will be submitted prior to the start of clinical testing. Method will be 
qualified for Phase I and II studies and will be validated prior to Phase III clinical testing. 
8.1.3.1.3 RSV Serum Anti-F IgA ELISA  
The anti-RSV F IgA ELISA will be performed at Sanofi HEXIM, Orlando, Florida. 
The ELISA method to be used is summarized below. The method is currently in development and 
a detailed procedure will be submitted prior to the start of clinical testing. Method will be 
characterized for Phase I and II studies and will be validated prior to Phase III clinical testing. 
8.2 
Safety Assessments  
This section presents safety assessments other than adverse events which are presented in 
Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Medical History  
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE or to a repetitive outpatient care will be 

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collected in the CRF. Collected information will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  
8.2.2 Physical Examinations  
At Visit 1 and Visit 8, the investigator or a designee will perform a clinical physical examination. 
Information will be recorded in the source document and in the CRF. 
 
8.2.3 Vital Signs  
Rectal pre-vaccination temperature will be systematically collected by the investigator on the 
source document. Tympanic, skin, and temporal artery thermometers must not be used. 
Height and weight will be collected at enrollment. 
8.2.4 Clinical Safety Laboratory Tests  
Not applicable. 
8.2.5 Pregnancy Testing  
Not applicable. 
8.2.6 Viremia/Vaccinemia  
Virus shedding will be evaluated and described in all pediatric participants at D01, D04, D08, 
D11, D15, D18, D22, D64, and D71. Presence of vaccine virus will be assessed in the ad-hoc 
close contact participants at the illness visit. Shedding of the attenuated RSV vaccine strain in 
nasal swab samples will be evaluated by RSVt qRT-PCR assay (as described in Section 8.1.2). 
8.3 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.2. 
AEs will be reported by the participants’ parents / legally acceptable representatives to the 
investigator, then by the investigator to the Sponsor. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.2. 

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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 each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited administration site reactions will be collected from the day of vaccination until 21 days 
after each vaccination (D01 to D22 and D57 to D78). 
Solicited systemic reactions will be collected from the day of vaccination until 21 days after each 
vaccination (D01 to D22 and D57 to D78). 
The solicited administration site reactions and systemic reactions that are pre-listed in the diary 
cards and CRF, together with the intensity scales, are presented in Appendix 10.2.5.1.1. 
Reactogenicity is to be reported only for IMPs. Refer to Table 6.1 to know which study 
interventions are considered as IMPs. 
Unsolicited Non-serious Adverse Events 
Unsolicited non-serious adverse events will be collected from the day of vaccination until 28 days 
after each vaccination (D01 to D29 and D57 to D85). 
The intensity grading scale for unsolicited non-serious adverse events is presented in 
Appendix 10.2.5.1.2. 
Medically Attended Adverse Events (MAAEs) 
MAAEs will be collected from the day of vaccination until 28 days after each vaccination (D01 to 
D29 and D57 to D85). 
Adverse Events of Special Interest (AESIs) 
AESIs will be collected from the day of vaccination until 28 days after each vaccination (D01 to 
D29 and D57 to D85). 
See Section 8.3.6 for the list of AESIs. 
SAEs 
Information on SAEs will be collected and assessed throughout the study, from D01 until 180 
days after the last vaccination. However, before the first study intervention administration, only 
SAEs related to study procedures are to be collected in the CRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.2. 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 information on AEs or SAEs 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 
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8.3.2 Method of Detecting AEs and SAEs  
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study participants’ parents / legally acceptable representatives 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’ Parents / LARs] will also be provided with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
participants’ parents / LARs on how to correctly use these tools. 
At specified intervals, the investigator or a designee will interview the participants’ parents / 
legally acceptable representatives to collect the information recorded in the diary card, and will 
attempt to clarify anything that is incomplete or unclear. All clinical study information gathered 
by the study site will be reported electronically by the investigator or 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 should be done at least 180 days after the last vaccination for all 
participants having received at least one dose of the study intervention, by interviewing 
participants’ parents / legally acceptable representatives either during a visit or over the telephone 
using a questionnaire to capture SAEs and AESIs, if applicable. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts, unless a participant’s parents / legally acceptable representatives 
refuse further contact. All AEs that are considered by the investigator as serious, or related to the 
study intervention administered, or that led to study or vaccination discontinuation, or AEs of 
special interest (as defined in Section 8.3.6), will be followed during the conduct of the study until 
resolution, stabilization, or the participant is lost to follow-up (as defined in Section 7.3). For 
related SAEs ongoing at last study visit, such follow-up may need to continue after the end of the 
study.  
Further information on follow-up procedures is provided in Appendix 10.2. 
8.3.4 Regulatory Reporting Requirements for SAEs  
• 
Prompt notification by the investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 

