Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccines With AS03 Adjuvant in Adults 18 Years of Age and Older as a Primary Series and Immunogenicity and Safety of a Booster Dose of SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (Two Monovalent and One Bivalent)
Phase: PHASE2
Conditions: COVID-19
Sponsor: Sanofi Pasteur, a Sanofi Company

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Title Page 
Protocol Title: 
Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccines with AS03 Adjuvant 
in Adults 18 Years of Age and Older as a Primary Series and Immunogenicity and Safety of a 
Booster Dose of SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (two Monovalent and 
one Bivalent) 
Study Code: VAT00002 
Amendment Number: Amendment 6 
Compounds: 
Original Phase II Cohort: 
SARS-CoV2 prefusion Spike delta TM (CoV2 preS dTM), monovalent D614 
AS03: Oil-in-water based adjuvant System containing α-Tocopherol and Squalene 
Supplemental Phase III Cohorts: 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, monovalent D614 (CoV2 preS dTM-
AS03 [D614]): monovalent vaccine with the Spike (S) protein sequence from the D614 variant 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, monovalent B.1.351 (CoV2 preS 
dTM-AS03 [B.1.351]): monovalent vaccine with the S protein sequence from the B.1.351 variant 
SARS-CoV2 prefusion Spike delta TM, monovalent B.1.351 (CoV2 preS dTM [B.1.351]): 
monovalent vaccine with the S protein sequence from the B.1.351 variant 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, bivalent D614/B.1.351 (CoV2 preS 
dTM-AS03 [D614 + B.1.351]): bivalent vaccine with the S protein sequence from the D614 
variant and the B.1.351 variant 
Brief Title: 
Study of Recombinant Protein Vaccines with Adjuvant as a Primary Series and as a Booster Dose 
against COVID-19 in Adults 18 Years of Age and Older   
Study Phase: Phase II/III 
Sponsor Name and Legal Registered Address: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Manufacturer: 
CoV2 preS dTM: Same as Sponsor 
AS03 adjuvant: GlaxoSmithKline (Vaccines) 
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NCT Number: NCT04762680

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Document History 
Previous 
Version 
Date 
Comments 
1.0 
05 October 2020 
Original, Phase III design submitted to Health 
Authorities for IND review 
2.0 
15 January 2021 
Design with Phase II only was submitted to the IRB, but 
was not submitted to Health Authorities 
3.0 
04 February 2021 
Original protocol version used in the study 
4.0 
08 April 2021 
Update due to CBER non-hold comment 
5.0 
10 June 2021 
Study design updated to add Supplemental Phase III 
Cohorts for Booster Study 1, version not submitted 
6.0 
02 August 2021 
Added conditional co-primary objectives for 
Supplemental Cohort 1 and relevant nonclinical non-
human primate (NHP) study result, not submitted to 
Health Authorities 
7.0 
31 August 2021 
Updated with minor changes to inclusion and exclusion 
criteria 
8.0 
12 October 2021 
Study design updated to remove bivalent vaccine 
candidate for protein-primed dosing groups, AESIs 
updated to include myocarditis and pericarditis, and a 
pooled primary series cohort added as possibility for the 
Cohort 1 and 2 Comparator Group  
9.0 
19 November 2021 
Study design updated to remove the bivalent vaccine 
candidate arm from Variant Prime Cohort 3 
Amendment 6 (20 January 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Protocol Amendment: 
The major protocol revisions and rationale for revisions from Version 9.0 to Version 10.0 are as 
shown below: 
Revision 
Rationale 
Throughout: 
Removed Supplemental Variant Prime 
Cohort 3  
1) Operational feasibility of enrolling SARS-CoV-2
naïve participants has become significantly more
challenging
2) While data would be supportive of the planned
indication, data are not required for regulatory
purposes
Throughout:  
Total participant numbers changed to 3660 
(was 4238) 
Total changed for removal of Variant Prime Cohort 3 
participants 
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Section 10.5 / Table 10.4 List of potential 
immune-mediated diseases 
Table replaced with an updated table; date 
updated in table title to “version: January-
2022” 
Updated for consideration of emerging possible 
immune-mediated pIMDs of interest in the context 
of COVID-19 vaccine safety monitoring. 
 
 
 
 
 
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Table of Contents  
Document History ............................................................................................................................ 3 
List of Tables .................................................................................................................................... 9 
List of Figures ................................................................................................................................ 11 
1 
Protocol Summary ........................................................................................................... 12 
1.1 
Synopsis .......................................................................................................................... 12 
1.2 
Schemas .......................................................................................................................... 37 
1.3 
Schedule of Activities (SoA) .......................................................................................... 41 
2 
Introduction ..................................................................................................................... 58 
2.1 
Study Rationale ............................................................................................................... 61 
2.2 
Background ..................................................................................................................... 62 
2.2.1 
Nonclinical Studies ....................................................................................................... 62 
2.2.2 
Previous Experience in Humans ................................................................................... 65 
2.3 
Benefit/Risk Assessment ................................................................................................ 68 
2.3.1 
Risks from Study Participation ..................................................................................... 70 
2.3.2 
Benefits from Study Participation ................................................................................ 73 
2.3.3 
Overall Benefit-Risk Conclusion .................................................................................. 73 
3 
Objectives and Endpoints ............................................................................................... 74 
4 
Study Design .................................................................................................................... 84 
4.1 
Overall Design ................................................................................................................ 84 
4.1.1 
Intervention Groups and Duration for the Original Phase II Cohort ............................ 91 
4.1.2 
Intervention Groups and Duration for Supplemental Phase III Cohorts ...................... 93 
4.2 
Scientific Rationale for Study Design ............................................................................. 95 
4.3 
Justification for Dose and Dosing Schedule ................................................................... 98 
4.4 
End of Study Definition ................................................................................................ 103 
5 
Study Population ........................................................................................................... 104 
5.1 
Inclusion Criteria .......................................................................................................... 104 
5.2 
Exclusion Criteria ......................................................................................................... 105 
5.3 
High Risk Medical Conditions ...................................................................................... 107 
5.4 
Representation of Study Subpopulations ...................................................................... 107 
5.5 
Lifestyle Considerations ............................................................................................... 107 
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5.6 
Screen Failures .............................................................................................................. 108 
6 
Study Intervention ......................................................................................................... 109 
6.1 
Study Interventions Administered ................................................................................ 109 
6.1.1 
Original Phase II Cohort Study Interventions ............................................................ 109 
6.1.2 
Supplemental Phase III Cohorts Study Interventions ................................................. 110 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 118 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 118 
6.3.1 
Randomization and Allocation Procedures ................................................................ 118 
6.3.2 
Blinding and Code-breaking Procedures .................................................................... 121 
6.4 
Study Intervention Compliance .................................................................................... 122 
6.5 
Dose Modifications ....................................................................................................... 122 
6.6 
Access to Authorized/Approved vaccine during the study ........................................... 122 
6.7 
Continued Access to Study Intervention After the End of the Study ........................... 123 
6.8 
Treatment of Overdose.................................................................................................. 123 
6.9 
Concomitant Therapy .................................................................................................... 123 
6.9.1 
Rescue Medicine ......................................................................................................... 124 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ........................................................................................ 125 
7.1 
Discontinuation of Study Intervention .......................................................................... 125 
7.1.1 
Temporary Contraindications ..................................................................................... 125 
7.1.2 
Definitive Contraindications ....................................................................................... 125 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................. 126 
7.3 
Lost to Follow-up .......................................................................................................... 127 
8 
Study Assessments and Procedures ............................................................................. 128 
8.1 
Baseline Assessments at the Time of Vaccination ....................................................... 131 
8.1.1 
Demographic Information and Risk Factor Data ....................................................... 131 
8.1.2 
Physical Examinations and Vital Signs ...................................................................... 132 
8.1.3 
Medical History .......................................................................................................... 132 
8.1.4 
Clinical Safety Laboratory Assessments .................................................................... 132 
8.1.5 
Baseline SARS-CoV-2 Antibody Screening .............................................................. 132 
8.1.6 
NAAT Assessment Prior to Vaccination .................................................................... 135 
8.2 
Immunogenicity Assessments ....................................................................................... 135 
8.2.1 
Primary Immunogenicity Assays ................................................................................ 135 
8.2.2 
Secondary Immunogenicity Assays ............................................................................ 136 
8.2.3 
Exploratory Immunogenicity Assays ......................................................................... 137 
8.3 
Safety Assessments ....................................................................................................... 139 
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8.3.1 
Definitions .................................................................................................................. 139 
8.3.2 
Schedule of Activities for COVID-19-like Illness ..................................................... 143 
8.3.3 
Nucleic Acid Amplification Test (NAAT) for Detection of Laboratory-
Confirmed SARS-CoV-2 infection ............................................................................ 146 
8.3.4 
ELECSYS Anti-SARS-CoV-2 Anti-N ECLIA .......................................................... 146 
8.3.5 
Physical Examinations ................................................................................................ 146 
8.3.6 
Vital Signs .................................................................................................................. 147 
8.4 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting............. 147 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ....................... 149 
8.4.2 
Method of Detecting AEs and SAEs .......................................................................... 150 
8.4.3 
Follow-up of AEs and SAEs ...................................................................................... 151 
8.4.4 
Regulatory Reporting Requirements for SAEs .......................................................... 151 
8.4.5 
Pregnancy ................................................................................................................... 151 
8.4.6 
Adverse Events of Special Interest ............................................................................. 152 
8.4.7 
Medically-Attended Adverse Events .......................................................................... 153 
8.5 
Pharmacokinetics .......................................................................................................... 153 
8.6 
Pharmacodynamics ....................................................................................................... 153 
8.7 
Genetics ......................................................................................................................... 153 
8.8 
Biomarkers .................................................................................................................... 153 
8.9 
Immunogenicity Assessments ....................................................................................... 153 
8.10 
Medical Resource Utilization and Health Economics .................................................. 153 
8.11 
Leftover Biological Samples and Use of Data .............................................................. 154 
9 
Statistical Considerations ............................................................................................. 155 
9.1 
Statistical Hypotheses ................................................................................................... 155 
9.1.1 
Original Phase II Cohort ............................................................................................. 155 
9.1.2 
Evaluation of Booster Candidates in Supplemental Cohorts 1 and 2 ......................... 155 
9.2 
Sample Size Determination ........................................................................................... 167 
9.2.1 
Original Phase II Cohort of VAT00002 ..................................................................... 167 
9.2.2 
Supplemental Phase III Cohorts 1 and 2 .................................................................... 167 
9.3 
Analysis Sets ................................................................................................................. 172 
9.4 
Statistical Analyses ....................................................................................................... 176 
9.4.1 
General Considerations ............................................................................................... 176 
9.4.2 
Statistical Considerations ........................................................................................... 176 
9.5 
Interim Analyses ........................................................................................................... 180 
10 
Supporting Documentation and Operational Considerations .................................. 182 
10.1 
Appendix: Regulatory, Ethical, and Study Oversight Considerations .......................... 182 
10.1.1 
Regulatory and Ethical Considerations ...................................................................... 182 
10.1.2 
Financial Disclosure ................................................................................................... 183 
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10.1.3 
Informed Consent Process .......................................................................................... 183 
10.1.4 
Data Protection ........................................................................................................... 184 
10.1.5 
Dissemination of Clinical Study Data ........................................................................ 186 
10.1.6 
Data Quality Assurance .............................................................................................. 187 
10.1.7 
Source Documents ...................................................................................................... 187 
10.1.8 
Study and Site Start and Closure ................................................................................ 188 
10.1.9 
Publication Policy ....................................................................................................... 188 
10.2 
Appendix: Clinical Laboratory Tests ............................................................................ 188 
10.3 
Appendix: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................. 190 
10.3.1 
Definition of AE ......................................................................................................... 190 
10.3.2 
Definition of SAE ....................................................................................................... 193 
10.3.3 
Recording and Follow-Up of AE and/or SAE ............................................................ 194 
10.3.4 
Reporting of SAEs ...................................................................................................... 196 
10.3.5 
Assessment of Intensity .............................................................................................. 197 
10.4 
Appendix: Collection of Pregnancy Information .......................................................... 203 
10.5 
Appendix: Adverse Events of Special Interest (AESIs) ............................................... 205 
10.6 
Appendix: Risk-based Approach .................................................................................. 210 
10.7 
Appendix: Abbreviations .............................................................................................. 211 
10.8 
Appendix: Protocol Amendment/Update History ......................................................... 214 
11 
References ...................................................................................................................... 229 
12 
Sponsor Signature Page ................................................................................................ 234 
 
