Immunogenicity and Safety of a Purified Vero Rabies Vaccine - Serum Free in Comparison With Verorab® and Imovax® Rabies, in a Pre-exposure Regimen in Both Pediatric and Adult Populations and a Single Booster Dose of Purified Vero Rabies Vaccine - Serum Free Administered at 1 Year Post-3-dose Primary Series, and Between 2 up to 3 Years Post-One Week 2-Dose Primary Series in a Subset of Adults in Thailand
Phase: PHASE3
Conditions: Rabies, Healthy Volunteers
Sponsor: Sanofi Pasteur, a Sanofi Company

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Immunogenicity and Safety of a Purified Vero Rabies Vaccine – 
Serum Free in Comparison with Verorab® and Imovax® Rabies, 
in a Pre-exposure Regimen in Both Pediatric and Adult 
Populations and a Single Booster Dose of Purified Vero Rabies 
Vaccine – Serum Free Administered at 1 Year Post-3-Dose 
Primary Series, and Between 2 up to 3 Years Post-One Week 
2-Dose Primary Series in a Subset of Adults in Thailand
Multi-center, observer-blind, controlled, randomized, Phase III study in 1700 subjects; ie, 505 subjects aged 1 year to < 18 years 
and 1195 adult subjects aged ≥ 18 years. Subjects will receive 2 or 3 vaccine injections in a primary series. 
Booster phase will be conducted in a blinded manner which includes a subset of 170 adult subjects who will receive a single 
booster dose of Purified Vero Rabies Vaccine – Serum Free 1 year post-3-dose primary series, in addition, to be conducted in an 
open-label manner which includes a subset of 230 adult subjects who will receive a single booster dose of Purified Vero Rabies 
Vaccine – Serum Free Between 2 up to 3 years post-one week 2-dose primary series, regardless of the vaccine used in the primary 
series.
Clinical Study Protocol, Amendment 5 
Health Authority File Number(s): 
BB-IND #: 
015026 
EudraCT #: 
Not applicable 
WHO Universal Study Number 
(UTN): 
U1111-1217-3241 
Study Code: 
VRV12 
Development Phase: 
Phase III 
Sponsor: 
Sanofi Pasteur 
14 Espace Henry Vallée, 69 007 Lyon, France 
Investigational Product(s): 
Purified Vero Rabies Vaccine – Serum Free (VRVg): Purified inactivated 
rabies vaccine prepared on Vero cell line 
Form / Route: 
Freeze-dried + solvent/Intramuscular 
Indication For This Study: 
Pre-exposure regimen in pediatric and adult populations 
Manufacturer: 
Same as Sponsor 
NCT Number: NCT04127786

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Principal Investigators:  
M.D. 
Chulalongkorn University, Bangkok, Thailand 
 
 M.D. 
Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand 
 
 M.D. 
Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand 
 
 M.D. 
Siriraj Hospital, Mahidol University, Bangkok, Thailand 
 
 M.D. 
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand 
Sponsor’s Responsible Medical 
Officer and Clinical Team 
Leader: 
 M.D. 
Global Clinical Development Strategy Expert - Vaccines 
Global Clinical Sciences, Sanofi Pasteur SA 
Address: 
21F One World Place, 32nd Street, Bonifacio Global City, 
Taguig 1 634, Philippines 
Tel:  
 
E-mail: 
 
Global Safety Officer: 
, MD 
Global Pharmacovigilance, Sanofi Pasteur Inc.  
Tel:  
     
E-mail: 
 
Clinical Study Manager: 
 
Clinical Department, Sanofi Pasteur, Ltd. 
Address: 
944 Mitrtown Office Tower, 28th Floor, Rama 4 Road, 
Wangmai, Pathumwan, Bangkok 10330, Thailand 
Tel:  
 
E-mail: 
 
Version and Date of the Protocol: 
Version 8.0 dated 12 June 2023 
 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to 3rd parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 

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History of Protocol Versions 
Version 
Date 
Comments 
1.0 
12 March 2019 
Internal version not submitted 
2.0 
26 March 2019 
Submitted to EC 
3.0 
18 July 2019 
Superseded by Version 4.0 dated 22 July 2019 due to an 
administrative change during the development of 
Amendment 1 
4.0 
22 July 2019 
Version submitted to IEC/IRB; 1st version used in the 
study 
5.0 
05 November 2021 
Version submitted to IEC/IRB; not used in the study 
6.0 
31 May 2022 
Version submitted to IEC/IRB; used in the study 
7.0 
17 November 2022 
Version submitted to IEC/IRB; used in the study 

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Table of Contents  
History of Protocol Versions ................................................................................................. 3 
List of Tables .......................................................................................................................... 9 
Synopsis ................................................................................................................................ 10 
Tables of Study Procedures ................................................................................................ 29 
List of Abbreviations ........................................................................................................... 36 
1 
Introduction ........................................................................................................... 39 
1.1 
Background ........................................................................................................... 39 
1.1.1 
Rabies Virus ....................................................................................................... 39 
1.1.2 
Rabies Disease .................................................................................................... 39 
1.1.3 
Rabies Vaccines .................................................................................................. 40 
1.2 
Background of the Investigational Product ........................................................... 40 
1.3 
Potential Benefits and Risks ................................................................................. 43 
1.3.1 
Potential Benefits to Subjects ............................................................................. 43 
1.3.2 
Potential Risks to Subjects ................................................................................. 43 
1.3.3 
Benefit and Risk Assessment During COVID-19 Pandemic ............................. 48 
1.4 
Rationale for the Study ......................................................................................... 49 
2 
Study Objectives .................................................................................................... 49 
2.1 
Primary Objective ................................................................................................. 49 
2.2 
Secondary Objectives ............................................................................................ 49 
3 
Investigators and Study Organization ................................................................. 50 
4 
Independent Ethics Committee/ Institutional Review Board ........................... 51 
5 
Investigational Plan ............................................................................................... 52 
5.1 
Description of the Overall Study Design and Plan ............................................... 52 
5.1.1 
Study Design ....................................................................................................... 52 
5.1.2 
Justification of the Study Design ........................................................................ 54 
5.1.3 
Study Plan ........................................................................................................... 56 
5.1.4 
Visit Procedures .................................................................................................. 61 
5.1.4.1 
For Cohort 1 ..................................................................................................... 61 
5.1.4.2 
For Cohort 2 ..................................................................................................... 66 
5.1.4.3 
Follow-up for Cohorts 1 and 2 ......................................................................... 70 

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5.1.5 
Planned Study Calendar ...................................................................................... 71 
5.1.6 
End of study definition ....................................................................................... 71 
5.2 
Enrollment and Retention of Study Population .................................................... 72 
5.2.1 
Recruitment Procedures ...................................................................................... 72 
5.2.2 
Informed Consent Procedures ............................................................................ 72 
5.2.3 
Screening Criteria ............................................................................................... 73 
5.2.4 
Inclusion Criteria ................................................................................................ 73 
5.2.5 
Exclusion Criteria ............................................................................................... 73 
5.2.6 
Medical History .................................................................................................. 75 
5.2.7 
Contraindications for Subsequent Vaccinations ................................................. 75 
5.2.7.1 
Temporary Contraindications ........................................................................... 75 
5.2.7.2 
Definitive Contraindications ............................................................................ 76 
5.2.8 
Coronavirus Disease 2019 (COVID-19) Vaccine .............................................. 77 
5.2.9 
Conditions for Withdrawal ................................................................................. 77 
5.2.10 
Lost to Follow-up Procedures ............................................................................. 78 
5.2.11 
Classification of Subjects Who Discontinue the Study ...................................... 78 
5.2.12 
Follow-up of Discontinuations ........................................................................... 79 
5.2.13 
Follow-up and Reporting of Pregnancies ........................................................... 79 
5.3 
Safety Emergency Call ......................................................................................... 80 
5.4 
Modification of the Study and Protocol ................................................................ 80 
5.4.1 
VRV12 Amendments Justification ..................................................................... 80 
5.5 
Interruption of the Study ....................................................................................... 83 
6 
Products Administered ......................................................................................... 83 
6.1 
Identity of the Investigational Products ................................................................ 83 
6.1.1 
Composition ........................................................................................................ 83 
6.1.2 
Preparation and Administration .......................................................................... 84 
6.1.3 
Dose Selection and Timing ................................................................................. 84 
6.2 
Identity of Control Product 1 ................................................................................ 84 
6.2.1 
Composition ........................................................................................................ 84 
6.2.2 
Preparation and Administration .......................................................................... 85 
6.2.3 
Dose Selection and Timing ................................................................................. 85 
6.3 
Identity of Control Product 2 ................................................................................ 85 
6.3.1 
Composition ........................................................................................................ 85 
6.3.2 
Preparation and Administration .......................................................................... 86 
6.3.3 
Dose Selection and Timing ................................................................................. 86 
6.4 
Identity of Other Product(s) .................................................................................. 86 
6.5 
Product Logistics .................................................................................................. 86 
6.5.1 
Labeling and Packaging ...................................................................................... 86 
6.5.2 
Product Shipment, Storage, and Accountability ................................................. 86 
6.5.2.1 
Product Shipment ............................................................................................. 86 

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6.5.2.2 
Product Storage ................................................................................................ 87 
6.5.2.3 
Product Accountability ..................................................................................... 87 
6.5.3 
Replacement Doses ............................................................................................. 87 
6.5.4 
Disposal of Unused Products .............................................................................. 87 
6.5.5 
Recall of Products ............................................................................................... 88 
6.6 
Blinding and Code-breaking Procedures .............................................................. 88 
6.7 
Randomization and Allocation Procedures ........................................................... 89 
6.8 
Treatment Compliance .......................................................................................... 90 
6.9 
Concomitant Medications and Other Therapies.................................................... 90 
7 
Management of Samples ....................................................................................... 91 
7.1 
Sample Collection ................................................................................................. 92 
7.2 
Sample Preparation ............................................................................................... 92 
7.3 
Sample Storage and Shipment .............................................................................. 92 
7.4 
Future Use of Stored Serum Samples for Research .............................................. 93 
8 
Clinical Supplies .................................................................................................... 93 
9 
Endpoints and Assessment Methods ................................................................... 94 
9.1 
Primary Endpoints and Assessment Methods ....................................................... 94 
9.1.1 
Safety .................................................................................................................. 94 
9.1.2 
Immunogenicity .................................................................................................. 94 
9.1.2.1 
Immunogenicity Endpoints .............................................................................. 94 
9.1.2.2 
Immunogenicity Assessment Methods............................................................. 94 
9.1.3 
Efficacy ............................................................................................................... 95 
9.2 
Secondary Endpoints and Assessment Methods ................................................... 95 
9.2.1 
Safety .................................................................................................................. 95 
9.2.1.1 
Safety Definitions ............................................................................................. 95 
9.2.1.2 
Safety Endpoints .............................................................................................. 97 
9.2.1.3 
Safety Assessment Methods ............................................................................. 98 
9.2.1.3.1 
Immediate Post-vaccination Observation Period ........................................... 98 
9.2.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Each 
Vaccination) ................................................................................................... 98 
9.2.1.3.3 
Unsolicited Adverse Events ......................................................................... 106 
9.2.1.3.4 
Adverse Events of Special Interest .............................................................. 107 
9.2.1.3.5 
Assessment of Causality .............................................................................. 108 
9.2.2 
Immunogenicity ................................................................................................ 108 
9.2.2.1 
Immunogenicity Endpoints ............................................................................ 108 
9.2.2.2 
Immunogenicity Assessment Methods........................................................... 109 
9.2.3 
Efficacy ............................................................................................................. 109 

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9.3 
Observational Endpoints and Assessment Methods ........................................... 109 
10 
Reporting of Serious Adverse Events ................................................................ 109 
10.1 
Initial Reporting by the Investigator ................................................................... 109 
10.2 
Follow-up Reporting by the Investigator ............................................................ 110 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study .......... 110 
10.4 
Assessment of Causality ..................................................................................... 110 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs ..................................... 111 
11 
Data Collection and Management ..................................................................... 111 
11.1 
Data Collection and CRB Completion ................................................................ 111 
11.2 
Data Management ............................................................................................... 112 
11.3 
Data Review ........................................................................................................ 113 
12 
Statistical Methods and Determination of Sample Size ................................... 113 
12.1 
Statistical Methods .............................................................................................. 113 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective ............................. 113 
12.1.1.1 
Hypotheses ..................................................................................................... 113 
12.1.1.2 
Statistical Methods ......................................................................................... 113 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ....................... 114 
12.1.2.1 
Hypotheses ..................................................................................................... 114 
12.1.2.2 
Statistical Methods ......................................................................................... 115 
12.1.3 
Exploratory Analyses ....................................................................................... 117 
12.2 
Analysis Sets ....................................................................................................... 117 
12.2.1 
Full Analysis Set ............................................................................................... 117 
12.2.2 
Safety Analysis Set ........................................................................................... 118 
12.2.3 
Per-Protocol Analysis Set ................................................................................. 118 
12.2.3.1 
Per-Protocol Analysis Set for D42 ................................................................. 118 
12.2.3.2 
Per-Protocol Analysis Set for D28 ................................................................. 119 
12.2.3.3 
Per-Protocol Analysis Set for Booster at M12 ............................................... 120 
12.2.3.4 
Per-Protocol Analysis Set for Booster at M24 up to M36 ............................. 120 
12.2.4 
Other Analysis Set(s) ........................................................................................ 121 
12.2.5 
Populations Used in Analyses .......................................................................... 121 
12.3 
Handling of Missing Data and Outliers .............................................................. 122 
12.3.1 
Safety ................................................................................................................ 122 
12.3.2 
Immunogenicity ................................................................................................ 122 
12.4 
Interim / Preliminary Analysis ............................................................................ 122 
12.5 
Determination of Sample Size and Power Calculation ....................................... 122 
12.5.1 
Primary Series ................................................................................................... 122 

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12.5.2 
Booster Phase ................................................................................................... 126 
13 
Ethical and Legal Issues and Investigator/ Sponsor Responsibilities ............. 127 
13.1 
Ethical Conduct of the Study/ Good Clinical Practice ........................................ 127 
13.2 
Source Data and Source Documents ................................................................... 127 
13.3 
Confidentiality of Data and Access to Subject Records ..................................... 128 
13.4 
Monitoring, Auditing, and Archiving ................................................................. 128 
13.4.1 
Monitoring ........................................................................................................ 128 
13.4.2 
Audits and Inspections ...................................................................................... 129 
13.4.3 
Archiving .......................................................................................................... 129 
13.5 
Financial Contract and Insurance Coverage ....................................................... 130 
13.6 
Stipends for Participation .................................................................................... 130 
13.7 
Publication Policy ............................................................................................... 130 
14 
Reference List ...................................................................................................... 131 
 

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List of Tables  
Table 5.1: Distribution of Subjects According to Vaccination Group ........................................... 53 
Table 5.2: Blood sampling and vaccination schedule for the 3-dose PrEP regimen + M12 
booster ............................................................................................................................................ 58 
Table 5.3: Blood sampling and vaccination schedule for the one week 2-dose PrEP regimen + 
immunogenicity persistence at M6, M12, M18, and pre-booster M24 up to M36 + M24 up to 
M36 booster .................................................................................................................................... 59 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales in 
infants and toddlers aged ≤ 23 months ......................................................................................... 100 
Table 9.2: Solicited injection site reactions: terminology, definitions, and intensity scales in 
children (aged 2 through 11 years) ............................................................................................... 101 
Table 9.3: Solicited injection site reactions: terminology, definitions, and intensity scales in 
adolescents and adults (aged ≥ 12 years) ..................................................................................... 102 
Table 9.4: Solicited systemic reactions: terminology, definitions, and intensity scales in 
infants and toddlers aged ≤ 23 months ......................................................................................... 103 
Table 9.5: Solicited systemic reactions: terminology, definitions, and intensity scales in 
children (aged 2 through 11 years), adolescents or adults (aged ≥ 12 years) ............................... 104 
Table 12.1: Sample size and power estimation for primary and key secondary 
immunogenicity objectives. .......................................................................................................... 125 
 

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Synopsis  
Company: 
Sanofi Pasteur 
Investigational Product: 
Purified Vero Rabies Vaccine – Serum Free (VRVg): Purified inactivated 
rabies vaccine prepared on Vero cell line  
Active Substance: 
Rabies virus – Wistar rabies virus strain PMWI 38 – 1 503 3M – grown on 
continuous Vero-SF cell cultures, inactivated by betapropiolactone 
Title of the Study: 
Immunogenicity and Safety of a Purified Vero Rabies Vaccine – Serum Free 
in Comparison with Verorab® and Imovax® Rabies, in a Pre-exposure 
Regimen in Both Pediatric and Adult Populations and Single Booster Dose of 
Purified Vero Rabies Vaccine – Serum Free Administered at 1 Year 
Post-3-dose Primary Series, and Between 2 up to 3 years Post-One Week 
2-dose Primary Series in a Subset of Adults in Thailand 
Development Phase: 
Phase III 
Study Sites: 
The study will be conducted in approximately 4 centers in Thailand. 
Investigators and sites are listed in the “List of Investigators and Centers 
Involved in the Study” document. 
Planned Study Period: 
Q4 2019 1st visit, 1st subject (FVFS) to Q3 2025 last contact, last subject 
(LCLS, consisting of a phone call [PC] and not a visit) 
Study Design, Schedule of Study 
Procedures, and Methodology: 
Controlled, randomized, multi-center 
Primary series will be observer-blinded for both Cohort 1 (3-dose 
pre-exposure prophylaxis [PrEP] regimen) and Cohort 2 (one week 2-dose 
PrEP regimen). 
Booster phase will be conducted in a blinded manner (vaccine received in the 
primary series) with an adult subset from Cohort 1 and hereafter referred as 
“Booster Phase Cohort 1” (with booster Dose 1 year after the 1st primary series 
vaccine injection). 
Evaluation of immunogenicity persistence after primary series and a booster 
phase will be conducted in an open-label manner with an adult subset from 
Cohort 2 and hereafter referred as “Immunogenicity Persistence and Booster 
Phase Cohort 2” (including blood samples collection at Month [M] 6, M12, 
M18, pre-booster between M24 up to M36, and post-booster between M24 up to 
M36+D14; and a booster dose between M24 up to M36). 
A total of 4 centers in Thailand have been taking part to this study. All the 4 
sites participated to Primary Series Cohort 1 and 2 out of the 4 sites 
participated in Booster Phase Cohort 1. One out of the 4 sites will participate 
in Cohort 2 (Primary Series Cohort 2 and Immunogenicity Persistence and 
Booster Phase Cohort 2). 
A total of 1700 healthy subjects are planned to be enrolled: 505 pediatric 
subjects (aged 1 year to < 18 years) and 505 adults (aged ≥ 18 years) to be 
vaccinated according to a 3-dose schedule PrEP regimen (Primary Series 
Cohort 1), and 690 adults (aged ≥ 18 years) to be vaccinated according to a 
one week 2-dose PrEP regimen (Primary Series Cohort 2). Randomization will 
be 3:1:1, (VRVg-2: Verorab vaccine: Imovax Rabies vaccine) in each age 
group:  

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Primary Series 
Pediatric Subjects: N= 505, in which pediatric subjects 
were only planned to receive a 3-dose PrEP regimen 
Primary Series Cohort 1: 
Group 1: VRVg-2                                        
Group 2: Verorab                             
Group 3: Imovax Rabies                  
Adult Subjects: N= 1195, in which: 
Primary Series Cohort 1: 505 adults were planned to 
receive a 3-dose PrEP regimen 
Group 1: VRVg-2                                        
Group 2: Verorab                             
Group 3: Imovax Rabies                  
Primary Series Cohort 2: 690 adults are planned to 
receive one week 2-dose PrEP regimen 
Group 4: VRVg-2                                        
Group 5: Verorab                             
Group 6: Imovax Rabies                  
 
 
 
 
 
N=303 
N=101 
N=101 
 
 
 
N=303 
N=101 
N=101 
 
 
N=414 
N=138 
N=138 
 
Booster Phase 
Two subsets of adult subjects will be randomized at enrollment to be part of 
booster phases.  
An adult subset from Cohort 1 will receive a booster dose of VRVg-2 at 1 year 
after the 1st vaccine injection of the primary series, regardless of what type of 
rabies vaccine was used in the primary series (Booster Phase Cohort 1). 
An adult subset from Cohort 2 will be followed up for evaluation of 
immunogenicity persistence after primary series (including blood samples 
collection at M6, M12, M18, pre-booster between M24 to M36, and post-
booster between M24 up to M36+D14) and will receive a booster dose of 
VRVg-2 between M24 to M36, regardless and not-blinded of what type of 
rabies vaccine was used in the primary series (Immunogenicity Persistence and 
Booster Phase Cohort 2). 
All efforts will be made to ensure that the randomization ratio of the primary 
series will be maintained in the adult booster subset (Cohort 1) or 
immunogenicity persistence and booster subset (Cohort 2). 
Booster Phase Cohort 1 (booster at M12 after the 1st vaccination in the 
primary series) 
Adult Subjects: N= 170 (3-dose PrEP regimen) 

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Group 1 (primed with VRVg-2) 
 
N=102 
Group 2 (primed with Verorab) 
 
N=34 
Group 3 (primed with Imovax Rabies) 
N=34 
 
Immunogenicity Persistence and Booster Phase Cohort 2 (blood samples 
collection for evaluation of immunogenicity persistence at M6, M12, M18, 
pre-booster between M24 to M36 after primary series, and post-booster 
between M24 up to M36+D14; and a booster dose between M24 up to M36 
after the 1st vaccination in the primary series with a new batch of VRVg-2 
doses) 
Adult Subjects: N= 230 (one week 2-dose PrEP regimen) 
Group 4 (primed with VRVg-2): 
 
N=138 
Group 5 (primed with Verorab): 
 
N=46 
Group 6 (primed with Imovax Rabies): 
N=46 
 
Pediatric subjects aged 1 year to less than 18 years will be in the study for 
about 7 months (including a 6-month follow-up).  
Adult subjects aged 18 years and older, will either be in the study for 7 months 
as the younger population, or they will stay for up to approximately 18 months 
(N = 170 adult subset in Booster Phase Cohort 1) or up to approximately 42 
months (N = 230 adult subset in Immunogenicity Persistence and Booster 
Phase Cohort 2). 
Visits (V) and PC 
Primary series 
For pediatric subjects and adults who received the 3-dose PrEP regimen 
(Primary Series Cohort 1), a total of 5 visits (V01 to V05) and 1 PC have been 
concluded. 
For adult subjects who are planned to receive one week 2-dose PrEP regimen 
(Primary Series Cohort 2), a total of 4 visits (V01 to V04) and 1 PC are 
outlined. 
Immunogenicity Persistence and Booster Phase 
Booster Phase Cohort 1: for the primary series 3-dose PrEP regimen + booster 
phase, a total of 8 visits (V01 to V08) and 2 PCs have been concluded. 
Immunogenicity Persistence and Booster Phase Cohort 2: for the primary 
series one week 2-dose PrEP regimen + immunogenicity persistence + booster 
phase, a total of 10 visits (V01 to V10) and 1 PC are outlined. 
 
Vaccination 
Pediatric subjects (505 subjects) and adult subjects (505 subjects) in Primary 
Series Cohort 1 received a total of 3 injections at D0, D7, and D28 through 
intramuscular (IM) route. Adult subjects in Primary Series Cohort 2 
(690 subjects) will receive a total of 2 injections in the primary series at Day 
(D)0 and D7 through IM route. 

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A subset of 170 adult subjects (Booster Phase Cohort 1) received a booster 
dose of VRVg-2 after 1 year (M12) regardless of the vaccine used in the 
primary series and a subset of 230 adult subjects (Immunogenicity Persistence 
and Booster Phase Cohort 2) will receive a booster dose of VRVg-2 between 2 
up to 3 years (M24-M36) regardless of the vaccine used in the primary series. 
Blood sampling 
Pediatric subjects and adult subjects (Primary Series Cohort 1) provided 3 
blood samples: at D0 (prior to the 1st vaccine injection), at D28 (21 days after 
the 2nd dose vaccine injection), and at D42 (14 days after the 3rd vaccine 
injection). Adult subjects in Primary Series Cohort 2 will provide 2 blood 
samples: at D0 (prior to the 1st vaccine injection) and D28 (21 days after the 
2nd dose vaccine injection). 
The adult subset who will be part of the Booster Phase Cohort 1 will have 2 
additional blood samples in the booster phase: at M12 (prior to the booster 
vaccine injection) and M12+D14 (14 days after booster vaccine injection), to 
evaluate immunogenicity in the booster phase. 
The adult subset who will be part of the Immunogenicity Persistence and 
Booster Phase Cohort 2 will have 5 additional blood samples: at M6, M12, 
M18, pre-booster between M24 up to M36, and post-booster between M24 up 
to M36+14D to evaluate immunogenicity persistence after the primary series 
and immunogenicity after booster.  
Collection of safety data 
All subjects will be kept under observation for 30 minutes after each 
vaccination to ensure their safety. 
All subjects will record information on experienced safety events in a diary 
card (DC) as follows: information about solicited reactions will be recorded 
during the 7 days following each vaccine injection, about unsolicited injection 
site reactions during the 28 days after each injection, and about unsolicited 
systemic adverse events (AEs) between each injection, and during the 28 days 
following the last injection. 
Pediatric subjects and adult subjects in Primary Series Cohort 1 recorded 
safety information in a Memory Aid (MA) from D56 (28 days following the 
3rd injection) until M7 for the subjects not involved in the booster phase, and 
until M12 for the adult subset in the Booster Phase Cohort 1; then from a 
booster vaccination (M12) until the end of the study (M18) for the adult subset 
in the Booster Phase Cohort 1. 
Adult subjects in Primary Series Cohort 2 (not involved in the Immunogenicity 
Persistence and Booster Phase Cohort 2 subset) will record safety information 
in a MA from D35 (28 days following the 2nd injection) until M6 (6-month 
safety follow-up after the last vaccination).  
Adult subjects in the Immunogenicity Persistence and Booster Phase Cohort 2 
subset will record safety information in a safety DC from D35 (28 days 
following the 2nd injection) until booster vaccination (M24 up to M36); and in 
a MA from 28 days after booster vaccination until the end of the study (M30 
up to M42, 6-month safety follow-up after the booster vaccination). 
Information about Serious Adverse Events (SAEs), Adverse events of Special 
Interest (AESIs), and cases of pregnancy were recorded throughout the study 

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for pediatrics and adults in Cohort 1; and this is up to 6 months after the 
booster dose for subset of adults in Cohort 1. 
Information about SAEs, AESIs, and cases of pregnancy will be recorded until 
6 months after the primary series (V05) and until 6 months after the booster 
dose for subset of adults in Cohort 2. Between the 6-month follow-up visit 
after primary series (V05) and booster dose visit (V08), AESIs will not be 
collected, only fatal SAEs and related SAEs will be collected. 
Study personnel will contact subjects by telephone at 6 months (+14 days) 
after the last primary vaccine injection (for subjects in Cohort 1, and for 
subjects in Primary Series Cohort 2 not involved in the Immunogenicity 
Persistence and Booster Phase Cohort 2 subset) and at 6 months (+14 days) 
after the booster dose for the collection of SAEs/AESIs. 
Interruption of the Study 
The study may be discontinued if new data about the investigational product 
resulting from this study or any other studies become available; or for 
administrative reasons; or on advice of the Sponsor, the Investigators, the 
Independent Ethics Committees (IECs)/ Institutional Review Boards (IRBs), 
or the governing regulatory authorities in the country where the study is taking 
place. 
If the study is prematurely terminated or suspended, the Sponsor shall 
promptly inform the Investigators, the IECs/IRBs, the regulatory authorities, 
and any contract research organization(s) (CROs) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the study subjects/ 
subjects’ parent or legally acceptable representative (LAR) and should assure 
appropriate subject therapy and/or follow-up. 
Primary Objective: 
Immunogenicity  
1) 
To demonstrate that VRVg-2 is non-inferior to Verorab and Imovax 
Rabies vaccines in each age group (pediatric and adult populations) 
when administered a 3-dose PrEP regimen, in terms of proportion of 
subjects achieving a rabies virus neutralizing antibody (RVNA) titer 
≥ 0.5 International units (IU)/mL at D42, ie, 14 days after the 3rd 
injection (for Primary Series Cohort 1) 
Primary Endpoints: 
• 
RVNA titers (IU/mL) measured by the Rapid Fluorescent Focus 
Inhibition Test (RFFIT) at D42 for pediatrics and adults (from Primary 
Series Cohort 1) 
• 
Subject with an RVNA titer ≥ 0.5 IU/mL at D42 

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Secondary Objectives: 
Safety 
• 
To describe the safety profile of VRVg-2 versus Verorab and Imovax 
Rabies vaccines, after each vaccine injection, in each age group (for 
Cohort 1 and Cohort 2). 
• 
To describe the safety of single booster dose of VRVg-2 among the 
subsets of adults following primary series of 3-dose primary series in 
addition to booster dose at M12 (for Booster Phase Cohort 1) 
• 
To describe the safety of single booster dose of VRVg-2 among the 
subsets of adults following one week 2-dose primary series in addition to 
booster dose between M24 up to M36 (for Immunogenicity Persistence 
and Booster Phase Cohort 2) 
Immunogenicity  
• 
To demonstrate that the observed proportion of subjects in the VRVg-2 
group (overall) achieving an RVNA titer ≥ 0.5 IU/mL at D42 is at least 
99%, with a lower limit of the 95% confidence interval (CI) of at least 
97% (for Primary Series Cohort 1), only if the primary objective is 
achieved 
• 
To demonstrate that VRVg-2 is non-inferior to Verorab and Imovax 
Rabies vaccines in each age group (pediatric and adult populations), in 
terms of proportion of subjects achieving an RVNA titer ≥ 0.5 IU/mL at 
D28, ie, 21 days after the 2nd injection (for pooled Primary Series Cohort 
1 and Cohort 2), only if the 1st secondary immunogenicity objective is 
achieved 
• 
To demonstrate that 2-dose VRVg-2 at D28 is non-inferior to 3-dose 
Imovax Rabies at D42 in each age group (pediatric and adult populations, 
respectively), in terms of proportion of subjects achieving an RVNA titer 
≥ 0.5 IU/mL, only if the 2nd secondary immunogenicity objective is 
achieved 
• 
To demonstrate that the observed proportion of subjects in the VRVg-2 
group (overall) achieving an RVNA titer ≥ 0.5 IU/mL at D28 is at least 
99%, with a lower limit of the 95% confidence interval (CI) of at least 
97% (for pooled Primary Series Cohort 1 and Cohort 2), only if the 3rd 
secondary immunogenicity objective is achieved 
• 
To demonstrate that 2-dose Imovax Rabies at D28 is non-inferior to 
3-dose Imovax Rabies at D42 in the overall subjects (pooled pediatric 
and adult subjects) in Cohort 1, in terms of proportion of subjects 
achieving an RVNA titer ≥ 0.5 IU/mL, only if the 4th secondary 
immunogenicity objective is achieved 
• 
To describe the immune response induced by VRVg-2 versus Verorab 
and Imovax Rabies vaccines at D28 (ie, 21 days after the 2nd injection), 
and at D42 (ie, 14 days after the 3rd injection) in all age groups (pediatric 
and adult populations) 
• 
To describe the immune response induced by VRVg-2 at D14 after a 
single dose booster of VRVg-2 administered at M12 after the primary 
series with VRVg-2, Verorab, or Imovax Rabies vaccines in the subset of 
adult subjects (for Booster Phase Cohort 1) 

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• 
To describe the persistence of immune response at M6, M12, M18, and 
pre-booster between M24 up to M36 post-primary series vaccination in 
the subset of adults who are randomized to receive a booster and 
completed the 2-dose vaccination in the primary series (for 
Immunogenicity Persistence and Booster Phase Cohort 2) 
• 
To describe the immune response induced by VRVg-2 at D14 after a 
single booster of VRVg-2 administered between M24 up to M36 after the 
primary series with VRVg-2, Verorab, or Imovax Rabies vaccines in the 
subset of adult subjects who are randomized to receive a booster and 
completed the 2-dose vaccination in the primary series (for 
Immunogenicity Persistence and Booster Phase Cohort 2) 

