Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccine Formulations (With or Without Adjuvant) in Healthy Adults 18 Years of Age and Older
Phase: PHASE1
Conditions: COVID-19 (Healthy Volunteers)
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccine Formulations (with or 
without adjuvant) in Healthy Adults 18 Years of Age and Older 
Study Code: VAT00001 
Protocol Version Number:  5.0 
Amendment Number: Amendment 1 
Compound: 
SARS-CoV2 prefusion Spike delta TM (CoV2 preS dTM): antigen Formulation 1 (low-dose 
[5 µg] or Formulation 2 (high-dose [15 µg]) 
AF03: CoV2 preS dTM-AF03, Squalene-based adjuvant 2.5% 
AS03: CoV2 preS dTM-AS03, Squalene-based adjuvant 2.1% 
Study Phase: Phase I/II 
Short Title: 
Study of Recombinant Protein Vaccine Formulations 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:  
CoV2 preS dTM and AF03 adjuvant: Same as Sponsor 
AS03 adjuvant: GlaxoSmithKline (Vaccines) 
Regulatory Agency Identifier Numbers: 
BB-IND: 23143 
WHO UTN: U1111-1250-4757 
Approval Date:  05 February 2021 
Medical Monitor Name and Contact Information are provided in the Operating Guidelines. 
The study centers, the Investigators at each center, and the Coordinating Investigator(s) are listed 
in a separate document. 
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Document History and Protocol Amendment Rationale 
Previous 
Version 
Date 
Comments 
1.0 
11 May 2020 
Submitted to CBER for pre-IND submission only. 
2.0 
24 July 2020 
Submitted to CBER for IND submission and to IRB only 
before study start. 
3.0 
26 August 2020 
Submitted to IRB 
4.0 
28 August 2020 
Version approved by IRB and first version used in the 
study 
 
Overall Rationale for Amendment 1: 
The protocol was amended from v4.0 dated 28 August 2020 for a study design change that allows 
participants, if they are eligible, to receive one of the COVID-19 vaccines currently available via 
emergency use authorization. In addition, the 4-month interim analysis will not be conducted as 
efficacy analysis is moved to the 6-month interim analysis. 
 
Major revisions between Version 4.0 and Version 5.0 
Revision 
Rationale 
Table 1.1 and Table 1.2: Collection of concomitant 
medications 
Revised to include participants can receive an 
approved/authorized COVID-19 vaccine  
Since the protocol was first approved, 2 
COVID-19 vaccines have received 
emergency use authorization by the FDA  
Section 7.1.2: language added to contraindications 
paragraph regarding subjects who receive an 
approved/authorized COVID-19 vaccine 
Since the protocol was first approved, 2 
COVID-19 vaccines have received 
emergency use authorization by the FDA 
Section 9.5: removed the sentence, “Another interim 
analysis will be performed on efficacy data obtained up to 
4-month follow up for assessment of early efficacy (Visit 
5 for participants in each cohort)”  
Efficacy analysis moved to the 6-month 
interim analysis; 4-month analysis not 
needed 
 
 
 
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Table of Contents 
Document History and Protocol Amendment Rationale ............................................................. 2 
List of Tables .................................................................................................................................... 7 
List of Figures .................................................................................................................................. 8 
1 
Protocol Summary ............................................................................................................. 9 
1.1 
Synopsis ............................................................................................................................ 9 
1.2 
Schema ............................................................................................................................ 15 
1.3 
Schedule of Activities (SoA) .......................................................................................... 16 
2 
Introduction ..................................................................................................................... 28 
2.1 
Study Rationale ............................................................................................................... 30 
2.2 
Background ..................................................................................................................... 30 
2.3 
Benefit/Risk Assessment ................................................................................................ 30 
2.3.1 
Risks from Study Participation ..................................................................................... 32 
2.3.2 
Benefits from Study Participation ................................................................................ 34 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 35 
3 
Objectives and Endpoints ............................................................................................... 35 
4 
Study Design .................................................................................................................... 37 
4.1 
Overall Design ................................................................................................................ 37 
4.2 
Scientific Rationale for Study Design ............................................................................. 40 
4.3 
Justification for Protein Dose Levels .............................................................................. 44 
4.4 
End of Study Definition .................................................................................................. 45 
5 
Study Population ............................................................................................................. 45 
5.1 
Inclusion Criteria ............................................................................................................ 45 
5.2 
Exclusion Criteria ........................................................................................................... 45 
5.3 
Lifestyle Considerations ................................................................................................. 47 
5.4 
Screen Failures ................................................................................................................ 48 
6 
Study Intervention ........................................................................................................... 48 
6.1 
Study Interventions Administered .................................................................................. 48 
6.2 
Preparation/Handling/Storage/Accountability ................................................................ 50 
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6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................ 51 
6.3.1 
Randomization and Allocation Procedures .................................................................. 51 
6.3.2 
Blinding and Code-breaking Procedures ...................................................................... 52 
6.4 
Study Intervention Compliance ...................................................................................... 53 
6.5 
Concomitant Therapy ...................................................................................................... 53 
6.5.1 
Rescue Medicine ........................................................................................................... 54 
6.6 
Dose Modification .......................................................................................................... 54 
6.7 
Intervention After the End of the Study .......................................................................... 54 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal .......................................................................................... 54 
7.1 
Discontinuation of Study Intervention ............................................................................ 54 
7.1.1 
Temporary Contraindications ....................................................................................... 54 
7.1.2 
Definitive Contraindications ......................................................................................... 55 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................ 55 
7.3 
Lost to Follow-up ............................................................................................................ 56 
8 
Study Assessments and Procedures ............................................................................... 56 
8.1 
Baseline Screening for SARS-CoV-2 antibodies ........................................................... 59 
8.2 
Efficacy and Immunogenicity Assessments ................................................................... 59 
8.2.1 
Immunogenicity Assessments ...................................................................................... 59 
8.2.1.1 
SARS-CoV-2 Neutralizing Antibody Assessment ..................................................... 59 
8.2.1.2 
SARS-CoV-2 Spike Protein Antibody Serum IgG ELISA ........................................ 59 
8.2.1.3 
Cellular-Mediated Immunity (using whole blood) ..................................................... 60 
8.2.2 
Efficacy Assessments ................................................................................................... 60 
8.2.2.1 
Definitions .................................................................................................................. 60 
8.2.2.2 
COVID-19-like Illness Surveillance .......................................................................... 62 
8.2.2.3 
SARS-CoV-2 Nucleoprotein Antibody Serum IgG ELISA ....................................... 62 
8.2.2.4 
Nucleic Acid Amplification Test (NAAT) for COVID-19 Case Detection ............... 63 
8.3 
Safety Assessments ......................................................................................................... 63 
8.3.1 
Medical History ............................................................................................................ 63 
8.3.2 
Physical Examinations .................................................................................................. 63 
8.3.3 
Vital Signs .................................................................................................................... 63 
8.3.4 
Clinical Safety Laboratory Assessments ...................................................................... 63 
8.4 
Adverse Events and Serious Adverse Events ................................................................. 64 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ......................... 66 
8.4.2 
Method of Detecting AEs and SAEs ............................................................................ 67 
8.4.3 
Follow-up of AEs and SAEs ........................................................................................ 68 
8.4.4 
Regulatory Reporting Requirements for SAEs ............................................................ 68 
8.4.5 
Pregnancy ..................................................................................................................... 68 
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8.4.6 
Adverse Events of Special Interest ............................................................................... 69 
8.4.7 
Medically Attended Adverse Events ............................................................................ 69 
8.5 
Treatment of Overdose ................................................................................................... 69 
8.6 
Pharmacokinetics ............................................................................................................ 69 
8.7 
Pharmacodynamics ......................................................................................................... 69 
8.8 
Genetics ........................................................................................................................... 70 
8.9 
Biomarkers ...................................................................................................................... 70 
8.10 
Immunogenicity Assessments ......................................................................................... 70 
8.11 
Medical Resource Utilization and Health Economics .................................................... 70 
9 
Statistical Considerations ............................................................................................... 70 
9.1 
Statistical Hypotheses ..................................................................................................... 70 
9.2 
Sample Size Determination ............................................................................................. 70 
9.3 
Populations for Analyses ................................................................................................ 71 
9.4 
Statistical Analyses ......................................................................................................... 72 
9.4.1 
General Considerations ................................................................................................. 72 
9.4.2 
Primary Endpoints ........................................................................................................ 72 
9.4.2.1 
Immunogenicity ......................................................................................................... 72 
9.4.2.2 
Safety .......................................................................................................................... 72 
9.4.3 
Secondary Endpoints .................................................................................................... 73 
9.4.3.1 
Immunogenicity ......................................................................................................... 73 
9.4.3.2 
Efficacy ...................................................................................................................... 73 
9.4.4 
Exploratory Endpoint ................................................................................................... 73 
9.4.4.1 
Immunogenicity ......................................................................................................... 73 
9.5 
Interim Analyses ............................................................................................................. 74 
9.6 
Data Monitoring Committee (DMC) .............................................................................. 74 
10 
Supporting Documentation and Operational Considerations .................................... 75 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations ............................ 75 
10.1.1 
Regulatory and Ethical Considerations ........................................................................ 75 
10.1.2 
Financial Disclosure ..................................................................................................... 75 
10.1.3 
Informed Consent Process ............................................................................................ 76 
10.1.4 
Data Protection and Future Use of Stored Samples ..................................................... 76 
10.1.5 
Committees Structure ................................................................................................... 78 
10.1.6 
Dissemination of Clinical Study Data .......................................................................... 78 
10.1.7 
Data Quality Assurance ................................................................................................ 78 
10.1.8 
Source Documents ........................................................................................................ 79 
10.1.9 
Study and Site Start and Closure .................................................................................. 79 
10.1.10 
Publication Policy ......................................................................................................... 80 
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10.2 
Appendix: Clinical Laboratory Tests .............................................................................. 80 
10.3 
Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................ 82 
10.3.1 
Definition of AE ........................................................................................................... 82 
10.3.2 
Definition of SAE ......................................................................................................... 84 
10.3.3 
Recording and Follow-Up of AE and/or SAE .............................................................. 86 
10.3.4 
Reporting of SAEs ........................................................................................................ 88 
10.3.5 
Assessment of Intensity ................................................................................................ 89 
10.3.5.1 
Tables for Clinical Abnormalities .............................................................................. 89 
10.3.5.1.1 
Solicited AR Intensity Grading Scale ...................................................................... 89 
10.3.5.1.2 
Unsolicited AE Intensity Grading Scale .................................................................. 94 
10.3.5.2 
Tables for Laboratory Abnormalities ......................................................................... 94 
10.4 
Appendix: Collection of Pregnancy Information ............................................................ 97 
10.5 
Appendix: AESIs ............................................................................................................ 99 
10.6 
Appendix: Risk-based Approach .................................................................................. 102 
10.7 
Appendix: Abbreviations .............................................................................................. 103 
10.8 
Appendix: Protocol Amendment/Update History ......................................................... 105 
11 
References ...................................................................................................................... 108 
12 
Sponsor Signature Page ................................................................................................ 111 
 
 
 
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List of Tables 
Table 1.1: Schedule of activities 1 (Cohort 1) ............................................................................... 17 
Table 1.2: Schedule of activities 2 (Cohort 2) ............................................................................... 22 
Table 1.3: Schedule of activities 3: Follow-up of COVID-19-like illness .................................... 27 
Table 2.1: Potential risks of clinical significance and risk management ...................................... 33 
Table 3.1: Objectives and endpoints ............................................................................................. 35 
Table 4.1: Overall design .............................................................................................................. 37 
Table 4.2: Planned sample size ..................................................................................................... 39 
Table 6.1: Identity of study interventions ...................................................................................... 48 
Table 8.1: Blood sampling per visit .............................................................................................. 58 
Table 8.2: COVID-19-like illness symptoms: CRF and Diary Card / Memory Aid terms ........... 61 
Table 10.1: Protocol-required safety laboratory assessments ....................................................... 81 
Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales ....... 90 
Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales ............. 92 
Table 10.4: Intensity thresholds for laboratories abnormalities .................................................... 95 
Table 10.5: List of potential immune-mediated diseases ............................................................ 100 
 
 
 
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List of Figures 
Figure 1.1: Graphical study design (Cohort 1) .............................................................................. 15 
Figure 1.2: Graphical study design (Cohort 2) .............................................................................. 16 
 
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1 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccine Formulations (with or 
without adjuvant) in Healthy Adults 18 Years of Age and Older 
Short Title: 
Study of Recombinant Protein Vaccine Formulations 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 declaration on 11 March 2020 of a pandemic 
(1). As of 25 August 2020, the virus has been detected in 188 countries/regions and infected over 
23.7 million individuals (2). 
The clinical profile of COVID-19, the illness caused by SARS-CoV-2, is variable (3). In the 
majority of cases, the manifestations are mild, or individuals may be asymptomatic. Among those 
with symptoms, typical presentations include fever, cough, and shortness of breath. More severe 
manifestations include acute hypoxemic respiratory failure requiring intubation and mechanical 
ventilation, in some cases resulting in death. Based on early data, adults over 50 years of age and 
individuals with chronic medical conditions are at a higher risk of severe outcomes and death. At 
present, no licensed vaccine exists for this strain nor any other coronaviruses.  
To address the urgent medical need caused by this outbreak, Sanofi Pasteur is developing a 
candidate vaccine consisting of a stabilized prefusion trimer of the SARS-CoV-2 Spike (S) protein 
based on the work by Wrapp et al (4). Sanofi Pasteur will apply the manufacturing technology that 
is used to produce commercialized recombinant hemagglutinin (HA) vaccine, Flublok®. It is 
anticipated that the recombinant protein vaccine will require an adjuvant to optimize the immune 
response and for dose-sparing potential. While Sanofi Pasteur’s proprietary AF03 adjuvant will be 
utilized for this vaccine development, it is anticipated that the demand for a protective vaccine 
will likely exceed the supply capacity for any single adjuvant; thus, a second adjuvant supplied by 
GlaxoSmithKline, AS03, will also be evaluated. 
The current first-in-human study will evaluate the immunogenicity and safety of the candidate 
vaccine with the goal of selecting a formulation, or formulations, and an injection schedule to 
proceed to efficacy evaluation as rapidly as possible.
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
Immunogenicity 
To describe the neutralizing antibody profile at 
Day (D)01, D22, and D36 of each study 
intervention group. 
Immunogenicity 
Neutralizing antibody titers 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 
Safety 
To describe the safety profile of all participants in 
each age group and each study intervention group 
up to 12 months post-last injection. 
Safety 
• 
Presence of unsolicited systemic adverse 
events (AEs) reported in the 30 minutes after 
each injection 
• 
Presence of solicited (pre-listed in the 
participant’s diary card and Case Report Form 
[CRF]) injection site reactions and systemic 
reactions 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 event 
(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 7 days post-last injection (ie, up to D09 
for Cohort 1 and up to D30 for Cohort 2) 
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Secondary  
 
Immunogenicity 
1) To describe binding antibody profile at D01, 
D22, D36, D181 (Cohort 1) or D202 (Cohort 
2), and D366 (Cohort 1) or D387 (Cohort 2) of 
each study intervention group. 
2) To describe the neutralizing antibody profile at 
D181 (Cohort 1) or D202 (Cohort 2) and D366 
(Cohort 1) and D387 (Cohort 2) of each study 
intervention group. 
Immunogenicity 
Binding antibody titers to full-length 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, D181 (Cohort 1) or D202 
(Cohort 2), and D366 (Cohort 1) or D387 
(Cohort 2)  
• 
Individual anti-S antibody concentration ratio 
(fold-rise in serum ELISA concentration post-
vaccination relative to D01) at D22, D36, 
D181 (Cohort 1) or D202 (Cohort 2), and 
D366 (Cohort 1) or D387 (Cohort 2)  
• 
Fold-rise in anti-S antibody concentration 
(post/pre) ≥ 2 and ≥ 4 at D22, D36, D181 
(Cohort 1) or D202 (Cohort 2), and D366 
(Cohort 1) or D387 (Cohort 2) 
Neutralizing antibody titers will be measured with 
the neutralization assay.  
• 
Antibody titer at D181 (Cohort 1) or D202 
(Cohort 2) and D366 (Cohort 1) or D387 
(Cohort 2) 
• 
Fold-rise (fold-rise in serum neutralization 
titer post-vaccination relative to D01) at D181 
(Cohort 1) or D202 (Cohort 2) and D366 
(Cohort 1) or D387 (Cohort 2) 
• 
2-fold and 4-fold rise in serum neutralization 
titer (post/pre) relative to D01 at D181 
(Cohort 1) or D202 (Cohort 2) and D366 
(Cohort 1) or D387 (Cohort 2) 
• 
Occurrence of neutralizing antibody 
seroconversion, defined as values below 
LLOQ at baseline with detectable 
neutralization titer above assay LLOQ at D181 
(Cohort 1) or D202 (Cohort 2) and D366 
(Cohort 1) or D387 (Cohort 2) 
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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 
Recombinant Protein 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 nucleic 
acid viral detection assay  
• 
Serologically-confirmed SARS-CoV-2 
infection is defined by SARS-CoV-2-specific 
antibody detection in a non-S ELISA 
• 
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 
 
