Immunogenicity and Safety of the First-in-Human SARS-CoV-2 mRNA Vaccine Formulation in Healthy Adults 18 Years of Age and Older
Phase: PHASE1
Conditions: COVID-19
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
Immunogenicity and Safety of the First-in-Human SARS-CoV-2 mRNA Vaccine Formulation in 
Healthy Adults 18 Years of Age and Older 
Study Code: VAW00001 
Protocol Version Number: 3.0 
Amendment Number: 1.0 
Compound: SARS-CoV-2 mRNA vaccine: ultra-low-dose (
 µg), low-dose (
 µg), or 
medium-dose (
 µg) 
Study Phase: Phase I/II 
Short Title: 
Study of mRNA Vaccine Formulation against COVID-19 in Healthy Adults 18 Years of Age and 
Older 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Manufacturer: 
Translate Bio 
29 Hartwell Ave, Lexington, MA 02421, USA 
Regulatory Agency Identifier Number(s): 
BB-IND: 26788 
WHO UTN: U1111-1251-5486
ClinicalTrials.gov: NCT04798027 
Approval Date: 08 April 2021 
Medical Monitor Name and Contact Information are provided in the Operating Guidelines. 
The study centers, the Investigators at each center, and the Coordinating Investigator are listed in 
a separate document. 
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Document History and Protocol Amendment Rationale 
 
Previous 
Version 
Date 
Comments 
1.0 
14 October 2020 
Original study design submitted to IRB for review. 
2.0 
02 February 2021 
First version used in the study 
IRB: Institutional Review Board 
* Version in bold font has been approved by the IEC(s) / IRB(s) and used in the study. 
Overall Rationale for the Amendment: 
Background 
In the original protocol, the first 15 participants to receive the SARS-CoV-2 mRNA vaccine were 
to be enrolled in a Safety Sentinel Cohort. These participants were to receive 2 injections of the 
study intervention, 21 days apart, in an open-label, dose-escalation manner. Five participants were 
to be enrolled in each of the 3 dose-level groups 
 
). 
As planned in the original protocol, 5 participants were assigned to the low dose-level of 
 μg, 
received their first injection, and were contacted by telephone on Day (D)03 to document local 
and systemic solicited reactions as well as unsolicited adverse events (AEs).
 
 
 
  
Further considerations of the safety data from the 5 participants assigned to the low-dose level 
group revealed the transient nature of the reported solicited Grade 3 adverse events. Given the fact 
that these AEs were self-limited (ie, no subject sought any medical attention) and no major safety 
concerns were identified, the Sponsor introduced 4 changes through a protocol amendment: 
1) add an “ultra-low-dose” arm of 
 µg
 
to evaluate 
 
 a lower dose-level range (ie, ultra-low- [
 µg], low- [
 µg], and 
medium- [
 µg] dose-levels); 
 
. 
2) increase the number of Sentinel Cohort participants from 5 to 10 in the dose-level groups that 
have yet to start enrollment (ie, ultra-low- and medium-dose-levels);  
3) add an expansion of the open-label Sentinel Cohort for the 
 µg dose-level to better 
understand the reactogenicity at this dose-level in a larger group of participants prior to 
escalation to the 
 µg dose. This possibility to expand the number of Sentinel Cohort 
participants will also be extended to the ultra-low- and medium-dose groups if needed; 
4) decrease the number of placebo recipients in the Full Enrollment Cohort. 
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Change 1: Introduction of an ultra-low-dose group 
 
 The introduction of an 
ultra-low-dose-level group is supported by preclinical immunogenicity data at  µg dose-level 
which is provided with the Investigator’s Brochure amendment. The initial Sentinel Cohort for 
this ultra-low-dose will include 10 participants with the option for an Expanded Sentinel Cohort if 
needed (as described below in Change 3). 
Change 2: Increase the number of Sentinel Cohort participants  
The number of Sentinel Cohort participants for both the ultra-low- (
 µg) and medium-dose 
(
 µg) groups will be increased from 5 to 10. This will help make a more comprehensive 
assessment of the safety and reactogenicity for each of these dose-level groups before study 
progression. 
Change 3: Expansion of the Sentinel Cohort 
The Sponsor decided to amend the protocol in order to add an Expanded Sentinel Cohort for the 
 µg dose-level and to introduce the option to expand the Safety Sentinel Cohort, if needed, for 
each of the remaining dose levels. The Expanded Sentinel Cohort for a corresponding dose-level 
may be triggered only after careful assessment of the Initial Sentinel Cohort for the frequency, 
severity, and duration of adverse events and proceed if there are no major safety concerns and the 
SMT judges that further data is needed to cautiously characterize the safety and reactogenicity of 
the vaccine at a given dose-level prior to triggering study progression decisions (within the same 
dose-level arm, or in relation to progression to other dose-levels). In case an Expanded Sentinel 
Cohort (15-20 participants) is initiated after the Initial Sentinel Cohort (5-10 participants) for a 
particular dose level, this will bring the total number of participants for that dose-level group to 
approximately 25 participants. The Expanded Sentinel Cohort will proceed in a similar manner to 
the Initial Sentinel Cohort using the same monitoring parameters and safety assessments. The 
D01-03 safety data for the Expanded Sentinel Cohort participants in that dose-level group will be 
reviewed by the Sponsor’s SMT.  
If no safety concern is identified for the 
 μg Expanded Sentinel Cohort, then the Initial Sentinel 
Cohort participants for the 
 μg group will be vaccinated. If the Expanded Sentinel Cohort for 
the 
 µg or 
 µg dose-level is triggered, the SMT assessment of safety and reactogenicity will 
help decide if further vaccinations for the corresponding dose-level will proceed. 
Change 4: Decrease the number of placebo recipients in the Full Enrollment Cohort 
In both age strata (ie, 18-49 years and ≥ 50 years), the number of participants in the placebo arm 
of the Full Enrollment Cohort has been decreased to half the number of participants in each of the 
vaccine arm. This will help decreasing the risk of exposing higher number of participants to 
placebo in the setting of Emergency Use Authorization vaccine rollout and expanding eligibility 
for vaccines. 
Summary 
Progression to the Full Enrollment Cohort for all eligible dose-levels will occur following the 
Complete Sentinel Early Safety Data Review (CS-ESDR) with evaluation of safety data up to D09 
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post first vaccination in all Sentinel Cohorts participants (ie, in all Initial and triggered Expanded 
Sentinel Cohorts). The open-label Sentinel Cohort will be followed by a randomized, modified 
double-blind, placebo-controlled Full Enrollment Cohort to evaluate the safety and 
immunogenicity of the formulations of the SARS-CoV-2 mRNA vaccine in healthy adult 
participants (18 years of age and older) in the United States (US) and Honduras. 
 
 
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Table of Contents 
Document History and Protocol Amendment Rationale ............................................................. 2 
List of Tables .................................................................................................................................... 9 
List of Figures ................................................................................................................................ 10 
1 
Protocol Summary ........................................................................................................... 11 
1.1 
Synopsis .......................................................................................................................... 11 
1.2 
Schema ............................................................................................................................ 20 
1.3 
Schedule of Activities (SoA) .......................................................................................... 23 
2 
Introduction ..................................................................................................................... 44 
2.1 
Study Rationale ............................................................................................................... 45 
2.2 
Background ..................................................................................................................... 46 
2.3 
Benefit/Risk Assessment ................................................................................................ 47 
2.3.1 
Risks from Study Participation ..................................................................................... 49 
2.3.2 
Benefits from Study Participation ................................................................................ 51 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 51 
3 
Objectives and Endpoints ............................................................................................... 51 
4 
Study Design .................................................................................................................... 55 
4.1 
Overall Design ................................................................................................................ 55 
4.2 
Scientific Rationale for Study Design ............................................................................. 61 
4.3 
Justification for Dose ...................................................................................................... 66 
4.4 
End of Study Definition .................................................................................................. 67 
5 
Study Population ............................................................................................................. 67 
5.1 
Inclusion Criteria ............................................................................................................ 68 
5.1.1 
Inclusion Criteria to be Checked at Screening Visit ..................................................... 68 
5.1.2 
Inclusion Criteria to be Checked at Visit 1 ................................................................... 68 
5.2 
Exclusion Criteria ........................................................................................................... 69 
5.2.1 
Exclusion Criteria to be Checked at Screening Visit ................................................... 69 
5.2.2 
Exclusion Criteria to be Checked at Visit 1 ................................................................. 71 
5.3 
Lifestyle Considerations ................................................................................................. 73 
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5.4 
Screen Failures ................................................................................................................ 73 
6 
Study Intervention ........................................................................................................... 74 
6.1 
Study Interventions Administered .................................................................................. 74 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 77 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 77 
6.3.1 
Randomization and Allocation Procedures .................................................................. 77 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 78 
6.4 
Study Intervention Compliance ...................................................................................... 80 
6.5 
Concomitant Therapy ...................................................................................................... 80 
6.5.1 
Rescue Medicine ........................................................................................................... 81 
6.6 
Dose Modification .......................................................................................................... 81 
6.7 
Intervention After the End of the Study .......................................................................... 81 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 81 
7.1 
Discontinuation of Study Intervention ............................................................................ 81 
7.1.1 
Temporary Contraindications ....................................................................................... 81 
7.1.2 
Definitive Contraindications ......................................................................................... 82 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 82 
7.3 
Lost to Follow-up ............................................................................................................ 83 
8 
Study Assessments and Procedures ............................................................................... 84 
8.1 
Baseline Screening for SARS-CoV-2 Antibodies .......................................................... 86 
8.2 
Immunogenicity and Efficacy Assessments ................................................................... 86 
8.2.1 
Immunogenicity Assessments ...................................................................................... 86 
8.2.1.1 
Primary Immunogenicity Assay ................................................................................. 86 
8.2.1.2 
Additional Immunogenicity Assays ........................................................................... 87 
8.2.2 
Efficacy Assessments ................................................................................................... 88 
8.2.2.1 
Definitions .................................................................................................................. 88 
8.2.2.2 
COVID-19-like Illness Surveillance .......................................................................... 90 
8.2.2.3 
ELECSYS Anti-SARS-CoV-2 ECLIA ...................................................................... 91 
8.2.2.4 
Nucleic Acid Amplification Test (NAAT) for COVID-19 Case Detection ............... 91 
8.3 
Safety Assessments ......................................................................................................... 92 
8.3.1 
Medical History ............................................................................................................ 92 
8.3.2 
Physical Examinations .................................................................................................. 92 
8.3.3 
Vital Signs .................................................................................................................... 92 
8.3.4 
Clinical Safety Laboratory Assessments ...................................................................... 92 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 93 
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8.4.1 
Sentinel Cohort ............................................................................................................. 93 
8.4.2 
Early Safety Data Review ............................................................................................. 95 
8.4.3 
Halting Rules for Entire Study ..................................................................................... 96 
8.4.4 
Time Period and Frequency for Collecting AE and SAE Information ......................... 97 
8.4.5 
Method of Detecting AEs and SAEs ............................................................................ 98 
8.4.6 
Follow-up of AEs and SAEs ........................................................................................ 98 
8.4.7 
Regulatory Reporting Requirements for SAEs ............................................................ 99 
8.4.8 
Pregnancy ..................................................................................................................... 99 
8.4.9 
Adverse Events of Special Interest ............................................................................... 99 
8.4.10 
Medically Attended Adverse Events .......................................................................... 100 
8.5 
Treatment of Overdose ................................................................................................. 100 
8.6 
Pharmacokinetics .......................................................................................................... 100 
8.7 
Pharmacodynamics ....................................................................................................... 100 
8.8 
Genetics ......................................................................................................................... 100 
8.9 
Biomarkers .................................................................................................................... 100 
8.10 
Immunogenicity Assessments ....................................................................................... 101 
8.11 
Medical Resource Utilization and Health Economics .................................................. 101 
9 
Statistical Considerations ............................................................................................. 101 
9.1 
Statistical Hypotheses ................................................................................................... 101 
9.2 
Sample Size Determination ........................................................................................... 101 
9.3 
Populations for Analyses .............................................................................................. 101 
9.4 
Statistical Analyses ....................................................................................................... 102 
9.4.1 
General Considerations ............................................................................................... 103 
9.4.2 
Primary Endpoints ...................................................................................................... 103 
9.4.2.1 
Immunogenicity ....................................................................................................... 103 
9.4.2.2 
Safety ........................................................................................................................ 103 
9.4.3 
Secondary Endpoints .................................................................................................. 103 
9.4.3.1 
Immunogenicity ....................................................................................................... 103 
9.4.3.2 
Efficacy .................................................................................................................... 104 
9.4.4 
Exploratory Endpoints ................................................................................................ 104 
9.4.4.1 
Immunogenicity ....................................................................................................... 104 
9.5 
Interim Analyses ........................................................................................................... 105 
9.6 
Data Monitoring Committee (DMC) ............................................................................ 106 
10 
Supporting Documentation and Operational Considerations .................................. 106 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations .......................... 106 
10.1.1 
Regulatory and Ethical Considerations ...................................................................... 106 
10.1.2 
Financial Disclosure ................................................................................................... 107 
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10.1.3 
Informed Consent Process .......................................................................................... 107 
10.1.4 
Data Protection and Future Use of Stored Samples ................................................... 108 
10.1.5 
Committees Structure ................................................................................................. 109 
10.1.6 
Dissemination of Clinical Study Data ........................................................................ 109 
10.1.7 
Data Quality Assurance .............................................................................................. 109 
10.1.8 
Source Documents ...................................................................................................... 110 
10.1.9 
Study and Site Start and Closure ................................................................................ 110 
10.1.10 
Publication Policy ....................................................................................................... 111 
10.2 
Appendix: Clinical Laboratory Tests ............................................................................ 111 
10.3 
Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .......................................................................... 114 
10.3.1 
Definition of AE ......................................................................................................... 114 
10.3.2 
Definition of SAE ....................................................................................................... 116 
10.3.3 
Recording and Follow-Up of AE and/or SAE ............................................................ 118 
10.3.4 
Reporting of SAEs ...................................................................................................... 120 
10.3.5 
Assessment of Intensity .............................................................................................. 121 
10.3.5.1 
Tables for Clinical Abnormalities ............................................................................ 121 
10.3.5.1.1 
Solicited AR Intensity Grading Scale .................................................................... 121 
10.3.5.1.2 
Unsolicited AE Intensity Grading Scale ................................................................ 127 
10.3.5.2 
Tables for Laboratory Abnormalities ....................................................................... 127 
10.4 
Appendix: Collection of Pregnancy Information .......................................................... 130 
10.5 
Appendix: AESIs .......................................................................................................... 132 
10.6 
Appendix: Risk-based Approach .................................................................................. 133 
10.7 
Appendix: Abbreviations .............................................................................................. 134 
11 
References ...................................................................................................................... 137 
12 
Sponsor Signature Page ................................................................................................ 140 
 
 
 
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List of Tables 
Table 1.1: Planned sample size (Sentinel Cohort; 18 through 49 years) ....................................... 16 
Table 1.2: Planned sample size (Full Enrollment Cohort) ............................................................ 17 
Table 1.3: Schedule of activities 1 (Sentinel Cohort, Initial and Expanded) ................................ 24 
Table 1.4: Schedule of activities 2 (Cohort 1 of Full Enrollment Cohort) .................................... 31 
Table 1.5: Schedule of activities 3 (Cohort 2 of Full Enrollment Cohort) .................................... 37 
Table 1.6: Schedule of activities 4 (Follow-up of COVID-19-like illness) .................................. 43 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 49 
Table 3.1: Objectives and endpoints ............................................................................................. 51 
Table 4.1: Overall design .............................................................................................................. 55 
Table 4.2: Planned sample size (Sentinel Cohort; 18 through 49 years) ....................................... 59 
Table 4.3: Full Enrollment Cohort - planned sample size ............................................................. 59 
Table 6.1: Identity of study interventions ...................................................................................... 75 
Table 8.1: Blood sampling volume per visit ................................................................................. 85 
Table 8.2: COVID-19-like illness symptoms: CRF and Diary Card/Memory Aid terms ............. 89 
Table 10.1: Protocol-required safety laboratory assessments ..................................................... 112 
Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales ..... 122 
Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales ........... 124 
Table 10.4: Intensity thresholds for laboratory abnormalities ..................................................... 128 
 
 
 
 
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List of Figures 
Figure 1.1: Graphical study design (Sentinel Cohort; Initial and Expanded) ............................... 21 
Figure 1.2: Graphical study design (Cohort 1 of Full Enrollment Cohort) ................................... 21 
Figure 1.3: Graphical study design (Cohort 2 of Full Enrollment Cohort) ................................... 22 
Figure 1.4: Previous Graphical design for Sentinel Cohort dose-escalation and Early Safety 
Data Review (Original Protocol version 2.0) ................................................................................ 22 
Figure 1.5: Current Graphical design for Sentinel Cohort ............................................................ 23 
 
 
 
 
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1 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
Immunogenicity and Safety of the First-in-Human SARS-CoV-2 mRNA Vaccine Formulation in 
Healthy Adults 18 Years of Age and Older 
Short Title: 
Study of mRNA Vaccine Formulation Against COVID-19 in Healthy Adults 18 Years of Age and 
Older 
Rationale: 
An outbreak of severe respiratory illnesses in Wuhan City, Hubei Province, China in 
December 2019 heralded the appearance of a novel coronavirus, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), in the human population. The rapid escalation of the 
outbreak led to a declaration by the World Health Organization on 20 January 2020 of a Public 
Health Emergency of International Concern, followed by a declaration on 11 March 2020 of a 
pandemic (1). As of 2 April 2021, the virus has been detected in 192 countries/regions and 
infected over 129 million individuals (2). Despite unprecedented measures of isolation, 
quarantine, social distancing, community containment, use of face covers/masks in public to curb 
the spread of the virus, and most recently, the emergency use authorization of SARS-CoV-2 
vaccines in the US and other locally approved/authorized SARS-CoV-2 vaccines, the global 
burden of SARS-CoV-2 infections and associated disease continue to grow steadily, highlighting 
the urgent need for safe and effective vaccines to meet the global need. 
The candidate vaccine is developed by Sanofi Pasteur in collaboration with Translate Bio using 
messenger ribonucleic acid (mRNA) technology and will be manufactured by Translate Bio. The 
mRNA encodes the full-length spike (S) protein from SARS-CoV-2, with 2 sets of mutations to 
stabilize the prefusion conformation of the protein. The mRNA is encapsulated within a novel 
lipid nanoparticle (LNP) vehicle 
. 
VAW00001 is a first-in-human Phase I/II multi-center study. The original study design comprised 
2 sequential cohorts: a lead-in open-label, dose-escalation Sentinel Cohort, followed by a 
randomized, modified double-blind, dose-ranging, placebo-controlled Full Enrollment Cohort, to 
evaluate the safety and immunogenicity of the SARS-CoV-2 mRNA vaccine in healthy adult 
participants (18 years of age and older) in the United States (US) and Honduras. The study was to 
evaluate both 1 injection (Cohort 1) and 2 injections, given 21 days apart (Sentinel Cohort and 
Cohort 2) for 3 different dose-levels 
 of the candidate 
mRNA vaccine with the goal of selecting the optimal dose and schedule to proceed to a Phase III 
study. 
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After careful assessment of the safety data from the 5 participants assigned to the low-dose level 
group for the frequency, severity, and duration of adverse events, the Sponsor decided to amend 
the study protocol. This protocol amendment adds an “ultra-low-dose” arm of 
 µg
 
 It 
also increases the number of Sentinel Cohort participants in both the ultra-low- (
 µg) and 
medium-dose (
 µg) groups from 5 to 10. Lastly, it introduces the possibility to expand any of 
the 3 dose-level groups of the Sentinel Cohort to further assess the D01-D03 safety data of the 
corresponding dose-level group. This option will be exercised for the low-dose group and remains 
as a possibility for the ultra-low- and medium-dose groups. With addition of an Expanded 
Sentinel Cohort, the Sentinel Cohort for each dose-level group could potentially include a total of 
approximately 25 participants. 
The longer-term objective remains to longitudinally define the safety and durability of the 
immune response induced by the SARS-CoV-2 mRNA vaccine over the 1-year study duration. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Safety 
To describe the safety profile of all participants in 
each age group and each study intervention group 
up to 12 months post-last dose. 
 
Safety 
• 
Presence of unsolicited systemic adverse 
events (AEs) reported in the 30 minutes after 
each injection 
• 
Presence of solicited injection site reactions 
and systemic reactions (pre-listed in the 
participant’s Diary Card [DC] and Case Report 
Form [CRF]) occurring up to 7 days after each 
injection 
• 
Presence of unsolicited AEs reported up to 
21 days after each injection 
• 
Presence of medically attended adverse events 
(MAAEs) throughout the study 
• 
Presence of serious adverse events (SAEs) and 
adverse events of special interest (AESIs) 
throughout the study 
• 
Presence of out-of-range biological test results 
up to 8 days post-last dose (ie, up to 
Day [D] 09 for Cohort 1 and up to D30 for 
Sentinel Cohort and Cohort 2) 
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Objectives 
Endpoints 
Immunogenicity 
To describe the neutralizing antibody profile at 
D01, D22, and D36 of each study intervention 
group. 
Immunogenicity 
Neutralizing antibody titers against the SARS-
CoV-2 D614G variant will be measured with the 
neutralization assay 
• 
Antibody titer at D01, D22, and D36 
• 
Fold-rise (fold-rise in serum antibody 
neutralization titer post-vaccination relative to 
D01) at D22, and D36 
• 
2-fold and 4-fold-rise in serum neutralization 
titer (post/pre) relative to D01 at D22, and 
D36 
• 
Occurrence of neutralizing antibody 
seroconversion defined as baseline values 
below lower limit of quantification (LLOQ) 
with detectable neutralization titer above assay 
LLOQ at D22 and D36 
Secondary  
 
Immunogenicity 
1) To describe binding antibody profile at D01, 
D22, D36, D91 (Cohort 1) or D112 (Sentinel 
Cohort and Cohort 2), D181 (Cohort 1) or 
D202 (Sentinel Cohort and Cohort 2), and 
D366 (Cohort 1) or D387 (Sentinel Cohort and 
Cohort 2) of each study intervention group. 
2) To describe the neutralizing antibody profile at 
D91 (Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2), D181 (Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 (Cohort 1) or 
D387 (Sentinel Cohort and Cohort 2) of each 
study intervention group. 
Immunogenicity 
Binding antibody titers to trimerized SARS-CoV-2 
S protein will be measured for each study 
intervention group with the enzyme-linked 
immunosorbent assay method 
• 
Individual anti-S antibody concentration at 
D01, D22, D36, D91 (Cohort 1) or D112 
(Sentinel Cohort and Cohort 2), D181 (Cohort 
1) or D202 (Sentinel Cohort and Cohort 2), 
and D366 (Cohort 1) or D387 (Sentinel 
Cohort and Cohort 2) 
• 
Individual anti-S antibody concentration ratio 
(fold-rise in serum ELISA concentration 
post-vaccination relative to D01) at D22, D36, 
D91 (Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2), D181 (Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 (Cohort 1) or 
D387 (Sentinel Cohort and Cohort 2) 
• 
Fold-rise in anti-S antibody concentration 
(post/pre) ≥ 2 and ≥ 4 at D22, D36, D91 
(Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2 ), D181 (Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 (Cohort 1) or 
D387 (Sentinel Cohort and Cohort 2) 
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Objectives 
Endpoints 
Neutralizing antibody titers against the SARS-
CoV-2 D614G variant will be measured with the 
neutralization assay 
• 
Antibody titer at D91 (Cohort 1) or D112 
(Sentinel Cohort and Cohort 2), D181 (Cohort 
1) or D202 (Sentinel Cohort and Cohort 2), 
and D366 (Cohort 1) or D387 (Sentinel 
Cohort and Cohort 2) 
• 
Fold-rise (fold-rise in serum neutralization 
titer post-vaccination relative to D01) at D91 
(Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2), D181 (Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 (Cohort 1) or 
D387 (Sentinel Cohort and Cohort 2)  
• 
2-fold and 4-fold-rise in serum neutralization 
titer (post/pre) relative to D01 at D91 (Cohort 
1) or D112 (Sentinel Cohort and Cohort 2 
D181 (Cohort 1) or D202 (Sentinel Cohort 
and Cohort 2), and D366 (Cohort 1) or D387 
(Sentinel Cohort and Cohort 2) 
• 
Occurrence of neutralizing antibody 
seroconversion, defined as values below 
LLOQ at baseline with detectable 
neutralization titer above assay LLOQ at D91 
(Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2), D181 (Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 (Cohort 1) or 
D387 (Sentinel Cohort and Cohort 2) 
Efficacy 
1) To describe the occurrence of 
virologically-confirmed COVID-19-like illness 
and serologically-confirmed SARS-CoV-2 
infection. 
2) To evaluate the correlation/association 
between antibody responses to SARS-CoV-2 
mRNA vaccine and the risk of 
virologically-confirmed COVID-19-like illness 
and/or serologically-confirmed SARS-CoV-2 
infection. 
Efficacy 
• 
Virologically-confirmed COVID-19-like 
illness as defined by specified clinical 
symptoms and signs and confirmed by a 
positive result for SARS-CoV-2 nucleic acid 
viral detection assay 
• 
Serologically-confirmed SARS-CoV-2 
infection as defined by SARS-CoV-2 
Nucleoprotein specific antibody detection 
immunoassay  
• 
Correlates of risk/protection based on 
antibody responses to SARS-CoV-2 as 
evaluated using virus neutralization or ELISA, 
considering virologically-confirmed 
COVID-19-like illness and/or 
serologically-confirmed SARS-CoV-2 
infection as defined above 
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Overall Design 
Type of design 
Phase I/II, first-in-human, multi-center, safety and immunogenicity 
study comprised of 2 sequential cohorts: 
• 
Lead-in, open-label, Sentinel Cohort (initial target of 
25 participants), with Complete Sentinel Early Safety Data 
Reviews (CS-ESDRs) 
In case an alert threshold is met in a dose-level group, the 
Sentinel Cohort for the corresponding dose-level group could 
be expanded to reach a total of approximately 25 participants 
• 
Randomized, modified double-blind, placebo-controlled Full 
Enrollment Cohort (initial target of 308 participants, but actual 
number could be lower as it will be determined by dose-levels 
progressing after CS-ESDR). Includes Cohort 1 and Cohort 2. 
Phase 
I/II 
Control method 
• 
Open-label, without placebo group for Sentinel Cohort 
• 
Placebo-controlled for Full Enrollment Cohort 
Study population 
Healthy, adults 18 years of age and older without prior serologic 
evidence of SARS-CoV-2 infection 
Countries 
United States, Honduras 
Level and method of blinding 
For Sentinel Cohort 
• 
Open-label without blinding of participants, site Investigators 
and staff, and Sponsor  
• 
No blinding for injection schedule as all participants will 
receive 2 vaccinations 
For Full Enrollment Cohort 
• 
Blinding for study intervention assignment (formulation): 
participants, outcome assessors, Investigators, laboratory 
personnel, Sponsor study staff  
• 
No blinding for injection schedule 
• 
Only study site staff who prepare and administer the vaccine 
and are not involved with the safety evaluations will be 
unblinded to study intervention assignment  
Study intervention assignment 
method 
Sentinel Cohort: sequentially assigned study intervention; 
Full Enrollment Cohort: randomization for study intervention and 
assigned stratification by age 
Disclosure Statement: 
This is a sequential group prevention study, stratified into 2 age groups based on age at 
enrollment: the younger adult age group (18-49 years) and the older adult age group (≥ 50 years). 
There will be up to 3 arms in the Sentinel Cohort followed by up to 8 arms in the Full Enrollment 
Cohort. The study will be done in an open-label fashion for the Sentinel Cohort and in a double-
blind manner for the Full Enrollment Cohort. 
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Number of Participants: 
The study targets enrollment of approximately 333 participants 18 years of age and older 
(165 adults 18 through 49 years of age and 168 adults 50 years of age and older), without 
evidence of previous SARS-CoV-2 infection. This number includes all 25 Initial Sentinel Cohort 
participants and all 308 Full Enrollment Cohort participants (see Table 1.1 and Table 1.2). 
However, the actual number of participants enrolled will depend on which dose-level are allowed 
to be evaluated in the Sentinel Cohort and the Full Enrollment Cohort. The number of participants 
may be higher if Expanded Sentinel Cohorts are exercised for all 3 dose-levels, and if all dose-
levels progress to the Full Enrollment Cohort (maximum number of study participants 
approximately 383); conversely, the number may be lower if not all the dose-levels are evaluated 
in the Sentinel Cohort or/and not all the dose-levels progress to the Full Enrollment Cohort.  
The study population to be enrolled will be comprised of 2 sequential cohorts: the Sentinel Cohort 
(initial target of 25 participants [younger adults only]. For each dose-level in the Sentinel Cohort, 
there is an option to expand the group with the inclusion of an additional 15 or 20 participants, 
depending on the number of participants initially enrolled in that dose-level group. Hence, the 
entire Sentinel Cohort could include approximately 75 participants, with approximately 
25 participants per each dose-level group. Following the assessment of the Sentinel Cohort, the 
Full Enrollment Cohort will be initiated (initial target of maximum 308 participants; the actual 
number will be determined by dose-levels progressing after the first Complete Sentinel ESDR [ie, 
CS-ESDR-1]). 
Intervention Groups and Duration: 
The Initial Sentinel Cohort participants will be 18 through 49 years of age and will be assigned to 
receive 2 injections of the study intervention, 21 days apart, in an open-label manner. Clinical 
safety laboratory evaluations will be performed at screening and 8 days after each injection. The 
number of participants to be enrolled in each dose-level group, with and without the possible 
expansion, are shown below in Table 1.1. 
Table 1.1: Planned sample size (Sentinel Cohort; 18 through 49 years) 
Cohort 
Group 
Dose-level* 
Initial 
Sentinel 
Cohort 
N 
Expanded 
Sentinel 
Cohort† 
N 
Total Sentinel 
Cohort 
N 
Sentinel 
Cohort: 
2 injections 
1 
 µg 
10 
15 
25 
2 
 µg 
5 
20 
25 
3 
 µg 
10 
15 
25 
* Formulation: SARS-CoV-2 mRNA: ultra-low-dose (
 µg); low-dose (
 µg); medium-dose (
 µg). 
† The Expanded Sentinel Cohort for a corresponding dose-level may be triggered only after careful assessment of 
the Initial Sentinel Cohort for the frequency, severity, and duration of adverse events and proceed if there are no 
major safety concerns and the SMT judges that further data is needed to cautiously characterize the safety and 
reactogenicity of the vaccine at a given dose-level prior to triggering study progression decisions. 
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The Full Enrollment Cohort includes both Cohort 1 and Cohort 2. Participants in Cohort 1 of the 
Full Enrollment Cohort (hereafter referred to as Cohort 1) will receive a single injection of study 
intervention while participants in Cohort 2 of the Full Enrollment Cohort (hereafter referred to as 
Cohort 2) will receive 2 vaccinations (to be given 21 days apart), of one of the study interventions 
(ultra-low-dose [
 µg], low-dose [
 µg], medium-dose [
 µg], or placebo) at D01 (VAC1). 
The Full Enrollment Cohort planned sample size, assuming all dose-levels progress to full 
enrollment, is shown in Table 1.2. 
Table 1.2: Planned sample size (Full Enrollment Cohort) 
Cohort 
Group 
Dose-level* 
N 
Total 
18-49 years 
≥ 50 years 
Cohort 1:  
1 injection 
1 
 µg 
20 
24 
44 
2 
 µg 
20 
24 
44 
3 
 µg 
20 
24 
44 
4 
Placebo 
10 
12 
22 
Cohort 2:  
2 injections 
5 
 µg 
20 
24 
44 
6 
 µg 
20 
24 
44 
7 
 µg 
20 
24 
44 
8 
Placebo 
10 
12 
22 
* Formulation: SARS-CoV-2 mRNA: ultra-low-dose (
 µg); low-dose (
 µg); medium-dose (
 µg). 
Note: A subset of up to 77 randomly selected participants in Cohort 2 (approximately 50% of participants in each 
of Groups 5 to 8, under 18-49 years and ≥ 50 years age sub-groups) will be included in an Additional 
Immunological Tests (AIT) subset. 
Sentinel Cohorts 
Participants in the Sentinel Cohort will receive the first injection of the study intervention (ultra-
low-dose [
 µg], low-dose [
 µg], or medium-dose [
 µg] at D01 (Vaccination [VAC] 1) in a 
staged fashion. The 5 participants assigned to the 
 μg dose-level received their first vaccination 
and were contacted by telephone on D03 to document local and systemic solicited reactions as 
well as unsolicited AEs during this period in the CRF. 
 