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Secondary Endpoints: 
Immunogenicity  
• 
RVNA titers (IU/mL) measured by RFFIT, summarized at the subject/ 
timepoint level: 
• 
RVNA titers at D0 and D28 for subjects in Primary Series Cohort 1 and 
Cohort 2, and at D42 for subjects in Primary Series Cohort 1; at M12 and 
M12+D14 for subjects in the Booster Phase Cohort 1; at M6, M12, M18, 
between M24 up to M36, and between M24 up to M36+D14 for subjects 
in Immunogenicity Persistence and Booster Phase Cohort 2 
• 
Subject with an RVNA titers ≥ 0.5 IU/mL at D0 and D28 for subjects in 
Primary Series Cohort 1 and Cohort 2, and at D42 for subjects in Primary 
Series Cohort 1; at M12 and M12+D14 for subjects in the Booster Phase 
Cohort 1; at M6, M12, M18, between M24 up to M36, and between M24 
up to M36+D14 for subjects in Immunogenicity Persistence and Booster 
Phase Cohort 2 
• 
Subject with an RVNA titer ≥ lower limit of quantitation (LLOQ) IU/mL 
at D0 and D28 for subjects in Primary Series Cohort 1 and Cohort 2, and 
at D42 for subjects in Primary Series Cohort 1; at M12 and M12+D14 for 
subjects in the Booster Phase Cohort 1; at M6, M12, M18, between M24 
up to M36, and between M24 up to M36+D14 for subjects in the 
Immunogenicity Persistence and Booster Phase Cohort 2 
• 
Individual RVNA titer ratio: D28/D0 for subjects in Primary Series 
Cohort 1 and Cohort 2; D42/D0 for subjects in Primary Series Cohort 1; 
M12/D0, 14 days after M12/D0, and 14 days after M12/M12, for subjects 
in Booster Phase Cohort 1; M6/D0, M12/D0, M18/D0, M24 up to 
M36/D0, 14 days after M24 up M36/D0, and 14 days after M24 up M36/ 
M24 up to M36 for subjects in Immunogenicity Persistence and Booster 
Phase Cohort 2 
• 
Individual RVNA titer ratio: D28/D0 for subjects in Primary Series 
Cohort 1 and Cohort 2; D42/D0 for subjects in Primary Series Cohort 1; 
M12/D0, 14 days after M12/D0, and 14 days after M12/M12, for subjects 
in Booster Phase Cohort 1; M6/D0, M12/D0, M18/D0, M24 up to 
M36/D0, 14 days after M24 up M36/D0, and 14 days after M24 up M36/ 
M24 up to M36 for subjects in Immunogenicity Persistence and Booster 
Phase Cohort 2 
• 
Subject with complete or incomplete neutralization at the starting dilution 
(1/5) of the RFFIT assay at subject with an RVNA titer ≥ LLOQ IU/mL 
at D0 and D28 for subjects in Primary Series Cohort 1 and Cohort 2, and 
at D42 for subjects in Primary Series Cohort 1; at M12 and M12+D14 for 
subjects in the Booster Phase Cohort 1; at M6, M12, M18, between M24 
up to M36, and between M24 up to M36+D14 for subjects in 
Immunogenicity Persistence and Booster Phase Cohort 2 
Safety 
• 
Occurrence of any unsolicited systemic AEs reported in the 30 minutes 
after each vaccine injection 
• 
Occurrence of solicited (pre-listed in the subject’s DC and electronic case 
report form [CRF]) injection site and systemic reactions occurring within 
7 days after each injection 

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• 
Occurrence of unsolicited (spontaneously reported) injection site 
reactions occurring within 28 days after each injection and unsolicited 
systemic AEs between each injection and up to 28 days after each 
injection 
• 
Occurrence of SAEs and AESIs within at least 6 months after each 
vaccination as applicable to Cohort 1 and Cohort 2 
SAEs (including AESIs) reporting includes occurrence, nature (Medical 
Dictionary for Regulatory Activities [MedDRA] preferred term), time of 
onset, duration, intensity, action taken, relationship to the product 
administered (for systemic AEs only), whether the event caused 
termination from the study, outcome, elapsed time from last 
administration (if less than 24h), relationship to study procedures, and 
seriousness criterion. 
Note: The following AESIs will be considered as SAEs and reported to the 
Sponsor: anaphylactic reactions, encephalitis, and convulsions. For each 
AESI, the standard case definitions from the Brighton Collaboration will be 
used. These AESIs have been defined based on existing post-marketing 
safety data of other rabies vaccines. However, encephalitis and convulsion 
are no longer considered as safety concern for Verorab and Imovax following 
a cumulative safety review (scientific literature and reported cases) which 
concluded on lack of evidence to suspect any causal relationship between 
these events and Verorab and Imovax. Safety concerns for VRVg are driven 
based on prior experience with Verorab (biological comparability). 
Encephalitis and convulsion remain AESI in ongoing studies for continuity 
purpose only. 
Note: Information about Serious Adverse Events (SAEs), Adverse events of 
Special Interest (AESIs) and cases of pregnancy were recorded throughout the 
study for pediatrics and adults in Cohort 1; and this is up to 6 months after the 
booster dose for subset of adults in Cohort 1. Information about SAEs, 
AESIs, and cases of pregnancy will be recorded until 6 months after the 
primary series (V05) and until 6 months after the booster dose for subset of 
adults in Cohort 2. Between the 6-month follow-up visit after primary series 
(V05) and booster dose visit (V08), AESIs will not be collected, only fatal 
SAEs and related SAEs will be collected. 
Planned Sample Size: 
Total 1700 subjects are planned to be enrolled (505 pediatric subjects and 
1195 adults) in 2 Cohorts. The attrition rate is anticipated as 15%. 
For pediatric subjects: 303 subjects in the VRVg-2 group, and 101 subjects in 
each of the control groups (Verorab and Imovax Rabies vaccines) will receive 
3 doses of vaccinations in the primary series. 
For adult subjects: 717 subjects in the VRVg-2 group, and 239 subjects in 
each of the control groups (Verorab and Imovax Rabies vaccines) will be 
enrolled by 2 Cohorts: 
• 
Cohort 1: 303 subjects in the VRVg-2 group, and 101 subjects in each of 
the control groups received 3-dose primary series 
• 
Cohort 2: 414 subjects in the VRVg-2 group, and 138 subjects in each of 
the control groups will receive one week 2-dose primary series 
Note: about 1/3 adult subjects are planned to receive a booster vaccination of 
VRVg-2 (Cohort 1: at 12 months; Cohort 2: at 24 up to 36 months) 

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Duration of Participation in the 
Study: 
The duration of each subject’s participation in the primary series of the study 
will be approximately 7 months (28 day-vaccination period followed by 
6-month safety follow-up period). For the subset of adult subjects in Booster 
Phase Cohort 1 who received a single booster dose of VRVg-2 (1 booster 
dose 365 days after primary series followed by 6-month safety follow-up 
period), the duration will be approximately 18 months.  
For Primary Series Cohort 2, the duration of each subject’s participation in 
the study will be approximately 7 months (one week vaccination period 
followed by 6-month safety follow-up period).  
For the subset of adult subjects in Immunogenicity Persistence and Booster 
Phase Cohort 2 who will be followed up for evaluation of immunogenicity 
persistence after primary series (including blood samples collection at M6, 
M12, M18, and between 24 up to 36 months) and who will receive a single 
booster dose of VRVg-2 (after the blood sample collection between 24 up to 
36 months), the duration will be approximately 30 to 42 months. 
Investigational Product: 
The investigational product is VRVg: Purified Vero Rabies Vaccine – Serum 
Free (purified inactivated rabies vaccine prepared on Vero cell line)  
 Form: 
Freeze-dried 
 Composition: 
Each 0.5 mL dose contains: 
Powder (VRVg-2): 
• 
Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3M 
strain:  2.5 IU (potency; NIH); 
• 
Stabilizer*: sufficient quantity (qs) 
• 
 
* The stabilizer (490 solution) is a mixture of amino acids (including trace 
amounts of phenylalanine), sugars (including the presence of sorbitol and 
trace amounts of saccharose), and sodium dihydrogen phosphate, di-sodium 
phosphate dihydrate, sodium glutamate, di-sodium edetate (EDTA), 
poloxamer P188 and urea in water for injections. 
• 
Diluent: 
• 
Sodium chloride: 2 mg 
• 
Water for injection: qs 0.5 mL 
 Route: 
IM 
Same batch (number to be disclosed at the time of report) was used for the 
primary series regardless of the number of doses and for the booster phase for 
subjects who received a 3-dose PrEP regimen (Primary Series Cohort 1) 
To be determined for the booster phase for subjects who received one 
week 2-dose PrEP regimen (Primary Series Cohort 2) 
 Batch Number: 
Control Product 1: 
Verorab vaccine: purified inactivated rabies vaccine prepared on Vero cell 
line 
 Form: 
Freeze-dried 
 Composition: 
Each 0.5 mL dose contains: 
Powder: 
• 
Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3 M strain: 
 2.5 IU (potency; NIH) 
• 
Maltose: qs 

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• 
Human albumin: qs 
 
• 
Diluent 
• 
Sodium chloride: 2 mg 
• 
Water for injection: qs 0.5 mL 
 Route: 
IM 
 Batch Number: 
To be determined 
Control Product 2: 
Imovax Rabies vaccine: purified inactivated rabies vaccine prepared on 
human diploid cell cultures 
 Form: 
Freeze-dried 
 Composition: 
Each dose contains: 
Powder: 
• 
Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3M strain: 
 2.5 IU (potency; NIH) 
• 
Human albumin ≤ 10 mg 
Diluent:  
• 
Water for injection: qs 1 mL 
 Route: 
IM 
 Batch Number: 
To be determined 
Inclusion Criteria: 
An individual must fulfill all of the following criteria to be eligible for study 
enrollment: 
1) Aged ≥ 1 year on the day of inclusiona 
2) Informed consent form (ICF) has been signed and dated by the subject 
and /or parent(s) or LAR and by an independent witness (if required by 
local regulations), as necessary; and Assent form (AF) has been signed 
and dated by the subject, as required. 
3) Subject (adult ≥18 years) or subject and parent/LAR (1 year to 
< 18 years) are able to attend all scheduled visits and to comply with all 
study procedures. 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from 
study enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential and not 
using an effective method of contraception or abstinence from at least 
4 weeks prior to the 1st vaccination until 1 month after each vaccination. 
To be considered of non-childbearing potential, a female must be pre-
menarche or post-menopausal for at least 1 year, or surgically sterile. 
2) Participation at the time of study enrollment or, planned participation 
during the present study period in another clinical study investigating a 
vaccine, drug, medical device, or medical procedure.  
                                                 
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3) Receipt of any vaccine in the 4 weeks (28 days) preceding the 1st study 
vaccination or planned receipt of any vaccine prior to V05 for pediatric 
subjects and adult subjects in Cohort 1, and prior to V04 for adult 
subjects in Cohort 2. 
4) Previous vaccination against rabies (in pre- or post-exposure regimen) 
with either the study vaccines or another vaccine. 
5) Bite by, or exposure to a potentially rabid animal in the previous 
6 months with or without post-exposure prophylaxis. 
6) Receipt of immune globulins, blood or blood-derived products in the past 
3 months. 
7) 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). 
8) At high risk for rabies exposure during the study. 
9) Known systemic hypersensitivity to any of the study/control vaccine 
components or history of a life-threatening reaction to the vaccines used 
in the study or to a vaccine containing any of the same substances. 
10) Self-reported thrombocytopenia, contraindicating IM vaccination. 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding 
inclusion, contraindicating IM vaccination.  
12) Deprived of freedom by an administrative or court order, or in an 
emergency setting, or hospitalized involuntarily. 
13) Current alcohol or substance abuse that, in the opinion of the 
Investigator, might interfere with the study conduct or completion.  
14) Chronic illness that, in the opinion of the Investigator, is at a stage where 
it might interfere with study conduct or completiona. 
15) Moderate or severe acute illness/infection (according to Investigator 
judgment) on the day of vaccination or febrile illness (temperature 
≥ 38.0°C). A prospective subject should not be included in the study until 
the condition has resolved or the febrile event has subsided. 
16) Personal History of Guillain-Barré syndrome. 
17) Identified as an Investigator or employee of the Investigator or study 
center with direct involvement in the proposed study, or identified as an 
immediate family member (ie, parent, spouse, natural or adopted child) 
of the Investigator or employee with direct involvement in the proposed 
study. 
Statistical Methods: 
The statistical analysis will be performed in 4 steps. 
• 
The 1st statistical analysis will be done once all immunogenicity data 
up to D28 (V03, 21 days after the 2nd vaccination) in the primary 
series of Cohort 2 and all safety data up to D35 (V04, 28 days after the 
2nd vaccination) in the primary series of Cohort 2 are available (ie, at 
the end of 6-month safety follow-up after booster phase in Cohort 1; 
and up to D35 [V04] in primary series in Cohort 2). The randomization 

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and vaccination exposure information for all enrolled subjects will be 
unblinded at the time of 1st statistical analysis. 
• 
The 2nd statistical analysis will be carried out once the 12-month 
immunogenicity persistence data and safety data in Cohort 2 (V06) are 
collected. 
• 
The 3rd statistical analysis will be carried out once all the 
immunogenicity and safety data up to 28 days after the booster 
vaccination in Cohort 2 (V10) are collected. 
• 
The 4th statistical analysis will be carried out once the 6-month safety 
follow-up data post the booster vaccination in Cohort 2 (M30 up to 
M42) are collected. 
Primary objective: Non-inferiority (NI) testing of 3-dose VRVg-2 versus 
3-dose Verorab and Imovax Rabies at D42 
In each age group, the immunogenicity of VRVg-2 will be compared to that 
of Verorab and Imovax Rabies vaccines at D42 for subjects in Primary 
Series Cohort 1, ie, 14 days after the 3rd vaccine injection, using a NI 
testing. 
For each comparison, the primary parameter will be the difference in the 
proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 between the 
2 compared vaccine groups. The hypotheses tested will be the following: 
H0: PVRVg-2-Pcontrol ≤ -5% 
H1: PVRVg-2-Pcontrol > -5% 
With P = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 
(%). 
VRVg-2 will be considered as non-inferior to the tested control if the 
hypothesis H0 is rejected. 
For the NI hypotheses, the statistical methodology will be based on the use 
of the two-sided 95% CI of the difference of proportions of subjects with an 
RVNA titer ≥ 0.5 IU/mL at D42. The 95% CI for differences will be 
calculated using the Wilson score method without continuity correction. 
Each NI will be demonstrated if the lower limit of the 95% CI of the 
difference of the 2 proportions PVRVg-2-Pcontrol is > -5%. 
The primary objective of NI will be demonstrated if each of the NI between 
VRVg-2 and both Verorab and Imovax Rabies vaccines is demonstrated in 
each age group, respectively, in Primary Series Cohort 1. 
Secondary objectives 
The hypotheses of secondary objectives will be tested only if the primary 
objective is met, and then the key secondary objectives will be evaluated 
sequentially following a fixed-sequence method. 
• 
Superiority in the VRVg-2 group at D42 
                                                 
a Chronic illness may include, but is not limited to, neurological, cardiopulmonary, gastrointestinal, renal, 
genitourinary, metabolic, hematologic, auto-immune, or psychiatric disorders or infection. 
 

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Only if the primary objective is achieved at D42, the 1st secondary objective 
will be assessed on subjects from the VRVg-2 group for subjects in Primary 
Series Cohort 1, and this objective will be reached if the observed 
proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 is higher 
than or equal to 99% and if the following H0 hypothesis is rejected: 
H0: PVRVg-2 < 97% 
H1: PVRVg-2 ≥ 97% 
This objective will be demonstrated if the overall observed proportion of 
subjects in VRVg-2 group in Primary Series Cohort 1 with an RVNA titer 
≥ 0.5 IU/mL at D42 is at least 99.0%, with the lower limit of the 95% CI of 
the proportion, calculated using the exact binomial distribution (Clopper 
Pearson method), is higher than or equal to 97%. 
• 
NI testing of 2-dose VRVg-2 versus 2-dose Verorab and Imovax 
Rabies at D28 
Only if the 1st secondary objective is achieved, and then based on the same 
approach as the primary objective testing, the 2nd secondary NI objective of 
VRVg-2 compared to each of the controls will be tested at D28 in each age 
group in pooled Primary Series Cohort 1 and Cohort 2 subjects.  
H0: PVRVg-2-Pcontrol ≤ -5% 
H1: PVRVg-2-Pcontrol > -5% 
With P = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 
(%). 
The secondary immunogenicity objective of NI at D28 will be demonstrated 
if each of the non-inferiority between VRVg-2 and both Verorab and 
Imovax Rabies vaccines is demonstrated for each age group, respectively, in 
pooled Primary Series Cohort 1 and Cohort 2. 
• 
NI testing of 2-dose VRVg-2 at D28 versus 3-dose Imovax Rabies at 
D42  
Only if the 2nd secondary objective is achieved, then the following NI 
hypotheses will be tested in each age group (Pediatric subjects: Cohort 1; 
Adult subjects: pooled Cohort 1 and Cohort 2), respectively: 
Pediatric subjects (Cohort 1 only): 
H0: PVRVg-2 at D28 (Group 1) – PImovax Rabies at D42 (Group 3) ≤ -10%  
H1: PVRVg-2 at D28 (Group 1) – PImovax Rabies at D42 (Group 3) > -10%  
Adult subjects (Pooled Cohorts 1 and 2): 
H0: PVRVg-2 at D28 (Groups 1+4) – PImovax Rabies at D42 (Group 3) ≤ -10%  
H1: PVRVg-2 at D28 (Groups 1+4) - PImovax Rabies at D42 (Group 3) > -10%  
With PVRVg-2 at D28 = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL 
at D28 for VRVg-2 (%), and PImovax Rabies at D42=proportion of subjects with an 
RVNA titer ≥ 0.5 IU/mL at D42 for Imovax Rabies (%). 
NI will be demonstrated for each hypothesis if the lower limit of the 95% CI 
of the difference of the 2 proportions (PVRVg-2 at D28 -PImovax Rabies at D42) is > -
10%, with a similar approach as the primary objective testing. 

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The 3rd secondary objective will be demonstrated if all null hypotheses are 
rejected. 
• 
Superiority in the VRVg-2 group at D28  
Only if the 3rd secondary objective is achieved, and then based on the same 
approach as the 1st secondary superiority objective testing at D42, the 4th 
secondary objective of superiority of VRVg-2 group at D28 will be assessed 
on overall subjects from VRVg-2 group in pooled Primary Series Cohort 1 
and Cohort 2, and this objective will be reached if the observed proportion 
of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 is higher than or equal 
to 99% and if the following H0 hypothesis is rejected 
H0: PVRVg-2 < 97% 
H1: PVRVg-2 ≥ 97% 
This objective will be demonstrated if the overall observed proportion of 
subjects in VRVg-2 group in pooled Primary Series Cohort 1 and Cohort 2 
with an RVNA titer ≥ 0.5 IU/mL at D28 is at least 99.0%, with the lower 
limit of the 95% CI of the proportion, calculated using the exact binomial 
distribution (Clopper Pearson method), is higher than or equal to 97%. 
• 
NI testing of 2-dose Imovax Rabies at D28 versus 3-dose Imovax 
Rabies at D42  
Only if the 4th secondary objective is achieved, then this objective will be 
tested with the following hypotheses in Imovax Rabies group in overall 
subjects (pooled pediatric and adult subjects) in Cohort 1 only: 
H0: PImovax Rabies at D28 (Group 3) - PImovax Rabies at D42 (Group 3) ≤ -10%  
H1: PImovax Rabies at D28 (Group 3) - PImovax Rabies at D42 (Group 3) > -10%  
With PImovax Rabies at D28 = proportion of subjects with an RVNA titer 
≥ 0.5 IU/mL at D28 for Imovax Rabies in Cohort 1 (%); PImovax Rabies at 
D42=proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 for 
Imovax Rabies in Cohort 1 (%). 
The null hypothesis will be rejected, and the objective will be achieved if the 
lower limit of the two-sided 95% CI for the difference of the 2 proportions 
(PImovax Rabies at D28 -PImovax Rabies at D42) is > -10%, which will be calculated using 
a generalized linear model (GLM) for repeated measured data with 
categorical response under binomial distribution (link function=identity). 
Other immunogenicity and safety objectives  
The analyses will be described by vaccine group, using descriptive statistical 
methods only without hypothesis testing. 
Datasets for analyses: 
For primary and key secondary immunogenicity objectives, the per-protocol 
analysis set (PPAS) will be used as the primary analysis set, and 
supplementary analysis will be performed on FAS or FASI, if necessary.  
For safety objectives, the safety analysis set (SafAS) will be used.  
Calculation of sample size: 
Primary series: 

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Original Plan for Cohort 1:  
An alpha level of 2.5% (one-sided hypothesis) has been chosen to calculate 
the sample size.  
Originally, assuming a proportion of subjects with an RVNA titer 
≥ 0.5 IU/mL of 99% for both VRVg-2 and control vaccines in each age 
group at D42, a clinical acceptable difference of -5% for the difference of 
proportions at D42 betweenVRVg-2 and the control vaccines, and a power 
of at least 95% for each of the NI testing in the primary objective, with an 
unbalanced randomization ratio of 3:1:1 (VRVg-2: Verorab vaccine: Imovax 
Rabies vaccine), 258 evaluable subjects in the VRVg-2 group, and 86 
evaluable subjects in each of the Verorab and Imovax Rabies vaccine groups 
who are planned to receive 3 vaccinations (at D0, D7, and D28) in primary 
series in each age group, will be necessary to provide a global power of 
81.8% for the primary NI objective, using the Farrington and Manning (FM) 
method. 
If the primary objective is met at D42, a total of 516 subjects evaluable in 
the VRVg-2 group will ensure 85.0% of power for the 1st secondary 
immunogenicity objective of superiority at D42. If the 1st secondary 
immunogenicity objective is met, overall power for the 2nd secondary 
immunogenicity NI objective of 2-dose VRVg-2 at D28 versus 2-dose 
comparator vaccines at D28 will be higher than 80%. 
Under the assumption that 15% of subjects will not be evaluable in the 
PPAS, 303 subjects in the VRVg-2 group and 101 subjects in each of the 
Verorab and Imovax Rabies vaccine groups must be enrolled in each age 
group of the study per the original plan, as Primary Series Cohort 1. 
 
Updated Plan for Cohort 1 and Cohort 2 (Protocol Amendments 2, 3, and 
4):  
According to the latest results from the VAJ00001 study and to be 
conservative, the estimation of proportion of adult subjects with an RVNA 
titer ≥ 0.5 IU/mL at D28 was adjusted from 99% to 96.5% for both VRVg-2 
and control vaccines. With the aim to secure the study power for the 2nd 
secondary immunogenicity NI objective at D28 and maintain the 
randomization ratio, 609 evaluable adults in the VRVg-2 group, and 203 
evaluable adults in each of the control vaccine group (Verorab and Imovax 
Rabies) will be necessary to provide a power of 81.7% to demonstrate the 
2nd secondary immunogenicity objective at D28, using the FM method. 
If the 2nd secondary immunogenicity objective is met at D28, a total of 867 
subjects evaluable in the VRVg-2 group will ensure 99.2% of power for the 
secondary objective of superiority for VRVg-2 at D28 in the overall subjects 
(pooled pediatric and adult subjects). 
Therefore, under the attrition rate of 15%, 690 additional adults (414 in 
VRVg-2; 138 in Verorab; 138 in Imovax Rabies) were planned to be 
enrolled in the study as Cohort 2 to receive 2 vaccinations at D0 and D7 in 
the primary series. Those 690 additional adults in Cohort 2 were planned to 
be pooled with the 505 adults enrolled in Cohort 1, for testing the 2nd 
secondary NI objective at D28. The 414 additional adults in VRVg-2 group 
in Cohort 2 were planned to be pooled with the 303 pediatric subjects and 

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303 adult subjects in VRVg-2 group in Cohort 1, for testing the secondary 
superiority objective for VRVg-2 at D28. 
Therefore, a total of 1700 subjects (505 pediatric subjects and 1195 adult 
subjects) were planned to be enrolled in total by 2 Cohorts, including 505 
pediatric subjects and 505 adult subjects in Cohort 1 who are planned to 
receive 3 doses of vaccinations in the primary series, and 690 adult subjects 
in Cohort 2 who were planned to receive 2 doses of vaccinations in the 
primary series. 
As a consequence, a total of 1708 subjects (505 pediatric subjects and 1203 
adult subjects) were actually enrolled, including 505 pediatric subjects and 
505 adult subjects in Cohort 1 and 698 adult subjects (including 8 
replacements) in Cohort 2. 
The 3:1:1 design is chosen to optimize the NI testing for immunogenicity 
and to increase the size of the safety database. 
 
Updated power estimations with additional objectives (Protocol 
Amendment 5):  
Based on live blinded data observed from Cohort 1, the estimated attrition 
rate of Cohort 1 was adjusted from 15% to about 13.5% at both D28 and 
D42 for pediatric subjects, and adjusted to about 21.0% at D28 and 19.8% at 
D42 for adult subjects, respectively. Assuming the actual attrition rate of 
adult subjects in Cohort 2 is similar to Cohort 1, the adjusted estimations for 
evaluable number of subjects in the PPAS in each age group are as below: 
• 
Pediatric subjects (Cohort 1 only): at both D28 and D42, there 
will be about 261 and 88 evaluable subjects in VRVg-2 group and 
each of the comparator vaccine groups, respectively.   
• 
Adult subjects: at D28, there will be about 570 and 190 evaluable 
subjects in VRVg-2 group and each of the comparator vaccine 
groups, respectively (pooled Cohort 1 and Cohort 2); at D42, 
there will be about 243 and 81 evaluable subjects in VRVg-2 
group and each of the comparator vaccine groups, respectively 
(Cohort 1 only).  
Moreover, 2 new secondary immunogenicity objectives were added, both 
with a NI margin of -10%: 
• 
To demonstrate the NI of 2-dose VRVg-2 at D28 versus 3-dose 
Imovax Rabies at D42 in each age group 
• 
To demonstrate the NI of 2-dose Imovax Rabies at D28 versus 3-
dose Imovax Rabies at D42 in the overall subjects (pooled 
pediatric and adult subjects) in Cohort 1  
Finally, the primary objective and all 5 key secondary immunogenicity 
objectives will be evaluated sequentially. Each of the key immunogenicity 
objective will be tested only if the previous objective is achieved.  
Based on the updated study objectives and the adjusted number of evaluable 
subjects in the PPAS, the power to demonstrate each of the key 
immunogenicity objectives is presented as below: 
 

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Key 
Objectives 
Age group 
Evaluable N  
in the PPAS 
Power 
(%) 
Primary 
Objective 
Pediatric Subjects 
(Cohort[C] 1) 
VRVg-2: 261 
Verorab: 88 
95.4a 
VRVg-2: 261 
Imovax Rabies: 88 
95.4 a 
Adult Subjects 
(C1) 
VRVg-2: 243 
Verorab: 81 
93.8 a 
VRVg-2: 243 
Imovax Rabies: 81 
93.8 a 
Overall: 80.0 a 
Secondary Objectives 
#1 
Overall 
(Pooled Pediatric and 
Adult Subjects in C1) 
VRVg-2: 504 
86.3 b 
#2 
Pediatric Subjects 
(C1) 
VRVg-2: 261 
Verorab: 88 
95.4 a 
VRVg-2: 261 
Imovax Rabies: 88 
95.4 a 
Adult Subjects 
(Pooled C1+C2) 
VRVg-2: 570  
Verorab: 190 
93.8 a 
VRVg-2: 570 
Imovax Rabies: 190 
93.8 a 
Overall: 80.1 a 
#3 
Pediatric Subjects 
(C1) 
VRVg-2 at D28: 261 
Imovax Rabies at D42: 88 
>99.9 a 
Adult Subjects 
(D28 from Pooled 
C1+C2, D42 from 
C1) 
VRVg-2 at D28 (Pooled 
Cohort 1+ Cohort 2): 570 
Imovax Rabies at D42: 81 
>99.9 a 
Overall: >99.9 a 
#4 
Overall  
(Pooled Pediatric and 
Adult Subjects in 
Pooled C1 and C2)  
VRVg-2: 831 
98.9 b 
#5 
Overall (Pooled 
Pediatric and Adult 
Subjects in C1 only) 
Imovax Rabies at D28: 168 
Imovax Rabies at D42: 168 
90.0 c 
a Power calculated using Farrington and Manning (FM) method. 
b Power calculated using Binomial Exact method. 
c Power calculated using simulation (10000 times, assuming correction coefficient [Rho]=0.5), 
based on general linear model (GLM) for repeated measured data with categorical response 
under binomial distribution (link function=identify).  
 
Booster Phase 
A subset of 170 adults from Cohort 1 (who received 3-dose PrEP regimen in 
the primary series) were included in the Booster Phase Cohort 1 at M12, in 
order to have 102 subjects who received the complete schedule with 
VRVg-2 vaccine (primary series + booster) in the FASB. 

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A subset of 230 adults from Cohort 2 (who will receive one week 2-dose 
PrEP regimen in the primary series) will be included in Immunogenicity 
Persistence and Booster Phase Cohort 2 (including blood samples collection 
at M6, M12, M18, pre-booster between M24 up to M36, and post-booster 
between M24 up to M36+D14, and a booster dose between M24 up to M36), 
in order to have 117 evaluable subjects who received the complete schedule 
with VRVg-2 vaccine (primary series + booster), assuming approximate 
15% of those 230 adult subjects will not be evaluable for booster 
immunogenicity evaluation at Year 2 up to Year 3 in the FASB. 