 
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List of Tables  
Table 1.1: Schedule of Activities for Original Phase II Cohort .................................................... 42 
Table 1.2: Schedule of Activities for Supplemental Cohorts 1 and 2 (Booster Arms Only) ........ 49 
Table 1.3: Schedule of Activities for Supplemental Cohorts Comparator Group ......................... 52 
Table 1.4: Schedule of Activities 2 (Follow-up of COVID-19-like Illness) for the Original 
Phase II Cohort and all Supplemental Phase III Cohorts .............................................................. 57 
Table 2.1: VAT00001 safety analysis set by injection group ....................................................... 66 
Table 2.2: Potential risks of clinical significance and risk management ...................................... 71 
Table 3.1: Objectives and endpoints ............................................................................................. 74 
Table 4.1: Overall design .............................................................................................................. 84 
Table 4.2: Planned Original Phase II Cohort sample size and approximate size of subsets ......... 91 
Table 4.3: Planned sample sizes for Supplemental Cohorts 1 and 2 ............................................. 93 
Table 4.4: Planned sample sizes for Supplemental Cohort 2 Exploratory B.1.351 Arms ............ 94 
Table 4.5: Approximate sample size of Supplemental Cohort subsets for variant testing in 
CMI/Mucosal/Variant Subset for Cohorts 1 and 2 ........................................................................ 94 
Table 4.6: GMTs and GMT ratios in non-naïve participants after 1 dose (D22) and naïve 
participants after 2 doses (D36) with the D614G pseudovirus neutralization assay 
(Monogram) in the 18-59 year old age group of VAT00002 (Populations, PPAS Naïve-
D01+D22, PPAS Non-naïve-D01+D22) ..................................................................................... 102 
Table 4.7: Comparison of ≥ 2-fold and ≥ 4-fold seroconversion rates with the D614G 
pseudovirus neutralization assay (Monogram) in non-naïve participants after 1 dose (D22) 
compared to naïve participants after 2 doses (D36) in the 18-59 year old age group of 
VAT00002 (Populations, PPAS Naïve-D01+D22, PPAS Non-naïve-D01+D22) ...................... 103 
Table 6.1: Identity of Original Phase II Cohort study interventions ........................................... 109 
Table 6.2: Identity of Monovalent (D614) study interventions ................................................... 111 
Table 6.3: Identity of Monovalent (B.1.351) study interventions ............................................... 113 
Table 6.4: Identity of Bivalent (D614 + B.1.351) study intervention ......................................... 116 
Table 8.1: Original Phase II Cohort: samples collected per visit ................................................ 129 
Table 8.2:  Participants in Supplemental Groups receiving a single booster dose: Cohort 1, 
Cohort 2 Main Arm, Cohort 2 Exploratory B.1.351 Arm: samples collected per visit ............... 130 
Table 8.3: Participants in Supplemental Cohorts Comparator Group receiving 2-dose 
schedule: samples collected per visit ........................................................................................... 131 
Table 8.4: COVID-19-like illness symptoms/conditions: CRF and Diary Card / Memory Aid 
terms ............................................................................................................................................ 141 
Table 9.1: Power estimations for Supplemental Cohorts 1 and 2 (18-55 years old) ................... 169 
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Table 9.2: Analysis set used in analyses ..................................................................................... 178 
Table 10.1: Protocol-required laboratory tests ............................................................................ 189 
Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales – 
Adults .......................................................................................................................................... 198 
Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales – 
Adults .......................................................................................................................................... 199 
Table 10.4: List of potential immune-mediated diseases (version: January-2022) ..................... 206 
 
 
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List of Figures  
Figure 1.1:  Graphical study design for Original Phase II Cohort ................................................. 37 
Figure 1.2: Graphical study design for Supplemental Cohorts 1 and 2 Booster Arms ................. 38 
Figure 1.3: Graphical study design for Supplemental Cohorts Comparator Group ...................... 39 
Figure 1.4: Follow-up of COVID-19-like illness for the Original Phase II Cohort and all 
Supplemental Phase III Cohorts .................................................................................................... 40 
Figure 9.1: Multiplicity adjustment strategy using Bonferroni and sequential testing method 
in Supplemental Cohort 1 and Supplemental Cohort 2 ............................................................... 156 
 