  
• The 5 participants in the low-dose (
 µg) group continued their participation in the study. 
Following the review of the D01-D09 safety and reactogenicity data, the SMT decided that 
administration of the second study intervention 21 days after the first one could proceed as 
planned in the original protocol.  
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• As per this protocol amendment, the ultra-low-dose (
 µg) group will be introduced. The 
10 participants in this new Sentinel Cohort group will receive their first vaccination and will 
be contacted by telephone on D03 to document local and systemic solicited reactions as well 
as unsolicited AEs during this period in the CRF. 
• Also, concurrent with the initiation of the 
 µg Initial Sentinel Cohort, as per this protocol 
amendment, the Expanded Sentinel Cohort for the low-dose (
 µg) group will enroll an 
additional 20 participants to better understand the reactogenicity at this dose-level in a larger 
group of participants. 
The progression of the Initial and possible Expanded Sentinel Cohorts are displayed in Figure 1.1. 
The Expanded Sentinel Cohort participants in the 
 µg dose-level will be contacted by telephone 
on D03 post-vaccination to document local and systemic solicited reactions as well as unsolicited 
AEs during this period. Based on the assessment of alert thresholds and other safety parameters 
for the 
 µg dose Expanded Sentinel Cohort, the SMT will determine whether or not the 10 
Initial Sentinel Cohort participants for the medium-dose-level of 
 μg will be vaccinated.  
In addition, ad hoc SMTs for any Sentinel Cohort group may occur to evaluate D01-D09 
additional safety data, including laboratory data as needed, to better understand safety. Such ad 
hoc SMT evaluations will inform study progression, especially if any Sentinel Cohort groups 
reach the time of second vaccination before the first Complete Sentinel ESDR (ie, CS-ESDR-1) 
takes place. 
For the 
 µg and 
 µg dose-level groups, an Expanded Sentinel Cohort may be triggered if an 
alert threshold (see list of threshold in Section 8.4.1) is met in the context of no major safety 
concerns and the SMT judges that further data is needed to cautiously characterize the safety and 
reactogenicity of the product at a given dose-level prior to triggering study progression decisions 
(within the same dose-level arm, or in relation to progression to other dose-levels). In case, the 
Expanded Sentinel Cohort for the ultra-low-dose is triggered, it may run concurrently with the 
medium-dose Initial or Expanded Sentinel Cohort groups (Figure 1.5). It is to be noted that, if 
vaccination in the ultra-low- and medium-dose Sentinel Cohort groups do not run concurrently, 
the possible triggering of an Expanded Sentinel Cohort for the ultra-low-dose group will not 
impact enrollment in the medium-dose group. 
Participants from the Sentinel Cohort will receive their second vaccination (VAC2), 21 days after 
VAC1, if deemed appropriate after SMT data review of safety and reactogenicity data post VAC1. 
Participants in each the ultra-low-, low-, and medium-dose groups will receive their second 
vaccination in the same fashion as the first vaccination with intervening SMTs assessing early 
reactogenicity. Participants will be contacted by phone on D03 to collect D01-03 safety data and 
SMT evaluation for each group of Sentinel participants. 
Complete Sentinel ESDR and Full Enrollment Cohort 
The CS-ESDR-1 will be performed for all Sentinel Cohort participants after safety data, including 
local and systemic AEs, unsolicited AEs, and biological safety laboratory parameters, is obtained 
from D01-D09 following the first injection. This unblinded review will be performed by the 
Sponsor during the SMT meeting. Progression to the Full Enrollment Cohort for selected or all of 
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the dose-levels will occur after CS-ESDR-1 with evaluation of safety data up to D09 post first 
vaccination in all Sentinel Cohorts participants. 
If no safety signals or major tolerability concerns are identified at CS-ESDR-1, the double-blind 
enrollment of up to 308 participants (vaccine and placebo groups) for the first vaccination of the 
Full Enrollment Cohort (Cohort 1 allocated to the single-injection schedule and Cohort 2 allocated 
to the 2-injection schedule) will be initiated. It is to be noted that the first vaccination in the Full 
Enrollment Cohort may be delayed until after the second vaccination of some of the Sentinel 
Cohort groups or even postponed until after CS-ESDR-2, if deemed necessary by the SMT. 
After CS ESDR-1, participants in Cohort 1 will receive their injection of study intervention while 
participants in Cohort 2 will receive the first of 2 injections of the study intervention at D01 
(VAC1). 
A subsequent safety review (CS-ESDR-2) is planned for all Sentinel Cohort participants during 
which the unblinded SMT will examine the available D22-D30 safety data post-second 
vaccination including local and systemic AEs, unsolicited AEs, and biological safety laboratory 
parameters, and all available MAAEs, SAEs, and AESIs for the Sentinel Cohort participants will 
also be reviewed. If no safety signals or major tolerability concerns are identified during this 
period in the Sentinel Cohort, then all participants in Cohort 2 will progress to get the second 
injection (VAC2). If a safety signal or a major tolerability concern is identified at CS-ESDR-2 for 
the Sentinel Cohort, then Cohort 2 participants for the corresponding dose-level may not receive 
their second vaccination. 
It should be noted that throughout the study, the SMT core members, consisting of Clinical Team 
Leader (Responsible Medical Officer [RMO]), Study Biostatistician, Pharmacovigilance Science 
Expert, and Global Safety Officer, will continuously review blinded safety data, except for the 
safety reviews for the Sentinel Cohort and the planned interim analyses, during which unblinded 
safety data will be reviewed. The blind will be broken at the group level for the Sponsor at the 
time of each interim analysis. Further unblinding may be necessary if any of the halting rules are 
met (see Section 8.4.3) or if there is any safety concern.   
Participants follow-up 
Participants will be followed over the duration of the study for development of symptoms of 
COVID-19-like illness. Participants will receive surveillance phone calls every 2 weeks (± 6 days, 
starting after the D43 contact to approximately 6 months) or may be contacted through alternative 
contact methods (text messages, email, and/or home visit) to enquire about the development of 
symptoms of COVID-19-like illness and to remind the participants to contact study staff if they 
experience symptoms of COVID-19-like illness. In addition, all participants will be instructed to 
contact the site if they experience symptoms of a COVID-19-like illness at any time during the 
study. The reporting of events temporally associated with COVID-19-like illness are outlined in 
Table 1.6. 
Duration of participation in the study 
The duration of each participant’s participation in the study will be approximately 365 days 
post-last injection: 
• Sentinel Cohort: approximately 386 days duration total 
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• Cohort 1 of Full Enrollment Cohort: approximately 365 days duration total 
• Cohort 2 of Full Enrollment Cohort: approximately 386 days duration total 
Authorized for emergency use and Approved SARS-CoV-2 vaccines 
If an authorized for emergency use/approved SARS-CoV-2 vaccine is available in the country or 
region where the study is conducted, investigators will discuss this information with prospective 
study participants at the time of informed consent who will be encouraged to obtain the 
approved/authorized SARS-CoV-2 vaccine if applicable to them. Recruitment and enrollment of 
eligible participants will proceed only if, despite encouragement, the candidate participant 
expresses no intention to seek an authorized or approved vaccine at least until completion of the 
key follow-up timepoint (D43) of this study for informing progression to further clinical 
development and dose selection.  
If the participant is enrolled and seeks vaccination of an authorized/approved COVID-19 vaccine 
outside of the study, he/she will be encouraged to discuss this intention proactively with the study 
investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved COVID-19 vaccine, this information would be collected and the 
participant’s data up to the point of receipt of authorized/approved COVID-19 vaccine will be 
included in the primary analysis for immunogenicity and safety. Participants will continue to be 
followed for the duration of the study as per scheduled visits and procedures. Participants will be 
invited to a visit prior to receiving the vaccine and requested to provide a blood sample for 
immunological assessment. Participants will not receive the second vaccination if they have 
received the authorized/approved COVID-19 vaccine between the first and second scheduled 
vaccination. 
Data Monitoring Committee: No 
1.2 
Schema 
The graphical design of VAW00001 study is presented in Figure 1.1 (for Sentinel Cohort), 
Figure 1.2 (for Cohort 1 of Full Enrollment Cohort), and Figure 1.3 (for Cohort 2 of Full 
Enrollment Cohort). The graphical design for the Sentinel Cohort dose-escalation and CS-ESDR 
timeline and enrollment of the original Protocol version 2.0 is presented in Figure 1.4. The 
lightning symbol indicates when the study was paused and the protocol amended. The updated 
graphical design for the Sentinel Cohort, including both the ultra-low-dose group and the possible 
Expanded Sentinel Cohort groups, is presented in Figure 1.5. 
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Figure 1.1: Graphical study design (Sentinel Cohort; Initial and Expanded)  
 
 
Figure 1.2: Graphical study design (Cohort 1 of Full Enrollment Cohort)   
 
 
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Figure 1.3: Graphical study design (Cohort 2 of Full Enrollment Cohort)  
 
Figure 1.4: Previous Graphical design for Sentinel Cohort dose-escalation and Early Safety 
Data Review (Original Protocol version 2.0) 
 
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Figure 1.5: Current Graphical design for Sentinel Cohort 
 
1.3 
Schedule of Activities (SoA) 
Visits procedures are detailed in the Operating Guidelines. 
 
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Table 1.3: Schedule of activities 1 (Sentinel Cohort, Initial and Expanded) 
Phase I/II Study, 8 Visits after Enrollment, 3 Telephone Calls, 2 Injections, 6 Blood Sample Time-points for Immunogenicity, Approximately 
13 Months Duration Per Participant  
Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
for enrollment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Point-of-care SARS-
CoV-2 antibody test 
(1 mL) †† 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Collection of 
demographic data 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Collection of 
medical history 
X 
Significant 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
 
 
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Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination* 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Pre-vaccination 
temperature 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Urine pregnancy test 
(if applicable)† 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
Contact IRT system 
for 
screening/participant 
number allocation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT system 
for unique dose 
number allocation 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Temporary and 
definitive 
contraindications 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Respiratory sample 
collection 
 
 
Can occur at any time during the study as unscheduled visit(s) (See also Schedule of Activities Table 1.6) 
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Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical safety 
laboratory 
assessments‡ 
(~15 mL) 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Serum samples for 
Ab assays (30 mL)§ 
X 
 
BL0001** 
 
 
BL0002** 
 
 
BL0003 
 
BL0004 
BL0005 
BL0006 
HIV, Hepatitis B, 
Hepatitis C 
serology†† (~5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vaccination  
X 
 
X  
(VAC1) 
 
 
X 
(VAC2) 
 
 
 
 
 
 
 
Immediate 
surveillance 
(30 minutes) 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Diary Card provided  
 
 
DC1‡‡ 
 
 
DC2††† 
 
 
DC3‡‡‡ 
 
DC4§§§ 
DC5**** 
 
Diary Card reviewed 
 
 
 
DC1§§ 
DC1§§ 
 
DC2§§ 
DC2§§ 
 
DC3§§ 
 
 
 
Diary Card collected 
 
 
 
 
 
DC1*** 
 
 
DC2*** 
 
DC3*** 
DC4*** 
DC5*** 
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Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of 
solicited injection 
site and systemic 
reactions 
X 
 
D01-D08 
(up to 7 days post-VAC1) 
D01-D08  
(up to 7 days post-VAC2) 
 
 
 
 
 
Collection of 
unsolicited AEs  
X 
 
D01-D22 
(up to 21 days post-VAC1) 
 
 
 
 
 
 
 
 
 
 
 
D01-D22 
(up to 21 days post-VAC2) 
 
 
 
Collection of 
concomitant 
medications 
X 
Reportable 
concomitant 
medication 
 
All reportable concomitant medications 
(including influenza and COVID-19 vaccination other than the study vaccine) 
Only influenza and COVID-19 
vaccination, and any COVID-19 
prophylaxis (eg, SARS-CoV-2 
antivirals, monoclonal antibodies, 
plasma) 
Telephone call 
X 
 
 
X†††† 
 
 
X†††† 
 
 
X†††† 
 
 
X††††† 
Passive surveillance 
X 
 
Participants will be instructed to contact the site if they experience symptoms of a COVID-19-like illness at any time during the 
study (See also Schedule of Activities Table 1.6) 
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Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active surveillance 
calls 
X 
 
 
 
 
 
 
 
 
TC to occur every 2 weeks 
(± 6 days) after the D43 contact 
until D202‡‡‡‡  
(See also Schedule of Activities 
Table 1.6 for follow-up) 
 
Collection of SAEs, 
AESIs§§§§, and 
MAAEs 
X 
 
To be reported at any time during the study 
Collection of 
pregnancies 
X 
 
End of phase 
participation 
record*****  
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
End of active phase 
participation record 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
12 month post-
VAC2 follow-up 
participation record 
(only for those 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
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Visit (V)/Contact 
Collection 
of 
information  
in the CRF 
Screening 
visit 
V01 
TC1 
V02 
V03 
TC2 
V04 
V05 
TC3 
V06 
V07 
V08 
††††† 
Study timelines 
(Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D03 
D09 
D22 
D24 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval 
(days) 
 
V01 – (1 
to 8 days) 
 
V01 + 
2 days 
V01 + 
8 days 
V01 + 21 
days 
V03 + 2 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 
21 days 
V03 + 90 
days 
V03 + 
180 days 
V03 + 
365 days 
Time windows 
(days) 
 
 
N/A 
N/A 
[+2 
days] 
[+7 days] 
N/A 
[+2 
days] 
[+7 days] 
[+2 
days] 
[+7 days] 
[+14 
days] 
[+14 
days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
discontinued early) 
††††† 
Abbreviations: Ab, antibody; AE, adverse event; AESI, adverse event of special interest; BL, blood sample (#); CRF, Case Report Form; D, Day; DC, Diary Card; HIV, human 
immunodeficiency virus; IRT, Interactive Response Technology; MAAE, medically attended AE; PT, prothrombin time; PTT, partial thromboplastin time; SAE, serious adverse 
event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TC, telephone call; V, Visit; VAC, Vaccination. 
* Targeted physical examination will be performed at screening. If needed, targeted physical examination based on medical history and Investigator’s discretion might be performed at 
V01.  
† Female participants of childbearing potential must have a negative urine pregnancy test prior to administration of study product. Urine pregnancy test is applicable to childbearing 
potential female participant (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile). Urine pregnancy test is to be 
performed at screening (performed within -D04 and -D01) and before vaccinations. 
‡ Safety laboratory assessments will include: serum chemistries (including liver enzymes and renal function); hematology (complete blood count with differential) and coagulation 
times (PT and PTT); urinalysis; Microscopy will be performed if urinalysis is abnormal. In cases of abnormal safety laboratory results, unscheduled visits may occur and laboratory 
tests may be checked based on Investigator’s judgment. Assessment of clinical safety laboratory parameters at screening must be performed within -D04 to -D01. 
§ If a participant seeks an authorized/approved COVID-19 vaccine, they will be invited to an unscheduled visit prior to receiving the vaccine and requested to provide a blood sample 
for serological assessment (UB0001). 
** BL0001 will be collected at pre-vaccination (baseline). BL0002 sample will be collected prior to D22 vaccination. 
†† Result of point-of-care SARS-CoV-2 antibody test must be obtained within -D04 to -D01. 
Assessment of clinical safety laboratory parameters must be performed within -D04 to -D01. 
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Screening activities like COVID-19 antibody test and blood and urine sampling for safety tests may be performed on the day of enrollment as long as the results to assess exclusion 
criteria are available prior to enrollment. 
Testing of HIV antibody, Hepatitis B surface antigen, Hepatitis B core antibody, and Hepatitis C antibody must be obtained within -D08 to -D01. This testing will be performed 
at the study center using local accepted diagnostic tests. It is to be noted that results for the above-mentioned HIV and Hepatitis serology tests obtained outside the study within 
4 weeks prior to V01 will be accepted. 
‡‡ Participants will use this DC1 to record information about solicited reactions, unsolicited AEs, SAEs, and AESIs from D01 to D08 after vaccination and will continue to record 
information about unsolicited AEs, SAEs, and AESIs from D09 to V03. 
§§ The Investigator or an authorized designee will remind the participants to bring back the DC at the next visit and will answer any questions. 
*** The Investigator or an authorized designee will interview the participants to collect the information recorded in the DC and will attempt to clarify anything that is incomplete or 
unclear. 
††† Participants will use this DC2 to record solicited reactions, unsolicited AEs, SAEs, and AESIs (from V03 to V04) and will continue to collect unsolicited AEs, SAEs, and AESIs 
(from V04 to V05). 
‡‡‡ Participants will use this DC3 for unsolicited AE follow-up until D43, and SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V05 to V06. 
§§§ Participants will use this DC4 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V06 to V07. 
**** Participants will use this DC5 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V07 to V08.  
†††† During the D43 telephone call, staff will review the DC3 pertaining to unsolicited AEs, SAE, AESI, and COVID-19-like illness between V05 and the call (data will be entered in 
the CRF) and will remind the participants to bring back the DC3 for V06. The D03 and D24 telephone calls will NOT be reported in the CRF (ie, only the data obtained from these 
telephone calls will be reported in the CRF). 
‡‡‡‡ The frequency of phone contacts will be once every 2 weeks (± 6 days) or may be completed through alternative contact methods (text message, email, and/or home visit). Prior 
to these specified time-points, active surveillance will still occur during the established contacts (phone calls and visits). 
§§§§ AESIs (serious and non-serious) will be collected throughout the study as SAEs to ensure that events are communicated to the Sponsor in an expedited manner and followed-up 
until the end of the follow-up period or resolution, as per the assigned causal relationship. These include protocol-specified AESIs: anaphylactic reactions, generalized convulsion, 
Guillain-Barré Syndrome, acute disseminated encephalomyelitis, thrombocytopenia, vasculitides, any new-onset chronic medical conditions, and AESIs related to SARS-CoV-2 
infection and COVID-19 disease.  
***** In case of participant discontinuation at a visit, the entire visit will be completed. 
††††† All participants will be scheduled to attend V08 for blood sampling and 12-Month (post-VAC2) Safety Follow-up. However, if any participants discontinue the study early, 
they are still to be followed for safety and are to be contacted with a Safety Follow-up call to identify the occurrence of any SAEs and AESIs that had not yet been reported. If 
discontinuation occurs at a scheduled visit, the participant will be provided a Memory Aid instead of a DC for SAE follow-up (including AESIs) until the Safety Follow-up call. If a 
participant discontinues between visits (with no Memory Aid provided yet), the participant will use the last DC received to collect information for the Safety Follow-up call. 
 
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Table 1.4: Schedule of activities 2 (Cohort 1 of Full Enrollment Cohort) 
Phase I/II Study, 7 Visits after Enrollment, 1 Telephone Call, 1 Injection, 6 Blood Sample Time-points, approximately 12 Months Duration Per 
Participant 
Visit (V)/Contact 
Collection  
of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
TC1 
V05 
V06 
V07††††† 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D36 
D43 
D91 
D181 
D366 
Time interval (days) 
 
V01 – (1 
to 8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 + 90 
days 
V01 + 180 
days 
V01 + 365 days 
Time windows (days) 
 
 
N/A 
[+2 
days] 
[+7 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
Informed consent for enrollment 
X 
X 
 
 
 
 
 
 
 
 
Point-of-care SARS-CoV-2 antibody 
test (1 mL) †† 
 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
 
 
 
 
 
Collection of medical history 
X 
Significant 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
Physical examination* 
 
X 
X 
 
 
 
 
 
 
 
Pre-vaccination temperature 
 
 
X 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable)† 
 
X 
X 
 
 
 
 
 
 
 
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Visit (V)/Contact 
Collection  
of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
TC1 
V05 
V06 
V07††††† 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D36 
D43 
D91 
D181 
D366 
Time interval (days) 
 
V01 – (1 
to 8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 + 90 
days 
V01 + 180 
days 
V01 + 365 days 
Time windows (days) 
 
 
N/A 
[+2 
days] 
[+7 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
Contact IRT system for 
screening/participant number allocation 
X 
X 
 
 
 
 
 
 
 
 
Contact IRT system for randomization 
and unique dose number allocation 
X 
 
X 
 
 
 
 
 
 
 
Respiratory sample collection 
 
 
Can occur at any time during the study as unscheduled visit(s) (See also Schedule of Activities Table 1.6) 
Clinical safety laboratory assessments‡ 
(~15 mL blood sample) 
X 
X 
 
X 
 
 
 
 
 
 
Serum samples for Ab assays (30 mL) § 
X 
 
BL0001** 
 
BL0002 
BL0003 
 
BL0004 
BL0005 
BL0006 
HIV, Hepatitis B, Hepatitis C 
serology†† (~5 mL) 
 
X 
 
 
 
 
 
 
 
 
Vaccination  
X 
 
X  
(VAC1) 
 
 
 
 
 
 
 
Immediate surveillance (30 minutes) 
X 
 
X 
 
 
 
 
 
 
 
Diary Card provided  
 
 
DC1‡‡ 
 
DC2††† 
DC3‡‡‡ 
 
DC4§§§ 
DC5**** 
 
Diary Card reviewed 
 
 
 
DC1§§ 
 
 
DC3§§ 
 
 
 
Diary Card collected 
 
 
 
 
DC1*** 
DC2*** 
 
DC3*** 
DC4***  
DC5*** 
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Visit (V)/Contact 
Collection  
of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
TC1 
V05 
V06 
V07††††† 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D36 
D43 
D91 
D181 
D366 
Time interval (days) 
 
V01 – (1 
to 8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 + 90 
days 
V01 + 180 
days 
V01 + 365 days 
Time windows (days) 
 
 
N/A 
[+2 
days] 
[+7 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
Collection of solicited injection site & 
systemic reactions 
X 
 
D01-D08 
(up to 7 days post-
VAC1) 
 
 
 
 
 
 
Collection of unsolicited AEs 
X 
 
D01-D22 
(up to 21 days post-VAC1) 
 
 
 
 
 
Collection of concomitant medications 
X 
Reportable 
concomitant 
medication 
 
All reportable concomitant 
medications 
(including influenza and COVID-19 
vaccination other than the study 
vaccine) 
Only influenza and COVID-19 vaccination, and any COVID-19 
prophylaxis (eg, SARS-CoV-2 antivirals, monoclonal antibodies, 
plasma)  
Telephone call 
X 
 
 
 
 
 
X†††† 
 
 
X††††† 
Passive surveillance 
X 
 
Participants will be instructed to contact the site if they experience symptoms of a COVID-19-like illness at 
any time during the study (See also Schedule of Activities Table 1.6) 
Active surveillance calls 
X 
 
 
 
 
 
TC to occur every 2 weeks 
(± 6 days) after the D43 contact 
until D181‡‡‡‡  
 
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Visit (V)/Contact 
Collection  
of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
TC1 
V05 
V06 
V07††††† 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D36 
D43 
D91 
D181 
D366 
Time interval (days) 
 
V01 – (1 
to 8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 + 90 
days 
V01 + 180 
days 
V01 + 365 days 
Time windows (days) 
 
 
N/A 
[+2 
days] 
[+7 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
(See also Schedule of Activities 
Table 1.6 for follow-up) 
Collection of SAEs, AESIs§§§§, and 
MAAEs 
X 
 
To be reported at any time during the study 
Collection of pregnancies 
X 
 
End of phase participation record***** 
X 
 
 
 
 
 
X 
X 
X 
 
End of active phase participation record 
X 
 
 
 
 
 
 
 