Overall Design 
Type of design 
Parallel group, first-in-human, dose-ranging, 
multi-center study with a Sentinel Safety Cohort 
and Early Safety Data Review (ESDR) 
Phase 
I/II 
Control method 
Placebo-controlled 
Study population 
Healthy, seronegative adults 18 years of age and 
older 
Countries 
United States 
Level and method of blinding 
• 
Blinding for vaccine group assignment 
(formulation and adjuvant): participants, 
outcome assessors, Investigators, laboratory 
personnel, Sponsor study staff (except those 
involved in ESDR, and for concerned 
participants only) 
• 
No blinding for injection schedule 
• 
No blinding for vaccine group assignment: 
those preparing/administering the study 
interventions 
Study intervention assignment method 
Randomization for study intervention and assigned 
stratification by age 
 
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Disclosure Statement: 
This is a parallel group prevention study, stratified into 2 age groups based on age 
at enrollment: the younger adult age group (18-49 years) will be randomly assigned 
to one of 11 arms; the older adult age group (≥ 50 years) will be randomly assigned 
to one of 10 arms. Participants, outcome assessors, Investigators, laboratory 
personnel, and the majority of sponsor study staff (except those involved in the 
ESDR and for concerned participants only) will be blinded to vaccine assignment 
group (formulation and adjuvant); injection schedule will be unblinded; and those 
preparing/administering the study interventions will be unblinded to vaccine group 
assignment.  
Number of Participants: 
Approximately 440 participants 18 years of age and older (300 adults 18 through 49 years of age 
and 140 adults 50 years of age and older) are planned to be randomized.  
As a precautionary step, a Sentinel Safety Cohort of 6 participants (younger adults only) within 
each dosing group from Cohort 1 will be enrolled. An ESDR will be performed, including 
evaluation of safety data and laboratory measures to D09 in Cohort 1 among younger adults 
18-49 years of age. Upon acceptable safety demonstrated from unblinded data review by limited 
members of the Sponsor Study Team (Responsible Medical Officer [RMO], Study Biostatistician 
and Programmer, Pharmacovigilance Science Expert, and Global Safety Officer), the remaining 
participants in Cohort 1 and all participants in Cohort 2 will be enrolled. 
Intervention Groups and Duration: 
A total of 440 participants are planned to be enrolled as shown below: 
Participants 18-49 years of age 
Cohort 
Group 
Dose Level* 
Adjuvant 
N 
Sentinel 
Safety† 
(N=30) 
Total 
(N=300) 
Cohort 1:  
1 injection 
1 
5 µg 
AF03 
6 
20 
2 
5 µg 
AS03 
6 
20 
3 
15 µg 
AF03 
6 
20 
4 
15 µg 
AS03 
6 
20 
5 
Placebo 
None 
6 
20 
Cohort 2:  
2 injections 
6 
5 µg 
AF03 
N/A 
20 
7 
5 µg 
AS03 
N/A 
60 
8 
15 µg 
AF03 
N/A 
20 
9 
15 µg 
AS03 
N/A 
60 
10 
15 µg 
None 
N/A 
20 
11 
Placebo 
None 
N/A 
20 
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Participants 50 years of age and older 
Cohort 
Group 
Dose Level* 
Adjuvant 
N 
(N=140) 
Cohort 1:  
1 injection 
1 
5 µg 
AF03 
10 
2 
5 µg 
AS03 
10 
3 
15 µg 
AF03 
10 
4 
15 µg 
AS03 
10 
5 
Placebo 
None 
10 
Cohort 2:  
2 injections 
6 
5 µg 
AF03 
10 
7 
5 µg 
AS03 
30 
8 
15 µg 
AF03 
10 
9 
15 µg 
AS03 
30 
10 
15 µg 
None 
N/A‡ 
11 
Placebo 
None 
10 
*Antigen Formulation naming for each dose level: CoV2 preS dTM antigen: Formulation 1 (low-dose [5 µg]); 
Formulation 2 (high-dose [15 µg]) 
† Sentinel Safety Cohort: 6 participants within each dosing group from Cohort 1 (18-49 years of age only) will be 
included in the Sentinel Safety Cohort. 
‡ As part of risk mitigation for enhanced COVID-19, the older age stratification (≥ 50 years) will not be allocated 
to this study arm. 
Note: A subset of 87 participants in Cohort 2 (60 participants 18-49 years of age [18 per group in AS03-adjuvanted 
vaccines; 6 per group in all other study groups]) and 27 participants ≥ 50 years of age [9 per group in 
AS03-adjuvanted groups; 3 per group in all other study groups, with the exception of the unadjuvanted group for 
which there will be no older adults]), will be randomly assigned to a cellular-mediated immune (CMI) subset. 
 
All participants will receive 1 injection of either one of the investigational study vaccine 
formulations or the placebo control at D01 (Vaccination [VAC] 1). Participants in Cohort 2 will 
receive a second injection of study vaccine formulation or placebo at D22 (VAC2).  
If a COVID-19 vaccine becomes available from a company other than Sanofi Pasteur, then 
participants are free to receive that vaccine. Participants who receive a COVID-19 vaccine will 
still be followed for safety until the end of the study but will be discontinued from study 
intervention administration thereafter. 
Enrolled participants who seek vaccination of an authorized/approved vaccine outside of the study 
will be encouraged to discuss this intention proactively with the study investigator and will be 
permitted to receive the authorized vaccine at any time. As efficacy has not been demonstrated for 
any of the investigational formulations under evaluation in the current study, it is not required to 
unblind participants to the VAT00001 study assignment prior to administration of an authorized 
COVID-19 vaccine. 
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If the participant receives the authorized/approved vaccine, this information would be collected 
and the participant’s data up to the point of receipt of authorized/approved 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 invited to provide a blood sample for 
immunological assessment. 
The duration of each participant’s participation in the study will be approximately 365 days 
post-last injection: 
• Cohort 1: approximately 365 days duration total 
• Cohort 2: approximately 386 days duration total 
Data Monitoring Committee: No 
1.2 
Schema 
The graphical design of VAT00001 study is as presented in Figure 1.1 (Cohort 1) and Figure 1.2 
(Cohort 2).  
Figure 1.1: Graphical study design (Cohort 1) 
Ab, antibody; BL, blood sample; TC, telephone call; V, visit; VAC, vaccination 
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Figure 1.2: Graphical study design (Cohort 2) 
Ab, antibody; BL, blood sample; CMI, cellular-mediated immunity; MC, mononuclear cell; TC, telephone 
call; V, visit; VAC, vaccination; WB, whole blood 
1.3 
Schedule of Activities (SoA) 
Visits and procedures are detailed in the Operating Guidelines.  
 
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Table 1.1: Schedule of activities 1 (Cohort 1) 
Phase I/II Study, 7 Visits, 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 
V01 
V02 
V03 
V04 
Telephone 
Call 
V05 
V06  
V07 or Safety 
Follow-up 
Call§§§§ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D36 
D43 
D113 
D181 
D366 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 +112 
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 
X 
X 
 
 
 
 
 
 
 
Point-of-care SARS-CoV-2 antibody test 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
 
 
 
 
Collection of medical history 
X 
Significant 
Medical 
History 
X 
 
 
 
 
 
 
 
Physical examination* 
 
X 
 
 
 
 
 
 
 
Pre-vaccination temperature 
 
X 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable) † 
 
X 
 
 
 
 
 
 
 
Contact IRT system for randomization, 
participant number, and unique dose 
number allocation. 
X 
X 
 
 
 
 
 
 
 
Respiratory sample collection 
 
Can occur at any time during the study as unscheduled visit(s) 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
V02 
V03 
V04 
Telephone 
Call 
V05 
V06  
V07 or Safety 
Follow-up 
Call§§§§ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D36 
D43 
D113 
D181 
D366 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 +112 
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: 
 
 
 
 
 
 
 
 
 
Clinical safety laboratory assessments ‡ 
(10 mL) 
    (All participants) 
X 
X§ 
X 
 
 
 
 
 
 
Serum samples for Ab assays (30 mL) 
    (All participants) 
X 
BL0001§ 
 
BL0002 
BL0003 
 
BL0004 
BL0005 
BL0006 
Vaccination (VAC) 
X 
X 
 
 
 
 
 
 
 
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‡‡ 
Collection of solicited injection site & 
systemic reactions 
X 
D01-D08 
 
 
 
 
 
 
Collection of unsolicited AEs 
X 
D01-D22 
 
 
 
 
 
Collection of concomitant medications 
X 
Reportable 
concomitant 
medication 
All reportable concomitant 
medications 
(including influenza vaccination) 
Influenza and COVID-19 vaccinations only 
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. 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
V02 
V03 
V04 
Telephone 
Call 
V05 
V06  
V07 or Safety 
Follow-up 
Call§§§§ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D36 
D43 
D113 
D181 
D366 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 +112 
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: 
 
 
 
 
 
 
 
 
 
Active surveillance calls 
X 
 
 
 
 
TC to occur every 2 weeks after the D43 
contact until D181§§§   
(See also Schedule of Activities Table 1.3 
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; DC, Diary Card; IRT, interactive 
response technology; MAAE, medically attended adverse event; S, Spike; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; V, visit; 
VAC, vaccination  
*Targeted physical examination based on the participant’s medical history and the examiner’s medical judgment will be performed at V01.  
† 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 before vaccination. 
‡ Safety laboratory assessments will include: Serum Chemistries (liver enzymes / Chem 7, lipase, and amylase); hematology (complete blood count with differential); Urinalysis; 
Microscopy. In cases of abnormal safety laboratory results, unscheduled visits may occur, based on Investigator’s judgment.  
§ BL0001 and the first safety laboratory assessment sample will be collected at pre-vaccination (baseline). 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
V02 
V03 
V04 
Telephone 
Call 
V05 
V06  
V07 or Safety 
Follow-up 
Call§§§§ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D36 
D43 
D113 
D181 
D366 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 +112 
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: 
 
 
 
 
 
 
 
 
 
** 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 SAEs, AESIs, and COVID-19-like illness follow-up from V03 to V04. 
*** Participants will use this DC3 for SAEs, AESIs, and COVID-19-like illness follow-up from V04 to V05. 
††† Participants will use this DC4 for SAEs, AESIs, and COVID-19-like illness follow-up from V05 to V06. 
‡‡‡ Participants will use this DC5 for SAEs, AESIs, and COVID-19-like illness follow-up from V06 to V07. 
§§§ 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: Anaphylactic reactions, Generalized convulsion, 
Thrombocytopenia, Lacrimal and salivary disorders (tearing, dry mouth, dry eyes), any new-onset chronic medical conditions, and potential immune-mediated diseases. 
†††† In case of participant discontinuation at a visit, the entire visit will be completed 
‡‡‡‡ During the D43 telephone call, staff will review the DC3 pertaining to SAE, AESI, and COVID-19-like illness between V04 and the call and will remind the participant to 
bring back the DC3 for V05. This telephone call will NOT be collected in the CRF. 
§§§§ 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 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
V02 
V03 
V04 
Telephone 
Call 
V05 
V06  
V07 or Safety 
Follow-up 
Call§§§§ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D36 
D43 
D113 
D181 
D366 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V01 + 35 
days 
V01 + 42 
days 
V01 +112 
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: 
 
 
 
 
 
 
 
 
 
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 1.2: Schedule of activities 2 (Cohort 2) 
Phase I/II Study, 7 Visits, 2 Telephone Calls, 2 Injections, 6 Blood Sample Time-points, Approximately 13 Months’ Duration Per Participant 
Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
Telephone 
Call 1 
V02 
V03 
V04 
Telephone 
Call 2 
V05 
V06 
V07 or 
Safety 
Follow-up 
Call***** 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D134 
D202 
D387 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V02 + 8 
days 
V02 + 14 
days 
V02 + 21 
days 
V02 + 112 
days 
V02 + 
180 days 
V02 + 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 
X 
X 
 
 
 
 
 
 
 
 
Point-of-care SARS-CoV-2 antibody 
test 
 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
 
 
 
 
 
Collection of medical history 
X 
Significant 
Medical 
History 
X 
 
 
 
 
 
 
 
 
Physical examination* 
 
X 
 
 
 
 
 
 
 
 
Pre-vaccination temperature 
 
X 
 
X 
 
 
 
 
 
 
Urine pregnancy test (if applicable) † 
 
X 
 
X 
 
 
 
 
 
 
Contact IRT system for 
randomization, participant number, 
and unique dose number allocation. 
X 
X 
 
 
 
 
 
 
 
 
Contact IRT system for unique dose 
number allocation. 
X 
 
 
X 
 
 
 
 
 
 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
Telephone 
Call 1 
V02 
V03 
V04 
Telephone 
Call 2 
V05 
V06 
V07 or 
Safety 
Follow-up 
Call***** 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D134 
D202 
D387 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V02 + 8 
days 
V02 + 14 
days 
V02 + 21 
days 
V02 + 112 
days 
V02 + 
180 days 
V02 + 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: 
 
 
 
 
 
 
 
 
 
 
Temporary and definitive 
contraindications 
X 
 
 
X 
 
 
 
 
 
 
Respiratory sample collection 
 
Can occur at any time during the study as unscheduled visit(s) 
Clinical safety laboratory 
assessments ‡ (10 mL) 
(All participants) 
X 
X§ 
 
 
X 
 
 
 
 
 
Serum samples for Ab assays 
(30 mL) 
(All participants) 
X 
BL0001§ 
 
BL0002§ 
 
BL0003 
 
BL0004 
BL0005 
BL0006 
 
Cellular-mediated Immunity (40 mL) 
(Subset of 87 participants in 
Cohort 2) 
X 
MC0001§ 
 
MC0002§ 
 
MC0003 
 
 
 
 
TruCulture (4 mL) 
(Subset of 87 participants in 
Cohort 2) 
X 
WB0001§ 
 
WB0002§ 
 
WB0003 
 
 
 
 
Vaccination (VAC) 
X 
X 
 
X 
 
 
 
 
 
 
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‡‡ 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
Telephone 
Call 1 
V02 
V03 
V04 
Telephone 
Call 2 
V05 
V06 
V07 or 
Safety 
Follow-up 
Call***** 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D134 
D202 
D387 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V02 + 8 
days 
V02 + 14 
days 
V02 + 21 
days 
V02 + 112 
days 
V02 + 
180 days 
V02 + 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: 
 
 
 
 
 
 
 
 
 
 
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 vaccination) 
Influenza and COVID-19 vaccinations 
only 
Telephone call 
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. 
Active surveillance calls 
X 
 
 
 
 
 
TC to occur every 2 weeks after the D43 
contact until D202**** 
(See also Schedule of Activities Table 1.3 
for follow-up) 
 
Collection of SAEs, AESIs††††, 
and MAAEs 
X 
To be reported at any time during the study 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
Telephone 
Call 1 
V02 
V03 
V04 
Telephone 
Call 2 
V05 
V06 
V07 or 
Safety 
Follow-up 
Call***** 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D134 
D202 
D387 
Time Interval (days) 
 
 
V01 + 8 
days 
V01 + 21 
days 
V02 + 8 
days 
V02 + 14 
days 
V02 + 21 
days 
V02 + 112 
days 
V02 + 
180 days 
V02 + 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: 
 
 
 
 
 
 
 
 
 
 
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 
discontinued early) ***** 
X 
 
 
 
 
 
 
 
 
X 
Abbreviations: Ab, Antibody; AE, adverse event; AESI, adverse event of special interest; BL, blood sample (#); CRF, Case Report Form; DC, Diary Card; IRT, interactive response 
technology; MAAE, medically attended adverse event; MC, mononuclear cell; S, Spike; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 
V, visit; VAC, Vaccination; WB, whole blood  
*Targeted physical examination based on the participant’s medical history and the examiner’s medical judgment will be performed at V01.  
† 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 before vaccination. 
‡ Safety laboratory assessments will include: Serum Chemistries (liver enzymes / Chem 7, lipase, and amylase); hematology (complete blood count with differential); Urinalysis; 
Microscopy. In cases of abnormal safety laboratory results, unscheduled visits may occur, based on Investigator’s judgment.  
§ BL0001, MC0001, WB0001 and the first safety laboratory assessment sample will be collected at pre-VAC1 (baseline); and BL0002, MC0002, and WB0002 samples will be 
collected at pre-VAC2. 
** 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 V02. 
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†† 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 V02 to V03) and will continue to collect unsolicited AEs, SAEs, and AESIs 
(from V03 to V04). 
*** Participants will use this DC3 for unsolicited AEs follow-up until D43 and SAEs, AESIs, and COVID-19-like illness follow-up from V04 to V05. 
††† Participants will use this DC4 for SAEs, AESIs, and COVID-19-like illness follow-up from V05 to V06. 
‡‡‡ Participants will use this DC5 for SAEs, AESIs, and COVID-19-like illness follow-up from V06 to V07. 
§§§ During the D09 telephone call, staff will review the DC1 for solicited reactions from D01 to D08 after vaccination, inquire whether the participant experiences any SAE or AESI 
not yet reported, and remind the participant to bring back DC1 for V02. This telephone call will NOT be documented in the CRF. 
**** 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: Anaphylactic reactions, Generalized convulsion, 
Thrombocytopenia, Lacrimal and salivary disorders (tearing, dry mouth, dry eyes), any new-onset chronic medical conditions, and potential immune-mediated diseases.  
‡‡‡‡ In case of participant discontinuation at a visit, the entire visit will be completed. 
§§§§ During the D43 telephone call, staff will review the DC3 pertaining to unsolicited AEs, SAE, AESI, and COVID-19-like illness between V04 and the call and will remind the 
participant to bring back the DC3 for V05. This telephone call will NOT be documented in the CRF. 
***** All participants will be scheduled to attend V07 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 1.3: Schedule of activities 3: 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 sample as soon as possible after illness start date‡ 
X 
 
 
Remind participant to complete Memory Aid or Diary Card 
X 
 
 
Collection of respiratory sample 
 
NPXXXX§ 
 
Collection of disease burden and health care information 
X 
X 
X 
Collection of treatments received during COVID-19-like illness  
X 
X 
X 
Collection of information on respiratory illness symptoms 
X 
X 
X 
* Initial illness identification phone call 
† Follow-up telephone call approximately 30 days after illness 
‡ Start of first clinical manifestation of COVID-19-like illness 
§ “X” indicates that the nasopharyngeal swab number will be unique to each site. Further details are provided in the Operating Guidelines. 
 