 
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1 
Protocol Summary  
1.1 
Synopsis  
Protocol Title: 
Immunogenicity and Safety of SARS-CoV-2 Recombinant Protein Vaccines with AS03 Adjuvant 
in Adults 18 Years of Age and Older as a Primary Series and Immunogenicity and Safety of a 
Booster Dose of SARS-CoV-2 Adjuvanted Recombinant Protein Vaccines (two Monovalent and 
one Bivalent) 
Brief Title: 
Study of Recombinant Protein Vaccines with Adjuvant as a Primary Series and as a Booster Dose 
against COVID-19 in 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 the declaration on 11 March 2020 of a 
pandemic (1). The virus has been detected in 222 countries/regions and led to significant 
morbidity, mortality, and economic impact (2).   
The clinical profile of COVID-19, the illness caused by SARS-CoV-2, is variable. In the majority 
of cases, the manifestations are mild or individuals may be asymptomatic (4). 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. While mostly self-limited, symptoms such as fatigue 
and dyspnea appear to persist up to 2 months after illness onset despite viral clearance (5). Based 
on early data, age over 50 years, chronic medical conditions, and race/ethnicity are important risk 
factors for severe outcomes and death due to COVID-19 (4) (6). A number of vaccine candidates 
in clinical development including viral vector-based vaccines, messenger ribonucleic acid 
(mRNA), protein subunit, and inactivated vaccines encoding the Spike (S)-protein of 
SARS-CoV-2 induce neutralizing antibodies. These include: 
• 2 COVID-19 mRNA vaccine candidates: 
o 
BNT162b2: International Non-Proprietary Name (INN)- COVID-19 mRNA vaccine 
(nucleoside-modified) from Pfizer/BioNTech (hereafter called Pfizer/BioNTech)  
o 
mRNA-1273: INN- COVID-19 mRNA vaccine (nucleoside modified) from Moderna 
(hereafter called Moderna) 
• 2 adenovirus-vectored vaccine candidates: 
o 
ChAdOx1-nCOV-19: INN- COVID-19 vaccine (ChAdOx1-S [recombinant]) vaccine 
from Oxford University/AstraZeneca (hereafter called Oxford 
University/AstraZeneca) 
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o 
Ad26.COV2-S: INN- COVID-19 vaccine (Ad26.COV2-S [recombinant]) from 
Johnson & Johnson/Janssen (hereafter called J&J/Janssen)  
These vaccine candidates have demonstrated efficacy against COVID-19 illness and severe 
disease in their Phase III clinical studies (7) (8) (9). Emergency authorization or other forms of 
regulatory approval have been granted in multiple countries for these as well as a number of other 
vaccines against COVID-19. 
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 S protein based 
on the work by Wrapp and colleagues (10). Sanofi Pasteur is applying the manufacturing 
technology used to produce recombinant influenza vaccine, which is commercialized in the 
United States (US) and the European Union (EU), to develop a vaccine that can be supplied at a 
large multi-national scale. The recombinant protein vaccine will be used in combination with an 
adjuvant system to optimize the immune response. AS03, an oil-in-water based adjuvant supplied 
by GlaxoSmithKline, will be utilized for this vaccine development. 
The safety and immunogenicity of the recombinant SARS-CoV-2 prefusion Spike delta TM 
(CoV2 preS dTM) vaccine adjuvanted with the AS03 or AF03 adjuvants was evaluated in the 
Phase I/II study (VAT00001) in healthy adults 18 years of age and older. The objective of the 
Phase I/II study was to inform dose selection, formulation choice and injection schedule selection 
for progression to Phase III. A low-dose and a high-dose antigen formulation, corresponding to an 
effective dose of 1.3 µg and 2.6 µg of CoV2 preS dTM antigen were evaluated in the study in 
combination with a fixed dose of either AS03 or AF03 adjuvant systems. Interim data showed 
that: 
• A 2-injection schedule of the adjuvanted protein was necessary to induce neutralizing 
antibodies. 
• The low-dose adjuvanted vaccine induced higher titers of neutralizing antibodies 
compared to high-dose unadjuvanted protein-alone vaccine demonstrating the benefit of 
the adjuvant. 
• The recombinant protein antigen adjuvanted with AS03 induced higher titers of 
neutralizing antibodies compared to both the AF03 adjuvanted group and compared to the 
unadjuvanted groups with a 2-injection schedule. 
• An antigen dose-response effect was observed with higher neutralizing antibody responses 
observed in the high-dose antigen groups compared to the low-dose antigen groups in the 
2-injection schedule adjuvanted arms. 
The high-dose group with AS03 administered in a 2-injection schedule induced the highest levels 
of neutralizing antibodies. However, even in the best performing vaccine group (2-injection 
schedule of high-dose + AS03), seroconversion rates were below 90% in all adults with lower 
rates in older adults (85% in 50 years of age and older, 62.5% in 60 years of age and older). The 
magnitude of neutralizing antibody responses was also lower in adults 50 years of age and older 
compared to that in the younger adult age group indicating the need for further optimization of the 
antigen formulation and dose (doses higher than the effective high dose of 2.6 µg of CoV2 preS 
dTM antigen are being evaluated in this Phase II study). In adjuvanted groups with the 2-injection 
schedule, there was no indication of a T-helper (Th)2 bias in the cell-mediated response with a 
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consistent elicitation of Interferon-gamma responses. At the interim analysis, no serious adverse 
events (SAEs) considered related to the vaccine were observed in any of the groups. Higher than 
expected Grade 3 reactogenicity was observed after the second injection in the adjuvanted groups. 
This reactogenicity profile was transient, self-limiting, non-serious, and did not lead to study 
withdrawal of any participant. This higher than expected reactogenicity is hypothesized to be due 
to higher than targeted content of Host-Cell Protein (HCP) in the Phase I/II clinical material. The 
lower than expected immunogenicity in combination with the higher than expected reactogenicity 
observed in the Phase I/II study indicates that assessment of optimized antigen formulations (with 
higher antigen dose and lower HCP content) is necessary to select a formulation to progress to 
Phase III evaluation.  
In addition, a nonclinical study in non-human primates (NHPs) (CoV2-04_NHP) using 
formulations with an effective antigen dose of 4 µg or 12 µg with AS03 adjuvant to assess 
efficacy against SARS-CoV-2 viral challenge was performed (11). Both vaccine doses conferred 
robust protection against viral replication in the lower and upper airways after a challenge with a 
virulent viral stock (NR-53780 BEI stock). Marked reduction of viral replication was 
demonstrated on D2 and D4, with a trend for a higher reduction in the high-dose vaccine group. 
The pathology and inflammation in the lungs induced by infection 7 days post-challenge was 
clearly reduced in the immunized rhesus macaques, and no increase in inflammatory cytokines or 
chemokines was observed. At both low and high doses, the AS03-adjuvanted vaccine elicited high 
humoral (binding, functional and neutralizing antibodies) and cellular (Th1/Th2 balanced 
S-specific cytokine responses and T follicular helper (Tfh) cells 2 weeks post-boost) responses. 
The high immunogenicity and efficacy demonstrated in rhesus macaques using 4 and 12 µg 
effective doses in this study supported the Original Phase II Cohort in this VAT00002 
dose-ranging clinical study assessing 5, 10, and 15 µg of CoV2 preS dTM vaccine antigen 
adjuvanted with AS03. 
Original Phase II Cohort 
The Original Phase II Cohort enrolled in VAT00002 corresponds to a Phase II, randomized, 
modified double-blind, multi-center, dose-finding study conducted in adults 18 years of age and 
older to evaluate the safety, reactogenicity, and immunogenicity of 2 injections of CoV2 preS 
dTM-AS03 adjuvanted vaccine (hereafter referred to as CoV2 preS dTM-AS03) administered by 
intramuscular (IM) route. In this study, 3 different antigen doses (effective doses of 5 µg, 10 µg, 
and 15 µg of CoV2 preS dTM monovalent D614 antigen) with a full dose of AS03 adjuvant are 
being evaluated. A 2-injection schedule with doses administered 21 days apart, as supported by 
data from the VAT00001 study, is being evaluated in the Original Phase II Cohort. 
Reactogenicity was assessed in all participants in this cohort by collecting solicited adverse events 
(AEs) for 7 days after each vaccination and unsolicited AEs through 21 days after the last 
vaccination. All participants are to provide information on SAEs, medically-attended adverse 
events (MAAEs), and adverse events of special interest (AESIs) for the duration of the study. 
Neutralizing and binding antibodies are to be assessed in all participants over multiple time points 
over the duration of the study. Cellular and mucosal responses are being assessed in a subset of 
participants. In addition, all episodes of COVID-19 will be collected over the duration of the 
study. 
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Interim safety, reactogenicity, and immunogenicity data from this Original Phase II Cohort 
informed the decisions to progress to a Phase III study and to select an antigen dose formulation 
for use in the Phase III. This interim analysis occurred after availability of reactogenicity data up 
to 21 days post-injection 2 and neutralizing antibody responses 14 days post-injection 2.  
Participants were to be categorized based on prior SARS-CoV-2 infection as naïve (not previously 
infected) and non-naïve (evidence of previous infection) determined serologically 
(Roche-Anti-N-Immunoassay and Roche Anti-S-Immunoassay) or virologically 
(Nucleic Acid Amplification Test [NAAT]). A naïve individual (no evidence of prior 
SARS-CoV-2 infection) is defined as being negative by the Anti-N-immunoassay and the 
Anti-S-immunoassay in serum sample(s) and a negative NAAT in a respiratory specimen at time 
of enrollment, while a non-naïve individual (evidence of prior SARS-CoV-2 infection) is defined 
as being positive by the Anti-N-immunoassay OR the Anti-S-immunoassay in serum sample(s) 
OR a positive NAAT in a respiratory specimen at time of enrollment. 
The immunogenicity and early safety of the candidate vaccine formulations has been established 
in the preliminary interim analysis recently completed. In naïve adults, a high proportion of 2-fold 
and 4-fold or greater rise in neutralizing antibody titers was observed after 2 injections in both 
younger and older adults with similar proportions observed across the different antigen dose 
groups. The magnitude of neutralizing antibody responses was higher in the 18 to 59 year old age 
groups compared to the ≥ 60 year old age groups at all antigen dosages. An increase in titers with 
an increase in antigen dose was observed in the 18 to 59 year old age group. A single injection in 
naïve adults did not generate meaningful neutralizing titers above background consistent with 
previous results in the Phase I/II study.  
In non-naïve adults, a single injection increased neutralizing antibody titers to levels above those 
observed after 2 injections in naïve adults in the overall study population. Based on these results, a 
total dose of ≤ 5 µg of S protein antigen was selected to be evaluated as booster vaccine 
candidates in the supplemental cohorts in this VAT00002 study. 
Supplemental Phase III Cohorts 
New, highly transmissible SARS-CoV-2 variants of concern have emerged and are spreading 
globally. The United Kingdom (UK) first identified a Variant of Concern called Alpha (B.1.1.7), 
which has been shown to be more transmissible and has since been detected in many other 
countries around the world (12). Other variants have emerged first identified in South Africa (Beta 
[B.1.351] variant), Brazil (Gamma [B.1.1.28 or P.1] variant), and India (Delta [B.1.617] variant) 
and have now been detected in other countries. A key question is whether currently authorized 
and available COVID-19 vaccines will be able to protect against infection or disease from these 
variants. Recent preliminary data using an adjuvanted protein sub-unit vaccine (Novavax) and the 
ChAdOx1 nCoV-19 vaccine (AZD1222 [Oxford University/AstraZeneca]) showed lower or no 
efficacy against mild to moderate COVID-19 in South Africa where Beta (B.1.351) predominated 
compared to higher efficacy observed for these vaccines in studies conducted in the UK (13) (14) 
(15) (9) (16). In a Phase III study of the Ad26CoV2.S vaccine (Johnson & Johnson/Janssen 
[J&J/Janssen]), significant efficacy was reported against moderate to severe-critical COVID-19 in 
South Africa where Beta (B.1.351) predominated during the surveillance period. These findings 
indicate that some prototype vaccines can confer meaningful protection against the Beta (B.1.351) 
variant, albeit lower than in settings where D614G and other variants predominated. Sera from 
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individuals immunized with prototype COVID-19 vaccines show an ability to neutralize the 
variants but to a lesser extent than the prototype strain. This decrease in neutralization is most 
notable against the Beta (B.1.351) variant which has a characteristic E484K mutation in the 
receptor-binding domain along with other mutations in the N-terminal domain of the S protein. 
These findings have led to the development of variant strain vaccines and regulatory guidance for 
the development of vaccines against the variant strains for products that have already 
demonstrated efficacy with the prototype vaccines (17). There has been particular emphasis on 
developing variant strain vaccines to protect against the Beta (B.1.351) variant. Ongoing evolution 
of SARS-CoV-2 variants, especially in light of the growing prevalence of vaccination and the 
selection pressure that this may exert raises the strong public health requirement for SARS-CoV-2 
vaccines, including those protective against emergent variants of concern. 
To address the emergence of variant strains, Sanofi Pasteur is developing monovalent and  
bivalent vaccines for use as a universal late booster and/or variant prime vaccines containing 
prototype D614 and/or the Beta (B.1.351) variants.  
Nonclinical studies were performed in NHP to document the CoV2 preS dTM-AS03 (D614) and 
variant vaccine formulations (monovalent B.1.351 and bivalent D614 + B.1.351) when used as a 
booster 7 months after a primary vaccination with different vaccine platforms. The role of AS03 
in potentiating the immune response was also evaluated as it is unknown if the adjuvant will be 
necessary in a boosting scenario.  
Vaccine encoding the Beta (B.1.351) variant was developed and the immunogenicity of a 
monovalent vaccine based on the B.1.351 Spike and a bivalent vaccine (D614 + B.1.351) was 
evaluated. A third immunization (booster) with monovalent (D614), monovalent (B.1.351) or 
bivalent (D614 + B.1.351) formulations, 7 months after a priming immunization with 
messenger ribonucleic acid (mRNA) or subunit vaccine, adjuvanted with AS03, was also 
evaluated (CoV2-07_NHP and CoV2-08_NHP). In order to address the risk of lower vaccine 
efficacy due to variants of concerns, vaccines containing the variant CoV2 preS dTM antigen 
(B.1.351) as a monovalent or bivalent (D614 + B.1.351) formulation were evaluated for 
immunogenicity and efficacy in a primary series given to naïve animals, and as a late booster 
given to NHPs previously vaccinated with subunit or mRNA COVID-19 vaccine candidates. 
In addition, the ability of the vaccine to elicit cross-neutralizing antibodies against Alpha 
(B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28 or P.1), Delta (B.1.617.2), and Epsilon (B.1.429), 
SARS-CoV-2 virus variants was evaluated in NHP samples using the lentivirus-based 
pseudo-neutralization assay.  
The nonclinical studies showed that the bivalent CoV2 preS dTM-AS03 (D614 + B.1.351) 
induced strong neutralizing antibody responses against the 4 variants of concern known to date: 
Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28 or P.1),and Delta (B.1.617.2) in naïve 
macaques. The benefit of a late booster dose with non-adjuvanted CoV2 preS dTM (B.1.351) or 
AS03-adjuvanted CoV2 preS dTM (D614), (B.1.351), or (D614 + B.1.351) was demonstrated in 
mRNA-primed and subunit-primed macaques. The booster vaccine induced very high neutralizing 
antibodies against the 4 variants of concern and robust neutralization of the distant SARS-CoV-1. 
Finally, preliminary data on efficacy in hamsters demonstrated that 2 doses of AS03-adjuvanted 
vaccine formulations (D614, B.1.351, and D614 + B.1.351) conferred protection against body 
weight loss caused by infection with the Beta (B.1.351) variant. 
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The Supplemental Phase III Cohorts of the VAT00002 study will be structured as follows:  
• Supplemental Cohort 1: adults 18 years of age and older who were vaccinated 
4 to < 10 months prior with an authorized/approved mRNA or adenovirus-vectored 
COVID-19 vaccine will be given Monovalent (D614) CoV2 preS dTM-AS03 (CoV2 preS 
dTM-AS03 [D614]) as a single booster injection.     
• Supplemental Cohort 2, Main Arms:  
o Adults 18 years of age and older who were vaccinated 4 to < 10 months prior with an 
authorized/approved mRNA or adenovirus-vectored COVID-19 vaccine will be 
randomized to receive a single booster injection of one of the following: 
▪ Monovalent (B.1.351) CoV2 preS dTM-AS03 (CoV2 preS dTM-AS03 [B.1.351]) 
▪ Bivalent (D614 + B.1.351) CoV2 preS dTM-AS03 (CoV2 preS dTM-AS03 [D614 
+ B.1.351]) 
o Adults 18 years of age and older who were vaccinated 4 to < 10 months prior with the 
protein-based vaccine in the Original Phase II Cohort will be randomized to receive a 
single booster injection of one of the following: 
▪ CoV2 preS dTM-AS03 (D614)  
▪ CoV2 preS dTM-AS03 (B.1.351) 
• Supplemental Cohort 2 Exploratory B.1.351 Arms: in these arms, different antigen 
doses of CoV2 preS dTM, monovalent B.1.351 (CoV2 preS dTM [B.1.351]) with and 
without adjuvants will be evaluated. Adults 18 years of age and older who received the 
Pfizer/BioNTech vaccine 4 to < 10 months prior will be randomized to receive a single 
booster injection of one of the following CoV2 preS dTM-AS03 (B.1.351) formulations: 
o 2.5 µg antigen with AS03 adjuvant 
o 2.5 µg antigen with half-dose AS03a adjuvant 
o 5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with no adjuvant 
• Supplemental Cohorts Comparator Group: SARS-CoV-2-naïve, unvaccinated, adults 
who are 18-55 years of age will be given CoV2 preS dTM-AS03 (D614) as a primary 
series vaccination of 2 injections given 21 days apart.      
• Supplemental Cohorts Subsets and Assessment of Immunogenicity to Emerging 
Variants of Concern: A randomized subset of 70 participants in Cohort 1 will be tested 
for additional SARS-CoV-2 variants of concern including Delta. No additional sample 
collection, procedures, or visits are required for this subset. A randomized subset of 
82 participants in Cohort 2 comprised of younger adults (18 to 55 years of age) will 
provide samples for cellular immune response and mucosal antibody assessments and will 
also be tested for additional variants of concern including Delta. 
                                                 
a The half dose of AS03 and the full dose of AS03 contain amounts of tocopherol of 5.93 mg and 11.86 mg, 
respectively 
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Objectives and Endpoints: 
Primary Safety (applicable to Original Phase II Cohort as well as Supplemental Phase III Cohorts) 
To assess the safety profile of all participants in 
each age group and in each study Intervention 
Group. 
• 
Presence of unsolicited systemic AEs reported in the 
30 minutes after each vaccination 
• 
Presence of solicited (pre-listed in the participant’s diary 
card [DC] and [electronic] Case Report Form [CRF]) 
injection site reactions and systemic reactions occurring 
up to 7 days after each vaccination  
• 
Presence of unsolicited AEs reported up to 21 days after 
the last vaccination  
• 
Presence of serious adverse events (SAEs) throughout the 
study 
• 
Presence of AESIs throughout the study 
• 
Presence of MAAEs throughout the study 
Primary Immunogenicity-Original Phase II Cohort 
To assess the neutralizing antibody profile 14 days 
after the last vaccination (D36) in SARS-CoV-2-
naïve adults in each study Intervention Group.  
Neutralizing antibody titers will be measured in SARS-CoV-
2-naïve participants for each study Intervention Group against 
the D614G variant. 
• 
Individual serum neutralizing titer at D01 and D36 
• 
Individual serum neutralization titer fold-rise 
post-vaccination relative to D01 at D36 
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D36 relative to D01 
• 
Responders in SARS-CoV-2 naive, defined as 
participants who had baseline values below lower limit of 
quantification (LLOQ) with quantifiable neutralization 
titer above assay LLOQ at D36  
Primary Immunogenicity-Supplemental Cohort 1  
Co-primary objectives: 
1) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is non-
inferior to the response induced by a two‑dose 
priming series with the CoV2 preS dTM-AS03 
(D614) vaccine in naïve, previously 
unvaccinated individuals. 
2) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is superior to 
that observed immediately before booster.  
Neutralizing antibody titers will be measured for each study 
Intervention Group against the D614G strain. 
• 
Individual serum neutralizing titer at D01 and D15 
(Intervention Group) 
• 
Individual serum neutralizing titer at D36 (Comparator 
Group) 
 