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• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
8.3.5 Pregnancy  
Not applicable as women of childbearing age will not receive the study intervention. 
8.3.6 Adverse Events of Special Interest  
The following AESIs will be collected: 
8.3.7 Medically Attended Adverse Events  
MAAEs will be collected using the same process as other AEs. See Appendix 10.2.1 for definition 
of MAAEs. 
8.4 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study. 
8.5 
Genetics  
Genetics are not evaluated in this study. 
8.6 
Biomarkers  
No other biomarkers than those described in the immunogenicity assessments section 
(Section 8.1.2) are evaluated in this study. The blood samples and nasal swabs collected during 
the study can be used to measure other immunogenicity assessments.  
8.7 
Immunogenicity Assessments  
See Section 8.1.2. 

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8.8 
Medical Resource Utilization and Health Economics  
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
8.9 
Leftover Biological Samples  
Any unused part of the biological samples collected for this study (blood sample and nasal swab) 
are being retained in long-term storage (for up to 25 years after the end of the study) to support 
answers to regulatory questions related to the product’s licensure and the potential revalidation of 
the study results. The biological samples will be securely stored at the Sponsor’s laboratory. 
The other biological samples collected to qualify the participant for inclusion in the study or to 
monitor his/her health during the study are dedicated for immediate use. If any of these biological 
samples are not completely used up, they will be destroyed at the latest at the end of the study or 
after the time requested by local law. 
8.10 Use of Biological Samples And Data For Future Research  
Future research may help further the understanding of disease and the development of new 
vaccines/medicines. Reuse of coded data and biological samples (leftover) will be limited to 
future scientific research conducted under a research plan for the purpose of diagnosing, 
preventing or treating diseases. The future research projects will be conducted under the 
Sponsor’s and/or its affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed 
the study intervention to the Sponsor or which is co-developing the study intervention with the 
Sponsor’s control, acting alone or in collaboration with research partners such as universities, 
research institutions or industrial partners with whom the coded data may be shared.  
Data and biological samples will be stored and used for future research only when consented to by 
participants (see Section 10.1.3) and, when applicable, further information on the future research 
has been provided to the study participants, unless prohibited by local laws or IRBs/IECs (in such 
case, consent for future use of samples will not be included in the local informed consent form 
[ICF]). The conditions for reuse will be adapted locally with the appropriate language in the ICF.  
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover samples. 
Data protection – Processing of coded clinical data  
The study participants will be provided with all mandatory details of the data processing in Part 2 
of the ICF. The Sponsor adopts safeguards for protecting participant confidentiality and personal 
data (see Section 10.1.4). 
Use of leftover samples for future research 
Remaining leftover samples will be used only after the study ends, ie end of study as defined in 
the study protocol. Additional nasal swab can be collected and used during the study conduct at a 
given timepoint (eg, illness visit) as defined in the study protocol. 
The study participants will be provided with all mandatory details of the use of their biological 
samples (leftover) in Part 2 of the ICF.  

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Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. 
Any samples remaining at the end of the retention period will be destroyed. If a participant 
requests destruction of his/her samples before the end of the retention period, the investigator 
must notify the Sponsor (or its contract organization) in writing. In such case, samples will be 
destroyed and related coded data will be anonymized unless otherwise required by applicable 
laws. 

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9 
Statistical Considerations  
The statistical analysis plan (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. 
9.1 
Statistical Hypotheses  
All analyses will be descriptive, no hypothesis will be tested. 
9.2 
Analysis Sets  
 For the purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Randomized 
Pediatric participants for whom a study intervention group has been 
allocated.  
Safety Analysis Set (SafAS) 
Pediatric participants who have received at least one study intervention 
administration. All pediatric participants will have their safety analyzed 
after each study intervention administration according to the study 
intervention they actually received, and after any study intervention 
administration according to the study intervention received at the first 
study intervention administration. 
Safety data recorded for a vaccine received out of the protocol design 
will be excluded from the analysis (and listed separately).  
Full Analysis Set (FAS) 
Subset of randomized pediatric participants who received at least 
one study intervention administration 
Pediatric participants will be analyzed according to the study 
intervention to which they were randomized. 
Per-protocol analysis set 
(PPAS) 
The PPAS is a subset of the FAS. 
 