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2 
Introduction 
Sanofi Pasteur’s Recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
protein vaccine is being developed in the setting of a pandemic for the active immunization for the 
prevention of SARS-CoV-2 infection and/or COVID-19 disease. The initial intended use of the 
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.  
The candidate antigen is a stabilized prefusion trimer of the SARS-CoV-2 S protein. The 
coronavirus Spike (S) protein is the major viral envelope glycoprotein and mediates attachment 
and entry into host cells. The S protein precursor is cleaved to form non-covalently associated 
subunits, S1 and S2 (5). The S protein appears on the surface of the virus as a mushroom-like 
structure, containing a cap of three S1 subunits and a stem of three S2 subunits. The S1 subunit 
contains the receptor binding domain (RBD), which attaches to the host cellular receptor. In the 
case of SARS-CoV-2, the receptor is Angiotensin Converting Enzyme-Related Peptidase 2, a 
membrane-bound carboxypeptidase localized to vascular endothelial as well as epithelial surfaces 
(6). The RBD is a major antigenic target for immune responses. The S2 domain contains the 
fusion peptide and transmembrane regions. Upon binding to the cellular receptor, S1 is cleaved 
from the virus and the S2 subunit undergoes a conformational change to mediate viral membrane 
fusion with the host cell membrane.  
Prior research with Middle East Respiratory Syndrome (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 (7). 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 HCoV-
NL63, MERS-CoV, and SARS-CoV-1, and by extrapolation to SARS-CoV-2 (4). The pre-fusion 
stabilized SARS-CoV-2 Spike construct to be evaluated in the current study is based on this 
research. 
The antigen will be manufactured using the same technology as is used to manufacture Flublok 
vaccine, which is a recombinant hemagglutinin (HA) vaccine licensed for the prevention of 
influenza in adults 18 years of age and older (8). In this system, the gene of interest is cloned into 
a baculovirus transfer vector, which is used to form recombinant baculoviruses. The viral stock is 
used to infect an insect cell line (ExpresSF+). The recombinant protein is expressed in the infected 
insect cells. After incubation, the recombinant protein is purified. This process is adaptable to a 
variety of antigens. Millions of doses of Flublok vaccine have been administered since its 
approval for human use corresponding to HAs of different influenza strains (H1, H3, and B) 
covering multiple influenza seasons. Additionally, the process has previously been applied to the 
development of candidate SARS-CoV-1 vaccines. Following the SARS outbreak, Protein 
Sciences developed candidate S protein vaccines, including a full-length S protein and a 
transmembrane-deleted ectodomain antigen. These were tested in a variety of preclinical models 
and found to induce neutralizing antibody responses and to be partially protective in a ferret 
challenge model. 
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It is anticipated that, owing to the need to mobilize naïve B and T cell responses, the magnitude 
and quality of the immune response to the candidate antigen will be enhanced through delivery 
with an adjuvant. This may allow for titration of the amount of antigen used; and, thus, be 
antigen-sparing and potentially increase the available supply of antigen. In addition, the adjuvant 
may influence the quality of the immune response. Prior mouse experiments with candidate 
SARS-CoV-1 vaccines had identified that recombinant S protein candidates were immunogenic 
and that adjuvantation with alum could improve the titer of neutralizing antibodies (9). However, 
in these experiments it was observed that mice receiving the alum-adjuvanted, recombinant S 
protein vaccine displayed immunopathology in the lungs that was suggestive of a T-helper (Th)2-
type response. Therefore, in this program to develop a SARS-CoV-2 vaccine with recombinant 
protein (SARS CoV2 prefusion Spike delta TM [SARS CoV2 preS dTM]), the adjuvants AS03 
and AF03, that may promote a more balanced Th1/Th2 response (10) (11), are being investigated.   
AS03 and AF03 are both oil-in-water emulsions containing squalene. Both have been evaluated in 
the context of pandemic or pre-pandemic influenza vaccines. Safety of AS03-adjuvanted products 
has been extensively evaluated and found to be generally well tolerated with an acceptable safety 
profile (12). AS03 was evaluated with pandemic H7 HA manufactured by Protein Sciences in 
humans, demonstrating robust neutralizing antibody responses and hemagglutination inhibition, 
together with an acceptable safety profile. As has been the case for several pandemic agents, 
unadjuvanted H7 HA-containing influenza vaccines were poorly immunogenic (13) (14). 
AF03 has been administered to over 1,500 humans in the setting of clinical trials and was 
approved for use in Europe as a component of Humenza®, an H1N1 pandemic influenza vaccine 
(15). In a more recent study, AF03 was demonstrated to have strong effects on the magnitude and 
breadth of neutralizing responses to influenza in mice (16). A preclinical study in macaques 
demonstrated a higher level of protection following AF03-adjuvanted vaccination from 
pneumonia and decrease severity of lung disease on challenge with the homologous H5N1 
influenza strain than alum-adjuvanted or unadjuvanted comparators. The protection was correlated 
with the level of neutralizing antibodies (17). Recent human clinical experience has included use 
of AF03 in combination with quadrivalent inactivated influenza antigens (n=40, 15 µg of HA per 
strain, total of 60 µg of protein) and quadrivalent baculovirus recombinant influenza antigens 
(n=40, 45 µg of HA per strain, total of 180 µg of protein manufactured by Protein Sciences) in a 
Phase I trial (NCT03945825); the formulations were found to be generally well tolerated, and 
review by the study Data and Safety Monitoring Board revealed no safety concerns. 
A potential safety issue with coronavirus vaccines is the ability to potentiate immunopathology in 
vaccinees upon exposure to wild-type virus (18). The molecular mechanism for this phenomenon, 
sometimes termed Antibody Dependent Enhancement, Vaccine-Associated Enhanced Respiratory 
Disease, or Immune Enhancement of viral infection, is also 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 cell response (9) (19) (20). It is anticipated that the design of the 
candidate SARS-CoV-2 antigen selected for this study will promote generation of robust 
neutralizing antibodies over binding antibodies, based on data generated with other coronavirus 
vaccine antigens (4) (7). The inclusion of adjuvanted formulations is anticipated to further 
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enhance the magnitude of neutralizing antibody responses and induce a balanced Th1/Th-2 cell 
responses (10) (11). Taken together, these strategies mitigate by design theoretical risks of 
immune enhancement of viral infection. 
2.1 
Study Rationale 
The current first-in-human study will evaluate the immunogenicity and safety of the candidate 
vaccine with the goal of selecting a formulation, or formulations, and a dosing schedule to 
proceed to efficacy evaluation as rapidly as possible. 
2.2 
Background 
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. The viral genome is packed into a capsid comprised of 
the viral nucleocapsid protein, which is in turn surrounded by an envelope. Viral proteins 
associated with the envelope include the S protein, which mediates viral attachment and entry into 
cells. 
The burden of SARS-CoV-2 morbidity and mortality has been catastrophic with greater than 
815,000 deaths recorded since first emerging in December 2019 among over 23.7 million 
confirmed cases (as of 25 August 2020) (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 economic consequences. A safe and effective vaccine would be a vital tool to 
address the significant medical and societal burden caused by the pandemic. 
The CoV2 preS dTM recombinant protein vaccine belongs to the pharmacotherapeutic group of 
“Other viral vaccines”. The vaccine contains recombinant S protein, stabilized to maintain native 
prefusion trimer configuration as present on the viral envelope. 
Further details of the chemistry, pharmacology, and safety of the CoV2 preS dTM recombinant 
protein vaccine are provided in the Investigator’s Brochure (IB). 
2.3 
Benefit/Risk Assessment 
The novel coronavirus outbreak started in December 2019 in Wuhan City, Hubei Province, China. 
Since the end of 2019, more than 80,000 COVID-19 cases have been reported in China, mostly in 
Hubei and surrounding provinces. Following the lock down in China, the incidence had decreased 
at the beginning of March but had already rapidly spread globally. As of 25 August 2020, the 
virus has been detected in 188 countries/regions, infected over 23.7 million individuals, and over 
815,000 persons have died from COVID-19 (2). 
The investigational recombinant protein vaccine consists of a stabilized prefusion trimer of the 
SARS-CoV-2 S protein. The coronavirus S protein precursor is cleaved to form non-covalently 
associated subunits, S1 and S2 (5). The S1 subunit contains the RBD, which attaches to the viral 
receptor; the RBD is the major antigenic target for immune responses. The S2 domain contains 
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the fusion peptide and transmembrane regions, which undergoes a conformational change to 
mediate viral fusion with the host cell. The S1 and S2 subunits combine as a trimer of each 
subunit.  
It is anticipated that owing to the need to mobilize naïve B and T cell responses, the magnitude of 
the immune response to the candidate antigen will be enhanced through delivery with an adjuvant. 
This may allow for titration of the amount of antigen used; and, thus, be antigen-sparing and 
potentially increase the available supply of antigen. In addition, the adjuvant may influence the 
character of the immune response. Prior mouse experiments with candidate SARS-CoV-1 
vaccines had identified that recombinant S protein candidates were immunogenic and that 
adjuvantation with alum could improve the titer of neutralizing antibodies (9). However, in these 
experiments it was observed that mice receiving the alum-adjuvanted, recombinant S protein 
vaccine displayed immunopathology in the lungs that was suggestive of a Th2-type response. 
Therefore, the adjuvants AS03 and AF03, that may promote a more balanced Th1/Th2 response 
(10) (11), will be investigated. 
A potential safety issue with coronavirus vaccines is the ability to potentiate immunopathology in 
vaccinees upon exposure to wild-type virus (18). 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. 
AF03 is a squalene emulsion-based adjuvant similar to MF59 and AS03 adjuvants but utilizes an 
alternative manufacturing process that involves phase inversion temperature emulsification and 
incorporates 2 non-ionic surfactants (15). During the 2009 H1N1 pandemic, Sanofi Pasteur 
developed an AF03 adjuvanted A/H1N1 pandemic influenza vaccine (Humenza) and performed 
clinical studies to support the licensure of the vaccine. Clinical trials using AF03 with A/H5N1 
and A/H1N1 pandemic influenza antigen have been performed in adults (21); elderly; and 
children, including infants (22). Taken together, the data from these studies showed that AF03 
enhanced the magnitude of antibody response, proportion of participants with seroprotective titers 
and durability of antibody responses. With regards to safety, the addition of AF03 was associated 
with a higher frequency of solicited injection site reactions as expected with any adjuvanted 
vaccine, while solicited systemic reactions and unsolicited adverse events (AEs) varied in each 
age group. Overall, AF03 appears to be safe and well tolerated when administered as half- or full-
dose (6.2 mg or 12.5 mg of squalene per vaccine dose) and in any age group. No safety signals 
were detected with AF03 adjuvanted pandemic influenza vaccines in any of the populations 
included in the clinical studies.  
Like AF03 adjuvant, AS03 is an oil-in-water emulsion containing squalene. To support the 
licensing of A/H1N1 pandemic influenza vaccines in elderly people, Pandemrix® and Arepanrix®, 
2 large clinical studies were carried out in participants aged 61 years and above (23). Additional 
clinical studies were conducted in adults ≥ 18 years of age, children from 6 months to 18 years, 
and older adults ≥ 65 years of age as well as post-licensure safety studies (12). All these studies 
but 2 were conducted with vaccine antigen of H1N1 strain. The 2 other clinical studies assessed 
the vaccines antigens H7N1 and H9N2 (24). Q-Pan®, an Influenza A (H5N1) Virus Monovalent 
Vaccine adjuvanted with AS03 is licensed by the US FDA. AS03 was also assessed in the 
development of an adjuvanted trivalent influenza vaccine (TIV). A Phase III efficacy trial 
evaluated efficacy of AS03-adjuvanted TIV compared to unadjuvanted TIV among 43,695 
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volunteers 65 years of age or older. Taken together, these studies and post-licensure data showed 
that AS03 enhanced antibody and T cell responses with an acceptable safety profile.  
Of note, based on the theoretical concern that vaccination with an adjuvanted vaccine containing 
potent immunostimulants may interfere with immunological self-tolerance, pIMDs (potential 
Immune-Mediated Diseases) are adverse events of special interest (AESIs) undergoing special 
safety monitoring for vaccines containing Adjuvant Systems. pIMDs are a subset of AEs that 
include autoimmune diseases and other inflammatory and/or neurological disorders of interest 
which may or may not have an autoimmune etiology (see Table 10.5 for a full list). 
The efficacy of the candidate vaccine formulations has not been established. CoV2 preS dTM 
Recombinant Protein Candidate 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.  
The CoV2 preS dTM vaccine is expected to confer protection against SARS-CoV-2 infection 
and/or COVID-19 disease and its complications with a clinical benefit of reduction of the 
associated burden of disease in population over 18 years of age. 
More detailed information about the known and expected benefits and risks, reasonably expected 
AEs, the potential risks, and uncertainties of CoV2 preS dTM vaccine may be found in the 
CoV2 preS dTM vaccine IB. 
In addition, information related to the AF03 adjuvant may be found in the AF03 IB. 
Also, more detailed information related to the AS03 adjuvant will be made available by 
GlaxoSmithKline (GSK). 
2.3.1 
Risks from Study Participation 
The potential risks of clinical significance and risk management are summarized in Table 2.1. 
 
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Table 2.1: Potential risks of clinical significance and risk management 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Risk Management 
Investigated Vaccine: CoV2 preS dTM (AF03 or AS03) 
Anaphylactic reactions 
Class-effect for all vaccines (even not 
adjuvanted)  
Observation period after vaccination 
for early detection and treatment 
Risk management will also be based 
on Exclusion criterion E08 (see 
Section 5.2). 
Enhanced COVID-19 
A potential safety issue with coronavirus 
vaccines is the ability to potentiate 
immunopathology in vaccinees upon 
exposure to wild-type virus (18). The 
molecular mechanism for this 
phenomenon, sometimes termed 
Antibody Dependent Enhancement, 
Vaccine-Associated Enhanced 
Respiratory Disease, or Immune 
Enhancement of viral infection, is also 
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 T-helper cell response 
(9) (19) (20) (25) 
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 antigen 
selected for this study will promote 
generation of robust neutralizing 
antibodies over binding antibodies, 
based on data generated with other 
coronavirus vaccine antigens (4) 
(7).  
The inclusion of adjuvanted 
formulations is anticipated to further 
enhance the magnitude of 
neutralizing antibody responses and 
induce a balanced Th1/Th-2 cell 
responses (10) (11).  
Taken together, these strategies 
mitigate by design theoretical risks 
of immune enhancement of viral 
infection. 
Individuals with chronic comorbid 
conditions considered to be 
associated with an increased risk of 
severe COVID-19 will be excluded 
(26). 
Number of study participants of 
older age group will be minimized 
to balance the theoretical risks and 
the ability to determine the 
consistency of the immune 
responses compared to younger 
adults.  
In addition, no older age group 
study participants are included in 
the antigen-only group (without 
adjuvant). 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Risk Management 
Potential Immune-Mediated 
Diseases 
Based on the theoretical concern that 
vaccination with an adjuvanted vaccine 
containing potent immunostimulants 
may interfere with immunological self-
tolerance, pIMDs are AESIs undergoing 
special safety monitoring for vaccines 
containing Adjuvant Systems. pIMDs 
are a subset of AEs that include 
autoimmune diseases and other 
inflammatory and/or neurological 
disorders of interest which may or may 
not have an autoimmune etiology. 
During the informed consent 
process, the participants enrolling in 
the study will be informed of this 
potential risk and the need to attend 
the clinic if they are unwell. pIMD 
is an AESI and will be collected 
until study end. The occurrence of 
pIMD cases will be described. 
Refer to IBs’ Section 5 and 
Section 6 for more 
information regarding 
potential risks. 
Refer to the IB Section 5 and Section 6 
for more information regarding the data 
from previous experience with the 
adjuvants in the investigated vaccine. 
 