 
Primary Immunogenicity-Supplemental Cohort 2 
Co-primary objectives: 
1) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine  that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
• 
Individual serum neutralizing titer at D01 and D15 
against the B.1.351 variant for the CoV2 preS dTM-AS03 
(B.1.351) vaccine and the CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine Intervention Groups. 
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vaccine induces an immune response that is 
non-inferior to the response induced by a 
two-dose priming series with the CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated individuals. 
2) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response that is 
superior to that observed immediately before 
booster.  
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain for the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Group. 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Secondary Immunogenicity-Original Phase II Cohort  
1) To assess the neutralizing antibody profile at 
D22, D78, D134, D202, D292, and D387 in 
SARS-CoV-2 naïve adults in each study 
Intervention Group. 
2) To assess the neutralizing antibody profile at 
D01, D22, D36, D78, D134, D202, D292, and 
D387 in each study Intervention Group for 
SARS-CoV-2 non-naïve participants. 
3) To assess the binding antibody profile at D01, 
D22, D36, D78, D134, D202, D292, and D387 
in each study Intervention Group in SARS-
CoV-2 naïve and non-naïve participants.  
Endpoints for secondary immunogenicity objectives #1 and 
#2: 
Neutralizing antibody titers will be measured in participants 
for each study Intervention Group against the D614G variant. 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise 
post-vaccination relative to D01 at each pre-defined time 
point  
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined post-
vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Endpoints for secondary immunogenicity objective #3: 
Binding antibody concentrations will be measured in 
participants for each study Intervention Group against the 
D614G variant. 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold-rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined post-
vaccination timepoint 
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Secondary Immunogenicity-Supplemental Cohort 1 
Conditional secondary objectives: conditional on 
meeting the primary objectives for Supplemental 
Cohort 1: 
1) To demonstrate, in adults 18-55 years of age, 
previously vaccinated with the CoV2 preS 
dTM-AS03 (D614) vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is noninferior 
to the response induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
2) To demonstrate, in adults 18-55 years of age, 
previously vaccinated with CoV2 preS dTM-
AS03 (D614) vaccine, that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
an immune response that is superior to that 
observed immediately before booster.  
Conditional secondary objectives: conditional on 
meeting the conditional secondary objectives (1) 
and (2) for Supplemental Cohort 1: 
3) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces an immune 
response that is non-inferior to the response 
induced by a two-dose priming series with 
CoV2 preS dTM-AS03 (D614) vaccine in 
naïve, previously unvaccinated individuals. 
4) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces an immune 
response that is superior to that observed 
immediately before booster. 
 
Conditional secondary objectives: conditional on 
meeting the conditional secondary objectives (3) 
and (4) for Supplemental Cohort 1: 
5) To demonstrate, in adults 18-55 years of age 
previously vaccinated with an 
adenovirus-vectored COVID-19 vaccine, that a 
booster dose of CoV2 preS dTM-AS03 (D614) 
vaccine induces an immune response that is 
non-inferior to the response induced by a 
two‑dose priming series with CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated, individuals.  
6) To demonstrate, in adults 18-55 years of age 
previously vaccinated with adenovirus-vectored 
COVID-19 vaccines, that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
Endpoints for conditional secondary objectives #1 and #2: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (group primed with CoV2 preS 
dTM-AS03 [D614] vaccine) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
 
Endpoints for conditional secondary objectives #3 and #4: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (groups primed with mRNA 
COVID-19 vaccines) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Endpoints for conditional secondary objectives #5 and #6: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (group primed with 
adenovirus-vectored COVID-19 vaccine) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Endpoints for secondary objectives #7 - #10: 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain, at D15 relative to D01, in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain, at D36 relative to D01 (Comparator Group) 
Endpoints for secondary objectives #11 - #14: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
Endpoints for secondary objective #15: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 to 
B.1.351 variant in the Comparator Group 
Endpoints for secondary objective #16: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
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an immune response that is superior to that 
observed immediately before booster. 
Conditional secondary objective: conditional on 
meeting the conditional secondary objectives (5) 
and (6) for Supplemental Cohort 1, the following 
objectives will be sequentially tested: 
7) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
a seroresponse that is non-inferior to the 
seroresponse induced by a two‑dose priming 
series with the CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
8) To demonstrate, in adults 18-55 years of age 
previously vaccinated with the CoV2 preS 
dTM-AS03 (D614) vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces a seroresponse that is noninferior to the 
seroresponse induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
9) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces a 
seroresponse that is non-inferior to the 
seroresponse induced by a two-dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
10) To demonstrate, in adults 18-55 years of age 
previously vaccinated with an adenovirus-
vectored COVID-19 vaccine, that a booster 
dose of CoV2 preS dTM-AS03 (D614) vaccine 
induces a seroresponse that is noninferior to the 
seroresponse induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
Secondary objectives: 
11) To describe, in adults 18-55 years of age 
previously vaccinated with the Moderna 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
12) To describe, in adults 18-55 years of age 
previously vaccinated with the 
Oxford/AstraZeneca vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (D614) vaccine.  
• 
Individual serum neutralizing titer at D01 and D36 
against the D614G strain in the Comparator Group 
Endpoints for secondary objective #17:  
• 
Individual serum neutralizing titer to the D614G strain 
and B.1.351 variant in each Intervention Group at each 
pre-defined timepoint 
• 
Individual serum neutralization titer fold-rise post-
vaccination to the D614G strain and B.1.351 variant at 
each pre-defined timepoint relative to D01 in each 
Intervention Group  
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) to the D614G strain and 
B.1.351 variant at each pre-defined timepoint relative to 
D01 in each study Intervention Group 
Endpoints for secondary objective #18: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objective #19: 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point relative to D01 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
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13) To describe, in adults 18-55 years of age 
previously vaccinated with the J&J/Janssen 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
14) To describe, in adults 18-55 years of age 
previously vaccinated with any COVID-19 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
15) To compare the neutralizing antibody profile to 
the B.1.351 variant at D01 and D15 in the 
booster groups and at D36 in the Comparator 
group. 
16) To compare the neutralizing antibody profile to 
the B.1.351 variant at D01 and D15 in the 
booster groups and neutralizing antibody 
profile to the D614G strain at D36 in the 
Comparator Group. 
17) To assess the neutralizing antibody profile to 
the D614G strain and to the B.1.351 variant at 
D29, D91, D181, and D366 overall, and by age 
group, by priming platform, and by priming 
vaccine. 
18) To describe the neutralizing antibody profile to 
the B.1.351 variant and to the D614G strain at 
D01 and D15 in adults older than 55 years of 
age in the booster group, overall, by priming 
platform, and by priming vaccine. 
19) To assess the binding antibody profile at D01, 
D15, D29, D91, D181, and D366 after booster 
immunization in adults previously vaccinated 
with COVID-19 vaccines, overall and by age 
group, by priming platform, and by priming 
vaccine. 
vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined 
post-vaccination timepoint 
Secondary Immunogenicity-Supplemental Cohort 2 
Conditional co-secondary objectives: conditional on 
meeting the primary immunogenicity objectives for 
Supplemental Cohort 2: 
1) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine induces 
an immune response that is non-inferior to the 
response induced by a two-dose priming series 
with CoV2 preS dTM-AS03 (D614) vaccine in 
naïve, previously unvaccinated individuals. 
2) To demonstrate in adults 18-55 years of age 
and previously vaccinated with an mRNA 
COVID-19 vaccine, that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response that is 
superior to that observed immediately before 
booster. 
Endpoints for conditional secondary objectives #1 and #2: 
• 
Individual serum neutralizing titer at D01 and D15 
against the B.1.351 variant for the CoV2 preS dTM-AS03 
(B.1.351) vaccine and the CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine Intervention Groups. 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain for the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Group. 
• 
Individual serum neutralizing titer against the D614 strain 
at D36 (Comparator Group) 
Endpoints for conditional secondary objectives #3: 
• 
Individual serum neutralizing titer at D15 against the 
B.1.351 variant for the CoV2 preS dTM-AS03 (B.1.351) 
vaccine and the CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine Intervention Groups  
• 
Individual serum neutralizing titer at D36 against the 
B.1.351 variant for the Comparator Group 
Endpoints for secondary objectives #4 - #5: 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
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Conditional secondary objective: conditional on 
meeting the primary immunogenicity objectives (1) 
and (2) and the co-secondary objectives for 
Supplemental Cohort 2: 
3) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response against 
the B.1.351 variant at D15 that is superior to 
that against the B.1.351 variant at D36 in the 
Comparator Group. 
Conditional secondary objectives: conditional on 
meeting the conditional secondary objective (3) for 
Supplemental Cohort 2, the following objectives 
will be sequentially tested: 
4) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces a seroresponse that is non-
inferior to the seroresponse induced by a 
two‑dose priming series with the CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated individuals. 
5) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine induces a 
seroresponse that is non-inferior to the 
seroresponse induced by a two-dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
Secondary objectives: 
6) To describe, in adults 18-55 years of age and 
previously vaccinated with an adenovirus-
vectored COVID-19 vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine compared to 
the response induced by a two dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
7) To describe, in adults 18-55 years of age and 
previously vaccinated with an adenovirus-
vectored COVID-19 vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
D01, against the B.1.351 variant for the CoV2 preS dTM-
AS03 (B.1.351) vaccine and the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Groups 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain for the CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine Intervention Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain at D36 relative to D01 (Comparator Group) 
Endpoints for secondary objectives #6 - #11: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain and to the B.1.351 variant in 
each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain and to the B.1.351 variant in each Intervention 
Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain and to the B.1.351 variant in 
each study Intervention Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain and to the B.1.351 variant 
in each study Intervention Group 
Endpoints for secondary objective #12: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 to the 
B.1.351 variant in the Comparator Group 
Endpoints for secondary objective #13: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 
against the D614G strain in the Comparator Group 
Endpoints for secondary objective #14: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
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AS03 (D614 + B.1.351) vaccine compared to 
that observed immediately before booster. 
8) To describe, in adults 18-55 years of age 
previously vaccinated with the Moderna 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine. 
9) To describe, in adults 18-55 years of age 
previously vaccinated with the 
Oxford/AstraZeneca vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine. 
10) To describe, in adults 18-55 years of age 
previously vaccinated with the J&J/Janssen  
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine. 
11) To describe, in adults 18-55 years previously 
vaccinated with any COVID-19 vaccine, the 
immune response a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine. 
12) To compare the neutralizing antibody profile to 
the B.1.351 variant at D15 in each study 
Intervention Group and D36 in the Comparator 
Group, overall, by priming platform, and by 
priming vaccine. 
13) To compare the neutralizing antibody profile 
against the D614G strain at D15 following a 
booster dose of CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine and at D36 in the 
Comparator Group. 
14) To describe, among adults previously primed 
with CoV2 preS dTM-AS03 (D614) vaccine, 
the immune response induced by a booster dose 
of  CoV2 preS dTM-AS03 (D614) vaccine or 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine, overall, by priming dose, and by age. 
15) To assess the neutralizing antibody profile to 
the D614G strain at D29, D91, D181, and 
D366 in each study Intervention Group, 
overall, by age group, by priming platform, and 
by priming vaccine. 
16) To assess the neutralizing antibody to the 
B.1.351 variant at D29, D91, D181, and D366 
in each study Intervention Group, overall, by 
age group, by priming platform, and by 
priming vaccine. 
17) To describe, in adults over 55 years of age, the 
neutralizing antibody profile to the B.1.351 
variant and to the D614G strain at D01 and 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objectives #15 and #16: 
neutralizing responses to be evaluated against the D614G 
strain and to the B.1.351 variant 
• 
Individual serum neutralizing titers in each Intervention 
Group at each pre-defined timepoint 
• 
Individual serum neutralization titer fold-rise post-
vaccination at each pre-defined timepoint relative to D01 
in each Intervention Group  
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined 
timepoint relative to D01 in each study Intervention 
Group 
Endpoints for secondary objective #17: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
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D15 by Intervention Group, overall, by priming 
platform, and by priming vaccine. 
18) To describe in adults previously vaccinated 
with the Pfizer/BioNTech vaccine the immune 
response (as assessed by pseudovirus 
neutralization assay geometric mean titers and 
geometric mean titer ratios) to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine 
exploratory formulations, overall and by age 
stratum. 
19) To assess the binding antibody profile at D01, 
D15, D29, D91, D181, and D366 after booster 
immunization in adults previously vaccinated 
with COVID-19 vaccines, overall and by age 
group, by priming platform, and by priming 
vaccine. 
Endpoints for secondary objective #18: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objective #19: 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined post-
vaccination timepoint 
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Secondary Safety-Original Phase II Cohort 
1) To describe the occurrences of laboratory-
confirmed symptomatic COVID-19 in all 
participants in each study Intervention Group. 
2) To describe the occurrences of serologically-
confirmed SARS-CoV-2 infection in each 
study Intervention Group. 
Endpoints for secondary safety objective #1: 
• 
Occurrences of laboratory-confirmed symptomatic 
COVID-19 (based on locally-confirmed or 
protocol-defined NAAT) 
• 
Occurrences of symptomatic COVID-19 episodes 
associated with hospitalization. 
• 
Occurrences of severe symptomatic COVID-19 
• 
Death associated with symptomatic COVID-19 
Endpoints for secondary safety objective #2: 
• 
Occurrences of serologically-confirmed SARS-CoV-2 
infection 
Secondary Safety-Supplemental Cohorts 1 and 2 
To describe the occurrences of laboratory-
confirmed symptomatic COVID-19, overall and in 
each study Intervention Group 
• 
Occurrences of laboratory-confirmed symptomatic 
COVID-19 (based on locally-confirmed or 
protocol-defined NAAT) 
• 
Occurrences of symptomatic COVID-19 episodes 
associated with hospitalization. 
• 
Occurrences of severe symptomatic COVID-19 
• 
Death associated with symptomatic COVID-19 
Exploratory Immunogenicity-Original Phase II Cohort  
1) To describe the ratio between neutralizing 
antibodies and binding antibodies. 
2) To assess the T-cell cytokine profile at D01, 
D22 and D36 in a subset of participants. 
3) To further assess the cellular immune response 
at D01, D22, D36, D134 and D387 in a subset 
of participants. 
4) To assess the mucosal antibody response at 
D01, D22, D36, and D134 in a subset of 
participants. 
5) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains  
Endpoint for exploratory immunogenicity objective #1: 
• 
Ratio between binding antibody (enzyme-linked 
immunosorbent assay [ELISA]) concentration and 
neutralizing antibody titer 
Endpoint for exploratory immunogenicity objective #2: 
• 
T-helper cell (Th)1 and Th2 cytokines measured in whole 
blood following stimulation with full-length S protein at 
D01, D22 and D36. 
Endpoint for exploratory immunogenicity objective #3: 
• 
Other cellular-mediated immunity (CMI) assessments 
may be performed by Intracellular Cytokine Staining 
or/and enzyme-linked immunospot (ELISpot) assays. 
Endpoints for mucosal antibody responses (objective #4) will 
be specified in a supplemental analysis plan. 
Endpoints for exploratory immunogenicity objective #5: 
• 
Neutralizing antibody responses to emergent variant 
strains will be measured in participants for each study 
Intervention Group: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined post-
vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
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LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Exploratory Immunogenicity-Supplemental Cohorts 
Supplemental Cohorts 1 and 2: 
1) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains 
2) To further describe humoral immune responses 
based on relevant emerging assays, if 
applicable 
Supplemental Cohort 2: 
3) To assess the cellular immune response at D01, 
D15, D29, D91, and D366 in a subset of 
participants. 
4) To assess the mucosal antibody response at 
D01, D15, and D91 in a subset of participants. 
5) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains 
6) To further describe humoral immune responses 
based on relevant emerging assays, if 
applicable 
Supplemental Cohorts 1 and 2: 
7) To describe the neutralizing antibody response, 
by presence or absence of baseline high-risk 
medical conditions 
 