 
X 
12 Month Follow-up participation 
record (only for those discontinued 
early)***** 
X 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: Ab, antibody; AE, adverse event; AESI, adverse event of special interest; BL, blood sample (#); CRF, Case Report Form; D, Day; DC, Diary Card; HIV, human 
immunodeficiency virus; IRT, Interactive Response Technology; MAAE, medically attended adverse event; PT, prothrombin time; PTT, partial thromboplastin time; SAE, serious 
adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TC, telephone call; V, Visit; VAC, vaccination. 
* Targeted physical examination will be performed at screening. If needed, targeted physical examination based on medical history and Investigator’s discretion might be performed at 
V01. 
† Female participants of childbearing potential must have a negative urine pregnancy test prior to administration of study product. Urine pregnancy test is applicable to childbearing 
potential female participant (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile). Urine pregnancy test is to be 
performed at screening (performed within -D04 and -D01) and before vaccination. 
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‡ Safety laboratory assessments will include: serum chemistries (including liver enzymes and renal function); hematology (complete blood count with differential) and coagulation 
times (PT and PTT); urinalysis; microscopy will be performed if urinalysis is abnormal. In cases of abnormal safety laboratory results, unscheduled visits may occur and laboratory 
tests may be checked based on Investigator’s judgment. Assessment of clinical safety laboratory parameters at screening must be performed within -D04 to -D01. 
§ If a participant seeks an authorized/approved COVID-19 vaccine, they will be invited to an unscheduled visit prior to receiving the vaccine and requested to provide a blood sample 
for serological assessment (UB0001). 
** BL0001 will be collected at pre-vaccination (baseline). 
†† Result of point-of-care SARS-CoV-2 antibody test must be obtained within -D04 to -D01. 
Assessment of clinical safety laboratory parameters must be performed within -D04 to -D01. 
Screening activities like COVID-19 antibody test and blood and urine sampling for safety tests may be performed on the day of enrollment as long as the results to assess exclusion 
criteria are available prior to enrollment. 
Testing of HIV antibody, Hepatitis B surface antigen, Hepatitis B core antibody, and Hepatitis C antibody must be obtained within -D08 to -D01. This testing will be performed 
at the study center using local accepted diagnostic tests. It is to be noted that results for the above-mentioned HIV and Hepatitis serology tests obtained outside the study within 
4 weeks prior to V01 will be accepted. 
‡‡ Participants will use this DC1 to record information about solicited reactions, unsolicited AEs, SAEs, and AESIs from D01 to D08 after vaccination and will continue to record 
information about unsolicited AEs, SAEs, and AESIs from D09 to V03. 
§§ The Investigator or an authorized designee will remind the participants to bring back the DC at the next visit and will answer any questions. 
*** The Investigator or an authorized designee will interview the participants to collect the information recorded in the DC and will attempt to clarify anything that is incomplete or 
unclear. 
††† Participants will use this DC2 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V03 to V04. 
‡‡‡ Participants will use this DC3 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V04 to V05. 
§§§ Participants will use this DC4 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V05 to V06. 
**** Participants will use this DC5 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V06 to V07. 
†††† During the D43 telephone call, staff will review the DC3 pertaining to SAE, AESI, and COVID-19-like illness between V04 and the call (data will be entered in the CRF) and 
will remind the participant to bring back the DC3 for V05. 
‡‡‡‡ The frequency of phone contacts will be once every 2 weeks (± 6 days) or may be completed through alternative contact methods (text message, email, and/or home visit). Prior 
to these specified time-points, active surveillance will still occur during the established contacts (phone calls and visits). 
§§§§AESIs (serious and non-serious) will be collected through the study as SAEs to ensure that events are communicated to the Sponsor in an expedited manner and followed-up until 
the end of the follow-up period or resolution, as per the assigned causal relationship. These include protocol-specified AESIs: anaphylactic reactions, generalized convulsion, 
Guillain-Barré Syndrome, acute disseminated encephalomyelitis, thrombocytopenia, vasculitides, any new-onset chronic medical conditions, and AESIs related to SARS-CoV-2 
infection and COVID-19 disease.  
***** In case of participant discontinuation at a visit, the entire visit will be completed. 
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††††† All participants will be scheduled to attend V07 for blood sampling and 12-Month Safety Follow-up. However, if any participants discontinue the study early, they are still to 
be followed for safety and are to be contacted with a 12-Month Safety Follow-up call to identify the occurrence of any SAEs and AESIs that had not yet been reported. If 
discontinuation occurs at a scheduled visit, the participant will be provided a Memory Aid instead of a DC for SAE follow-up (including AESIs) until the 12-Month Safety Follow-up 
call. If a participant discontinues between visits (with no Memory Aid provided yet), the participant will use the last DC received to collect information for the 12-Month Safety 
Follow-up call.
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Table 1.5: Schedule of activities 3 (Cohort 2 of Full Enrollment Cohort)  
Phase I/II Study, 8 Visits after Enrollment, 1 Telephone Call, 2 Injections, 6 Blood Sample Time-points, approximately 13 Months Duration 
Per Participant 
Visit (V)/Contact 
Collection of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
V05 
TC1 
V06 
V07 
V08‡‡‡‡‡ 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval (days) 
 
V01 – (1 to 
8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 21 
days 
V03 + 90 
days 
V03 + 180 
days 
V03 + 365 
days 
Time windows (days) 
 
 
N/A 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
Informed consent for 
enrollment 
X 
X 
 
 
 
 
 
 
 
 
 
Point-of-care SARS-CoV-2 
antibody test (1 mL) †† 
 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Collection of demographic 
data 
X 
X 
 
 
 
 
 
 
 
 
 
Collection of medical history 
X 
Significant 
Medical 
History 
X 
X 
 
 
 
 
 
 
 
 
Physical examination* 
 
X 
X 
 
 
 
 
 
 
 
 
Pre-vaccination temperature 
 
 
X 
 
X 
 
 
 
 
 
 
Urine pregnancy test (if 
applicable)† 
 
X 
X 
 
X 
 
 
 
 
 
 
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Visit (V)/Contact 
Collection of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
V05 
TC1 
V06 
V07 
V08‡‡‡‡‡ 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval (days) 
 
V01 – (1 to 
8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 21 
days 
V03 + 90 
days 
V03 + 180 
days 
V03 + 365 
days 
Time windows (days) 
 
 
N/A 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT system for 
screening/participant number 
allocation 
X 
X 
 
 
 
 
 
 
 
 
 
Contact IRT system for 
randomization and unique 
dose number allocation 
X 
 
X 
 
 
 
 
 
 
 
 
Contact IRT system for 
unique dose number 
allocation 
X 
 
 
 
X 
 
 
 
 
 
 
Temporary and definitive 
contraindications 
X 
 
 
 
X 
 
 
 
 
 
 
Respiratory sample collection 
 
 
Can occur at any time during the study as unscheduled visit(s) (See also Schedule of Activities Table 1.6) 
Clinical safety laboratory 
assessments‡ (~15 mL blood 
sample) 
X 
X 
 
X 
 
X 
 
 
 
 
 
Serum samples for Ab assays 
(30 mL)§ 
X 
 
BL0001** 
 
BL0002** 
 
BL0003 
 
BL0004 
BL0005 
BL0006 
HIV, Hepatitis B, Hepatitis C 
serology†† (~5 mL) 
 
X 
 
 
 
 
 
 
 
 
 
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Visit (V)/Contact 
Collection of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
V05 
TC1 
V06 
V07 
V08‡‡‡‡‡ 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval (days) 
 
V01 – (1 to 
8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 21 
days 
V03 + 90 
days 
V03 + 180 
days 
V03 + 365 
days 
Time windows (days) 
 
 
N/A 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
AIT (40 mL) and TruCulture 
(4 mL) (Subset of up to 
77 participants) ‡‡ 
X 
 
MC0001** 
WB0001** 
 
MC0002** 
WB0002** 
 
MC0003 
WB0003 
 
MC0004 
 
 
Vaccination  
X 
 
X  
(VAC1) 
 
X 
(VAC2) 
 
 
 
 
 
 
Immediate surveillance 
(30 minutes) 
X 
 
X 
 
X 
 
 
 
 
 
 
Diary Card provided  
 
 
DC1§§ 
 
DC2‡‡‡ 
 
DC3§§§ 
 
DC4**** 
DC5†††† 
 
Diary Card reviewed 
 
 
 
DC1*** 
 
DC2*** 
 
DC3*** 
 
 
 
Diary Card collected 
 
 
 
 
DC1††† 
 
DC2††† 
 
DC3††† 
DC4††† 
DC5††† 
Collection of solicited 
injection site & systemic 
reactions 
X 
 
D01-D08 
(up to 7 days post-
VAC1) 
D01-D08  
(up to 7 days post-VAC2) 
 
 
 
 
 
Collection of unsolicited AEs  
X 
 
D01-D22 
(up to 21 days post-VAC1) 
 
 
 
 
 
 
 
 
 
D01-D22 
(up to 21 days post-VAC2) 
 
 
 
Collection of concomitant 
medications 
X 
Reportable 
concomitant 
medication 
 
All reportable concomitant medications 
(including influenza and COVID-19 vaccination other than the study vaccine) 
Only influenza and COVID-19 
vaccination, and any COVID-19 
prophylaxis (eg, SARS-CoV-2 
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Visit (V)/Contact 
Collection of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
V05 
TC1 
V06 
V07 
V08‡‡‡‡‡ 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval (days) 
 
V01 – (1 to 
8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 21 
days 
V03 + 90 
days 
V03 + 180 
days 
V03 + 365 
days 
Time windows (days) 
 
 
N/A 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
antivirals, monoclonal antibodies, 
plasma)  
Telephone call 
X 
 
 
 
 
 
 
X‡‡‡‡ 
 
 
X††††† 
Passive surveillance 
X 
 
Participants will be instructed to contact the site if they experience symptoms of a COVID-19-like illness at any time 
during the study (See also Schedule of Activities Table 1.6) 
Active surveillance calls 
X 
 
 
 
 
 
 
TC to occur every 2 weeks (± 6 days) 
after the D43 contact until D202§§§§  
(See also Schedule of Activities 
Table 1.6 for follow-up) 
 
Collection of SAEs, 
AESIs*****, and MAAEs 
X 
 
To be reported at any time during the study 
Collection of pregnancies 
X 
 
End of phase participation 
record††††† 
X 
 
 
 
 
 
 
X 
X 
X 
 
End of active phase 
participation record 
X 
 
 
 
 
 
 
 
 
 
X 
12 month post-VAC2 follow-
up participation record (only 
X 
 
 
 
 
 
 
 
 
 
X 
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Visit (V)/Contact 
Collection of 
information  
in the CRF 
Screening 
visit 
V01 
V02 
V03 
V04 
V05 
TC1 
V06 
V07 
V08‡‡‡‡‡ 
Study timelines (Day [D]) 
 
D(-08) to 
D(-01)†† 
D01 
D09 
D22 
D30 
D36 
D43 
D112 
D202 
D387 
Time interval (days) 
 
V01 – (1 to 
8 days) 
 
V01 + 8 
days 
V01 + 21 
days 
V03 + 8 
days 
V03 + 14 
days 
V03 + 21 
days 
V03 + 90 
days 
V03 + 180 
days 
V03 + 365 
days 
Time windows (days) 
 
 
N/A 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+2 days] 
[+7 days] 
[+14 days] 
[+14 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
for those discontinued early) 
‡‡‡‡‡   
Abbreviations: Ab, antibody; AE, adverse event; AESI, adverse event of special interest; AIT, Additional Immunological Tests; BL, blood sample (#); CRF, Case Report 
Form; D, Day; DC, Diary Card; HIV, human immunodeficiency virus; IRT, Interactive Response Technology; MAAE, medically attended AE; MC, mononuclear cell; PT, 
prothrombin time; PTT, partial thromboplastin time; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TC, telephone call; V, Visit; 
VAC, Vaccination; WB, whole blood. 
* Targeted physical examination will be performed at screening. If needed, targeted physical examination based on medical history and Investigator’s discretion might be performed at 
V01.  
† Female participants of childbearing potential must have a negative urine pregnancy test prior to administration of study product. Urine pregnancy test is applicable to childbearing 
potential female participant (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile). Urine pregnancy test is to be 
performed at screening (performed within -D04 and -D01) and before vaccinations. 
‡ Safety laboratory assessments will include: serum chemistries (including liver enzymes and renal function); hematology (complete blood count with differential) and coagulation 
times (PT and PTT); urinalysis; microscopy will be performed if urinalysis is abnormal. In cases of abnormal safety laboratory results, unscheduled visits may occur and laboratory 
tests may be checked based on Investigator’s judgment. Assessment of clinical safety laboratory parameters at screening must be performed within -D04 to -D01. 
§ If a participant seeks an authorized/approved COVID-19 vaccine, they will be invited to an unscheduled visit prior to receiving the vaccine and requested to provide a blood sample 
for serological assessment (UB0001). 
** BL0001, MC0001, and WB0001 samples will be collected at pre-VAC1 (baseline). BL0002, MC0002, and WB0002 samples will be collected at pre-VAC2. 
†† Result of point-of-care SARS-CoV-2 antibody test must be obtained within -D04 to -D01. 
Assessment of clinical safety laboratory parameters must be performed within -D04 to -D01. 
Screening activities like COVID-19 antibody test and blood and urine sampling for safety tests may be performed on the day of enrollment as long as the results to assess exclusion 
criteria are available prior to enrollment. 
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Testing of HIV antibody, Hepatitis B surface antigen, Hepatitis B core antibody, and Hepatitis C antibody must be obtained within -D08 to -D01. This testing will be performed 
at the study center using local accepted diagnostic tests. It is to be noted that results for the above-mentioned HIV and Hepatitis serology tests obtained outside the study within 
4 weeks prior to V01 will be accepted. 
‡‡ If a participant seeks an authorized/approved COVID-19 vaccine at or after D50 but before D112, they will be invited to an unscheduled visit prior to receiving the vaccine and 
requested to provide a blood sample for assessment (UM0001). 
§§ Participants will use this DC1 to record information about solicited reactions, unsolicited AEs, SAEs, and AESIs from D01 to D08 after vaccination and will continue to record 
information about unsolicited AEs, SAEs, and AESIs from D09 to V03. 
*** The Investigator or an authorized designee will remind the participants to bring back the DC at the next visit and will answer any questions. 
††† The Investigator or an authorized designee will interview the participants to collect the information recorded in the DC and will attempt to clarify anything that is incomplete or 
unclear. 
‡‡‡ Participants will use this DC2 to record solicited reactions, unsolicited AEs, SAEs, and AESIs (from V03 to V04) and will continue to collect unsolicited AEs, SAEs, and AESIs 
(from V04 to V05). 
§§§ Participants will use this DC3 for unsolicited AE follow-up until D43, and SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V05 to V06. 
**** Participants will use this DC4 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V06 to V07. 
†††† Participants will use this DC5 for SAE follow-up (including AESIs) and COVID-19-like illness follow-up from V07 to V08. 
‡‡‡‡ During the D43 telephone call, staff will review the DC3 pertaining to unsolicited AEs, SAE, AESI, and COVID-19-like illness between V05 and the call (data will be entered in 
the CRF) and will remind the participants to bring back the DC3 for V06. 
§§§§The frequency of phone contacts will be once every 2 weeks (± 6 days) or may be completed through alternative contact methods (text message, email, and/or home visit). Prior 
to these specified time-points, active surveillance will still occur during the established contacts (phone calls and visits). 
*****AESIs (serious and non-serious) will be collected throughout the study as SAEs to ensure that events are communicated to the Sponsor in an expedited manner and followed-up 
until the end of the follow-up period or resolution, as per the assigned causal relationship. These include protocol-specified AESIs: anaphylactic reactions, generalized convulsion, 
Guillain-Barré Syndrome, acute disseminated encephalomyelitis, thrombocytopenia, vasculitides, any new-onset chronic medical conditions, and AESIs related to SARS-CoV-2 
infection and COVID-19 disease. 
††††† In case of participant discontinuation at a visit, the entire visit will be completed. 
‡‡‡‡‡ All participants will be scheduled to attend V08 for blood sampling and 12-Month (post-VAC2) Safety Follow-up. However, if any participants discontinue the study early, 
they are still to be followed for safety and are to be contacted with a Safety Follow-up call to identify the occurrence of any SAEs and AESIs that had not yet been reported. If 
discontinuation occurs at a scheduled visit, the participant will be provided a Memory Aid instead of a DC for SAE follow-up (including AESIs) until the Safety Follow-up call. If a 
participant discontinues between visits (with no Memory Aid provided yet), the participant will use the last DC received to collect information for the Safety Follow-up call. 
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Table 1.6: Schedule of activities 4 (Follow-up of COVID-19-like illness) 
Contact Type 
Initial Telephone Call* 
Visit 
Follow-up 
Telephone Call† 
Verify information on COVID-19-like illnesses and schedule 
appointment for collection of respiratory samples as soon as 
possible after illness start date‡ 
X 
 
 
Collection of information on respiratory illness symptoms 
X 
X 
X 
Remind participant to complete Memory Aid or Diary Card 
X 
X 
X 
Collection of respiratory specimen 
 
NPXXXX§ 
 
Collection of disease burden and health care information 
X 
X 
X 
Collection of treatments received during COVID-19-like illness 
X 
X 
X 
* Initial illness identification phone call. During the illness episode, participants may be contacted by the site staff for medical monitoring. The frequency of 
contact for medical monitoring is at the discretion of the investigator. 
† Follow-up telephone call approximately 30 days after onset of illness 
‡ Start of first clinical manifestation of COVID-19-like illness, unless during the first reactogenicity period (D01-D09) when the sample may be collected up to 
D09, at the Investigator’s discretion.  
§ “X” indicates that the nasopharyngeal swab number will be unique to each site. Further details are provided in the Operating Guidelines. A nasopharyngeal swab 
for central laboratory testing will be collected. A sample for local laboratory testing (clinical care) may be collected in addition to the NP swab for central 
laboratory testing. The swab will not be collected during a CLI visit if the date of collection is more than 14 days after resolution of symptoms. 
 
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2 
Introduction 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that 
emerged in the human population and has led to a pandemic of acute respiratory disease named 
COVID-19. Coronaviruses are a family of large, enveloped, positive-sense, single-stranded 
ribonucleic acid (RNA) viruses that infect a wide variety of mammalian and avian species. In the 
last 20 years, 3 zoonotic coronaviruses are known to have crossed species to cause SARS in 
humans, which include SARS-CoV, SARS-CoV-2, and the more distantly related Middle East 
Respiratory Syndrome coronavirus (MERS-CoV) (3). Coronavirus entry into the host cells is 
mediated by the transmembrane spike (S) glycoprotein which permits both the binding to the host 
cell receptor (via the S1 subunit) and the fusion of viral and cellular membranes (via the S2 
subunit). Recent work has shown that the SARS-CoV-2 receptor binding gene region is similar to 
SARS-CoV and uses the same receptor, angiotensin-converting enzyme 2 on the human cell 
surface (4). 
Prior research with MERS-CoV identified that the introduction of double proline substitutions 
(2P) at the beginning of the central helix of the S2 subunit could stabilize the structure and prevent 
conformational changes in the S trimer (5). When used to immunize mice, the MERS-CoV 2P 
construct was associated with improved breadth and potency of neutralizing responses compared 
to monomeric MERS-CoV S1 or wild-type S. This strategy was identified as being of general 
relevance to betacoronaviruses, which include Human Coronavirus (HCoV)-NL63, MERS-CoV, 
and SARS-CoV-1, and by extrapolation to SARS-CoV-2 (6). The prefusion stabilized 
SARS-CoV-2 S construct to be evaluated in the current study is based on this research. 
To address the urgent medical need caused by the COVID-19 outbreak, Sanofi Pasteur is 
developing a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine consisting of an mRNA 
encoding the full-length sequence for the prefusion stabilized form of the SARS-CoV-2 surface S 
protein with 2 sets of mutations, one set (2P) in the S2 portion of the S protein that locks the 
expressed S protein in the prefusion conformation, and second set (GSAS) at the S1/S2 cleavage 
site which prevents the cleavage of the expressed protein into the S1 and S2 subunits. The mRNA 
vaccine is complexed with a novel lipid nanoparticle (LNP) vehicle 
 
. Prior to this study, neither the LNP nor the mRNA targeted in this study have been 
administered to humans before. However, studies with the SARS-CoV-2 mRNA vaccine in 
rabbits 
, mice 
, hamsters 
 
, and non-human primates (NHP; 
 
) support the safety, immunogenicity, and protective efficacy of this vaccine 
(for more details see the Investigator's Brochure). The investigational vaccine candidate uses a 
technology platform developed with an ongoing collaboration between Translate Bio and Sanofi 
Pasteur and will be manufactured by Translate Bio. 
A potential safety issue with coronavirus vaccines is the ability to potentiate immunopathological 
manifestations in vaccinees upon further exposure to wild-type virus (7). The molecular 
mechanism for this immunopathogenesis is not fully understood. In the context of coronavirus 
infections, various factors have been suggested as potentially contributing to the phenomenon. 
These include the epitope targeted, the method of delivery of the antigen, the magnitude of the 
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immune responses, the balance between binding and functional antibodies, the elicitation of 
antibodies with functional characteristics such as binding to particular Fc receptors, and the nature 
of the T-helper (Th) cell response (8) (9) (10). It is anticipated that the design of the candidate 
SARS-CoV-2 mRNA vaccine selected for this study will promote the generation of neutralizing 
antibodies over binding antibodies, based on data generated with other coronavirus vaccine 
antigens (5) (6) and mRNA vaccines may be inclined to produce a favorable Th1/Th2 response, 
likely predominantly Th1 biased (11). Taken together, these strategies are designed to mitigate the 
theoretical risks of immune enhancement of viral infection. 
The initial intended use of the SARS-CoV-2 mRNA vaccine is for adults, 18 years of age and 
older. It is planned that studies to support use of the vaccine in children 6 months to 17 years of 
age will be conducted after the initial data from studies in adults are available.  
2.1 
Study Rationale 
VAW00001 is a first-in-human Phase I/II, multi-center study comprised of 2 sequential cohorts: a 
lead-in open-label Sentinel Cohort, followed by a randomized, modified double-blind, dose-
ranging, placebo-controlled Full Enrollment Cohort, to evaluate the safety and immunogenicity of 
the SARS-CoV-2 mRNA vaccine, in healthy adult participants (18 years of age and older) in the 
United States (US) and Honduras. In its original design, the study was to evaluate 3 different 
dose-levels 
 of the candidate mRNA vaccine with the goal 
of selecting the optimal dose and schedule to proceed to a Phase III study.
 
 
Further considerations of the safety data from the 5 participants assigned to the low-dose level 
group revealed the transient nature of the reported Grade 3 adverse events. Given the fact that 
these AEs were self-limited (ie, no subject sought any medical attention) and no major safety 
concerns were identified, the Sponsor decided to introduce 4 changes through a protocol 
amendment:  
1) add a “ultra-low-dose” arm of 
 µg 
 
intended to evaluate 
 
a lower dose-level range (ie, ultra-low- [
 µg], low- [
 µg], and 
medium- [
 µg] dose-levels);  
2) increase the number of Sentinel Cohort participants from 5 to 10 in the dose-level groups that 
have yet to start enrollment (ie, 
 µg and 
 µg);  
3) add an expansion of the open-label Sentinel Cohort for the 
 µg dose-level to better 
understand the reactogenicity at this dose-level in a larger group of participants prior to 
escalation to the 
 µg dose. This possibility to expand the number of Sentinel Cohort 
participants will also be extended to the ultra-low- and medium-dose groups if needed; 
4) decrease the number of placebo recipients in the Full Enrollment Cohort. 
The longer-term objective remains to longitudinally define the safety and durability of the 
immune response induced by the SARS-CoV-2 mRNA vaccine over the 1 year study duration. 
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2.2 
Background 
The burden of SARS-CoV-2 morbidity and mortality has been catastrophic with greater than 
2.8 million deaths recorded since first emerging in December 2019 among over 129 million 
confirmed cases (as of 02 April 2021) (2). In many locations, the rapid emergence of COVID-19 
has overwhelmed the capacity of health systems to provide care for COVID-19-affected patients, 
let alone unaffected patients. Interventions to reduce transmission through reduction of population 
contact has had drastic economic consequences. At present, 2 COVID-19 mRNA vaccines, 
BNT162b2 from Pfizer and BioNTech and mRNA-1273 from Moderna, and 2 viral vector 
vaccines, ChAdOx1-nCOV-19 from Oxford University/AstraZeneca and Janssen COVID-19 
vaccine (Ad26.COV2.S) from Johnson & Johnson have reported efficacy against COVID-19 
illness and severe disease in their Phase III clinical studies (12) (13) (14) (15). Emergency 
authorization or other forms of regulatory approval for these and additional other SARS CoV-2 
vaccine candidates have been granted in multiple countries for the prevention of COVID-19. 
Given the ongoing medical and societal burden caused by SARS CoV2 infections, developing 
safe and effective vaccines remains a vital tool to address the global pandemic. The circulating 
virus has continued to evolve with the emergence of highly transmissible SARS CoV-2 variants of 
concern impeding the control of new infections. No single vaccine company could meet the needs 
for a worldwide vaccination strategy and continued vaccine development is crucial. 
The clinical profile of COVID-19, the illness caused by SARS-COV-2, is variable and our 
understanding about its clinical profile is evolving (16). Asymptomatic infections appear frequent 
but prospective longitudinal studies are lacking. Some individuals who are initially asymptomatic 
may with time progress to recognizable symptoms, especially if monitored closely (17). The 
spectrum of symptomatic disease can vary from mild and without pulmonary involvement to 
life-threatening and fatal disease. In a report from the Chinese Center for Disease Control and 
Prevention describing 44 672 confirmed cases, disease severity was reported as 81% mild, 
14% severe, and 5% critical in adults. The overall case fatality rate is reported as 2.3% but as high 
as 49% for those with critical illness (18). Typical initial symptomatic disease is characterized by 
fever, respiratory symptoms including cough and dyspnea, and fatigue, and are not easily 
distinguishable from other viral respiratory infections. Among hospitalized patients, symptoms 
may progress rapidly within a week to worsening hypoxia and pneumonia, severe respiratory 
compromise requiring mechanical ventilatory support, shock, cardiac injury, thromboembolic 
events, and death. In severe disease, a hyperinflammatory syndrome notable for cytokine release 
of proinflammatory cytokines has been appreciated and associated with severe illness and fatal 
outcome (19). Adults over 50 years of age and individuals with comorbidities like cardiovascular 
disease, diabetes mellitus, hypertension, obesity, and underlying pulmonary disease are at 
increased risk of adverse outcomes. 
Emerging trends in vaccine development have focused on using mRNA technology to make novel 
vaccine candidates. This unique technology features engineered mRNA encoding an antigen of 
interest that is packaged and delivered to human target cells. The mRNA is encapsulated within an 
LNP which protects the mRNA from degradation and promotes fusogenicity and the efficient 
uptake of the LNP-mRNA complex within the target cell (20). Once internalized into the cell, the 
mRNA sequence is released from within the LNP into the cytoplasm, translated into protein by 
the human cell’s own machinery, and post-translationally modified resulting in a properly folded 
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protein for antigen presentation. The mRNA vaccine and LNP are considered intrinsically 
immunogenic, thus, obviating the need for additional adjuvant enhancement. 
The mRNA vaccines could demonstrate significant advantages over traditional vaccines. These 
advantages include 1) shorter manufacturing time, 2) rapid development of new targets, 3) cell 
free development with no infectious elements used in their manufacturing process, and 4) 
potential to include multiple immunogens in the same vaccine. However, the challenges with 
mRNA vaccines are that 1) the mRNA has to be protected from nuclease degradation until the 
mRNA can be translated into protein, 2) there is a need to assure enough mRNA gets translated 
into the antigen of interest, 3) the long term safety and immunogenicity are not yet well 
established, and 4) thermal stability may be limited with storage requiring infrastructure to 
maintain cold chain with present vaccines in study.  
Further details of the chemistry, pharmacology, and safety of the SARS-CoV-2 mRNA vaccine 
are provided in the IB. 
2.3 
Benefit/Risk Assessment 
While mRNA vaccines for infectious diseases have been generally well tolerated, the safety 
profile of mRNA vaccines is influenced by the LNP (21) (22). The investigational vaccine is 
complexed with a novel LNP vehicle 
. The safety and 
immunogenicity of the LNP 
 was initially tested at Sanofi Pasteur in both 
mouse and NHP models using mRNA encoding influenza hemagglutinin (HA) where it was found 
to be well tolerated and induced potent HA neutralizing antibodies. Dose-ranging studies in New 
Zealand White rabbits using an influenza antigen and the candidate LNP supported the safety of 
LNP for the range of mRNA doses selected for this study (refer to the IB). Therefore, the early 
nonclinical safety data generated for the LNP with influenza mRNA is supportive for the 
tolerability of our SARS-CoV-2 mRNA vaccine candidate. A subsequent repeat dose toxicity 
study showed 3 intramuscular (IM) injections of the SARS-CoV-2 mRNA vaccine at 3 weeks 
interval, up to the dose level of 
 µg mRNA/injection were locally and systemically well 
tolerated (refer to the IB for details). In preclinical studies, SARS-CoV-2 mRNA vaccine induced 
dose-dependent S-specific binding and neutralizing antibody response with Th1-biased cellular 
responses in the mouse and NHP animal models (23).  
A potential safety issue with coronavirus vaccines is the ability to potentiate immunopathological 
manifestations in vaccinees upon further exposure to wild-type virus. The potential for a 
coronavirus vaccine to exacerbate disease is a theoretical concern that has not been documented to 
date, but that will be explained as a theoretical risk in the informed consent document and will be 
monitored throughout the study. 
The efficacy of the candidate vaccine has not been established. SARS-CoV-2 mRNA vaccine 
benefit/risk profile is expected to be positive based on available evidence. Study participation and 
study conduct is considered fundamental from the societal perspective towards the goal of finding 
a vaccine to help control the pandemic and decrease individual and public health burden of 
COVID-19 illness and SARS-CoV-2 infection. 
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The SARS-CoV-2 mRNA vaccine offers the potential of protection against SARS-CoV-2 
infection and COVID-19 disease and its complications with a clinical benefit of reduction of the 
associated burden of disease in a population 18 years of age and older. 
More detailed information about the known and expected benefits and risks, reasonably expected 
adverse events (AEs), the potential risks, and uncertainties of SARS-CoV-2 mRNA vaccine may 
be found in the SARS-CoV-2 mRNA IB. 
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2.3.1 
Risks from Study Participation 
The potential risks of clinical significance with respect to administration and vaccination of the 
SARS-CoV-2 mRNA vaccine are summarized in Table 2.1. 
Table 2.1: Potential risks of clinical significance and risk management 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
Investigated Vaccine: SARS-CoV-2 mRNA vaccine 
Anaphylactic reactions 
Class-effect for all vaccines 
(even non-adjuvanted) (24) 
Observation period after 
vaccination for early detection 
and treatment. 
Risk management will also be 
based on Exclusion criterion E07 
(see Section 5.2.1 and 
Section 5.2.2). 
Enhanced COVID-19 
A theoretical safety issue with 
coronavirus vaccines is the 
ability to potentiate the 
frequency and severity of the 
clinical manifestations of 
COVID-19 in vaccinees upon 
further exposure to wild-type 
virus (7). The molecular 
mechanism for this 
immunopathogenesis is not fully 
understood. In the context of 
coronavirus infections, various 
factors have been suggested as 
potentially contributing to the 
phenomenon. These include the 
epitope targeted, the method of 
delivery of the antigen, the 
magnitude of the immune 
responses, the balance between 
binding and functional 
antibodies, the elicitation of 
antibodies with functional 
characteristics such as binding to 
particular Fc receptors, and the 
nature of the Th response (8) (9) 
(10). 
COVID-19-like illness will be 
part of the efficacy objective 
with active and passive 
surveillance. 
It is anticipated that the design of 
the candidate SARS-CoV-2 
mRNA vaccine selected for this 
study will: 
• 
Promote the generation of 
neutralizing antibodies over 
binding antibodies, based on 
data generated with other 
coronavirus vaccine antigens 
(5) (6). 
• 
Produce a favorable T-helper 
(Th)1/Th2 response, likely 
predominantly Th1 biased 
(11). 
Individuals with chronic 
comorbid conditions considered 
to be associated with an 
increased risk of severe 
COVID-19 will be excluded as a 
strategy to mitigate the potential 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Risk Management 
risk of disease enhancement 
(25). 
Taken together, these strategies 
are designed to mitigate the 
theoretical risks of immune 
enhancement of viral infection. 
Refer to IB Section 6 for more 
information regarding potential 
risks. 
Refer to the IB Section 4 for 
more information regarding the 
data from previous non-human 
experience with the LNP.  
 