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Tables of Study Procedures  
3-Dose Primary Series – Pediatrics and Adults (Primary Series Cohort 1) 
Phase III Study, 5 Visits, 1 Phone Call, 3 Vaccinations, 3 Blood Samples, 7 Months Period per Subject 
Visit 
V01 
V02 
V03 
V04 
V05 
Phone Call 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
VAC3 =  
VAC1+28D 
 
VAC3+14D 
 
VAC3+28D 
  
VAC3*+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D42 
±3D 
D56 
±3D 
M7 
+14D 
Informed consent signed† 
 
√ 
 
 
 
 
 
Demographic data 
√ 
 
 
 
 
 
Urine pregnancy test‡ 
√ 
√ 
√ 
 
 
 
Physical examination§ 
√ 
√ 
√ 
√ 
√ 
 
Past and current significant 
medical history  
√ 
 
 
 
 
 
Inclusion & exclusion criteria 
√ 
 
 
 
 
 
Randomization/ IRT call 
√ 
√ 
√ 
 
 
 
Blood sampling for serology**  
BL01 
 
BL02 
BL03 
 
 
Vaccine injection 
√ 
√ 
√ 
 
 
 
30-minute observation period 
√ 
√ 
√ 
 
 
 
Diary Card (DC) 
 
 
 
 
 
 
Memory Aid (MA) 
 
 
 
 
 
 
                Provided 
DC1 
DC2 
DC3 
 
MA1 
 
                Checked 
 
DC1 
DC2 
DC3 
DC3  
MA1 
                Collected 
 
DC1 
DC2 
 
DC3 
 
Injection site reactions and 
Systemic Event Assessment 
√ 
√ 
√ 
√ 
√ 
 
Temporary contraindications 
 
√ 
√ 
 
 
 
Definitive contraindications 
 
√ 
√ 
 
 
 
Reportable concomitant 
medication 
√ 
√ 
√ 
√ 
√ 
 
Termination Record 
 
 
 
 
√ 
 
Pregnancy cases 
Collected throughout the entire study period 
SAEs and AESIs 
Collected throughout the entire study period 
* VAC3 or last vaccine injection in the event of early terminated subject contacted for the 6 months follow-up period through a 
phone call  
†In addition if applicable, one AF has to be signed by subjects as required by local Ethics Committee or country regulations 
‡ For subjects of childbearing potential 
§ Complete physical examination at V01 and medically-driven physical examination for remaining visits 
** Blood sample volume drawn from subjects aged 1 year to < 2 years will be 3 mL for subjects ≥ 2 years to < 18 years will be 
5 mL, and for subjects ≥18 years will be 6 mL 

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One Week 2-Dose Primary Series – Adults (Cohort 2) 
Phase III Study, 4 Visits, 1 Phone Call, 2 Vaccinations, 2 Blood Samples, approximately 7 Months Period 
per Subject 
Visit 
V01 
V02 
V03 
V04 
Phone Call‡ 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
  
VAC1+28D 
 
VAC2+28D 
  
VAC2*+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D35 
±3D 
M6 
+14D 
Informed consent signed 
 
√ 
 
 
 
 
Demographic data 
√ 
 
 
 
 
Urine pregnancy test‡ 
√ 
√ 
 
 
 
Physical examination§ 
√ 
√ 
√ 
√ 
 
Past and current significant medical 
history  
√ 
 
 
 
 
Inclusion & exclusion criteria 
√ 
 
 
 
 
Randomization/ IRT call 
√ 
√ 
 
 
 
Blood sampling for serology**  
BL01 
 
BL02 
 
 
Vaccine injection 
√ 
√ 
 
 
 
30-minute observation period 
√ 
√ 
 
 
 
Diary Card (DC) 
 
 
 
 
 
Memory Aid (MA) 
 
 
 
 
 
                Provided 
DC1 
DC2 
 
MA 
 
                Checked 
 
DC1 
DC2 
DC2 
MA 
                Collected 
 
DC1 
  
DC2 
 
Injection site reactions and Systemic 
Event Assessment 
√ 
√ 
√ 
√ 
 
Temporary contraindications 
 
√ 
 
 
 
Definitive contraindications 
 
√ 
 
 
 
Reportable concomitant medication 
√ 
√ 
√ 
√ 
 
Termination Record 
 
 
 
√ 
 
Pregnancy cases 
Collected throughout the entire study period 
SAEs and AESIs 
Collected throughout the entire study period 
* VAC2 or last vaccine injection in the event of early terminated subject contacted for the 6 months follow-up period through a 
phone call  
‡ For subjects of childbearing potential 
§ Complete physical examination at V01 and medically-driven physical examination for remaining visits 
**Blood sample volume drawn from subjects ≥ 18 years will be 6 mL 
‡ Administrative calls: in the interim between 6-month phone call after last vaccination in the primary series and booster dose, 
the study staff is encouraged (but not obligated) to contact the participants to check on their general well-being and interest to 
continue with the study  
 

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3-Dose Primary Series + M12 Booster – Adult Subset (Cohort 1) 
Phase III Study, 8 Visits, 2 Phone Calls, 3 Vaccinations, 1 Booster Dose, 5 Blood Samples, approximately 18 Months Period per Subject 
 Visit 
V01 
V02 
V03 
V04 
V05 
Phone Call 
V06 
V07 
V08 
Phone Call 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
VAC3 =  
VAC1+28D 
 
VAC3+14D 
 
VAC3+28D 
  
VAC3*+6M 
Booster 
VAC4=  
VAC1+12M 
D14 post-
booster dose  
VAC4+14D 
D28 post-
booster 
dose  
VAC4+28D 
6-month follow-
up post-booster 
dose  
VAC4+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D42 
±3D 
D56 
±3D 
M7 
+14D 
M12 
+14D 
M12+D14 
+1D 
M12+D28 
±3D 
M18 
+14D 
Informed consent signed 
 
√ 
 
 
 
 
 
 
 
 
 
Demographic data 
√ 
 
 
 
 
 
 
 
 
 
Urine pregnancy test‡ 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
Physical examination§ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
√ 
 
Past and current significant 
medical history  
√ 
 
 
 
 
 
√ 
 
 
 
Inclusion & exclusion criteria 
√ 
 
 
 
 
 
 
 
 
 
Randomization/ IRT call 
√ 
√ 
√ 
 
 
 
 
 
 
 
Blood sampling for serology** 
BL01 
 
BL02 
BL03 
 
 
BL04 
BL05 
 
 
Vaccine injection 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
30-minute observation period 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
Diary Card (DC) 
 
 
 
 
 
 
 
 
 
 
Memory Aid (MA) 
 
 
 
 
 
 
 
 
 
 
                Provided 
DC1 
DC2 
DC3 
 
MA1 
 
DC4 
 
MA2 
 
                Checked 
 
DC1 
DC2 
DC3 
DC3 
MA1 
MA1 
DC4 
DC4 
MA2 
                Collected 
 
DC1 
DC2 
 
DC3 
 
MA1 
 
DC4 
 

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 Visit 
V01 
V02 
V03 
V04 
V05 
Phone Call 
V06 
V07 
V08 
Phone Call 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
VAC3 =  
VAC1+28D 
 
VAC3+14D 
 
VAC3+28D 
  
VAC3*+6M 
Booster 
VAC4=  
VAC1+12M 
D14 post-
booster dose  
VAC4+14D 
D28 post-
booster 
dose  
VAC4+28D 
6-month follow-
up post-booster 
dose  
VAC4+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D42 
±3D 
D56 
±3D 
M7 
+14D 
M12 
+14D 
M12+D14 
+1D 
M12+D28 
±3D 
M18 
+14D 
Injection site reactions and 
Systemic Event Assessment 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
 
 
Temporary contraindications 
 
√ 
√ 
 
 
 
√ 
 
 
 
Definitive contraindications 
 
√ 
√ 
 
 
 
√ 
 
 
 
Reportable concomitant 
medication 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
√ 
 
Termination Record 
 
 
 
 
 
 
 
 
√ 
 
Pregnancy cases 
Collected throughout the entire study period 
SAEs and AESIs 
Collected throughout the entire study period 
* VAC3 or last vaccine injection in the event of early terminated subject contacted for the 6 months follow-up period through a phone call 
‡ For subjects of childbearing potential 
§ Complete physical examination at V01 and medically-driven physical examination for remaining visits 
** Blood sample volume drawn will be 6 mL. 

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One Week 2-Dose Primary Series + Blood Samples for Immunogenicity Persistence at M6, M12, M18, pre-booster M24-M36 + M24-M36 Booster – Adult 
Subset (Cohort 2) 
Phase III Study, 10 Visits, 1 Phone Call, 2 Vaccinations, 1 Booster Dose, 7 Blood Samples, approximately 42 Months Period per Subject 
Visit 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Phone Call 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
VAC1+28D VAC2+28D VAC2+6M VAC2+12M VAC2+18M 
Booster 
VAC3=  
VAC1+24M up 
to 36M 
D14 post-
booster dose  
VAC3+14D 
D28 post-
booster dose  
VAC3+28D 
6-month 
follow-up post-
booster dose  
VAC3+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D35  
±3D 
M6 
+14D  
M12  
+14D 
M18  
+14D 
M24 up to M36 
+14D 
[M24 up to 
M36+14D] 
+14D 
+1D 
[M24 up to 
M36+14D] 
+D28 
±3D 
M30 up to 
M42+14D 
Informed consent signed 
√ 
 
 
 
 
 
 
 
 
 
 
Demographic data 
√ 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test‡ 
√ 
√ 
 
 
 
 
 
√ 
 
 
 
Physical examination§ 
√ 
√ 
√ 
√ 
 
 
 
√ 
 
√ 
 
Past and current 
significant medical 
history  
√ 
 
 
 
 
 
 
√ 
 
 
 
Inclusion & exclusion 
criteria 
√ 
 
 
 
 
 
 
 
 
 
 
Randomization/ IRT call 
√ 
√ 
 
 
 
 
 
 
 
 
 
Blood sampling for 
serology**  
BL01 
 
BL02 
 
BL03 
BL04 
BL05 
BL06 
BL07 
 
 
Vaccine injection 
√ 
√ 
 
 
 
 
 
√ 
 
 
 
30-minute observation 
period 
√ 
√ 
 
 
 
 
 
√ 
 
 
 
Diary Card (DC) 
 
 
 
 
 
 
 
 
 
 
 

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Visit 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Phone Call 
Visit interval 
VAC1 
VAC2=  
VAC1+7D 
VAC1+28D VAC2+28D VAC2+6M VAC2+12M VAC2+18M 
Booster 
VAC3=  
VAC1+24M up 
to 36M 
D14 post-
booster dose  
VAC3+14D 
D28 post-
booster dose  
VAC3+28D 
6-month 
follow-up post-
booster dose  
VAC3+6M 
Indicative days (D) 
D0 
D7 
+1D 
D28 
±3D 
D35  
±3D 
M6 
+14D  
M12  
+14D 
M18  
+14D 
M24 up to M36 
+14D 
[M24 up to 
M36+14D] 
+14D 
+1D 
[M24 up to 
M36+14D] 
+D28 
±3D 
M30 up to 
M42+14D 
Memory Aid (MA) 
 
 
 
 
 
 
 
 
 
 
 
Provided 
DC1 
DC2  
 
 
 
 
 
DC3 
 
MA 
 
Checked 
 
DC1 
DC2 
DC2 
 
 
 
 
DC3 
DC3 
MA 
Collected 
 
DC1 
 
DC2 
 
 
 
 
 
DC3 
 
Diary Card (DC) SAE 
Follow-Up 
Provided 
 
 
 
 
 
DC SAE 
 
 
 
 
 
 
 
Checked 
Collected 
 
 
 
 
DC SAE 
 
DC SAE 
 
DC SAE 
 
DC SAE 
DC SAE 
 
 
 
Injection site reactions 
and Systemic Event 
Assessment 
√ 
√ 
√ 
√ 
 
 
 
√ 
 
 
 
Temporary 
contraindications 
 
√ 
 
 
 
 
 
√ 
 
 
 
Definitive 
contraindications 
 
√ 
 
 
 
 
 
√ 
 
 
 
Reportable concomitant 
medication 
√ 
√ 
√ 
√ 
√† 
√† 
√† 
√ 
√ 
√ 
 
Termination Record 
 
 
 
 
 
 
 
 
 
√ 
 
Pregnancy cases 
Collected throughout the entire study period*** 
SAEs and AESIs 
Collected throughout the entire study period*** 

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‡ For subjects of childbearing potential 
§ Complete physical examination at V01 and medically-driven physical examination for remaining visits 
** Blood sample volume drawn will be 6 mL  
† Only for concomitant medication belonging to categories 2 or 3 (refer to Section 6.9) 
***Information about SAEs, AESIs, and cases of pregnancy will be recorded until 6 months after the primary series and until 6 months after the booster dose for adults in Cohort 2. Between the 6-month follow-up visit 
after primary series (V05) and booster dose visit (V08), AESIs will not be collected, only fatal SAEs and related SAEs will be collected.   

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List of Abbreviations  
ACIP 
Advisory Committee on Immunization Practices  
AE 
Adverse event 
AESI 
Adverse event of special interest 
AF 
Assent Form 
AR 
Adverse reaction 
CBER 
Center for Biologics Evaluation and Research 
CDM 
Clinical Data Management 
CI 
Confidence Interval 
COVID-19 
coronavirus disease 2019 
CPRV 
Chromatographically purified rabies vaccine 
CQA 
Clinical Quality Assessment 
CRA 
Clinical Research Associate 
CRO 
Contract research Organization 
CRB 
(electronic) Case report book [all the case report forms for a subject] 
CRF 
(electronic) Case report form 
CTA 
Clinical trial agreement 
CTL 
Clinical Team Leader 
D 
Day 
DC 
Diary card 
EDC 
Electronic data capture 
EDTA 
Di-sodium edetate 
EEA 
European Economic Area  
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FASB 
Full Analysis Set for Booster 
FASI 
Full Analysis Set for Immunogenicity 
FDA 
Food and Drug Administration 
FITC 
Fluorescein isothiocyanate 
FM 
Farrington and Manning 
FVFS 
First visit, first subject 
FVLS 
First visit, last subject 

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GCDSE 
Global Clinical Development Strategy Expert 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GMT 
Geometric Mean Titer 
GPV 
Global Pharmacovigilance 
GSO 
Global Safety Officer 
HIV 
Human immunodeficiency virus 
HRIG 
Human rabies immunoglobulin  
IATA 
International Air Transport Association 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ID 
intradermal 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IME 
Important medical event 
IND 
Investigational new drug (application) 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IU 
International units 
LAR 
Legally acceptable representative 
LCLS 
Last contact, last subject 
LLOQ 
Lower limit of quantification 
LLT 
Lowest level term 
M 
Month 
MA 
Memory aid 
MAAE 
Medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
NA 
Not applicable 
NI 
Non-inferiority 
NSAID 
Non-steroidal anti-inflammatory drug 
PC 
Phone call 
PDCO 
Pediatric Committee 

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PEP 
Post-exposure prophylaxis 
PI 
Product Information 
PPAS 
Per-protocol analysis set 
PrEP 
Pre-exposure prophylaxis 
PVRV 
Purified Vero Rabies Vaccine 
qs 
Sufficient quantity 
RFFIT 
Rapid Fluorescent Focus Inhibition test 
 
RIG 
rabies immunoglobulin 
RMO 
Responsible Medical Officer 
RNA 
Ribonucleic acid 
RVNA 
Rabies virus neutralizing antibody 
SAE 
Serious adverse event 
SafAS 
Safety analysis set 
SafASB 
Safety analysis set for booster 
SF 
Serum free 
SmPC 
Summary of Product Characteristics 
SMT 
Safety Management Team 
TMF 
Trial Master File 
UN 
United Nations 
US 
United States 
V 
Visit 
VRVg 
Purified Vero Rabies Vaccine – Serum Free 
WHO 
World Health Organization 
 

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1 
Introduction  
1.1 
Background  
The investigational product assessed in this study is VRVg, a vaccine against rabies.  
Rabies is an infectious disease present worldwide, but mainly in developing countries, especially 
in Africa and Asia, where over 99% of human rabies deaths occur. The epidemiology of human 
rabies is an exact reflection of the epizootiology of the disease in animals. From the public health 
viewpoint, the dog or other canid species are the main vectors responsible for most infections in 
humans (1) (2). 
Rabies is responsible for approximately 59 000 human deaths each year. It should be emphasized, 
however, that the widespread underreporting of rabies cases implies that the actual number of 
deaths is likely to be higher. Importantly, the majority of deaths occur in children younger than 
15 years in poor and rural areas of Asia and Africa (1) (3) (4). The control of rabies in domestic 
and wild animals through animal control and vaccination programs, and the development of better 
human rabies vaccines and immunoglobulins remain critical to rabies prevention worldwide.  
1.1.1 
Rabies Virus  
Rabies is caused by Rabies virus, the 1st genotype in the genus Lyssavirus, from the 
Rhabdoviridae family. It has 2 known vectors: carnivores (worldwide) and bats (Americas). This 
genotype is the main cause of rabies in humans. The virus core contains viral ribonucleic acid 
(RNA), a nucleocapsid protein, a phosphoprotein, and a viral transcriptase. On the outside, there 
is a matrix protein and a glycoprotein that includes the epitopes that induce neutralizing 
antibodies (2). 
1.1.2 
Rabies Disease  
Rabies is a disease transmitted by infected (rabid) animals, usually through biting. The incubation 
period in humans is usually 20-60 days, but can be as short as <1 week, and as long as >6 months, 
or even several years. At 1st, infection presents with non-specific symptoms, including fever, 
headache, and malaise. There is often local tingling and severe pruritus at the site of the bite in the 
days following the contact. This is followed by central neurological signs, including anxiety, 
agitation, and delirium, often occurring a considerable time after the initial exposure. Periods of 
irritation are usually alternating with periods during which the patient is fully oriented (2). The 
virus will then spread from the brain to highly innervated areas, including the salivary glands 
causing hypersalivation, and other symptoms such as hydrophobia, aerophobia, and 
hyperventilation. In some cases, a paralytic form rather than an encephalitic form can be seen (5). 
Fever is usually present, but the sensory abilities of the patient are not affected. Within 2 weeks 
after onset of the neurological signs, coma usually sets in. There is no known treatment for rabies, 
and death is generally unavoidable. Few recoveries have been described, but these patients were 
usually left with permanent severe neurological disabilities. 
Infection takes place when saliva from an infected animal (or even human being) comes in contact 
with mucosal membranes. Immediately after exposure, the virus is still cell-free, allowing prompt 

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local treatment with disinfectants and antiserum to reduce the risk of infection. In the absence of 
the latter, the virus, which is highly neurotropic, will access peripheral nerves and possibly muscle 
cells near the location where the initial contact occurred. Virus shedding in the saliva coincides 
with the appearance of the 1st clinical symptoms (6) (7). 
While rabies is present worldwide, the most affected areas are the tropical countries in Asia, 
Africa, and Latin America, with over 99% of human rabies deaths occurring in developing 
countries (8). 
In Asia, rabies remains to be a major burden with an estimated 35 172 human deaths per year (8). 
In Thailand, the 2018 Surveillance data showed 16 fatal cases from 13 provinces, representing a 
rate of 0.02 per hundred thousand population. Proportion of males to females is 1:0.60. The most 
common age group is 35-44 years (25.0%), 55-64 years (25.0%), > 65 years (12.5%) respectively 
(9). According to the National Disease Surveillance System, in 2020 there were 3 human rabies 
deaths in different provinces in Thailand (namely Nongkhai, Sakaeo and Sisaket). As to the report 
covering the period in 2021 up to May 15th, 1 death occurred in Buriram province. The deceased 
was bitten by his dog that was bitten by a stray dog (10). 
Human death from rabies can be effectively prevented either by post-exposure treatment after a 
rabies exposure or by PrEP to subjects with a high risk of exposure. More than 15 million people 
receive post-exposure treatments each year after being exposed to animals suspected of having 
rabies (11). Pre-exposure vaccination is recommended for all individuals at increased risk of 
contracting rabies, either because of their residence or the nature of their occupation such as 
laboratory staff, veterinarians, animal handlers, wildlife officers with frequent exposure to 
potentially infected animals, or persons traveling to rabies enzootic areas (12) (13). 
1.1.3 
Rabies Vaccines  
The currently available vaccines recommended by the World Health Organization (WHO) are 
prepared on various cell substrates, such as human diploid cells, primary cells of hamster kidney, 
chicken or duck embryo fibroblasts, and continuous cell lines, like Vero cells (like Purified Vero 
Rabies Vaccine). These purified and beta-propriolactone-inactivated viral vaccines were 
developed in the 1960s to replace the 1st rabies vaccines prepared on animal nervous tissue, 
responsible for neurological disorders (14) (15) (16). 
1.2 
Background of the Investigational Product  
Currently, Sanofi Pasteur has 2 rabies vaccines registered worldwide and available on the market: 
Imovax® Rabies and Verorab®. Imovax Rabies, a human diploid cell vaccine, was 1st licensed in 
1975. It has been registered and marketed in 15 countries, including the United States (US), 
Canada, Australia, and 9 European Economic Area (EEA) countries. On the other hand, a Purified 
Vero Rabies Vaccine (PVRV), was 1st licensed in France in 1985 under the commercial name of 
Verorab and is extensively registered worldwide in 80 countries including 10 EEA countries but 
not in the US, Canada, and Australia. Both vaccines have a well-defined safety and 
immunogenicity profile (15) (16). 

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In addition to Imovax  Rabies and Verorab  vaccines, Sanofi Pasteur developed a 
chromatographically purified rabies vaccine (CPRV) prepared on Vero cells that was evaluated in 
the US and filed in the American Food and Drug Administration (FDA) under IND (BB-IND 
6 042) in the 1990s. Although this vaccine was licensed in France and had an adequate immune 
and safety profiles, it was never commercialized due to industrial constraints. 
In an effort to further improve the available rabies vaccines and optimize the manufacturing 
process and life cycle management, Sanofi Pasteur is developing a PVRV – serum free, 
henceforth referred to as VRVg.  
VRVg is issued from the Wistar Rabies Pitman Moore/WI 38 1503-3M strain. VRVg is highly 
purified with very low residual DNA content (< 100 pg per dose) and it is produced without raw 
material derived from human or animal origin and without antibiotics. VRVg is compliant with 
standards set by the European Union Pharmacopoeia, the WHO, and the US FDA.  
 
 
The clinical development of VRVg aims at demonstrating adequate immunogenicity versus the 
reference vaccines, and confirmation of the safety profile of the vaccine in all populations (for 
PrEP and post-exposure prophylaxis [PEP] of rabies), in order to provide the grounds for 
worldwide licensure in all age ranges. 
VRVg development has been conducted through stepwise adjustments based on various 
regulatory, pharmaceutical, and /or clinical rationales. As summarized below, 2 formulations 
referred to as VRVg-1 and VRVg-2, have been subsequently explored and tested in 6 clinical 
studies. Their performance has been evaluated through the non-inferior immunogenicity to 
licensed vaccines (whether Verorab or Imovax Rabies vaccines) based on the well-established 
surrogate clinical endpoint of seroconversion (percentage of subjects achieving a rabies virus 
neutralizing antibody [RVNA] titer of at least 0.5 international units (IU)/mL, as measured by the 
Rapid Fluorescent Focus Inhibition test [RFFIT]). 
VRVg-1 formulation 
VRVg-1 was used in 5 clinical studies comprising both PrEP and simulated PEP regimensa 
(Phase II: VRV01, VRV02, VRV04, and VRV06, and Phase III: VRV08)b. VRVg-1 was non-
inferior to Verorab vaccine in VRV01 and VRV08 and Imovax Rabies vaccine in VRV06, with 
the expected level of seroconversions (ie, > 99% subjects with RVNA titer ≥ 0.5 IU/mL). 
 
                                                 
a PrEP regimen: 3 injections at Day D0, D7, and D28; simulated PEP (ESSEN regimen): 5 injections at D0, D3, D7, 
D14, and D28.  
b VRV01 (PrEP in adults), VRV02 (PrEP in adults), VRV04 (simulated PEP with HRIG administration at D0 in 
adults), VRV06 (PrEP in children ≥ 2 years), and VRV08 (simulated PEP in children ≥ 10 years and adults).   
 

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Consequently, Sanofi Pasteur decided to modify the initial formulation of VRVg-1 in order to 
ensure an enhanced vaccine immune response. 
The safety profile of VRVg-1 was satisfactory and similar to that of Verorab and Imovax Rabies 
vaccine, with a trend towards a lower incidence of solicited injection site reactions. 
VRVg-2 formulation 
This 2nd formulation, referred to as VRVg-2, differs from VRVg-1 in that the antigen (Ag) 
content is increased, 
A dose-ranging study (VRV11; PEP study 
in simulated conditions with human rabies immunoglobulin (HRIG) administration at D0 in 
adults) compared 3 VRVg-2 dosages (low, medium, and high) with increasingly higher Ag 
amounts than VRVg-1a, versus VRVg-1 and Imovax Rabies vaccine.  
Briefly, VRV11 demonstrated a satisfactory safety profile of all VRVg-2 dosages, VRVg-1 and 
Imovax Rabies vaccine, with a trend for less adverse reactions in the VRVg groups than in the 
Imovax Rabies vaccine group in terms of solicited injection site and solicited systemic reactions 
and less unsolicited adverse events (AEs). Immunology results showed a dose-response 
relationship between the Ag amount administered and the seroconversion rates at D14, as well as 
the Geometric Mean Titers (GMTs) at all time points. VRVg-2 High dose was, therefore, the 
preferred formulation/dosage, since it showed an immune response similar (in terms of 
seroconversion) or higher (in terms of GMTs) to that of Imovax Rabies vaccine. It should be 
noted, however, that neither VRVg-2 (3 dosages), nor VRVg-1, nor Imovax Rabies vaccine 
reached a 99.0% seroconversion rate at D14. A 99% seroconversion rate was reached at D28 by 
VRVg-2 high dose and Imovax Rabies (Per-Protocol Population). As reported with other licensed 
vaccines (18) (19) (20), these results might be explained by an interference of the 
immunoglobulins co-administered through the IM route at D0. 
The next step in VRVg clinical development will consist of 2 Phase III non-inferiority (NI) 
studies which will compare the selected dose in VRV11 (VRVg-2 high doseb) with the 2 rabies 
vaccines marketed by Sanofi Pasteur (Verorab and Imovax Rabies vaccines); ie, this study 
(VRV12), is being carried out in the pediatric and adult populations using the PrEP regimen. 
Further, the PEP regimen with D0 HRIG administration is being assessed in the adult population 
(VRV13). 
                                                 
a  
b  For simplicity, VRVg-2 high dose (selected formulation/dose for this and future VRVg studies), will be referred 
henceforth to as VRVg-2 in this document.  

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1.3 
Potential Benefits and Risks  
1.3.1 Potential Benefits to Subjects  
Vaccination is the most effective preventive measure against rabies. Verorab is 
WHO-prequalified and specifically recommended by WHO (21). Imovax Rabies is recommended 
by the Advisory Committee on Immunization Practices (ACIP) (22). Subjects receiving VRVg-2 
are expected to be protected against infection in the event of contact with the virus.  
Subjects receiving VRVg-2 are expected to be protected against infection in the event of contact 
with the virus.  
Moreover, most of the subjects are expected to have reached RVNA titers ≥ 0.5 IU/mL after 
completion of the primary series with the 2- or 3-dose PrEP regimen and almost all are to reach 
this level after a single booster of the vaccine after being primed with those regimens (13) (20) 
(22) (23). All subjects in the study are healthy therefore each subjects’ RVNA titer ≥ 0.5 IU/mL is 
unnecessary for their life. If a subject had RVNA titers < 0.5 IU/mL at all timepoints after the 
primary or booster series, the Investigator may decide based on clinical judgment to offer an 
additional single vaccination of a local licensed rabies vaccine (as chosen by the Investigator) and 
administer according to the local Summary of Product Characteristics (SmPC) or national 
guidelines, and if the subject / subject’s legally acceptable representative (LAR) agree. Such 
vaccine is offered outside of the scope of the protocol (ie, no safety nor immunogenicity data will 
be collected after this vaccine injection), free of charge at the study site. 
As a standard approach, subjects may require additional vaccination in the event of exposure to 
the virus, regardless of the vaccine received in the context of this study. 
1.3.2 Potential Risks to Subjects  
VRVg-2 
Previously, the same order Ag quantity as VRVg-2 to be used in VRV12 has been evaluated in a 
clinical study during the development of a CPRV vaccine with satisfactory safety profile. 
Results from the precedent VRV11 study indicated that the safety profile of VRVg-2 (3 distinct 
doses tested) and VRVg-1 did not significantly differ from each other. Also, a trend for less solicited 
injection site and solicited systemic reactions, and unsolicited AEs were noted in the VRVg groups 
compared to the Imovax Rabies vaccine group. 
Based on the above, the potential risks of administration of VRVg-2 can be assimilated to those 
previously observed for VRVg-1 during clinical studies where this formulation was included (pre-
exposure regimens VRV01, VRV02, and VRV06, and post-exposure regimens VRV08, VRV04, 
and VRV11). 
 The following suspected adverse reactions and frequencies have been reported:  
• Very common (≥ 10%): injection site pain, malaise, headache, and myalgia 

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• Common (≥ 1% and < 10%): Pyrexia, injection site erythema, injection site swelling 
• Uncommon (≥ 0.1% and < 1%): lymphadenopathy, abdominal pain, diarrhea, dry mouth, 
nausea, asthenia, chills, fatigue, bronchitis, dizziness and somnolence, pharyngolaryngeal 
pain, pruritus, pruritus generalized, urticaria and flushing; injection site reactions such as 
injection site discomfort, hemorrhage, induration, hematoma/bruising, and pruritus 
• Rare (≥ 0.01% and < 1%): vertigo, vomiting, injection site warmth, injection site anesthesia, 
immune hypersensitivity, musculoskeletal pain, skin reaction with rash and pruritus, rash 
(local and generalized) 
To note that, the ARs reported only once in humans are not considered as expected ARs when the 
biological plausibility of the event being triggered by the vaccine is considered very low, and/or 
when they are symptoms of other listed events. However, if these ARs become common or there 
is new evidence of the biological plausibility of the event being triggered by the vaccine, the ARs 
will be considered as expected. Based on this rationale, the following rare cases of ARs 
(occurrence < 1/1000; only once) fall within this category:  
• 
Oral herpes, sinusitis, abdominal rigidity (low biological plausibility)  
• 
Oral hypoesthesia (symptoms of anxiety-related reactions or hypersensitivity), cold 
sweat, hyperhidrosis (symptoms of anxiety-related reactions or pyrexia), cough 
(symptoms of hypersensitivity) (low biological plausibility) 
The VRVg-2 dose that will be used in this study has been administered to a limited number of 
adult subjects (N=80) in VRV11, following a post-exposure regimen (5 injections within 28 days) 
with HRIG administration on the 1st day of vaccination. The AEs and frequencies reported, 
matched those of VRVg-1 reported as “Very common”: injection site pain, feeling unwell, 
headache, and muscle pain, and “Common”: fever, injection site redness and/or swelling, with the 
addition of injection site paresthesia, injection site hematoma/bruising, injection site pruritus, and 
diarrhea, also as common events. However, due to the limited sample size (N=80), events were 
considered as “common” even after a single occurrence of the reaction. 
 Thus, all suspected adverse reactions observed with 
Verorab (see below) are considered as possible risks for VRVg (including VRVg-1 and VRVg-2). 
Thus, all identified and potential risks of Verorab are considered as potential risks for VRVg, 
even though they have not been observed with VRVg specifically to date.  
Verorab Vaccine 
The following risks have been identified with the use of Verorab vaccine as currently reported in 
the approved SmPC: 
The following AEs are derivate from several clinical studies where Verorab vaccine has been used 
in both pre-exposure and post-exposure schedules in adults and children > 2 years old: 
 

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Adverse Reactions 
Adults 
≥ 18 years 
Pediatric Population  
under 18 years old 
Frequency 
Frequency 
Blood and lymphatic system disorders 
Lymphadenopathy 
Common 
Common 
Immune system disorders 
Allergic reactions (eg, rash, urticaria, 
pruritus) 
Uncommon 
Uncommon 
Anaphylactic reactions and angioedema 
Not known 
Not known 
Metabolism and nutrition disorders 
Decreased appetite 
Uncommon 
Common 
Nervous system disorders 
Headache 
Very common 
Very common 
Dizziness/vertigo 
Uncommon 
- 
Irritability (in infants/young children) 
- 
Very common 
Somnolence (in infants/young children) 
- 
Very common 
Insomnia (in infants/young children) 
- 
Common 
Ear and labyrinth disorders 
Sudden hearing loss, which may persist 
Not known 
Not known 
Respiratory, thoracic and mediastinal disorders 
Dyspnea 
Rare 
- 
Gastrointestinal disorders 
• 
Nausea 
Uncommon 
- 
• 
Abdominal pain 
Uncommon 
Uncommon 
• 
Diarrhea 
Uncommon 
- 
• 
Vomiting 
- 
Uncommon 
Musculoskeletal and connective tissue disorders 
• 
Myalgia 
Very common 
Very common 
• 
Arthralgia 
Uncommon 
- 
General disorders and administration site conditions 
Injection site pain 
Very common 
Very common 
Injection site erythema 
Common 
Common 
Injection site pruritus 
Common 
- 
Injection site swelling 
Common 
Common 

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Adverse Reactions 
Adults 
≥ 18 years 
Pediatric Population  
under 18 years old 
Frequency 
Frequency 
Injection site induration 
Common 
- 
Malaise 
Very common 
Very common 
Influenza-like syndrome 
Common 
 
Fever 
Common 
Common 
Asthenia 
Uncommon 
- 
Chills 
Uncommon 
Uncommon 
Inconsolable crying (in infants/young 
children) 
- 
Very common 
Frequency display uses the following convention: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 
and < 1/100); rare (≥ 1/10 000 and < 1/1.000); very rare (< 1/10 000); not known (cannot be estimated from the available data) 

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Imovax Rabies Vaccine 
The following risks have been identified with the use of Imovax Rabies as currently reported in 
the approved SmPC which is the Reference Safety Information for comparator in this study:  
 
Undesirable Effects 
Adults 
≥ 18 years 
Children and Adolescents 
up to 17 years old 
Frequency 
Frequency 
Clinical studies 
Blood and lymphatic system disorders 
Lymphadenopathy 
Uncommon 
- 
Gastrointestinal disorders 
Nausea 
Common 
- 
Abdominal pain 
Uncommon 
- 
Diarrhea 
Uncommon 
- 
Vomiting 
Uncommon 
- 
General disorders and administration site conditions 
Injection site pain 
Very common 
Very common 
Malaise 
Very common 
Very common  
Injection site erythema 
Common 
Common 
Injection site swelling/ edema/ 
induration 
Common 
Common 
Fever 
Common 
Common 
Injection site pruritus 
Common 
Uncommon 
Injection site hematoma/ 
Ecchymosis 
Common 
Uncommon 
Fatigue/ asthenia 
Common 
- 
Shivering 
Uncommon 
- 
Nervous system disorders 
Headache 
Very common 
Very common 
Dizziness 
Uncommon 
Uncommon 
Paresthesia 
Uncommon 
- 
Musculoskeletal and connective tissue disorders 
Myalgia 
Very common 
Very common 
Arthralgia 
Uncommon 
Uncommon 