 
Endpoints for exploratory immunogenicity objective #1 and 
#5: 
Neutralizing antibody responses to emergent variant strains 
will be measured: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] at each pre-defined post-vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Endpoint for exploratory immunogenicity objective #2 and 
#6: 
• 
Biomarker measurement at baseline and/or post-
vaccination visits 
Endpoint for exploratory immunogenicity objective #3: 
• 
Other CMI assessments may be performed by 
Intracellular Cytokine Staining or/and enzyme-linked 
immunospot (ELISpot) assays. 
Endpoint for mucosal antibody responses (objective #4) will 
be specified in a supplemental analysis plan 
Endpoints for exploratory immunogenicity objective #7: 
Neutralizing antibody responses to D614G and B.1.351 strains 
will be measured: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] at each pre-defined post-vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
 
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Overall Design 
Type of design 
Parallel, multi-center 
Phase 
II/III 
Control method (for Supplemental 
Phase III Cohorts only) 
active comparator  
(comparator = CoV2 preS dTM-AS03 [D614] administered as a 
2-injection primary series) 
Study population 
Adults 18 years of age and older 
Countries 
Original Phase II Cohort: United States, Honduras  
Supplemental Phase III Cohorts: to be determined (TBD) 
Level and method of blinding 
Original Phase II Cohort: Modified double-blind 
(observer-blind) 
• 
Blinding for vaccine group assignment: participants, outcome 
assessors, Investigators, laboratory personnel, Sponsor study 
staff, those administering the study intervention if not involved 
in preparing study intervention 
• 
No blinding for vaccine group assignment: those preparing the 
study interventions 
Supplemental Phase III Cohorts: 
• 
Supplemental Cohorts Comparator Group will be open-label. 
• 
Supplemental Cohort 1 Booster Group will be open-label. 
• 
Supplemental Cohort 2 will involve sequential randomization 
to main arms (CoV2 preS dTM-AS03 [D614], CoV2 preS 
dTM-AS03 [B.1.351], and CoV2 preS dTM-AS03 [D614 + 
B.1.351]) followed by randomization to exploratory CoV2 
preS dTM-AS03 (B.1.351) arms after filling the former. 
Intervention and exploratory groups will be modified double-
blind (observer-blinded) as described 
Study intervention assignment 
method 
Participants will be screened for eligibility criteria at the time of 
inclusion. 
Original Phase II Cohort: 
The randomization was stratified by age groups (18-59 years of 
age and 60 years of age and older), baseline SARS-CoV-2 rapid 
serodiagnostic test positivity (Positive/Negative), and high-risk 
medical conditions (Yes/No). 
Eligible participants were randomly assigned to one of 3 study 
groups in a 1:1:1 ratio, corresponding to one of 3 formulations of 
CoV2 preS dTM-AS03 vaccine (with different antigen doses). 
Supplemental Phase III Cohorts: 
• 
Supplemental Cohort 1: previously-vaccinated participants 
will be stratified based on the priming vaccine received 
4 to < 10 months prior and by age group (18-55 years of age 
and 56 years of age and older) and will receive a single booster 
dose of CoV2 preS dTM-AS03 (D614).  
• 
Supplemental Cohort 2, Main Arms:  
Participants previously vaccinated with an 
authorized/approved mRNA or adenovirus-vectored 
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COVID-19 vaccine will be stratified based on the vaccine 
received 4 to < 10 months prior and by age group (18-55 years 
of age and 56 years of age and older) and randomly assigned 
to 1 of the following booster formulations in a 1:1 ratio: 
o CoV2 preS dTM-AS03 (B.1.351) 
o CoV2 preS dTM-AS03 (D614 + B.1.351) 
Participants previously vaccinated with CoV2 preS 
dTM-AS03 (D614) as a primary series in the Original Phase II 
Cohort will be stratified by age group (18-55 years of age and 
56 years of age and older) and randomly assigned to 1 of the 
following booster formulations in a 9:1 ratio for younger 
adults (D614:B.1.351) and a 1:1 ratio for older adults:  
o CoV2 preS dTM-AS03 (D614) 
o CoV2 preS dTM-AS03 (B.1.351) 
• 
Supplemental Cohort 2 Exploratory B.1.351 Arms: 
Participants previously vaccinated with the Pfizer/BioNTech 
mRNA vaccine will be enrolled after completion of enrollment 
of the above booster arms in Cohort 2 and will be stratified by 
age group (18-55 years of age and 56 years of age and older) 
and randomly assigned to receive 1 of the following CoV2 
preS dTM (B.1.351) formulations in a 1:1:1:1 ratio: 
o 2.5 µg antigen with AS03 adjuvant 
o 2.5 µg antigen with half-dosea AS03 adjuvant 
o 5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with no adjuvant 
• 
Supplemental Cohorts Comparator Group: SARS-CoV-2-
naïve, unvaccinated, adults who are 18-55 years of age will be 
given CoV2 preS dTM-AS03 (D614) as a primary series 
vaccination of 2 injections given 21 days apart.      
• 
Supplemental Cohort Subsets and Assessment of 
Immunogenicity to Emerging Variants of Concern: A 
randomized subset of 70 participants in Cohort 1 will be tested 
for additional SARS-CoV-2 variants of concern including 
Delta. No additional sample collection, procedures, or visits 
are required for this subset. A randomized subset of 
82 participants in Cohort 2  comprised of younger adults (18 to 
55 years of age) will provide samples for cellular immune 
response and mucosal antibody assessments and will also be 
tested for additional variants of concern including Delta. 
Disclosure Statement: 
Original Phase II Cohort and Supplemental Cohort 2 Intervention Groups:  Participants, outcome 
assessors, Investigators, laboratory personnel, Sponsor study staff, and those administering the 
study intervention if not involved in preparing the study intervention will be blinded to 
                                                 
a  The half dose of AS03 and the full dose of AS03 contain amounts of tocopherol of 5.93 mg and 11.86 mg, 
respectively 
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Intervention Group; and those preparing the study interventions will be unblinded to vaccine 
assignment group. This does not apply to the Supplemental Cohort 1 Booster Group and the 
Supplemental Cohorts Comparator Group which will be open-label. 
Number of Participants: 
Original Phase II Cohort: A total of 720 participants were planned to be enrolled. After 
stratification by age-group (18-59 years and ≥ 60 years), baseline SARS-CoV-2 rapid 
serodiagnostic test positivity (Positive/Negative [as determined at the time of enrollment]) and 
high-risk medical conditions (Yes/No), participants will be randomly assigned to the study 
groups. 
For all study arms, half of the participants were to be 18-59 years of age and half of the 
participants were to be 60 years of age or older. Additionally, up to 20% of participants in each 
study group were allowed to be test-positive on the rapid serodiagnostic test at enrollment. A 
randomized subset of 120 rapid diagnostic test-negative participants stratified by age-group 
(20 participants/study group/age-group) was to provide samples for cellular immune response and 
mucosal antibody assessments. 
Supplemental Phase III Cohorts: A total of approximately 3660 participants are planned to be 
enrolled and will be stratified as follows: 
Supplemental Cohort 1: Adults vaccinated 4 to < 10 months prior will be stratified by primary 
vaccine and by age to receive a single booster dose of CoV2 preS dTM-AS03 (D614):  
• Primed with Pfizer/BioNTech: 
o 18-55 years of age: 215 participants 
o 56 years of age and older: 50 participants 
• Primed with Moderna: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• Primed with Oxford University/AstraZeneca: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• Primed with J&J/Janssen: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
Supplemental Cohort 2, Main Arms: Adults vaccinated 4 to < 10 months prior will be stratified 
by primary vaccine and by age and randomized to receive 1 of the following as a single booster 
dose: 
• Primed with Pfizer/BioNTech: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 515 participants 
▪ 56 years of age and older: 50 participants 
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o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 515 participants 
▪ 56 years of age and older: 50 participants 
• Primed with CoV2 preS dTM-AS03 (actual numbers will depend on eligibility and 
consent for Cohort 2 participation of participants enrolled in the Original Phase II Cohort; 
numbers below are estimates and subject to change): 
o CoV2 preS dTM-AS03 (D614): 
▪ 18-55 years of age: 270 participants 
▪ 56 years of age and older: 75 participants 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 30 participants 
▪ 56 years of age and older: 75 participants 
• Primed with Moderna: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
• Primed with Oxford University/AstraZeneca: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
• Primed with J&J/Janssen: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
Supplemental Cohort 2 Exploratory B.1.351 Arms: Adults vaccinated 4 to < 10 months prior 
with the Pfizer/BioNTech mRNA vaccine will be stratified by age and randomized to receive a 
single booster dose of 1 of the following CoV2 preS dTM (B.1.351) formulations: 
• 2.5 µg antigen with full-dose AS03 adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 2.5 µg antigen with half-dose AS03 adjuvant: 
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o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 5 µg antigen with half-dose AS03 adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 5 µg antigen with no adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
Supplemental Cohorts Comparator Group: SARS-CoV-2-naïve, unvaccinated, adults will be 
enrolled into a parallel, non-randomized arm and receive CoV2 preS dTM-AS03 (D614) as a 
primary series vaccination of 2 injections given 21 days apart: 
• 18-55 years of age only: 515 participants 
Supplemental Cohorts Subsets and Assessment of Immunogenicity to Emerging Variants of 
Concern: A randomized subset of 70 participants in Cohort 1 will be tested for additional 
SARS-CoV-2 variants of concern including Delta. No additional sample collection, procedures, or 
visits are required for this subset. A randomized subset of 82 participants in Cohort 2 comprised 
of younger adults (18 to 55 years of age) will provide samples for cellular immune response and 
mucosal antibody assessments and will also be tested for additional variants of concern including 
Delta. 
Intervention Groups and Duration for Original Phase II Cohort: 
Planned primary series sample size and approximate size of subsets 
 