The pediatric participants presenting with at least one of the following 
relevant protocol deviations will be excluded from the PPAS: 
• Pediatric participant did not meet all protocol-specified inclusion 
criteria or met at least one of the protocol-specified exclusion criteria 
• Pediatric participant did not receive first study intervention 
administration at D01 
• Pediatric participant received a study intervention at D01 other than 
the one that he / she was randomized to receive  
• Preparation and / or administration of study intervention at D01 not 
done as per-protocol 
• Pediatric participant NOT having at least 4 nasal swabs (with a valid 
result) between D08 and D22, with a maximum of 5 days’ time interval 

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between 2 consecutive nasal swabs 
• Pediatric participant received a protocol-prohibited therapy before 
collection of nasal swabs between D08 and D22 
• Pediatric participant with an emergency unblinding performed by the 
investigator before collection of nasal swab at D22 
• Pediatric participant who was RSV exposed before study intervention 
administration at D01 
Other analysis set 
An analysis set will be used to document transmission of vaccine virus 
in the ad-hoc close contact participants 
9.3 
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. 
9.3.1 General Considerations  
The statistical methodology will be based on the use of two-sided 95% CIs. 
All endpoints will be summarized by study intervention group. For the main parameters, 95% CI 
of point estimates will be calculated using the normal approximation for quantitative data and 
using the exact binomial distribution (Clopper-Pearson method) for proportions. 
For immunogenicity data, assuming that log10 transformation of the titers/titer ratio follows a 
normal distribution, first, the mean and 95% CIs will be calculated on log10 (titers/titers ratio) 
using the usual calculation for normal distribution. Then, antilog transformations will be applied 
to the results of calculations, to compute geometric mean titers (GMTs) and geometric mean titer 
ratios (GMTRs) and their 95% CIs. 
Viral shedding, vaccine virus stability (pediatric participants receiving placebo and ad-hoc close 
contact participants), and safety analyses will be performed on the SafAS. Immunogenicity 
analyses will be presented on the FAS. Transmissibility analyses will be performed on the SafAS 
and PPAS as well as on other analysis set (ad-hoc close contact participants). 
9.3.2 Primary Endpoints  
Vaccine virus transmission 
Presence of vaccine virus detected by RSVt qRT-PCR in nasal swabs after the first study 
intervention administration (D01, D04, D08, D11, D15, D18, and D22) will be summarized in 
pediatric participants receiving placebo with 95% CIs: 
• Number and percentage of participants with vaccine virus detected at each timepoint 
• Number and percentage of participants with vaccine virus detected in at least one nasal 
swab 

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Vaccine virus shedding 
Titer of vaccine virus shedding quantified by RSVt qRT-PCR in nasal swabs after each study 
intervention administration will be summarized at each timepoint (D01, D04, D08, D11, D15, 
D18, D22, D64, and D71) in pediatric participants by study intervention group with 95% CIs. 
Vaccine virus stability 
Presence of any vaccine virus mutation will be described in pediatric participants receiving 
placebo and ad-hoc close contact participants and may be described as well in a subset of pediatric 
participants receiving RSVt vaccine. Further details will be provided in the SAP. 
9.3.3 Secondary Endpoints  
Immunogenicity 
The following immunogenicity endpoints will be summarized at each timepoint (D01, D57, and 
D85) in pediatric participants by study intervention group with 95% CIs: RSV A serum 
neutralizing antibody titers and RSV serum anti-F IgG antibody titers. The 95% CIs for the GMTs 
and GMTRs will be calculated using a normal approximation of log-transformed titers. The 95% 
CIs for the proportions will be based on the Clopper-Pearson method. 
Safety 
The safety parameters, including frequencies of immediate reactions, solicited reactions, 
unsolicited AEs, AESIs, MAAEs, and SAEs will be described after each and any study 
intervention administration in pediatric participants by study intervention group with the 95% CIs 
of point estimates calculated using the exact binomial distribution (Clopper-Pearson method) for 
proportions. 
Vaccine virus transmission 
Presence of vaccine virus detected by RSVt qRT-PCR in nasal swabs after the second study 
intervention administration (D64 and D71) will be summarized in pediatric participants receiving 
placebo with 95% CIs: 
• Number and percentage of participants with vaccine virus detected at each timepoint 
• Number and percentage of participants with vaccine virus detected in at least one nasal 
swab 
9.3.4 Exploratory Endpoints  