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. 
Participant contact with other 
individuals when visiting study site 
(study site to set up system) should 
be minimized  
Protective material (eg, masks for 
participants, clothing, goggles) to be 
used in sites. 
Home visit option for completion of 
study procedures in the setting of 
containment measures to minimize 
exposure.  
2.3.2 
Benefits from Study Participation 
While the benefit and risks of the candidate vaccine formulations 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.  
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2.3.3 
Overall Benefit-Risk Conclusion 
Considering the significant medical need, scale of the pandemic, urgent requirement for measures 
to address the pandemic, 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 
 
Immunogenicity 
To describe the neutralizing antibody profile 
at D01, D22, and D36 of each study 
intervention group. 
Immunogenicity 
Neutralizing antibody titers 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 
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 (pre-listed in the participant’s diary card 
and Case Report Form [CRF]) injection site reactions and 
systemic reactions 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 7 days 
post-last dose (ie, up to D09 for Cohort 1 and up to D30 for 
Cohort 2) 
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Secondary  
 
Immunogenicity 
1) To describe binding antibody profile at 
D01, D22, D36, D181 (Cohort 1) or D202 
(Cohort 2), and D366 (Cohort 1) or D387 
(Cohort 2) of each study intervention 
group.  
2) To describe the neutralizing antibody 
profile at D181 (Cohort 1) or D202 
(Cohort 2) and D366 (Cohort 1) or D387 
(Cohort 2) of each study intervention 
group. 
Immunogenicity 
Binding antibody titers to full-length SARS-CoV-2 Spike 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, 
D181 (Cohort 1) or D202 (Cohort 2), and D366 (Cohort 1) or 
D387 (Cohort 2)  
• 
Individual anti-S antibody concentration ratio (fold-rise in 
serum ELISA concentration post-vaccination relative to D01) 
at D22, D36, D181 (Cohort 1) or D202 (Cohort 2), and D366 
(Cohort 1) or D387 (Cohort 2)  
• 
Fold-rise in anti-S antibody concentration (post/pre) ≥ 2 and 
≥ 4 at D22, D36, D181 (Cohort 1) or D202 (Cohort 2), and 
D366 (Cohort 1) or D387 (Cohort 2) 
Neutralizing antibody titers will be measured with the 
neutralization assay.  
• 
Antibody titer at D181 (Cohort 1) or D202 (Cohort 2) and 
D366 (Cohort 1) or D387 (Cohort 2)  
• 
Fold-rise (fold-rise in serum neutralization titer post-
vaccination relative to D01) at D181 (Cohort 1) or D202 
(Cohort 2) and D366 (Cohort 1) or D387 (Cohort 2)  
• 
2-fold and 4-fold rise in serum neutralization titer [post/pre] 
relative to D01 at D181 (Cohort 1) or D202 (Cohort 2) and 
D366 (Cohort 1) or D387 (Cohort 2) 
• 
Occurrence of neutralizing antibody seroconversion, defined 
as values below LLOQ at baseline with detectable 
neutralization titer above assay LLOQ at D181 (Cohort 1) or 
D202 (Cohort 2) and D366 (Cohort 1) or D387 (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 Recombinant Protein 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 
nucleic acid viral detection assay  
• 
Serologically-confirmed SARS-CoV-2 infection as defined 
by SARS-CoV-2-specific antibody detection in a non-S 
ELISA  
• 
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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Exploratory 
 
Immunogenicity 
1) To describe cellular immune response 
profile at D01, D22, and D36 for each 
study intervention group in a subset of 
Cohort 2. 
2) To describe the ratio between neutralizing 
antibodies and binding antibodies. 
Immunogenicity 
• 
T-helper cell (Th)1 and Th2 cytokines will be measured in 
whole blood following stimulation with full-length S protein 
and/or pools of S-antigen peptides 
• 
Ratio between binding antibody (ELISA) concentration and 
neutralizing antibody titer 
Other 
To evaluate other emerging biomarkers as 
effect modifiers or as correlates of risk / 
protection. 
Biomarker measurement at baseline and/or post-vaccination visits 
(D22, D36, D113 [Cohort 1] or D134 [Cohort 2], D181 [Cohort1] 
or D202 [Cohort 2]), and D366 [Cohort 1] or D387 [Cohort 2]) 
4 
Study Design 
4.1 
Overall Design 
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design 
Type of design 
Parallel group, first-in-human, placebo-controlled, dose-
ranging, multi-center study with a Sentinel Safety Cohort 
and Early Safety Data Review (ESDR) 
Phase 
I/II 
Control method 
Placebo-controlled 
Study population 
Healthy, seronegative adults 18 years of age and older 
Level and method of blinding 
• 
Blinding for vaccine group assignment (formulation 
and adjuvant): participants, outcome assessors, 
Investigators, laboratory personnel, Sponsor study staff 
(except those involved in ESDR, and for concerned 
participants only) 
• 
No blinding for injection schedule 
• 
No blinding for vaccine group assignment: those 
preparing/administering the study interventions 
Study intervention assignment method 
Enrollment will be stratified by age: 300 participants 18-49 
years of age and 140 participant ≥ 50 years of age. All 
440 participants will be randomized to receive either 1 
injection (Cohort 1) or 2 injections (Cohort 2) of the study 
intervention to which they are randomized.  
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Number of participants 
Approximately 440 participants 18 years of age and older 
(300 adults 18 through 49 years of age and 140 adults 
≥ 50 years of age) are planned to be randomized 
Intervention groups 
Within each cohort:  
• 
participants aged 18-49 years:  
• 
will be randomized to 6 groups to receive 
Antigen Formulation 1 (low-dose [5 µg]) with 
either AF03 or AS03 adjuvant; Formulation 
2 (high-dose [15 µg]) with either AF03, AS03, or 
no adjuvant; or placebo (Note: unadjuvanted arm 
included in Cohort 2 only) 
• 
N = 20 participants in each group, except for 
AS03-adjuvanted groups in Cohort 2 with 
60 participants in each group 
• 
participants aged ≥ 50 years:  
• 
will be randomized to 5 groups to receive 
Antigen Formulation 1 (low-dose [5 µg]) or 
Formulation 2 (high-dose [15 µg]) each with 
either AF03 or AS03; or placebo 
• 
N = 10 participants in each group, except for 
AS03-adjuvanted groups in Cohort 2 with 
30 participants in each group 
See also Table 4.2 below. 
Total duration of study participation 
Approximately 365 days post-last dose: 
• 
Cohort 1: approximately 365 days duration total 
• 
Cohort 2: approximately 386 days duration total 
Countries 
United States 
Use of an Independent Data Monitoring 
Committee, Dose Escalation Committee, or 
similar review group 
NO 
 
A total of 440 participants are planned to be enrolled. At the time of inclusion, participants will be 
screened for SARS-CoV-2 seropositivity status and stratified according to age. Those who are 
seronegative will be randomized as shown in Table 4.2. 
As a precautionary step, a Sentinel Safety Cohort of 6 participants (younger adults only) within 
each dosing group from Cohort 1 will be enrolled. An Early Safety Data Review (ESDR) will be 
performed, including evaluation of safety data and laboratory measures to D09 in Cohort 1 among 
younger adults 18-49 years of age. Upon acceptable safety demonstrated from unblinded data 
review by limited members of the Sponsor Study Team (RMO, Biostatistician and Programmer, 
Pharmacovigilance Science Expert, and Global Safety Officer), the remaining participants in 
Cohort 1 and all participants in Cohort 2 will be enrolled. Further details are provided in 
Section 8.4. 
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Table 4.2: Planned sample size 
Participants 18-49 years of age 
Cohort 
Group 
Dose Level* 
Adjuvant 
N 
Sentinel Safety† 
(N=30) 
Total 
(N=300) 
Cohort 1:  
1 injection 
1 
5 µg 
AF03 
6 
20 
2 
5 µg 
AS03 
6 
20 
3 
15 µg 
AF03 
6 
20 
4 
15 µg 
AS03 
6 
20 
5 
Placebo 
None 
6 
20 
Cohort 2:  
2 injections 
6 
5 µg 
AF03 
N/A 
20 
7 
5 µg 
AS03 
N/A 
60 
8 
15 µg 
AF03 
N/A 
20 
9 
15 µg 
AS03 
N/A 
60 
10 
15 µg 
None 
N/A 
20 
11 
Placebo 
None 
N/A 
20 
Participants 50 years of age and older 
Cohort 
Group 
Dose Level* 
Adjuvant 
N 
(N=140) 
Cohort 1:  
1 injection 
1 
5 µg 
AF03 
10 
2 
5 µg 
AS03 
10 
3 
15 µg 
AF03 
10 
4 
15 µg 
AS03 
10 
5 
Placebo 
None 
10 
Cohort 2:  
2 injections 
6 
5 µg 
AF03 
10 
7 
5 µg 
AS03 
30 
8 
15 µg 
AF03 
10 
9 
15 µg 
AS03 
30 
10 
15 µg 
None 
N/A‡ 
11 
Placebo 
None 
10 
*Antigen Formulation naming for each dose level: CoV2 preS dTM antigen: Formulation 1 (low-dose [5 µg]); Formulation 2 
(high-dose [15 µg]) 
† Sentinel Safety Cohort: 6 participants within each dosing group from Cohort 1 (18-49 years of age only) will be included in 
the Sentinel Safety Cohort. 
‡ As part of risk mitigation for enhanced COVID-19, the older age stratification (≥ 50 years) will not be allocated to this study 
arm. 
Note: A subset of 87 participants in Cohort 2 (60 participants 18-49 years of age [18 per group in AS03-adjuvanted vaccines; 6 
per group in all other study groups]) and 27 participants ≥ 50 years of age [9 per group in AS03-adjuvanted groups; 3 per group 
in all other study groups, with the exception of the unadjuvanted group for which there will be no older adults]), will be 
randomly assigned to a cellular-mediated immune (CMI) subset. 
 