Study Intervention Groups 
 
Group 1 
Group 2 
Group 3 
 
CoV2 preS 
dTM-AS03  
(5 µg antigen) 
CoV2 preS 
dTM-AS03 
(10 µg antigen) 
CoV2 preS 
dTM-AS03 
(15 µg antigen) 
Total Overall 
240 
240 
240 
SARS-CoV-2 
serodiagnostic test at 
baseline 
Negative 
At least 192* 
At least 192* 
At least 192* 
Positive 
Up to 48† 
Up to 48† 
Up to 48† 
Age Groups 
Adults (18-59 years) 
120 
120 
120 
Older adults (≥ 60 years) 
120 
120 
120 
Cellular Immunity and Mucosal subset‡ 
40 
(20/age group) 
40 
(20/age group) 
40 
(20/age group) 
* 96 per age group 
† up to 24 per age group 
‡ Participants SARS-CoV-2 serodiagnostic test negative at baseline would be randomized to this subset. 
All participants in the Original Prime Cohort primary series were to receive 2 vaccine injections 
given at 3 weeks apart: the first injection will be at D01 (Vaccination [VAC] 1) and the second 
injection will be at D22 (VAC2). Blood samples were planned to be collected from all participants 
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prior to each injection, 14 days, 2 months, 4 months, 6 months, 9 months, and 12 months after last 
injection. Blood samples collected from all participants will be used for serological assessments in 
the study. Whole blood, peripheral blood mononuclear cells (PBMCs), and saliva samples will be 
collected from a subset of participants to assess cellular immune responses and mucosal antibody 
responses. Participants were asked to inform Investigators if they seek vaccination of an 
authorized/approved vaccine.  
All participants will be followed for the duration of the study to capture occurrences of 
COVID-19 through passive surveillance wherein participants will be instructed to contact the site 
if they experience symptoms/conditions of a COVID-19-like illness at any time during the study. 
In addition, active surveillance will be undertaken in all participants wherein all participants will 
be contacted once every 2 weeks starting after the D43 contact to enquire about development of 
COVID-19-like illness. 
The duration of participation in the Original Phase II Cohort will be approximately 365 days 
post-injection 2 (ie, approximately 386 days total).  
In the event that the vaccine formulation evaluated in this study is deemed safe and effective by 
regulatory authorities, this authorized/approved vaccine may be offered to eligible participants in 
this study who received a formulation considered less effective to that authorized by the 
regulatory authorities, if permitted by local regulations and in alignment with local 
recommendations. 
If an approved/authorized vaccine is available in the country or region where the study is 
conducted, Investigators were to discuss this information with prospective study participants at the 
time of informed consent to encourage them to obtain the approved/authorized vaccine if 
applicable to them. Recruitment of eligible participants will proceed only if, despite 
encouragement, the candidate participant expressed no intention to seek an authorized or approved 
vaccine at least until completion of the key follow-up timepoint (D43) for informing progression 
to Phase III and dose selection. 
If the participant is enrolled and seeks vaccination of an authorized/approved vaccine outside of 
the study, he/she will be encouraged to discuss this intention proactively with the study 
Investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved 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. If the visit occurs more than 1 month after the D134 visit, a PBMC sample will also 
be collected if the participant is in the cellular immunity and mucosal subset instead of the D387 
sample. Participants will not receive the second vaccination if they have received the 
authorized/approved vaccine between the first and second scheduled vaccination. 
If a participant elects to transition from the Original Phase II Cohort to Supplemental Cohort 2, 
the participant should be scheduled to complete the next  planned visit. Enrollment (V01) to the 
Supplement Cohort may be performed on another day, to be scheduled as soon as possible after 
the Original Phase II Cohort visit. All required procedures for the Original Cohort visit and the 
Supplemental Cohort 2 visit should be conducted for each visit, respectively. 
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Intervention Groups and Duration for Supplemental Phase III Cohorts: 
Planned sample sizes for Supplemental Cohorts 1 and 2 
 
Cohort 1 
Cohort 2 Main Arms 
Comparator 
 
Booster 
Booster 
Booster 
Booster 
Primary 
Series 
 
CoV2 preS 
dTM-AS03 
(D614) 
 
CoV2 preS 
dTM-AS03 
(B.1.351) 
 
CoV2 preS 
dTM-AS03 
(D614 + 
B.1.351) 
CoV2 preS 
dTM-AS03 
(D614) 
 
CoV2 preS 
dTM-AS03 
(D614) 
 
Total Overall 
565 
970 
865 
345 
515 
SARS-CoV-2-naïve, Unvaccinated, 
Adults (18-55 years) 
-- 
-- 
-- 
-- 
515 
Pfizer/BioNTech 
Adults (18-
55 years) 
215 
515 
515 
-- 
-- 
Older 
adults 
(≥ 56 years) 
50 
50 
50 
-- 
-- 
CoV2 preS 
dTM-AS03 
(Original Phase II 
Cohort participants) 
Adults (18-
55 years) 
-- 
30 
-- 
270 
-- 
Older 
adults 
(≥ 56 years) 
-- 
75 
-- 
75 
-- 
Moderna 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older 
adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
Oxford University/ 
AstraZeneca 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older 
adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
J&J/Janssen 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older 
adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
 
 
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Planned sample sizes for Supplemental Cohort 2 Exploratory B.1.351 Arms 
 
CoV2 preS dTM (B.1.351) Treatment Groups 
 
2.5 µg with 
full-dose 
AS03 
5 µg with 
half-dose 
AS03 
5 µg with no 
adjuvant 
2.5 µg with 
half-dose 
AS03 
Total Overall 
100 
100 
100 
100 
Age Groups 
Adults (18-55 years) 
75 
75 
75 
75 
Older adults 
(≥ 56 years) 
25 
25 
25 
25 
 
Supplemental Cohort 1 and Cohort 2 Booster Arms Only: all participants will receive a single 
booster dose (VAC) at D01. Blood samples will be collected from all participants prior to the 
booster injection, 14 days, 1 month, 3 months, 6 months, and 12 months after the injection. 
Supplemental Cohorts Comparator Group: all participants will receive 2 vaccine injections 
given 3 weeks apart: the first injection will be at D01 (VAC1) and the second injection will be at 
D22 (VAC2). Blood samples will be collected from all participants prior to each injection, 14 
days, 4 months, 6 months, 9 months, and 12 months after last injection. 
Approximate sample size of Supplemental Cohort subsets and Variant Testing for 
CMI/Mucosal Subset for Cohorts 1 and 2 
 
Cohort 1* 
Cohort 2* 
 
Variant 
Testing Only 
Participants in the 
Pfizer/BioNTech 
Group 
Participants in the 
CoV2 preS 
dTM-AS03 Group 
(Original Phase II 
Cohort) 
Total Overall 
70 
52 
30 
CoV2 preS dTM-AS03 (D614) 
44 
-- 
27 
CoV2 preS dTM-AS03 (B.1.351) 
-- 
26 
3 
 CoV2 preS dTM-AS03 (D614 + B.1.351) 
-- 
26 
-- 
Comparator 
26 
-- 
-- 
*All subset participants will be 18-55 years of age only  
Supplemental Cohorts Subsets and Assessment of Immunogenicity to Emerging Variants of 
Concern: A randomized subset of 70 participants in Cohort 1, will be tested for additional 
SARS-CoV-2 variants of concern including Delta. No additional sample collection, procedures, or 
visits are required for this subset. A randomized subset of 82 participants in Cohort 2 comprised 
of younger adults (18 to 55 years of age) will provide samples for cellular immune response and 
mucosal antibody assessments and will also be tested for additional variants of concern including 
Delta. 
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For all cohorts: blood samples collected from all participants will be used for serological 
assessments in the study. Whole blood, PBMCs, and saliva samples will be collected from a 
subset of participants in Cohort 2 to assess cellular immune responses and mucosal antibody 
responses. 
Reactogenicity will be assessed by collecting solicited AEs for 7 days after each vaccination, 
unsolicited AEs for 21 days after the last vaccination, and SAEs, MAAEs, and AESIs for the 
duration of the study. 
All Supplemental Phase III Cohort participants will be followed for the duration of the study to 
capture occurrences of COVID-19 through passive surveillance wherein participants will be 
instructed to contact the site if they experience symptoms/conditions of a COVID-19-like illness 
at any time during the study. In addition, participants will be contacted once every 2 weeks 
starting at D43 (for the Original Phase II Cohort and Supplemental Phase III Cohorts Comparator 
Group) and D30 (for Supplemental Phase III Cohorts 1 and 2 Booster Groups) to inquire about the 
development of symptoms/conditions of COVID-19-like illness and to remind participants to 
contact study staff if they experience symptoms/conditions of COVID-19-like illness or if they 
have a positive COVID-19 test from any other source. 
The duration of participation in the study for each participant will be: 
• Supplemental Cohorts 1 and 2: approximately 365 days post-booster injection (ie, 
approximately 366 days total)  
• Supplemental Cohorts Comparator Group approximately 365 days post-injection 2 (ie, 
approximately 386 days total) 
Data Monitoring/Other Committee: 
Not Applicable 
 
 
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1.2 
Schemas  
The graphical designs for the VAT00002 study are presented as follows: 
• Figure 1.1: Original Phase II Cohort 
• Figure 1.2: Booster arms for Supplemental Cohorts 1 and 2  
• Figure 1.3: Supplemental Cohorts Comparator Group  
• Figure 1.4: Design for COVID-19-like illness follow-up for the Original Series and all 
Supplemental Cohorts  
 
Figure 1.1:  Graphical study design for Original Phase II Cohort 
 
BL, blood sample; MC; mononuclear cell sample; SA, saliva sample; TC, telephone call; V, visit; VAC, vaccination; 
WB, whole blood sample; MC/SA are only for selected participants 
* During the D09, D30, and D43 telephone call, staff will review the DC pertaining to solicited AEs (D09 and D30 
only), unsolicited AEs, SAEs, AESIs, MAAEs and COVID-19 like illness since the last visit and will remind 
participants to bring the DC for the next visit. Data on unsolicited AEs, SAEs, AESIs, MAAEs collected at the D43 
telephone call will be collected in the CRF prior to the D78 visit. These telephone calls will NOT be collected in the 
CRF. 
For the V08 contact or phone call, all participants will be scheduled to attend V08 for blood sampling and the 
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. 
 
 
 
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Figure 1.3: Graphical study design for Supplemental Cohorts Comparator Group 
 
 
BL, blood sample; TC, telephone call; V, visit; VAC, vaccination 
* During the D09, D30, and D43 telephone call, staff will review the DC pertaining to solicited AEs (D09 and D30 
only), unsolicited AEs, SAEs, AESIs, MAAEs and COVID-19 like illness since the last visit and will remind 
participants to bring the DC for the next visit. Data on unsolicited AEs, SAEs, AESIs, MAAEs collected at the D43 
telephone call will be collected in the CRF prior to the D78 visit. These telephone calls will NOT be collected in the 
CRF. 
For the V08 contact or phone call, all participants will be scheduled to attend V08 for blood sampling and the 
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. 
 
 
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Figure 1.4: Follow-up of COVID-19-like illness for the Original Phase II Cohort and all 
Supplemental Phase III Cohorts 
 
CLI, COVID-like illness (visit) 
* The frequency of contact for medical monitoring is up to the discretion of the Investigator. 
At the CLI01 visit, participants will be provided with a pulse oximeter and asked to record pulse oximetry readings 
twice a day from onset of illness until the results of the respiratory swab collected for NAAT testing at CLI01 are 
available. Continuation of pulse oximetry readings by the participant after availability of test results will be based on 
Investigator judgment. 
‡ Follow-up telephone call approximately 30 days after onset of illness. If symptoms are ongoing 30 days after illness 
onset, a second telephone call 60 days after onset of illness will be scheduled. 
 