Study Procedures 
Vasovagal reactions (near-
syncope or syncope), or 
psychogenic reactions to 
needle (vaccine injection or 
blood sampling) 
Anxiety-related reactions can 
occur following, or even before, 
any vaccination as a psychogenic 
response to the needle injection 
or blood draw, and may be 
accompanied by several 
neurological signs such as 
transient visual disturbance, 
paresthesia or seizure-like 
activity. 
Observation period after 
vaccination for early detection 
and treatment. 
Theoretical risk that 
participant can be exposed to 
other SARS-CoV-2 infected 
individuals 
SARS-CoV-2 infection is highly 
contagious. SARS-CoV-2 
spreads through respiratory 
secretion or droplets. 
Transmission may also be 
possible via contaminated 
surfaces.  
Exposure can theoretically occur 
as a result of study procedures, 
including visits to the 
investigational sites and physical 
interactions with study staff. 
Study sites are to set up 
appropriate infection control 
measures to prevent participants 
from getting exposed during the 
study visits. Details to be 
described in the operating 
procedures.  
Participant contact with other 
individuals when visiting study 
site (study site to set up system) 
should be minimized. 
Protective material (eg, masks 
and gowns) to be used in sites. 
Home visit option for 
completion of study procedures 
in the setting of containment 
measures to minimize exposure. 
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2.3.2 
Benefits from Study Participation 
While the benefit and risks of the candidate vaccine formulation at the individual level are largely 
unknown, study participation and study conduct is considered fundamental from the societal 
perspective towards the goal of finding a vaccine to help control the pandemic and decrease 
individual and public health burden of COVID-19 illness and SARS-CoV-2 infection.  
2.3.3 
Overall Benefit-Risk Conclusion 
Considering the significant medical need, scale of the pandemic, urgent requirement for measures 
to curb the disease, together with actions taken to minimize risk to participants enrolled in the 
study, there is no unreasonable and significant risk of illness or injury for the participants. 
3 
Objectives and Endpoints 
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
Safety 
To describe the safety profile of all 
participants in each age group and each 
study intervention group up to 
12 months post-last dose. 
Safety 
• 
Presence of unsolicited systemic AEs reported in 
the 30 minutes after each injection 
• 
Presence of solicited injection site reactions and 
systemic reactions (pre-listed in the participant’s 
Diary Card [DC] and Case Report Form [CRF]) 
occurring up to 7 days after each injection 
• 
Presence of unsolicited AEs reported up to 21 days 
after each injection 
• 
Presence of medically attended adverse events 
(MAAEs) throughout the study 
• 
Presence of serious adverse events (SAEs) and 
adverse events of special interest (AESIs) 
throughout the study 
• 
Presence of out-of-range biological test results up 
to 8 days post-last dose (ie, up to Day [D] 09 for 
Cohort 1 and up to D30 for Sentinel Cohort and 
Cohort 2) 
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Objectives 
Endpoints 
Immunogenicity 
To describe the neutralizing antibody 
profile at D01, D22, and D36 of each 
study intervention group. 
Immunogenicity 
Neutralizing antibody titers against the SARS-CoV-2 
D614G variant will be measured with the neutralization 
assay 
• 
Antibody titer at D01, D22, and D36 
• 
Fold-rise (fold-rise in serum antibody neutralization 
titer post-vaccination relative to D01) at D22, and 
D36 
• 
2-fold and 4-fold-rise in serum neutralization titer 
(post/pre) relative to D01 at D22, and D36 
• 
Occurrence of neutralizing antibody seroconversion 
defined as baseline values below lower limit of 
quantification (LLOQ) with detectable 
neutralization titer above assay LLOQ at D22 and 
D36 
Secondary 
 
Immunogenicity 
1) To describe binding antibody 
profile at D01, D22, D36, D91 
(Cohort 1) or D112 (Sentinel 
Cohort and Cohort 2), D181 
(Cohort 1) or D202 (Sentinel 
Cohort and Cohort 2), and D366 
(Cohort 1) or D387 (Sentinel 
Cohort and Cohort 2) of each study 
intervention group. 
2) To describe the neutralizing 
antibody profile at D91 (Cohort 1) 
or D112 (Sentinel Cohort and 
Cohort 2), D181 (Cohort 1) or D202 
(Sentinel Cohort and Cohort 2), and 
D366 (Cohort 1) or D387 (Sentinel 
Cohort and Cohort 2) of each study 
intervention group. 
 
Immunogenicity 
Binding antibody titers to trimerized SARS-CoV-2 S 
protein will be measured for each study intervention 
group with the enzyme-linked immunosorbent assay 
(ELISA) method 
• 
Individual anti-S antibody concentration at D01, 
D22, D36, D91 (Cohort 1) or D112 (Sentinel 
Cohort and Cohort 2), D181 (Cohort 1) or D202 
(Sentinel Cohort and Cohort 2), and D366 
(Cohort 1) or D387 (Sentinel Cohort and Cohort 2) 
• 
Individual anti-S antibody concentration ratio (fold-
rise in serum ELISA concentration post-vaccination 
relative to D01) at D22, D36, D91 (Cohort 1) or 
D112 (Sentinel Cohort and Cohort 2), D181 
(Cohort 1) or D202 (Sentinel Cohort and Cohort 2), 
and D366 (Cohort 1) or D387 (Sentinel Cohort and 
Cohort 2) 
• 
Fold-rise in anti-S antibody concentration (post/pre) 
≥ 2 and ≥ 4 at D22, D36, D91 (Cohort 1) or D112 
(Sentinel Cohort and Cohort 2), D181 (Cohort 1) or 
D202 (Sentinel Cohort and Cohort 2), and D366 
(Cohort 1) or D387 (Sentinel Cohort and Cohort 2) 
Neutralizing antibody titers against the SARS-CoV-2 
D614G variant will be measured with the neutralization 
assay 
• 
Antibody titer at D91 (Cohort 1) or D112 (Sentinel 
Cohort and Cohort 2), D181 (Cohort 1) or D202 
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Objectives 
Endpoints 
(Sentinel Cohort and Cohort 2), and D366 
(Cohort 1) or D387 (Sentinel Cohort and Cohort 2) 
• 
Fold-rise (fold-rise in serum neutralization titer 
post-vaccination relative to D01) at D91 (Cohort 1) 
or D112 (Sentinel Cohort and Cohort 2), D181 
(Cohort 1) or D202 (Sentinel Cohort and Cohort 2), 
and D366 (Cohort 1) or D387 (Sentinel Cohort and 
Cohort 2) 
• 
2-fold and 4-fold-rise in serum neutralization titer 
(post/pre) relative to D01 at D91 (Cohort 1) or 
D112 (Sentinel Cohort and Cohort 2), D181 
(Cohort 1) or D202 (Sentinel Cohort and Cohort 2), 
and D366 (Cohort 1) or D387 (Sentinel Cohort and 
Cohort 2) 
• 
Occurrence of neutralizing antibody 
seroconversion, defined as values below LLOQ at 
D91 (Cohort 1) or D112 (Sentinel Cohort and 
Cohort 2), baseline with detectable neutralization 
titer above assay LLOQ at D181 (Cohort 1) or 
D202 (Sentinel Cohort and Cohort 2), and D366 
(Cohort 1) or D387 (Sentinel Cohort and Cohort 2) 
Efficacy 
1) To describe the occurrence of 
virologically-confirmed 
COVID-19-like illness and 
serologically-confirmed 
SARS-CoV-2 infection. 
2) To evaluate the 
correlation/association between 
antibody responses to SARS-CoV-2 
mRNA vaccine and the risk of 
virologically-confirmed 
COVID-19-like illness and/or 
serologically-confirmed 
SARS-CoV-2 infection. 
Efficacy 
• 
Virologically-confirmed COVID-19-like illness as 
defined by specified clinical symptoms and signs 
and confirmed by a positive result for SARS-CoV-2 
nucleic acid viral detection assay 
• 
Serologically-confirmed SARS-CoV-2 infection as 
defined by SARS-CoV-2 Nucleoprotein specific 
antibody detection immunoassay  
• Correlates of risk/protection based on antibody 
responses to SARS-CoV-2 as evaluated using virus 
neutralization or ELISA, considering virologically-
confirmed COVID-19-like illness and/or 
serologically-confirmed SARS-CoV-2 infection as 
defined above 
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Objectives 
Endpoints 
Exploratory 
 
Immunogenicity 
1) To assess the T-cell cytokine profile 
at D01, D22 and D36 in the AIT 
subset. 
2) To further assess the cellular 
immune response at D01, D22, D36, 
and D112 in the AIT subset. 
Immunogenicity 
• 
T-helper cell (Th1) and Th2 cytokines measured in 
whole blood following stimulation with full-length 
S protein at D01, D22 and D36 
• 
T cell responses measured in PBMCs following 
stimulation with full-length S protein and pools of 
S antigen peptides by intracellular cytokine staining 
at D01, D22 and D36 
• 
Spike–Specific IgG/IgA Memory B Cells measured 
by FluoroSpot assay in peripheral blood 
mononuclear cells after polycloncal stimulation 
before vaccination (D01) and at 3-month after 
second vaccination (D112) 
3) To describe the ratio between 
neutralizing antibodies and binding 
antibodies. 
• Ratio between binding antibody (ELISA) 
concentration and neutralizing antibody titer 
4) To describe the neutralizing 
antibody response to emergent 
SARS-CoV-2 variant strains at each 
pre-defined time point of each study 
intervention group. 
Neutralizing antibody titers against the SARS-CoV-2 
variant strains will be measured with the neutralization 
assay 
• 
Antibody titer at each pre-defined time point 
• 
Fold-rise (fold-rise in serum antibody neutralization 
titer post-vaccination relative to D01) at each pre-
defined time point 
• 
2-fold rise and 4-fold-rise in serum neutralization 
titer (post/pre) at each pre-defined post-vaccination 
timepoint 
• 
Responders, defined as participants who had 
baseline values below LLOQ with detectable 
neutralization titer above assay LLOQ at each pre-
defined post-vaccination timepoint and participants 
with baseline values above LLOQ with a 4-fold 
increase in neutralizing antibody titers at each pre-
defined post-vaccination timepoint 
Other 
To evaluate other emerging biomarkers 
for immune profiling (further 
characterization of humoral and/or 
cellular responses which may include 
cell profiling), as effect modifiers (may 
include viral characterization) or as 
correlates of risk/protection. 
Biomarker measurement at baseline, respiratory 
samples, and/or post-vaccination visits (D22, D36, D91 
[Cohort 1] or D112 [Sentinel Cohort and Cohort 2], 
D181 [Cohort 1] or D202 [Sentinel Cohort and Cohort 
2]), and D366 (Cohort 1) or D387 (Sentinel Cohort and 
Cohort 2) 
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4 
Study Design 
4.1 
Overall Design 
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design 
Type of design 
Phase I/II, first-in-human, multi-center, safety and 
immunogenicity study comprised of 2 sequential cohorts: 
• Lead-in, open-label, Sentinel Cohort (initial target of 
25 participants) with Complete Sentinel Early Safety 
Data Reviews (CS-ESDRs) 
In case an alert threshold is met in a dose-level group, 
the Sentinel Cohort for the corresponding dose-level 
group could be expanded to reach a total of 
approximately 25 participants (Table 1.1). 
• Randomized, modified double-blind, placebo-controlled 
Full Enrollment Cohort (initial target of 308 participants, 
but actual number could be lower as it will be 
determined by dose-levels progressing after CS-ESDR). 
Includes Cohort 1 and Cohort 2 (Table 1.2). 
Phase 
I/II 
Control method 
• Open-label, without placebo group for Sentinel Cohort 
• Placebo-controlled for Full Enrollment Cohort 
Study population 
Healthy, adults 18 years of age and older without prior 
serologic evidence of SARS-CoV-2 infection 
Level and method of blinding 
For Sentinel Cohort 
• Open-label without blinding of participants, site 
Investigators and staff, and Sponsor  
• No blinding for injection schedule as all participants will 
receive 2 vaccinations 
For Full Enrollment Cohort 
• Blinding for vaccine group assignment (formulation): 
participants, outcome assessors, Investigators, laboratory 
personnel, Sponsor study staff  
• No blinding for injection schedule 
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• Only study site staff who prepare and administer the 
vaccine and are not involved with the safety evaluations 
will be unblinded to study intervention assignment  
Study intervention assignment 
method 
The entire study population will be comprised of 
2 sequential cohorts: the Sentinel Cohort and the Full 
Enrollment Cohort. 
• Sentinel Cohort: participants will be 18-49 years of age 
and will be assigned to receive 2 injections of one of the 
3 dose-levels of the study vaccine, 21 days apart, 
enrolled in an open-label, dose-escalation manner. The 
Sentinel Cohort is comprised of the Initial Sentinel 
Cohorts for the 
 µg and the 
 µg dose-levels and the 
Expanded Sentinel Cohort for the 
 µg (Figure 1.5). As 
the study progresses, further addition of participants can 
occur from the 
 µg Initial Sentinel participants and/or 
possibly the 
 µg and 
 µg Expanded Sentinel 
Cohorts. 
• Full Enrollment Cohort: participants will be 18 years of 
age and above and will be randomized to receive either 
1 injection (Cohort 1) or 2 injections, 21 days apart 
(Cohort 2), of one of the 3 dose-levels of the study 
vaccine or placebo. The Full Enrollment Cohort will be 
stratified by age: targeting a total of up to 
140 participants in the 18 through 49 years and up to 
168 participants in the ≥ 50 years age groups. 
Number of participants 
• a target of 25 participants in the Initial Sentinel Cohort 
(if the 
 µg dose escalation is reached) and 
20 participants in the Expanded Sentinel Cohort for the 
 µg dose-level; additional participants if other dose-
level groups of the Sentinel Cohort are expanded; 
• a target of 308 participants in the Full Enrollment Cohort 
(if all doses progress); 
• 5 participants 18 through 49 years of age have already 
been enrolled in the Initial Sentinel Cohort for the low-
dose group. 
Intervention groups 
Sentinel Cohort: participants will be assigned to one of the 
3 groups to receive the ultra-low-dose (
 µg), low-dose 
(
 µg), or medium-dose (
 µg). Participants in this cohort 
will be dosed in a stepwise open-label manner. 
Full Enrollment Cohort: within each cohort (ie, Cohort 1 and 
Cohort 2), participants will be randomized to up to 4 groups 
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to receive the ultra-low-dose (
 µg), low-dose (
 µg), 
medium-dose (
 µg), or placebo. 
The ratio for each active arm selected for progression into 
the Full Enrollment Cohort versus placebo will be 2:1 (ie, 
ratio of 2:2:2:1 if all dose levels advance into the Full 
Enrollment Cohort). 
See also  Table 4.2 and Table 4.3 below. 
Total duration of study 
participation 
Approximately 365 days post-last dose: 
• All Sentinel Cohort participants: approximately 386 days 
duration total 
• Cohort 1 of Full Enrollment Cohort: approximately 365 
days duration total 
• Cohort 2 of Full Enrollment Cohort: approximately 386 
days duration total 
Countries 
United States, Honduras 
Use of an Independent Data 
Monitoring Committee, Dose-
Escalation Committee, or 
similar review group 
No 
Modification of Study Design Following the Protocol Amendment 
In the original protocol, the first 15 participants to receive the SARS-CoV-2 mRNA vaccine were 
to be enrolled in a Safety Sentinel Cohort. These participants were to receive 2 injections of the 
study intervention, 21 days apart, in an open-label, dose-escalation manner. Five participants were 
to be enrolled in each of the 3 dose-level groups 
 
 as shown in Figure 1.4. 
As planned in the original protocol, 5 participants were assigned to the low-dose-level of 
 μg, 
received their first injection, and were contacted by telephone on D03 to document local and 
systemic solicited reactions as well as unsolicited adverse events (AEs). 
 
 
  
• The 5 participants in the low-dose (
 µg) group continued their participation in the study. 
Following the review of the D01-D09 safety and reactogenicity data, the SMT decided that 
administration of the second study intervention 21 days after the first one could proceed as 
planned in the original protocol.  
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• As per this protocol amendment, the ultra-low-dose (
 µg) group will be introduced. The 
10 participants in this new Sentinel Cohort group will receive their first vaccination and will 
be contacted by telephone on D03 to document local and systemic solicited reactions as well 
as unsolicited AEs during this period in the CRF. 
• Also, concurrent with the initiation of the 
 µg Initial Sentinel Cohort, as per this protocol 
amendment, the Expanded Sentinel Cohort for the 
 µg dose will enroll an additional 20 
participants to better understand the reactogenicity at this dose-level in a larger group of 
participants. 
The progression of the Initial and possible Expanded Sentinel Cohorts are displayed in Figure 1.1. 
The Expanded Sentinel Cohort participants in the 
 µg dose-level will be contacted by telephone 
on D03 post-vaccination to document local and systemic solicited reactions as well as unsolicited 
AEs during this period. Based on the assessment of alert thresholds and other safety parameters 
for the 
 µg dose Expanded Sentinel Cohort, the SMT will determine whether or not the 
10 Initial Sentinel Cohort participants for the medium-dose-level of 
 μg will be vaccinated.  
In addition, ad hoc SMTs for any Sentinel Cohort group may occur to evaluate D01-D09 
additional safety data, including laboratory data as needed, to better understand safety. Such ad 
hoc SMT evaluations will inform study progression, especially if any Sentinel Cohort groups 
reach the time of second vaccination before CS-ESDR-1 takes place. 
For the 
 µg and 
 µg dose-level groups, an Expanded Sentinel Cohort may be triggered if an 
alert threshold (see list of threshold in Section 8.4.1) is met in the context of no major safety 
concerns and the SMT judges that further data is needed to cautiously characterize the safety and 
reactogenicity of the product at a given dose-level prior to triggering study progression decisions 
(within the same dose-level arm, or in relation to progression to other dose-levels). In case, the 
Expanded Sentinel Cohort for the ultra-low-dose is triggered, it may run concurrently with the 
medium-dose Initial or Expanded Sentinel Cohort groups (Figure 1.5). It is to be noted that, if 
vaccination in the ultra-low- and medium-dose Sentinel Cohort groups do not run concurrently, 
the possible triggering of an Expanded Sentinel Cohort for the ultra-low-dose group will not 
impact enrollment in the medium-dose group. 
Intervention Groups 
The Initial Sentinel Cohort participants will be 18 through 49 years of age and will be assigned to 
receive 2 injections of the study intervention, 21 days apart, in an open-label manner. Clinical 
safety laboratory evaluations will be performed at screening and 8 days after each injection. The 
5 participants in the low-dose group have already been enrolled. The total number of participants 
to be enrolled in the Sentinel Cohort, including possibly expanded dose-level groups, is shown in 
Table 4.2. 
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Table 4.2: Planned sample size (Sentinel Cohort; 18 through 49 years) 
Cohort 
Group 
Dose-level* 
Initial 
Sentinel 
Cohort 
N 
Expanded 
Sentinel 
Cohort† 
N 
Total Sentinel 
Cohort 
Sentinel 
Cohort: 
2 injections 
1 
 µg 
10 
15 
25 
2 
 µg 
5 
20 
25 
3 
 µg 
10 
15 
25 
* Formulation: SARS-CoV-2 mRNA: ultra-low-dose (
 µg); low-dose (
 µg); medium-dose (
 µg). 
† The Expanded Sentinel Cohort for a corresponding dose-level may be triggered only after careful assessment of 
the Initial Sentinel Cohort for the frequency, severity, and duration of adverse events and proceed if there are no 
major safety concerns and the SMT judges that further data is needed to cautiously characterize the safety and 
reactogenicity of the vaccine at a given dose-level prior to triggering study progression decisions. 
The Full Enrollment Cohort includes both Cohort 1 and Cohort 2. Participants in Cohort 1 of the 
Full Enrollment Cohort (hereafter referred to as Cohort 1) will receive a single injection of study 
intervention while participants in Cohort 2 of the Full Enrollment Cohort (hereafter referred to as 
Cohort 2) will receive 2 vaccinations (to be given 21 days apart), of one of the study interventions 
(ultra-low-dose [
 µg], low-dose [
 µg], medium-dose [
 µg] or placebo) at D01 (VAC1). 
The Full Enrollment Cohort planned sample size, assuming all dose-levels progress to full 
enrollment, is presented in Table 4.3. 
Table 4.3: Full Enrollment Cohort - planned sample size 
Cohort 
Group 
Dose-level* 
N 
Total 
18-49 years 
≥ 50 years 
Cohort 1:  
1 injection 
1 
 µg 
20 
24 
44 
2 
 µg 
20 
24 
44 
3 
 µg 
20 
24 
44 
4 
Placebo 
10 
12 
22 
Cohort 2:  
2 injections 
5 
 µg 
20 
24 
44 
6 
 µg 
20 
24 
44 
7 
 µg 
20 
24 
44 
8 
Placebo 
10 
12 
22 
* Formulation: SARS-CoV-2 mRNA: ultra-low-dose (
 µg); low-dose (
 µg); medium-dose (
 µg). 
Note: A subset of up to 77 randomly selected participants in Cohort 2 (approximately 50% of participants in each 
of Groups 5 to 8, under 18-49 years and ≥ 50 years age sub-groups) will be included in an Additional 
Immunological Tests (AIT) subset. 
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Study Design 
Sentinel Cohorts 
Participants in the Sentinel Cohort will receive the first injection of the study intervention (ultra-
low-dose [
 µg], low-dose [
 µg], or medium-dose [
 µg] at D01 (Vaccination [VAC] 1) in a 
staged fashion. Refer to Figure 1.5 for the graphical design of the Sentinel Cohort. 
Participants from the Sentinel Cohort will receive their second vaccination (VAC2), 21 days after 
VAC1, if deemed appropriate after SMT data review of safety and reactogenicity data post VAC1. 
Participants in each the ultra-low-, low-, and medium-dose groups will receive their second 
vaccination in the same fashion as the first vaccination with intervening SMTs assessing early 
reactogenicity. Participants will be contacted by phone on D03 to collect D01-03 safety data and 
SMT evaluation for each group of Sentinel participants. 
Complete Sentinel ESDR and Full Enrollment Cohort 
The first CS-ESDR (ie, CS-ESDR-1) will be performed for all Sentinel Cohort participants after 
safety data, including local and systemic AEs, unsolicited AEs, and biological safety laboratory 
parameters, is obtained from D01-D09 following the first injection. This unblinded review will be 
performed by the Sponsor during the SMT meetings. Details of the planned safety parameters and 
alert thresholds to be examined for the Sentinel Cohort CS-ESDR safety analysis are provided in 
Section 8.4.2. Progression to the Full Enrollment Cohort for selected or all of the dose levels will 
occur after CS-ESDR-1 with evaluation of safety data up to D09 post first vaccination in all 
Sentinel Cohorts participants. 
If no safety signals or major tolerability concerns are identified at CS-ESDR-1, the double-blind 
enrollment of up to 308 participants (vaccine and placebo groups) for the first vaccination of the 
Full Enrollment Cohort (Cohort 1 allocated to the single-injection schedule and Cohort 2 allocated 
to the 2-injection schedule) will be initiated. It is to be noted that the first vaccination in the Full 
Enrollment Cohort may be delayed until after the second vaccination of some of the Sentinel 
Cohort groups or even postponed until after CS-ESDR-2, if deemed necessary by the SMT. 
After CS ESDR-1, participants in Cohort 1 will receive their injection of study intervention while 
participants in Cohort 2 will receive the first of 2 injections of the study intervention at D01 
(VAC1). 
A subsequent safety review (CS-ESDR-2) is planned for all Sentinel Cohort participants during 
which the unblinded SMT will examine the available D22-D30 safety data post-second 
vaccination including local and systemic AEs, unsolicited AEs, and biological safety laboratory 
parameters, and all available MAAEs, SAEs, and AESIs for the Sentinel Cohort participants will 
also be reviewed. If no safety signals or major tolerability concerns are identified during this 
period in the Sentinel Cohort, then all participants in Cohort 2 will progress to get the second 
injection (VAC2). If a safety signal or a major tolerability concern is identified at CS-ESDR-2 for 
the Sentinel Cohort, then Cohort 2 participants for the corresponding dose-level may not receive 
their second vaccination. 
It should be noted that throughout the study, the SMT core members, consisting of Clinical Team 
Leader (Responsible Medical Officer [RMO]), Study Biostatistician, Pharmacovigilance Science 
Expert, and Global Safety Officer, will continuously review blinded safety data, except for the 
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safety reviews for the Sentinel Cohort and the planned interim analyses, during which unblinded 
safety data will be reviewed. Further unblinding may be necessary if any of the halting rules are 
met (see Section 8.4.3) or if there is any safety concern.   
Participants follow-up 
Participants will be followed over the duration of the study for development of symptoms of 
COVID-19-like illness. Participants will receive surveillance phone calls every 2 weeks (± 6 days 
starting after the D43 contact to approximately 6 months) or may be contacted through alternative 
contact methods (text messages, email, and/or home visit) to enquire about the development of 
symptoms of COVID-19-like illness and to remind the participants to contact study staff if they 
experience symptoms of COVID-19-like illness. In addition, all participants will be instructed to 
contact the site if they experience symptoms of a COVID-19-like illness at any time during the 
study. The reporting of events temporally associated with COVID-19-like illness are outlined in 
Table 1.6. 
Authorized for emergency use and Approved SARS-CoV-2 vaccines 
If an approved/authorized SARS-CoV-2 vaccine is available in the country or region where the 
study is conducted, investigators will discuss this information with prospective study participants 
at the time of informed consent who will be encouraged to obtain the approved/authorized 
SARS-CoV-2 vaccine if applicable to them. Recruitment and enrollment of eligible participants 
will proceed only if, despite encouragement, the candidate participant expresses no intention to 
seek an authorized or approved vaccine at least until completion of the key follow-up timepoint 
(D43) of this study for informing progression to further clinical development and dose selection.  
If the participant is enrolled and seeks vaccination of an authorized/approved COVID-19 vaccine 
outside of the study, he/she will be encouraged to discuss this intention proactively with the study 
investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved COVID-19 vaccine, this information would be collected and the 
participant’s data up to the point of receipt of authorized/approved COVID-19 vaccine will be 
included in the primary analysis for immunogenicity and safety. Participants will continue to be 
followed for the duration of the study as per scheduled visits and procedures. Participants will be 
invited to a visit prior to receiving the vaccine and requested to provide a blood sample for 
immunological assessment. Participants will not receive the second vaccination if they have 
received the authorized/approved COVID-19 vaccine between the first and second scheduled 
vaccination. 
4.2 
Scientific Rationale for Study Design 
Rationale for Development Approach 
Sanofi Pasteur’s development of the SARS-CoV-2 mRNA vaccine candidate is taking place in the 
setting of a pandemic. At present, 2 COVID-19 mRNA vaccines and 1 viral vector vaccine have 
received authorization for emergency use in the US and in several countries; however, there is still 
a need for more vaccines to meet the global demand. As such, the emphasis of the development 
plan is to rapidly generate data required to support approval and vaccine deployment in the field. 
This setting mandates consideration of reasonable measures to accelerate development. This 
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first-in-human study proposes several elements to speed up clinical evaluation and are integrated 
into the study design while providing required data for the adequate assessment of the immune 
response profile and safety of the candidate vaccine through efficacy evaluation.  
Most current Sponsors of clinical studies for COVID-19 vaccines have accelerated the clinical 
development of mRNA vaccines based on preclinical safety and toxicological studies for their 
platform LNP complexed with mRNA encoding antigens from other pathogens (different than 
SARS-CoV-2) and not based on specific studies for the SARS-CoV-2/lipid combination. In early 
development, the safety and immunogenicity of the LNP 
 was initially tested 
at Sanofi Pasteur in both mouse and NHP models using mRNA encoding influenza hemagglutinin 
(HA) where it was found to be well tolerated and induced potent HA neutralizing antibodies in the 
range of doses selected for this study. Subsequently, a repeated dose nonclinical toxicology study 
in New Zealand White rabbits with the SARS-CoV-2 mRNA vaccine candidate showed that 3 IM 
injections of the SARS-CoV-2 mRNA vaccine at 3 weeks interval, up to the dose level of 
 µg 
mRNA/injection were locally and systemically well tolerated (data are summarized in the IB). In 
preclinical studies, SARS-CoV-2 mRNA vaccine induced dose-dependent S-specific binding and 
neutralizing antibody response with Th1-biased cellular responses in the mouse model. In the 
NHP model, the SARS-CoV-2 mRNA vaccine induced dose-dependent S-specific binding and 
neutralizing antibody response at doses as low as  µg. Th1-biased cellular responses were 
observed for the 
 µg, 
 µg, and 
 µg (not assessed at the  µg dose in NHP). Moreover, 
hamster challenge studies, designed to assess the protective efficacy of the SARS CoV-2 mRNA 
Vaccine against viral infection and disease, demonstrated that both single- or 2-dose intramuscular 
administration at clinically relevant dose levels protected against COVID-19 disease, as measured 
by the complete prevention of challenge virus induced weight loss and prevention of lung 
infection in vaccinated hamster (refer to the Investigator’s Brochure [IB] for details). Additional 
nonclinical safety evaluations will proceed in parallel to the Phase III clinical study. 
This first-in-human study (VAW00001) design will target an Initial Sentinel Cohort of up to 
25 participants (younger adults only). The option of an Expanded Sentinel Cohort for a 
corresponding dose-level may be triggered if there are no major safety concerns and the SMT 
judges that further data is needed to cautiously characterize the safety and reactogenicity of the 
vaccine at a given dose-level prior to triggering study progression decisions (within the same 
dose-level arm, or in relation to progression to other dose-levels);
 