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All participants will receive 1 injection of either one of the investigational study vaccine 
formulations or the placebo control at Day (D)01 (Vaccination [VAC] 1). Participants in Cohort 2 
will receive a second injection (of the same intervention as received at D01) of study vaccine 
formulation or placebo at D22 (VAC2). 
If a COVID-19 vaccine becomes available from a company other than Sanofi Pasteur, then 
participants are free to receive that vaccine. Participants who receive a COVID-19 vaccine will 
still be followed for safety until the end of the study but will be discontinued from study 
intervention administration thereafter. 
4.2 
Scientific Rationale for Study Design 
Rationale for Development Approach 
The development approach for the CoV2 preS dTM vaccine candidate is undergirded by the fact 
that it is taking place in the setting of a pandemic. As such, the emphasis of the development plan 
is rapidly generating the data required to support approval and vaccine deployment to the field. 
Acceleration of the evaluation in this first-in-human trial is justified by the extensive 
characterization available for both the manufacturing system used to produce the recombinant 
antigen and the adjuvants to be administered in the trial.  
The manufacturing platform is the same as is used to produce Flublok vaccine, a licensed 
recombinant HA influenza vaccine. In the context of influenza vaccine development, thousands of 
younger and older adults have received proteins manufactured utilizing the same technology and 
process employed for this CoV2 preS dTM vaccine candidate. Furthermore, millions of younger 
and older adults have received recombinant protein vaccines using this manufacturing system 
post-marketing, at total protein doses several times higher than the highest dose targeted in the 
present study (quadrivalent Flublok vaccine contains a total of 180 µg of HA protein; the highest 
dose of this CoV2 preS dTM vaccine is 15 µg in the study). While clinical and post-marketing 
experience with proteins manufactured with the baculovirus manufacturing system is specific for 
influenza proteins, it is relevant to point out that these include different proteins (H1, H3, B 
Yamagata, B Victoria HAs), with each one changed over time to support the recommended 
compositions of seasonal influenza vaccines. This provides reassurance about the safety of the 
protein manufacturing platform, at protein doses higher than planned in this study, and for a 
variety of different protein constructs.  
AF03 was administered to more than 1500 individuals as part of the clinical development of 
adjuvanted influenza vaccines. This included exposure of children and adults, including elderly 
adults; more than 200 older adults received inactivated influenza vaccine in combination with 
AF03. No safety concerns were identified in these studies, and AF03 adjuvanted vaccines were 
safe and well tolerated. The clinical development of AF03-adjuvanted H1N1 influenza vaccine led 
to regulatory approval of the Humenza vaccine by the European Medicines Agency (EMA).  
AS03 has been administered to thousands of individuals (adults and elderly) as part of clinical 
trials of influenza vaccines as well as other vaccines (27). Notably, more than 20,000 older adults 
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received AS03-adjuvanted influenza vaccine in a large, multi-country efficacy trial (24). 
Furthermore, hundreds of millions of doses of AS03-adjuvanted H1N1 vaccines were 
administered post-licensure in the context of H1N1 pandemic control. The vaccines were found to 
be well tolerated. Of note, an increased risk of narcolepsy was observed in some individuals after 
the vaccination campaign with Pandemrix in 2009-2010. A similar risk of narcolepsy was not 
identified with other non-adjuvanted influenza vaccines or other AS03-adjuvanted vaccines, like 
Arepanrix (28) (29). Current data suggest that cases of narcolepsy seen immediately following the 
2009/2010 pandemic were the result of an immune cascade, triggered by CD4 T cell cross-
reactivity to HA proteins from the H1N1 virus itself and hypocretin. This conclusion is consistent 
with the position reached by the EMA in 2016 when it concluded that: “Based on the evidence 
generated so far, a hypothesis that takes into account the potential role of antigen is more likely to 
explain the increased risk of narcolepsy observed with Pandemrix than hypotheses that are based 
on a direct role for the AS03 adjuvant” (30).  
Recombinant proteins produced in the baculovirus manufacturing platform by Protein Sciences 
have been administered with both AF03 and AS03. AF03 was administered to 40 adults 
18 through 45 years of age in a Phase I trial (NCT03945825) as the adjuvant of a quadrivalent 
recombinant influenza vaccine (total of 180 µg of HA protein, 4 different HA proteins at 45 µg 
each). The study is ongoing, and more than 8 months of follow-up have been completed; and 
Independent Data and Monitoring Committee (IDMC) has evaluated the safety data and has not 
raised any safety concerns. AS03 was administered to 184 adults 18 through 49 years of age with 
an H7 recombinant influenza vaccine in study BP-I-17-002 (NCT03283319) sponsored by the 
Biomedical Advanced Research and Development Authority (BARDA). The AS03 adjuvanted H7 
recombinant protein vaccine was found to be safe and well tolerated and led to robust immune 
responses.  
As a precautionary step, a Sentinel Safety Cohort of 6 participants (younger adults only) within 
each dosing group from Cohort 1 will be enrolled. An ESDR will be performed, including 
evaluation of safety data and laboratory measures to D09 in Cohort 1 among younger adults 
18-49 years of age. Upon acceptable safety demonstrated from unblinded review by limited 
members of the Sponsor Study Team (RMO, Biostatistician and Programmer, Pharmacovigilance 
Science Expert, and Global Safety Officer), the remaining participants in Cohort 1 and all 
participants in Cohort 2 will be enrolled. A non-clinical toxicology study in New Zealand White 
Rabbits is planned and will provide rabbit first-dose safety data prior to initiation of human 
clinical testing. Additional non-clinical safety evaluations will proceed in parallel to this human 
clinical trial. 
Data up to D43, in addition to preclinical data, will support the selection of a formulation or 
formulations and dosing schedule to proceed to further testing in Phase III. 
Rationale for Injection Schedule 
In the setting of a pandemic, a single injection would be ideal to be able to protect vaccinees as 
early as possible and better manage vaccine supply. However, given the lack of pre-existing 
immune responses to SARS-CoV-2, it is most likely that 2 injections may be necessary.  
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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.  
In addition to antibody response 21 days after the first injection, durability after a single injection 
also needs to be taken into account for schedule selection decisions, 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 the novel coronavirus. A further 
consideration is allowing sufficient time for contraction of innate immune responses and 
expansion of the adaptive immune response after dosing, which would be underestimated if 
evaluated too soon after the dose. In this regard, at least fourteen days after a second dose is 
deemed sufficient, based on experience with other vaccines (27) (31) (32).Therefore, antibody 
titers at D22 (21 days after the first injection) and D36 (14 days after a second injection) after a 
single injection or after 2 injections are considered relevant for informing schedule selection. 
Rationale for Primary Immunogenicity Endpoint 
Human experimental coronavirus infection studies have identified that the presence of 
pre-challenge neutralizing antibodies were predictive of protection from infection or symptoms 
following challenge (33) (34). For this reason, neutralizing responses are expected to provide the 
most relevant functional evaluation of immune responses for this vaccine candidate. 
Rationale for Study Population 
The study will enroll participants with no history of COVID-19 or serologic evidence of 
SARS-CoV-2 infection by rapid diagnostic test at the baseline visit. Inclusion of individuals with 
prior exposure to SARS-CoV-2 would be expected to influence immunogenicity measures. This 
trial is geared to identifying the dose-level of CoV2 preS dTM 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. 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.  
The study will be conducted in adults 18 years of age and older. Clinical and epidemiological data 
from the COVID-19 pandemic have consistently indicated a higher risk of severe complications 
and death in older adults (35) (36). Therefore, it is considered of great relevance to generate data 
in the older adult population to inform schedule and formulation selection that will serve the 
general adult population, including those at particular risk of poor outcomes. A Sentinel Safety 
Cohort among younger adults is included to provide preliminary short-term safety data prior to 
enrollment of older adult participants. The study incorporates several measures to mitigate the 
theoretical risk of vaccine-associated ERD. These include a higher representation of the younger 
adult strata for the same reason, given that adults over 50 years of age have also been 
overrepresented in studies describing critical illness and death, although to a lesser degree than 
those older than 75 years (35). Therefore, the proposed design aims at generating data that will 
allow selection of the relevant formulations and injection schedule accounting for potential age 
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effects. Data for each formulation will be generated in both younger adults and older adults, 
allowing the evaluation of the consistency in the patterns of immune response for each 
formulation between the 2 age strata; additionally, aggregated “main” effects by age will be 
evaluable by comparing pooled older adult data (n=120 across vaccine formulations) and pooled 
younger adult data (n=240 across vaccine formulations with corresponding data in the older 
strata).  
Evidence to date indicates that individuals with chronic medical conditions are at increased risk of 
severe outcomes associated with COVID-19 (37). The exclusion of individuals with chronic 
underlying conditions is considered an additional risk mitigation measure to address the 
theoretical phenomenon of immune enhancement. Clinical and epidemiological data indicates that 
the overrepresentation of older adults among those with critical or fatal COVID-19 illness is 
meaningfully ameliorated when stratified/controlled for the presence of chronic medical 
conditions (26). Exclusion of individuals with chronic medical conditions from this trial mitigates 
the potential (theoretical) risk of exacerbating the occurrence of critical or fatal outcomes as a 
result of study participation. 
Rationale for Active Arms 
The study aims at selecting schedule and formulation to progress to further clinical development. 
The importance of the schedule evaluation has been stated above, and it is the justification for 
inclusion of Cohort 1 and Cohort 2 in each age strata in the study. Within each cohort, the study 
design allows the evaluation of the candidate vaccine protein dose level (2 different dose levels) 
adjuvanted with AS03 or AF03. A range of dose level evaluation is of particular interest in the 
setting of a pandemic: if adequate responses are observed with lower doses of antigen, higher 
number of doses of vaccine could be supplied to address the anticipated large demand that will be 
needed to end the pandemic. 
Within Cohort 2, the study includes an arm with the higher dose level of protein antigen alone 
(unadjuvanted). This arm allows the evaluation and demonstration of the expected adjuvant 
effects (magnitude and quality of the immune response and dose-sparing effect). While it is 
anticipated that an adjuvanted formulation will be optimal, this study design will allow the 
generation of empirical data supporting such assumption. The unadjuvanted arm is restricted to 
the younger adult stratum, as a risk mitigation measure: previous studies with SARS-CoV-1 
inactivated and protein-based vaccines suggested the possibility of vaccine-induced 
immunopathology upon viral infection when used alone or with a Th2-based adjuvant (alum) (9). 
AS03 and AF03 adjuvants have been generally associated with a balanced Th1/Th2 immune 
response (10) (11). Exclusion of unadjuvanted arms from the older adult stratum mitigates the 
potential (theoretical) risk of vaccine-induced immunopathology occurring in those who are 
already at higher risk of more severe COVID-19 illness. 
Rationale for Higher Sample Size for AS03 Cohort 2 Arms, and Rationale for Including AF03 
Given the large clinical and post-marketing experience with AS03, in addition to its readiness for 
large-scale supply and the extensive and multi-national regulatory experience, higher priority will 
be given to AS03 adjuvanted formulations for advancement into Phase III development. 
Nevertheless, generating meaningful Phase I/II clinical data with AF03 adjuvanted formulations is 
still of interest for several reasons: 1) AF03 can serve as an alternative adjuvant system, should 
any issues arise during development with AS03; 2) the AF03 adjuvant may still allow to increase 
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future supply, in the event supply beyond AS03 capacity is possible with the recombinant protein 
and needed to address the pandemic; 3) the AF03 adjuvant may be of interest in the future if 
COVID-19 becomes seasonal, in which case a co-formulated vaccine would be attractive; in such 
circumstances, co-formulation with AF03 will be more feasible than with AS03 as both protein 
and adjuvant are proprietary to Sanofi Pasteur. The higher priority given to AS03 adjuvanted 
formulations and the higher likelihood of robust immune responses with a 2-injection schedule 
provides rationale to generate more precise data for AS03 formulations in Cohort 2 of this 
Phase I/II study; this is the justification for a sample size of 90 across age groups for the AS03 
adjuvanted arms in Cohort 2. All other arms in the study will have a size of 30 total, except for the 
un-adjuvanted arm which would only comprise 20 younger adults. 
Rationale for Blinding 
This is an observer-blind study for formulation and adjuvant. Owing to the need for mixing of 
study formulations from separately supplied antigen, adjuvants, and / or diluent, the person 
preparing and administering the vaccine will be unblinded to vaccine group assignment. Blinding 
of all “observers” will minimize the risk of bias arising from the possibility of consciously or 
unconsciously influencing the reporting of study outcome measures due and knowledge of the 
formulation administered. 
Rationale for Placebo 
Placebo, rather than a benefit licensed vaccine, will be used for comparison to vaccine to allow 
safety comparisons between vaccine and placebo as there are no other licensed COVID-19 
vaccines on the market. The inclusion of placebo groups will also maintain the blind, allowing the 
unbiased evaluation of clinical outcomes related to COVID-19-like illness and SARS-CoV-2 
infection by treatment group (secondary efficacy objective). 
4.3 
Justification for Protein Dose Levels 
Dose levels are based on data from previous studies with AF03 for Sanofi Pasteur’s Influenza 
vaccine products, a study done with Sanofi Pasteur-manufactured monovalent H7N9 influenza 
vaccine adjuvanted with AS03 or MF59 (38), and on studies done with Panblok H7 adjuvanted 
with AS03 and MF59. Additionally, formulations of SARS candidates and recently reported data 
from candidate SARS-CoV-2 vaccines that were developed and tested preclinically informed the 
range of antigen dosing that was considered. 
• For Sanofi Pasteur’s pandemic influenza vaccine projects, the main doses evaluated with H1 
and H5 antigens adjuvanted with AF03 were 3.8 µg, 7.5 µg, and 15 µg.  
• For monovalent H7N9 influenza vaccine, 2 doses of 3.75 µg, 7.5 µg or 15 µg of H7 antigen 
adjuvanted with AS03 were compared to a variety of other formulations and vaccine 
combinations, including 2 doses of 45 µg of H7 antigen alone. 
• For Panblok H7, the doses evaluated in Study BP-I-17-002 with MF59 and AS03 were: 
3.75 µg, 7.5 µg, and 15 µg.  
• For Protein Sciences’ SARS-CoV dTM S protein vaccine, the doses evaluated with or without 
Alhydrogel® were 5 µg, 15 µg, and 45 µg.  
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• A recombinant prefusion stabilized SARS-CoV-2 S protein vaccine manufactured in 
baculovirus expression system was tested in non-human primates at doses of 1 µg, 5 µg, and 
25 µg, delivered with a proprietary adjuvant (39).  
• An inactivate whole virus SARS-CoV-2 candidate vaccine adjuvant with Alum was tested in 
non-human primates at doses of 2 µg and 8 µg per dose (40). 
It is unknown how immunogenic the CoV2 preS dTM vaccine will be compared to recombinant 
influenza antigens. Assuming conservatively that it will be weakly immunogenic, the responses 
following administration of H7 Panblok with MF59 and AS03 are informative. H7 (in common 
with H5) is weakly immunogenic (13) (14) and could frame dosing expectations under this 
conservative assumption.  
The homologous and heterologous seroprotection (hemagglutination inhibition [HAI] titer ≥ 1:40) 
rate responses at D50 to H7 with MF59 were generally lower than H7 with AS03. With AS03, 
homologous and heterologous HAI seroprotection rates above 95% were seen with the 7.5 µg and 
the 15 µg dose groups, and homologous seroprotection responses of 94.6% were seen with the 
3.75 µg dose. With MF59, the homologous HAI seroprotection responses seen with the highest 
dose (15 µg) were lower than the heterologous HAI seroprotection observed with the lowest dose 
of AS03 (3.75 µg). These findings highlight that even for immunogens considered poorly 
immunogenic, robust immune responses can be generated with lower antigen doses when 
delivered in a 2-dose series with a suitable adjuvant.  
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 SoA. 
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. 
5.1 
Inclusion Criteria 
Participants are eligible for the study only if all of the following criteria are met: 
I01: 
Aged 18 years of age or older on the day of inclusion 
I02: 
Informed consent form has been signed and dated 
I03: 
Able to attend all scheduled visits and to comply with all study procedures 
5.2 
Exclusion Criteria 
Participants are not eligible for the study if any of the following criteria are met: 
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E01: 
Participant is pregnant, or lactating, or of childbearing potential and not using an 
effective method of contraception or abstinence from at least 4 weeks prior to the first 
vaccination until at least 12 weeks after the last vaccination. To be considered of non-
childbearing potential, a female must be post-menopausal for at least 1 year or 
surgically sterile. 
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: 
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 vaccines.a  
E04: 
Prior administration of a coronavirus vaccine (severe acute respiratory syndrome 
coronavirus 2 [SARS-CoV-2], SARS-CoV, Middle East Respiratory Syndrome 
[MERS-CoV]) 
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: 
History of SARS-CoV-2 infection, confirmed either clinically, serologicallyb, or 
microbiologically 
E08: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to a vaccine containing any of the same substancesc 
E09: 
Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination 
based on Investigator’s judgment 
E10: 
Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating IM vaccination based on Investigator’s judgment 
                                                 
 
a While receipt of any vaccine as listed in this criterion is exclusionary for this study,  enrolled participants are free to 
receive an authorized/approved COVID-19 vaccine during the follow-up period. As efficacy has not been 
demonstrated for any of the investigational formulations under evaluation in the current study, it is not required to 
unblind participants to the VAT00001 study assignment prior to administration of an authorized COVID-19 
vaccine. If the participant receives the authorized/approved vaccine, this information would be collected and the 
participant’s data up to the point of receipt of authorized/approved 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. (see Section 7.1.2: Definitive Contraindications). 
b Potential study participants will need to have a negative SARS-CoV-2 antibody test at time of enrollment. 
c The components of SARS-CoV-2 Recombinant Protein vaccine are listed in Section 6.1 and in the SARS-CoV-2 
Recombinant Protein Investigator’s Brochure. In addition, information for the AF03 adjuvant are listed in the 
AF03 Investigator’s Brochure. 
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E11: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily 
E12: 
Current alcohol abuse or drug addiction  
E13: 
Chronic illness or condition considered to potentially increase the risk for severe 
COVID illnessa (26) or that, in the opinion of the Investigator, is at a stage where it 
might interfere with study conduct or completionb 
E14: 
Moderate or severe acute illness/infection (according to Investigator 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 
E15: 
Receipt of any therapy known to have in-vitro antiviral activity against SARS-CoV-2c 
within 72 hours prior to the first blood draw 
E16: 
Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (ie, 
parent, spouse, natural or adopted child) of the Investigator or employee with direct 
involvement in the proposed study 
E17: 
Residence in a nursing home or long-term care facility 
E18: 
Health care workers providing direct patient care for COVID-19 patients 
E19: 
Participants with active or prior documented autoimmune disorder (such as potential 
immune-mediated diseases [pIMDs]) 
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. 
                                                 
 
a Factors that may increase the risk of severe COVID illness include: autoimmune disease (see also Appendix 10.5 for 
a list of potential immune-mediated medical conditions); cerebrovascular disease; chronic pulmonary disease 
(including asthma, chronic obstructive pulmonary disease, emphysema, cystic fibrosis, pulmonary fibrosis); 
current smoking or former smoking; 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; thalassemia. 
b Chronic illness may include, but is not limited to, psychiatric disorders. 
c Therapy/treatment including, but not limited to, favipiravir, lopinavir/ritonavir, remdesivir, arbidol, chloroquine, 
hydroxychloroquine. 
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5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents. 
6 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Study Interventions Administered 
Study interventions are described in Table 6.1. 
Table 6.1: Identity of study interventions 
CoV2 preS dTM-AF03 
Intervention 
Name 
CoV2 preS dTM-AF03 
(low-dose) 
CoV2 preS dTM-AF03 
(high-dose) 
Study Groups 
1 and 6 
3 and 8 
Use 
Experimental 
Type  
Vaccine 
Dose Formulation 
Liquid, mix at bedside pre-injection according to dose preparation protocol 
Unit Dose 
Strengths 
Each 0.5 mL dose of Study Intervention will contain the following: 
• preS-deltaTM monovalent: 
prefusion S delta TM COVID19 
antigen, low-dose (5 µg) 
• preS-deltaTM monovalent: 
prefusion S delta TM COVID19 
antigen, high-dose (15 µg) 
Excipients/Diluent Each mono-dose vial of squalene-based AF03 adjuvant 2.5% contains: 
• Diluent: Phosphate-buffered saline (PBS) 
 
 
• Sorbitan monooleate (Dehymuls SMO™) 
 
 
(1.85 mg) 
• POE (12) Cetostearyl ether (Kolliphor CS12™) 
 
(2.38 mg) 
• Mannitol 
 
 
 
 
 
 
(2.31 mg) 
Dosage Level 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
Cohort 1 : 1 injection / Cohort 2 : 2 injections, 21 days apart 
Route of 
Administration 
IM injection 
Site of 
Administration 
Deltoid muscle in the upper arm 
Sourcing 
Provided by the Sponsor 
Packaging and 
Labeling 
Each study intervention will be provided in an individual box (antigen and 
adjuvant will be kitted together in a 2-vial 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 US requirement. 
Batch Number 
TBD 
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CoV2 preS dTM-AS03 
Intervention 
Name 
CoV2 preS dTM-AS03 
(low-dose) 
CoV2 preS dTM-AS03 
(high-dose) 
Study Groups 
2 and 7 
4 and 9 
Use 
Experimental 
Type  
Vaccine 
Dose Formulation 
Liquid, mix at bedside pre-injection according to dose preparation protocol 
Unit Dose 
Strengths 
Each 0.5 mL dose of Study Intervention will contain the following: 
• preS-deltaTM monovalent: 
prefusion S delta TM COVID19 
antigen, low-dose (5 µg) 
• preS-deltaTM monovalent: 
prefusion S delta TM COVID19 
antigen, high-dose (15 µg) 
Excipients/Diluent Each multi-dose vial of squalene-based AS03 adjuvant 2.1% contains: 
• Diluent: PBS 
 
 
 
 
• Tocopherol (antioxidant) 
 
 
 
(11.86 mg) 
• Polysorbate 80 (Tween®80)   
 