 
 
 
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1.3 
Schedule of Activities (SoA)  
Visit procedures are detailed in the Operating Guidelines. 
Table 1.1 presents the overall study Schedule of Activities (SoA) for the Original Phase II Cohort.   
Table 1.2 presents the overall study SoA for the booster arms of Supplemental Cohorts 1 and 2. 
Table 1.3 presents the overall study SoA for the Supplemental Cohorts Comparator Group.  
Table 1.4 presents the SoA for the follow-up of COVID-19-like illness for the Original Phase II 
Cohort and Supplemental Cohorts. 
 
 
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Table 1.2: Schedule of Activities for Supplemental Cohorts 1 and 2 (Booster Arms Only) 
Booster Arms Only*: Phase II/III Study, 6 Visits, 1 Phone call, 1 Vaccination, 6 Blood Sample Time points, Approximately 12 Months’ 
Duration Per Participant 
Visit (V) / Contact 
Collection  
of information  
in the CRF 
V01 
V02 
TC1‡‡ 
V03 
V04 
V05 
V06 Or Safety 
Follow-up ‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
 D15 
D22 
D29 
D91 
D181 
D366 
Time interval (days) 
 
 
V01 + 14 
days 
V01 + 21 
days 
V01+28 days 
V01 +90 days 
V01 +180 
days 
V01 +365 days 
Time windows (days) 
 
N/A 
[+2 days] 
[+2 days] 
[+7 days] 
[+7 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
Informed consent 
X 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Collection of demographic data 
X 
X 
 
 
 
 
 
 
Collection of previous COVID-19 vaccination 
X 
X 
 
 
 
 
 
 
Collection of significant medical history 
including high risk medical conditions 
X 
X 
 
 
 
 
 
 
Physical examination** 
 
X 
 
 
 
 
 
 
Pre-vaccination temperature 
 
X 
 
 
 
 
 
 
Urine/serum pregnancy test (if applicable)† 
 
X 
 
 
 
 
 
 
Contact IRT system for randomization, 
participant number, and unique dose number 
allocation 
X 
X 
 
 
 
 
 
 
Nasopharyngeal sample collection 
X 
X 
 
 
 
 
 
 
Blood sampling (BL): Serum samples for Ab 
assays (30 mL) 
X 
BL0001 
BL0002 
 
BL0003 
BL0004 
BL0005 
BL0006 
PBMCs for Cellular immune responses 
(40 mL)§ 
 
MC0001 
MC0002 
 
MC0003 
MC0004 
 
MC0005 
Saliva samples for mucosal immunity§ 
 
SA0001 
SA0002 
 
 
SA0003 
 
 
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Visit (V) / Contact 
Collection  
of information  
in the CRF 
V01 
V02 
TC1‡‡ 
V03 
V04 
V05 
V06 Or Safety 
Follow-up ‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
 D15 
D22 
D29 
D91 
D181 
D366 
Time interval (days) 
 
 
V01 + 14 
days 
V01 + 21 
days 
V01+28 days 
V01 +90 days 
V01 +180 
days 
V01 +365 days 
Time windows (days) 
 
N/A 
[+2 days] 
[+2 days] 
[+7 days] 
[+7 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
Vaccination (VAC) 
X 
X 
 
 
 
 
 
 
Telephone call 
 
 
 
X 
 
 
 
X 
Immediate surveillance (30 minutes) 
X 
X 
 
 
 
 
 
 
DC provided  
 
DC1 §§ 
 
 
DC2 ‡‡‡ 
DC3 §§§ 
 
 
DC reviewed 
 
 
DC1 *** 
 
 
 
DC3 *** 
 
DC collected 
 
 
 
 
DC1 ††† 
DC2 ††† 
 
DC3 ††† 
Collection of solicited injection site & systemic 
reactions 
X 
D01-D08 (up to 7 days post-VAC 
 
 
 
 
 
Collection of unsolicited AEs  
X 
D01-D22 
(up to 21 days post-VAC) 
 
 
 
Collection of concomitant medications 
X 
Reportable 
concomitant 
medication 
All reportable concomitant 
medications 
(including influenza and COVID-19 
vaccination) 
 
Influenza and COVID-19 vaccination, COVID-19 prophylaxis (eg, SARS-CoV-2 
antivirals, monoclonal antibodies, plasma) only 
Active surveillance 
X 
 
 
 
Participants will be contacted once every 2 weeks starting at D30 to 
inquire about the development of symptoms/conditions of COVID-like 
illness and to remind participants to contact study staff if they experience 
symptoms/conditions of 
Passive surveillance  
X 
Participants will be instructed to contact the site if they experience symptoms/conditions of a COVID-19-like illness or if they 
have a positive COVID-19 test from any other source at any time during the study. 
Collection of SAEs, MAAEs, and AESIs**** 
X 
To be reported at any time during the study 
Collection of pregnancies 
X 
To be reported at any time during the study 
End of active phase participation record†††† 
X 
 
 
X 
 
 
 
X 
12 Month Post-VAC1 Follow-up participation 
record (only for those discontinued early) ‡‡‡‡ 
X 
 
 
 
 
 
 
X 
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Abbreviations: Ab, Antibody; AE, adverse event; AESI, adverse event of special interest; BL, blood sample (#); CRF, (electronic) Case Report Form; DC, Diary Card; IRT, Interactive Response 
Technology; MAAE, medically-attended adverse event; MC, mononuclear cell sample (#); SA, saliva sample (#); SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; V, visit; VAC, Vaccination 
*Supplemental Cohorts Comparator Group participants will receive a 2 injection primary series vaccination.  
**Targeted physical examination based on the participant’s medical history and the examiner’s judgment will be performed at V01. 
† Urine or serum pregnancy test is applicable to childbearing potential female participants (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or 
surgically sterile). Urine or serum pregnancy test is to be performed before vaccination. 
§ These samples will be collected only from a subset of participants in Cohort 2 who received the Pfizer/BioNTech vaccine priming series only.   
§§ Participants will use this DC1 to record information about solicited reactions, unsolicited AEs, SAEs, MAAEs, and AESIs from D01 to D15 after vaccination and will continue to record information 
about unsolicited AEs, SAEs, MAAEs, and AESIs from D16 to V03. In addition, the participant will use the DC to report the information related to COVID-19-like illness. 
*** 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 SAEs, MAAEs, and AESIs. In addition, the participant will use the DC to report the information related to COVID-19-like illness. 
§§§ Participants will use this DC3 to record SAEs, MAEs, AESIs, and information related to COVID-19-like-illness from V04 to V06. 
**** AESIs (serious and non-serious) will be collected throughout the study and will be communicated to the Sponsor in an expedited manner similar to the reporting of SAEs and followed-up until the 
end of the follow-up period or resolution, as per the assigned causality. These include: Anaphylactic reactions, Generalized convulsion, Thrombocytopenia, Thrombosis with thrombocytopenia syndrome, 
Myocarditis, Pericarditis, and potential immune-mediated diseases (pIMDs). 
†††† In case of participant discontinuation at a visit, the entire visit will be completed. 
‡‡‡‡ All participants will be scheduled to attend V06 for blood sampling and 12-Month (post-VAC) 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. For participants who have prematurely terminated the study, the site should attempt to 
contact them and complete this 12-month safety follow-up (and all other 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. 
 
 
 
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Table 1.3: Schedule of Activities for Supplemental Cohorts Comparator Group 
Phase II/III Study, 8 Visits, 3 Telephone Calls, 2 Vaccinations, 8 Blood Sample Time points, Approximately 13 Months’ Duration Per 
Participant 
Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
TC1‡‡ 
V02 
TC2‡‡ 
V03 
TC3‡‡ 
V04 
V05 
V06 
V07 
V08 or 
Safety 
Follow-up 
‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D78 
D134 
D202 
D292 
D387 
Time interval (days) 
 
 
V01 +8 
days 
V01 +21 
days 
V02 +8 
days 
V02+14 
days 
V02+21 
days 
V02 +56 
days 
V02 +112 
days 
V02 +180 
days 
V02 +270 
days 
V02+365 
days 
Time windows (days) 
 
N/A 
[+2days] 
[+3 days] 
[+2 days] 
[+3 days] 
[+2 days] 
[+9 days] 
[+14 days] 
[+21 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 rapid 
serodiagnostic test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Collection of demographic 
data 
X 
X 
 
 
 
 
 
 
 
 
 
 
Collection of significant 
medical history including 
high risk medical 
conditions 
X 
X 
 
 
 
 
 
 
 
 
 
 
Collection of risk factors 
for SARS-CoV-2 exposure 
and COVID-19 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination* 
 
X 
 
 
 
 
 
 
 
 
 
 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
TC1‡‡ 
V02 
TC2‡‡ 
V03 
TC3‡‡ 
V04 
V05 
V06 
V07 
V08 or 
Safety 
Follow-up 
‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D78 
D134 
D202 
D292 
D387 
Time interval (days) 
 
 
V01 +8 
days 
V01 +21 
days 
V02 +8 
days 
V02+14 
days 
V02+21 
days 
V02 +56 
days 
V02 +112 
days 
V02 +180 
days 
V02 +270 
days 
V02+365 
days 
Time windows (days) 
 
N/A 
[+2days] 
[+3 days] 
[+2 days] 
[+3 days] 
[+2 days] 
[+9 days] 
[+14 days] 
[+21 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-vaccination 
temperature 
 
X 
 
X 
 
 
 
 
 
 
 
 
Urine/serum 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 
 
 
 
 
 
 
 
 
Temporary and definitive 
contraindications 
X 
 
 
X 
 
 
 
 
 
 
 
 
Nasopharyngeal sample 
collection 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Blood sampling (BL): 
Serum samples for Ab 
assays (30 mL)** 
X 
BL0001‡ 
 
BL0002‡ 
 
BL0003 
 
 
BL0004 
BL0005 
BL0006 
BL0007 
Vaccination (VAC) 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Telephone call 
 
 
X‡‡ 
 
X‡‡ 
 
X‡‡ 
 
 
 
 
X †††† 
Immediate surveillance (30 
minutes) 
X 
X 
 
X 
 
 
 
 
 
 
 
 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
TC1‡‡ 
V02 
TC2‡‡ 
V03 
TC3‡‡ 
V04 
V05 
V06 
V07 
V08 or 
Safety 
Follow-up 
‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D78 
D134 
D202 
D292 
D387 
Time interval (days) 
 
 
V01 +8 
days 
V01 +21 
days 
V02 +8 
days 
V02+14 
days 
V02+21 
days 
V02 +56 
days 
V02 +112 
days 
V02 +180 
days 
V02 +270 
days 
V02+365 
days 
Time windows (days) 
 
N/A 
[+2days] 
[+3 days] 
[+2 days] 
[+3 days] 
[+2 days] 
[+9 days] 
[+14 days] 
[+21 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
DC provided  
 
DC1 § 
 
DC2 ‡‡‡ 
 
 
 
DC3 §§ 
 
 
 
 
DC reviewed 
 
 
DC1 *** 
 
DC2 *** 
DC2 ‡‡ 
DC2 *** 
 
DC3 *** 
DC3 *** 
DC3 *** 
 
DC collected 
 
 
 
DC1 ††† 
 
 
 
DC2 ††† 
 
 
 
DC3 ††† 
Collection of solicited 
injection site & systemic 
reactions  
X 
D01-D08 
(up to 7 days post-
VAC1) 
D01-D08 (up to 7 days 
post-VAC2) 
 
 
 
 
 
 
 
Collection of unsolicited 
AEs  
X 
D01-D22 
(up to 21 days post-VAC1) 
 
 
 
 
 
 
 
 
 
 
D01-D22 
(up to 21 days post-VAC2) 
 
 
 
 
 
Collection of concomitant 
medications 
X 
Reportable 
concomitant 
medication 
All reportable concomitant medications 
(including influenza and COVID-19 vaccination) 
Influenza and COVID-19 vaccination, COVID-19 prophylaxis (eg, 
SARS-CoV-2 antivirals, monoclonal antibodies, plasma) only 
Active surveillance 
X 
 
 
 
 
 
Participants will be contacted once every 2 weeks starting at D43 to inquire about 
the development of symptoms/conditions of COVID-like illness and to remind 
participants to contact study staff if they experience symptoms/conditions of 
COVID-like illness or if they have a positive COVID-19 test from any other source. 
Passive surveillance 
X 
Participants will be instructed to contact the site if they experience symptoms/conditions of a COVID-19-like illness or if they have a positive COVID-
19 test from any other source at any time during the study. 
Collection of SAEs, 
MAAEs, and AESIs**** 
X 
To be reported at any time during the study 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
TC1‡‡ 
V02 
TC2‡‡ 
V03 
TC3‡‡ 
V04 
V05 
V06 
V07 
V08 or 
Safety 
Follow-up 
‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D78 
D134 
D202 
D292 
D387 
Time interval (days) 
 