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Undesirable Effects 
Adults 
≥ 18 years 
Children and Adolescents 
up to 17 years old 
Frequency 
Frequency 
Immune system disorders 
Allergic reaction with skin 
involvement or respiratory 
involvement 
Uncommon 
 
- 
 
Angioedema 
Rare 
- 
POST-MARKETING EXPERIENCE 
Nervous system disorders 
Encephalitis 
Not known 
Not known 
Convulsions 
Not known 
Not known 
Neuropathies  
Not known 
Not known 
Immune system disorders 
Anaphylactic reactions 
Not known 
Not known 
Serum sickness-like reactions 
Not known 
Not known 
Frequency display uses the following convention: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 
and < 1/100); rare (≥ 1/10 000 and < 1/1.000); very rare (< 1/10 000); not known (cannot be estimated from the available data). 
When medicinal products prepared from human blood or plasma are administered, the possibility 
of transmitting infective agents cannot be excluded despite strict control procedures and 
extraction/purification processes. This also applies to unknown or emerging viruses and other 
pathogens. 
1.3.3 Benefit and Risk Assessment During COVID-19 Pandemic  
A potential benefit of the PrEP in an endemic country is the study subjects to be primed against 
rabies in the context of coronavirus disease 2019 (COVID-19) and potential situations of 
lockdown that may limit access to healthcare infrastructures. 
Rabies vaccines would not cause immune suppression. Therefore, the risk of the subjects having 
COVID-19 will be similar to the general population. However, the risk of exposure to infected 
people cannot be completely excluded as the subjects may need to be exposed to public areas (eg, 
commute to the site and at the site). 
Risk mitigation: 
• The study staff will comply and abide by local regulations and measures to mitigate the spread 
of COVID-19 infection as prescribed by the local authorities. The study (Cohort 2) will not 
start until the local confinement measures linked to the COVID-19 pandemic are lifted by the 
local authorities. 
The Sponsor will perform a risk assessment of the study and implement measures that prioritize 
subject safety (main criteria) and data validity in agreement with the Investigators, IRB/EC, Thai 

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FDA, Central Research Ethics Committee in Thailand and European Medicines Agency (EMA) 
applicable recommendations (24) (25). These assessments will be documented. 
1.4 
Rationale for the Study  
Previous Phase II clinical study (VRV11) concluded that VRVg-2 compared favorably in terms of 
seroconversion rate and GMTs (all time points), to Imovax Rabies in a simulated PEP ESSEN 
Regimen with HRIG administration at D0, in the adult population. 
Following up on these results, the objective of phase III VRV12 is to demonstrate the vaccine’s 
adequate immunogenicity and non-inferior immune response versus current Rabies 
vaccines-Standard of Care (Verorab or Imovax Rabies vaccines) and to confirm its satisfying 
safety profile in the pediatric and adult population in a PrEP regimen. See Section 5.1.2 for further 
details. 
2 
Study Objectives  
2.1 
Primary Objective  
To demonstrate that VRVg-2 is non-inferior to Verorab and Imovax Rabies vaccines in each age 
group (pediatric and adult populations) when administered as a 3-dose PrEP regimen, in terms of 
proportion of subjects achieving an RVNA titer ≥ 0.5 IU/mL at D42, ie, 14 days after the 3rd 
injection (for Primary Series Cohort 1). 
The endpoint(s) for the primary objective(s) are presented in Section 9.1.2. 
2.2 
Secondary Objectives  
Safety 
• To describe the safety profile of VRVg-2 versus Verorab and Imovax Rabies vaccines, after 
each vaccine injection, in each age group (for Cohort 1 and Cohort 2). 
• To describe the safety of a single booster dose of VRVg-2 among the subsets of adults 
following primary series of 3-dose primary series in addition to booster dose at M12 (for 
Booster Phase Cohort 1) 
• To describe the safety of a single booster dose of VRVg-2 among the subsets of adults 
following one week 2-dose primary series in addition to booster dose between M24 up to M36 
(for Immunogenicity Persistence and Booster Phase Cohort 2) 
Immunogenicity  
• To demonstrate that the observed proportion of subjects in the VRVg-2 group (overall) 
achieving an RVNA titer ≥ 0.5 IU/mL at D42 is at least 99%, with a lower limit of the 95% 
confidence interval (CI) of at least 97% (for Primary Series Cohort 1), only if the primary 
objective is achieved 

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• To demonstrate that VRVg-2 is non-inferior to Verorab and Imovax Rabies vaccines in each 
age group (pediatric and adult populations), in terms of proportion of subjects achieving an 
RVNA titer ≥ 0.5 IU/mL at D28, ie, 21 days after the 2nd injection (for pooled Primary Series 
Cohort 1 and Cohort 2), only if the 1st secondary immunogenicity objective is achieved 
• To demonstrate that 2-dose VRVg-2 at D28 is non-inferior to 3-dose Imovax Rabies at D42 in 
each age group (pediatric and adult populations, respectively), in terms of proportion of 
subjects achieving an RVNA titer ≥ 0.5 IU/mL, only if the 2nd secondary immunogenicity 
objective is achieved 
• To demonstrate that the observed proportion of subjects in the VRVg-2 group (overall) 
achieving an RVNA titer ≥ 0.5 IU/mL at D28 is at least 99%, with a lower limit of the 95% 
confidence interval (CI) of at least 97% (for pooled Primary Series Cohort 1 and Cohort 2), 
only if the 3rd secondary immunogenicity objective is achieved 
• To demonstrate that 2-dose Imovax Rabies at D28 is non-inferior to 3-dose Imovax Rabies at 
D42 in the overall subjects (pooled pediatric and adult subjects) in Cohort 1, in terms of 
proportion of subjects achieving an RVNA titer ≥ 0.5 IU/mL, only if the 4th secondary 
immunogenicity objective is achieved 
• To describe the immune response induced by VRVg-2 versus Verorab and Imovax Rabies 
vaccines at D28 (ie, 21 days after the 2nd injection), and at D42 (ie, 14 days after the 3rd 
injection) in all age groups (pediatric and adult populations) 
• To describe the immune response induced by VRVg-2 at D14 after a single booster dose of 
VRVg-2 administered at M12 after the primary series with VRVg-2, Verorab, or Imovax 
Rabies vaccines in the subset of adult subjects (for Booster Phase Cohort 1) 
• To describe persistence of the immune response at M6, M12, M18, and pre-booster between 
M24 up to M36 post-primary series vaccination in the subset of adults who are randomized to 
receive a booster and completed the 2-dose vaccination in the primary series (for 
Immunogenicity Persistence and Booster Phase Cohort 2) 
• To describe the immune response induced by VRVg-2 at D14 after a single booster dose of 
VRVg-2 administered between M24 up to M36 after the primary series with VRVg-2, 
Verorab, or Imovax Rabies vaccines in the subset of adult subjects who are randomized to 
receive a booster and completed the 2-dose vaccination in the primary series (for 
Immunogenicity Persistence and Booster Phase Cohort 2) 
The endpoint(s) for the secondary objective(s) are presented in Section 9.2.1.2 for safety and in 
Section 9.2.2.1 for immunogenicity. 
3 
Investigators and Study Organization  
A total of 4 centers in Thailand have been taking part to this study. All the 4 sites participated to 
Primary Series Cohort 1 and 2 out of the 4 sites participated in Booster Phase Cohort 1. One out 
of the 4 sites will participate in Cohort 2 (Primary Series Cohort 2, and Immunogenicity 
Persistence and Booster Phase Cohort 2). Details of the study centers and the Investigators at each 
center, are provided in the “List of Investigators and Centers Involved in the Study” document. 

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Monitoring and Data Management activities will be conducted by a Contract Research Organization 
(CRO), under the responsibility of the Sponsor. 
No independent data monitoring committee (IDMC) is planned to be set up for this study as the 
investigational vaccine was shown to be safe and well-tolerated in a previous clinical study conducted 
with VRVg-2 (ie, VRV11), and several other clinical studies conducted with the precedent 
formulation VRVg-1 (ie, VRV01 in adults, VRV08 in subjects from 10 years of age, VRV02 in 
adults, VRV04 in adults, VRV06 in children, VRV11 in adults). It is also to be noted, that VRVg 
constitutes an improvement of Verorab in terms of the purification process, and technological 
innovation in vaccine manufacturing and characterization. 
Consequently, the wide post-marketing experience of Verorab vaccine 
and adequate safety profile is considered supportive of VRVg safety profile. 
There will be an internal Safety Management Team (SMT) review performed on a regular basis as 
part of an ongoing safety review. This SMT led by the Global Safety Officer (GSO) includes core 
representatives from the Global Pharmacovigilance (GPV) Department and the Clinical 
Department. Reviews will be performed in a blinded manner. 
4 
Independent Ethics Committee/ Institutional Review Board  
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the 1st subject, this protocol, the informed consent form (ICF), the assent form (AF), 
the subject recruitment procedures, and any other written information to be provided to subjects 
must be approved by, and/ or receive favorable opinion from, the appropriate Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and/ or 
the Sponsor are responsible for obtaining this approval and/ or favorable opinion before the start 
of the study. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator to 
the Sponsor together with the composition of the IEC/ IRB (the names and qualifications of the 
members attending and voting at the meetings). 
According to the local requirements, the Investigator will submit written summaries of the status 
of the study to the IEC / IRB annually, or more frequently if requested. All Serious Adverse 
Events (SAEs) occurring during the study that are related to the product administered will be 
reported by the Investigator to the IEC / IRB, according to the IEC/ IRB policy. 

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5 
Investigational Plan  
5.1 
Description of the Overall Study Design and Plan  
5.1.1 Study Design  
This will be a multi-center, observer-blind, controlled, randomized, Phase III study in 
1700 healthy subjects (505 pediatric subjects [aged 1 year to < 18 years] and 1195 adults subjects 
[aged ≥18 years]). Pediatric subjects (505 subjects) and adult subjects (505 subjects) in Primary 
Series Cohort 1 received primary series of 3 vaccine injections of VRVg-2 (Group 1), Verorab 
vaccine (Group 2) or Imovax Rabies vaccine (Group 3), at day [D] 0, D7, and D28. Adult subjects 
in Primary Series Cohort 2 will be vaccinated according to a one week 2-dose schedule PrEP 
regimen of either VRVg-2 (Group 4), Verorab vaccine (Group 5) or Imovax Rabies vaccine 
(Group 6) at D0 and D7. 
Primary series will be observer-blinded for both Cohort 1 (3-dose PrEP regimen) and Cohort 2 
(one week 2-dose PrEP regimen). Booster Phase Cohort 1 will be conducted in a blinded manner 
(vaccine received in the primary series) with an adult subset from Cohort 1 (with booster dose 
1 year after the 1st primary series vaccine injection). Evaluation of immunogenicity persistence 
after primary series and a booster phase will be conducted in an open-label manner with an adult 
subset from Cohort 2 (Immunogenicity Persistence and Booster Phase Cohort 2) (see Section 6.6 
for details). 
A total of 4 centers in Thailand have been taking part to this study. All the 4 sites participated to 
Primary Series Cohort 1 and 2 out of the 4 sites participated in Booster Phase Cohort 1. One out 
of the 4 sites will participate in Cohort 2 (Primary Series Cohort 2, and Immunogenicity 
Persistence and Booster Phase Cohort 2). 
A subset of 170 adult subjects from Primary Series Cohort 1 received a booster dose of VRVg-2 
after 1 year (M12) regardless the vaccine used in the primary series. A subset of 230 adult 
subjects from Primary Series Cohort 2 will be followed up for evaluation of immunogenicity 
persistence after primary series (including blood sample collection at M6, M12, M18, and pre-
booster between M24 up to M36) and will receive a booster dose of VRVg-2 between M24 up to 
M36 regardless of the vaccine received in the primary series. The randomization and vaccination 
during the primary series and booster phase for Cohort 1 were conducted in a blinded manner (see 
Section 6.6). Similarly, for Cohort 2, randomization and vaccination from the enrollment up to 
V04 (28 days after the last vaccination in the primary series) will be conducted in a blinded 
manner, and then the study data will be locked and unblinded for the 1st statistical analysis as 
defined in Section 12.4. 
The booster dose vaccination in the Immunogenicity Persistence and Booster Phase Cohort 2 will 
be conducted in an open-label manner with a new batch of VRVg-2; as a reminder, the laboratory 
analysts will remain blinded during the whole study.  
All efforts will be made to ensure that the randomization ratio of the primary series will be 
maintained in the booster subsets. 

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For Primary Series Cohort 1, the duration of each subject’s participation in the study will be 
approximately 7 months (28 day-vaccination period followed by a 6-month safety follow-up 
period). For the subset of adult subjects in Booster Phase Cohort 1 who received a single booster 
dose of VRVg-2, the duration will be approximately 18 months (1 booster dose 365 days after 
primary series followed by 6-month safety follow-up period). 
For Primary Series Cohort 2, the duration of each subject’s participation in the study will be 
approximately 7 months (one week vaccination period followed by a 6-month safety follow-up 
period). For the subset of adult subjects in Immunogenicity Persistence and Booster Phase 
Cohort 2 who will be followed up for evaluation of immunogenicity persistence after primary 
series (including blood sample collection at M6, M12, M18, and pre-booster between M24 up to 
M36) and who will receive a single booster dose of VRVg-2 (between M24 up to M36), the 
duration will be approximately 30 to 42 months. 
Vaccination will be administered through the intramuscular (IM) route. Subjects will be 
randomized 3:1:1 (Groups 1, 2, and 3 in Cohort 1; and Groups 4, 5, and 6 in Cohort 2; 
respectively) with the resulting number of subjects assigned to each study group shown in 
Table 5.1. 
 
Table 5.1: Distribution of Subjects According to Vaccination Group  
NA: Not applicable 
Pediatric subjects and adult subjects in Primary Series Cohort 1 provided 3 blood samples: at D0 
(prior to the 1st vaccine injection), at D28 (21 days after the 2nd vaccine injection), and D42 (14 
days after the 3rd vaccine injection). Adult subjects in Primary Series Cohort 2 will provide 
 
 
Vaccine 
Number of 
adult subjects 
Number of 
pediatric subjects 
Primary 
Series 
Cohort 1 
3-dose PrEP 
regimen 
Group 1 
VRVg-2 
303 
303 
Group 2 
Verorab 
101 
101 
Group 3 
Imovax Rabies 
101 
101 
Cohort 2 
one week 2-
dose PrEP 
regimen 
Group 4 
VRVg-2  
414 
NA 
Group 5 
Verorab 
138 
NA 
Group 6 
Imovax Rabies 
138 
NA 
Booster 
Phase 
Cohort 1 
(M12) 
Group 1 
VRVg-2 (primed with VRVg-2) 
102 
NA 
Group 2 
VRVg-2 (primed with Verorab) 
34 
NA 
Group 3 
VRVg-2 (primed with Imovax 
Rabies)  
34 
NA 
Cohort 2 
(M24 up to 
M36) 
Group 4 
VRVg-2 (primed with VRVg-2) 
138 
NA 
Group 5 
VRVg-2 (primed with Verorab) 
46 
NA 
Group 6 
VRVg-2 (primed with Imovax 
Rabies) 
46 
NA 

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2 blood samples: at D0 (prior to the 1st vaccine injection) and D28 (21 days after the 2nd dose 
vaccine injection). 
The adult subset of subjects who were part of the Booster Phase Cohort 1 had 2 additional blood 
samples: at M12 (prior to the booster vaccine injection), and M12 +D14 (14 days after booster 
vaccine injection). 
The adult subset of subjects who will be part of the Immunogenicity Persistence and Booster 
Phase Cohort 2 will have 5 additional blood samples: at M6, M12, M18, pre-booster between 
M24 up to M36, and post-booster between M24 up to M36+D14 (14 days after booster vaccine 
injection). 
Safety will be assessed in all subjects during the vaccination period and up to 28 days after 
vaccinations, in terms of occurrence of AEs, SAEs and Adverse Events of Special Interest 
(AESIs). In addition, SAEs and AESIs will be collected up to 6 months after the last vaccination 
in all subjects. The duration of the safety follow-up is planned to be until 6 months after the last 
dose of vaccine in the primary series and up to approximately 18 or approximately 30 to 42 
months for the subsets of adult subjects who will receive the single booster dose (Cohorts 1 and 2, 
respectively). For adult subjects in Immunogenicity Persistence and Booster Phase Cohort 2, 
between the 6-month follow-up visit after primary series (V05) and booster dose visit (V08), 
AESIs will not be collected, only fatal SAEs and related SAEs will be collected. 
5.1.2 Justification of the Study Design  
VRV12 will use the PrEP regimen. In detail, the performance of VRVg-2 will be demonstrated 
through the NI to both Verorab vaccine and Imovax Rabies vaccine, in terms of proportion of 
subjects achieving an RVNA titer ≥ 0.5 IU/mLa at D42 (ie, 14 days after the 3rd vaccine injection 
[primary objective]). 
In VRV12, safety and immunogenicity data will be generated in the pediatric population 
(aged 1 year to < 18 years) and in adults (aged ≥ 18 years). The age range and the design have 
been approved by EMA, Pediatric Committee (PDCO), Center for Biologics Evaluation and 
Research (CBER) (including the Pediatric Study Plan)b. The inclusion of subjects aged < 2 years 
was a PDCO request since this group is also at risk of rabies. For example, in a recent study 
conducted in the Philippines (27), 2.8% (17/600) were bitten subjects aged between 11 months 
and 2 years. It has been reported around 1% of children aged < 2 years had animal attacks in 
Thailand (28). Moreover, it is expected an adequate safety and immunogenicity profile in this age 
based on the results observed with VRVg-1 in children aged > 2 years and data obtained with 
Verorab in children aged ≤ 2 years in PrEP (28) (29) (30) and PEP (31) (32) (33). 
                                                 
a  An RVNA titer ≥ 0.5 IU/mL is the worldwide recognized surrogate marker of protection for the rabies vaccines. 
b  
 

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The 3-dose schedule of PrEP immunization in Primary Series Cohort 1 is based on ACIP 2008 
recommendations on PrEP (ie, 3 IM dose schedule on D0, D7, and D21 or D28) (34). It should be 
noted that the latest guidance from the WHO from April 2018 recommends a PrEP regimen 
consisting of 2 IM doses instead of 3 (D0 and D7) (13). 
Both guidelines were covered by the original study design. Recently, the ACIP guidelines adopted 
the same one week 2-dose PrEP regimen in February and June 2021 meetings (35), hence the 
amendment of the protocol to collect more data and information to substantiate the safety and 
immunogenicity of the one week 2-dose regimen for PrEP rabies immunization. This 
recommendation has been adopted by the director of Centers for Disease Control and Prevention 
and will become official after it is published in the Morbidity and Mortality Weekly Report. 
The study design of VRV12 will enable the evaluation of the NI against the reference vaccines 
after 3 doses (primary objective) and after 2 doses (secondary objectives), to cover the 
recommended PrEP regimens by both guidelines. Further, the VRV12 study intends to document 
a single booster dose after the 3-dose and one week 2-dose PrEP regimens for people whose 
occupation puts them at continual or frequent risk of exposure according to the WHO guidelines 
(34) (35) (36) and to accommodate CBER recommendations 
. Previous studies conducted with VRVg-1 showed an adequate 
immune response at D14 after a single dose of booster in adults, which also supports the current 
design of the study. The inclusion of children for the booster subset was not justified due to 
ethical reasons and due to the available evidence of similar immune responses to rabies vaccines 
in children and adults. Regarding the time of the booster, the US ACIP 2008 guidelines 
recommended that an IM booster dose of vaccine should be administered if the serum titer falls to 
maintain a serum titer corresponding to a value of at least complete neutralization at a 1:5 serum 
dilution by the RFFIT, every 6 months for the continuous risk category and up to 2 years for the 
frequent risk category group. Therefore, the time of the single booster and persistence assessment 
was set for 1 year after the 3-dose PrEP regimen. The new US ACIP 2021 guidelines 
recommended the time of the booster according to 5 different risk categories. The widest time 
window is recommended for the population who have elevated risk of recognized exposures that 
is sustained (eg, animal care professionals, veterinary students, etc.), who will have a serological 
test once between 1 and 3 years or a booster dose no sooner than 21 days and no later than year 3. 
Therefore, a single booster between 2 up to 3 years will be administered after 2-dose primary 
series in this Amendment 3 of the VRV12 protocol, a pre-booster blood sample will be taken at 
M24 up to M36, and a post-booster blood sample will be taken at 14 days after M24 up to M36 to 
evaluate immunogenicity of booster in Cohort 2. 
 two major 
additional objectives were added ie, the evaluation of superiority in VRVg-2 group after 2 doses 
in the overall population from VRVg-2 group and the assessment of immunogenicity persistence 
at M6, M12, and M18 after the 2-dose regimen in the primary series of Cohort 2.  
Moreover, in an effort to maximize the value of the data generated with VRV12 actual sample 
size, 2 new secondary objectives were added: to demonstrate the NI of a 2-dose VRVg-2 at D28 
versus 3-dose Imovax Rabies at D42 in each age group; and to demonstrate the NI of a 2-dose 
Imovax Rabies at D28 versus 3-dose Imovax Rabies at D42 in each age group, both with a NI 
margin of -10% for each of these 2 new secondary objectives.  
The reference vaccines (Verorab and Imovax Rabies vaccines) are both current standards of care 
employed globally. Their inclusion as controls/comparators aims to support VRVg licensure 

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worldwide. 
The selection of Thailand as the country for VRV12 is driven by the enzootic character of rabies 
in Thailand, which enables the conduct of rabies studies in the pediatric population, and also 
because both Verorab and Imovax Rabies are licensed in Thailand and can be used as controlsa. 
An early Safety Data Review is not judged necessary in this study. Data from the initial VRVg 
formulation (VRVg-1) in the adult population (VRV01, VRV08, VRV02, and VRV04) and 
pediatric population (VRV08 and VRV06) have consistently indicated a favorable safety profile 
comparable to the Verorab and Imovax Rabies vaccines. In addition, the safety profile of VRVg-2 
(all dosages) has been shown to be comparable to that of VRVg-1 in the adult population 
(VRV11). No safety concerns are therefore expected with VRVg-2. An internal ongoing safety 
review will be performed by the SMT, which includes safety signal detection. 
5.1.3 Study Plan  
The study plan is summarized in the Table of Study Procedures 
Recruitment and Information of Subjects: 
Before inclusion in the study, the Investigator will orally inform potentially eligible subjects 
and/or their parents about the study. They will be given an oral description of the study design, 
presenting the general benefits and risks related to the study. They will be informed that they may 
return and receive further information and sign the full informed consent during the recruitment 
period. The process of subject recruitment and any oral or written information that will be 
provided to the subjects must be documented. This will be available in the Investigator’s file and 
the Trial Master File (TMF). 
It should be noted that subjects who may have been pre-screened may not necessarily be included 
in the study if the required number of subjects have already been recruited. 
Informed consent and assent, if applicable will be obtained before inclusion of the subject in the 
study (see Section 5.2). 
Study Description: 
After having signed the ICF/AF, eligible subjects will be included in the study, and will provide 
the initial blood sample. 
Eligible pediatric subjects and adult subjects in Primary Series Cohort 1 received a total of 3 
injections (1 injection at D0, D07, and D28) and adult subjects in Primary Series Cohort 2 will 
receive a total of 2 injections in the primary series (at D0 and D7). 
A subset of 170 adult subjects (Booster Phase Cohort 1) received a single booster injection of 
VRVg-2 at M12 after the 1st vaccination of the primary series, and a subset of 230 adult subjects 
(Immunogenicity Persistence and Booster Phase Cohort 2) will receive a booster dose of VRVg-2 
between 24 up 36 months (M24 up to M36) regardless of the vaccine used in the primary series. 
                                                 
a  

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All subjects will be observed for safety for 30 minutes after each vaccination, and any 
AE/reaction occurring between each vaccination and up to 28 days after the last vaccination will 
be recorded by the subjects in a diary card (DC). The Investigator or delegate will transcribe the 
DC information into the electronic case report form (CRF) after interviewing the subject. In 
addition, all SAEs and AESIs will be recorded throughout the study, ie, up to 6 months after the 
last injection of the primary series and post-booster dose. 
Immunogenicity will be assessed in pediatric subjects and adult subjects in Primary Series 
Cohort 1 included in the study, before the 1st vaccine injection (VAC1) (D0), before VAC3 
(D28), and 14 days after VAC3 (D42), and at D0 (prior to the 1st vaccine injection) and D28 
(21 days after the one week 2-dose vaccine injection) in adult subjects in Primary Series Cohort 2. 
For the adult subset in Booster Phase Cohort 1, the immunogenicity of the booster dose will be 
assessed before VAC4 (M12) and 14 days after VAC4 (M12 +D14). For the adult subset in 
Immunogenicity Persistence and Booster Phase Cohort 2, the persistence of immune response 
after primary series will be assessed at M6, M12, M18, and pre-booster between M24 up to M36, 
and the immunogenicity of the booster dose will be assessed before booster (M24 up to M36), and 
14 days after booster (M24 up to M36+D14). 
Blood Sampling: 
Pediatric subjects and adult subjects in Primary Series Cohort 1 provided a total of 3 blood 
samplesa and adult subjects in Primary Series Cohort 2 will provide 2 blood samples to assess the 
immune response induced by the rabies vaccines. The subsets of adult subjects from Booster 
Phase Cohort 1 and Immunogenicity Persistence and Booster Phase Cohort 2 will provide 2 and 5 
more blood samples, respectively. 
Table 5.2 and Table 5.3 below outline the schedule of blood sampling and vaccine injection. 
                                                 
a  Blood sample volume drawn from subjects 1 year to <2 years will be 3 mL, for subjects ≥2 years to <18 years will be 5 mL, 
and for subjects ≥18 years will be 6 mL. 

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Table 5.2: Blood sampling and vaccination schedule for the 3-dose PrEP regimen + M12 
booster  
 
Primary series 
Pediatrics and Adults (Cohort 1) 
Booster phase 
Adult Subset from Cohort 1 
 
V01 
V02 
V03 
V04 
V05 
Phone call 
V06 
V07 
V08 
Phone call 
Visit 
interval 
VAC1 
VAC2=  
VAC1+7D 
VAC3=  
VAC1+ 
28D 
 
VAC3+ 
14D 
 
VAC3+ 
28D 
 
VAC3+ 
6M 
VAC4= 
VAC1+ 
12M 
 
VAC4+ 
14D 
 
VAC4+ 
28D 
 
VAC4+6M 
Blood 
sampling* 
BL01 
 
BL02 
BL03 
 
 
BL04 
BL05 
 
 
Vaccine 
Injection 
x 
x 
x 
 
 
 
x 
 
 
 
*Blood sample volume drawn from subjects aged 1 year to < 2 years will be 3 mL, for subjects ≥ 2 years to < 18 years will be 
5 mL, and for subjects ≥ 18 years will be 6 mL

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Table 5.3: Blood sampling and vaccination schedule for the one week 2-dose PrEP regimen 
+ immunogenicity persistence at M6, M12, M18, and pre-booster M24 up to M36 + M24 up 
to M36 booster  
 
 
Primary series 
Adults (Cohort 2) 
Immunogenicity Persistence and Booster phase  
Adult Subset from Cohort 2 
 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Phone call 
Visit interval 
VAC1 
VAC2= 
VAC1+7D 
VAC1+ 
28D 
VAC2+ 
28D 
VAC2+
6M 
VAC2+
12M 
VAC2+
18M 
VAC3= 
VAC1+ 
24M up 
to 36M 
VAC3+ 
14D 
VAC3+ 
28D 
VAC3+ 
6M 
Blood 
sampling* 
BL01 
 
BL02 
 
BL03 
BL04 
BL05 
BL06 
BL07 
 
 
Vaccine 
Injection 
x 
x 
 
 
 
 
 
x 
 
 
 
*Blood sample volume drawn from subjects ≥ 18 years will be 6 mL 
 
Collection of Safety Data: 
At each visit, study staff will either check and/or collect the safety DCs provided to all subjects to 
report safety data. A Memory Aid (MA) will be provided to the subjects at V05 (all pediatric 
subjects and adult subjects in Primary Series Cohort 1), at V08 (adult subjects in Booster Phase 
Cohort 1), at V04 (adult subjects in Primary Series Cohort 2), and at V10 (adult subjects in 
Immunogenicity Persistence and Booster Phase Cohort 2) to collect SAEs and AESIs up to the 
end of the study. 
Pediatric subjects and adult subjects in Primary Series Cohort 1 will record safety information in a 
MA from D56 (28 days following the 3rd injection) until M7 (ie, end of the 6-month follow-up 
after primary series) for the subjects not involved in the booster phase, and until M12, and then up 
to the end of the study (M18) for the adult subset involved in the booster phase (Booster Phase 
Cohort 1). 
Adult subjects in Primary Series Cohort 2 will record safety information in a MA from D35 (28 
days following the 2nd injection) until M6 (ie, end of the 6-month follow-up after primary series). 
Adult subjects in Immunogenicity Persistence and Booster Phase Cohort 2 will record safety 
information: 
• In a safety DC from D35 (28 days following the 2nd injection) up to the booster vaccine 
injection at M24-M36. 

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• In a MA from 28 days after the booster dose up to the end of the study (ie, 6 month-follow-up 
post-booster vaccine injection)  
Management of Subjects in Case of Rabies Exposure 
The management of subjects in case of rabies exposure will follow the local practice. PEP is 
recommended for people with WHO category II or III exposures. For category III, PEP indicated 
with rabies vaccine and rabies immunoglobulin (RIG) (37). 
 
Category  
Contact type 
Procedure 
I (Contact without infection) 
Touching or feeding animals, licks on 
intact skin 
Clean the contact area 
No vaccination require 
II (Contact with possibility of 
infection) 
Category II Nibbling of uncovered skin, 
minor scratches or abrasions without 
bleeding, licks on broken skin 
Washing, flushing the wound  
Rabies vaccine 
III (Contact with high possibility of 
infection) 
Single or multiple transdermal bites or 
scratches; contamination of mucous 
membrane with saliva from licks 
Having wound, contact animal 
secretions, carcass of animal body, 
animal brain. Pealing animal skin, 
dissect animal body. 
Take any raw meat or product made 
from rabies infected animal 
Washing, flushing the wound Rabies 
vaccine plus RIG as soon as possible 
 
• Vaccination can be given in 2 different routes:  
1.  IM route  
 
*According to Thai National Recommendation, D30 is also acceptable 
According to 2018 WHO guidelines, one site IM dose can be given at D0, D3, D7, and 
between D14–D28. 
2. Intradermal (ID) 

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*According to Thai National Recommendation, D30 is also acceptable 
As a Sponsor procedure, subjects will not receive any further investigational/control product, but 
can stay in the study for safety collection and blood sampling 
5.1.4 Visit Procedures  
5.1.4.1 For Cohort 1  
Visit (V) 01 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) After signature of the ICF and/ or AF, as applicable, inclusion and exclusion criteria will be 
checked. 
2) Collect demographic data. 
3) Urine pregnancy test, if woman of childbearing potential. 
4) Conduct a physical examination, including temperature, weight and height to determine the 
Body Mass Index. 
5) Obtain past and current medical history. 
6) For woman of childbearing potential, check the use of effective methods of contraception 
(example of effective methods of contraception include hormonal implants, intrauterine 
devices [hormonal or non-hormonal], adequate compliance with oral contraceptive pills, 
hormonal patch and adequate condom use with spermicide [sponge, contraceptive foam or 
cream]). 
7) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
8) Contact the Interactive Response Technology (IRT) system for randomization; allocation of 
subject number, dose number/product assignment, and booster phase involvement. 
9) A blood sample will be collected (3 mL for subject 1 year to < 2 years, 5 mL for subjects 
≥ 2 to < 18 years, and 6 mL for subjects ≥ 18 years). 
10)  Review warnings and precautions to vaccination. 