 
(4.86 mg) 
Dosage Level 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
Cohort 1 : 1 injection / Cohort 2 : 2 injections, 21 days apart 
Route of 
Administration 
IM injection 
Site of 
Administration 
Deltoid muscle in the upper arm 
Sourcing 
CoV preS dTM : Provided by the Sponsor 
AS03: Provided by GSK 
Packaging and 
Labeling 
Each study intervention will be provided in an individual box (antigen and 
adjuvant will be kitted together in a 2-vial 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 US requirement. 
Batch Number 
TBD 
CoV2 preS dTM 
Intervention Name 
CoV2 preS dTM 
(high-dose) 
Study Groups 
10  
(18-49 years of age in Cohort 2 only) 
Use 
Experimental 
Type  
Vaccine 
Dose Formulation 
Liquid, mix at bedside pre-injection according to dose preparation protocol 
Unit Dose 
Strengths 
Each 0.5 mL dose of CoV2 preS dTM antigen (high-dose) will contain the 
following: 
• preS-deltaTM monovalent: prefusion S delta TM COVID19 antigen, 
high-dose (15 µg) 
Excipients/Diluents 
Diluent : PBS 
Dosage Level 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
Cohort 1 : 1 injection / Cohort 2 : 2 injections, 21 days apart 
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Route of 
Administration 
IM injection 
Site of 
Administration 
Deltoid muscle in the upper arm 
Sourcing 
Provided by the Sponsor 
Packaging and 
Labeling 
Each study intervention will be provided in an individual box (antigen and 
diluent will be kitted together in a 2-vial 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 US 
requirement. 
Batch Number 
TBD 
Placebo 
Intervention Name 
Placebo 
Study Groups 
5 and 11 
Use 
Placebo - comparator 
Type  
Vaccine 
Dose Formulation 
Liquid, in a single-vial presentation 
Unit Dose 
Strengths 
0.9% normal saline  
Dosage Level 
0.5 mL per dose 
Number of Doses / 
Dosing Interval 
Cohort 1 : 1 injection / Cohort 2 : 2 injections, 21 days apart 
Route of 
Administration 
IM injection 
Site of 
Administration 
Deltoid muscle in the upper arm 
Sourcing 
Provided by the Sponsor 
Packaging and 
Labeling 
Each study intervention will be provided in an individual box similar to the kits 
used for other study interventions. 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 US requirement. 
Batch Number 
TBD 
 
6.2 
Preparation/Handling/Storage/Accountability 
Detailed guidance and information are provided in the Operating Guidelines. 
1) The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2) Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
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3) The CoV2 preS dTM antigen will be mixed with the mono-dose vial of AF03 adjuvant, multi-
dose vial of AS03 adjuvant, or PBS at the site prior to administration. Vaccine formulations 
will be prepared in the CoV2 preS dTM antigen vials by adding an equal volume of adjuvant 
(AF03 or AS03) or PBS. 
4) 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). 
5) 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 
On the day of enrollment, participants who meet the eligibility criteria and sign the Informed 
Consent Form (ICF) will be stratified by 2 age groups (18-49 years and ≥ 50 years) and then be 
randomly assigned to receive 1 injection (Cohort 1) or 2 injections (Cohort 2) of CoV2 preS DTM 
investigational study vaccine or placebo. As shown in Table 4.2, within each cohort:  
• participants aged 18-49 years:  
• 
will be randomized to 6 groups to receive Antigen Formulation 1 (low-dose [5 µg]) with 
either AF03 or AS03 adjuvant; Formulation 2 (high-dose [15 µg]) with either AF03, 
AS03, or no adjuvant; or placebo (Note: unadjuvanted arm included in Cohort 2 only)  
• 
N = 20 participants in each group, except for AS03-adjuvanted groups in Cohort 2 with 
60 participants in each group 
• participants aged ≥ 50 years:  
• 
will be randomized to 5 groups to receive Antigen Formulation 1 (low-dose [5 µg]) or 
Formulation 2 (high-dose [15 µg]) each with either AF03 or AS03; or placebo 
• 
N = 10 participants in each group, except for AS03-adjuvanted groups in Cohort 2 with 
30 participants in each group 
The study will initially enroll 30 participants (6 within each dosing group from Cohort 1) 
18-49 years of age, who will comprise the Sentinel Safety Cohort. Participants in this cohort will 
receive 1 injection of study intervention to which they were randomized, and safety and laboratory 
parameters up to D09 will be evaluated. Upon demonstration of acceptable safety, the remaining 
participants in Cohort 1 and all participants in Cohort 2 will be enrolled and randomized. 
A subset of 87 participants in Cohort 2 (60 participants 18-49 years of age [18 per group in AS03-
adjuvanted vaccines; 6 per group in all other study groups]) and 27 participants ≥ 50 years of age 
[9 per group in AS03-adjuvanted groups; 3 per group in all other study groups, with the exception 
of the unadjuvanted group for which there will be no older adults]), will be randomly assigned to 
a cellular-mediated immune (CMI) subset. 
Site staff will connect to the Interactive Response Technology (IRT), enter the identification, 
security information, and confirm a minimal amount of data in response to IRT prompts. The IRT 
will then provide the group assignment and have the site staff confirm it. The full detailed 
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procedures for group 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 
The study will be performed in a modified double-blind (observer-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 and efficacy evaluation will know which vaccine is administered 
• Testing laboratories will be blinded 
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 of individual participants 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 Board/Independent Ethics Committee (IRB / 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 Sanofi Pasteur’s files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
A request for the code to be broken may also be made by the Global Pharmacovigilance (GPV) 
Department through an internal system for reporting to Health Authorities in the case of an SAE, 
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 vaccine or group assignment) will not be communicated to either the Investigator 
or the immediate team working on the study, except for the GPV representative. 
The code-breaking procedures are described in the Operating Guidelines. 
                                                 
 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 
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The blind will be broken by the Sponsor at the time of the ESDR (with access to study 
intervention assignments [for the Sentinel Safety Cohort participants only] to a limited number of 
Sponsor Study Staff members comprising the Core Safety Management Team) and at the time of 
the first interim analysis after the first database lock. However, participant-level data will be 
maintained blinded on site until the end of the study/until the interim Clinical Study Report 
approval. 
6.4 
Study Intervention Compliance 
The following measures will ensure that the study interventions are administered as planned 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 will be collected in the CRF from the day of each vaccination to the end 
of the solicited and unsolicited follow-up period after each vaccination, with the exception of 
influenza vaccination which will be collected throughout the study.  
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Three standard 
categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], systemic 
steroids/corticosteroids) 
• Category 2: medications impacting or that may have an impact on the immune response (eg, 
hydroxychloroquine, other vaccines, blood products, antibiotic classes that may interfere with 
bioassays used by the Global Clinical Immunology [GCI] department or other testing 
laboratories, systemic steroids/corticosteroids, immune-suppressors, immune-modulators with 
immunosuppressive properties, anti-proliferative drugs such as DNA synthesis inhibitors) 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, systemic steroids/corticosteroids) 
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Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical treatments, ophthalmic and ear treatments will not be recorded. Topical analgesics should 
not be applied at the site of vaccination; however, if they are applied inadvertently to the vaccination 
site, they should be recorded as a Category 1 medication in this specific instance. 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to one of the pre-listed categories. Medications will not be coded. 
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 one of the vaccines formulations evaluated in this study is demonstrated safe and 
efficacious and is authorized/approved by the FDA, such vaccine formulation(s) may be offered 
as soon as possible to participants in this study who received placebo or different formulations, if 
permitted by local regulations. 
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 Cohort 2 only.  
These sections are not applicable to Cohort 1 as they are planned to receive only 1 vaccination in 
the study. 
7.1.1 
Temporary Contraindications 
Should a participant experience one of the conditions listed below, the Investigator will postpone 
further vaccination until the condition is resolved. Postponement must still be within the 
timeframe for vaccination indicated in the SoA. 
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 
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. 
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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: 
Grade 3 AE, assessed as related to the 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 
In the event of a local or national immunization program with a SARS-CoV-2 or a COVID-19 
pandemic vaccine, participants who receive SARS-CoV-2 or a COVID-19 pandemic vaccine at 
any time during the study will not be withdrawn from the study. As efficacy has not been 
demonstrated for any of the investigational formulations under evaluation in the current study, it is 
not required to unblind participants to the VAT00001 study assignment prior to administration of 
an authorized COVID-19 vaccine. 
If the participant receives an authorized approved COVID-19 vaccine, this information would be 
collected and the participant’s data up to the point of receipt of authorized/approved 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. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
• The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: AE, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant. 
• The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws consent, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
• Withdrawn participants will not be replaced. 
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Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information. See Section 7.3 for definition of “lost to follow-up”. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required study 
visit or cannot be contacted as planned in the SoA: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible 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 reason for discontinuation. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 10.1. 
8 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• 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. 
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Urine, blood, 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 340 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 per visit 
N=440 
D1 
D09 
D22 
D30 
D36 
D113/D134 
D181/D202 
D366/D387 
Vaccination 
X 
 
X* 
 
 
Safety Labs 
Cohorts 1 and 2 
Cohort 1 only 
 
Cohort 2 only 
 
 
 
 
Sera (N=440) 
BL0001 
 
BL0002 
 
BL0003 
BL0004 
BL0005 
BL0006 
SARS CoV2 Microneut 
X 
 
X 
 
X 
X 
X 
Anti-S IgG ELISA 
X 
 
X 
 
X 
 
X 
X 
Anti-N IgG ELISA 
X 
 
X 
 
X 
X 
X 
X 
Anti-PanCoV IgG ELISA 
X 
 
 
 
PBMC/CMI (N=87) 
MC0001* 
 
MC0002* 
 
MC0003* 
 
Whole Blood (N=87) 
WB0001* 
 
WB0002* 
 
WB0003* 
 
 
 
COVID PCR on 
respiratory sample † 
Illness visit 
POC Rapid Test ‡ 
X 
 
 
 
* Cohort 2 only 
† 1 swab per illness visit; until day 366/387 
‡ Test at site 
 
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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 by a lateral flow immunoassay. 
8.2 
Efficacy and Immunogenicity Assessments 
8.2.1 
Immunogenicity Assessments 
8.2.1.1 
SARS-CoV-2 Neutralizing Antibody Assessment 
SARS-CoV-2 neutralizing antibodies will be measured using a neutralization assay.  
Serum samples are mixed with constant concentration of the SARS-CoV2 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 (HRP) Immunoglobulin G (IgG) 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. 
8.2.1.2 
SARS-CoV-2 Spike Protein Antibody Serum IgG ELISA 
SARS-CoV-2 anti-S protein IgG antibodies will be measured using an ELISA. Microtiter plates 
will be coated with SARS-CoV-2 Spike 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. 
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8.2.1.3 
Cellular-Mediated Immunity (using whole blood) 
Cytokines will be measured in whole blood following stimulation with full-length S protein and/or 
pools of S-antigen peptides. 
8.2.2 
Efficacy Assessments 
8.2.2.1 
Definitions 
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 diary cards / memory aids (Table 8.2). 
Any ONE of the following (that persist for a period of at least 12 hours or reoccur within a 
12-hour period): 
• Cough (dry or productive) 
• Fever 
• Anosmia 
• Ageusia 
• Chillblains (COVID-toes) 
• Difficulty breathing or shortness of breath 
• Clinical or radiographic evidence of pneumonia  
• Any hospitalization with the following clinical diagnosis:  
• Stroke, myocarditis, myocardial infarction 
• Thromboembolic event (blood clots [eg, pulmonary embolism, deep vein thrombosis, 
stroke]) 
• Purpura fulminans  
OR  
Any TWO of the following (that persist for a period of at least 12 hours or reoccur within a 
12-hour period): 
• Pharyngitis 
• Chills  
• Myalgia  
• Headache 
• Rhinorrhea 
• Abdominal pain  
• At least one of nausea, diarrhea, vomiting 
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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 higher 
Anosmia 
Loss of smell 
Ageusia 
Loss of taste 
Chillblains  
Pain, redness, sores in your fingers and toes 
exposed to cold 
Difficulty breathing  
Difficulty breathing  
Shortness of breath 
Feeling short winded 
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 
Pharyngitis 
Sore Throat 
Chills 
Chills 
Myalgia 
Muscle aches and pains 
Headache 
Headache 
Rhinorrhea 
Runny nose 
Abdominal Pain 
Belly pain 
Nausea 
Feeling queasy 
Diarrhea 
Loose stools 
Vomiting 
Throwing up 
 