A CS-ESDR will be performed, including evaluation of safety data through D08 and 
laboratory measures on D09. Upon acceptable safety demonstrated from unblinded review by the 
SMT with limited members of the Sponsor Study Team (RMO, Biostatistician and Programmer, 
Pharmacovigilance Science Expert, and Global Safety Officer), the participants in Cohort 1 and 
Cohort 2 will be enrolled.  
The goal of VAW00001 study will be to select a dose and a vaccination schedule to proceed for 
further clinical evaluation as rapidly as possible. Data up to D43, in addition to preclinical data, 
will support the selection of a dose and schedule to proceed to further clinical development. The 
longer term objective is to longitudinally define the safety and durability of the immune response 
induced by the SARS-CoV-2 mRNA vaccine over the 1 year study duration.  
The key readouts informing the decisions to be applied in future clinical development will include 
data for all participants, who received the 1- or 2-injection schedules. Participants will belong to 
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either the younger (18-49 years of age) or the older (50 years of age and above) age stratum. The 
critical data includes the data through D43 post-last vaccination for all participants, including 
participants enrolled in the Sentinel Cohort, and covers: 
a) Safety: immediate AEs, local and systemic reactogenicity through D08, biological safety 
parameters on D09 post each injection, unsolicited AEs, MAAEs, AESIs, and SAEs through 
D21 post each injection 
b) Neutralizing antibody and binding antibody profiles at D01, D22, and D36  
c) Measurement of Th1 and Th2 cytokines in whole blood following stimulation with 
full-length S protein at D01, D22, and D36 in a randomized subset of Cohort 2 participants 
The criteria utilized to define progression to further clinical development will include the above 
clinical data but will also take into account nonclinical safety, immunogenicity, and efficacy (after 
virus challenge) data.  
Given the important public health need, initial intended use of the SARS-CoV-2 mRNA vaccine is 
for adults, 18 years of age and older. It is planned that studies to support use of the vaccine in 
children 6 months to 17 years of age will be conducted after the initial data from studies in adults 
are available.  
Rationale for Injection Schedule 
This Phase I/II study will evaluate 2 different vaccination schedules: 1 vaccination or 
2 vaccinations, given 21 days apart. In the setting of a pandemic, a single injection would be ideal 
to be able to protect vaccinees as early as possible. However, given the lack of pre-existing 
immune responses to SARS-CoV-2, it is possible that 2 injections will be necessary.  
A separation of 21 days for the 2-injection schedule is proposed for this program, mirroring the 
schedule that was evaluated and approved for pandemic influenza vaccines to address the 2009 
H1N1 influenza pandemic (AS03 adjuvanted vaccines Pandemrix™, Arepanrix™; and AF03 
adjuvanted Humenza vaccine). This schedule results in a second injection of the vaccine being 
administered earlier than with other common vaccines with longer separations between injections 
(ie, 28 days), thus aiming at earlier generation of potentially protective immune responses. This 
may be of particular interest in an ongoing pandemic setting and is also supported by the 
preclinical studies for the SARS CoV-2 mRNA vaccine.  
In addition to antibody response 21 days after injection, durability after a single injection also 
needs to be taken into account for schedule selection, as peak immune responses after 1 injection 
may be adequate but could (at least theoretically) wane rapidly, potentially leaving vaccinees at 
risk in the event of ongoing circulation of novel coronavirus. Therefore, antibody titers at D22 
(21 days after the first vaccination) and D36 (14 days after the second vaccination) after 1 or after 
2 injections are considered relevant for informing schedule selection. 
Rationale for Study Arms  
Participants in the Sentinel Cohort will receive injections of the study intervention (ultra-low-dose 
[
 µg], low-dose [
 µg], or medium-dose [
 µg]) at D01 (VAC1) and D22 (VAC2) in a staged 
fashion. Participants in Cohort 1 and Cohort 2 are planned to receive 1 injection of the study 
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intervention (ultra-low-dose [
 µg], low-dose [
 µg], medium-dose [
 µg], or placebo) at D01 
(VAC1). Participants in Cohort 2 of the Full Enrollment Cohort will receive a second vaccination 
of study intervention (same study intervention as received at D01) at D22 (VAC2). Comparisons 
between Cohort 1 and Cohort 2 will inform decisions on schedule selection. Comparison between 
dose-levels for safety and immunogenicity will inform decisions on dose selection for the 
Phase III study. The placebo arm in the Full Enrollment Cohort allows for blinding and also 
provides background information for safety assessments.  
Rationale for Immunogenicity Objectives and Endpoints 
The primary immunogenicity endpoint, based on neutralizing antibodies, is expected to provide 
the most relevant evaluation of functional immune responses for this vaccine candidate, supported 
by controlled human infection studies that have identified the presence of pre-challenge 
neutralizing antibodies as predictive of protection from coronavirus infection or symptoms 
following challenge (26) (27). 
This study will also include exploratory immunogenicity objectives to further describe the 
immune response, including T cell and memory B cell responses at D01, D22, D36, and D112 for 
each study intervention group in a subset of up to 77 participants. Based on the preclinical studies 
undertaken with prior SARS vaccine candidates, and the possible immunopathologic mechanisms 
identified in these studies, the Sponsor proposes to evaluate cytokine secretion associated with a 
Th1 and Th2 T-cell profile generated following vaccination. To balance operational 
considerations and to improve the interpretability of cell-mediated immunity (CMI) data given the 
limited experience with CMI measurements for this pathogen, a longitudinal sampling strategy 
was prioritized over increasing sample collection at a single post-vaccination time-point. Thus, 
CMI studies will be performed in a subset of randomized participants in Cohort 2 of the Full 
Enrollment Cohort, with samples obtained at baseline, and following first and second injection. In 
addition, to characterize the relative induction of functional to total antibody responses generated 
following vaccination, the ratio between neutralizing antibodies and binding antibodies will be 
described. Given the emerging knowledge about SARS-CoV-2 evolution and variants prevalence 
across the globe, exploratory endpoints will include the evaluation of immune responses directed 
towards relevant viral variants.  
Rationale for Study Population 
The study will enroll participants with no history of COVID-19 and no serologic evidence of 
SARS-CoV-2 infection by rapid diagnostic test at the screening visit. Inclusion of individuals with 
prior exposure to SARS-CoV-2 would be expected to influence immunogenicity measures. The 
aim of this study is to identify the dose-level of SARS-CoV-2 mRNA vaccine formulation that 
best supports an immune response in the naïve population, considered the population most at need 
for a preventive solution against SARS-CoV-2. While protection against reinfection after natural 
infection is not yet clearly demonstrated, data from human challenge models with other 
coronaviruses suggests at least short to midterm protection (28) (26). In addition, studies in NHPs 
indicate that animals infected with SARS-CoV-2 are protected against reinfection at least in the 
short term (29). While there are reports of previously infected individuals that re-test positive to 
SARS-CoV-2, it is not clear at present whether this is the result of sampling or testing limitations 
(intermittent false negativity), reactivation of the virus, or reinfection. Preliminary data also 
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indicate that in the majority of instances where this has been reported, individuals are 
asymptomatic or have milder symptoms. Taken together, all this information suggests that 
SARS-CoV-2 seropositive individuals may be protected from reinfection, and if reinfection or 
recurrence occurs, the burden of illness is likely to be smaller and potentially associated with 
lesser impact on public health compared to that of seronegative persons. Therefore, the 
immunogenicity and safety data in this study are targeted to be generated in individuals without 
evidence of prior exposure to SARS-CoV-2 infection.  
In this study, we plan to enroll adults 18 years of age and older. Clinical and epidemiological data 
from the COVID-19 pandemic have consistently indicated a higher burden of disease with higher 
risk of severe complications and death in older adults (30). Because of this, we believe including 
older adults in the study is of great relevance to generate data to inform schedule selection that 
will serve the general adult population.  
Clinical and epidemiological data also indicate that advanced age and those with chronic medical 
conditions are at increased risk of severe outcomes associated with COVID-19. The excess 
mortality from COVID-19 illness in the elderly may also be compounded by the higher 
prevalence of comorbidities in this age group (31) (32). Exclusion of individuals with chronic 
medical conditions from this study mitigates the potential risk of exacerbating poor outcomes as a 
result of study participation. The exclusion of individuals with chronic underlying conditions is 
also considered a risk mitigation measure to address the theoretical phenomenon of immune 
enhancement in this study population (17). 
Another risk mitigation strategy is to restrict enrollment for the Sentinel Cohort to younger adults 
18 through 49 years of age. After performing CS-ESDR-1 and if no safety signals or major 
tolerability concerns are identified in this cohort of younger participants, full enrollment will be 
opened to all younger and older age groups simultaneously. The simultaneous enrollment based 
on the inclusion of healthy older adults, at higher risk for severe outcomes and without evidence 
of previous SARS-CoV-2 infection is warranted and will prevent a delay in the program and allow 
rapid data generation to support further clinical development.  
No upper age range is specified as long as other inclusion/exclusion criteria are met. Complete 
exclusion of older individuals from the study would compromise the timely progression of the 
clinical development plan and the deployment of the vaccine to the field (if a sequential 
enrollment of older adults was required), or result in selection of a formulation without knowledge 
about immunogenicity and safety patterns in older adults (if program progression was only 
informed by data from younger adults).  
Furthermore, the Full Enrollment Cohort proposes a relatively balanced representation of the 
younger and older adult strata (ie, up to 140 in younger adults; and up to 168 in older adults; with 
younger adult data further informed by data generated in the Sentinel Cohorts). Data for each dose 
will be generated in both younger adults and older adults, allowing the evaluation of the 
consistency in the patterns of immune response for each dose between the 2 age strata; 
additionally, aggregated “main” effects by age will be evaluable by comparing pooled older adult 
data (enrollment target of approximately 144 participants across vaccine dose-levels) and pooled 
younger adult data (enrollment target of approximately 145 participants across vaccine dose-
levels).  
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Rationale for Blinding 
In the Sentinel Cohort there will be no blinding. However, the Full Enrollment Cohort will be 
double-blind for study intervention (SARS-CoV-2 mRNA vaccine and placebo). Owing to the 
need for mixing of study formulation and diluent to prepare the vaccine, the person preparing and 
administering the study intervention will be unblinded to study intervention assignment. Blinding 
of all other people will minimize the risk of bias arising from the possibility of consciously or 
unconsciously influencing the reporting of study outcome measures and knowledge of the 
formulation administered. 
Rationale for Placebo in Full Enrollment Cohort 
Placebo, rather than a benefit licensed vaccine, will be used for comparison to vaccine to allow 
safety comparisons between vaccine and placebo as currently emergency use authorized 
COVID-19 vaccines are not widely available. The number in the placebo group have been 
decreased to expose fewer participants to placebo. The inclusion of placebo group will also 
maintain the blind, allowing the unbiased evaluation of safety, immunogenicity, and clinical 
outcomes related to COVID-19-like illness and SARS-CoV-2 infection by treatment group. 
Rationale for Staged Enrollment of Study Intervention Groups in Sentinel Cohort 
The proposed Sentinel Cohort will enroll 10 participants for the ultra-low-dose (
 µg) group, 
5 participants for the low-dose group (
 µg), and 10 participants for the medium-dose (
 µg) 
group. All 3 arms can possibly be expanded to a total of approximately 25 participants per dose-
level group in case further data is needed to cautiously characterize the safety and reactogenicity 
of the product at a given dose-level. The Expansion of the Sentinel Cohort 
 
and expansion of the ultra-low- 
or/and medium-dose levels remain as optional. Following amendment of the protocol, the Sentinel 
Cohort will still be enrolled in a dose-escalation manner (for the medium-dose arm) as opposed to 
in a simultaneous fashion. It is generally expected that reactogenicity to vaccine candidates will be 
higher with higher antigen doses. As neither the vaccine candidates nor the LNP utilized in this 
study have been administered to humans before, a cautious sequential approach is advised to 
allow close monitoring of safety/reactogenicity parameters to inform progression from low to 
higher doses. 
4.3 
Justification for Dose 
The selection of the lower-dose formulation for this study is based on the safety and 
immunogenicity from nonclinical studies, on data generated with other mRNA vaccines in 
nonclinical and human studies. Following the safety and reactogenicity data obtained in the 
5 participants in the low-dose group of the Sentinel Cohort, the dose-level range the Sponsor 
originally intended to evaluate 
 was lowered (ie, ultra-
low-, low-, and medium-dose-levels).  
Nonclinical Dose Ranging Safety Studies (nonclinical toxicology) of the LNP 
 
 with an influenza mRNA antigen identified the no-observed-adverse-effect level 
(NOAEL) at 
 µg 
. Initial entry doses selected for this study (
 µg, 
 µg, and 
 µg 
) were all below this NOAEL and were further supported by a Good Laboratory 
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Practice toxicology study. Information gathered based on the experience of other mRNA vaccine 
candidates were also supportive of this dose range. Nonclinical studies performed at Sanofi 
Pasteur in collaboration with Translate Bio have indicated 
 
 has been 
utilized as the LNP in studies evaluating pandemic influenza vaccine candidates (33) that showed 
robust immune responses with doses of 25-50 µg of mRNA. In addition, data with another mRNA 
SARS-CoV-2 vaccine candidate suggested antibody responses similar or higher to those observed 
in convalescent sera with mRNA dose-levels of 25 µg and 100 µg and responses greater for 
individuals receiving the 100 µg dose; they also reported high frequency of Grade 3 systemic 
reactogenicity with a dose-level of 250 µg of mRNA (34). The other mRNA vaccine candidate 
was tested at 2 dose-levels (50 µg and 100 µg) in a Phase II study, and a 100 µg dose progressed 
to a Phase III study and is currently under emergency use authorization (EUA).  
 
 
 
 
 
 
 
 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the last contact 
planned in the Schedule of Activities (SoA) (Section 1.3). 
The end of the study is defined as the date of the last contact of the last participant in the study. 
However, for periodic safety reports, the study is considered completed when the Clinical Study 
Report is finalized. 
5 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
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5.1 
Inclusion Criteria 
5.1.1 
Inclusion Criteria to be Checked at Screening Visit 
Participants are eligible for the screening only if all of the following criteria are met: 
I01: 
Aged ≥ 18 yearsa on the day of inclusion 
I02: 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions applies:  
• Is of non-childbearing potential. To be considered of non-childbearing potential, a 
female must be pre-menarche or post-menopausal for at least 1 year, or surgically 
sterile.  
OR 
• Is of childbearing potential and agrees to use an effective contraceptive method or 
abstinence from at least 4 weeks prior to the first vaccination until at least 12 weeks 
after the last vaccination.  
A participant of childbearing potential must have a negative highly sensitive 
pregnancy test (urine or serum as required by local regulation) within 8 hours before 
the study intervention, see Section 8.4.8 Pregnancy testing.  
I03: 
Informed Consent Form (ICF) has been signed and dated 
I04: 
Able to attend all scheduled visits and to comply with all study procedures 
I05: 
Participant not eligible to receive, based on local guidance, or if eligible does not 
intend to receive an authorized/approved COVID-19 vaccine from first vaccination 
until completion of the key timepoint of D43 of follow-up of this studyb 
5.1.2 
Inclusion Criteria to be Checked at Visit 1 
Participants are eligible for the study enrollment only if all of the following criteria are met: 
I01: 
Aged ≥ 18 yearsc on the day of inclusion 
                                                 
a “≥ 18 years” means from the day of the 18th birthday onwards, with no upper age limit. 
b While recruitment of eligible participants will proceed only if the candidate participant expresses no intention to 
seek an authorized or approved vaccine until completion of the key follow-up timepoint (D43), if the participant is 
enrolled and seeks vaccination of an authorized/approved COVID-19 vaccine outside of the study, he/she will be 
encouraged to discuss this intention proactively with the trial investigator and will be permitted to receive the 
authorized vaccine at any time. If the participant receives the authorized/approved COVID-19 vaccine, this 
information would be collected and the participant’s data up to the point of receipt of authorized/approved 
COVID-19 vaccine will be included in the primary analysis for immunogenicity and safety. Participants will 
continue to be followed for the duration of the trial as per scheduled visits and procedures. Participants will not 
receive the second vaccination if they have received the authorized/approved COVID-19 vaccine between the first 
and second scheduled vaccination (see Section 7.1.2 : Definitive Contraindications). 
c “≥ 18 years” means from the day of the 18th birthday onwards, with no upper age limit. 
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I02: 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions applies:  
• Is of non-childbearing potential. To be considered of non-childbearing potential, a 
female must be pre-menarche or post-menopausal for at least 1 year, or surgically 
sterile.  
OR 
• Is of childbearing potential and agrees to use an effective contraceptive method or 
abstinence from at least 4 weeks prior to the first vaccination until at least 12 weeks 
after the last vaccination.  
A participant of childbearing potential must have a negative highly sensitive 
pregnancy test (urine or serum as required by local regulation) within 8 hours before 
the study intervention, see Section 8.4.8 Pregnancy testing.  
I04: 
Able to attend all scheduled visits and to comply with all study procedures 
I05: 
Participant not eligible to receive, based on local guidance, or if eligible does not 
intend to receive an authorized/approved COVID-19 vaccine from first vaccination 
until completion of the key timepoint of D43 of follow-up of this studya 
5.2 
Exclusion Criteria 
5.2.1 
Exclusion Criteria to be Checked at Screening Visit 
Participants are not eligible for screening if any of the following criteria are met: 
E01: 
History of COVID-19 disease or prior severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection confirmed serologically  
E02: 
Participation at the time of study enrollment (or in the 30 days preceding the first 
study vaccination) or planned participation during the present study period in another 
clinical trial investigating a vaccine, drug, medical device, or medical procedure 
E03: 
Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle 
East Respiratory Syndrome coronavirus [MERS-CoV]) 
                                                 
a While recruitment of eligible participants will proceed only if the candidate participant expresses no intention to 
seek an authorized or approved vaccine until completion of the key follow-up timepoint (D43), if the participant is 
enrolled and seeks vaccination of an authorized/approved COVID-19 vaccine outside of the study, he/she will be 
encouraged to discuss this intention proactively with the trial investigator and will be permitted to receive the 
authorized vaccine at any time. If the participant receives the authorized/approved COVID-19 vaccine, this 
information would be collected and the participant’s data up to the point of receipt of authorized/approved 
COVID-19 vaccine will be included in the primary analysis for immunogenicity and safety. Participants will 
continue to be followed for the duration of the trial as per scheduled visits and procedures. Participants will not 
receive the second vaccination if they have received the authorized/approved COVID-19 vaccine between the first 
and second scheduled vaccination (see Section 7.1.2: Definitive Contraindications). 
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E04: 
Receipt of any vaccine in the 30 days preceding the first study vaccination or planned 
receipt of any vaccine in the 30 days following the last study vaccination except for 
influenza vaccination, which may be received at least 2 weeks before and a minimum 
of 2 weeks after study vaccinesa 
E05: 
Receipt of immune-globulins, blood or blood-derived products in the past 3 months 
E06: 
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) 
E07: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to a vaccine containing any of the same substancesb 
E08: 
Self-reported thrombocytopenia, contraindicating intramuscular vaccination based on 
Investigator’s judgment 
E09: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination based on Investigator’s judgment 
E10: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily 
E11: 
Current alcohol abuse or drug addiction  
E12: 
Chronic illness or condition considered to potentially increase the risk for severe 
COVID illnessc (25) or that, in the opinion of the Investigator, is at a stage where it 
might interfere with study conduct or completiond 
E13: 
Known liver disease or fatty liver 
E14: 
Residence in a nursing home or long-term care facility 
E15: 
Health care workers providing direct patient care for COVID-19 patients 
E16: 
Participants with active or prior documented autoimmune disorder  
                                                 
a While receipt of any vaccine as listed in this criterion is exclusionary for this study, participants are free to receive 
another available COVID-19 vaccine. Participants who receive another COVID-19 vaccine outside this study will 
still be followed for safety until the end of the study, but will be discontinued from study intervention 
administration thereafter (see Section 7.1.2: Definitive Contraindications). 
b The components of SARS-CoV-2 mRNA vaccine are listed in Section 6.1 and in the SARS-CoV-2 mRNA 
Investigator’s Brochure. 
c Factors that may increase the risk of severe COVID illness include: autoimmune disease; cerebrovascular disease; 
chronic pulmonary disease (including moderate-severe asthma, chronic obstructive pulmonary disease, emphysema, 
cystic fibrosis, pulmonary fibrosis); current smoking or chronic smoking in the past year; current vaping; diabetes 
mellitus; cardiovascular disease (including hypertension); chronic renal disease; chronic liver disease; 
immunocompromised condition; neurologic disorder (including dementia), obesity (body mass index ≥ 30); sickle 
cell disease; known thalassemia; and Down syndrome. 
d Chronic illness may include, but is not limited to, psychiatric disorders. 
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E17: 
Moderate or severe acute illness/infection (according to Investigator’s judgment) on 
the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A 
prospective participant should not be included in the study until the condition has 
resolved or the febrile event has subsided 
E18: 
Receipt of any therapy known to have in-vitro antiviral activity against SARS-CoV-2 
within 72 hours prior to BL00001 blood drawa or planned use of such therapy 
72 hours prior to BL0002 or BL0003 (study immunogenicity blood draws at D22 and 
D36) 
E19: 
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 participant has a primary physician who is not the Investigator, the site should contact this 
physician, with the participant’s consent to inform him/her of the participant’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.2.2 
Exclusion Criteria to be Checked at Visit 1  
Participants are not eligible for the study enrollment if any of the following criteria are met: 
E01: 
History of COVID-19 disease or prior severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection confirmed serologically  
E02: 
Participation at the time of study enrollment (or in the 30 days preceding the first 
study vaccination) or planned participation during the present study period in another 
clinical trial investigating a vaccine, drug, medical device, or medical procedure 
E03: 
Prior administration of a coronavirus vaccine (SARS-CoV-2, SARS-CoV, Middle 
East Respiratory Syndrome coronavirus [MERS-CoV]) 
E04: 
Receipt of any vaccine in the 30 days preceding the first study vaccination or planned 
receipt of any vaccine in the 30 days following the last study vaccination except for 
influenza vaccination, which may be received at least 2 weeks before and a minimum 
of 2 weeks after study vaccinesb  
E05: 
Receipt of immune-globulins, blood or blood-derived products in the past 3 months 
                                                 
a Therapy/treatment including, but not limited to, favipiravir, lopinavir/ritonavir, remdesivir, arbidol, chloroquine, 
hydroxychloroquine, ivermectin. 
b While receipt of any vaccine as listed in this criterion is exclusionary for this study, participants are free to receive 
another available COVID-19 vaccine. Participants who receive another COVID-19 vaccine outside this study will 
still be followed for safety until the end of the study, but will be discontinued from study intervention 
administration thereafter (see Section 7.1.2: Definitive Contraindications). 
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E06: 
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) 
E07: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to a vaccine containing any of the same substancesa 
E08: 
Self-reported thrombocytopenia, contraindicating intramuscular vaccination based on 
Investigator’s judgment 
E09: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination based on Investigator’s judgment 
E10: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily 
E11: 
Current alcohol abuse or drug addiction  
E12: 
Chronic illness or condition considered to potentially increase the risk for severe 
COVID illnessb (25) or that, in the opinion of the Investigator, is at a stage where it 
might interfere with study conduct or completionc 
E13: 
Known liver disease or fatty liver 
E14: 
Residence in a nursing home or long-term care facility 
E15: 
Health care workers providing direct patient care for COVID-19 patients 
E16: 
Participants with active or prior documented autoimmune disorder  
E17: 
Moderate or severe acute illness/infection (according to Investigator’s judgment) on 
the day of vaccination or febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]). A 
prospective participant should not be included in the study until the condition has 
resolved or the febrile event has subsided. 
E18: 
Receipt of any therapy known to have in-vitro antiviral activity against SARS-CoV-2 
within 72 hours prior to BL00001 blood drawd or planned use of such therapy 
                                                 
a The components of SARS-CoV-2 mRNA vaccine are listed in Section 6.1 and in the SARS-CoV-2 mRNA 
Investigator’s Brochure. 
b Factors that may increase the risk of severe COVID illness include: autoimmune disease; cerebrovascular disease; 
chronic pulmonary disease (including moderate-severe asthma, chronic obstructive pulmonary disease, emphysema, 
cystic fibrosis, pulmonary fibrosis); current smoking or chronic smoking in the past year; current vaping; diabetes 
mellitus; cardiovascular disease (including hypertension); chronic renal disease; chronic liver disease; 
immunocompromised condition; neurologic disorder (including dementia), obesity (body mass index ≥ 30); sickle 
cell disease; known thalassemia; and Down syndrome. 
c Chronic illness may include, but is not limited to, psychiatric disorders. 
d Therapy/treatment including, but not limited to, favipiravir, lopinavir/ritonavir, remdesivir, arbidol, chloroquine, 
hydroxychloroquine, ivermectin. 
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72 hours prior to BL0002 or BL0003 (study immunogenicity blood draws at D22 and 
D36 
E19: 
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 
E20: 
Platelet count, renal function tests (serum creatinine), liver function tests (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, 
prothrombin time [PT], partial thromboplastin time [PTT] with international 
normalized ratio [INR]), screening laboratory results that fall into the range of values 
that are Grade 1 or greater. For the remaining screening laboratory parameters that fall 
into the range of values that are Grade 2 or greater OR Grade 1 that are deemed 
clinically significant in the opinion of the Investigator (Grade 1 values for laboratory 
parameters other than those specified here and deemed not clinically significant may 
be enrolled at the Investigator’s discretion). 
E21: 
Positive test for chronic active Hepatitis B surface antigen, Hepatitis B core antibody, 
Hepatitis C antibody, or human immunodeficiency virus (HIV) antibody, either from 
testing conducted within 4 weeks prior to enrollment or from blood work collected at 
screening visit 
If the participant has a primary physician who is not the Investigator, the site should contact this 
physician, with the participant’s consent to inform him/her of the participant’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.3 
Lifestyle Considerations 
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria not met, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened. 
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6 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: routine vaccines administered outside of study protocol are not considered as study 
interventions.  
6.1 
Study Interventions Administered 
Study interventions are described in Table 6.1. 
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Table 6.1: Identity of study interventions 
Intervention Name 
SARS-CoV-2 mRNA 
(ultra-low-dose) 
SARS-CoV-2 mRNA 
(low-dose) 
SARS-CoV-2 mRNA 
(medium-dose) 
Placebo 
Study Groups 
Group 1 (Sentinel Cohort), 
Groups 1 and 5 (Full Enrollment 
Cohort) 
Group 2 (Sentinel Cohort), 
Groups 2 and 6 (Full Enrollment 
Cohort) 
Group 3 (Sentinel Cohort), 
Groups 3 and 7 (Full Enrollment 
Cohort) 
Groups 4 and 8 (Full 
Enrollment Cohort) 
Refer to Table 4.2 and Table 4.3 for group numbers. 
Use 
Experimental 
Experimental 
Experimental 
Placebo - comparator 
Type 
Vaccine 
Vaccine 
Vaccine 
Vaccine 
Dose Formulation 
Sterile suspension (white to off-white), single use dose vial diluted with buffer at the study site according to 
dose preparation protocol 
Liquid, in a single-vial 
presentation 
Unit Dose Strengths 
Each 0.5 mL dose of study intervention after dilution will contain the following: 
• 0.9% normal saline 
• SARS-CoV-2 mRNA, ultra-
low-dose (
 µg) 
• LNP 
 