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11) Inject the appropriate study vaccine (VAC1) on the opposite side to that of the blood 
sampling. 
12) Keep the subject under observation for 30 minutes and record any adverse reaction in the 
source document. 
13) The 1st diary card (DC1), the thermometer and the ruler will be provided to the subject or 
subjects’ parents/ LAR and explanation on how to use them will be given by the blinded staff 
member. 
14) Remind the subject or subjects’ parent/ LAR to bring back the DC when they return for V02 
at a specified date and time. 
15) Subject or subject's parent/ LAR will be reminded to notify the site in case of SAE and AESI. 
16) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
17) The source documents and relevant CRF pages for this visit will be completed. 
V02 (7 [+1] days after VAC1): Collection of Safety Information and Vaccination 
1) DC1 will be collected and checked by the blinded Investigator/staff, different from the person 
performing the vaccination.  
2) Urine pregnancy test, if woman of childbearing potential. 
3) Conduct a physical examination, including temperature.  
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Check contraindication for subsequent vaccinations (see Section 5.2.7). 
6) Contact the IRT system for dose number/product assignment (see Section 6.6). 
7) Subjects will receive the 2nd injection (VAC2) from the unblinded staff member in the 
opposite arm as compared to VAC1 and will stay at the center for the 30-minute observation 
period following vaccination. Safety assessment will be made by the blinded Investigator, 
different from the person performing the vaccination. 
8) DC2 will be provided to the subject or the subjects’ parent/ LAR. 
9) The source documents and the relevant CRF pages for this visit will be completed. 
10) Remind the subject or subjects’ parent/ LAR to bring back the DC when they return for V03 at 
a specified date and time. 
11) Remind the subject or subjects’ parent/ LAR to notify the site in case of a SAE and AESI.  
12) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
13) Complete the relevant source document information and CRF pages for this visit. 

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V03 (28 [±3] days after VAC1) for Pediatrics and Adults in Primary Series Cohort 1: 
Collection of Safety Information, Blood Sample, and Vaccination 
1) DC2 will be collected and checked by the blinded Investigator/staff, different from the person 
performing vaccination. 
2) Urine pregnancy test, if woman of childbearing potential for subjects in Primary Series 
Cohort 1. 
3) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
4) Conduct a physical examination, including temperature. 
5) Check contraindication for subsequent vaccinations (see Section 5.2.7) for subjects in Primary 
Series Cohort 1. 
6) Contact the IRT system for dose number/product assignment (see Section 6.6) for subjects in 
Primary Series Cohort 1. 
7) A blood sample will be collected (3 mL for subject 1 year to < 2 years, 5 mL for subjects ≥ 2 
to < 18 years, and 6 mL for subjects ≥ 18 years). 
8) Only subjects from pediatric subjects and adult subjects in Primary Series Cohort 1 will 
receive the 3rd injection (VAC3) from the unblinded staff member in the opposite arm as 
compared to VAC2 and will stay at the center for the 30-minute observation period following 
vaccination. Safety assessment will be made by the blinded Investigator, different from the 
person performing the vaccination. 
9) DC3 will be provided only to pediatric subjects and adult subjects in Primary Series Cohort 1 
or the subjects’ parent/ LAR. 
10) The source documents and the relevant CRF pages for this visit will be completed. 
11) Remind the subject or subjects’ parent/ LAR to bring back the DC when they return for V04 at 
a specified date and time. 
12) Remind the subject or subjects’ parent/ LAR to notify the site in case of a SAE and AESI.  
13) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
14) Complete the relevant source document information and CRF pages for this visit. 
V04 (42 [±3] days after VAC1) for Pediatrics and Adults in Primary Series Cohort 1: 
Collection of Safety Information and Blood Sample 
1) DC3 will be checked by the blinded Investigator/ staff, different from the person performing 
the vaccination and will be given back to subjects or subjects’ parent/ LAR. 
2) Conduct a physical examination, including temperature. 
3) A blood sample will be collected only (3 mL for subject 1 year to < 2 years, 5 mL for subjects 
≥ 2 to < 18 years, and 6 mL for subjects ≥ 18 years). 

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4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Subject or subject's parent/ LAR will be reminded to notify the site in case of SAE and AESI. 
6) The source documents and relevant CRF pages for this visit will be completed. 
V05 (56 [±3] days after VAC1) for Pediatrics and Adult Subjects in Primary Series Cohort 
1: Collection of Safety Information  
1) DC3 will be collected and checked by the blinded Investigator/staff, different from the person 
performing the vaccination. 
2) Conduct a physical examination. 
3) Give the MA1 to record any SAEs or AESIs that may occur during the safety follow-up. 
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Subject or subject's parent/LAR will be reminded to notify the site in case of SAE and AESI. 
6) The source documents and relevant CRF pages for this visit will be completed. 
7) Complete the study termination record. 
6-month Safety Follow-up Phone Call (PC) (M7+14D) after the Primary Series  
Subject or subject's parent/ LAR will be contacted by phone by the blinded personnel 6 months 
after the 3rd vaccination. Information recorded in MA1 will be checked. 
Further details on the visit procedures can be found in the Operating Guidelines. 
V06 (12 months [+14 days] after VAC1): Collection of Safety Information, Blood Sample, 
and Booster Injection - for Adult Subjects in Booster Phase Cohort 1 
1) MA1 will be collected and checked by the blinded Investigator/staff, different from the person 
performing vaccination. 
2) Urine pregnancy test, if woman of childbearing potential. 
3) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
4) A blood sample will be collected (6 mL). 
5) Conduct a physical examination, including temperature. 
6) Obtain past and significant current medical history. Check contraindication for subsequent 
vaccinations (see Section 5.2.7). 
7) Subjects will receive the booster injection (VAC4) from the unblinded staff member in the 
opposite arm as compared to VAC3 and will stay at the center for the 30-minute observation 
period following vaccination. Safety assessment will be made by the blinded Investigator, 
different from the person performing the vaccination. 
8) DC4 will be provided to the subject. 

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9) The source documents and the relevant CRF pages for this visit will be completed. 
10) Remind the subject or to bring back the DC when they return for V07 at a specified date and 
time. 
11) Remind the subject to notify the site in case of a SAE and AESI.  
12) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
13) Complete the relevant source document information and CRF pages for this visit. 
V07 (12 months + 14 [+1] days after VAC1): Collection of Safety Information and Blood 
Sample - for Adult Subjects in Booster Phase Cohort 1 
1) DC4 will be checked by the blinded Investigator/staff, different from the person performing 
the vaccination. 
2) A blood sample will be collected (6 mL). 
3) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
4) Subject will be reminded to notify the site in case of SAE and AESI. 
5) The source documents and relevant CRF pages for this visit will be completed. 
V08 (12 months + 28 [±3] days after VAC1): Collection of Safety Information - for Adult 
Subjects in Booster Phase Cohort 1 
1) DC4 will be collected and checked by the blinded Investigator/staff, different from the person 
performing the vaccination. 
2) Conduct a physical examination. 
3) Give the subject the MA2 to record any SAEs or AESIs that may occur during the safety 
follow-up. 
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Subject will be reminded to notify the site in case of SAE and AESI. 
6) The source documents and relevant CRF pages for this visit will be completed. 
7) Complete the study termination record. 
6-month Safety Follow-up PC After Booster Injection (M18+14D): for Adult Subjects in 
Booster Phase Cohort 1 
1) Subject will be contacted by phone by the blinded personnel 6 months after the booster 
vaccination. Information recorded in MA2 will be checked. 
Further details on the visit procedures can be found in the Operating Guidelines. 

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5.1.4.2 For Cohort 2  
Visit (V) 01 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) After signature of the ICF, inclusion and exclusion criteria will be checked. 
2) Collect demographic data. 
3) Urine pregnancy test, if woman of childbearing potential. 
4) Conduct a physical examination, including temperature, weight and height to determine the 
Body Mass Index. 
5) Obtain past and current medical history. 
6) For woman of childbearing potential, check the use of effective methods of contraception 
(example of effective methods of contraception include hormonal implants, intrauterine 
devices [hormonal or non-hormonal], adequate compliance with oral contraceptive pills, 
hormonal patch and adequate condom use with spermicide [sponge, contraceptive foam or 
cream]). 
7) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
8) Contact the IRT system for randomization; allocation of subject number, dose 
number/product assignment, and booster phase involvement. 
9) A blood sample will be collected (6 mL). 
10)  Review warnings and precautions to vaccination. 
11) Inject the appropriate study vaccine (VAC1) on the opposite side to that of the blood 
sampling. 
12) Keep the subject under observation for 30 minutes and record any adverse reaction in the 
source document. 
13) The 1st diary card (DC1), the thermometer and the ruler will be provided to the subject and 
explanation on how to use them will be given by the blinded staff member. 
14) Remind the subject to bring back the DC when they return for V02 at a specified date and 
time. 
15) Subject will be reminded to notify the site in case of SAE and AESI. 
16) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
17) The source documents and relevant CRF pages for this visit will be completed. 

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V02 (7 [+1] days after VAC1): Collection of Safety Information and Vaccination 
1) DC1 will be collected and checked by the blinded Investigator/staff, different from the person 
performing the vaccination.  
2) Urine pregnancy test, if woman of childbearing potential. 
3) Conduct a physical examination, including temperature.  
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Check contraindication for subsequent vaccinations (see Section 5.2.7). 
6) Contact the IRT system for dose number/product assignment (see Section 6.6). 
7) Subjects will receive the 2nd injection (VAC2) from the unblinded staff member in the 
opposite arm as compared to VAC1 and will stay at the center for the 30-minute observation 
period following vaccination. Safety assessment will be made by the blinded Investigator, 
different from the person performing the vaccination. 
8) DC2 will be provided to the subject. 
9) The source documents and the relevant CRF pages for this visit will be completed. 
10) Remind the subject to bring back the DC2 when they return for V03 at a specified date and 
time. 
11) Remind the subject to notify the site in case of a SAE and AESI.  
12) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
13) Complete the relevant source document information and CRF pages for this visit. 
V03 (28 [+3] days after VAC1): Collection of Safety Information and Blood Sample  
1) DC2 will be checked by the blinded Investigator/staff, different from the person performing 
vaccination. 
2) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
3) Conduct a physical examination, including temperature. 
4) A blood sample will be collected (6 mL). 
5) Remind the subject to notify the site in case of a SAE and AESI.  
6) For woman of childbearing potential: remind the subject to notify the site in case of 
pregnancy. 
7) Complete the relevant source document information and CRF pages for this visit. 
 
 

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V04 (35 [±3] days after VAC1): Collection of Safety Information 
1) DC2 will be collected and checked by the blinded Investigator/ staff, different from the 
person performing the vaccination. 
2) Conduct a physical examination, including temperature. 
3) Give the MA (to adult subjects who will only participate in Primary Series Cohort 2) or DC 
SAE (to adult subjects who will participate to the Immunogenicity Persistence and Booster 
Phase Cohort 2) to record SAEs or AESIs that may occur during the safety follow-up. 
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Subject will be reminded to notify the site in case of SAE and AESI. 
6) Complete the study termination record for adult subjects who will only take part to the 
Primary Series Cohort 2 
7) The source documents and relevant CRF pages for this visit will be completed. 
6-month Safety Follow-up PC (M6+14D) After the Primary Series – for Adult Subjects in 
Primary Series Cohort 2 
1) Subject will be contacted by phone by the blinded personnel 6 months after the 2nd 
vaccination. Information recorded in MA1 will be checked. 
2) Further details on the visit procedures can be found in the Operating Guidelines. 
V05 (6 months +14D after VAC2): 6-month Safety Follow-up after the Primary Series and 
Blood Sample - for Adult Subjects in Immunogenicity Persistence and Booster Phase Cohort 
2  
1) DC SAE will be checked by the Investigator/staff, different from the person performing 
vaccination. 
2) A blood sample will be collected (6 mL). 
3) Collect reportable categories 2 and 3 concomitant medications in the CRF (see Section 6.9). 
4) Subject will be reminded to notify the site in case of SAE and AESI. 
5) The source documents and relevant CRF pages for this visit will be completed. 
V06 (12 months +14 days after VAC2): Collection of Safety Information and Blood Sample - 
for Adult Subjects in Immunogenicity Persistence and Booster Phase Cohort 2 
1) DC SAE will be checked by the Investigator/staff, different from the person performing 
vaccination. 
2) A blood sample will be collected (6 mL). 

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3) Collect reportable categories 2 and 3 concomitant medications in the CRF (see Section 6.9). 
4) Subject will be reminded to notify the site in case of SAE (to Investigator: note that only fatal 
SAEs and related SAEs need to be reported at this visit). 
5) The source documents and relevant CRF pages for this visit will be completed. 
V07 (18 months +14 days after VAC2): Collection of Safety Information and Blood Sample - 
for Adult Subjects in Immunogenicity Persistence and Booster Phase Cohort 2 
1) DC SAE will be checked by the Investigator/staff, different from the person performing 
vaccination. 
2) A blood sample will be collected (6 mL). 
3) Collect reportable categories 2 and 3 concomitant medications in the CRF (see Section 6.9). 
4) Subject will be reminded to notify the site in case of SAE (to Investigator: note that only fatal 
SAEs and related SAEs need to be reported at this visit). 
5) The source documents and relevant CRF pages for this visit will be completed. 
V08 (between 24 and up to 36 months +14 days after VAC1): Collection of Safety 
Information, Blood Sample, and Booster Injection - for Adult Subjects in Immunogenicity 
Persistence and Booster Phase Cohort 2 
1) DC SAE will be checked and collected by the Investigator/staff, different from the person 
performing vaccination. 
2) Urine pregnancy test, if woman of childbearing potential. 
3) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
4) A blood sample will be collected (6 mL). 
5) Conduct a physical examination, including temperature. 
6) Obtain past and significant current medical history. Check contraindication for subsequent 
vaccinations (see Section 5.2.7). 
7) Subjects will receive the booster injection (VAC3) from the unblinded staff member in the 
opposite arm as compared to VAC2 and will stay at the center for the 30-minute observation 
period following vaccination. 
8) DC3 will be provided to the subject. 
9) Subject will be reminded to notify the site in case of SAE and AESI. 
10) For woman of childbearing potential: remind the subject to notify the site in case of pregnancy 
11) The source documents and the relevant CRF pages for this visit will be completed. 
12) Remind the subject to bring back the DC3 when they return for V09 at a specified date and 
time. 

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V09 ([between 24 months and up to 36 months+14D] +14 [+1] days after VAC1): Collection 
of Safety Information and Blood Sample - for Adult Subjects in Immunogenicity Persistence 
and Booster Phase Cohort 2 
1) DC3 will be checked by the Investigator/staff. 
2) A blood sample will be collected (6 mL). 
3) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
4) Subject will be reminded to notify the site in case of SAE and AESI. 
5) The source documents and relevant CRF pages for this visit will be completed. 
V10 ([between 24 months and up to 36 months+14D] +28 [±3] days after VAC1): Collection 
of Safety Information and Blood Sample - for Adult Subjects in Immunogenicity Persistence 
and Booster Phase Cohort 2 
1) DC3 will be collected and checked by the Investigator/staff. 
2) Conduct a physical examination. 
3) Give the subject the MA to record any SAEs or AESIs that may occur during the safety 
follow-up. 
4) Collect ongoing medications including other therapies in the source document and reportable 
concomitant medication in the CRF (see Section 6.9). 
5) Subject will be reminded to notify the site in case of SAE or AESI. 
6) The source documents and relevant CRF pages for this visit will be completed. 
7) Complete the study termination record. 
6-month Safety Follow-up PC after the Booster Injection (M30 up to M42 +14D): for Adult 
Subjects in Immunogenicity Persistence and Booster Phase Cohort 2 
Subject will be contacted by phone by the Investigator/staff 6 months after the booster 
vaccination. Information recorded in MA will be checked. 
Further details on the visit procedures can be found in the Operating Guidelines. 
5.1.4.3 Follow-up for Cohorts 1 and 2  
Follow-up of Subjects With RVNA Titer ≤ 0.5 IU/mL After Completion of the 2- or 3-dose 
PrEP Regimen With Rabies Vaccine (and Booster Dose for Adult Subset): 
As stated in Section 1.3.1, if a subject had RVNA titers < 0.5 IU/mL at all timepoints after the 
primary or booster series, the Investigator may decide based on clinical judgment to offer an 
additional single vaccination of a local licensed rabies vaccine (as chosen by the Investigator) and 
administer according to the local SmPC / Product Information (PI) or national guidelines, and if 
the subject / subject’s LAR agree. Adult subjects randomized in the Immunogenicity Persistence 

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and Booster Phase Cohort 2 need to complete all the visits in this phase before being offered to 
receive benefit vaccine if the Investigator deemed necessary. 
Follow-up of Subjects With Related AEs or With AEs That Led to Study/Vaccination 
Discontinuation: 
Unless a subject or subject’s parent/LAR refuses further contact, each subject who experiences an 
AE (whether serious or non-serious) during the study must be followed until the condition 
resolves, becomes stable, or becomes chronic (even after the end of the subject’s participation in 
the study) if either of the following is true: 
• The AE is considered by the Investigator to be related to the product administered 
• The AE caused the discontinuation of the subject from the study or vaccination 
5.1.5 Planned Study Calendar  
The following dates are approximate. The actual dates may differ as, for example, the study will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
FVFS (first visit, first subject) to LCLS (last contact, last subject): October 2019 – September 
2025 
Inclusion period – FVFS to FVLS (first visit, last subject): October 2019 – February 2023 
Primary vaccination period: October 2019 – February 2023 
Booster vaccination period: October 2020 – March 2025 
End of study Booster Phase Cohort 1: August 2021 
End of study Immunogenicity Persistence and Booster Phase Cohort 2: September 2025 
Date of Final Clinical Study Report: March 2026 
5.1.6 End of study definition  
A subject is considered to have completed the study if the subject has completed the last contact 
planned in the Table of Study Procedures. 
The end of the study is defined as the date that the last results have been released for samples 
collected at Visit 9, Cohort 2, related to primary and secondary endpoints. The end of the study 
must be achieved no later than 9 months after the last contact of the last subject in the study. 
However, for periodic safety reports, the study is considered completed when the clinical study 
report is finalized.  

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5.2 
Enrollment and Retention of Study Population  
5.2.1 Recruitment Procedures  
Before the start of the study, the Investigator or delegate will contact an appropriate pool of 
potential subjects or parent of potential subjects and invite them to participate in the study. The 
site will ensure that any advertisements used to recruit subjects (letters, pamphlets, posters) are 
submitted to the Sponsor prior to submission to the IEC/ IRB for approval. 
Recruitment procedures and materials will be submitted for IEC/ IRB approval or favorable 
opinion before implementation. 
5.2.2 Informed Consent Procedures  
Informed consent is the process by which a subject and/or an appropriate and LAR voluntarily 
confirms his or her willingness to participate or let his/her child participate in a particular study. 
Informed consent must be obtained before any study procedures are performed. The process is 
documented by means of a written, signed, and dated ICF and /or AF. A separate AF will be 
provided for subjects aged 13 to less than 18 years or for subjects aged 7 to 12 years. The AF is in 
addition to, not in place of, an ICF that is signed by the parent/ LAR. 
In accordance with GCP, prior to signing and dating the consent form, the subject and/or 
parent/LAR must be informed by appropriate study personnel about all aspects of the study that 
are relevant to making the decision to participate and must have sufficient time and opportunity to 
ask any questions. 
The actual ICF and AFs used at each center may differ, depending on local regulations and IEC/ 
IRB requirements. However, all versions must contain the standard information found in the 
sample ICF provided by the Sponsor. Any change to the content of the ICF must be approved by 
the Sponsor and the IEC/ IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s or LAR’s willingness 
to continue participation in the study, this will be communicated to him/ her in a timely manner. 
Such information will be provided via a revised ICF or an addendum to the original ICF and via a 
revised AF or an addendum to the original AF. 
Informed consent forms and AFs will be provided in duplicate, or a photocopy of the signed 
consent will be made. The original will be kept by the Investigator, and the copy will be kept by 
the subject or subject’s parent/LAR. 
Documentation of the consent process should be recorded in the source documents. 
In the context of this clinical study, subject will be receiving different vaccination regimens, ie, 
2- or 3-dose PrEP regimen. Subject has the chance of receiving vaccine not yet licensed 
(VRVg-2) or the vaccine that was previously licensed in Thailand (Imovax® Rabies) or currently 
licensed there (Verorab®). In addition, subject or subject’s parent/LAR needs to give consent and 
comply with other study-related activities which are not usually part of the treatment process, ie, 
blood draws, filling up of DCs, MA, scheduled visits, phone calls from study staff and, if woman 
of childbearing potential, other procedures such as urine pregnancy test before each vaccination or 

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follow-up of the subject’s health and the newborn’s health in case of pregnancy will be carried 
out. 
5.2.3 Screening Criteria  
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4 Inclusion Criteria  
An individual must fulfill all of the following criteria to be eligible for study enrollment: 
1) Aged ≥ 1 year on the day of inclusiona 
2) ICF has been signed and dated by the subject and/or parent(s) or LAR and by an independent 
witness (if required by local regulations), as necessary; and AF has been signed and dated by 
the subject, as required 
3) Subject (adult ≥ 18 years) or subject and parent/LAR (1 year to < 18 years) are able to attend 
all scheduled visits and to comply with all study procedures. 
5.2.5 Exclusion Criteria  
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential and not using an effective 
method of contraception or abstinence from at least 4 weeks prior to the 1st vaccination and 
1 month after each vaccination. To be considered of non-childbearing potential, a female 
must be pre-menarcheb or post-menopausal for at least 1 year, or surgically sterile. 
2) Participation at the time of study enrollment or, planned participation during the present study 
period in another clinical study investigating a vaccine, drug, medical device, or medical 
procedure. 
3) Receipt of any vaccine in the 4 weeks (28 days) preceding the 1st study vaccination or 
planned receipt of any vaccine prior to V05 for pediatric subjects and adult subjects in 
Cohort 1, and prior to V04 for adult subjects in Cohort 2. 
4) Previous vaccination against rabies (in pre- or post-exposure regimen) with either the study 
vaccines or another vaccine. 
5) Bite by, or exposure to a potentially rabid animal in the previous 6 months with or without 
PEP. 
6) Receipt of immune globulins, blood or blood-derived products in the past 3 months. 
                                                 
a " ≥ 1 year" means from the day of the 1st birthday onwards, with no upper age limit 
b Pre-menarche females will declare by themselves that they have not yet started menstruation. If a young female 
subject reaches menarche during the study, then she is to be considered as a woman of childbearing potential from 
that time forward. 
1 

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7) 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). 
8) At high risk for rabies exposure during the studya. 
9) Known systemic hypersensitivity to any of the study/control vaccine components, or history 
of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any 
of the same substancesb. 
10) Self-reported thrombocytopenia, contraindicating IM vaccination. 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating IM vaccination.  
12) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily. 
13) Current alcohol or substance abuse that, in the opinion of the Investigator, might interfere 
with the study conduct or completion.  
14) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with study conduct or completionc. 
15) Moderate or severe acute illness/infection (according to Investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 38.0°C). A prospective subject should not be 
included in the study until the condition has resolved or the febrile event has subsided. 
16) Personal History of Guillain-Barré syndrome. 
17) Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (ie, parent, 
spouse, natural or adopted child) of the Investigator or employee with direct involvement in 
the proposed study. 
If the subject has a primary physician who is not the Investigator, if feasible the site should 
contact this physician with the subject’s consent to inform him/ her of the subject’s participation 
in the study. In addition, the site should ask this primary physician to verify exclusion criteria 
relating to previous therapies, such as receipt of blood products or previous vaccines. 
                                                 
a Such as veterinarians and their staff, animal handlers, rabies researchers, and certain laboratory workers. 
b The components of VRVg-2 are listed under Section 6 Investigational Product and in the Investigator’s Brochure 
Section 3.2. The components of Verorab and Imovax Rabies vaccines are listed under Section 6 Control Products, eg, 
traces of polymyxin B, streptomycin, or neomycin. 
c Chronic illness may include, but is not limited to, neurological, cardiopulmonary, gastrointestinal, renal, 
genitourinary, metabolic, hematologic, auto-immune, or psychiatric disorders or infection. 
 

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5.2.6 Medical History  
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the subject is or has been followed by a physician or conditions/illnesses that could resume 
during the course of the study or lead to an SAE or to a repetitive outpatient care will be collected 
in the case report book (CRB). The significant medical history section of the CRB contains a core 
list of body systems and disorders that could be used to prompt comprehensive reporting, as well 
as space for the reporting of specific conditions and illnesses. 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. Given the current COVID-19 pandemic, the medical history must actively include if 
suspected/ confirmed COVID-19 happened and the dates. The use of medications (prescribed or 
out-of-the-counter) such as chloroquine and hydroxychloroquine within at least 2 months before 
enrollment and during the conduct of the study should be recorded, given their interference with 
rabies vaccines (38). 
5.2.7 Contraindications for Subsequent Vaccinations  
5.2.7.1 Temporary Contraindications  
Should a subject 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 Table of Study Procedures (except for VAC2 in 
Cohort 2 which can be given after resolution of temporary contraindication(s) to permit the 
subject fully benefit from the rabies vaccination). If any dose is delayed, the subsequent doses 
should be delayed according to the original time interval. 
• Moderate or severe acute illness/infection (according to Investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 38.0°C). 
• For Primary Series Cohort 2: unplanned administration of a vaccine other than the study 
vaccine between D0 and last primary vaccination (D07-VAC2). Since this is a PrEP study and 
the subjects will benefit from the rabies vaccination, the subject can receive the 2nd rabies 
primary dose at least 4 weeks after receipt of another vaccine (out of window) but will be 
excluded from the Per-Protocol Analysis Set (PPAS) – see Section 12.2.4. 
• For Immunogenicity Persistence and Booster Phase Cohort 2: administration of a vaccine 
other than the study vaccine 4 weeks prior to or planned administration within 4 weeks after 
booster vaccination, only if the delayed booster vaccination can still be maintained within the 

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allowed time window (M24-36 +14 days). If the allowed time window cannot be applied; 
please refer to Section 5.2.7.2. 
• Note: Vaccinations other than study vaccine consist of prohibited therapies within 28 days 
before and after each study vaccination (Section 6.9), their administration results in exclusion 
from PPAS and protocol deviation. The decision whether or not this would consist of a 
significant non-compliance with the protocol (condition for withdrawal from the study) 
depends on Investigator’s judgment. There are no restrictions for receipt of other vaccines, 
including COVID-19 vaccination, in other study time frames: between V05 (Cohort 1) or V04 
(Cohort 2) and 4 weeks before booster visit, or > 28 days after booster vaccination. 
5.2.7.2 Definitive Contraindications  
Should a subject experience 1 of the conditions listed below, the Investigator will discontinue 
vaccination: 
• Pregnancy, as indicated by a positive urine test. 
• Anaphylactic or other significant allergic reaction to the previous dose of vaccine. 
• Immunoglobulin, blood or blood-derived products received in the past 3 months or ongoing at 
the visit. 
• Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy in the past 
6 months or ongoing at the visit, or long-term systemic corticosteroid therapy (for more than 
2 consecutive weeks in the past 3 months before the visit). 
• Human immunodeficiency virus (HIV) seropositivity. 
• Thrombocytopenia, bleeding disorder or receipt of anticoagulants contraindicating IM 
vaccination. 
• For Primary Series Cohort 1: administration of a vaccine other than the study vaccine between 
D0 and last primary vaccination (VAC3) or planned administration before V05. 
• For Booster Phase Cohort 1: administration of a vaccine other than the study vaccine 4 weeks 
prior to or planned administration within 4 weeks after booster vaccination. 
• For Immunogenicity Persistence and Booster Phase Cohort 2: administration of a vaccine 
other than the study vaccine 4 weeks prior to or planned administration within 4 weeks after 
booster vaccination, only if the temporary contraindication for the booster (see 
Section 5.2.7.1) could not be applied since it would not permit to keep visits schedule within 
the allowed window. 
• An SAE related to the study vaccines following a vaccination. 
• Any potential contact with rabies virus during the course of the study. 
• Reporting of Guillain-Barré syndrome. 
Subjects with a definitive contraindication will continue to be followed up for the study-defined 
safety and immunogenicity assessments, as applicable. 

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5.2.8 Coronavirus Disease 2019 (COVID-19) Vaccine  
Should the COVID-19 vaccination campaign be implemented during the study for the population 
eligible to participate or participating in the study, applicable country recommendations will be 
implemented. If a subject is eligible to participate, it is recommended the subject prioritize the 
COVID-19 vaccination and delay the time of the enrollment according to the exclusion criterion 
specified in Section 5.2.5. If the subject was already enrolled in the study, when possible and 
unless recommended otherwise, as per national public health policies or Investigator judgment, a 
4-week interval between any study vaccine dose and the COVID vaccine dose(s) is desirable. 
When the subject is already enrolled in the study if a COVID-19 vaccine dose is received during 
one study vaccine solicited reactogenicity period it would not be possible to differentiate systemic 
reactions between them. Likewise, if the COVID-19 vaccine is received between a study vaccine 
dose and the collection of blood, it will not be possible (at this point) to rule out an 
immunogenicity interaction. Therefore, in any of the 2 situations, it is recommended that the 
subject will not be withdrawn from the study and should continue within the full analysis set 
(FAS). 
The type of COVID-19 vaccine received (including tradename) and the date/time of its 
administration(s) should be documented in the concomitant medications CRF. 
Wherever possible, the site of injection of study vaccines should be in the limb separate from the 
limb in which the COVID-19 vaccine is administered (if it has already been administered). 
Likewise, and if on the control of the study site, any COVID-19 vaccine scheduled to be received 
after administration of study vaccines should not be received in the same limb as study vaccines. 
Where it is not possible to have study vaccines and COVID-19 vaccine administered in separate 
limbs, a distance of at least 1 inch/ 2.5 cm should be maintained between the 2 administration 
sites. 
5.2.9 Conditions for Withdrawal  
Subjects and/or subject’s parent/LAR will be informed that they have the right to withdraw and/or 
withdraw their child from the study at any time.  
• At the discretion of the Investigator or Sponsor due to safety concerns or significant non-
compliance with the protocol (based on the Investigator’s judgment), without the subject’s 
permission (withdrawal) 
• At the request of the subject (dropout) 
The following will result in automatic withdrawal or exclusion of a subject from the study: 
• Significant non-compliance with the protocol, based on the Investigator’s judgment 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and in the CRB. 
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “AEs”) or for another reason. 
Withdrawn subjects may be replaced. 

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Subjects included in the Immunogenicity Persistence and Booster Phase Cohort 2 (adult subset) 
will not be withdrawn from the study if they fail to come to one or more visits prior to booster 
dose (at M6, M12, and/or M18).   
5.2.10 Lost to Follow-up Procedures  
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (ie, documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the source documents. 
5.2.11 Classification of Subjects Who Discontinue the Study  
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the CRB. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion instructions for additional details and 
examples): 
Adverse Event 
To be used when the subject is permanently terminated from the study 
because of an AE (including an SAE), as defined in Section 9.2.1.1. 
This category also applies if the subject experiences a definitive 
contraindication that is an SAE or AE. 
Lost to Follow-up 
To be used when the subject cannot be found or contacted in spite of efforts 
to locate him/her before the date of his/her planned last visit, as outlined in 
Section 5.2.10. The certified letter was sent by the Investigator and returned 
unsigned, and the subject or parent/guardian did not give any other news 
and did not come to any following visit. 
Protocol Deviation 
To be used: 
• 
In case of significant non-compliance with the protocol (eg, deviation of 
the Inclusion / Exclusion criteria, non-compliance with time windows, 
administration of other vaccine, blood sampling or vaccination refusal, 
missed injection/treatment, or error in the vaccine/treatment 
administration) 
• 
If the subject experiences a definitive contraindication that is not an 
SAE or AE 
• 
The subject or the parent/guardian signed the certified letter sent by the 
Investigator but did not give any other news and did not come to any 
following visit 
Withdrawal by Subject or 
Parent / Guardian / 
Legally Acceptable 
Representative 
To be used: 
• 
When the subject or parent/guardian indicated unwillingness to continue 
in the study 
• 
When the subject or parent/guardian made the decision to discontinue 
participation in the study for any personal reason other than an SAE/AE 
(eg, subject is relocating, inform consent withdrawal, etc.) 