Virologically-confirmed COVID-19 illness 
Virologically-confirmed COVID-19 illness is 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 
Serologically-confirmed SARS-CoV-2 infection is defined as a positive result in serum for 
presence of antibodies specific to non-Spike protein of SARS-CoV-2 detected by ELISA. 
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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 at any time during the study. 
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 D57 (2 weeks after 
D43 contact) after vaccination and continuing until D181 (Cohort 1) or D202 (Cohort 2). The 
frequency of contacts will be once every 2 weeks. Prior to these specified time-points, active 
surveillance will still occur during the established contacts (phone calls and visits) as described in 
the SoA. After active surveillance has ended at D181 (Cohort 1) or D202 (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). The respiratory 
sample will be obtained as soon as possible from the onset of clinical manifestations of 
COVID-19-like illness. 
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).  
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. 
In the event that a respiratory sample swab cannot be collected, the research site will still obtain 
the above information. All participants reporting a COVID-19-like illness will have a 30-day 
follow-up telephone call. 
8.2.2.3 
SARS-CoV-2 Nucleoprotein Antibody Serum IgG ELISA 
SARS-CoV-2 anti-nucleoprotein antibodies will be measured using an ELISA. Microtiter plates 
will be coated with SARS-CoV-2 nucleoprotein 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.   
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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. 
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 is extracted. The purified 
template is then evaluated by an NAAT using SARS-CoV-2 specific primers to specifically 
amplify SARS-CoV-2 targets.  
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 designated visits, the Investigator or a delegate will perform a targeted physical examination 
based on the participant’s medical history and the examiner’s medical judgment. 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 before each 
vaccination. 
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• See Appendix 10.2 for the list of clinical laboratory tests to be performed and to the SoA 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 injection 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. 
• 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. 
• 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. 
• 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). 
An ESDR will be performed for Sentinel Safety Cohort participants. The goal of ESDR is to allow 
the preliminary safety assessment for a cautious, step-wise approach to vaccine administration, 
starting with participants aged 18-49 years, as there is no previous human data for the CoV2 preS 
dTM candidate vaccine. 
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Sentinel Safety Cohort 
The participants’ enrollment will include the following sequential steps: 
• Step 1:  
• Thirty participants aged 18-49 years from Cohort 1 will be enrolled in the Sentinel Safety 
Cohort, whereafter enrollment will be paused.  
• Six participants will be randomly assigned to each of the 5 dosing groups defined in 
Cohort 1: 5 µg and 15 µg AF03-adjuvanted groups, 5 µg and 15 µg AS03-adjuvanted 
groups, and placebo. 
• Early safety data collection is planned 8 days after the completion of the vaccination (D09, 
including safety laboratory data); and ESDR is to be planned as soon as possible. Limited 
members of the Sponsor Study Team (RMO, Biostatistician and Programmer, 
Pharmacovigilance Science Expert, and Global Safety Officer) will review unblinded 
safety data and will provide their recommendation to continue the recruitment.  
• Step 2: If there is no safety signal after the ESDR after the completion of the vaccination in 
Sentinel Safety Cohort, recruitment will reopen to all dosing groups and both age strata.  
ESDR 
The safety data collected for ESDR for Sentinel Safety Cohort will be reviewed by the 
Investigator. The intensity of non-serious AEs/adverse reactions (ARs) will be assessed using the 
Sanofi Pasteur scale. 
The following safety parameters will be assessed as part of the early safety data review for the 
Sentinel Safety Cohort participants after the first injection of CoV2 preS dTM candidate vaccine: 
• 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  
If any of the below criteria are met, the 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. Enrollment will be paused during the ESDR, and the following 
safety parameters will be examined: 
• ≥ 2 participants per dosing group (n=6) experiencing Grade 3 systemic reaction (without 
concurrent infectious disease) 
• ≥ 2 participants per dosing group (n=6) experiencing Grade 3 solicited injection site pain 
• ≥ 2 participants per dosing group (n=6) experiencing Grade 3 unsolicited non serious 
reactions (reactions not explained by any other possible etiology)  
• ≥ 2 participants with Grade 3 laboratory AE (Grade 3 abnormality if Grade 1 or 2 at baseline) 
of the same type (reactions not explained by any other possible etiology) 
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• ≥ 2 participants with Grade 2 laboratory AE (Grade 2 abnormality if normal at baseline) of the 
same type (reactions not explained by any other possible etiology) and judged by the 
Investigator to be clinically meaningful 
• Any related SAEs 
Following the ESDR and resumption of enrollment and dosing, occurrence of any one of these 
criteria will result in a pause in enrollment and vaccination pending Sponsor decision. The study 
status and final Sponsor decision will be submitted for notification to the IRB/IEC. 
Halting Rules throughout the Study 
Blinded safety data will be reviewed by limited members of the Sponsor Study Team (RMO, 
Biostatistician and Programmer, Pharmacovigilance Science Expert, and Global Safety Officer) at 
regular intervals to identify any new safety signals or safety concerns during the conduct of the 
study. A pause might be recommended 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 if: 
• Any of the following events, assessed as related to the vaccine by the Investigator and the 
Sponsor, are reported in the study: 
• SAE  
• New Onset of Potential immune-mediated diseases (pIMDs) 
• Ulceration, abscess or necrosis at the injection site  
• Four or more participants across treatment groups experience the same Grade 3 AE of the 
same type in the absence of any other etiology 
• Two or more participants across treatment groups experience the same Grade 3 laboratory 
abnormality assessed by the investigator as clinically significant 
• Any of the following events, suggestive of vaccine associated enhanced disease, are detected 
in the study including: 
• Any death due to SARS-CoV-2 infection 
• ˃ 10% of the study population is hospitalized due to SARS-CoV-2 infection 
• ≥ 4 ICU admissions among participants ≥ 50 years due to SARS-CoV-2 infection 
• ≥ 8 ICU admissions among participants 18-49 years due to SARS-CoV-2 infection 
Case unblinding may be performed if necessary. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
Immediate Post-vaccination Observation Period 
Participants will be kept under observation for 30 minutes after each vaccination to ensure their 
safety. The post-vaccination observation should be documented in the source document. 
Reactogenicity 
Solicited injection site reactions will be collected from D01 to D08 after each vaccination. 
Solicited systemic reactions will be collected from D01 to D08 after each vaccination. 
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The solicited injection site reactions and systemic reactions that are pre-listed in the diary cards 
and CRF, together with the intensity scales, are presented in Appendix 10.3.5.1.1. 
Unsolicited 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, from inclusion until 12 months after the 
last vaccination (up to D366 for Cohort 1 and up to D387 for Cohort 2). However, before the first 
study intervention administration, only SAEs related to study procedures are to be collected (eg, 
SAEs related to blood sampling). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will not be recorded on the AE section of the CRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 10.3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor.  
Medically Attended Adverse Events (MAAEs) 
MAAEs will be collected at any time during the study. 
Adverse Events of Special Interest (AESIs) 
AESIs will be collected at any time during the study. 
See Section 8.4.6 for the list of AESIs. 
8.4.2 
Method of Detecting AEs and SAEs 
Individual diary cards, specifically designed for this study by the Sponsor and provided to the 
study sites, will be given to study participants for the recording of daily safety information. These 
diary cards will include pre-listed terms and intensity scales as well as areas for free text to 
capture additional safety information or other relevant details. Participants will also be provided 
with rulers for measuring the size of injection site reactions, and with standard digital 
thermometers for measuring daily temperatures. To ensure consistency of reporting, the study 
sites will instruct participants on how to correctly use these tools. 
At specified intervals, the Investigator or an authorized designee will interview the participants to 
collect the information recorded in the diary card and will attempt to clarify anything that is 
incomplete or unclear. All clinical study information gathered by the study site will be reported 
electronically by the Investigator or authorized designee using a web-based CRF. Any information 
that was not documented in the diary card will first be captured in the source document and then 
reported electronically. 
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The 12-month (post-last injection) follow-up will be done by interviewing participants either 
during a visit or over the telephone 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. 
8.4.3 
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. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB / IEC, and investigators. 
• For all studies except those investigating medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 
file it and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5 
Pregnancy 
Pregnancy is an exclusion criterion for enrollment in this study, but a participant could potentially 
become pregnant during her participation.  
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until delivery by the Investigator and recorded in the Pregnancy CRF. Any 
data collected after CRF lock will be transmitted to the pharmacovigilance department on the 
paper form. 
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• 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. 
8.4.6 
Adverse Events of Special Interest 
AESIs will include: 
• Anaphylactic reactions, Generalized convulsion, Thrombocytopenia, Lacrimal and salivary 
disorders (tearing, dry mouth, dry eyes). 
• New-onset chronic medical conditions (NOCMCs) and pIMDs (see Appendix 10.5). 
8.4.7 
Medically Attended Adverse Events 
MAAEs will be collected using the same process as other AEs. See Appendix 10.3.1 for definition 
of MAAEs. 
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 
Pharmacokinetics 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. 
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8.8 
Genetics 
Genetics are not evaluated in this study. 
8.9 
Biomarkers 
Besides the biomarkers described in the immunogenicity and efficacy assessments sections 
(Section 8.2.1 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. 
8.10 Immunogenicity Assessments 
See Section 8.2.1. 
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), 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 
formulations of the study vaccine when compared to placebo. A total of 440 participants will be 
enrolled. 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 [N=240], ≥ 50 years [N=120]), dose (low [N=180], high [N=180]), 
injection schedule (1-injection [N=120], 2-injection [N=240]), adjuvant type (AS03 [N=240], 
AF03 [N=120]), overall adjuvant (high-dose with adjuvants [N=180], high-dose without adjuvants 
[N=20]), and dose-sparing adjuvant (low-dose with adjuvants [N=180], high-dose without 
adjuvants [N=20]).  
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9.3 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Randomized 
All participants with a randomized group that has been allocated by 
IRT 
Safety Analysis Set (SafAS) 
Subset of randomized participants who have received at least one 
injection of study intervention. Participants will have their safety 
analyzed according to the study intervention they actually received. 
Safety data recorded for a vaccine received out of the protocol design 
will be excluded from the analysis (and listed separately). 
Full analysis set (FAS) 
Subset of randomized participants who received at least 1 injection of 
the study intervention. Participants will be analyzed according to the 
study intervention group to which they were randomized. 
Per-protocol analysis set 
(PPAS) 
Subset of the FAS. Participants presenting with at least one of the 
following relevant conditions will be excluded from the PPAS: 
• 
Participant did not meet all protocol-specified inclusion criteria or 
met at least one of the protocol-specified exclusion criteria  
• 
Participant did not 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 a Category 2 or Category 3 therapy / 
medication / as stated in Section 6.5 
• 
Participant with positive test results 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 
CMI (PPAS-CMI) 
Subset of PPAS excluding participants who provided all post-dose 
CMI samples outside the proper time window or no post-dose CMI 
sample was drawn. 
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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 critical endpoints including but not limited to primary and 
secondary endpoints. 
All statistical analyses will be performed under the responsibility of the Sponsor’s Biostatistics 
Platform using the SAS® software, Version 9.4 or above (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% CIs for the GMTs/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 GMT titers and occurrence of neutralizing antibody 
seroconversion. When the outcome/dependent variable is a continuous numerical variable, linear 
models may be utilized; when the outcome/dependent variable is a categorical variable, logistic 
regression models may be utilized. Explanatory/independent variables inserted in these models 
would include age group (18-49 years, ≥ 50 years), antigen dose level (low or high), and adjuvant 
(none, AS03, AF03). Models evaluating antibody titers or rates at D36 as the outcome variable 
would include also an explanatory variable corresponding to the injection schedule (1-injection, 
2-injections). Multiplicative interaction terms will be included in expanded models to assess for 
evidence of effect modification. Non-significant interaction terms can be removed from the 
models. 
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. 
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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. 
The 95% CIs for the anti-S antibody concentration and anti-S antibody concentration 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 anti-S antibody 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 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 ELISA assay from any post-baseline sampling time point 
compared to the baseline value, as measured in a SARS-CoV-2 non-S ELISA. 
Correlates of risk / protection analysis will be performed based on antibody responses to SARS-
CoV-2 as evaluated using virus neutralization and binding antibody (ELISA), considering cases of 
virologically-confirmed COVID-19 and/or serologically-confirmed SARS-CoV-2 infection as 
defined above. Detailed statistical methods will be described in an SAP. 
Efficacy analyses will be performed on FAS and PPAS-IAS, unless otherwise specified. 
9.4.4 
Exploratory Endpoint 
9.4.4.1 
Immunogenicity 
Th1 and Th2 cytokines will be measured and summarized for individual and aggregate study 
arms. 
Detailed CMI analyses will be defined in the SAP. The CMI analysis will be based on PPAS-CMI 
set. 
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 
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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. 
9.5 
Interim Analyses 
An interim analysis will be performed on data collected for primary immunogenicity and 
exploratory CMI objectives obtained up to D36 and primary safety data collected up to D43, upon 
the data availability and when a partial database lock has been conducted. Statistical analysis of 
data described above will be conducted to support formulation selection for further investigation. 
The analyses results 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. 
After the 6-month data have been collected, a further interim analysis will be performed on 
immunogenicity, safety, and efficacy endpoints. The study blind will be broken at the group level 
to the Sponsor at that time. At the time of protocol Amendment 1, a partial database lock has been 
conducted. 
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. 
The SAP will describe the planned interim analyses in greater detail. 
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 for halting rules). 
9.6 
Data Monitoring Committee (DMC) 
Not applicable.  
 
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10 Supporting Documentation and Operational Considerations 
10.1 Appendix: Regulatory, Ethical, and Study Oversight Considerations 
Note: The term “participant” is used throughout this protocol. However, the term “subject” will be 
used in the CRF in order to comply with the Clinical Data Interchange Standards Consortium 
(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 
• The protocol, protocol amendments, ICF, Investigator Brochure (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 or the Sponsor (according to local regulations) 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 
• 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• The Investigator will be responsible for 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. 
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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 IEC / IRB 
requirements. However, all versions must contain the standard information found in the 
sample ICF provided by the Sponsor. Any change to the content of the ICF must be approved 
by the Sponsor and the IEC / IRB prior to the form being used. 
• If new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study, this will be communicated to him / her in a timely manner. 
Such information will be provided via a revised ICF or an addendum to the original ICF. 
• Participants must be re-consented to the most current version of the ICF during their 
participation in the study. 
• A copy of the ICF must be provided to the participant. 
• 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 IEC / IRB 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 Global Data Protection Regulation (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. 
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• Participants race and ethnicity will be collected in this study because these data are required 
by regulatory agencies (41). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred to the 
Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
• Participant data will be used for this study and in support of the whole drug development 
program for the Investigational Product, including negotiations with payers and publication of 
results. 
• Any unused part of the serum, respiratory, or PBMC samples will be securely stored at the 
Sanofi Pasteur laboratory (GCI) or Contract Research Organization for 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. 
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. 
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10.1.5 Committees Structure 
Participant safety will be continuously monitored by the Sponsor’s internal safety review 
committee which includes safety signal detection at any time during the study. 
10.1.6 Dissemination of Clinical Study Data 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance, and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data Quality Assurance 
• All participant data relating to the study will be recorded on electronic CRF unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of 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). 
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• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
10.1.8 Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Detailed guidance and information are provided in the Operating Guidelines. 
10.1.9 Study and Site Start and Closure 
Details on which clinical supplies are provided by the Sponsor or the site are described in the 
Operating Guidelines. 
The study start date is considered the date of the first visit planned in the SoA of the first 
participant. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study-site has all the documents necessary for archiving and a study-site 
closure visit has been performed along with a Site Close Out Form submitted to the IRB, as 
required. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
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• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication Policy 
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: Clinical Laboratory Tests 
A urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) will be performed before each vaccination. 
• 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. 
• Pregnancy Testing 
 
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Table 10.1: Protocol-required safety laboratory assessments 
Laboratory 
Assessments 
Time period for 
assessment 
Parameters 
Hematology 
Cohort 1: 
D01 and V02 (D09) 
Cohort 2: D01 and 
V03 (D30) 
Platelet Count  
White blood cell (WBC) count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Cohort 1: 
D01 and V02 (D09) 
Cohort 2: D01 and 
V03 (D30) 
Blood urea 
nitrogen 
(BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum Glutamic-
Oxaloacetic 
Transaminase (SGOT) 
Total and 
direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
(ALT)/ Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
Total 
Protein 
 
Glucose 
(nonfasting) 
 
Alkaline phosphatase 
 
Lipase 
 
 
 
Amylase 
 
 
 
Routine 
Urinalysis 
Cohort 1: 
D01 and V02 (D09) 
Cohort 2: D01 and 
V03 (D30) 
• 
Glucose, protein, blood, leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
Cohort 1: pre-injection 
1 at D01  
Cohort 2: pre-
injections 1 and 2 at 
D01 and V02 (D22), 
respectively 
Highly sensitive urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential*) 
D01 
Rapid diagnostic testing for SARS-CoV2 antibody screening 
* To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or 
surgically sterile. 
Investigators must document their review of each laboratory safety report. 
Participants, outcome assessors, Investigators, laboratory personnel, and the majority of sponsor 
study staff (except those involved in the ESDR and for concerned participants only) will be 
blinded to vaccine assignment group (formulation and adjuvant); injection schedule will be 
unblinded; and those preparing/administering the study interventions will be unblinded to vaccine 
group assignment. 
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, 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 AE (MAAE)  
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 e-mail will be considered a physician office visit for the purpose of 
MAAE collection. This includes medical advice seeking during the study visit or routine 
medical care. This definition excludes pediatric check-ups, follow-up visits of chronic 
conditions with an onset prior to entry in the study, and solicited reactions.  
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 AE/AR: 
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. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
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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. 
Potential Immune-Mediated Disease (pIMDs): pIMDs constitute a group of AEs that 
includes diseases which are clearly autoimmune in etiology and other inflammatory and/or 
neurologic disorders which may or may not have autoimmune etiologies. pIMDs currently in 
effect are presented in Appendix 10.5:Adverse Events of Special Interest. 
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 AE/AR 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and/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: 
                                                 
 
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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• 
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) 
• 
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. 
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• 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. 
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 e-mail address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.com 
• By express mail, to the following address: 
 
 
Global Pharmacovigilance, Sanofi Pasteur 
 
 
Discovery Drive 
 
 
Swiftwater, PA 18370 
 
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Safety Emergency Call 
If, as per the Investigator's judgment, a participant experiences a medical emergency, the 
Investigator may contact the Sponsor's RMO for advice on how to address any study-related 
medical question or problem. If the RMO is not available, then the Investigator may contact the 
Call Center—available 24 hours a day, 7 days a week—that will forward all safety emergency 
calls to the appropriate primary or back-up Sanofi Pasteur contact, as needed. The toll-free 
contact information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department. 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.3.2. 
10.3.5 Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 
10.3.5.1 Tables for Clinical Abnormalities 
10.3.5.1.1 Solicited AR Intensity Grading Scale 
 
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Table 10.2: 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 
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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 
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 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Definition 
Elevation of temperature to 
≥°38.0°C (≥ 100.4°F) 
Pain or discomfort in the head or 
scalp. Does not include migraine. 
General ill feeling. 
Malaise is a generalized feeling of 
discomfort, illness, or lack of well-
being that can be associated with a 
disease state. It can be accompanied 
by a sensation of exhaustion or 
inadequate energy to accomplish 
usual activities. 
Muscle aches and pains are 
common and can involve more than 
one muscle at the same time. 
Muscle pain can also involve the 
soft tissues that surround muscles. 
These structures, which are often 
referred to as connective tissues, 
include ligaments, tendons, and 
fascia (thick bands of tendons). 
Does not apply to muscle pain at 
the injection site which should be 
reported as injection site pain. 
Intensity scale* 
Grade 1: ≥ 38.0°C to ≤ 38.4°C, 
or ≥ 100.4°F to ≤ 101.1°F 
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. 
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Grade 2: ≥ 38.5°C to ≤ 38.9°C, 
or ≥ 101.2°F to ≤ 102.0°F 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
Grade 2: A type of adverse event 
that is usually alleviated with 
additional therapeutic intervention. 
The event interferes with usual 
activities of daily living, causing 
discomfort but poses no significant 
or permanent risk of harm to the 
research participant. 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Diary card: 
Grade 1: No interference with usual 
activities 
Grade 2: Some interference with 
usual activities 
Grade 3: Significant; prevents usual 
activities 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Diary card: 
Grade 1: No interference with usual 
activities 
Grade 2: Some interference with 
usual activities 
Grade 3: Significant; prevents usual 
activities 
Grade 3: A type of adverse event 
that interrupts usual activities of 
daily living, or significantly affects 
clinical status, or may require 
intensive therapeutic intervention. 
Diary card: 
Grade 1: No interference with usual 
activities 
Grade 2: Some interference with 
usual activities 
Grade 3: Significant; prevents usual 
activities 
MedDRA: Medical Dictionary for Regulatory Activities 
* For all reactions 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 diary card, and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this study is oral. 
10.3.5.1.2 Unsolicited AE Intensity Grading Scale 
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.3.5.1.1). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
CRF: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• 
Diary card: No interference with usual activities. 
• Grade 2 
• 
CRF: A type of adverse event that is usually alleviated with additional therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
• 
Diary card: Some interference with usual activities. 
• Grade 3 
• 
CRF: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• 
Diary card: Significant; prevents usual activities. 
10.3.5.2 Tables for Laboratory Abnormalities 
The pre-defined intensity thresholds for laboratories abnormalities are shown in Table 10.4. 
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Table 10.4: Intensity thresholds for laboratories abnormalities 
Endpoint 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
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 
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 
Absolute Lymphocytes Decreased – 
cell/mm3 
750 – 1,000  
500 – 749  
< 499  
Absolute Neutrophils Decreased – 
cell/mm3 
1,500 – 2,000  
1,000 – 1,499  
< 999  
Absolute Eosinophils – cell/mm3 
650 – 1500  
1501 - 5000  
> 5000  
Platelets Decreased – cell/mm3 
125,000 – 140,000 
100,000 – 124,000 
≤ 99,000 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
≥ 2.1 or requires 
dialysis 
Blood Urea Nitrogen (BUN) – mg/dL  
23 – 26  
27 – 31  
> 31 or require 
dialysis  
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  
Glucose – Hyperglycemia (fasting) – 
mg/dL 
100 - 110 
111 - 125 
> 125 
Total Protein – Hypoproteinemia – 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
Alkaline phosphate 
(Increase by factor) 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
≥ 3.1 ULN 
LFT (ALT, AST) 
(Increase by factor) 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
≥ 5.1 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 
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Endpoint 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe  
(Grade 3) 
Bilirubin – with normal LFT  
(Increase by factor) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
 ≥ 2.1 ULN 
Pancreatic enzymes – amylase, lipase  
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
≥ 2.1 ULN 
Urine - protein 
Trace 
1+ 
2+ 
Urine - glucose 
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; CPK, creatine phosphokinase; 
CRP, C-reactive protein; dL, deciliter; gm, gram; LFT, liver function test; mg, milligram; mm3, cubic millimeter; 
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 postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1) Premenarchal 
2) Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
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 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• 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 
Events potentially associated with coronavirus vaccine 
Anaphylactic reactions 
Generalized convulsion 
Thrombocytopenia 
 