• SARS-CoV-2 mRNA, low-dose 
(
 µg) 
• LNP 
 
• SARS-CoV-2 mRNA, 
medium-dose (
 µg) 
• LNP 
 
The investigational product will be formulated as a single dose of an mRNA-LNP complex and will be 
diluted to the required mRNA dose at the study site using a buffer diluent. 
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Intervention Name 
SARS-CoV-2 mRNA 
(ultra-low-dose) 
SARS-CoV-2 mRNA 
(low-dose) 
SARS-CoV-2 mRNA 
(medium-dose) 
Placebo 
Excipients/Diluent 
None 
Dosage Level 
0.5 mL per dose 
0.5 mL per dose 
0.5 mL per dose 
0.5 mL per dose 
Number of 
Doses/Dosing Interval 
Sentinel Cohort: 2 injections, 21 days apart 
Cohort 1: 1 injection 
Cohort 2: 2 injections, 21 days apart 
Cohort 1: 1 injection 
Cohort 2: 2 injections, 21 
days apart 
Route of 
Administration 
Intramuscular injection 
Intramuscular injection 
Intramuscular injection 
Intramuscular injection 
Site of Administration 
Deltoid muscle in the upper arm 
Deltoid muscle in the upper arm 
Deltoid muscle in the upper arm 
Deltoid muscle in the 
upper arm 
Sourcing 
Provided by the Sponsor 
Provided by the Sponsor 
Provided by the Sponsor 
Provided by the Sponsor 
Packaging and 
Labeling 
Each study intervention will be provided in an individual box. Each study intervention (vial) will bear one fixed label and each box will 
bear detachable label(s) and one fixed label containing the dose number. All will be labeled as required per country requirement. 
Batch Number 
To be determined 
To be determined 
To be determined 
To be determined 
 
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6.2 
Preparation/Handling/Storage/Accountability 
The investigational product will be formulated as a single dose of mRNA-LNP complex and will 
be diluted to the required mRNA dose at the study site using a buffer diluent. The product should 
be stored at -80°C prior clinical use. 
Detailed guidance and information are provided in the Operating Guidelines. 
1) The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3) The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
4) Further guidance and information for the final disposition of unused study interventions are 
provided in the Operating Guidelines. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization and Allocation Procedures 
For the Sentinel Cohort: On the day of enrollment, participants 18 to 49 years of age only, who 
meet the eligibility criteria and have signed the Informed Consent Form (ICF), will be assigned to 
the Sentinel Cohort. In this cohort, initially about 25 participants are targeted to be sequentially 
assigned to receive one of the 3 dose-levels (10 participants in the ultra-low-dose [
 µg] group; 
5 participants in the low-dose [
 µg; already dosed before protocol amendment] group; 
10 participants in the medium-dose [
 µg] group as shown in Table 4.2. Participants in this 
cohort will receive 2 injections of the study intervention separated by 21 days. Additional 
participants may be sequentially assigned to a particular dose-level if and when the Expanded 
Cohort for the corresponding lose level is triggered. At the time of this protocol amendment, the 
Expanded Sentinel Cohort for the low-dose (
 µg) has been exercised, and enrollment of an 
additional 20 participants at this dose-level is targeted.  
For the Full Enrollment Cohort: On the day of randomization, participants who meet the eligibility 
criteria and sign the ICF will be stratified by 2 age groups (18-49 years and ≥ 50 years) and then 
be randomly assigned (1:1) to receive 1 injection (Cohort 1) or 2 injections (Cohort 2) of the 
SARS-CoV-2 mRNA vaccine or placebo (as shown in Table 4.3). Within each cohort, participants 
will be randomized to up to 4 groups to receive SARS-CoV-2 mRNA vaccine (ultra-low-dose 
[
 µg], low-dose [
 µg], medium-dose [
 µg], or placebo. The ratio for each active arm 
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selected for progression into the Full Enrollment Cohort versus placebo will be 2:1 (ie, ratio of 
2:2:2:1 if all dose levels advance into the Full Enrollment Cohort).  
A subset of up to 77 randomly selected participants in Cohort 2 (50% of participants in each group 
in each age strata), will be part of the AIT subset and will have additional blood samples collected 
at D01, D22, D36, and D112 for further immune response characterization and assessment. 
IRT Details for All Participants 
Site staff will connect to the IRT at screening visit, enter the identification, security information, 
and confirm a minimal amount of data in response to IRT prompt. At the screening visit, the IRT 
will provide the participant number. At V01, the IRT will provide the cohort and dose number 
assignment and have the site staff confirm it. The full detailed procedures for cohort and dose 
number allocation are described in the Operating Guidelines. If the participant is not eligible to 
participate in the study, then the information will only be recorded on the participant recruitment 
log. 
Participant numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier). For example, 
Participant 840000100005 is the fifth participant enrolled in Center Number 1 in the US 
(840 being the US country code).  
Participant numbers should not be reassigned for any reason. The randomization codes will be 
kept securely in the IRT system. 
6.3.2 
Blinding and Code-breaking Procedures 
For Sentinel Cohort 
• The study is unblinded for the Sentinel Cohort 
For Full Enrollment Cohort 
• Conducted in a modified double-blind fashion 
• Investigators and study staff who conduct the safety assessment and the participant will not 
know which vaccine is administered in order to decrease the risk of potential bias 
• Only the study site staff who prepare and administer the vaccine and are not involved with the 
safety evaluation will know which vaccine is administered 
• Testing laboratories will be blinded 
• Sponsor study team will be blinded, unless unblinding is necessary if the halting rules are met 
(see Section 8.4.3) or if there is any safety concern 
At the time of the interim analysis (see Section 9.5), unblinding at the group-level will take place 
to inform Sponsor decision on further clinical development. Individual level code will be 
maintained by the independent unblinded statistician until the end of the study. In addition to that, 
Global Clinical Immunology (GCI) and other laboratories undertaking assays for the study will be 
kept blinded until all test results are released.  
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The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the participant. Code-breaking should be limited to the 
participant(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur RMO if a 
participant’s code was broken. All contact attempts with the Sponsor prior to unblinding are to be 
documented in the source documents, and the code-breaking CRF is to be completed. 
The Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) must be notified of 
the code-breaking, in accordance with local regulations. All documentation pertaining to the event 
must be retained in the site’s study records and, in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
A request for the code to be broken may also be made by the Global Pharmacovigilance (GPV) 
Department through an internal system for reporting to Health Authorities in the case of an 
unexpected SAE considered causally related, as described in International Council for 
Harmonisation (ICH) E2Aa. In this case, the code will be broken only for the participant(s) in 
question. The information resulting from code-breaking (ie, the participant’s trial intervention or 
group assignment) will not be communicated to either the Investigator or the immediate team 
working on the study, except for the GPV representative.  
The code-breaking procedures are described in the Operating Guidelines. 
An unblinded review will be done by the Sponsor at the time of the SMT reviews and CS-ESDRs 
for the Sentinel Cohort participants only.  
A preliminary interim safety and immunogenicity analysis can be performed inclusive of up to 
D43 data for participants enrolled into the Sentinel Safety Cohorts. 
At the time of the key interim analysis, the blind will be broken at the group level for the Sponsor, 
including data collected up to D43 in both the Sentinel and the Full Enrollment Cohorts that will 
inform further development decisions, after the first database lock; the SMT will review group 
blinded data at interim analyses with safety outputs. For the rest of the time, SMT will review 
blinded data for remainder of the study. During the study, if any of the halting rules are met (see 
Section 8.4.3) or if there is any safety concern, unblinding may be necessary. The participant level 
data will be maintained blinded on-site until the end of the study/until the interim Clinical Study 
Report approval, with study participants, study Investigators and testing laboratories remaining 
blinded at the individual level for the duration of the study, unless unblinding is required to 
maintain the safety and welfare of participants. 
                                                 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 
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6.4 
Study Intervention Compliance 
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any noncompliance is documented so that it can be accounted for in the data 
analyses: 
• All vaccinations will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose(s) given to each participant, and unused or wasted doses 
6.5 
Concomitant Therapy 
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions/AEs during study participation. 
Documentation in the CRF of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of first vaccination. This may include 
medications of interest that were started prior to the day of vaccination or stopped prior to 
enrollment. 
Reportable medications/vaccinations will be collected in the CRF from the day of each study 
vaccination to the end of the solicited and unsolicited follow-up period after each vaccination (for 
Sentinel Cohort and Cohort 2: up to D43; Cohort 1: up to D22). The exception is influenza and 
COVID-19 vaccinations, which will be collected throughout the study in all participants. In 
addition, any medications used for COVID-19 prophylaxis (eg, SARS-CoV-2 antivirals, 
monoclonal or polyclonal antibodies or plasma) will be collected throughout the study in all 
participants.  
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, systemic 
steroids/corticosteroids) 
• Category 2: medications impacting or that may have an impact on the immune response 
(eg, hydroxychloroquine, other vaccines, blood products, systemic steroids/corticosteroids, 
immune-suppressors, immune-modulators with immunosuppressive properties, 
immunoglobulins, anti-proliferative drugs such as deoxyribonucleic acid (DNA) synthesis 
inhibitor ) 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, systemic steroids/corticosteroids) 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic and ear treatments will not be recorded. Topical analgesics should not be 
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applied at the site of vaccination; however, if they are applied inadvertently to the vaccination site, 
they should be recorded as a Category 1 medication in this specific instance. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to one of the pre-listed categories. Medications will not be coded. 
6.5.1 
Rescue Medicine 
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available on-site in the event of an anaphylactic, vasovagal, or other immediate allergic 
reaction. 
6.6 
Dose Modification 
Not applicable. 
6.7 
Intervention After the End of the Study 
In the event that the SARS-CoV-2 mRNA vaccine is demonstrated to be safe and efficacious in 
future development, the vaccine may be offered to the participants in the VAW00001 study who 
received either placebo or a different/lower dose of the SARS-CoV-2 mRNA vaccine that was 
demonstrated to be efficacious in the Phase III study, as soon as possible following completion of 
the VAW00001 study. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
Section 7.1.1 and Section 7.1.2 are applicable to the Sentinel Cohort and Cohort 2 only.  
These sections are not applicable to Cohort 1 as participants in this cohort are planned to receive 
only 1 vaccination in the study. 
7.1.1 
Temporary Contraindications 
Should a participant experience 1 of the conditions listed below, the Investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the SoA (Section 1.3). 
TCI01: 
Febrile illness (temperature ≥ 38.0°C [≥ 100.4°F]) or moderate or severe acute 
illness/infection on the day of vaccination, according to Investigator judgment  
TCI02: 
Receipt of any vaccine (other than the study vaccine[s]) in the 21 days preceding the 
second study vaccination or planned receipt of any vaccine in the 30 days following 
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the second study vaccination except for influenza vaccination, which may be received 
at least 2 weeks before and a minimum of 2 weeks after study vaccines. This 
exception includes monovalent pandemic influenza vaccines and multivalent influenza 
vaccines. 
7.1.2 
Definitive Contraindications 
Participants will permanently discontinue (definitive discontinuation) study intervention for the 
reasons listed below. These participants must not receive any additional dose of study intervention 
but should continue to be followed for safety. Additional unscheduled visits may be performed for 
safety reasons and information will be reported in the source documents. 
Should a participant experience 1 of the conditions listed below, the Investigator will discontinue 
vaccination: 
DCI01: 
Pregnancy, as indicated by a positive urine test  
DCI02: 
An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
DCI03: 
SAE assessed as related to the study vaccine following the previous dose of vaccine, 
based on Investigator’s judgment 
DCI04: 
A Grade 3 AE, assessed as related to the first study vaccine, that, in the opinion of the 
Investigator, may place the participant at unreasonable or significant risk of injury or 
illness following repeat exposure to study vaccine 
DCI05: 
Symptomatic COVID-19 infection confirmed by NAAT in the period between the first 
study vaccination (V01) and the day corresponding to the second study vaccination 
(V03) 
DCI06: 
Receipt of COVID-19 vaccine (other than the study vaccine) or anti-SARS-CoV-2 
monoclonal or polyclonal antibody in the period between the first study vaccination 
(V01) and the day corresponding to the second study vaccination (V03) 
If the participant is enrolled and seeks vaccination of an authorized/approved COVID-19 vaccine 
outside of the study, he/she will be encouraged to discuss this intention proactively with the study 
investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved COVID-19 vaccine, this information would be collected and the 
participant’s data up to the point of receipt of authorized/approved COVID-19 vaccine will be 
included in the primary analysis for immunogenicity and safety. Participants will be invited to a 
visit prior to receiving the vaccine and requested to provide a blood sample for immunological 
assessment. Participants will continue to be followed for the duration of the study as per 
scheduled visits and procedures except for receipt of the second vaccination as detailed above. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
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• 
The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: AE, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant. 
• 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws consent, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
• 
Withdrawn participants will not be replaced. 
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for definition of “lost to follow-up”. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or cannot be contacted as planned in the SoA (Section 1.3): 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods), or at least to determine his/her health status while fully respecting 
his/her rights. These contact attempts should be documented in the participant’s source 
documents. 
• 
Should the participant continue to be unreachable, he/she will be considered discontinued 
from the study with lost to follow-up as a reason for discontinuation. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1. 
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8 
Study Assessments and Procedures 
• 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Urine, blood, and respiratory samples will be collected as described in the SoA tables 
(Section 1.3). The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, is not planned to exceed 405 mL 
(cumulative total) (see Table 8.1). Repeat or unscheduled samples may be taken for safety reasons 
or for technical issues with the samples. 
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Table 8.1: Blood sampling volume per visit 
 
Screening** 
D01 
D09 
D22 
D30 
D36 
D91/D112 
D181/D202 
D366/D387 
Vaccination 
 
X 
 
X* 
 
 
 
 
SARS-CoV-2 antibody screen baseline (1 mL) 
X  
 
 
 
 
 
 
 
 
Screening serology (HIV Ab, HBsAg, HBcAb, 
HCV Ab) (~5 mL)* 
X 
Safety laboratory assessments (~15 mL at each time-point) 
Hematology† 
X 
 
X 
 
X‡ 
 
 
 
 
Biochemistry and other serum tests† 
X 
 
X 
 
X‡ 
 
 
 
 
PT and PTT with INR 
X 
 
X 
 
X‡ 
 
 
 
 
Antibody assays (30 mL at each time-point) 
 
BL0001 
 
BL0002 
 
BL0003 
BL0004 
BL0005 
BL0006 
SARS-CoV-2 Neutralization assay  
 
X 
 
X 
 
X 
X 
X 
X 
Anti-Spike protein IgG ELISA 
 
X 
 
X 
 
X 
X 
X 
X 
SARS-CoV-2 Nucleoprotein specific 
antibody detection immunoassay 
 
X 
 
X 
 
X 
X 
X 
X 
SARS-CoV-2 specific adaptive immune 
responses (44 mL [4ml for WB and 40 mL for 
MC samples] at each time-point)§ 
 
MC0001 
WB0001 
 
MC0002 
WB0002 
 
MC0003 
WB0003 
MC0004 
 
 
 
Abbreviations: BL, blood sample (#);ELISA, enzyme-linked immunosorbent assay; HBcAb, Hepatitis B core antibody; HBsAg, Hepatitis B surface antigen; HCVAb, Hepatitis C virus antibody; HIV, 
human immunodeficiency virus; IgG, immunoglobulin G; INR, international normalized ratio; MC, mononuclear cell; PT, prothrombin time; PTT, partial thromboplastin time; SARS-CoV-2, severe acute 
respiratory syndrome coronavirus 2; WB, whole blood.  
* Results for these serology tests obtained within 4 weeks prior to V01 will be accepted. 
† Hematology, biochemistry, other serum tests, and urine testing are listed in Table 10.1. 
‡ Only for Sentinel Cohort and Cohort 2. 
§ Only for randomly chosen participants in the AIT subset of Cohort 2 in Full Enrollment Cohort. Memory B Cell quantification will be performed on MC0001 and MC0004. Intracellular Cytokine 
Staining will be performed on MC0001, MC0002, and MC0003. 
** COVID-19 antibody test and blood and urine sampling for safety tests may be performed on the day of enrollment as long as the results to assess exclusion criteria are available prior to enrollment. 
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Guidance and information for the sample collection, preparation, storage, and shipment are 
provided in the Operating Guidelines. 
8.1 
Baseline Screening for SARS-CoV-2 Antibodies  
A blood sample will be obtained before study enrollment to exclude from participation individuals 
with evidence of SARS-CoV-2 antibodies. 
8.2 
Immunogenicity and Efficacy Assessments 
8.2.1 
Immunogenicity Assessments 
8.2.1.1 
Primary Immunogenicity Assay 
SARS-CoV-2 Pseudovirus Neutralization Assay 
The SARS-CoV-2 Pseudovirus Neutralization Assay evaluates the level of neutralizing SARS-
CoV-2 pseudovirus antibodies present in the human serum samples. Pseudotyped virus particles 
are made from a modified Vesicular Stomatitis Virus (VSVΔG) backbone and bear the spike 
glycoprotein of the SARS-CoV-2 from which the last nineteen (19) amino acids of the 
cytoplasmic tail were removed. The pseudoparticles contain a Luciferase reporter used for 
detection. 
Seven two-fold serial dilutions of heat-inactivated human serum samples are prepared in 96-well 
transfer plate(s). The SARS-CoV-2 pseudovirus is added sequentially to the serum dilutions at a 
target working dilution (to obtain approximately 75,000-300,000 RLU/well) and incubated at 
37°C with 5% CO2 supplementation for 60 ± 5 minutes. Serum-virus complexes are then 
transferred onto plates, previously seeded overnight with Vero E6 cells, and incubated at 37°C 
and with 5% CO2 supplementation for 20 ± 2 hours. Following this incubation, the luciferase 
substrate is added to the cells in order to assess the level of luminescence per well. The plate(s) 
are then read on a luminescence plate reader. The intensity of the luminescence is quantified in 
relative luminescence units (RLU) and is inversely proportional to the level of neutralizing 
antibodies present in the serum. The neutralizing titer of a serum sample is calculated as the 
reciprocal serum dilution corresponding to the 50% neutralization antibody titer (NT50) for that 
sample. 
This assay will be used to measure neutralizing antibody responses to the homologous vaccine 
strain (D614G variant) at all timepoints in all participants. In addition, the assay may be used to 
measure antibody responses against other emergent variants (eg, B.1.351, B.1.1.7, P.1) for 
exploratory analyses. 
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8.2.1.2 
Additional Immunogenicity Assays 
SARS-CoV-2 Neutralizing Antibody Assessment (SP) 
SARS-CoV-2 neutralizing antibodies will be measured using a live virus neutralization assay in 
all participants at all timepoints and may serve as a supportive assay for the primary endpoint. 
Serum samples are mixed with constant concentration of the SARS-CoV-2 virus. A reduction in 
virus infectivity (viral antigen production) due to neutralization by antibody present in serum 
samples can be detected by ELISA. After washing and fixation, SARS-CoV-2 antigen production 
in cells can be detected by successive incubations with an anti-SARS-CoV-2-specific antibody, 
horseradish peroxide immunoglobulin G conjugate, and a chromogenic substrate. The resulting 
optical density (OD) is measured using a microplate reader. The reduction in SARS-CoV-2 
infectivity as compared to that in the virus control wells constitutes a positive neutralization 
reaction indicating the presence of neutralizing antibodies in the serum sample. 
Serum IgG Antibodies to SARS-CoV-2 Spike Protein Using ELISA 
SARS-CoV-2 anti-S protein IgG antibodies will be measured using an ELISA to assess total 
antibodies to the S protein antigen elicited by the vaccine. Microtiter plates will be coated with 
SARS-CoV-2 S protein antigen diluted in coating buffer to the optimal concentration. 
Plates may be blocked by the addition of a blocking buffer to all wells and incubation for a 
defined period. Following incubation, plates will be washed. All controls, reference, and samples 
will be pre-diluted with dilution buffer. The pre-diluted controls, reference and samples will then 
be further serially diluted in the wells of the coated test plate.   
The plates will be incubated for a defined period. Following incubation, plates will be washed, an 
optimized dilution of goat anti-human IgG enzyme conjugate will be added to all wells, and plates 
will be further incubated. Following this incubation, the plates will be washed, and enzyme 
substrate solution will be added to all wells. Plates will be incubated for a defined period to allow 
the substrate to develop. Substrate development will be stopped by the addition of a stop solution 
to each well. An ELISA microtiter plate reader will be used to read the test plates using assay 
specific SoftMax Pro templates. 
The average OD value for the plate blank will be subtracted from all the ODs within each plate. 
The sample titers will be derived using the measured values of the blanks, controls, and the 
reference standard curve, which will be included on each assay plate within the run. 
Additional Immunological Tests 
Helper T cell TruCulture 
The T cell analysis in the whole blood, collected, using Myraid’s TruCulture whole blood 
collection and culture system, will enable consistent, reliable assessment of the T helper cells 
polarization. The TruCulture tube containing the stimulant or antigen of choice, allows almost 
instantaneous stimulation of the cells in the presence of all the blood components, after the blood 
is drawn into the tube and therefore, minimizes variability that may arise due to the handling and 
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manipulation of blood, including processing for PBMC. Preliminary results in our laboratories 
and previous reports in the literature have shown the robustness of the method (35). The assay 
relies on the fact that the T helper cytokines are secreted in a single tubes post stimulation and 
supernatant are collected 24 or 48hrs. A panel of cytokine using the Luminex xMAP technology 
from Myriad RBM, will be measured to determine the status of the T helper cell polarization. 
Memory B cell FluoroSpot 
Memory B-cells (MBC) secreting Spike specific-IgG and IgA antibodies will be quantified in 
PBMCs from selected timepoints using a fluorescent immunospot (FluoroSpot) assay. The spike-
specific memory B-cell response will be assessed by plating the in-vitro stimulated (R848 and IL-
2) PBMC on an ELISPOT/FluoroSpot plate that is pre-coated with the Spike protein. The 
activated B-cells will secrete antibodies of different isotypes and specificities, but only those with 
a specificity to the pre-coated Spike proteins will be captured and detected by fluorescent-
conjugated detection antibodies capable of recognizing bound IgG or IgA antibodies. Spike-
specific IgG and IgA memory responses will be compared to the total IgG and IgA response seen 
in wells that are pre-coated with human capture antibodies directed against IgG and IgA and 
plated with stimulated PBMCs. 
8.2.2 
Efficacy Assessments 
8.2.2.1 Definitions 
Virologically-confirmed COVID-19-Like Illness 
Defined as a positive result for SARS-CoV-2 by Nucleic Acid Amplification Test (NAAT) on a 
respiratory sample in association with a COVID-19-like illness. 
Serologically-confirmed SARS-CoV-2 Infection 
Defined as a positive result in serum for the presence of antibodies specific to the nucleoprotein of 
SARS-CoV-2 detected by electrochemiluminescence immunoassay (ECLIA). 
SARS-CoV-2 Infection 
A positive result for SARS-CoV-2 by NAAT on a respiratory sample OR positive result in serum 
for presence of antibodies specific to the nucleoprotein of SARS-CoV-2 detected by ECLIA. 
COVID-19-Like Illness 
Symptoms of COVID-19-like illness are as listed below, along with an accompanying tabulation 
of terms used in the CRFs versus DCs/Memory Aids (Table 8.2). 
New onset of any ONE of the following (that persists for a period of at least 24 hours or reoccurs 
within a 12-hour period): 
• Cough (dry or productive) 
• Fever (measured temperature > 100.4ºF or > 38ºC) 
• Difficulty breathing or shortness of breath 
• Anosmia 
• Ageusia 
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• Chilblains (COVID-toes) 
• Clinical or radiographic evidence of pneumonia 
• Myocarditis, myocardial infarction 
• Thromboembolic event (blood clots [eg, pulmonary embolism, deep vein thrombosis, 
stroke]) 
• Purpura fulminans 
 