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9.3.5 Other Analysis  
As exploratory analysis, probability of transmission of vaccine virus will be calculated for the 
pediatric participants using Greenwood / Reed-Frost models after each administration of study 
intervention.  
9.4 
Interim Analyses  
An unblinded interim analysis will be performed in Q4, 2023 on available data collected from 
D01 (V01) to D22 (V07), irrespective of study enrollment status. An additional unblinded interim 
analysis will be performed once all data collected from D01 (V01) to D22 (V07) from all 
participants is available. The interim analyses will include baseline immunogenicity, safety, and 
shedding / transmission up to 21 days after the first administration, in order to share preliminary 
data to Health Authorities.  
Randomization code will be broken for the Sponsor but blinding will be maintained at sites and 
participants/parents levels. 
No statistical adjustment is necessary because no hypotheses will be tested. 
This study will not include an early safety data review.  
The SAP will describe the planned interim analyses in greater detail. 

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9.5 
Sample Size Determination  
No sample size calculation was done as there are no statistical hypotheses in this study. A total of 
100 pediatric participants (ie, 50 per study intervention group) are planned to be enrolled, based 
on clinical feasibility. 
10 
Supporting Documentation and Operational Considerations  
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations  
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. Similarly, “legally acceptable representative” is used in the protocol 
whereas “guardian” is used in the CRF. 
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) guidelines 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, ICFs, IB, and other relevant documents (eg, advertisements) must be submitted 
to an IRB/IEC by the investigator or the Sponsor (according to local regulations) and reviewed 
and approved by the IRB/IEC before the study is initiated 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants 
• The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC, if applicable  
• 
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 

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unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, investigators should seek independent 
ethical advice before determining next steps. 
• In case the participant has decided to opt out, the investigator must record in the 
site medical files that she/he does not want to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the investigator’s contract. 
10.1.3 Informed Consent Process  
• The investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participants or the participants’ parents / legally acceptable 
representatives and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study). 
• Participants must be informed that their participation is voluntary. Participants and 
participants’ parents / legally acceptable representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 

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privacy and data protection requirements including those of the GDPR and of the French law, 
where applicable, and the IRB/IEC or study center. 
• Depending on local legal and regulatory requirements, a separate assent form signed by the 
participant may be required for minor ad-hoc close contact participants. The assent form is in 
addition to, not in place of, an ICF that is signed by the parent / legally acceptable 
representative (and by an independent witness if required). 
• 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 or parents’ / 
legally acceptable representatives’ willingness to continue participation in the study, this will 
be communicated to him / her in a timely manner. Such information will be provided via a 
revised ICF or an addendum to the original ICF. 
• Participants/ parent/LAR must be reconsented to the most current version of the ICF(s) during 
their participation in the study. Where participants are not in the study anymore, the Sponsor 
must define if those participants must or not re-consent or be informed of the revision (eg, if 
the processing of personal data is modified, if the Sponsor changes). 
• A copy of the ICF(s) must be provided to the participant or participants’ parents / legally 
acceptable representatives. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones) and future research. Each option is subject to an 
independent consent and must be confirmed by ticking checkboxes in ICF Part 3, each checkbox 
corresponding to a specific use: consent for storage and use of coded data for future research; 
consent for use of leftover samples and associated coded data for future research, and consent for 
performance of genetic analyses on biological samples. The investigator or authorized designee 
will explain to each participant why data and samples are important for future research. 
Participants / parent/LAR will be told that they are free to refuse to participate and may withdraw 
their consent at any time and for any reason during the storage period. 
Recruitment Procedures 
Participants will be recruited from the general population. Before start of the study, the 
investigator will contact parents/LARs of an appropriate pool of potential participants and invite 
them to participate in the study. The sites will ensure that any advertisements used to recruit 
participants (letters, pamphlets, posters, etc) are submitted to Sanofi prior to submission to the 
IEC / IRB for approval. Detailed guidance and information will be provided separately. 
Emphasis will be placed on trying to enroll twin pediatric participants. 