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5.2.12 Follow-up of Discontinuations  
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the study because of an AE or a protocol deviation.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
withdrew informed consent and specified that they do not want to be contacted again and it is 
documented in the source document, the site will not attempt to obtain further safety information. 
If the subject’s status at the end of the study is “Withdrawal by Subject or Parent / Guardian / 
LAR”, the site will attempt to contact them for the 6-month follow-up except if they specified that 
they do not want to be contacted again and it is documented in the source document. 
5.2.13 Follow-up and Reporting of Pregnancies  
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy during the primary series and if at 
least 1 dose of the study vaccine(s) has been administered, the subject will not be discontinued 
from the study, but no further vaccination will be administered until after delivery (if applicable 
and still within the study vaccination window). However, the subject will be followed for safety 
assessment (and may be followed for immunogenicity assessment, if applicable). 
All pregnancy cases should be reported if they occurred: 
- 
Throughout the entire study period (for subjects in Cohort 1 and for subjects in Primary 
Series Cohort 2)  
- 
From the first vaccination in Primary Series until the end of the 6-month follow-up after 
Primary Series or from the Booster Injection until the end of the 6-month follow-up after 
Booster Injection (for subject in Immunogenicity Persistence and Booster Phase Cohort 2).  
To report the pregnancy case, the Investigator must fill out Pregnancy Reporting forms in the 
electronic data capture (EDC) system and inform the Sponsor within 1 month of identifying a 
pregnancy case. 
If the EDC system is not available, the Investigator must fill out a paper Pregnancy Reporting 
Form (provided by the Sponsor at the start of the study) and inform the Sponsor within 1 month of 
identifying a pregnancy case. 
Study staff must then maintain contact with the subject to obtain information about the outcome 
(ie, details about the delivery and the newborn, or about pregnancy termination) and must update 
the Pregnancy Reporting forms even after the end of the study. This information should be 
provided to the Sponsor within 1 month of delivery. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, blighted 
ovum, fetal death, stillbirth, and congenital anomalies reported in the baby are always considered 
as SAEs, and the information should be provided to the Global Pharmacovigilance (GPV) 
Department regardless of when the SAE occurs (eg, even after the end of the study). 

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5.3 
Safety Emergency Call  
If, as per the Investigator’s judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor’s Responsible Medical Officer (RMO) for advice on how to address any 
study-related medical question or problem. If the RMO is not available, then the Investigator may 
contact the Call Center available 24 hours a day, 7 days a week—that will forward all safety 
emergency calls to the appropriate primary or back-up Sanofi Pasteur contact, as needed. The 
toll-free contact information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department (please refer to 
Section 10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.6. 
5.4 
Modification of the Study and Protocol  
Any amendments to this study plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments (eg, those that affect the conduct of the study or the safety of 
subjects) require IEC / IRB approval, and must also be forwarded to regulatory authorities. 
An administrative / non-substantial amendment to a protocol is one that modifies some 
administrative, logistical, or other aspect of the study but does not affect its scientific quality or 
have an impact on the subjects’ safety. The IECs / IRBs must approve all amendments linked to 
administrative changes. 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IEC / IRB approval has already been given, are not initiated without IEC/ IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.4.1 VRV12 Amendments Justification  
Amendment 2 
As explained in Section 5.1.2, the VRV12 study was planned to document the NI of the 3-dose 
PrEP regimen recommended by the ACIP 2008 guidelines (34) as a primary endpoint and the one 
week 2-dose PrEP regimen recommended by the WHO 2018 guidelines, 
Protocol amendment 2 was developed to conservatively adjust the estimation of seroconversion 
rate at D28 for adults subjects in VRVg-2 and the control vaccines from 99% to 96.5% according 
to the latest results from VAJ00001 study and to ensure the statistical power of the secondary 
objective to demonstrate that VRVg-2 is non-inferior to Verorab and Imovax Rabies vaccines in 
each age group (pediatric and adult population), in terms of proportion of subjects achieving an 
RVNA titer ≥ 0.5 IU/mL at D28 based on the above-adjusted estimation. This will be 

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accomplished by increasing the sample size of the adult population assuming a lower estimation 
of seroconversion rate at D28 based on the following rationale: 
• Originally, the sample size and statistical power calculated for the NI assessment at D28 after 
the one week 2-dose PrEP regimen vaccination was based on available literature at the time 
(39) (40) (41) (42) (43) (44) (45) (46), which showed pediatric and adult population may have 
around 99% of seroconversion rates between 2 weeks (D21) and 3 weeks (D28) after the 2nd 
vaccination dose using Verorab or Imovax Rabies intramuscularly. However, to be on the 
conservative side, this seroconversion rate assumption should be adjusted to take into account 
the latest results of the VAJ00001 study conducted by the Sponsor. The VAJ00001 study was 
carried out to document the NI of the one week 2-dose PrEP regimen versus the 3-dose PrEP 
regimen using Imovax rabies, and to describe the immunogenicity and safety of the one week 
2-dose PrEP regimen using IM or intradermal routes with Verorab or Imovax Rabies vaccines 
in healthy subjects aged 2 up to 65 years in the Philippines. The one week 2-dose PrEP arms 
using IM route showed that 100% of the pediatric population achieved RVNA 
titer ≥ 0.5 IU/mL at D21 for both vaccines, while 93.9% of the adult population who received 
Imovax Rabies and 97.1 % who received Verorab achieved RVNA titer ≥ 0.5 IU/mL at D21 
in the PPAS. Therefore, the estimation of seroconversion rate at D28 for adult population was 
adjusted from 99% to 96.5%. 
• There are differences and similarities between VAJ00001 and VRV12 studies that should be 
taken into account to reassess the assumptions of the VRV12 study: 
• The age of the population included: variability of primary immune response to rabies 
vaccines has been previously described, some individuals responding earlier and producing 
high titers (early/high responders) while others respond later and produce lower titers 
(late/low responders), this is particularly relevant in adults (47) (48). VRV12 study will 
include subjects who are older than 65 years old and tend to be late/ low responders. 
• The time points used to assess the one week 2-dose PrEP regimen: The timepoint 21 days 
after the 1st injection (ie, 14 days after the 2nd dose) may be too early to observe 
seroconversion in all subjects in the VAJ00001 study. Clinical studies evaluating the kinetics 
of the immune response after rabies injection in naïve healthy individuals have shown that 
following primary vaccination series of Imovax Rabies at D0, D7, and D28, neutralizing 
antibodies were formed as early as 7 days of vaccination, while the highest IgG antibody 
titers were found at 2–4 weeks after a 3rd injection (49) (50) (51) (52). Although the 
timepoint at D28 may benefit the assessment of the one week 2-dose PrEP in the VRV12 
Study, there is limited evidence in the current literature of how the kinetics of the immune 
response will be 3 weeks after a 2nd injection in the elderly population. 
• The RFFIT method: both studies will use the same RFFIT method. This has been recently 
validated (53) and the known variability of the method should be considered (54) (55). 
• There are scientific rationale and product constraints that justifies increasing only the adult 
population by receiving a one week 2-dose PrEP regimen, as follows: 
• It is expected that the estimation of seroconversion rate at D42 is 99.0% for both adult and 
pediatric populations and so that the statistical power for the primary objective at D42 is the 
same as the original estimations. Therefore, there is no need to increase the sample size for 
the primary objective. 

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Therefore, the increase of the sample size will ensure the evaluation of immunogenicity of the 
one week 2-dose PrEP regimen at D28 which is anticipated to be the most used worldwide 
since it is recommended by the new ACIP 2021 guidelines and the WHO 2018 guidelines. 
The adjusted assumption of seroconversion and the updated calculation of the sample size and 
statistical power for the key objectives in the primary series are explained in Section 12.5. 
In addition, as explained in Section 5.1.2, protocol amendment 2 also incorporated a single 
booster between 2 and up to 3 years with a new batch of VRVg-2 as recommended in the new 
ACIP 2021 guidelines. The booster evaluation is confirming the assessment of the PrEP regimens, 
since it is expected good boostability of immunity in subjects at risk of rabies exposure (eg, one 
single IM booster dose) or primed patients who were exposed to rabies and will receive a PEP 
regimen (eg, one IM dose at D0 and D3). In the VAJ00001 study, a high immune response was 
observed in all age classes after the simulated PEP regimens which confirm the efficiency of these 
PrEP and PEP regimens in subjects aged 2 up to 65 years. These findings are consistent with 
those from recent studies (56) (57) (58) (59) and confirmed the adequate priming conferred by the 
one week 2-dose PrEP regimen in all subjects. The VRV12 results of a single IM booster dose are 
expected to document the boostability after the one week 2-dose PrEP regimen. 
Amendment 3 
 this protocol amendment 3 adds a secondary objective to 
demonstrate the acceptability of the immune response at D28 of a 1-week 2-dose PrEP regimen. It 
also adds the evaluation of persistence of the immune response at M6, M12, M18 and pre-booster 
between M24 up to M36 after a 2-dose primary series in the subset of adults who are randomized 
to be part of the Immunogenicity Persistence and Booster Phase Cohort 2. 
Amendment 4 
As stated in Section 1.3.1, most of the subjects are expected to have reached RVNA titers 
≥ 0.5 IU/mL after the completion of the 2- or 3-dose PrEP regimen of rabies vaccine (and booster 
dose for adult subsets) (61) (62). Depending on Investigator’s clinical judgment, subjects with 
RVNA titers < 0.5 IU/mL at all timepoints may be offered an additional injection of a local 
licensed rabies vaccine chosen by the Investigator and administered according to the local SmPC / 
PI or national guidelines and if the subject / subject’s LAR agree. Such vaccine is offered outside 
of the scope of the protocol (ie, no safety nor immunogenicity data will be collected after this 
vaccine injection), free of charge at the study site. This is the Investigator's responsibility to 
decide which vaccine will be the most appropriate for giving real benefit to the subject. 
Moreover, Section 5.2.9 was updated to avoid any unnecessary subjects’ withdrawal due to  
missing visits (at M6, M12, and/or M18) during the Immunogenicity Persistence and Booster 
Phase Cohort 2 (adult subset). Section 6.7 was updated to clarify the subject number assigning 
rule was different between Cohort 1 and Cohort 2, due to different IRT settings. 
Amendment 5 
Protocol amendment 5 adds 2 secondary objectives to demonstrate the NI of a 2-dose VRVg-2 
PrEP at D28 versus 3-dose Imovax Rabies PrEP at D42 in each age group, and also to 

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demonstrate NI of 2-dose Imovax Rabies PrEP at D28 versus 3-dose Imovax Rabies PrEP at D42 
in each age group, both with a NI margin of -10%for each of these 2 new secondary objectives. 
5.5 
Interruption of the Study  
The study may be discontinued if new data about the investigational product resulting from this or 
any other studies become available; or for administrative reasons; or on the advice of the Sponsor, 
the Investigators, the IECs/IRBs, or the governing regulatory authorities in Thailand where the 
study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by applicable regulatory requirements. The 
Investigator shall promptly inform the study subjects/subjects’ parents/guardians and should 
assure appropriate subject therapy and/or follow-up. 
6 
Products Administered  
6.1 
Identity of the Investigational Products  
The investigational product is VRVg: PVRV – Serum Free (purified inactivated rabies vaccine 
prepared on Vero cell line): 
• VRVg-2 is the formulation used.  
Form:  
freeze-dried 
Route:  
IM injection into the deltoid muscle (or anterolateral thigh for toddlers) 
6.1.1 Composition  
Each 0.5 mL dose of VRVg-2 reconstituted vaccine contains: 
• Powder (VRVg-2): 
• 
Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3M strain:  2.5 IU (potency; 
NIH); 
• 
Stabilizer*: sufficient quantity (qs) 
• 
* The stabilizer (490 solution) is a mixture of amino acids (including trace amounts of 
phenylalanine), sugars (including the presence of sorbitol and trace amounts of saccharose), 
and sodium dihydrogen phosphate, di-sodium phosphate dihydrate, sodium glutamate, di-
sodium edetate (EDTA), poloxamer P188 and urea in water for injections. 
• Diluent: 
• 
Sodium chloride: 2 mg 
• 
Water for injection: qs 0.5 mL 

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Powder and diluent batch numbers are to be determined.  
6.1.2 Preparation and Administration  
The procedures for preparing and administering VRVg-2 are as follows: 
The products will be placed at room temperature for few minutes (in order to bring the liquid to 
room temperature). The diluent, contained in a pre-filled syringe, will be injected into the vial 
containing the powder of rabies virus. The mixture will then be gently swirled to obtain a 
homogenous suspension. To administer the vaccine, the entire volume of the solution 
(approximately 0.5 mL) is withdrawn and injected with a new needle intramuscularly in the 
deltoid (or anterolateral thigh for toddlers), within 1 hour after reconstitution of the vaccine. 
Vaccinations should be performed on alternative sides, at least 3 cm apart from the previous 
injection site; eg, the 1st injection in the left deltoid, the 2nd in the right deltoid and so on (or 
anterolateral thigh for toddlers). 
Note: The freeze-dried vaccine is white homogenous; after reconstitution, the vaccine is limpid to 
opalescent and colorless. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.5.1), and extraneous particulate matter and/ or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 
As there are no preservatives in the vaccine, the mixture must be administered immediately 
(within 1 hour) after reconstitution. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the CRB. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1 000), must be available on site 
in the event of an anaphylactic, vasovagal, or other immediate allergic reaction. 
6.1.3 Dose Selection and Timing  
 The dose selected for the present study is based upon results obtained in 
VRV11 study (Phase II dose ranging study).  
6.2 
Identity of Control Product 1  
Verorab®: purified inactivated rabies vaccine prepared on Vero cell line 
Form:  
freeze-dried 
Route:  
IM injection into the deltoid muscle (or anterolateral thigh for toddlers) 
6.2.1 Composition  
Each 0.5 mL dose contains: 
 

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• Powder: 
• Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3M strain:  2.5 IU (potency; 
NIH) 
• 
Maltose: qs 
• 
Human albumin: qs 
 
• Diluent 
• 
Sodium chloride: 2 mg 
• 
Water for injection: qs 0.5 mL 
Powder and diluent batch numbers are to be determined. 
6.2.2 Preparation and Administration  
Preparation and administration of the Verorab vaccine will follow the same steps as preparation 
and administration of the investigational vaccine, VRVg-2, as described in Section 6.1.2.  
Note: The powder is a white homogeneous pellet; after reconstitution, the vaccine is a limpid 
homogeneous solution. 
Precautions for use are the same as for VRVg-2 and are described in Section 6.1.2. 
In addition, traces of neomycin, streptomycin, and polymyxin are used during the production 
process of Verorab and can be found in the final product. Therefore, caution must be exercised 
when the vaccine is administered to subjects with hypersensitivity (not known or not disclosed by 
the subject) to these antibiotics and other antibiotics of the same class. Appropriate treatment in 
case of anaphylactic reactions to these antibiotics must therefore be available.  
6.2.3 Dose Selection and Timing  
Verorab vaccine will be administered according to the recommendations described in the package 
insert of the licensed vaccine. 
6.3 
Identity of Control Product 2  
Imovax® Rabies: purified inactivated rabies vaccine prepared on human diploid cell cultures  
Form:  
freeze-dried 
Route:  
IM injection into the deltoid muscle (or anterolateral thigh for toddlers) 
6.3.1 Composition  
Each dose contains: 
• Powder: 
• 
Rabies Virus – Wistar Rabies Pitman Moore/WI 38 1503-3M strain:  2.5 IU (potency; 
NIH) 
• 
Human albumin: 50 mg 

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• Diluent:  
 
• Water for injection: qs 1 mL 
Powder and diluent batch numbers are to be determined.  
6.3.2 Preparation and Administration  
The procedures for preparing and administering the control product are the same as those 
described for the study product in Section 6.1.2, with the exception that the diluent volume is 
approximately 1 mL and, hence, the entire volume of the vaccine solution to be injected is 
approximately 1 mL. 
Note: The freeze-dried vaccine is creamy white to orange; after reconstitution, the vaccine is pink 
to red. 
Each dose may contain undetectable traces of neomycin, used during vaccine production. 
Therefore, caution must be exercised when the vaccine is administered to subjects with 
hypersensitivity (not known or not disclosed by the subject) to this antibiotic and other antibiotics 
of the same class. Appropriate treatment in case of anaphylactic reactions to these antibiotics must 
therefore be available. 
6.3.3 Dose Selection and Timing  
Imovax Rabies vaccine will be administered according to the recommendations described in the 
package insert of the licensed vaccine. 
6.4 
Identity of Other Product(s)  
Not applicable 
6.5 
Product Logistics  
6.5.1 Labeling and Packaging  
Each dose of the different rabies vaccines (VRVg, Verorab and Imovax Rabies vaccines) will be 
in an individual box that will be identified by a dose number. Each box will contain a vial with the 
powder of rabies virus and a pre-filled syringe containing the diluent. Each box of vaccine dose 
will bear both detachable and fixed labels for identification. The labeling of vials, syringes and 
boxes will be done according to Thai regulation requirements. 
6.5.2 Product Shipment, Storage, and Accountability  
6.5.2.1 Product Shipment  
The Investigational Product Manager or designee will contact the Investigator or a designee to 
determine the dates and times of delivery of products. 

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Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (ie, verification of the temperature recorders). If there 
is an indication that the cold chain was broken, this person should immediately quarantine the 
product, alert the Sanofi Pasteur representative and request authorization from Sanofi Pasteur to 
use the product. See Operating Guidelines for further instructions. 
6.5.2.2 Product Storage  
The Investigator will be personally responsible for product management or will designate a staff 
member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C and should be protected from light. 
The vaccines must not be frozen. The temperature must be monitored and documented (see the 
Operating Guidelines) for the entire time that the vaccines are at the study site. In case of 
accidental freezing or disruption of the cold chain, vaccines must not be administered and must be 
quarantined, and the Investigator or authorized designee should contact the Sanofi Pasteur 
representative for further instructions. 
6.5.2.3 Product Accountability  
The person in charge of product management at the site will maintain records of product delivery 
to the study site, product inventory at the site, the dose(s) given to each subject, and the disposal 
of or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
CRB. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the study site’s product accountability records against 
the record of administered doses in the CRBs and the communication from the IRT (if 
applicable). 
In case of any expected or potential shortage of product during the study, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.5.3 Replacement Doses  
If a replacement dose is required (eg, because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must either contact the IRT to receive the new dose 
allocation, or follow the instructions given in the Operating Guidelines. 
6.5.4 Disposal of Unused Products  
Unused or wasted products will be either disposed of or returned to the Sponsor in accordance 
with the instructions in the Operating Guidelines. Product accountability will be verified 
throughout the study period. 

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6.5.5 Recall of Products  
If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
6.6 
Blinding and Code-breaking Procedures  
The study will be conducted in an observer-blind manner for all vaccinations (except for the 
booster vaccination in Immunogenicity Persistence and Booster Phase Cohort 2): 
• Unblinded staff member(s), independent of the safety evaluation and other study evaluations, 
will prepare and administer the vaccine 
• The blinded staff member(s), including the Investigator (for Cohort 1 and Primary Series 
Cohort 2), in charge of safety assessment, will not know which vaccine is administered 
• The subject and subject's parent/ LAR will remain blinded (for Cohort 1 and Primary Series 
Cohort 2) and will not know which vaccine is administered: the product will not be prepared 
in their presence and the product will be hidden.  
The blinded staff members, including the Investigator (for Cohort 1 and Primary Series Cohort 2), 
responsible for safety assessment will not attend the vaccination session. However, they will 
remain available in case of emergency (eg, anaphylactic shock). 
In addition to the subjects, health care providers, data collectors, outcome assessors (eg, 
Investigator who assess the safety), the Sponsor personnel (eg, Clinician, Data Management, 
Biostatistician) will remain blinded until the 1st statistical analysis. The laboratory analysts who 
will be involved in the blood sample testing will remain blinded during the whole study.  
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the subject. Code-breaking should be limited to the 
subject(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur RMO if a 
subject’s code was broken. All contact attempts with the Sponsor prior to unblinding are to be 
documented in the source documents, and the code-breaking CRF is to be completed. 
A request for the code to be broken may also be made: 
• by the GPV Department through an internal system for reporting to health authorities in the 
case of an SAE as described in ICH E2A. In this case, the code will be broken only for the 
subject(s) in question. The information resulting from code-breaking (ie, the subject’s vaccine 
or group assignment) will not be communicated to either the Investigator or the immediate 
team working on the study, except for the GPV representative.  
The IEC / IRB must be notified of the code-breaking. All documentation pertaining to the event 
must be retained in the site’s study records and, in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 

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The code will be broken at the time of the 1st statistical analysis (ie, 28 days after the 2nd 
vaccination which is at the end of vaccination active phase in the primary series of Cohort 2). 
However, the laboratory personnel who conducts the serology test for blood sample will remain 
blinded during the whole study.  
6.7 
Randomization and Allocation Procedures  
An IRT system will be used. The full detailed procedure for randomization will be described in 
the Operating Guidelines given to the Investigator and the staff in charge of these operations at 
each site. 
Separate randomization listings will be created for Cohort 1 and Cohort 2, respectively. 
At V01 (D0), the qualified staff member will contact the IRT system to assign a subject number 
of a 12-digit string (a 3-digit country identifier, a 4-digit study center identifier, and a 5-digit 
subject identifier). The 1st digit of the subject identifier will be a predefined figure (“0” for 
pediatric population and “1” for adult population). The 2nd digit of the subject identifier will 
represent the adult subjects participating in the booster phase or not (“0” for adults included only 
in the Primary Series Cohort 1 without booster vaccination, “1” for adult included in the Primary 
Series Cohort 1 with the booster phase at M12 [Booster Phase Cohort 1], “2” for adult included 
only in the Primary Series Cohort 2 without booster vaccination, and "3" for adults included in the 
Primary Series Cohort 2 with the evaluation of Immunogenicity Persistence (at M6, M12, M18, 
and pre-booster between M24 up to M36 after primary series) and Booster Phase at M24 up to 
M36 [Immunogenicity Persistence and Booster Phase Cohort 2]). In Cohort 1, the last 3 digits of 
the subject’s identifier represent the enrollment sequence of the subject in each site, and the 
subject number will be sequential regardless of the participation in the booster phase. In Cohort 2, 
the last 3 digits of the subject’s identifier represent the sequence number of a subject’s 
randomization sequence at D0 in each vaccination schedule subset (primary series only, or 
primary series with immunogenicity persistency and booster phase) within each site, and the 
sequence number will be start from 001 within each stratum.  
Some examples: 
• Subject 764000100005 is the 5th pediatric enrolled in Center Number 1 and will only be part 
of the Primary Series in Cohort 1 (764 being the Thailand country code) 
• Subject 764000211005 is the 5th adult enrolled in Center Number 2 and will be part of the 
Booster Phase Cohort 1  
• Subject 764000212008 is the 8th adult enrolled to participate in the Primary Series only 
without Immunogenicity Persistence and Booster Phase in Cohort 2, in Center Number 2  
• Subject 764000213008 is the 8th adult enrolled to participate in the Primary Series with 
Immunogenicity and Persistence and Booster Phase in Cohort 2, in Center Number 2  
• Subject 764000210006 is the 6th adult enrolled in Center Number 2, and will only be part of 
the Primary Series in Cohort 1 and not be part of the Booster Phase Cohort 1 (subject number 
will be continuous regardless of the participation in the booster phase) 

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The IRT system will define which product/dose number will be administered for each vaccination 
and will determine, at D0, if the subject from the adult population will participate to the booster 
phase or not. 
Randomization, managed by the IRT system, will be performed using the permuted block method 
with stratification on centers and age group (adults [≥18 years] and children [1 year to < 12 years 
and ≥ 12 to < 18 years]). This guarantees, at any time and in each center and each age group, the 
right number of subjects with respect to the randomization scheme that has been defined for the 
study.  
Subject numbers should not be reassigned for any reason. The Clinical Quality Assessment 
(CQA) Department at Sanofi Pasteur will hold the randomization codes of doses in a secured 
location. 
6.8 
Treatment Compliance  
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified study personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site, product inventory at the site, dose(s) given to each 
subject, and the disposal of unused or wasted doses 
6.9 
Concomitant Medications and Other Therapies  
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions / AEs during study participation. 
Documentation in the CRB of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of 1st vaccination. This may include 
medications of interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRB from the day of each vaccination to the end 
of the solicited and unsolicited follow-up period. 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Three 
standard categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], 
steroids/corticosteroids and other immunomodulators) 
• Category 2: medications impacting or that may have an impact on the immune response (eg, 
other vaccines, blood products, antibiotic classes that may interfere with bioassays used by the 
Global Clinical Immunology [GCI] department, steroids/corticosteroids, immune-suppressors, 

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immune-modulators with immunosuppressive properties, anti-proliferative drugs such as 
DNA synthesis inhibitors)  
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, steroids/corticosteroids) 
Additionally, given the COVID-19 pandemic and the possible use of medications with or without 
medical prescription, medications that interfere with the immune response should be actively 
evaluated. For instance, chloroquine or hydroxychloroquine received within at least 2 months 
before and during data collection should be clearly reported due to the possible interference with 
rabies vaccines (38) (62). For use of COVID-19 vaccines during the study period, please refer to 
Section 5.2.8. 
The information reported in the CRB for each reported medication will be limited to: 
• Trade name. 
• Origin of prescription: prophylaxis Yes/No. Medication(s) prescribed for AE prophylaxis will 
be recorded in the Action Taken of the AE collection tables. 
• Medication category (1, 2, or 3). 
• Start and stop dates. 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded. Topical analgesics should not be 
applied at the site of vaccination; however, if they are applied inadvertently to the vaccination site, 
they should be recorded as a category 1 medication in this specific instance. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to one of the pre-listed categories. Medications will not be coded. 
7 
Management of Samples  
Blood samples for the assessment of antibody responses will be collected: 
• At V01, V03, and V04 for pediatrics and adults in Cohort 1, as well as at V06 and V07 for 
adults who will also participate in Booster Phase Cohort 1. 
• At V01 and V03 for adults in Primary Series Cohort 2, as well as at V05, V06, V07, V08, and 
V09 for adults who will also participate in Immunogenicity Persistence and Booster Phase 
Cohort 2. 
See the Tables of Study Procedures and Section 5.1.3 for details of the sampling schedule. 

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7.1 
Sample Collection  
Blooda will be collected in tubes provided by or recommended by the Sponsor. Immediately prior 
to the blood draw, the staff member performing the procedure will verify the subject’s identity as 
well as the assigned subject’s number and sampling stage on the pre-printed label and will attach 
the label to the tube. When vaccination and blood sample collection occur at the same visit and 
vaccine is given only in one of the arms, blood is to be taken from the limb opposite to the one 
that will be used for vaccination, if possible. 
7.2 
Sample Preparation  
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
Following the blood draw, the tubes are to be left undisturbed, positioned vertically and not 
shaken, for a minimum of 1 hour and a maximum of 24 hours to allow the blood to clot.  
Samples can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be 
refrigerated at a temperature of + 2°C to + 8°C up to a maximum of 24 hours. The samples are 
then centrifuged, and the serum is transferred to the appropriate number of aliquoting tubes.  
These tubes are pre-labeled with adhesive labels that identify the study code, the subject’s 
number, and the sampling stage.  
The subject’s number and the date of sampling, the number of aliquots obtained, and the subject’s 
consent for future use of his/her samples are to be specified on a sample identification list. These 
previous items, as well as the date and time of preparation, are to be recorded in the source 
document. Space is provided on the sample identification list to record comments regarding the 
quality of samples. 
7.3 
Sample Storage and Shipment  
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented in the appropriate form 
during the entire study. If it rises above -10°C for any period of time, the Clinical Samples 
Logistics representative must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratories will be made only after appropriate monitoring, and following 
notification of the Clinical Samples Logistics representative. Sera will be shipped frozen, using 
dry ice to maintain them in a frozen state, in the packaging container provided by the carrier. 
Again, temperatures will be monitored. Shipments must be compliant with the United Nations 
(UN) Class 6.2 specifications and the International Air Transport Association (IATA) 602 
packaging instructions. 
                                                 
a  Blood sample volume drawn from subjects 1 year to < 2 years will be 3 mL, for subjects ≥ 2 years to < 18 years will be 5 mL, 
and for subjects ≥ 18 years will be 6 mL. 

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Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines. 
Any unused part of the serum samples will be securely stored for any testing directly related to 
this study at the Sanofi Pasteur serology laboratory (GCI) for up to 25 years after the end of the 
study. 
7.4 
Future Use of Stored Serum Samples for Research  
Subjects or subjects’ parent/LAR will be asked to indicate in the ICF whether they will permit the 
future use of any leftover stored serum samples for additional research not related to this study. If 
they consent, leftover serum samples will be securely stored at GCI for up to 25 years after the 
end of the study. If they refuse permission, the samples will not be used for any testing other than 
that directly related to this study. If they agree to this use, they will not be paid for giving 
permission. Anonymity of samples will be ensured. The aim of any possible future research is 
unknown today and may not be related to this particular study. It may be to improve the 
knowledge of vaccines or infectious diseases, or to improve existing tests or develop new tests to 
assess vaccines. Human genetic tests will never be performed on these samples without specific 
individual informed consent. 
8 
Clinical Supplies  
Sanofi Pasteur will supply the study sites with protocols, ICFs/AFs, CRBs, SAE reporting forms, 
DCs, MAs, and other study documents, as well as with the following study materials: all study 
vaccines, blood collection tubes, cryotubes, cryotube storage boxes, cryotube labels, temperature 
recorders, shipping containers, rulers, and digital thermometers. 
The means for performing EDC will be defined by Sanofi Pasteur. If a computer is provided by 
Sanofi Pasteur, it will be retrieved at the end of the study. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and/ or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines.  

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9 
Endpoints and Assessment Methods  
9.1 
Primary Endpoints and Assessment Methods  
9.1.1 Safety  
There are no primary objectives for safety. 
9.1.2 Immunogenicity  
9.1.2.1 Immunogenicity Endpoints  
The primary endpoint(s) for the evaluation of immunogenicity are: 
• RVNA titers (IU/mL) measured by the RFFIT at D42 for pediatrics and adults in Primary 
Series Cohort 1: 
• Subject with an RVNA titer ≥ 0.5 IU/mL at D42 
9.1.2.2 Immunogenicity Assessment Methods  
The assay method to quantify neutralizing antibodies against rabies virus in human serum samples 
is the RFFIT. The method involves reaction of rabies virus specific antibodies present in serum 
with a standardized challenge dosage of rabies virus (CVS-11) in a micro-neutralization cell 
culture. The presence of non-neutralized rabies virus in the serum-virus mixture is detected in the 
infected cells by direct fluorescence antibody method using fluorescein isothiocyanate (FITC) 
conjugated anti-rabies monoclonal immunoglobulin. The rabies virus in micro-neutralization cell 
culture is enumerated in scanned images generated from a cell imaging reader. The absence of 
infectivity (no fluorescent cells) constitutes a positive neutralization reaction, indicating the 
presence of RVNA in the serum. On the contrary, the infection of cells in culture indicates the 
absence of RVNA in the serum. 
The highest dilution of the serum that neutralizes 50% of the challenge virus is the endpoint 
antibody titer. The RVNA concentration is expressed in IU/mL and is determined by calibrating 
the 50% neutralization endpoint antibody titer of the test serum to the 50% neutralization endpoint 
titer of an internal reference serum which was calibrated against the 1st or 2nd WHO international 
standard for anti-rabies immunoglobulin. Titers (IU/mL) will be obtained in duplicates for each 
tested sample, and the individual geometric mean of duplicates calculated as needed.  
LLOQ for the RFFIT assay is 0.2 IU/mL. Samples calculated to a value less than LLOQ will be 
reported as < LLOQ. 
Virus neutralization will also be assessed as complete (absence of fluorescent cells) or incomplete 
(presence of fluorescent cells) at the subject/timepoint level at the starting dilution (1/5) of the 
RFFIT assay. Samples may be assessed in duplicates and the result summarized as: complete or 
incomplete (if both duplicates show complete or incomplete neutralization, respectively) or 
undetermined, if duplicates give different results. 

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9.1.3 Efficacy  
No clinical efficacy data will be obtained in the study. 
9.2 
Secondary Endpoints and Assessment Methods  
9.2.1 Safety  
9.2.1.1 Safety Definitions  
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
Therefore, an AE may be: 
• A new illness 
• The worsening of a pre-existing condition 
• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the actions taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the study period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing medical 
condition worsens following study interventions in frequency or intensity, or if according to the 
Investigator there is a change in its clinical significance, this change should be reported as an AE 
(exacerbation). This applies equally to recurring episodes of pre-existing conditions (eg, asthma) 
if the frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3 (see Section 9.2.1.3.3). This is not the same as 
serious, which is based on subject/ event outcome or action criteria usually associated with events 
that pose a threat to a subject’s life or functioning. Seriousness, not severity, serves as a guide for 
defining regulatory reporting obligations. 
An SAE is any untoward medical occurrence that at any dose. 