OR  
New onset of any TWO of the following that are present at the same time (both symptoms that 
persist for a period of at least 24 hours or reoccurs within a 12-hour period): 
• Pharyngitis 
• Chills  
• Myalgia  
• Fatigue (malaise) 
• Headache 
• Rhinorrhea or nasal congestion 
• Abdominal pain  
• At least one of nausea or vomiting 
• Diarrhea 
Table 8.2: COVID-19-like illness symptoms: CRF and Diary Card/Memory Aid terms 
CRF term 
Diary Card/Memory Aid term 
Cough 
Cough 
Fever 
Temperature measured as > 100.4ºF or > 38ºC 
Shortness of breath  
Difficulty breathing or feeling short winded 
Anosmia 
Loss of smell 
Ageusia 
Loss of taste 
Chilblains  
Pain, redness, sores in your fingers and toes exposed to cold 
Pneumonia 
Infection of the lungs 
Stroke 
Stroke 
Myocarditis 
Heart inflammation 
Myocardial infarction 
Heart attack 
Thromboembolic event 
Blood clots 
Purpura fulminans 
A type of purplish skin rash 
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CRF term 
Diary Card/Memory Aid term 
Pharyngitis 
Sore throat 
Chills 
Chills 
Myalgia 
Muscle aches and pains 
Fatigue (malaise) 
Feeling unwell / tired 
Headache 
Headache 
Rhinorrhea 
Runny nose 
Nasal congestion 
Stuffy nose 
Abdominal pain 
Belly pain 
Nausea 
Feeling queasy 
Vomiting 
Throwing up 
Diarrhea 
Loose stools 
8.2.2.2 
COVID-19-like Illness Surveillance 
Passive Surveillance 
Following randomization and vaccination, all participants will be instructed to contact the site if 
they experience symptoms of a COVID-19-like illness listed in the DC at any time during the 
study or if they seek medical care for their symptoms or if they have a positive COVID-19 test 
from any other source. 
Active Surveillance 
Following randomization and vaccination, active surveillance will be used to identify potential 
COVID-19 clinical illness cases. 
All participants will be contacted by study site or delegated call center starting on D57 (2 weeks 
after D43 contact) and continuing until D181 (Cohort 1) or D202 (Sentinel Cohort and Cohort 2). 
The frequency of phone contacts will be once every 2 weeks (± 6 days) or may be completed 
through alternative contact methods (text message, email, and/or home visit). Prior to these 
specified time-points, active surveillance will still occur during the established contacts (phone 
calls and visits) as described in the SoA (Section 1.3). After active surveillance has ended at D181 
(Cohort 1) or D202 (Sentinel Cohort and Cohort 2), passive surveillance will continue through the 
end of the study as previously stated above. 
Collection of Respiratory Samples 
For the duration of the study, the site will arrange for a respiratory sample to be taken if the 
participant experiences symptoms of COVID-19-like illness (see Section 8.2.2.1). After the onset 
of symptoms of COVID-19-like illness, the respiratory sample will be obtained as soon as 
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possible, unless during the first reactogenicity period (D01-D09) when the sample may be 
collected up to D09, at the Investigator’s discretion.  
All respiratory samples will be submitted for analysis by SARS-CoV-2 NAAT and a positive 
result will be considered a virologically-confirmed COVID-19-like illness (see Section 8.2.2.4). 
The samples (confirmed by SARS-CoV-2 NAAT) will be stored in a SP Sample Biorepository for 
further viral characterization, if needed. 
If the respiratory sample swab cannot be collected, the research site will still collect the 
information mentioned below. 
Reporting of Events Temporally Associated with a COVID-19-like Illness 
In addition to obtaining a respiratory sample, the site will collect detailed information about the 
symptoms, severity and duration of illness, as well as information on healthcare utilization events 
(hospitalizations, emergency room visits, and non-routine office visits [including urgent care 
visits]) and medication use (eg, antibiotics, antivirals). These are also outlined in Table 1.6. 
In the event of hospitalization during the course of illness, detailed information on the course of 
the illness including duration of symptoms, oxygen requirements, laboratory tests, imaging 
investigations (including computerized tomography), use of mechanical ventilation and other 
respiratory support medications used, and outcome will be collected. 
All participants reporting a COVID-19-like illness will have a 30-day follow-up telephone call. 
8.2.2.3 
ELECSYS Anti-SARS-CoV-2 ECLIA 
Elecsys® (Roche Diagnostics) Anti-SARS-CoV-2 is an immunoassay intended for qualitative 
detection of antibodies to SARS-CoV-2 in human serum. The assay uses a recombinant protein 
representing the nucleoprotein antigen. Sample, biotinylated SARS-CoV-2-specific recombinant 
antigen and SARS-CoV-2-specific recombinant antigen labeled with a ruthenium complex are 
first incubated and form a sandwich complex. After addition of streptavidin-coated microparticles, 
the complex becomes bound to the solid phase via interaction of biotin and streptavidin. The 
reaction mixture is aspirated into the measuring cell where the microparticles are magnetically 
captured onto the surface of the electrode. Unbound substances are then removed with 
ProCell/ProCell M/ProCell II M. Application of a voltage to the electrode then induces 
chemiluminescent emission which is measured by a photomultiplier. Results are determined 
automatically by the software by comparing the electrochemiluminescence signal obtained from 
the reaction product of the sample with the signal of the cutoff value previously obtained by 
calibration. 
8.2.2.4 
Nucleic Acid Amplification Test (NAAT) for COVID-19 Case Detection 
In the assay, respiratory samples will be collected and the RNA will be extracted. The purified 
template is then evaluated by a NAAT using SARS-CoV-2 specific primers to specifically 
amplify SARS-CoV-2 targets.  
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8.3 
Safety Assessments 
This section presents safety assessments other than AEs which are presented in Section 8.4. 
Planned time-points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1 
Medical History 
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the participant is or has been followed by a physician or conditions/illnesses that could 
resume during the course of the study or lead to an SAE or to a repetitive outpatient care will be 
collected in the CRF. 
8.3.2 
Physical Examinations 
At the screening visit, the Investigator or a delegate will perform a targeted physical examination. 
At Visit 01, a targeted physical examination might be performed based on the participant’s 
medical history and Investigator’s discretion. Information will be recorded in the source 
document. 
8.3.3 
Vital Signs 
Oral pre-vaccination temperature and other vital signs will be systematically collected by the 
Investigator on the source document. Tympanic, skin, and temporal artery thermometers must not 
be used. 
8.3.4 
Clinical Safety Laboratory Assessments 
Urine pregnancy testing will be performed in women of childbearing potential at the screening 
visit and before each vaccination.  
• 
See Appendix 10.2 for the complete list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency. 
• 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by 
the Investigator or medical monitor. 
o If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
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o All protocol-required laboratory assessments, as defined in Appendix 10.2, must be 
conducted in accordance with the laboratory manual/operating guidelines and the SoA 
(Section 1.3). 
o If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory of choice require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE), then the results 
must be recorded in the CRF. 
8.4 
Adverse Events and Serious Adverse Events 
Safety will be described in all study participants. 
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.3. 
AEs will be reported by the participants to the Investigator, then by the Investigator to the 
Sponsor. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
8.4.1 
Sentinel Cohort 
SMT Meetings 
The participants enrolled in the Sentinel Cohort (see Overall Design, Section 4.1) will be closely 
followed-up by the SMT (Figure 1.5). 
The SMT will perform an unblinded review to evaluate the D01-D03 and D22-D24 safety data 
and the following safety parameters will be assessed: immediate reactions, solicited injection site 
and systemic reactions, unsolicited AEs reported as vaccine related by the Investigator, SAEs, and 
AESIs. 
Initial Sentinel Cohort (low-dose; 
 µg, N=5) 
If any of the below alert threshold criteria are met for the D01-D03 safety data of the low-dose 
group in the Initial Sentinel Cohort (N=5 participants), a decision will be made as to whether the 
second injection can be administered: 
• ≥ 1 participant experiencing Grade 3 systemic reaction (without concurrent infectious disease)  
• ≥ 1 participant experiencing Grade 3 solicited injection site pain 
• ≥ 1 participant experiencing Grade 3 unsolicited non-serious reactions (reactions not 
explained by any other possible etiology)  
• Any related SAEs, or, any Intensive Care Unit (ICU) admission for SARS-CoV-2 infection 
regardless of relationship to vaccination 
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Initial Sentinel Cohort (ultra-low- [
 µg) and medium- [
 µg] dose; N=10 in each group) 
If any of the below alert threshold criteria are met for the D01-D03 safety data of the ultra-low- 
and medium- dose groups in the Initial Sentinel Cohort (N=10 participants in each group), a 
decision will be made as to whether the second injection can be administered: 
• ≥ 2 participants experiencing Grade 3 systemic reaction (without concurrent infectious 
disease)  
• ≥ 2 participants experiencing Grade 3 solicited injection site pain 
• ≥ 2 participants experiencing Grade 3 unsolicited non-serious reactions (reactions not 
explained by any other possible etiology)  
• Any related SAEs, or, any ICU admission for SARS-CoV-2 infection regardless of 
relationship to vaccination 
Expanded Sentinel Cohort (all dose-levels) 
If any of the below alert threshold criteria are met for the D01-D03 safety data of any dose-level 
group in the Expanded Sentinel Cohort for the participants enrolled beyond the initial Sentinel 
Cohort (N= between 15-20 participants, depending on dose-level group [15 potential additional 
participants added for ultra-low and medium dose levels, and 20 participants added for the low-
dose level), a decision will be made as to whether subsequent vaccinations for a specific dose-
level or corresponding escalation dose-levels will be allowed to resume or not: 
• > 20% of participants experiencing Grade 3 systemic reaction (without concurrent infectious 
disease)  
• > 20% of participants experiencing Grade 3 solicited injection site pain 
• > 20% of participants experiencing Grade 3 unsolicited non-serious reactions (reactions not 
explained by any other possible etiology)  
• Any related SAEs, or, any ICU admission for SARS-CoV-2 infection regardless of 
relationship to vaccination 
Ad hoc SMT Meetings 
In addition, ad hoc SMTs for any Sentinel Cohort group may occur to evaluate D01-D09 
additional safety data, including laboratory data as needed, to better understand safety. Such ad 
hoc SMT evaluations will inform study progression, especially if any Sentinel Cohort groups 
reach the time of second vaccination before CS-ESDR-1 takes place. In case of D01-D09 SMT, 
the parameters listed above for the corresponding Initial or Expanded Sentinel Cohort along with 
the additional evaluation of laboratory safety parameters will be assessed for: 
Initial Sentinel Cohort (low-dose; 
 µg, N=5): 
• ≥ 1participant with Grade 3 laboratory AE  
• ≥ 1 participant with Grade 2 laboratory AE (reactions not explained by any other possible 
etiology) and judged by the Investigator to be clinically meaningful 
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Initial Sentinel Cohort (ultra-low- [
 µg] and medium- [
 µg] dose; N=10 in each group) 
• ≥ 2 participants with Grade 3 laboratory AE  
• ≥ 2 participants with Grade 2 laboratory AE (reactions not explained by any other possible 
etiology) and judged by the Investigator to be clinically meaningful 
Expanded Sentinel Cohort (all dose-levels) 
• > 20% of participants with Grade 3 laboratory AE  
• > 20% of participants with Grade 2 laboratory AE (reactions not explained by any other 
possible etiology) and judged by the Investigator to be clinically meaningful. 
8.4.2 
Early Safety Data Review 
Sentinel Cohort Safety Evaluation and Safety Parameters 
Two Complete Sentinel ESDRs (CS-ESDR-1 and CS-ESDR-2) will be performed for the Sentinel 
Cohort. The goal of the CS-ESDRs is to allow the preliminary safety and laboratory parameter 
assessment of safety data after the first (D01-D09) and the second (D22-D30) vaccine 
administration to all Initial and all triggered Expanded Cohort participants. 
Clinical safety laboratory evaluations will be performed at screening and 8 days after each 
injection. The first CS-ESDR will be performed for all Sentinel Cohort participants after safety 
data, including local and systemic AEs, unsolicited AEs, and biological safety laboratory 
parameters, is obtained from D01-D09 following the first injection. This unblinded review will be 
performed by the Sponsor during the SMT meetings.  
If no safety signals or major tolerability concerns are identified at CS-ESDR-1, the double-blind 
enrollment of up to 308 participants (vaccine and placebo groups) for the first vaccination of the 
Full Enrollment Cohort (Cohort 1 allocated to the single-injection schedule and Cohort 2 allocated 
to the 2-injection schedule) will be initiated. It is to be noted that the first vaccination in the Full 
Enrollment Cohort may be delayed until after the second vaccination of some of the Sentinel 
Cohort groups or even postponed until after CS-ESDR-2, if deemed necessary by the SMT. 
It is understood that this review is based on preliminary data that have been validated but not 
subject to database lock. (The usual and ongoing process of monitoring safety signals outside of 
those specified in the protocol-defined early interim safety analysis will continue unchanged.) 
The following safety parameters will be assessed as part of the CS-ESDR: 
• Immediate reactions 
• Solicited injection site and systemic reactions 
• Laboratory abnormalities (including hematology, chemistry, coagulation time, and urinalysis) 
• Unsolicited AEs reported as vaccine related by the Investigator 
• SAEs and AESIs  
Enrollment will be paused during the SMT meeting and the sentinel safety parameters noted will 
be examined. If any of the below criteria are met for the D01-D09 safety and laboratory data, the 
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data on the particular alert threshold event will be reviewed by the SMT and a decision will be 
made as to whether subsequent vaccinations in the study will be allowed to resume or not: 
• > 20% of participants experiencing Grade 3 systemic reaction (without concurrent infectious 
disease) that last for at least 3 days at Grade 3 intensity 
• > 20% of participants experiencing Grade 3 solicited injection site pain 
• > 20% of participants experiencing Grade 3 unsolicited non serious reactions (reactions not 
explained by any other possible etiology) 
• > 20% of participants with Grade 3 laboratory AE 
• > 20% of participants with Grade 2 laboratory AE (reactions not explained by any other 
possible etiology) and judged by the Investigator to be clinically meaningful 
• Any related SAEs or any ICU admission for SARS-CoV-2 infection regardless of relationship 
to vaccination 
A subsequent safety review (CS-ESDR-2) is planned for the Sentinel Cohort participants during 
which the unblinded SMT will examine the available D22-D30 safety data post-second 
vaccination including local and systemic AEs, unsolicited AEs, and biological safety laboratory 
parameters, and all available MAAEs, SAEs, and AESIs for the Sentinel Cohort participants will 
also be reviewed. If no safety signals or major tolerability concerns are identified during this 
period in the Sentinel Cohort, then all participants in Cohort 2 will progress to get the second 
injection (VAC2). If a safety signal or a major tolerability concern is identified at CS-ESDR-2 for 
the Sentinel Cohort, then Cohort 2 participants for the corresponding dose-level may not receive 
their second vaccination. 
8.4.3 
Halting Rules for Entire Study 
An SMT will review the safety data at regular intervals, to identify any new safety signals or 
safety concerns during the conduct of the study. The SMT is empowered to recommend a pause in 
both recruitment and/or further vaccination while it investigates any potential signal or concern. 
Enrollment will be paused during the review and the data will be examined.  
Enrollment and/or further vaccination will be paused if the following alert thresholds are 
identified: 
• 
Any SAEs assessed as related to the vaccine by the Investigator and the Sponsor  
• 
≥ 2 participants experiencing ulceration, abscess or necrosis at the injection site that is 
considered related to the study vaccine by the Investigator and the Sponsor 
• 
For each vaccine group advanced to the Full Enrollment Cohort (ie, potentially Groups 1 to 3 
and Groups 5 to 7, N=44 participants per group [Table 4.3]), ≥ 4 participants experiencing 
any Grade 3 AE (systemic reactions lasting for at least 3 days at Grade 3 intensity, unsolicited 
AEs and/or clinical laboratory abnormality) in the absence of any other etiology 
• 
Events suggestive of vaccine-associated enhanced disease, including:  
• Any death due to SARS-CoV-2 infection  
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• > 10% of the study population enrolled at any given time is hospitalized due to 
SARS-CoV-2 infection 
• ≥ 3% of study participants ≥ 50 years enrolled at any given time are admitted to the ICU 
due to SARS-CoV-2 infection 
• ≥ 3% of study participants 18 to 49 years enrolled at any given time are admitted to the 
ICU due to SARS-CoV-2 infection 
In addition, ad hoc SMT reviews will occur immediately in the event halting rules are met. Case 
unblinding may be performed if necessary or if any of the halting rules are met.  
8.4.4 
Time Period and Frequency for Collecting AE and SAE Information 
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from D01 through D08 after each vaccination. 
Solicited systemic reactions will be collected from D01 through D08 after each vaccination. 
The solicited injection site reactions and systemic reactions that are pre-listed in the DCs and 
CRF, together with the intensity scales, are presented in Appendix 10.3.5.1.1. 
Unsolicited Adverse Events 
Unsolicited AEs include unsolicited non-serious AEs and SAEs. The intensity grading scale for 
unsolicited non-serious AEs is presented in Appendix 10.3.5.1.2. Unsolicited non-serious AEs 
will be collected from D01 to D22 after each vaccination. 
SAEs will be collected and assessed throughout the study, ie, before the start of study intervention 
but after obtaining informed consent until 12 months after the last vaccination (up to D366 for 
Cohort 1 and up to D387 for Sentinel Cohort and Cohort 2) or the day of study discontinuation for 
participants who discontinue permanently. However, before the first study intervention 
administration, only SAEs related to study procedures are to be collected (eg, SAEs related to 
blood sampling or study procedure performed during a screening visit). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the AE section of the CRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor.  
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Medically Attended Adverse Events  
MAAEs will be collected at any time during the study. 
Adverse Events of Special Interest  
AESIs will be collected at any time during the study. 
See Section 8.4.9 for the list of AESIs. 
8.4.5 
Method of Detecting AEs and SAEs 
Individual DCs, specifically designed for this study by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information. These DCs 
will include pre-listed terms and intensity scales as well as areas for free text to capture additional 
safety information or other relevant details. Participants will also be provided with rulers for 
measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
participants on how to correctly use these tools. 
At specified intervals, the Investigator or an authorized designee will interview the participants to 
collect the information recorded in the DC and will attempt to clarify anything that is incomplete 
or unclear. All clinical study information gathered by the study site will be reported electronically 
by the Investigator or authorized designee using a web-based CRF. Any information that was not 
documented in the DC will first be captured in the source document and then reported 
electronically. 
The 12-month (post-last injection) follow-up will be done by interviewing participants during a 
visit (or over the telephone for participants who discontinue early from the study) using a 
questionnaire to capture SAEs and AESIs, if applicable. 
The method of recording, evaluating, and assessing causal relationship of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.6 
Follow-up of AEs and SAEs 
Unless a participant refuses further contact, each participant who experiences an AE (whether 
serious or non-serious) during the study must be followed until the condition resolves, becomes 
stable, or becomes chronic (even after the end of the participant’s participation in the study) if 
either of the following is true: 
• 
The AE is considered by the Investigator to be related to the study intervention administered 
• 
The AE caused the discontinuation of the participant from the study or from vaccination 
The Investigator will inform the Sponsor of the date of final disappearance of the event or the date 
of “chronicity” establishment. 
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8.4.7 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. 
• 
For all studies except those investigating medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
• 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.8 
Pregnancy 
Pregnancy is an exclusion criterion for enrollment in this study, but a participant could potentially 
become pregnant during her participation.  
• 
Details of all pregnancies in female participants will be collected by the Investigator after the 
start of study intervention and until delivery and recorded in the Pregnancy CRF. Any data 
collected after CRF lock will be transmitted to the pharmacovigilance department on the 
paper form. 
• 
The collection period of pregnancy information will correspond at least to the period during 
which the participant is requested to be under contraception. (according to protocol: effective 
method of contraception or abstinence from at least 4 weeks prior to the first vaccination until 
at least 12 weeks after the last vaccination). If there are any pregnancies during this period, 
follow-up should be conducted up to delivery: this will be covered by the 12-month 
surveillance of the study. 
• 
If a pregnancy is reported, the Investigator should inform the Sponsor within 1 month of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.4. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.9 
Adverse Events of Special Interest 
AESIs will include: 
• 
Protocol-specified AESIs: Anaphylactic reactions, generalized convulsion, Guillain-Barré 
Syndrome (GBS), acute disseminated encephalomyelitis (ADEM), thrombocytopenia, and 
vasculitides 
• 
New-onset chronic medical conditions (NOCMCs) 
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• 
AESIs related to SARS-CoV-2 infection and COVID-19 disease (see Appendix 10.5).  
8.4.10 Medically Attended Adverse Events 
Medically-attended AEs will be collected using the same process as other AEs. See 
Appendix 10.3.1 for definition of MAAEs. 
8.5 
Treatment of Overdose 
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the Investigator should: 
1) Contact the RMO immediately 
2) Closely monitor the participant for any AE/SAE 
3) Document the quantity of the excess of the overdose in the source documents 
8.6 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.7 
Pharmacodynamics 
As with most vaccines for active immunization, the mechanism of action consists of the induction 
of immune responses against the antigens contained in the vaccine. Therefore, the 
pharmacodynamic profile of the investigational study intervention is defined by its 
immunogenicity profile. 
8.8 
Genetics 
Genomic analysis for immune cell profiling and sequencing as related to the exploratory 
endpoints in establishing biomarkers or vaccine-induced molecular signatures to characterize the 
immune profiles associated with SARS-CoV-2 vaccination may be performed. 
8.9 
Biomarkers 
Besides the biomarkers described in the immunogenicity and efficacy assessments sections 
(Section 8.2.1.1 and Section 8.2.2, respectively), other emerging biomarkers may be evaluated in 
this study which may be relevant for evaluating scientific aspects of COVID-19 illness, or 
SARS-CoV-2 infection, or for the evaluation of effect modification, correlates of risk/protection, 
or participants’ baseline characteristics. 
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8.10 Immunogenicity Assessments 
See Section 8.2.1.1. 
8.11 Medical Resource Utilization and Health Economics 
Medical Resource Utilization will be collected as part of COVID illness in this study (see 
Section 8.1 and Section 8.2.2.2), as well as for SAE narrative and categorization. 
9 
Statistical Considerations 
9.1 
Statistical Hypotheses 
All analyses will be descriptive; no hypotheses are planned to be tested.  
9.2 
Sample Size Determination 
This is a first-in-human study to assess the safety profile and immune responses to different doses 
of the study vaccine when compared to placebo. The study targets enrollment of approximately 
333 participants 18 years of age and older, including the 5 participants already vaccinated in the 
low-dose group. The actual number of participants enrolled will depend on which dose-level 
groups are allowed to be evaluated in the Sentinel Cohort and the Full Enrollment Cohort. The 
number may be higher if Expanded Sentinel Cohorts are exercised for all dose-levels, and if all 
dose-levels progress to the Full Enrollment Cohort (maximum number of study participants 
approximately 383); conversely, the number may be lower if not all the dose-levels are evaluated 
in the Sentinel Cohort or/and not all the dose-levels progress to the Full Enrollment Cohort. 
No formal power calculation has been performed. The sample size was determined based on 
logistical considerations and common practices for first-in-human trials.  
Vaccine arms will be aggregated to perform complementary assessments on the following main 
effects: age (18-49 years, ≥ 50 years), dose (ultra-low, low, medium), and injection schedule (1-
injection, 2-injection). 
9.3 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Enrolled 
All participants with a dose-level group that has been allocated by IRT 
Safety Analysis Set (SafAS) 
Subset of enrolled participants who have received at least 1 injection of 
study intervention. Participants will have their safety analyzed 
according to the study intervention they actually received.  
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Population 
Description 
Safety data recorded for a vaccine received out of the protocol design 
will be excluded from the analysis (and listed separately). 
Full Analysis Set (FAS) 
Subset of enrolled participants who received at least 1 injection of the 
study intervention. Participants will be analyzed according to the 
intervention to which they were enrolled. 
Per-Protocol Analysis Set 
(PPAS) 
Subset of the FAS. Participants presenting with at least 1 of the 
following relevant conditions will be excluded from the PPAS: 
• 
Participant did not meet all protocol-specified inclusion criteria or 
met at least 1 of the protocol-specified exclusion criteria  
• 
Participant did not complete the protocol-defined vaccination 
schedule 
• 
Participant received a study intervention other than the one that 
he/she was randomized to receive 
• 
Preparation and/or administration of study intervention was not 
done as per-protocol 
• 
Participant did not receive study intervention in the proper time 
window 
• 
Participant received an authorized/approved COVID-19 vaccine 
prior to D36 visit 
• 
Participant with a positive test result in the ELISA and/or 
neutralization test at baseline 
Additional conditions for exclusion may be identified during the review 
of protocol deviations; such conditions will be documented in the 
Statistical Analysis Plan (SAP). 
Per-Protocol Analysis Set for 
Immunogenicity (PPAS-IAS) 
Subset of PPAS excluding participants who provided all post-dose 
serology samples outside the proper time window or no post-dose 
serology sample was drawn. 
Per-Protocol Analysis Set for 
AIT (PPAS-AIT) 
Subset of PPAS excluding participants who provided all post-dose AIT 
samples outside the proper time window or no post-dose AIT sample 
was drawn. 
9.4 
Statistical Analyses 
The SAP will be finalized prior to database lock and it will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key secondary 
endpoints. 
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All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, Version 9.4 or newer (SAS Institute, Cary, North Carolina, 
USA). 
9.4.1 
General Considerations 
All analyses will be descriptive. Summaries will be provided for main effects (see Section 9.2) as 
well as individual study arms. Details will be provided in the SAP. 
9.4.2 
Primary Endpoints 
9.4.2.1 Immunogenicity 
The primary endpoints for the evaluation of immunogenicity are based on neutralizing antibody 
titers, which will be measured with the neutralization assay. The statistical analyses that will be 
performed for the following primary endpoints are as presented in Table 3.1. 
Pre-vaccination titers at < LLOQ will be converted to half LLOQ. 
The 95% confidence intervals (CIs) for the geometric mean titers (GMTs)/geometric mean 
concentrations (GMCs) and GMT ratios will be calculated using normal approximation of 
log-transformed titers. The 95% CIs for the proportions will be based on the Clopper-Pearson 
method. The ratios of GMTs will be obtained between groups with the 95% CIs calculated using 
normal approximation of log-transformed titers. The differences in the seroconversion rates 
between groups will be computed along with the 2 sided 95% CIs by the Wilson-Score method 
without continuity correction. Additional parameters may be displayed as appropriate.  
Additionally, to evaluate independent determinants of primary immunogenicity endpoints, 
regression models may be constructed for log-transformed titers and occurrence of neutralizing 
antibody seroconversion. For continuous type of dependent variable, linear models will be 
utilized; for binary type of dependent variable, logistic regression model will be utilized. 
Explanatory/independent variables inserted in these models would include main (aggregate) 
effects including age effects and injection schedule effect.  
Immunogenicity analyses will be performed on PPAS-IAS, unless otherwise specified. 
9.4.2.2 Safety 
The primary endpoints for the evaluation of safety are as presented in Table 3.1. Primary safety 
endpoints will be summarized by vaccine group, as well as aggregate groups specified in the SAP. 
The 95% CIs will be calculated using the Clopper-Pearson method.  
The SafAS will be used for the safety analyses. 
9.4.3 
Secondary Endpoints 
9.4.3.1 Immunogenicity 
The secondary endpoints for the evaluation of immunogenicity are as presented in Table 3.1.  
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The 95% CIs for the antibody titer (or concentration) and ratio will be calculated using normal 
approximation of log-transformed titers. The 95% CIs for the proportions will be based on the 
Clopper-Pearson method. The ratios of antibody titer (or concentration) will be obtained between 
groups with the 95% CIs calculated using normal approximation of log-transformed titers. The 
differences in the seroconversion rates between groups will be computed along with the 2-sided 
95% CIs by the Wilson-Score method without continuity correction. Additional parameters may 
be displayed as appropriate. 
Regression models may be utilized for further assessment of secondary immunogenicity 
endpoints, as described in Section 9.4.2.1. 
Immunogenicity analyses will be performed on PPAS-IAS, unless otherwise specified. 
9.4.3.2 
Efficacy 
Virologically-confirmed COVID-19-like illness is defined by the occurrence of a COVID-19 
illness as described in Section 8.2.2.1, associated with a positive NAAT for SARS-CoV-2 in a 
respiratory sample. 
Serologically-confirmed SARS-CoV-2 infection is defined as a change from negative to positive 
(see Section 8.2.2.1) in the non-S immunoassay from any post-baseline sampling time-point 
compared to the baseline value, as measured in a SARS-CoV-2 Nucleoprotein specific antibody 
detection immunoassay. 
Correlates of risk/protection analysis will be performed based on antibody responses to 
SARS-CoV-2 as evaluated using virus neutralization or binding antibody (ELISA), considering 
cases of virologically-confirmed COVID-19-like illness and/or serologically-confirmed 
SARS-CoV-2 infection as defined above. Detailed statistical methods will be described in the 
SAP. 
Efficacy analyses will be performed on FAS and PPAS-IAS, unless otherwise specified. 
9.4.4 
Exploratory Endpoints 
9.4.4.1 Immunogenicity 
The AIT subset analyses will be defined in the SAP. The AIT subset analyses will be based on 
PPAS-AIT set. For this subset, Th1 and Th2 cytokines will be measured and summarized for 
individual and aggregate study arms. 
The ratio between binding antibody (ELISA) concentration and neutralizing antibody titer will be 
summarized for individual and aggregate study arms. The ratio (neutralizing antibody/binding 
antibody) will be calculated as difference in log10 scale and with the 95% CIs calculated using 
normal approximation will be provided. The analyses will be performed on PPAS-IAS, unless 
otherwise specified. 
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9.5 
Interim Analyses 
A preliminary interim analysis will be performed on safety and immunogenicity data collected up 
to D43 for participants enrolled into the Sentinel Safety Cohorts. Database will be cleaned with a 
partial database lock conducted.  
A key interim analysis will be performed on data collected for primary immunogenicity and 
exploratory AIT subset objectives obtained up to D36 and primary safety objectives through D43 
inclusive of both Sentinel and Full Enrollment Cohorts, upon the data availability and when a 
partial database lock has been conducted. Statistical analysis of data described above will be 
conducted to support further investigating the study vaccine formulation. The analysis results of 
the interim analysis (inclusive of the Full Enrollment Cohort) will also be generated to 
communicate with regulatory agencies. The study blind will be broken at the group level to the 
Sponsor at that time. 
Harm analysis assessed based on split of COVID-19 cases will be conducted based on SafAS at 
all planned interim analyses. Participants will be analyzed according to the group to which they 
were randomized. For the assessment, all vaccine arms will be pooled, and all placebo arms will 
be pooled as well. The timing of the first harm assessment is planned at the interim analysis and 
will be based on data up to D43. 
The assessment for COVID-19 will be implemented separately using a one-sided conditional 
exact binomial test of H0: p ≤ “number of participants in the pooled vaccine arm”/“total number 
of participants” versus H1: p > “number of participants in the pooled vaccine arm”/“total number 
of participants”, where p is the binomial probability that a case participant is assigned to the 
vaccine group conditional on the observed total number of cases. The test will be performed at the 
same pre-specified one-sided nominal/unadjusted alpha-level of 0.05 (unadjusted). The bounds for 
harm monitoring are computed under the null hypothesis that VE=0%.  
If a null hypothesis is rejected and boundary is met, SMT will be notified immediately of the 
potential harm signal to make an assessment of whether modifications in study conduct and/or 
monitoring should be implemented. 
Another interim analysis will be performed on data collected for immunogenicity, safety, efficacy, 
and harm up to the 3-month time point (D91 for Cohort 1 and D112 for Sentinel Cohort and 
Cohort 2).  
After the 6-month data (D181 for Cohort 1 and D202 for Sentinel Cohort and Cohort 2) have been 
collected, a further interim analysis will be performed on immunogenicity, safety, and efficacy 
endpoints. 
A final analysis for all data collected will be conducted once the 12-month safety data have been 
collected and the final database lock has occurred. 
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study (see also 
Section 8.4.1 for Sentinel Cohort dose-escalation, Section 8.4.2 for CS-ESDR details, and 
Section 8.4.3 for halting rules for the entire study). 
The SAP will describe the planned interim analyses and CS-ESDRs in greater detail. 
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9.6 
Data Monitoring Committee (DMC) 
Not applicable. 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations 
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(CDISC) requirements. 
10.1.1 Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator or the Sponsor 
(according to local regulations) and reviewed and approved by the IRB/IEC before the study 
is initiated 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants 
• The Investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC (in addition to summaries required from the Sponsor)  
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
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applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
• In case the participant has decided to opt out, the Investigator must record in the 
site medical files that he/she does not want to know about such findings. 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
10.1.2 Financial Disclosure 
Information related to financial disclosure is described in the Investigator’s contract. 
10.1.3 Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• The actual ICF used at each center may differ, depending on local regulations and IRB/IEC 
requirements. However, all versions must contain the standard information found in the 
sample ICF provided by the Sponsor. Any change to the content of the ICF must be approved 
by the Sponsor and the IRB/IEC prior to the form being used. 
• If new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study, this will be communicated to him/her in a timely manner. 
Such information will be provided via a revised ICF or an addendum to the original ICF. 
• Participants must be re-consented to the most current version of the ICF during their 
participation in the study. 
• A copy of the ICF must be provided to the participant. 
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The ICF will contain a specific section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. 
Recruitment Procedures 
Before the start of the study, the Investigator or sub-Investigator will contact an appropriate pool 
of potential participants and invite them to participate in the study. The site will ensure that any 
advertisements used to recruit participants (eg, letters, pamphlets, posters) are submitted to Sanofi 
Pasteur prior to submission to the IRB/IEC for approval. 
10.1.4 Data Protection and Future Use of Stored Samples 
• All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with 
all applicable laws and regulations including the GDPR. Data collected must be adequate, 
relevant and not excessive, in relation to the purposes for which they are collected. Each 
category of data must be properly justified and in line with the study objective. 
• Participants’ race and ethnicity will be collected in this study because these data are required 
by regulatory agencies (36). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred to the 
Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant as described in the ICF. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
• Participant data will be used for this study and in support of the whole drug development 
program for the Investigational Product, including negotiations with payers and publication of 
results. 
• Any unused part of the serum, respiratory, or peripheral blood mononuclear cell (PBMC) 
samples will be securely stored at a Sanofi Pasteur facility or Contract Research Organization 
up to 25 years after the end of the study. Unused samples may also be sent to another long-
term repository, as necessary. These samples are being retained in long-term storage to 
support answers to regulatory questions related to the product’s licensure and the potential 
revalidation of the study results. 
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The other biological samples collected to qualify the participant for inclusion in the study or to 
monitor his/her health are dedicated for immediate use. In case they are not completely used 
up, they will be destroyed at the latest at the end of the study or after the time requested by 
local law. 
In addition, participants will be asked to indicate in the ICF whether they will permit the 
future use of any unused stored serum samples for tests not related to the study objectives. If 
they refuse permission, the samples will not be used for any testing other than that directly 
related to this study. If they agree to this use, they will not be paid for giving permission. 
Anonymity of samples will be ensured. The aim of any possible future research is unknown 
today and may not be related to this particular study. It may be to improve the knowledge of 
vaccines or infectious diseases, or to improve existing tests or develop new tests to assess 
vaccines. Human genetic tests will never be performed on these samples without specific 
individual informed consent. 
10.1.5 Committees Structure 
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study. 
10.1.6 Dissemination of Clinical Study Data 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data Quality Assurance 
• All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
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• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
10.1.8 Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, screening logs, informed consent/assent forms, telephone contact logs, and worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Detailed guidance and information are provided in the Operating Guidelines. 
10.1.9 Study and Site Start and Closure 
Details on which clinical supplies are provided by the Sponsor or the site are described in the 
Operating Guidelines. 
The study start date is considered the date of the first visit planned in the SoA (Section 1.3) of the 
first participant. 
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The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study site has all the documents necessary for archiving and a study site 
closure visit has been performed along with a Site Close Out Form submitted to the IRB, as 
required. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication Policy 
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: Clinical Laboratory Tests 
• The tests detailed in Table 10.1 will be performed by the site-selected local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• A urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) will be performed at screening and before each vaccination. Refer to 
Section 5.1.1 and Section 5.1.2 for pregnancy inclusion criteria.  
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Table 10.1: Protocol-required safety laboratory assessments 
Laboratory 
assessments 
Time period for assessment 
Parameters 
Hematology 
Cohort 1: Screening (between 
-D04 and -D01) and V02 
(D09) 
Sentinel Cohort & Cohort 2: 
Screening (between -D04 and  
-D01), V02 (D09), and V04 
(D30) 
• 
White blood cell (WBC) count with differential: 
o Neutrophils 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils 
• 
Hemoglobin 
• 
Platelet count  
Clinical 
Chemistry 
Cohort 1: Screening (between 
-D04 and -D01) and V02 
(D09) 
Sentinel Cohort & Cohort 2: 
Screening (between -D04 and  
-D01), V02 (D09), and V04 
(D30) 
• 
Sodium  
• 
Potassium 
• 
Blood Urea Nitrogen 
• 
Creatinine  
• 
Glucose (nonfasting)  
• 
Aspartate aminotransferase (AST)/Serum 
Glutamic-Oxaloacetic Transaminase (SGOT) 
• 
Alanine Aminotransferase (ALT)/Serum 
Glutamic-Pyruvic Transaminase (SGPT) 
• 
Alkaline phosphatase  
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total protein 
Coagulation 
parameters 
Cohort 1: Screening (between 
-D04 and -D01) and V02 
(D09) 
Sentinel Cohort & Cohort 2: 
Screening (between -D04 and  
-D01), V02 (D09), and V04 
(D30) 
• 
PT 
• 
PTT 
• 
INR 
Routine 
Urinalysis 
Cohort 1: Screening (between 
-D04 and -D01) and V02 
(D09) 
Sentinel Cohort & Cohort 2: 
Screening (between -D04 and  
-D01), V02 (D09), and V04 
(D30) 
• 
Glucose, protein, blood, leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood or protein is 
abnormal) 
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Laboratory 
assessments 
Time period for assessment 
Parameters 
Other 
Screening 
Tests 
Cohort 1: Screening (between 
-D04 and -D01), V01 (D01) 
Sentinel Cohort & Cohort 2: 
Screening (between -D04 and  
-D01), V01 (D01), V03 (D22) 
Highly sensitive urine human chorionic gonadotropin 
(hCG) pregnancy test (as needed for women of 
childbearing potential)* 
Screening (between -D08 and  
-D01). Results for serology 
tests obtained within 4 weeks 
prior to V01 will be accepted. 
• 
HIV antibody  
• 
Hepatitis B surface antigen 
• 
Hepatitis B core antibody  
• 
Hepatitis C antibody 
Screening (between -D04 and  
-D01; All participants) 
SARS-CoV-2 antibody 
*To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically 
sterile 
It is to be noted that COVID-19 antibody test and blood and urine sampling for safety tests may 
be performed on the day of enrollment as long as the results to assess exclusion criteria are 
available prior to enrollment. 
Investigators must document their review of each laboratory safety report. 
For all participants, laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
 