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10.1.4 Data Protection  
All personal data collected and/or processed in relation to this study will be handled in compliance 
with all applicable Privacy & Data Protection laws and regulations, including the GDPR. The 
study Sponsor is the Sanofi company responsible for ensuring compliance with this matter, when 
processing data from any individual who may be included in the Sanofi databases, including 
investigators, nurses, experts, service providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant personal data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participants’ race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only by 
the unique identifier; participant names or any information which would make the participant 
identifiable will not be transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with applicable data protection laws. The level of disclosure must also 
be explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “product 
development program”, ie, for this study as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers and 
publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) or to 
Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 

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

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10.1.5 Committees Structure  
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study. The Sponsor’s 
internal safety review committee, led by the PV representative and the RMO and designee(s), will 
be responsible for the blinded review, assessment, and evaluation of safety data generated from 
this study. This committee is empowered to recommend a pause in recruitment and/or further 
vaccination while it investigates any potential signal or concern. 
10.1.6 Dissemination of Clinical Study Data  
Study participants 
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results. 
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 vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
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: vivli.org. 
Professionals involved in the study or in the drug development program. 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organizations”. 
10.1.7 Data Quality Assurance  
• All participant data relating to the study will be recorded on electronic CRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF Completion Instructions. 

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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. 
• Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact patient safety and/or reliability of study results. These predefined parameters will be 
monitored during the study, and important deviations from the QTLs and remedial actions 
taken will be summarized in the clinical study report. 
• Monitoring details describing strategy including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
• The protocol will be signed by the RMO, and a Protocol Investigator Agreement Form (PIAF) 
will be signed by all investigators. The clinical study report will be signed by the RMO and 
the coordinating investigator. In case no coordinating investigator has been designated, it will 
be the responsibility of the RMO or designee(s) to identify the signatory investigator. 
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. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 

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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. 
10.1.9 Study and Site Start and Closure  
Study personnel will be informed of which clinical supplies will be provided by the Sponsor or 
the site. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study-site has all the documents necessary for archiving and a study-site 
closure visit has been performed along with a 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: 
For study termination: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 
Publication Policy  
Information related to publication policy is described in the investigator’s contract. 

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10.2 Appendix: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
10.2.1 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 condition 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 that 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, nasal congestion 
occurring between the day of vaccination and the next 21 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  
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. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (eg, regulators) 
might also be warranted. 
Medically Attended AE (MAAE):  
An MAAE is a new onset or a worsening of a condition that prompts the participant or 
participant’s parent/legally acceptable representative to seek unplanned medical advice at a 
physician’s office or Emergency Department. Physician contact made over the phone or by e-
mail will be considered a physician office visit for the purpose of MAAE collection. This 
includes medical advice seeking during the study visit or routine medical care. This definition 
excludes pediatric check-ups, follow-up visits of chronic conditions with an onset prior to entry 
in the study, and solicited reactions. 

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10.2.2 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) that 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  
• 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 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, 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. 

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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. 
10.2.3 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: 
• 
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: 

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• 
Not related – The AE is clearly / most probably caused by other etiologies such as 
participants’ underlying condition, therapeutic intervention, or concomitant therapy; or 
the delay between vaccination and the onset of the AE is incompatible with a causal 
relationship; or the AE started before the first vaccination (screening phase, if 
applicable) 
• 
Related – There is a “reasonable possibility” that the AE was caused by the 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. 
 
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. 

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• 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. 
10.2.4 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). 
 
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: +33 160 497 070 
• 
In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: CL-CPV-Receipt@sanofi.com  
• 
By express mail, to the following address: Global Pharmacovigilance, Sanofi Pasteur, 
Discovery Drive, Swiftwater, PA 18370 
 
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 Sponsor contact, as needed. The toll-free contact 
information for the Call Center will be provided separately. 
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. 

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10.2.5 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”. 
10.2.5.1 Tables for Clinical Abnormalities  
10.2.5.1.1 Solicited AR Intensity Grading Scale  

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Table 10.1: 
 

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Table 10.2: Solicited systemic reactions: terminology, definitions, and intensity scales – Infants and toddlers aged ≤ 23 months  
CRF term (MedDRA 
lowest level term 
[LLT]) 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
Diary card term 
Temperature 
Vomiting 
Abnormal crying 
Drowsiness 
Loss of appetite 
Irritability 
Definition 
Elevation of 
temperature to 
≥°38.0°C (≥ 100.4°F) 
Vomiting does not 
include spitting up 
Inconsolable crying 
without a determined 
reason 
Reduced interest in 
surroundings, or 
increased sleeping 
See intensity scale 
An excessive response to 
stimuli: increased 
fussiness, whining, and 
fretfulness despite 
attempts to comfort the 
infant and despite 
caregiver responses that 
would normally be 
soothing 
Intensity scale* 
Grade 1:  
≥ 38.0°C to ≤ 38.5°C 
or ≥ 100.4°F to ≤ 101.3°F 
Grade 1: 
CRF and DC: 1 episode 
per 24 hours 
Grade 1:  
CRF and DC: < 1 hour 
Grade 1:  
CRF and DC: Sleepier 
than usual or less 
interested in 
surroundings 
Grade 1:  
CRF and DC: Eating 
less than normal 
Grade 1:  
CRF and DC: Easily 
consolable 
 