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• Results in death 
• Is life-threateninga 
• Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability/ incapacityc 
• Is a congenital anomaly/ birth defect 
• Is an important medical event (IME) 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as IMEs that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the health of the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These IMEs 
should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse, new-onset diabetes, or autoimmune disease. 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
The following additional definitions are used by Sanofi Pasteur: 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the product administered) that occur within the 1st 30 minutes after vaccination. 
Solicited Reaction: 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) pre-listed in the protocol and CRB (eg, injection site pain 
or headache occurring between D0 and D7 post-vaccination). 
By definition, solicited reactions are to be considered as being related to the product administered. 
For injectable vaccines, solicited reactions can either be solicited injection site reactions or 
solicited systemic reactions. 
                                                 
a  The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or outpatient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 

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Unsolicited AE/ AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions pre-listed in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between D0 
and D7 is a solicited reaction (ie, pre-listed in the protocol and CRB), then a headache starting on 
D7 is a solicited reaction, whereas headache starting on D8 post-vaccination is an unsolicited AE. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
Injection Site Reaction: 
An injection site reaction is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions. They are considered to be related to the product administered. 
Systemic AE: 
Systemic AEs are all AEs that are not injection or administration site reactions. They, therefore, 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (eg, erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An AESI is one of scientific and medical concern specific to the Sponsor’s product or program, 
for which ongoing monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the study Sponsor to 
other parties (eg, regulators) might also be warranted. 
AEs of special interest are AEs that are considered by the Sponsor to be relevant for the 
monitoring of the safety profile of the investigational vaccine. The following AESIs are defined: 
anaphylactic reactions, encephalitis, and convulsions. 
9.2.1.2 Safety Endpoints  
The secondary endpoints for the evaluation of safety are: 
• Occurrence of any unsolicited systemic AEs reported in the 30 minutes after each vaccine 
injection 
• Occurrence of solicited (pre-listed in the subject’s DC and electronic CRF) injection site and 
systemic reactions occurring within 7 days after each injection 
• Occurrence of unsolicited (spontaneously reported) injection site reactions occurring within 
28 days after each injection and unsolicited systemic AEs up to 28 days after each injection 
• Occurrence of SAEs and AESIs within at least 6 months after each vaccination as applicable 
to Cohort 1 and Cohort 2.  
• SAEs (including AESIs) reported throughout the study, including occurrence, nature (Medical 
Dictionary for Regulatory Activities [MedDRA] preferred term), time of onset, duration, 
intensity, action taken, relationship to the product administered (for systemic AEs only), 

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whether the event caused termination from the study, outcome, elapsed time from last 
administration (if less than 24h), relationship to study procedures, and seriousness criterion 
Note: The following AESIs will be considered as SAEs and reported to the Sponsor: anaphylactic 
reactions, encephalitis, and convulsions. For each AESI, the standard case definitions from the 
Brighton Collaboration will be used. These AESIs have been defined based on existing post-
marketing safety data of other rabies vaccines. 
Note: Information about SAEs, AESIs, and cases of pregnancy were recorded throughout the 
study for pediatrics and adults in Cohort 1; and this is up to 6 months after the booster dose for 
subset of adults in Cohort 1. Information about SAEs, AESIs, and cases of pregnancy will be 
recorded until 6 months after the primary series (V05) and until 6 months after the booster dose 
for subset of adults in Cohort 2. Between the 6-month follow-up visit after primary series (V05) 
and booster dose visit (V08), AESIs will not be collected, only fatal SAEs and related SAEs will 
be collected. 
9.2.1.3 Safety Assessment Methods  
At each visit, the blinded Investigator or a delegate will perform a clinical or medically-driven 
physical examination and will ask the subject or subject’s parent/LAR about any solicited 
reactions and unsolicited AEs recorded in the DC and/or MA, as well as about any other AEs that 
may have occurred since the previous visit. All relevant data will be transcribed into the CRB 
according to the instructions provided by the Sponsor. 
9.2.1.3.1 Immediate Post-vaccination Observation Period  
Subjects will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. Any AE 
that occurs during this period will be noted on the source document and recorded in the CRB, as 
follows: 
• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected) 
• Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded in the CRB in the same way as any reactions starting on the day of vaccination  
• SAEs will be recorded in the CRB and reported to the Sponsor in the same way as any other 
SAEs, according to the procedures described in Section 10 
9.2.1.3.2 Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Each Vaccination)  
After each vaccination, subjects or subjects’ parent/LAR will be provided with a DC, a digital 
thermometer, and a flexible ruler, and will be instructed how to use them. The following items 
will be recorded by the subjects in the DC on the day of vaccination and for the next 7 days (ie, 
D0 through D7) until resolution: 
• Daily temperature, with the route by which it was taken 

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• Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
• Action taken for each event (eg, medication) 
The action(s) taken by the subject or subject’s parent/LAR to treat and/or manage any 
solicited reactions will be classified in the CRB using the following list (all applicable items 
should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination 
 
Table 9.1 to Table 9.3 and Table 9.4 to Table 9.5 present, respectively, the injection site reactions 
and systemic reactions that are pre-listed in the DCs and CRB, together with the intensity scales. 
 

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Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales in infants and toddlers aged ≤ 23 months  
CRB term 
(MedDRA lowest 
level term [LLT])* 
Injection site tenderness 
Injection site erythema 
Injection site swelling 
MedDRA PT† 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Tenderness 
Redness 
Swelling 
Definition 
Pain when the injection site is touched or 
injected limb mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale§ 
 
Grade 1: Minor reaction when injection site 
is touched 
Grade 2: Cries or protests when injection site 
is touched 
Grade 3: Cries when injected limb is 
mobilized, or the movement of the injected 
limb is reduced 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
* The MedDRA (Version 22.0 or higher) lowest level term (LLT) will be used in the protocol and CRF 
† The MedDRA LLT will be used in the protocol and in analyzing and reporting the reactions (clinical study report, summary documents) 
§ For the subjective reaction of tenderness, parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and 
swelling, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 

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Table 9.2: Solicited injection site reactions: terminology, definitions, and intensity scales in children (aged 2 through 11 years)  
CRB term 
(MedDRA lowest 
level term [LLT])* 
Injection site pain 
Injection site erythema 
Injection site swelling  
MedDRA PT† 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when 
the injection site is touched or injected limb 
is mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale§ 
 
Grade 1: Easily tolerated 
Grade 2: Sufficiently discomforting to 
interfere with normal behavior or activities 
Grade 3: Incapacitating, unable to perform 
usual activities 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
* The MedDRA (Version 22.0 or higher) lowest level term (LLT) will be used in the protocol and CRF 
† The MedDRA LLT will be used in the protocol and in analyzing and reporting the reactions (clinical study report, summary documents) 
§For the subjective reaction of pain, subjects or parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and 
swelling, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 

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Table 9.3: Solicited injection site reactions: terminology, definitions, and intensity scales in adolescents and adults (aged ≥ 12 years)  
CRB term (MedDRA 
lowest level term 
[LLT])* 
Injection site pain 
Injection site erythema 
Injection site swelling  
MedDRA PT† 
Injection site pain 
Injection site erythema 
Injection site swelling 
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when the injection 
site is touched or injected limb is mobilized 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to disperse, 
swelling may be either soft (typically) or firm 
(less typical) to touch and thus can be best 
described by looking at the size of the swelling 
Intensity scale§ 
 
Grade 1: A type of AEs that is usually transient and 
may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere 
with usual activities of daily living. 
Grade 2: A type of AEs that is usually alleviated with 
additional therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to 
the research subject. 
Grade 3: A type of AEs that interrupts usual activities 
of daily living, or significantly affects clinical status, or 
may require intensive therapeutic intervention. 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
* The MedDRA (Version 22.0 or higher) lowest level term (LLT) will be used in the protocol and CRF 
† The MedDRA LLT will be used in the protocol and in analyzing and reporting the reactions (clinical study report, summary documents) 
§For the subjective reaction of pain, subjects or parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and 
swelling, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis 

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Table 9.4: Solicited systemic reactions: terminology, definitions, and intensity scales in infants and toddlers aged ≤ 23 months  
CRB term 
(MedDRA lowest 
level term [LLT])* 
Fever 
Vomiting 
Crying abnormal  
Drowsiness 
Appetite lost 
Irritability 
MedDRA PT† 
Pyrexia 
Vomiting  
Crying 
Somnolence 
Decreased 
appetite 
Irritability 
Diary card term 
Temperature 
Vomiting 
Abnormal crying 
Drowsiness 
Loss of appetite 
Irritability 
Definition 
Elevation of 
temperature to 
≥°38.0°C (≥ 100.4°F) 
Vomiting does not 
include spitting up 
Inconsolable crying 
without a determined 
reason 
Reduced interest in 
surroundings, or 
increased sleeping 
See intensity scale An excessive response to 
stimuli: increased fussiness, 
whining, and fretfulness 
despite attempts to comfort 
the toddler and despite 
caregiver responses that 
would normally be soothing 
Intensity scale§ 
Grade 1:  
≥ 38.0°C to ≤ 38.5°C 
or ≥ 100.4°F to ≤ 101.3°F 
Grade 1: 1 episode per 
24 hours 
Grade 1: < 1 hour 
Grade 1: Sleepier than 
usual or less interested 
in surroundings 
Grade 1: Eating 
less than normal 
Grade 1: Easily consolable 
 
Grade 2: 
> 38.5°C to ≤ 39.5°C 
or > 101.3°F to ≤ 103.1°F 
Grade 2: 2–5 episodes 
per 24 hours 
Grade 2: 1–3 hours  
Grade 2: Not interested 
in surroundings or did 
not wake up for a feed / 
meal 
Grade 2: Missed 1 
or 2 feeds / meals 
completely 
Grade 2: Requiring increased 
attention 
 
Grade 3: > 39.5°C 
or > 103.1°F 
Grade 3: ≥ 6 episodes 
per 24 hours or 
requiring parenteral 
hydration 
Grade 3: > 3 hours 
Grade 3: Sleeping most 
of the time or difficult 
to wake up 
Grade 3: Refuses 
≥ 3 feeds / meals 
or refuses most 
feeds / meals 
Grade 3: Inconsolable 
* The MedDRA (Version 22.0 or higher) lowest level term (LLT) will be used in the protocol and CRF 
† The MedDRA LLT will be used in the protocol and in analyzing and reporting the reactions (clinical study report, summary documents) 
§ For all reactions but fever, parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and the 
classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 

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Table 9.5: Solicited systemic reactions: terminology, definitions, and intensity scales in children (aged 2 through 11 years), adolescents or adults 
(aged ≥ 12 years)  
CRB term (MedDRA 
lowest level term 
[LLT])* 
Fever 
Headache 
Malaise 
Myalgia 
MedDRA PT† 
Pyrexia 
Headache 
Malaise 
Myalgia 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Definition 
Elevation of temperature to 
≥°38.0°C (≥ 100.4°F) 
Pain or discomfort in the head or 
scalp. Does not include migraine. 
General ill feeling 
Malaise is a generalized feeling of 
discomfort, illness, or lack of well-
being that can be associated with a 
disease state. It can be accompanied 
by a sensation of exhaustion or 
inadequate energy to accomplish 
usual activities. 
Muscle aches and pains are 
common and can involve more than 
one muscle at the same time. 
Muscle pain can also involve the 
soft tissues that surround muscles. 
These structures, which are often 
referred to as connective tissues, 
include ligaments, tendons, and 
fascia (thick bands of tendons). 
Does not apply to muscle pain at 
the injection site which should be 
reported as injection site pain. 
Intensity scale§ 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to ≤ 101.1°F 
Grade 1: A type of AEs that is 
usually transient and may require 
only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 
Grade 1: A type of AEs that is 
usually transient and may require 
only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 
Grade 1: A type of AEs that is 
usually transient and may require 
only minimal treatment or 
therapeutic intervention. The event 
does not generally interfere with 
usual activities of daily living. 

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CRB term (MedDRA 
lowest level term 
[LLT])* 
Fever 
Headache 
Malaise 
Myalgia 
MedDRA PT† 
Pyrexia 
Headache 
Malaise 
Myalgia 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
 
Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to ≤ 102.0°F 
Grade 2: A type of AEs that is 
usually alleviated with additional 
therapeutic intervention. The event 
interferes with usual activities of 
daily living, causing discomfort but 
poses no significant or permanent 
risk of harm to the research subject. 
Grade 2: A type of AEs that is 
usually alleviated with additional 
therapeutic intervention. The event 
interferes with usual activities of 
daily living, causing discomfort but 
poses no significant or permanent 
risk of harm to the research subject. 
Grade 2: A type of AEs that is 
usually alleviated with additional 
therapeutic intervention. The event 
interferes with usual activities of 
daily living, causing discomfort but 
poses no significant or permanent 
risk of harm to the research subject. 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of AEs that 
interrupts usual activities of daily 
living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Grade 3: A type of AEs that 
interrupts usual activities of daily 
living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Grade 3: A type of AEs that 
interrupts usual activities of daily 
living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
* The MedDRA (Version 22.0 or higher) lowest level term (LLT) will be used in the protocol and CRF 
† The MedDRA LLT will be used in the protocol and in analyzing and reporting the reactions (clinical study report, summary documents) 
§ For all reactions but fever, subjects or parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and 
the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
 

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Important Notes for the Accurate Assessment of Temperature: 
Subjects or subjects’ parents/legally acceptable representatives are to measure body temperature 
once per day, preferably always at the same time. The optimal time for measurement is the 
evening, when body temperature is the highest. Temperature is also to be measured at the time of 
any apparent fever. The observed daily temperature and the route of measurement are to be 
recorded in the DC/MA, and the highest temperature will be recorded by the site in the CRB. The 
preferred route for this study is axillary for toddlers and children; oral for adolescent and adults. 
Pre-vaccination temperature is also systematically collected by the Investigator on the source 
document. Tympanic thermometers must not be used. 
9.2.1.3.3 Unsolicited Adverse Events  
In addition to recording solicited reactions, subjects or subjects’ parents/legally acceptable 
representatives will be instructed to record any other medical events that may occur between each 
vaccination and during the 28-day period after the last vaccination and the booster vaccination. 
Space will be provided in the DC for this purpose. 
Information on SAEs will be collected and assessed throughout the study, from inclusion until 6 
months after the last vaccination. Any SAE occurring at any time during the study will be 
reported by the Investigator in the CRB according to the completion instructions provided by the 
Sponsor; this includes checking the “Serious” box on the AE CRF and completing the appropriate 
Safety Complementary Information CRFs. All information concerning the SAE is to be reported 
either as part of the initial reporting or during follow-up reporting if relevant information became 
available later (eg, outcome, medical history, results of investigations, copy of hospitalization 
reports). In case a subject experiences febrile convulsion (neurological event associating fever and 
seizure), the assessment will be performed according to the “Guideline for definition and 
collection of cases of febrile convulsion”, and this event will be considered an SAE. 
See Section 10 for further details on SAE reporting. 
For each unsolicited AE (whether serious or non-serious), the following information is to be 
recorded: 
• Start and stop datesa  
• Intensity of the event: 
For measurable unsolicited AEs that are part of the list of solicited reactions, the size of the 
AE as well as the temperature for fever will be collected and analyzed based on the 
corresponding scale used for solicited reactions (see Table 9.1 to Table 9.5). 
All other unsolicited AEs will be classified according to the following intensity scale: 
                                                 
a  The stop date of all related AEs will be actively solicited. For other events, the Investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the study will be 
considered as ongoing at the end of the study. 

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• Grade 1: A type of AEs that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Grade 2: A type of AEs that is usually alleviated with additional therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject. 
• Grade 3: A type of AEs that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
• Whether the AE was related to the investigational product (for unsolicited systemic AEs) 
The Investigator will assess the causal relationship between the AE and the investigational 
product as either “Not related” or “Related”, as described in Section 9.2.1.3.5. 
• Action taken for each AE (eg, medication) 
The action(s) taken by the subject or subject’s parent/LAR to treat and/or manage any 
unsolicited AEs will be classified in the CRB using the following list (all applicable items 
should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Discontinuation of study vaccination 
• Whether the AE was serious 
For each SAE, the Investigator will complete all seriousness criteria that apply (outcome, 
elapsed time, and relationship to study procedures) 
• Whether the AE caused study discontinuation 
9.2.1.3.4 Adverse Events of Special Interest  
The following AESIs will be assessed during the overall conduct of the study: 
• Anaphylactic reactions  
• Encephalitis  
• Convulsions 
These AESIs are considered by the Sponsor to be relevant for the monitoring of the safety profile 
of investigational products. They will be collected during the entire participation of a subject in 
the study and are to be reported as SAEs according to the procedure described in Section 10. 
These AESIs have been defined based on existing post-marketing safety data of other rabies 
vaccines. For each AESI, the standard case definitions from the Brighton Collaboration will be 
used (63) (64) (65). 

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9.2.1.3.5 Assessment of Causality  
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
the product administered as either not related or related, based on the following definitions: 
Not related – The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before the given vaccination 
Related – There is a “reasonable possibility” that the AE was caused by the product 
administered, meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all AEs reported at the injection site (whether solicited or unsolicited) and 
all solicited systemic AEs are considered to be related to the administered product and therefore 
are referred to as reactions and do not require the Investigator’s opinion on relatedness. 
AEs likely to be related to the product, whether serious or not, that persist at the end of the study 
will be followed up by the Investigator until their complete disappearance or the stabilization of 
the subject’s condition. The Investigator will inform the Sponsor of the date of final 
disappearance of the event or the date of “chronicity” establishment. 
9.2.2 Immunogenicity  
9.2.2.1 Immunogenicity Endpoints  
The secondary endpoints for the evaluation of immunogenicity are:  
• 
RVNA titers (IU/mL) measured by RFFIT, summarized at the subject/ timepoint level: 
• 
RVNA titers at D0 and D28 for subjects in Primary Series Cohort 1 and Cohort 2, and at 
D42 for subjects in Primary Series Cohort 1; at M12 and M12+D14 for subjects in the 
Booster Phase Cohort 1; at M6, M12, M18, between M24 up to M36, and between M24 
up to M36+D14 for subjects in Immunogenicity Persistence and Booster Phase Cohort 2 
• 
Subjects with an RVNA titer ≥ 0.5/mL at D0 and D28 for subjects in Primary Series 
Cohort 1 and Cohort 2, and at D42 for subjects in Primary Series Cohort 1; at M12 and 
M12+D14 for subjects in the Booster Phase Cohort 1; at M6, M12, M18, between M24 
up to M36, and between M24 up to M36+D14 for subjects in Immunogenicity Persistence 
and Booster Phase Cohort 2 
• 
Subject with an RVNA titer ≥ LLOQ IU/mL at D0 and D28 for subjects in Primary Series 
Cohort 1 and Cohort 2, and at D42 for subjects in Primary Series Cohort 1; at M12 and 
M12+D14 for subjects in the Booster Phase Cohort 1; at M6, M12, M18, between M24 
up to M36, and between M24 up to M36+D14 for subjects in Immunogenicity Persistence 
and Booster Phase Cohort 2 
• 
Individual RVNA titer ratio: D28/D0 for subjects in Primary Series Cohort 1 and Cohort 
2, and D42/D0 for subjects in Primary Series Cohort 1; M12/D0, 14 days after M12/D0, 
and 14 days after M12/M12 for subjects in Booster Phase Cohort 1; M6/D0, M12/D0, 

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M18/D0, M24 up to M36/D0, 14 days after M24 up to M36/D0, and 14 days after M24 up 
to M36/M24 up to M36 for subjects in Immunogenicity Persistence and Booster Phase 
Cohort 2 
• 
Subject with complete or incomplete neutralization at the starting dilution (1/5) of the 
RFFIT assay at subject with an RVNA titer ≥ LLOQ IU/mL at D0 and D28 for subjects in 
Primary Series Cohort 1 and Cohort 2, and D42 for subjects in Primary Series Cohort 1; 
M12 and M12+D14 for the Booster Phase Cohort 1; at M6, M12, M18, between M24 up 
to M36, and between M24 up to M36+D14 for the Immunogenicity Persistence and 
Booster Phase Cohort 2 
9.2.2.2 Immunogenicity Assessment Methods  
The immunogenicity assessment methods for the secondary endpoints are the same as those 
presented in Section 9.1.2.2. 
9.2.3 Efficacy  
No clinical efficacy data will be obtained in the study. 
9.3 
Observational Endpoints and Assessment Methods  
There are no observational objectives in this study. 
10 
Reporting of Serious Adverse Events  
To comply with current regulations on SAE reporting to health authorities, the Investigator must 
document all SAEs regardless of causal relationship and notify the Sponsor and the Clinical 
Research Associate (CRA) within the notification timelines stated in the following sections. The 
Investigator will give access and provide the Sponsor and the CRA with all necessary information 
to allow the Sponsor to conduct a detailed analysis of the safety of the investigational product(s). 
It is the responsibility of the Investigator to request all necessary documentation (eg, medical 
records, discharge summary, autopsy) in order to provide comprehensive safety information. All 
relevant information must then be transcribed onto the AE CRF and the appropriate Safety 
Complementary Information CRFs. 
10.1 Initial Reporting by the Investigator  
SAEs occurring during a subject’s participation in the study or experiment must be reported 
within 24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must be reported, 
even if the Investigator considers that it is not related to the vaccine. The Investigator (licensed 
physician [MD or DO]) must validate the information entered on the AE CRF by completing the 
Investigator validation form. 
The Investigator must indicate on the AE CRF that the event was serious and must complete the 
relevant SAE section of this form as well as the appropriate Safety Complementary Information 

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CRFs. An e-mail alert will automatically be sent by the EDC system to the GPV mailbox, the 
CRA and the Global Clinical Development Strategy Expert (GCDSE) with relevant SAE 
information details. 
If the EDC system is unavailable, the site must notify the Sponsor, using the paper version of the 
CRB, as described in the Operating Guidelines. 
The Investigator must complete the paper copies of the AE CRF and of the appropriate Safety 
Complementary Information CRFs and send them to the Sponsor by one of the following means: 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: CL-CPV-Receipt@sanofi.com 
• Fax: +33 (0) 1 60 49 70 70 
When the EDC system becomes available, the Investigator must transcribe the information from 
the paper forms into the EDC system. 
If there is a need for urgent consultation, the Investigator is to contact the RMO. If the RMO 
cannot be reached, the Investigator may contact the Call Center as described in Section 5.3. 
10.2 Follow-up Reporting by the Investigator  
The AE CRF completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (eg, outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Safety Complementary Information CRFs. 
An e-mail alert will be sent automatically to the GPV Department and the CRA. Copies of 
documents (eg, medical records, discharge summary, autopsy) may be requested by the GPV 
Department. 
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study  
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
investigational product(s), other products (eg, a benefit vaccine), or to the experiment must also 
be reported as soon as possible. In such a case, the reporting procedure to be followed is identical 
to that described in Section 10.1. 
10.4 Assessment of Causality  
The causal relationship between the SAE and the product administered will be evaluated by the 
Investigator as described in Section 9.2.1.3.5. 
Following this, the Sponsor’s GSO will also assess the causal relationship to the product, based on 
the available information and current medical knowledge. 
The causal relationship to study procedures will be also assessed in the CRB. 

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The decision to modify or discontinue the study may be made after mutual agreement between the 
Sponsor and the Investigator(s).  
10.5 Reporting SAEs to Health Authorities and IECs / IRBs  
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO will notify the Investigators in writing of the occurrence of any reportable 
SAEs. The Investigators will be responsible for informing the IECs or IRBs that reviewed the 
study protocol. 
11 
Data Collection and Management  
11.1 Data Collection and CRB Completion  
Individual DCs, specifically designed for this study by the Sponsor and provided to the study 
sites, will be given to study subjects for the recording of daily safety information as described in 
Section 9.2.1.3. These DCs will include pre-listed terms and intensity scales (see Table 9.1 to 
Table 9.5) as well as areas for free text to capture additional safety information or other relevant 
details. Subjects or subjects’ parents/legally acceptable representatives will also be provided with 
rulers for measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
subjects or subjects’ parents/legally acceptable representatives on how to correctly use these tools.  
The 6-month safety follow-up will be done by interviewing subjects either during a visit or over 
the telephone using a questionnaire to capture SAEs and AESIs, if applicable. A MA/DC SAE 
may be provided to the subjects or subjects’ parents/LAR at the preceding study visit to help them 
record information on events occurring between this visit and the 6-month follow-up. 
Relevant information will be transcribed into the AE CRF. Any SAEs captured during this 
6-month follow-up period will be reported and followed up as per the normal process for 
reporting SAEs. For periods between the 6-month safety follow-up and the next booster 
vaccination, the relevant information will be collected as described in Tables of Study Procedures 
and Visit Procedures (see Section 5.1.4). 
At specified intervals, the blinded Investigator or an authorized designee will interview the 
subjects or subjects’ parents/legally acceptable representatives to collect the information recorded 
in the DC and will attempt to clarify anything that is incomplete or unclear. All clinical study 
information gathered by the study site will be reported electronically by the Investigator or 
authorized designee using a web-based CRB. (Any information that was not documented in the 
DC will 1st be captured in the source document and then reported electronically.) The CRB has 
been designed specifically for this study under the responsibility of the Sponsor, using a validated 
electronic records/ electronic signature-compliant platform (21 CFR Part 11). 

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To ensure the correct and consistent completion of the CRBs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion instructions will be provided to assist with data entry during the course of the study. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in study personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any study personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trial will be initiated in the EDC system at the time of the 1st data entry to track all modifications 
and ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRBs; must provide explanations for all missing information; and must sign the CRB using 
an e-signature. 
11.2 Data Management  
Management of SAE and Pregnancy Data 
During the study, SAE data (reported on the AE, Death, and Safety Complementary Information 
CRFs) and pregnancy data (reported by the Investigator on ePregnancy Forms) will be integrated 
into the Sponsor’s centralized GPV database upon receipt of these forms and after a duplicate 
check. Each case will be assigned a case identification number. Each case will be assessed by the 
case management platform or its delegate before being reported to the relevant authorities as 
necessary. The assessment of related cases will be done in collaboration with the GSO and the 
RMO. Follow-up information concerning a completed case will be entered into the GPV database, 
and a new version of the case will be created. 
The information from the GPV database cases will be reconciled with that in the clinical database. 
Management of Clinical and Laboratory Data 
Clinical data, defined as all data reported in the CRB, and laboratory data will be handled by the 
Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
During the study, clinical data reported in the CRBs will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and/ or consistency checks will be 
systematically applied to detect errors or omissions. In addition, data reviews may be performed 
several times by the Sponsor’s staff in the course of the study. Any questions pertaining to the 
reported clinical data will be submitted to the Investigator for resolution using the EDC system. 
Each step of this process will be monitored through the implementation of individual passwords 
to maintain appropriate database access and to ensure database integrity. 

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The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical Datawarehouse. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review  
A blind review of the data is anticipated through the data review process led by Data Management 
before database lock.  
12 
Statistical Methods and Determination of Sample Size  
12.1 Statistical Methods  
The statistical analysis will be performed under the responsibility of the Sponsor’s Biostatistics 
platform with the SAS software, at least version 9.4 (SAS Institute, Cary, North Carolina, USA). 
More details of the study objectives, statistical hypotheses, and success criteria will be provided in 
the statistical analysis plan (SAP), where applicable. 
12.1.1 Hypotheses and Statistical Methods for Primary Objective  
12.1.1.1 Hypotheses  
In each age group of Primary Series Cohort 1, the immunogenicity of VRVg-2 will be compared 
to that of Verorab and Imovax Rabies vaccines at D42, ie, 14 days after the 3rd vaccine injection, 
using NI testing. For each comparison, the primary parameter will be the difference in the 
proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 between the 2 compared vaccine 
groups. The hypotheses tested will be the following: 
H0: PVRVg-2-Pcontrol ≤ -5% 
H1: PVRVg-2-Pcontrol > -5% 
With P = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 (%). 
VRVg-2 will be considered as non-inferior to the tested control if the hypothesis H0 is rejected.  
12.1.1.2 Statistical Methods  
For the NI hypotheses testing, the statistical methodology will be based on the use of the 
two-sided 95% CI of the difference of proportions of subjects with an RVNA titer ≥ 0.5 IU/mL at 
D42 between the vaccine groups. The 95% CI for differences will be calculated using the Wilson 
score method without continuity correction (66). 

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NI will be demonstrated if the lower limit of the 95% CI of the difference of the 2 proportions 
PVRVg-2-Pcontrol is > -5%. 
The primary objective of NI will be demonstrated if each of the NI between VRVg-2 and both 
Verorab and Imovax Rabies vaccines is demonstrated in each age group, respectively, in Primary 
Series Cohort 1. 
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives  
12.1.2.1 Hypotheses  
The secondary hypotheses testing will be considered only if the primary objective is met, and then 
the secondary objectives will be evaluated sequentially following a fixed-sequence method as 
specified below (67) (68) (69). 
• Superiority in the VRVg-2 group at D42  
Only if the primary objective is achieved at D42, the 1st secondary objective will be assessed on 
overall subjects from the VRVg-2 group in Primary Series Cohort 1, and this objective will be 
reached if the observed proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 is higher 
than or equal to 99% and if the following H0 hypothesis is rejected.  
H0: PVRVg-2 < 97%  
H1: PVRVg-2 ≥ 97%  
With P = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 (%). 
• NI testing of 2-dose VRVg-2 versus 2-dose Verorab and Imovax Rabies at D28  
Only if the 1st secondary objective is achieved at D42, the 2nd secondary NI objective at D28 will 
be assessed on each age group of pooled Primary Series Cohort 1 and Cohort 2. The 
immunogenicity of VRVg-2 will be compared to that of Verorab and Imovax Rabies vaccines at 
D28, ie, 21 days after the 2nd vaccine injection, using NI testing. For each comparison, the 
primary parameter will be the difference in the proportion of subjects with an RVNA titer 
≥ 0.5 IU/mL at D28 between the 2 compared vaccine groups. The hypotheses tested will be the 
following: 
H0: PVRVg-2-Pcontrol ≤ -5%  
H1: PVRVg-2-Pcontrol > -5%  
With P= proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 (%). 
• NI testing of 2-dose VRVg-2 at D28 versus 3-dose Imovax Rabies at D42  
Only if the 2nd secondary objective is achieved, then the following NI hypotheses will be tested 
in each age group (Pediatric subjects: Cohort 1; Adult subjects: pooled Cohort 1 and Cohort 2), 
respectively: 
Pediatric subjects (Cohort 1 only): 
H0: PVRVg-2 at D28 (Group 1) – PImovax Rabies at D42 (Group 3) ≤ -10%  

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H1: PVRVg-2 at D28 (Group 1) – PImovax Rabies at D42 (Group 3) > -10%  
Adult subjects (Cohorts 1 and 2): 
H0: PVRVg-2 at D28 (Groups 1+4) – PImovax Rabies at D42 (Group 3) ≤ -10%  
H1: PVRVg-2 at D28 (Groups 1+4) - PImovax Rabies at D42 (Group 3) > -10%  
With PVRVg-2 at D28 = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 for VRVg-2 
(%), and PImovax Rabies at D42 = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D42 for 
Imovax Rabies (%). 
• Superiority in the 2-dose VRVg-2 group at D28 
Only if the 3rd secondary NI objective is achieved, the 4th secondary superiority objective at D28 
will be assessed on overall subjects from the VRVg-2 group in pooled Primary Series Cohort 1 
and Cohort 2, and this objective will be reached if the observed proportion of subjects with an 
RVNA titer ≥ 0.5 IU/mL at D28 is higher than or equal to 99% and if the following H0 hypothesis 
is rejected: 
H0: PVRVg-2 < 97%  
H1: PVRVg-2 ≥ 97%  
With P= proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 (%). 
• NI testing of 2-dose Imovax Rabies at D28 versus 3-dose Imovax Rabies at D42  
Only if the 4th secondary objective is achieved, then the 5th secondary NI objective will be tested 
with the following hypotheses in Imovax Rabies group in overall subjects (pooled pediatric and 
adult subjects) in Cohort 1 only: 
H0: PImovax Rabies at D28 (Group 3) - PImovax Rabies at D42 (Group 3) ≤ -10%  
H1: PImovax Rabies at D28 (Group 3) - PImovax Rabies at D42 (Group 3) > -10%  
With PImovax Rabies at D28 = proportion of subjects with an RVNA titer ≥ 0.5 IU/mL at D28 for 
Imovax Rabies in Cohort 1 (%), and PImovax Rabies at D42 = proportion of subjects with an RVNA titer 
≥ 0.5 IU/mL at D42 for Imovax Rabies in Cohort 1 (%). 
12.1.2.2 Statistical Methods  
• Superiority in the VRVg-2 group at D42  
Only if the primary objective is achieved at D42, the superiority testing will be assessed on 
overall subjects from VRVg-2 group in Primary Series Cohort 1, and will be demonstrated if the 
overall observed proportion of subjects in VRVg-2 group in Cohort 1 with an RVNA titer 
≥ 0.5 IU/mL at D42 is at least 99.0%, with the lower limit of the 95% CI of the proportion of 
subjects with an RVNA titer ≥ 0.5 IU/mL at D42, calculated using the exact binomial distribution 
(Clopper Pearson method) (70), is higher than or equal to 97%. 
• NI testing of 2-dose VRVg-2 versus 2-dose Verorab and Imovax Rabies at D28  
Only if the 1st secondary superiority objective in the VRVg-2 group at D42 is achieved, based on 

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the same approach as the primary objective testing, the NI of VRVg-2 compared to each of the 
controls will be tested at D28 in each age group in pooled Primary Series Cohort 1 and Cohort 2 
subjects, based on the use of the two-sided 95% CI of the difference of proportions at D28, 
calculated using the Wilson score method without continuity correction (66). The secondary 
immunogenicity objective of NI at D28 will be demonstrated if each of the non-inferiority 
between VRVg-2 and both Verorab and Imovax Rabies vaccines is demonstrated in each age 
group, respectively, in pooled Primary Series Cohort 1 and Cohort 2. 
• NI testing of 2-dose VRVg-2 at D28 versus 3-dose Imovax Rabies at D42 
NI will be demonstrated for each hypothesis if the lower limit of the 95% CI of the difference of 
the 2 proportions (PVRVg-2 at D28 -PImovax Rabies at D42) is > -10%, with a similar approach as the testing 
for primary objective. 
The 3rd secondary immunogenicity objective will be demonstrated if all null hypotheses are 
rejected. 
• Superiority in the VRVg-2 group at D28 
Only if the 3rd secondary objective is achieved, based on the same approach as the secondary 
superiority objective testing at D42, the superiority of VRVg-2 group at D28 will be assessed on 
overall subjects from VRVg-2 group in pooled Primary Series Cohort 1 and Cohort 2, and the 
superiority objective at D28 will be demonstrated if the overall observed proportion of subjects in 
VRVg-2 group in pooled Cohort 1 and Cohort 2 with an RVNA titer ≥ 0.5 IU/mL at D28 is at 
least 99.0%, with lower limit of the 95% CI of the proportion of subjects with an RVNA titer 
≥ 0.5 IU/mL at D28, calculated using the exact binomial distribution (Clopper Pearson method) 
(70), is higher than or equal to 97%. 
• NI testing of 2-dose Imovax Rabies at D28 versus 3-doses Imovax Rabies at D42 
The null hypothesis will be rejected, and this objective will be achieved if the lower limit of the 
two-sided 95% CI of the difference of the 2 proportions (PImovax Rabies at D28 -PImovax Rabies at D42) is > -
10%, which will be calculated using a generalized linear model (GLM) for repeated measured 
data with categorical response under binomial distribution (link function=identity) (71). 
• Other secondary immunogenicity and safety objectives 
All other secondary endpoints will be described by age group and vaccine group using descriptive 
statistical methods without hypothesis testing, as follows. 
Immunogenicity Endpoints 
The analysis of RVNA titers after vaccination series will be done per age group and vaccine 
group, using the endpoints defined in Section 9.1.2.1. The analysis of booster results will be done 
overall and according to the vaccine received in the primary series. 
Assuming that log10 transformation of the titers/ratios follows a normal distribution, at first, the 
mean and 95% CI will be calculated on log10 (titers/ratios) using the usual calculation for normal 
distribution, then antilog transformations will be applied to the results of calculations, in order to 
provide GMTs/GMTRs and their 95% CIs. 
The exact binomial distribution for percentages (Clopper Pearson’s method), quoted by 
Newcombe (70) will be used for the single proportions. 