 
 
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10.3 Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, electrocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
Other Definitions 
Adverse Reaction: 
All noxious and unintended responses to a study intervention related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a study intervention” means that a causal relationship between a 
study intervention and an AE is at least a reasonable possibility) 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs 
(including those related to the study intervention administered) that occur within the first 30 
minutes after vaccination. 
Medically Attended Adverse Event:  
An MAAE is a new-onset or a worsening of a condition that prompts the participant to seek 
unplanned medical advice at a physician’s office or Emergency Department. Physician contact 
made over the phone or by email will be considered a physician office visit for the purpose of 
MAAE collection. This includes medical advice seeking during the study visit or routine 
medical care. This definition excludes pediatric check-ups, follow-up visits of chronic 
conditions with an onset prior to entry in the study, and solicited reactions.  
Injection Site Reaction/Administration Site Reactions: 
An injection/administration site reaction is an AR at and around the injection/administration 
site. Injection/administration site reactions are commonly inflammatory reactions. They are 
considered to be related to the study intervention administered. 
Systemic Adverse Event/Adverse Reaction: 
Systemic AEs are all AEs that are not injection or administration site reactions. They should 
therefore include systemic manifestations such as headache, fever, as well as localized or 
topical manifestations that are not associated with the vaccination or administration site (eg, 
erythema that is localized but that is not occurring at the injection site). 
Systemic AEs assessed as related to study intervention are referred as systemic ARs. Solicited 
systemic reactions occurring during the specified collection period are always considered 
related to the study vaccine even if there is evidence or alternative etiology. 
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Adverse Event of Special Interest: 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s study intervention or program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the study Sponsor to other parties (eg, regulators) might 
also be warranted. 
New-Onset Chronic Medical Conditions (NOCMCs):  
NOCMCs are defined as any new ICD-10 diagnosis (10th revision of the International 
Statistical Classification of Diseases and Related Health Problems) that is applied to the 
participant during the course of the study, after receipt of the study agent, that is expected to 
continue for at least 3 months and requires continued health care intervention. 
Reactogenicity/Solicited Reactions: 
A solicited reaction is an “expected” adverse reaction (sign or symptom) observed and reported 
under the conditions (nature and onset) pre-listed in the protocol and CRF (eg, injection site 
pain or headache occurring between the day of vaccination and the next 7 days).  
By definition, solicited reactions are considered as being related to the study intervention 
administered. 
For injectable vaccines, solicited reactions can either be solicited injection/administration site 
reactions or solicited systemic reactions. 
Unsolicited Adverse Event/Adverse Reaction: 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and/or onset window post-vaccination. For 
example, varicella or a solicited term such as headache starting after the solicited observation 
period (headache starting on Day 10 post-vaccination in the case where headache occurring 
between the day of vaccination and the next 7 days is pre-listed in the protocol and CRF as a 
solicited reaction). 
An unsolicited AR is an unsolicited AE that is considered related to study intervention. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
10.3.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
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b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other important medical event 
• Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
health of the participant or may require intervention to prevent one of the other outcomes 
listed in the above definition. These important medical events should also usually be 
considered serious. 
• 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse, new-onset diabetes or autoimmune 
disease. 
Note: Serious and severe are not synonymous. The term severe is often used to describe the 
intensity of a specific event as corresponding to Grade 3. This is not the same as serious, which is 
based on participant/event outcome or action criteria usually associated with events that pose a 
threat to a participant’s life or functioning. 
 
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10.3.3 Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the CRF pages. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to the 
Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Causal Relationship 
By convention, all AEs reported at the injection site (whether solicited or unsolicited) and all 
solicited systemic AEs are considered to be related to the study intervention and therefore are 
referred to as reactions and do not require the Investigator’s opinion on relatedness. 
• Causal relationship of unsolicited systemic AEs and SAEs will be recorded as follows: 
• 
For non-serious unsolicited systemic AEs (except for non-serious AESIs), relationship 
to study intervention will usually be assessed by the Investigator only.   
• 
For SAEs and non-serious AESIs, relationship to study intervention will be assessed 
by both the Investigator and the Sponsor. Sponsor assessment is entered in the GPV 
database only.   
• 
For SAEs only, the causal relationship to study procedures (related/not related to study 
procedures) will be assessed by both the Investigator and the Sponsor. Sponsor 
assessment is entered in the GPV database only. 
• The Investigator will assess the causal relationship between each unsolicited systemic AE 
and the study intervention administereda as either not related or related, based on the 
following definitions: 
• 
Not related – The AE is clearly/most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; 
or the AE started before the first vaccination (screening phase, if applicable) 
                                                 
a Study intervention administered can correspond to either the investigational product or other products when no 
investigational product is administered at the visit 
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• 
Related – There is a “reasonable possibility” that the AE was caused by the study 
intervention administered, meaning that there is evidence or arguments to suggest a 
causal relationship 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causal relationship. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the Investigator always make an assessment of causal relationship for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causal relationship in light of follow-up 
information and send a SAE follow-up report with the updated causal relationship 
assessment. 
• The causal relationship assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causal relationship of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, when available the Investigator will provide the Sponsor with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
• Adverse events likely to be related to the study intervention, whether serious or not, that 
persist at the end of the study will be followed-up by the Investigator until their complete 
disappearance or the stabilization of the participant’s condition. The Investigator will 
inform the Sponsor of the date of final disappearance of the event or the date of 
“chronicity” establishment. 
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10.3.4 Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the Sponsor will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. The site will enter the 
SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken off-line, 
then the site can report this information on a paper SAE form (see next section). 
• Details regarding SAE reporting can be found in the Operating Guidelines. 
 
SAE Reporting to the Sponsor via Paper CRF 
• The SAE paper CRF can be sent to the Sponsor by one of the following means: 
• 
By fax, to the following number: 570-957-2782 
• 
In PDF format to the following email address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.coam  
• 
By express mail, to the following address:  
 
 
Global PharmacoVigilance, Sanofi Pasteur 
 
 
Discovery Drive 
 
 
Swiftwater, PA 18370 
 
Safety Emergency Call 
If, as per the Investigator's judgment, a participant experiences a medical emergency, the 
Investigator may contact the Sponsor's RMO for advice on how to address any study-related 
medical question or problem. If the RMO is not available, then the Investigator may contact the 
Call Center—available 24 hours a day, 7 days a week—that will forward all safety emergency 
calls to the appropriate primary or back-up Sanofi Pasteur contact, as needed. The toll-free 
contact information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department. 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.3.2. 
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10.3.5 Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 
10.3.5.1 Tables for Clinical Abnormalities 
10.3.5.1.1 Solicited AR Intensity Grading Scale 
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Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales  
CRF term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when the injection site 
is touched or injected limb is mobilized 
Presence of a redness 
including the approximate 
point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale* 
 
CRF: 
Grade 1: A type of adverse event that is usually transient 
and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with 
usual activities of daily living. 
Grade 2: A type of adverse event that is usually alleviated 
with additional therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the 
research participant. 
Grade 3: A type of adverse event that interrupts usual 
activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Diary card: 
Grade 1: No interference with usual activities 
Grade 2: Some interference with usual activities 
Grade 3: Significant; prevents usual activities 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
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MedDRA: Medical Dictionary for Regulatory Activities 
* For the subjective reaction of pain, participants will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and swelling, they will record 
just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
 
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Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
Diary card 
term 
Temperature 
Headache 
Feeling unwell or 
feeling tired 
Muscle aches and pains 
Joint pain 
Chills 
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. 
Pain in a joint or joints  
Sensation of cold  
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CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
Intensity 
scale* 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to 
≤ 101.1°F 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
 
Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to 
≤ 102.0°F 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
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CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Diary card: 
Grade 1: No 
interference with usual 
activities 
Grade 2: Some 
interference with usual 
activities 
Grade 3: Significant; 
prevents usual activities 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Diary card: 
Grade 1: No 
interference with usual 
activities 
Grade 2: Some 
interference with usual 
activities 
Grade 3: Significant; 
prevents usual activities 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Diary card: 
Grade 1: No 
interference with usual 
activities 
Grade 2: Some 
interference with usual 
activities 
Grade 3: Significant; 
prevents usual activities 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Diary card: 
Grade 1: No 
interference with usual 
activities 
Grade 2: Some 
interference with usual 
activities 
Grade 3: Significant; 
prevents usual activities 
Grade 3: A type of 
adverse event that 
interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Diary card: 
Grade 1: No 
interference with usual 
activities 
Grade 2: Some 
interference with usual 
activities 
Grade 3: Significant; 
prevents usual activities 
MedDRA: Medical Dictionary for Regulatory Activities 
* For all reactions but fever, participants will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and the classification as 
Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
 
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Important Notes for the Accurate Assessment of Temperature: 
Participants are to measure body temperature once per day, preferably always at the same time. 
The optimal time for measurement is the evening, when body temperature is the highest. 
Temperature is also to be measured at the time of any apparent fever. The observed daily 
temperature and the route of measurement are to be recorded in the DC, and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this study is oral. 
10.3.5.1.2 Unsolicited AE Intensity Grading Scale 
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.3.5.1.1). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
CRF: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• 
DC: No interference with usual activities. 
• Grade 2 
• 
CRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• 
DC: Some interference with usual activities. 
• Grade 3 
• 
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
DC: Significant; prevents usual activities. 
10.3.5.2 Tables for Laboratory Abnormalities 
The pre-defined intensity thresholds for laboratories abnormalities are shown in Table 10.4. 
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Table 10.4: Intensity thresholds for laboratory abnormalities 
Endpoint 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Above normal WBC – cell/mm3 
10,800 – 15,000 
15,001 – 20,000 
≥ 20,001 
Below normal WBC – cell/mm3 
2,500 – 3,500 
1,500 – 2,499 
≤ 1,499 
Hemoglobin (Female) – gm/dL 
11.0 – 12.0 
9.5 – 10.9 
≤ 9.4 
Hemoglobin (Female) 
(Change from baseline value) – gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
≥ 2.1 
Hemoglobin (Male) – gm/dL 
12.5 – 13.5 
10.5 – 12.4 
< 10.5 
Hemoglobin (Male) 
(change from baseline value) – gm/dL 
Any decrease – 1.5 
1.6 – 2.0 
≥ 2.1 
Platelets decreased – cell/mm3 
125,000 – 140,000 
100,000 – 
124,000 
≤ 99,000 
Absolute neutrophil decrease – cell/mm3 
1,500 – 2,000  
1,000 – 1,499  
< 999  
Absolute lymphocyte decrease – cell/mm3 
750 – 1,000  
500 – 749  
< 499  
Absolute eosinophil – cell/mm3 
650 – 1500  
1501 - 5000  
> 5000  
Sodium – Hyponatremia – mEq/L  
132 – 134  
130 – 131  
< 130  
Sodium – Hypernatremia – mEq/L  
144 – 145  
146 – 147  
> 148  
Potassium – Hyperkalemia – mEq/L  
5.1 – 5.2  
5.3 – 5.4  
> 5.4 
Potassium – Hypokalemia – mEq/L  
3.5 – 3.6  
3.3 – 3.4  
< 3.3  
Blood Urea Nitrogen (BUN) – mg/dL  
23 – 26  
27 – 31  
> 31 or require 
dialysis  
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
≥ 2.1 or requires 
dialysis 
Glucose – Hyperglycemia (random) – 
mg/dL  
110 - 125 
126 - 200 
> 200 
Total protein – Hypoproteinemia – g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
LFT (ALT, AST) 
(Increase by factor)  
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
≥ 5.1 ULN 
Alkaline phosphate 
(Increase by factor) 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
≥ 3.1 ULN 
Bilirubin – with any increase in LFT 
(Increase by factor) 
1.1 – 1.25 x ULN 
1.26 – 1.5 x 
ULN 
≥ 1.51 ULN 
Bilirubin – with normal LFT  
(Increase by factor) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
 ≥ 2.1 ULN 
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Endpoint 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
PT – increase by factor (prothrombin time) 
1.0 – 1.10 x ULN 
1.11 – 1.20 x 
ULN 
1.21 – 1.25 x ULN 
PTT – increase by factor (partial 
thromboplastin time) 
1.0 – 1.2 x ULN 
1.21 – 1.4 x 
ULN 
1.41 – 1.5 x ULN 
Urine - glucose 
Trace 
1+ 
2+ 
Urine - protein 
Trace 
1+ 
2+ 
Urine – blood (microscopic - RBCs per high 
power field (rbc/hpf) 
1 - 10 
11 - 50 
> 50 and/or gross 
blood 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; dL, deciliter; gm, gram; L, liter; 
LFT, liver function test; mEq, milliequivalent; mg, milligram; mm3, cubic millimeter; PT, prothrombin time; PTT, 
partial thromboplastin time; RBC, red blood cell; ULN, upper limit of normal; WBC, white blood cell. 
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10.4 Appendix: Collection of Pregnancy Information 
DEFINITIONS: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the Following Categories are not Considered WOCBP 
1) Premenarchal 
2) Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Post-menopausal female 
• 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• 
A high follicle stimulating hormone (37) level in the post-menopausal range may be 
used to confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment. 
COLLECTION OF PREGNANCY INFORMATION 
The collection period of pregnancy information will correspond at least to the period during which 
the participant is requested to be under contraception. (according to protocol: effective method of 
contraception or abstinence from at least 4 weeks prior to the first vaccination until at least 
12 weeks after the last vaccination). If there are any pregnancy during this period, follow-up 
should be conducted up to delivery: this will be covered by the 12-month surveillance of the 
study. 
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Female Participants who Become Pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information together with the 
contraceptive method if any will be recorded on the appropriate form and submitted to the 
Sponsor within 1 month of learning of a participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date but will be in accordance with local regulations. 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth (occurring at 
> 22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.7. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• In case of pregnancy during the primary series and if at least 1 dose of the study vaccine(s) 
has been administered, the participant 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 participant will be followed for safety assessment (and 
may be followed for immunogenicity assessment, if applicable). 
• If primary series have been completed and the delivery occurs between the primary series and 
the booster, the booster dose can be administered. However, if vaccination is a 
contraindication for lactation (ie, live-attenuated vaccine), the participant may not be 
vaccinated with a booster dose. 
 
 
 
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10.5 Appendix: AESIs 
Protocol-Specified AESIs 
• Anaphylactic reactions 
• Generalized convulsion 
• Guillain-Barré Syndrome (GBS)  
• Acute disseminated encephalomyelitis (ADEM) 
• Thrombocytopenia  
• Vasculitides 
• NOCMCs 
AESIs Related to SARS-CoV-2 Infection and COVID-19 Disease 
Immunologic 
• 
Enhanced disease following immunization 
Respiratory 
• 
Acute respiratory distress syndrome 
Cardiac  
Acute cardiac injury including: 
• 
Microangiopathy 
• 
Heart failure and cardiogenic shock 
• 
Stress cardiomyopathy 
• 
Coronary artery disease 
• 
Arrhythmia 
• 
Myocarditis, Pericarditis 
Endocrine 
• 
Pancreatitis 
• 
Subacute thyroiditis 
Hematologic 
Coagulation disorder 
• 
Deep vein thrombosis 
• 
Pulmonary embolus 
• 
Cerebrovascular stroke 
• 
Limb ischemia 
• 
Hemorrhagic disease 
Musculoskeletal 
• 
Rhabdomyolysis 
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Renal  
• 
Acute kidney injury 
Gastrointestinal  
• 
Liver injury 
Neurologic  
• 
GBS 
• 
Anosmia, Ageusia 
• 
Meningoencephalitis 
Dermatologic  
• 
Chilblain-like lesions 
• 
Single organ cutaneous vasculitis 
• 
Erythema multiforme 
10.6 Appendix: Risk-based Approach 
ICH E6-R2 guideline for GCP is introducing the « risk-based approach » concept which permits 
to focus efforts on what is critical for a study and most specifically on Critical Data and Critical 
Processes. Critical data and processes are defined for the study with associated risks in the Study 
Risk Management Plan. 
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10.7 Appendix: Abbreviations 
2P 
 
double proline 
Ab 
 
antibody 
ADEM 
acute disseminated encephalomyelitis 
AE 
 
adverse events 
AESI  
adverse event of special interest 
AIT 
 
Additional Immunological Tests 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
AR 
 
adverse reactions 
BL 
 
blood sample (#) 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMI  
cell-mediated immunity 
CRF  
case report form 
CS-ESDR 
Complete Sentinel Early Safety Data Review 
D 
 
Day 
DC 
 
diary card 
DMC  
Data Monitoring Committee 
DNA  
deoxyribonucleic acid 
ECG  
electrocardiogram 
ECLIA 
electrochemiluminescence immunoassay 
ELISA  
enzyme-linked immunosorbent assay 
ESDR  
Early Safety Data Review 
FAS 
 
Full Analysis Set 
FDA  
Food and Drug Administration 
FSH 
 
follicle stimulating hormone 
GBS  
Guillain-Barré Syndrome 
GCI 
 
Global Clinical Immunology 
GCP  
Good Clinical Practice 
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GDPR  
General Data Protection Regulation 
GMC  
geometric mean concentration 
GMT  
geometric mean titer 
GPV  
Global Pharmacovigilance 
HA 
 
hemagglutinin 
hCG  
human chorionic gonadotropin 
HCoV  
Human Coronavirus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
 
human immunodeficiency virus 
HRT  
hormonal replacement therapy 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
ICU 
 
intensive care unit 
IEC 
 
Independent Ethics Committees 
IgG 
 
immunoglobulin G 
INR 
 
international normalized ratio 
IRB 
 
Institutional Review Boards 
IRT 
 
Interactive Response Technology 
 
 
 
 
 
LLOQ  
lower limit of quantification 
LNP  
lipid nanoparticle 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV Middle East Respiratory Syndrome coronavirus 
mRNA 
messenger ribonucleic acid 
  
 
 
 
NAAT  
nucleic acid amplification test 
NHP  
non-human primate 
NOAEL 
no-observed-adverse-effect level 
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NOCMC 
new-onset chronic medical conditions 
OD 
 
optical density 
PBMC  
peripheral blood mononuclear cell 
 
 
 
PPAS  
per-protocol analysis set 
PPAS-AIT 
per-protocol analysis set for AIT 
PPAS-IAS 
per-protocol analysis set for immunogenicity 
PT 
 
prothrombin time 
PTT 
 
partial thromboplastin time 
RMO  
Responsible Medical Officer 
RNA  
ribonucleic acid 
S 
 
spike 
SAE  
serious adverse event 
SafAS  
Safety Analysis Set 
SAP 
 
Statistical Analysis Plan 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 
SGOT  
Serum Glutamic-Oxaloacetic Transaminase 
SGPT  
Serum Glutamic-Pyruvic Transaminase 
SMT  
Safety Management Team 
SoA 
 
Schedule of Activities 
SUSAR 
suspected unexpected serious adverse reactions 
TC 
 
telephone call 
Th 
 
T-helper cell 
VAC  
Vaccination (as in Vaccination #) 
US 
 
United States 
 
 
 
WOCBP 
Woman of Childbearing Potential 
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Duffy D, Rouilly V, Braudeau C, Corbière V, Djebali R, Ungeheuer MN, et al. 
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36. 
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37. 
Flaherman VJ, Afshar Y, Boscardin J, Keller RL, Mardy A, Prahl MK, et al. Infant 
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12 Sponsor Signature Page 
 
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Document Number
CLI_00321998
Version Number
3.0
Project Code
COVID-19 mRNA
Artifact Name
Protocol Body
-
-
-
Approver Name
Date
(Universal Time)
Reason for Signature
Approval
-
-
 
Sanofi Pasteur 
Confidential/Proprietary Information 
VAW00001
Protocol Version 3.0
551 - SARS-CoV-2 mRNA vaccine
Page 141 of 141
VV-TMF-585476   Protocol 2021-04-08 | VV-TMF-585476 | 3.0