Grade 2: 
> 38.5°C to ≤ 39.5°C 
or > 101.3°F to ≤ 103.1°F 
Grade 2:  
CRF and DC: 2–
5 episodes per 24 hours 
Grade 2:  
CRF and DC: 1–3 hours  
Grade 2: 
CRF and DC: Not 
interested in 
surroundings or did not 
wake up for a feed / 
meal 
Grade 2:  
CRF and DC: Missed 1 
or 2 feeds / meals 
completely 
Grade 2:  
CRF and DC: Requiring 
increased attention 

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CRF term (MedDRA 
lowest level term 
[LLT]) 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
 
Grade 3:  
> 39.5°C 
or > 103.1°F 
Grade 3  
CRF: ≥ 6 episodes per 
24 hours or requiring 
parenteral hydration 
DC: at least 6 episodes 
per 24 hours or 
requiring intravenous 
hydration (fluids 
administered in the arm 
or leg) 
Grade 3:  
CRF and DC: > 3 hours 
Grade 3:  
CRF and DC: Sleeping 
most of the time or 
difficult to wake up 
Grade 3:  
CRF and DC: Refuses ≥ 
3 feeds / meals or 
refuses most feeds / 
meals 
Grade 3:  
CRF: Inconsolable 
DC: Inconsolable (cannot 
be comforted) 
* For all reactions (except fever), the scale will be provided in the CRF and the intensity will be transcribed from the diary card. For fever, the body temperature will be recorded, and the 
classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 

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Important notes for the accurate assessment of temperature: 
Participants’ parents / legally acceptable representatives are to measure body temperature once per 
day, preferably always at the same time, and using the same standard unit of the considered 
country (Celsius or Fahrenheit) consistently. The optimal time for measurement is the evening, 
when body temperature is the highest. Temperature is also to be measured at the time of any 
apparent fever. The observed daily temperature and the route of measurement are to be recorded 
in the diary card / memory aid, and the highest temperature will be recorded by the site in the 
CRF. The preferred route for this study is rectal. 
10.2.5.1.2 Serious and Non-serious Unsolicited AE Intensity Grading Scale  
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.2.5.1.1). 
All other unsolicited AEs, including SAEs, will be classified according to the following intensity 
scale: 
10.3 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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10.4 Appendix: Protocol Amendment History  
The Protocol Amendment Rationale for the current amendment is located directly before the 
Table of Contents. 
 
Protocol Update from Version 1.0 (01 August 2022) to Version 2.0 (13 October 2022): 
The updates of protocol version 1.0 to protocol version 2.0 were administrative with the purpose 
of correction of errors, harmonization of text, and updating information. 
Protocol Amendment 1: from Version 2.0 (13 October 2022) to Version 3.0 (26 June 2023): 
The updates of protocol version 2.0 to protocol version 3.0 were administrative with the purpose 
of including clinical sites in the United States in addition to sites in Puerto Rico. 
 

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10.5 Appendix: Abbreviations  
AE 
 
adverse event 
AESI  
adverse event of special interest 
AR 
 
adverse reaction 
ARI 
 
acute respiratory illness 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CRB  
case report book 
CRF 
 
case report form 
DC 
 
diary card 
DNA  
deoxyribonucleic acid 
ELISA  
Enzyme-linked Immuno-adsorbant Assay 
FAS 
 
full analysis set 
GCP  
Good Clinical Practice 
GDPR  
General Data Protection Regulation 
GMT  
geometric mean titer 
GMTR 
geometric mean titer ratio 
GPV  
Global Pharmacovigilance 
HIV 
 
human immunodeficiency virus 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
IDFU  
investigational directions for use 
IEC 
 