Events potentially associated with AFO3 adjuvant use 
Dry eyes 
Tearing  
Dry mouth 
 
Events potentially associated with the adjuvants use (AF03 or AS03) and/or coronavirus 
vaccine 
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. 
pIMDs:  
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune 
diseases and other inflammatory and/or neurologic disorders of interest which may or may not 
have an autoimmune etiology. AEs that need to be recorded and reported as pIMDs include those 
listed in Table 10.5. 
However, the Investigator will exercise their medical and scientific judgment in deciding whether 
other diseases have an autoimmune origin (that is pathophysiology involving systemic or organ-
specific pathogenic autoantibodies) and should also be recorded as a pIMD. 
When there is enough evidence to make any of the diagnoses mentioned in Table 10.5, the AE 
must be reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the final or 
definitive diagnosis has been determined, and alternative diagnoses have been eliminated or 
shown to be less likely. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard questionnaire 
and a list of preferred terms (PTs) and PT codes corresponding to the above diagnoses will be 
available to investigators at study start. 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the Investigator (or 
designate) must complete, date and sign an electronic Expedited Adverse Events Report. 
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Table 10.5: List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and paresis 
(eg, Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome*, 
including Miller Fisher 
syndrome and other variants. 
• 
Acute disseminated 
encephalomyelitis*, including 
site specific variants, eg, 
noninfectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic inflammatory 
demyelinating 
polyneuropathy. 
- 
Multifocal motor 
neuropathy. 
- 
Polyneuropathies 
associated with 
monoclonal gammopathy. 
• 
Narcolepsy*. 
• 
Systemic lupus erythematosus 
and associated conditions. 
• 
Systemic scleroderma 
(systemic sclerosis), 
including: 
• 
Diffuse scleroderma. 
• 
CREST syndrome. 
• 
Idiopathic inflammatory 
myopathies, including: 
• 
Dermatomyositis. 
• 
Polymyositis. 
• 
Anti-synthetase syndrome. 
• 
Rheumatoid arthritis and 
associated conditions 
including: 
• 
Juvenile idiopathic arthritis. 
• 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, 
including: 
- 
Ankylosing spondylitis. 
- 
Reactive arthritis 
(Reiter’s syndrome). 
- 
Undifferentiated 
spondyloarthritis. 
- 
Psoriatic arthritis. 
- 
Enteropathic arthritis. 
• 
Relapsing polychondritis. 
• 
Mixed connective tissue 
disorder. 
• 
Gout. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid, and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localized scleroderma 
(morphea). 
Vasculitis 
Blood disorders 
Others 
• 
Large vessels vasculitis* 
including: 
- 
Giant cell arteritis 
(temporal arteritis). 
- 
Takayasu’s arteritis. 
• 
Medium sized and/or small 
vessels vasculitis* including: 
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic anemia. 
• 
Autoimmune glomerulonephritis 
including: 
- 
IgA nephropathy. 
- 
Glomerulonephritis rapidly 
progressive. 
- 
Membranous 
glomerulonephritis. 
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- 
Polyarteritis nodosa. 
- 
Kawasaki’s disease. 
- 
Microscopic polyangiitis. 
- 
Wegener’s granulomatosis 
(granulomatosis with 
polyangiitis). 
- 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis or eosinophilic 
granulomatosis with 
polyangiitis). 
- 
Buerger’s disease 
(thromboangiitis 
obliterans). 
- 
Necrotizing vasculitis 
(cutaneous or systemic). 
- 
Antineutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type 
unspecified). 
- 
Henoch-Schonlein purpura 
(IgA vasculitis). 
- 
Behcet’s syndrome. 
- 
Leukocytoclastic 
vasculitis. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
- 
Membranoproliferative 
glomerulonephritis. 
- 
Mesangioproliferative 
glomerulonephritis. 
- 
Tubulointerstitial nephritis 
and uveitis syndrome. 
• 
Ocular autoimmune diseases 
including: 
• 
Autoimmune uveitis. 
• 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory bowel disease, 
including: 
- 
Crohn’s disease. 
- 
Ulcerative colitis. 
- 
Microscopic colitis. 
- 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave’s or Basedow’s disease. 
• 
Diabetes mellitus type 1. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune 
syndrome. 
• 
Autoimmune hypophysitis. 
* Events potentially associated with coronavirus vaccine 
 
 
 
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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 
AE 
 
 
Adverse Events 
AESI  
 
Adverse events of special interest 
AR 
 
 
Adverse reactions 
BARDA 
 
Biomedical Advanced Research and Development Authority 
CI 
 
 
Confidence interval 
CMI 
 
 
Cellular-mediated Immunity 
CoV2 preS dTM:  
SARS-CoV2 prefusion Spike delta TM 
CPE 
 
 
Cytopathic effect 
CRF 
 
 
Case report form 
D 
 
 
Day 
DMC  
 
Data Monitoring Committee 
ELISA  
 
Enzyme-linked immunosorbent assay 
EMA  
 
European Medicines Agency 
FAS 
 
 
Full analysis set 
GCI 
 
 
Global Clinical Immunology 
GCP 
 
 
Good Clinical Practice 
GMC  
 
Geometric mean concentration 
GMT  
 
Geometric mean titer 
GPV  
 
Global Pharmacovigilance 
GSK  
 
GlaxoSmithKline 
HA 
 
 
hemagglutinin 
HAI 
 
 
hemagglutination inhibition 
IDMC  
 
Independent Data and Monitoring Committee 
IB 
 
 
Investigator’s Brochure 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Council for Harmonization 
IgG 
 
 
Immunoglobulin G 
IDMC  
 
Independent Data Monitoring Committee 
IEC 
 
 
Independent Ethics Committees 
IMP 
 
 
Investigational Medicinal Product 
IRB 
 
 
Institutional Review Boards 
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IRT 
 
 
Interactive Response Technology 
LLOQ  
 
lower limit of quantification 
MAAE 
 
medically attended adverse event 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MERS  
 
Middle East Respiratory Syndrome 
NAAT  
 
nucleic acid amplification test 
NIMP  
 
Non- Investigational Medicinal Product 
NOCMC 
 
new-onset chronic medical conditions 
OD 
 
 
Optical density 
pIMD  
 
potential immune-mediated disease 
PPAS  
 
Per-protocol analysis set 
PPAS-CMI 
 
Per-protocol analysis set for CMI 
PPAS-IAS 
 
Per-protocol analysis set for immunogenicity 
PT 
 
 
preferred term 
RBD  
 
receptor binding domain 
RMO  
 
Responsible Medical Officer 
S 
 
 
Spike 
SAE 
 
 
Serious adverse events 
SafAS  
 
Safety Analysis Set 
SAP 
 
 
Statistical analysis plan 
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2 
SoA 
 
 
Schedule of Activities 
TBD  
 
to be determined 
TIV 
 
 
trivalent influenza vaccine 
VAC  
 
Vaccination (as in Vaccination #) 
WOCBP 
 
Woman of Childbearing Potential 
 
 
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10.8 Appendix: Protocol Amendment/Update History 
Revisions and rationale for revisions for protocol Version 2.0, Version 3.0, and Version 4.0 are as 
follows. 
Protocol Version 2.0, dated 24 July 2020 (was an update only before study start)) 
The protocol was updated from the Version 1.0 mainly due to CBER feedback from the pre-IND 
submission, along with other feedback from GlaxoSmithKline. 
Revision 
Rationale 
Population: No upper limit on age 
It is considered of great relevance to generate data in the older 
adult population to inform schedule and formulation selection 
that will serve the general adult population, including those at 
particular risk of poor outcomes. CBER concurred and agreed to 
no upper age limit. 
Sentinel Safety Cohort and Early Safety 
Data Review added (with halting rules) 
As Phase I/II VAT00001 is a relatively large first-in-human study 
of novel antigen and adjuvant combinations, to improve the 
safety of the protocol, CBER requested a small sentinel cohort 
made up of participants 18-49 years of age in Cohort 1 (single 
dose). If safety data and laboratory measures to D09 in Cohort 1 
are considered as acceptable based on unblinded data review by 
limited members of the Sponsor Study Team (Responsible 
Medical Officer, Study Biostatistician and Programmer, 
Pharmacovigilance Science Expert, and Global Safety Officer) 
and do not meet any halting rules, concurrent enrollment and 
vaccinations at all dose levels in both age groups may proceed as 
planned. 
Removed 45 µg formulation 
Recently reported and historical data suggest that antigen doses 
lower than 45 µg can result in robust immune responses. The 
choice of antigen dose is also driven by the industrial capacity 
needed to support the number of doses required for a pandemic 
response. 
Sample Sizes revised throughout 
Due to addition of Sentinel Safety Cohort, removal of 45 µg 
formulation, and increased focus on the AS03 adjuvant. 
Blood Sample 3 (BL0003) (Cohort 1 and 
Cohort 2) and PBMC Sample 3 
(MC0003) (Cohort 2) changed from Day 
(D)43 to D36; D43 Visit replaced by 
telephone call 
Post-vaccination 2 samples (BL0003 and MC0003) for Cohort 2 
were shifted from D43 to D36 as a means of acceleration of 
serological data for early information on vaccine performance. 
The D43 blood sample for Cohort 1 was also shifted to D36 for 
consistency. D43 contact then became a telephone call for safety 
only. 
Blood Draw added at Month 12 resulting 
in a Visit 7 for both Cohorts instead of 
12-month safety follow-up call 
Per CBER feedback: To further evaluate safety (risk of vaccine-
enhanced disease), monitoring for the occurrence and severity of 
NAAT- and serologically-confirmed COVID-like illness 
extended to 12 months after the last vaccination. 
Additions and revisions for text on 
narcolepsy / pIMD 
Since narcolepsy is part of the list of Potential Immune-Mediated 
Diseases, it will be included in the risk ‘Potential Immune-
Mediated Diseases’. 
Additions of terms in list of Adverse 
Events of Special Interest (AESIs) 
Following Safety Platform for Emergency Vaccines (SPEAC) 
and Priority List of AESI: COVID-19 dated 25 May 2020 
(Version 2.0), “Generalized convulsion” and 
“Thrombocytopenia” have been added as AESIs. 
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Exclusion Criteria: 
Added footnote to criterion #3: 
"While receipt of any vaccine as listed in 
this criterion is exclusionary for this 
study, if a COVID-19 vaccine becomes 
available from a company other than 
Sanofi Pasteur, then participants are free 
to receive that vaccine. Participants who 
receive a COVID-19 vaccine 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)." 
Added to Criterion #12 footnote: 
"current vaping" 
Added new previous vaccination 
criterion: 
- 
Prior administration of a coronavirus 
vaccine (severe acute respiratory 
syndrome coronavirus 2 [SARS-
CoV-2], SARS-CoV, Middle East 
Respiratory Syndrome [MERS-
CoV]) 
Added 3 new criteria for risk-
management: 
- 
Residence in a nursing home or 
long-term care facility 
- 
Health care workers providing direct 
patient care for COVID-19 patients 
- 
Participants with active or prior 
documented autoimmune disorder 
(such as potential immune-mediated 
diseases [pIMDs]) 
Revisions made due to CBER/GSK feedback: 
- 
Per FDA guidance, it needs to be clear that participants may 
choose to receive an approved COVID-19 vaccine if 
available from another company. 
- 
Previous plan was to exclude former and current smokers. 
For completeness, criterion is extended to exclude persons 
who currently vape. 
- 
Although there are currently no licensed/marketed COVID 
vaccines at the moment, participants may have participated in 
another COVID study. 
- 
Added 3 exclusion criteria for persons at higher risk for 
severe COVID-19 disease or at increased risk for exposure to 
SARS-CoV-2. 
 
Protocol Version 3.0 (dated 26 August 2020) and Version 4.0 (dated 27 August 2020)  
The protocol was updated from Version 2.0 (dated 24 July 2020) to Version 3.0 (dated 
26 August 2020) due to CBER feedback from its review of the IND submission. One day after 
approval of Version 3.0 on 26 August 2020, additional revisions were requested by CBER on 
27 August 2020, resulting in Version 4.0.  
Version 3.0 was submitted to the IRB; however, since the protocol was pulled less than 1 day 
later, the below revisions section includes changes between Version 2.0 through Version 4.0, 
inclusive. 
 
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Major revisions between Version 2.0 and Version 3.0 
Revision 
Rationale 
Section 8.4: Halting Rules subheading 
Revised pause bullets #4 and #5 
Revised per CBER feedback: 
Halting Rules throughout the Study, ≥10% of 
participants equates to at least n=44 across 
treatment groups who could have a Grade 3 
AE of the same type before the study is 
halted and ≥5% of participants equates to at 
least n=22 across treatment groups who 
could have Grade 3 laboratory abnormalities 
of the same type before the study is halted. 
These numbers exceed the thresholds that we 
recommended in our pre-IND comments and 
could result in an unreasonable risk of injury 
or harm.  
Section 8.4: ESDR subheading 
If any of the below criteria are met, the 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. Enrollment will be 
paused during the ESDR, and the following safety 
parameters will be examined: 
•
≥ 2 participants per dosing group (n=6) experiencing 
Grade 3 systemic reaction (without concurrent infectious 
disease)
•
≥ 2 participants per dosing group (n=6) experiencing 
Grade 3 solicited injection site pain
•
≥ 2 participants per dosing group (n=6) experiencing 
Grade 3 unsolicited non serious reactions (reactions not 
explained by any other possible etiology)
•
≥ 2 participants with Grade 3 laboratory AE (Grade 3 
abnormality if Grade 1 or 2 at baseline) of the same type 
(reactions not explained by any other possible etiology)
•
≥ 2 participants with Grade 2 laboratory AE (Grade 2 
abnormality if normal at baseline) of the same type
(reactions not explained by any other possible etiology) 
and judged by the Investigator to be clinically 
meaningful
Changed bullet #4 to from “3” to “2” to 
make it consistent with the overall halting 
rules (3 would be less strict than the overall 
halting rules). 
Major revision between Version 3.0 and Version 4.0 
Revision 
Rationale 
For Section 4.2: "Scientific Rationale for Study Design", 
sentence below was removed: 
The adjuvants that will be utilized in this study also have a 
well-established safety profile”.  
Given ongoing concerns for potential 
immune-mediated adverse events and the 
relatively small clinical trial safety database 
for AF03, this sentence was requested to be 
deleted by CBER on 27 AUG 2020.  
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Wang H ZY, Huang B, Deng W, Quan Y, Wang W. Development of an inactivated 
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12 Sponsor Signature Page 
 
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Document Number
CLI_00310431
Version Number
5.0
Project Code
COVID-19
Artifact Name
Protocol Body
-
-
-
Approver Name
Date
(Universal Time)
Reason for Signature
Approval
-
-
 
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