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Reverse Cumulative Distribution Curves will be plotted in all vaccine groups at D0, D28 for 
subjects in Primary Series Cohort 1 and Cohort 2, and at D42 for subjects in Primary Series 
Cohort 1; at M12, M12+D14 for subjects in Booster Phase Cohort 1; at M6, M12, M18, between 
M24 up to M36, and between M24 up to M36+D14 for subjects in Immunogenicity Persistence 
and Booster Phase Cohort 2. 
Safety Endpoints 
The safety analysis will report the occurrence of solicited reactions and the incidence of 
unsolicited AEs, including SAEs and AESIs, over the safety observation period by age group and 
vaccine group. Injection site reactions will be collected up to 7 days after each injection, systemic 
AEs will be collected between each vaccination and up to 28 days after the last injection. The 
following AEs will be considered as AESIs: anaphylactic reactions, encephalitis and convulsions. 
In order to avoid any under-estimation of the incidences, the number of subjects with documented 
safety will be used as the denominator of the frequencies. 
For safety parameters, 95% CIs of point estimates of proportion will be calculated using the exact 
binomial distribution (Clopper Pearson method) for proportions (70). 
12.1.3 Exploratory Analyses  
With the aim to provide the same standards and granularity in terms of investigational results 
across VRVg studies, and comply with health authorities requirements (72), the possible influence 
of several covariates on the safety and immunogenicity results will be studied using descriptive 
statistics. Thus, the main immunogenicity and safety parameters will be described according to 
gender, age group (1 year to < 12 years and ≥ 12 years for children; and 18 to 40 years, 41 to 
< 65 years, and ≥ 65 years for adults), ethnicity (only if more than 5% of subjects had different 
ethnicity), race (only if more than 5% of subjects had different race), and center. Race and 
ethnicity will be defined according to current guidelines (72). 
Other analyses will be defined in the SAP, if applicable. 
12.2 Analysis Sets  
12.2.1 Full Analysis Set  
The FAS is defined as the subset of randomized subjects who received at least 1 dose of the study 
vaccines in the primary series. 
The Full Analysis Set for Immunogenicity (FASI) is defined as a subset of the FAS, including all 
subjects from FAS who have a baseline titer lower than 0.5 IU/mL. 
FAS for Immunogenicity Persistence (FASP) is defined as the subset of randomized subjects from 
Cohort 2 who received a complete primary rabies vaccination series (ie, one week 2-dose PrEP 
regimen), and have at least one valid post-vaccination serology result at M6, M12, M18 or M24 
up to M36. 
FASI for Immunogenicity Persistence (FASIP) is defined as the subset of FASP, including all 
subjects from the FASP with a baseline titer lower than 0.5 IU/mL. 

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The Full Analysis Set for Booster at M12 (FASB1) is defined as the subset of subjects who 
received the booster dose at M12, after a complete primary rabies vaccination series (ie, 3-dose 
pre-exposure regimen) in Cohort 1. 
The Full Analysis Set for Booster at M24 up to M36 (FASB2) is defined as the subset of subjects 
who received the booster dose between M24 up to M36, after a complete primary rabies 
vaccination series (ie, one week 2-dose pre-exposure regimen) in Cohort 2. 
The Full Analysis Set for Immunogenicity for Booster at M12 (FASIB1) is defined as the subset 
of FASB1, including all subjects from FASB1 who have a baseline titer lower than 0.5 IU/mL. 
The Full Analysis Set for Immunogenicity for Booster at M24 up to M36 (FASIB2) is defined as 
the subset of FASB2, including all subjects from FASB2 who have a baseline titer lower than 0.5 
IU/mL. 
The analysis of immunogenicity addresses endpoints involving pre- and post-injection titers. The 
analysis will include all available data for each time point. 
12.2.2 Safety Analysis Set  
The Safety Analysis Set (SafAS) is defined for each dose as the subset of subjects having received 
this dose. All subjects will have their safety analyzed after each dose according to the vaccine 
they actually received and for the primary series, and after any dose according to the vaccine 
received at the first dose.  
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). Thus, if a subject does not receive any vaccine at a given visit or 
if the vaccine received does not correspond to any protocol group at a specific dose, the subject is 
excluded from the SafAS at this dose; however, the subject will be included in the analysis for all 
doses combined (referred to as analysis “after any dose”) according to the 1st dose received that 
corresponds to a protocol group. 
The Safey Analysis Set for booster (SafASB) is defined as the subset of subjects who received the 
booster dose (VRVg-2 vaccine). The corresponding vaccination group will be determined by the 
actual vaccination group in the Primary Series Cohort 1 (Groups 1, 2, and 3) or Cohort 2 
(Groups 4, 5, and 6). 
12.2.3 Per-Protocol Analysis Set  
The PPAS is defined for each key objective. Adherence to the definition of the PPAS may also be 
decided during the blinded data review, ie, before breaking the code and locking the database. 
12.2.3.1 Per-Protocol Analysis Set for D42  
The PPAS for D42 is a subset of the FAS which will be used for primary objective assessment at 
D42 (V04) for subjects in Primary Series Cohort 1. The subjects presenting with at least one of 
the following relevant protocol deviations before D42 (ie, 14 days after the 3rd vaccine injection) 
will be excluded from the PPAS for D42: 

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• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not complete the 3-dose vaccination schedule 
• Subject received a vaccine other than the one that he/ she was randomized to receive 
• Preparation and/ or administration of vaccine was not done as per-protocol 
• Subject did not receive vaccine in the proper time window 
• Vaccination Dose 2 in [D07-D09] 
• Vaccination Dose 3 in [D25-D31] 
• Subject did not provide post-dose 3 serology sample at V04 in the proper time window [D11, 
D17] post the third vaccination (ie, VAC3 +14D ±3D) or a post-dose 3 serology sample was 
not drawn at V04 
• Subject received a protocol-prohibited therapy/medication/vaccine (belonging to categories 2 
and 3) before V04 (D42) 
• Subject’s serology sample is missing or did not produce valid test results at D0 or D42 
• Seropositive subject at D0, ie, RVNA titer ≥ LLOQ 
• Subject developed a protocol-specified withdrawal criterion during the study but was not 
withdrawn before V04 (D42) 
12.2.3.2 Per-Protocol Analysis Set for D28  
The PPAS for D28 is also subset of the FAS, which will be used for secondary NI objective 
evaluation at D28 (V03) for subjects in Primary Series Cohort 1 and Cohort 2. The subjects 
presenting with at least one of the following relevant protocol deviations before D28 (ie, 21 days 
after the 2nd vaccine injection) will be excluded from the PPAS for D28: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not complete the 2-dose vaccination schedule at D0 (V01) and D7 (V02) 
• Subject received a vaccine other than the one that he/ she was randomized to receive at the 1st 
2 doses 
• Preparation and/or administration of vaccine was not done as per-protocol at D0 (V01) and D7 
(V02) 
• Subject did not receive 2nd vaccine injection in the proper time window 
• Vaccination Dose 2 in [D07-D09] 
• Subject did not provide post-dose 2 serology sample at V03 in the proper time window 
[D25-D31] or a post-dose 2 serology sample was not drawn at V03 

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• Subject received a protocol-prohibited therapy/medication/vaccine (belonging to categories 2 
and 3) before V03 (D28) 
• Subject’s serology sample is missing or did not produce valid test results at D0 or D28 
• Seropositive subject at D0, ie, RVNA titer ≥ LLOQ 
• Subject developed a protocol-specified withdrawal criterion during the study but was not 
withdrawn before V03 (D28) 
12.2.3.3 Per-Protocol Analysis Set for Booster at M12  
The PPAS for Booster at M12 (V07) is a subset of the FASB1, which will be used for evaluation 
of immunogenicity objective in the booster phase of Cohort 1, for a subset of adults who received 
a 3 doses regimen and received a single booster dose of VRVg-2 one year after the first 
vaccination of the primary series (ie, at M12). The adult subjects in Booster Phase Cohort 1, 
presenting with at least one of the following relevant protocol deviations before M12+D14 (ie, 
14 days after the booster dose injection) will be excluded from the PPAS for Booster at M12: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject received a vaccine other than the one that he/ she was randomized to receive in either 
primary series or booster phase 
• Preparation and/ or administration of vaccine was not done as per-protocol in either primary 
series or booster phase 
• Subject did not receive booster vaccine in the proper time window at V06 
• Vaccination 4 in [M12, M12 +14D] after Vaccination Dose 1 
• Subject did not provide post-booster dose serology sample at V07 in the proper time window 
[D14, D15] post the booster vaccination (VAC 4) or a post-booster dose serology sample was 
not drawn at V07 
• Subject received a protocol-prohibited therapy/medication/vaccine (belonging to categories 2 
and 3) before V07 (M12 + D14) 
• Subject’s serology sample is missing or did not produce valid test results at V06 (booster 
vaccination) or V07 (D14 after booster vaccination) 
• Seropositive subject at D0, ie, RVNA titer ≥ LLOQ 
• Subject developed a protocol-specified withdrawal criterion during the study but was not 
withdrawn before V07 (M12 + D14) 
12.2.3.4 Per-Protocol Analysis Set for Booster at M24 up to M36  
The PPAS for Booster at M24 up to M36 (V09) is a subset of the FASB2, which will be used for 
evaluation of immunogenicity objective in the booster phase for Cohort 2, for a subset adult who 
received a one week 2-dose regimen in the primary series, and received a single booster dose of 

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VRVg-2 between 2 up to 3 years after the first vaccination of the primary series (ie, at M24 up to 
M36). The adult subjects in Immunogenicity Persistence and Booster Phase Cohort 2 presenting 
with at least one of the following relevant protocol deviations before M24 up to M36+D14 (ie, 14 
days after the booster dose injection) will be excluded from the PPAS for Booster at M24 up to 
M36: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject received a vaccine other than the one that he/ she was randomized to receive in either 
primary series or booster phase 
• Preparation and/ or administration of vaccine was not done as per-protocol in either primary 
series or booster phase 
• Subject did not receive booster vaccine in the proper time window at V08 
• Vaccination 3 in [between M24 up to M36, between M24 up to M36 +14D after 
Vaccination dose 1] 
• Subject did not provide post-booster dose serology sample at V09 in the proper time window 
[D14, D15] post the booster vaccination (VAC 3), or a post-booster dose serology sample was 
not drawn at V09 (D14 after booster vaccination) 
• Subject received a protocol-prohibited therapy/medication/vaccine (belonging to categories 2 
and 3) before V09 (D14 after booster vaccination) 
• Subject’s serology sample is missing or did not produce valid test results at V08 (booster 
vaccination) or V09 (D14 after booster vaccination) 
• Seropositive subject at D0, ie, RVNA titer ≥ LLOQ 
• Subject developed a protocol-specified withdrawal criterion during the study but was not 
withdrawn before V09 (D14 after booster vaccination) 
12.2.4 Other Analysis Set(s)  
Other analysis sets will be defined in the SAP, if applicable. 
12.2.5 Populations Used in Analyses  
For the primary and key secondary immunogenicity objectives with hypothesis testing, the 
analyses will be performed on the PPAS primarily, and then on the FASI / FAS as supplementary 
analysis, if necessary. The subjects will be analyzed by the vaccine group to which they were 
randomized in the primary series.  
The safety analysis will be performed on the SafAS, and the subjects will be analyzed according 
to the vaccine they actually received in the primary series.  
More detail for the analysis populations will be defined in the SAP, if necessary. 
The safety analysis for booster phase will be performed on the SafASB, and the subjects will be 
analyzed according to the vaccine they actually received in the first dose in primary series. 

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12.3 Handling of Missing Data and Outliers  
12.3.1 Safety  
No replacement will be done as it is expected that the degree of missing safety data will be very 
low. 
Missing data in vaccine studies are mostly due to dropouts. The dropouts due to AEs or lost to 
follow-up subjects will be identified and discussed in the study report. 
12.3.2 Immunogenicity  
No replacement will be done as it is expected that the degree of missing safety data will be very 
low. 
No test or search for outliers will be performed. 
12.4 Interim / Preliminary Analysis  
The statistical analysis will be performed in 4 steps: 
• The 1st statistical analysis will be done once all immunogenicity data up to D28 (V03, 21 days 
after the 2nd vaccination) in the primary series of Cohort 2 and all safety data up to D35 (V04, 
28 days after the 2nd vaccination) in the primary series of  Cohort 2 are available (ie, at the 
end of 6-month safety follow-up after booster phase in Cohort 1; and up to D35 [V04] in 
primary series in Cohort 2). The randomization and vaccination exposure information for all 
enrolled subjects will be unblinded at the time of 1st statistical analysis. 
• The 2nd statistical analysis will be carried out once the 12-month immunogenicity persistence 
data and safety data in Cohort 2 (V06) are collected. 
• The 3rd statistical analysis will be carried out once all the immunogenicity and safety data up 
to 28 days after the booster vaccination in Cohort 2 (V10) are collected. 
• The 4th statistical analysis will be carried out once the 6-month safety follow-up data post the 
booster vaccination in Cohort 2 (M30 up to M42) are collected. 
No statistical adjustment is necessary because there are no repeat analyses of the same parameter.  
12.5 Determination of Sample Size and Power Calculation  
12.5.1 Primary Series  
Original Plan for Cohort 1:  
An alpha level of 2.5% (one-sided hypothesis), has been chosen to calculate the sample size.  
Originally, assuming a proportion of subjects with an RVNA titer ≥ 0.5 IU/mL of 99% for both 
VRVg-2 and control vaccines in each age group at D42, a clinical acceptable difference of -5% 
for the difference of proportions at D42 betweenVRVg-2 and the control vaccines, and a power of 

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at least 95% for each of the NI testing in the primary objective, with and an unbalanced 
randomization ratio of 3:1:1 (VRVg-2: Verorab vaccine: Imovax Rabies vaccine), 258 evaluable 
subjects in the VRVg-2 group, and 86 evaluable subjects in each of the Verorab and Imovax 
Rabies vaccine groups who are planned to receive 3 vaccinations (at D0, D7 and D28) in primary 
series in each age group, will be necessary to provide a global power of 81.8% for the primary NI 
objective, using the Farrington and Manning (FM) method. 
If the primary objective is met at D42, a total of 516 subjects evaluable in the VRVg-2 group will 
ensure 85.0% of power for the 1st secondary immunogenicity objective of superiority at D42. If 
the 1st secondary immunogenicity objective is met, overall power for the 2nd secondary 
immunogenicity NI objective of 2-dose VRVg-2 at D28 versus 2-dose comparator vaccines at 
D28 will be higher than 80%. 
Under the assumption that 15% of subjects will not be evaluable in the PPAS, 303 subjects in the 
VRVg-2 group and 101 subjects in each of the Verorab and Imovax Rabies vaccine groups must 
be enrolled in each age group of the study per the original plan, as Primary Series Cohort 1. 
 
Updated Plan for Cohort 1 and Cohort 2 (Protocol Amendments 2, 3, and 4):  
According to the latest results from the VAJ00001 study and to be conservative, the estimation of 
proportion of adult subjects with an RVNA titer ≥ 0.5 IU/mL at D28 was adjusted from 99% to 
96.5% for both VRVg-2 and control vaccines. With the aim to secure the study power for the 2nd 
secondary immunogenicity NI objective at D28 and maintain the randomization ratio, 609 
evaluable adults in the VRVg-2 group, and 203 evaluable adults in each of the control vaccine 
group (Verorab and Imovax Rabies) will be necessary to provide a power of 81.7% to 
demonstrate the 2nd secondary immunogenicity objective at D28, using the FM method. 
If the 2nd secondary immunogenicity objective is met at D28, a total of 867 subjects evaluable in 
the VRVg-2 group will ensure 99.2% of power for the secondary objective of superiority for 
VRVg-2 at D28 in the overall subjects (pooled pediatric and adult subjects). 
Therefore, under the attrition rate of 15%, 690 additional adults (414 in VRVg-2; 138 in Verorab; 
138 in Imovax Rabies) were planned to be enrolled in the study as Cohort 2 to receive 2 
vaccinations at D0 and D7 in the primary series. Those 690 additional adults in Cohort 2 were 
planned to be pooled with the 505 adults enrolled in Cohort 1, for testing the 2nd secondary NI 
objective at D28. The 414 additional adults in VRVg-2 group in Cohort 2 were planned to be 
pooled with the 303 pediatric subjects and 303 adult subjects in VRVg-2 group in Cohort 1, for 
testing the secondary superiority objective for VRVg-2 at D28.  
Therefore, a total of 1700 subjects (505 pediatric subjects and 1195 adult subjects) were planned 
to be enrolled in total by 2 Cohorts, including 505 pediatric subjects and 505 adult subjects in 
Cohort 1 who are planned to receive 3 doses of vaccinations in the primary series, and 690 adult 
subjects in Cohort 2 who were planned to receive 2 doses of vaccinations in the primary series. 
As a consequence, a total of 1708 subjects (505 pediatric subjects and 1203 adult subjects) were 
actually enrolled, including 505 pediatric subjects and 505 adult subjects in Primary Series 
Cohort 1 and 698 adult subjects (including 8 replacements) in Cohort 2. 

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The 3:1:1 design is chosen to optimize the NI testing for immunogenicity and to increase the size 
of the safety database. 
 
Updated power estimations with additional objectives (Protocol Amendment 5):  
Based on live blinded data observed from Cohort 1, the estimated attrition rate of Cohort 1 was 
adjusted from 15% to about 13.5% at both D28 and D42 for pediatric subjects, and adjusted to 
about 21.0% at D28 and 19.8% at D42 for adult subjects, respectively. Assuming the actual 
attrition rate of adult subjects in Cohort 2 is similar to Cohort 1, the adjusted estimations for 
evaluable number of subjects in the PPAS in each age group are as below: 
• 
Pediatric subjects (Cohort 1 only): at both D28 and D42, there will be about 261 and 88 
evaluable subjects in VRVg-2 group and each of the comparator vaccine groups, 
respectively.   
• 
Adult subjects: at D28, there will be about 570 and 190 evaluable subjects in VRVg-2 
group and each of the comparator vaccine groups, respectively (pooled Cohort 1 and 
Cohort 2); at D42, there will be about 243 and 81 evaluable subjects in VRVg-2 group 
and each of the comparator vaccine groups, respectively (Cohort 1 only).  
Moreover, 2 new secondary immunogenicity objectives were added, both with a NI margin of 
10%: 
• 
To demonstrate the NI of 2-dose VRVg-2 at D28 versus 3-dose Imovax Rabies at D42 in 
each age group  
• 
To demonstrate the NI of 2-dose Imovax Rabies at D28 versus 3-dose Imovax Rabies at 
D42 in the overall subjects (pooled pediatric and adult subjects) in Cohort 1 
Finally, the primary objective and all 5 key secondary immunogenicity objectives will be 
evaluated sequentially. Each of the key immunogenicity objective will be tested only if the 
previous objective is achieved.  
Based on the updated study objectives and the adjusted number of evaluable subjects in the PPAS, 
the power to demonstrate each of the key immunogenicity objectives is presented Table 12.1. 
 
 
 

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Table 12.1: Sample size and power estimation for primary and key secondary 
immunogenicity objectives.  
 
Key 
Immunogenicity 
Objective 
Age group 
Evaluable N  
in the PPAS 
Estimation/Margin 
Power 
(%) 
Primary 
Objective 
Pediatric Subjects 
(Cohort[C] 1) 
VRVg-2: 261 
Verorab: 88 
Seroconversion (SC) rate 
at D42: 99.0% 
NI margin: -5% 
 
95.4a 
VRVg-2: 261 
Imovax Rabies: 88 
Same as above 
95.4 a 
Adult Subjects 
(C1) 
VRVg-2: 243 
Verorab: 81 
Same as above 
93.8 a 
VRVg-2: 243 
Imovax Rabies: 81 
Same as above 
93.8 a 
Overall: 80.0 a 
Key Secondary Objectives 
#1 
Overall 
(Pooled Pediatric and 
Adult Subjects in C1) 
VRVg-2: 504 
Sufficiency threshold:  
SC rate at D42 ≥99.0%, 
with lower limit (LL) of 
95%CI ≥97.0% 
86.3 b 
#2 
Pediatric Subjects 
(C1) 
VRVg-2: 261 
Verorab: 88 
SC rate at D28: 99.0% 
NI margin: -5% 
95.4 a 
VRVg-2: 261 
Imovax Rabies: 88 
Same as above 
95.4 a 
Adult Subjects 
(Pooled C1+C2) 
VRVg-2: 570 
Verorab: 190 
SC rate at D28: 96.5% 
NI margin: -5% 
93.8 a 
VRVg-2: 570 
Imovax Rabies: 190 
Same as above 
93.8 a 
Overall: 80.1 a 
#3 
Pediatric Subjects 
(C1) 
VRVg-2 at D28: 261 
Imovax Rabies at D42: 88 
SC rate at D28: 99.0% 
SC rate at D42: 99.0% 
NI margin: -10% 
>99.9 a 
Adult Subjects 
(D28 from Pooled 
C1+C2, D42 from C1) 
VRVg-2 at D28 (Pooled 
Cohort 1+ Cohort 2): 570 
Imovax Rabies at D42: 81 
SC rate at D28: 96.5% 
SC rate at D42: 99.0%NI 
margin: -10% 
>99.9 a 
Overall: >99.9 a 
#4 
Overall  
(Pooled Pediatric and 
Adult Subjects in 
Pooled C1 and C2)  
VRVg-2: 831 
Sufficiency threshold:  
SC rate at D42 ≥99.0%, 
with LL of 95%CI 
≥97.0% 
98.9 b 
#5 
Overall (Pooled 
Pediatric and Adult 
Subjects in C1 only) 
Imovax Rabies at D28: 168 
Imovax Rabies at D42: 168 
SC rate at D28: 96.5% 
SC rate at D42: 99.0% 
NI margin: -10% 
90.0 c 
a Power calculated using Farrington and Manning (FM) method. 
b Power calculated using Binomial Exact method. 

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c Power calculated using simulation (10000 times, assuming correction coefficient [Rho]=0.5), based on general 
linear model (GLM) for repeated measured data with categorical response under binomial distribution (link 
function=identify).  
12.5.2 Booster Phase  
A subset of 170 adults in Primary Series Cohort 1 who received the 3-dose PrEP regimen in the 
primary series will be included in the booster phase in M12 of the study; having 102 subjects 
receiving the complete 3 doses regimen schedule with VRVg-2 (primary series + booster) and 
170 subjects receiving VRVg-2 as a booster (regardless the vaccine received in the primary 
series) in the FASB will provide the following level of precision around the expected percentage 
of subjects with an RVNA titer ≥ 0.5 IU/mL at D14 after the booster vaccination at M12: 
 
Number of 
subjects with 
RVNA titer 
≥ 0.5 IU/mL on 
M12+D14 
FASB1 – VRVg-2 group (N=102) 
Number of 
subjects with 
RVNA titer 
≥ 0.5 IU/mL on 
M12+D14 
FASB1 (N=170) 
% observed 
95% CI 
% observed 
95% CI 
102 
100.0 
(96.45 – 100) 
170 
100.0 
(97.85 – 100) 
101 
99.0 
(94.66 – 99.98) 
169 
99.4 
(96.77 – 99.99) 
100 
98.0 
(93.1 – 99.76) 
168 
98.8 
(95.81 – 99.86) 
99 
97.1 
(91.64 – 99.39) 
167 
98.2 
(94.93 – 99.63) 
98 
96.1 
(90.26 – 98.92) 
166 
97.6 
(94.09 – 99.36) 
Note: The 95% CI for the single proportion is calculated using the exact binomial method (Clopper Pearson method), quoted by 
Newcombe (70). 
A subset of 230 adults who received the one week 2-dose PrEP regimen will be included in the 
Immunogenicity Persistence and Booster Phase Cohort 2. Assuming approximate 15% of subjects 
will not be evaluable in the FASB for booster evaluation at M24 up to M36, having 117 evaluable 
subjects receiving the complete 2 doses regimen schedule with VRVg-2 (primary series + booster) 
and 195 evaluable subjects receiving VRVg-2 as a booster (regardless the vaccine received in the 
primary series) will provide the following level of precision around the expected percentage of 
subjects with an RVNA titer ≥ 0.5 IU/mL at D14 after the booster vaccination at M24 up to M36: 
 

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Number of 
subjects with 
RVNA titer 
≥ 0.5 IU/mL on 
M24 up to 
M36+D14 
FASB2 – VRVg-2 group (N=117) 
Number of 
subjects with 
RVNA titer 
≥ 0.5 IU/mL on 
M24 up to 
M36+D14 
FASB2 (N=195) 
% observed 
95% CI 
% observed 
95% CI 
117 
100.00 
(96.90; 100) 
195 
100.00 
(98.13; 100) 
116 
99.15 
(95.33; 99.98) 
194 
99.49 
(97.18; 99.99) 
115 
98.29 
(93.96; 99.79) 
193 
98.97 
(96.34; 99.88) 
114 
97.44 
(92.69; 99.47) 
192 
98.46 
(95.57; 99.68) 
113 
96.58 
(91.48; 99.06) 
191 
97.95 
(94.83; 99.44) 
Note: The 95% CI for the single proportion is calculated using the exact binomial method (Clopper Pearson method), quoted by 
Newcombe (70). 
13 
Ethical and Legal Issues and Investigator/ Sponsor Responsibilities  
13.1 Ethical Conduct of the Study/ Good Clinical Practice  
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and/ or national 
regulations and directives. 
13.2 Source Data and Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, informed consent/ AFs, telephone contact logs, and worksheets. The purpose of study 
source documents is to document the existence of subjects and to substantiate the integrity of the 
study data collected. Investigators must maintain source documents so that they are accurate, 
complete, legible, and up to date. 
For missing or discrepant data on a DC, the blinded study coordinator will obtain verbal 
clarification from the subject, enter the response into the “Investigator’s comment” page of the 
DC, and transfer the information to the CRB. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the study, regardless of the outcome. 

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13.3 Confidentiality of Data and Access to Subject Records  
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality 
agreement with Sanofi Pasteur. In the event a subject’s medical records are not at the 
investigational site, it is the responsibility of the Investigator to obtain those records if needed. 
All personal data collected related to subjects, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the Global Data Protection Regulation. Data collected 
must be adequate, relevant and not excessive, in relation to the purposes for which they are 
collected. Each category of data must be properly justified and in line with the study objective. 
Subject’s race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (72) (see Section 12.1.3). 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the subjects, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
13.4 Monitoring, Auditing, and Archiving  
13.4.1 Monitoring  
Before the start of the study (ie, before the inclusion of the 1st subject), the Investigators and the 
Sponsor’s staff or a representative will meet at the site-initiation visit to discuss the study protocol 
and the detailed study procedures. Emphasis will be placed on inclusion and exclusion criteria, 
visit timing, safety procedures, informed consent procedures, SAE reporting procedures, CRB 
completion, and the handling of samples and products. The Sponsor’s staff or a representative will 
ensure and document that all material to be used during the study has been received at the site; 
and that the study Investigator team and local Sponsor/delegate staff have been properly informed 
about the study, GCP and regulatory requirements, and the Sponsor’s procedures. Specific 
training sessions for the study Investigator team and the CRAs on these topics may be performed 
as necessary and should be documented. 
The following instruction manuals will be provided: the CRF Completion Instructions for entering 
data into the CRB, and the Operating Guidelines for detailed study procedures such as the product 
management and sample-handling procedures. 

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

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Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the study will be kept by the Sponsor in the TMF. Data on AEs are included 
in the TMF. All data and documents will be made available if requested by relevant authorities. 
13.5 Financial Contract and Insurance Coverage  
A Clinical Study Agreement will be signed by all the parties involved in the study’s performance, 
if relevant. The Sponsor has an insurance policy to cover any liabilities that may arise from use of 
the product and/ or the study protocol. 
13.6 Stipends for Participation  
Expenses that are directly related to the subject’s participation in the study (for example cost of 
transportation for attending visits) will be compensated. Subjects/parents/legal representatives 
will not receive any remuneration for participation in the study. 
13.7 Publication Policy  
Data derived from this study are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the study must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the study, any participating center may 
publish or otherwise use its own data provided that any publication of data from the study gives 
recognition to the study group. In addition, Sanofi Pasteur shall be offered an association with all 
such publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study at least 90 days prior to submission for publication / 
presentation. Any information identified by Sanofi Pasteur as confidential must be deleted prior to 
submission, it being understood that the results of this study are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 

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