Independent Ethics Committees 
IMP 
 
investigational medicinal product 
IR 
 
Investigator Registry 
IRB 
 
Institutional Review Boards 
IRT 
 
Interactive Response Technology 
LAR  
legally acceptable representative 
LRI 
 
lower respiratory infection 

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MAAE 
medically attended adverse event 
MAARI 
medically attended acute respiratory illness 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
 
negative control 
NIH 
 
National Institutes of Health 
NIMP  
non-investigational medicinal product 
NS 
 
nasal swab 
PFU 
 
plaque forming units 
PIAF  
Protocol Investigator Agreement Form 
PPAS  
per-protocol analysis set 
PV 
 
pharmacovigilance 
qRT-PCR 
quantitative reverse transcriptase polymerase chain reaction 
QTL  
quality tolerance limit 
RMO  
Responsible Medical Officer 
RNA  
ribonucleic acid 
RSV  
Respiratory Syncytial Virus 
SAE 
 
serious adverse event 
SafAS  
safety analysis set 
SAP 
 
statistical analysis plan 
SIP 
 
Shared Investigator Platform 
SoA 
 
schedule of activities 
SUSAR 
suspected unexpected serious adverse reactions 
TBD  
to be determined 
URI 
 
upper respiratory infection 
VTM  
Viral Transport Media 
WT 
 
wild type 

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10.6 References  
1. 
Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The 
burden of respiratory syncytial virus infection in young children. N Engl J Med. 2009;360(6):588-
98. 
2. 
Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, 
regional, and national disease burden estimates of acute lower respiratory infections due to 
respiratory syncytial virus in young children in 2015: a systematic review and modelling study. 
Lancet. 2017;390(10098):946-58. 
3. 
O'Brien K, Baggett HC, Brooks WA, Feikin DR, Hammitt LL, Higdon MM, et al. Causes 
of severe pneumonia requiring hospital admission in children without HIV infection from Africa 
and Asia: the PERCH multi-country case-control study. Lancet. 2019;394(10200):757-79. 
4. 
Wright PF, Karron RA, Belshe RB, Thompson J, Crowe JE, Jr., Boyce TG, et al. 
Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine 
candidate in infancy. J Infect Dis. 2000;182(5):1331-42. 
5. 
Karron RA, Wright PF, Belshe RB, Thumar B, Casey R, Newman F, et al. Identification of 
a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly 
attenuated in infants. J Infect Dis. 2005;191(7):1093-104. 
6. 
Wright PF, Karron RA, Madhi SA, Treanor JJ, King JC, O'Shea A, et al. The interferon 
antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for 
humans. J Infect Dis. 2006;193(4):573-81. 
7. 
Wright PF, Karron RA, Belshe RB, Shi JR, Randolph VB, Collins PL, et al. The absence 
of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of 
live, attenuated, respiratory syncytial virus vaccines. Vaccine. 2007;25(42):7372-8. 
8. 
Malkin E, Yogev R, Abughali N, Sliman J, Wang CK, Zuo F, et al. Safety and 
immunogenicity of a live attenuated RSV vaccine in healthy RSV-seronegative children 5 to 24 
months of age. PLoS One. 2013;8(10):e77104. 
9. 
Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, et al. A gene 
deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved 
antibody responses in children. Sci Transl Med. 2015;7(312):312ra175. 
10. 
Buchholz UJ, Cunningham CK, Muresan P, Gnanashanmugam D, Sato P, Siberry GK, et 
al. Live respiratory syncytial virus (RSV) vaccine candidate containing stabilized temperature-
sensitivity mutations is highly attenuated in RSV-seronegative infants and children. J Infect Dis. 
2018;217(9):1338-46. 
11. 
McFarland EJ, Karron RA, Muresan P, Cunningham CK, Valentine ME, Perlowski C, et 
al. Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate With Deletion of RNA 
Synthesis Regulatory Protein M2-2 is Highly Immunogenic in Children. J Infect Dis. 
2018;217(9):1347-55. 
12. 
Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory 
syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am 
J Epidemiol. 1969;89(4):422-34. 

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13. 
Collins PL, Melero JA. Progress in understanding and controlling respiratory syncytial 
virus: still crazy after all these years. Virus Res. 2011;162(1-2):80-99. 
14. 
Collins PL, Hill MG, Camargo E, Grosfeld H, Chanock RM, Murphy BR. Production of 
infectious human respiratory syncytial virus from cloned cDNA confirms an essential role for the 
transcription elongation factor from the 5' proximal open reading frame of the M2 mRNA in gene 
expression and provides a capability for vaccine development. Proc Natl Acad Sci U S A. 
1995;92(25):11563-7. 
15. 
Ramaswamy M, Shi L, Varga SM, Barik S, Behlke MA, Look DC. Respiratory syncytial 
virus nonstructural protein 2 specifically inhibits type I interferon signal transduction. Virology. 
2006;344(2):328-39. 
16. 
Lo MS, Brazas RM, Holtzman MJ. Respiratory syncytial virus nonstructural proteins NS1 
and NS2 mediate inhibition of Stat2 expression and alpha/beta interferon responsiveness. J Virol. 
2005;79(14):9315-9. 
17. 
Spann KM, Tran KC, Chi B, Rabin RL, Collins PL. Suppression of the induction of alpha, 
beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in 
human epithelial cells and macrophages [corrected]. J Virol. 2004;78(8):4363-9. 
18. 
Valarcher JF, Furze J, Wyld S, Cook R, Conzelmann KK, Taylor G. Role of alpha/beta 
interferons in the attenuation and immunogenicity of recombinant bovine respiratory syncytial 
viruses lacking NS proteins. J Virol. 2003;77(15):8426-39. 
19. 
Liesman RM, Buchholz UJ, Luongo CL, Yang L, Proia AD, DeVincenzo JP, et al. RSV-
encoded NS2 promotes epithelial cell shedding and distal airway obstruction. J Clin Invest. 
2014;124(5):2219-33. 
20. 
Karron RA, Luongo C, Mateo JS, Wanionek K, Collins PL, Buchholz UJ. Safety and 
Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-
Seronegative Children. J Infect Dis. 2020;222(1):82-91. 
21. 
The National Institute of Health. The U.S. National Library of Medicine. Evaluating the 
Infectivity, Safety, and Immunogenicity of Recombinant Live-Attenuated RSV Vaccines RSV 
ΔNS2/Δ1313/I1314L or RSV 276 in RSV-Seronegative Infants 6 to 24 Months of Age. [Internet]. 
[cited 2022 May 20]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT03227029?term=NCT03227029&cond=RSV+Infection&d
raw=2&rank=1. 
22. 
The National Institute of Health. The U.S. National Library of Medicine. Evaluating the 
Safety and Immune Response to a Single Dose of a Respiratory Syncytial Virus (RSV) Vaccine in 
Infants and Children. [Internet]. [cited 2022 May 20]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01893554. 
23. 
Karron RA, Wright PF, Crowe JE, Jr., Clements-Mann ML, Thompson J, Makhene M, et 
al. Evaluation of two live, cold-passaged, temperature-sensitive respiratory syncytial virus 
vaccines in chimpanzees and in human adults, infants, and children. J Infect Dis. 
1997;176(6):1428-36. 

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24. 
Karron RA, Belshe RB, Wright PF, Thumar B, Burns B, Newman F, et al. A live human 
parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants. Pediatr Infect 
Dis J. 2003;22(5):394-405. 
25. 
Karron RA, Casey R, Thumar B, Surman S, Murphy BR, Collins PL, et al. The cDNA-
derived investigational human parainfluenza virus type 3 vaccine rcp45 is well tolerated, 
infectious, and immunogenic in infants and young children. Pediatr Infect Dis J. 
2011;30(10):e186-91. 
26. 
Englund JA, Karron RA, Cunningham CK, Larussa P, Melvin A, Yogev R, et al. Safety 
and infectivity of two doses of live-attenuated recombinant cold-passaged human parainfluenza 
type 3 virus vaccine rHPIV3cp45 in HPIV3-seronegative young children. Vaccine. 
2013;31(48):5706-12. 
27. 
Greenberg DP, Walker RE, Lee MS, Reisinger KS, Ward JI, Yogev R, et al. A bovine 
parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy. J Infect Dis. 
2005;191(7):1116-22. 
28. 
Bernstein DI, Falloon J, Yi T. A randomized, double-blind, placebo-controlled, phase 1/2a 
study of the safety and immunogenicity of a live, attenuated human parainfluenza virus type 3 
vaccine in healthy infants. Vaccine. 2011;29(40):7042-8. 
29. 
Bernstein DI, Malkin E, Abughali N, Falloon J, Yi T, Dubovsky F. Phase 1 study of the 
safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus 
type 3 vaccine in seronegative children. Pediatr Infect Dis J. 2012;31(2):109-14. 
30. 
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1. July 2017.  Available 
from: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
 

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