 
V01 +8 
days 
V01 +21 
days 
V02 +8 
days 
V02+14 
days 
V02+21 
days 
V02 +56 
days 
V02 +112 
days 
V02 +180 
days 
V02 +270 
days 
V02+365 
days 
Time windows (days) 
 
N/A 
[+2days] 
[+3 days] 
[+2 days] 
[+3 days] 
[+2 days] 
[+9 days] 
[+14 days] 
[+21 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of pregnancies 
X 
To be reported at any time during the study 
End of phase participation 
record 
 
 
 
 
 
 
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, (electronic) Case Report Form; DC, Diary Card; IRT, Interactive Response 
Technology; MAAE, medically-attended adverse event; MC, mononuclear cell sample (#); SA, saliva sample (#); SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; TC, telephone call; V, visit; VAC, Vaccination;  
*Targeted physical examination based on the participant’s medical history and the examiner’s judgment will be performed at V01. 
† Urine or serum pregnancy test is applicable to childbearing potential female participants (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or 
surgically sterile). Urine or serum pregnancy test is to be performed before vaccination. 
‡ BL0001 and BL0002 will be collected pre-vaccination.  
** If a participant seeks an authorized/approved vaccine, they will be invited to an unscheduled visit prior to receiving the vaccine and requested to provide a blood sample for serological assessment.  
‡‡ During the telephone call, staff will review the DC pertaining to solicited AEs, unsolicited AEs, SAEs, MAAEs, AESIs and COVID-19 like illness since the last visit and will remind participants to 
bring the DC for the next visit. These telephone calls will NOT be collected in the CRF. 
§ Participants will use this DC1 to record information about solicited reactions, unsolicited AEs, SAEs, MAAEs, and AESIs from D01 to D08 after vaccination and will continue to record information 
about unsolicited AEs, SAEs, MAAEs, and AESIs from D09 to V02. In addition, the participant will use the DC to report the information related to COVID-19-like illness. 
*** 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. 
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Visit (V) / Contact 
Collection  
of 
information  
in the CRF 
V01 
TC1‡‡ 
V02 
TC2‡‡ 
V03 
TC3‡‡ 
V04 
V05 
V06 
V07 
V08 or 
Safety 
Follow-up 
‡‡‡‡ 
Study timelines (Day [D]) 
 
D01 
D09 
D22 
D30 
D36 
D43 
D78 
D134 
D202 
D292 
D387 
Time interval (days) 
 
 
V01 +8 
days 
V01 +21 
days 
V02 +8 
days 
V02+14 
days 
V02+21 
days 
V02 +56 
days 
V02 +112 
days 
V02 +180 
days 
V02 +270 
days 
V02+365 
days 
Time windows (days) 
 
N/A 
[+2days] 
[+3 days] 
[+2 days] 
[+3 days] 
[+2 days] 
[+9 days] 
[+14 days] 
[+21 days] 
[+21 days] 
[+21 days] 
Visit procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
‡‡‡ Participants will use this DC2 to record solicited reactions, unsolicited AEs, SAEs, MAAEs, and AESIs (from V02 to TC2) and will continue to collect unsolicited AEs, SAEs, MAAEs, and 
AESIs (from TC2 to V04). In addition, the participant will use the DC to report the information related to COVID-19-like illness. 
§§ Participants will use this DC3 to record SAEs, MAEs, AESIs, and information related to COVID-19-like-illness from V04 to V08. 
**** AESIs (serious and non-serious) will be collected throughout the study and will be communicated to the Sponsor in an expedited manner similar to the reporting of SAEs and followed-up until 
the end of the follow-up period or resolution, as per the assigned causality. These include: Anaphylactic reactions, Generalized convulsion, Thrombocytopenia, Thrombosis with thrombocytopenia 
syndrome, Myocarditis, Pericarditis, and potential immune-mediated diseases (pIMDs). 
†††† In case of participant discontinuation at a visit, the entire visit will be completed. 
‡‡‡‡ All participants will be scheduled to attend V08 for blood sampling and 12-Month (post-VAC2) Safety Follow-up. However, if any participants discontinue the study early, they are still to be 
followed for safety and are to be contacted with a Safety Follow-up call to identify the occurrence of any SAEs and AESIs that had not yet been reported. If discontinuation occurs at a scheduled visit, 
the participant will be provided a Memory Aid instead of a DC for SAE follow-up (including AESIs) until the Safety Follow-up call. If a participant discontinues between visits (with no Memory Aid 
provided yet), the participant will use the last DC received to collect information for the Safety Follow-up call. For participants who have prematurely terminated the study, the site should attempt to 
contact them and complete this 12-month safety follow-up (and all other scheduled safety follow-ups), except if they specified that they do not want to be contacted again and it is documented in the 
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Table 1.4: Schedule of Activities 2 (Follow-up of COVID-19-like Illness) for the Original Phase II Cohort and all Supplemental Phase III 
Cohorts 
Contact type 
Initial Telephone 
Call* 
CLI01 
Follow-up Telephone Call† 
 
 
As soon as possible 
after symptom onset 
30 days after symptom onset 
Verify information on COVID-19-like illness, remind participant of use of pulse oximeter** 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 specimen 
 
NPXXXX§ 
 
Collection of disease burden and health care information during COVID-19-like illness 
X 
X 
X 
Collection of treatments received during COVID-19-like illness 
X 
X 
X 
* Initial illness identification phone call. During the illness episode, participants may be contacted by the site staff for medical monitoring. The frequency of contact for medical 
monitoring is at the discretion of the Investigator. 
† Follow-up telephone call approximately 30 days after onset of illness. If symptoms are ongoing 30 days after illness onset, a second telephone call 60 days after onset of illness 
will be scheduled. 
‡ 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. A nasopharyngeal swab for central 
laboratory testing will be collected. A sample for local laboratory testing (clinical care) may be collected in addition to the NP swab for central laboratory testing. The swab will not 
be collected during a CLI visit if the date of collection is more than 14 days after resolution of symptoms. 
**At the CLI01 visit, participants will be provided a pulse oximeter, explained about its use, and asked to record pulse oximetry readings every day from the CLI01 visit until the 
results of the NP swab at CLI01 and any other swab collected for local NAAT testing at CLI01 are available. Participants will be instructed to contact sites if the reading were to be 
lower than a threshold value (eg, 93% or equivalent based on altitude). Participant-recorded pulse oximeter readings are for safety monitoring and will not be collected in the diary 
card or CRF. Continuation of pulse oximetry readings by the participant after availability of test results will be based on Investigator judgment. Pulse oximeter readings collected by 
the site or a health care provider (eg, Emergency Room) will be collected in the CRF to determine severity of the COVID-19 episode. 
 
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2 
Introduction  
An outbreak of severe respiratory illnesses in Wuhan City, Hubei Province, China in December 
2019 heralded the appearance of a novel coronavirus, 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 the 
declaration on 11 March 2020 of a pandemic (1). The virus has been detected in 222 
countries/regions and led to significant morbidity, mortality, and economic impact (2). 
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. The clinical profile of COVID-19, the illness caused by SARS-CoV-2, is variable 
(18). In the majority of cases, the manifestations are mild, or individuals may be asymptomatic 
(4). 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. While mostly self-limited, 
symptoms such as fatigue and dyspnea appear to persist for up to 2 months after illness onset 
despite viral clearance (5). 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 (4) (6).  
A number of vaccine candidates in clinical development including viral vector-based vaccines, 
messenger ribonucleic acid (mRNA), protein subunit, and inactivated vaccines encoding the Spike 
(S)-protein of SARS-CoV-2 induce neutralizing antibodies. These include: 
• 2 COVID-19 mRNA vaccine candidates 
o BNT162b2: International Non-Proprietary Name (INN)- COVID-19 mRNA vaccine 
(nucleoside-modified) from Pfizer/BioNTech (hereafter called Pfizer/BioNTech)  
o mRNA-1273: INN- COVID-19 mRNA vaccine (nucleoside modified) from Moderna 
(hereafter called Moderna) 
• 2 adenovirus-vectored vaccine candidates 
o ChAdOx1-nCOV-19: INN- COVID-19 vaccine (ChAdOx1-S [recombinant]) vaccine 
from Oxford University/AstraZeneca (hereafter called Oxford University/AstraZeneca) 
o Ad26.COV2-S: INN- COVID-19 vaccine (Ad26.COV2-S [recombinant]) from 
Johnson & Johnson/Janssen (hereafter called J&J/Janssen)  
These vaccine candidates have demonstrated efficacy against COVID-19 illness and severe 
disease in their Phase III clinical studies (7) (8) (9). Emergency authorization or other forms of 
regulatory approval have been granted in multiple countries for vaccines against COVID-19. 
Sanofi Pasteur’s CoV2 preS dTM-AS03 vaccine is being developed in the setting of a pandemic 
for the active immunization and prevention of SARS-CoV-2 infection and COVID-19 disease. 
The initial intended use of the vaccine is for adults, 18 years of age and older. Studies including 
pediatric populations will be completed later since this population is at lower risk to develop 
severe complications. A study to evaluate safety and immunogenicity in pregnant females will 
also be completed later once results of nonclinical development and reproductive toxicity are 
available and initial results demonstrating safety and a positive benefit-risk in humans are 
available. 
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The candidate antigen is a stabilized prefusion trimer of the SARS-CoV-2 S protein. The 
coronavirus 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 (19). 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 (ACE2), a 
membrane-bound carboxypeptidase localized to vascular endothelial as well as epithelial surfaces 
(20). 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 (21). 
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-OC43, MERS-CoV, and SARS-CoV-1, and by extrapolation to 
SARS-CoV-2 (10). The prefusion stabilized SARS-CoV-2 S construct to be evaluated in the 
current study is based on this research. 
The S1 subunit and RBD of the prefusion SARS-CoV-2 S antigen used in this vaccine is similar 
in sequence to the S antigens encoded by the mRNA vaccine constructs that have been shown to 
induce neutralizing antibody responses and confer robust efficacy against COVID-19 (7) (8), 
suggesting that other vaccines capable of inducing similar levels of neutralizing antibodies may 
also provide protection. 
The antigen will be manufactured using the same technology as is used to manufacture a 
recombinant quadrivalent influenza vaccine (rQIV), licensed in the US and EU and 
commercialized as Flublok® and Supemtek®, respectively for the prevention of influenza in adults 
18 years of age and older (22). In this manufacturing platform, 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 by a series of filtration and 
chromatography steps. This process is adaptable to manufacture a variety of antigens. Millions of 
doses of recombinant influenza vaccine (trivalent and quadrivalent formulations) have been 
administered since its approval in the US for human use corresponding to hemagglutinins (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, candidate S protein vaccines were developed, 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 in mice and ferrets and 
to be partially protective in a ferret challenge model. 
The magnitude and quality of the immune response to the candidate antigen will be enhanced 
through delivery with an adjuvant. In addition, the adjuvant may influence the quality of the 
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immune response. Previous clinical studies with rH5 HA and rH7 HA pandemic antigens in naïve 
individuals show that a 2-dose immunization regimen of antigen was poorly immunogenic in 
comparison to antigen delivered with an adjuvant (23). This may allow for titration of the amount 
of antigen used and, thus, be antigen-sparing and potentially increase the available supply of 
antigen doses. 
AS03 is an oil-in-water emulsion containing -tocopherol and squalene. Safety of 
AS03-adjuvanted products has been extensively evaluated and found to be generally well 
tolerated with an acceptable safety profile (24). AS03 has been approved as a component of 
Pandemrix and Arepanrix, two H1N1 pandemic influenza vaccines. AS03 was also evaluated with 
pandemic H7 rHA 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 (25) (26). In addition to a Phase I/II study using the Sanofi Pasteur CoV2 preS dTM  
antigen with AS03-adjuvanted system (NCT04537208), AS03 has also been used in combination 
with other AS03-adjuvanted recombinant S proteins (Medicago [NCT04450004] (27) and Clover 
Biopharmaceuticals [NCT04405908]). 
A potential (yet theoretical) safety concern with coronavirus vaccines is the ability to  potentiate 
immunopathology in vaccinees upon exposure to wild-type virus (28), called vaccine associated 
enhanced disease (VAED) The theoretical molecular mechanism for this phenomenon, 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 (29) (30) (31). It is anticipated 
that the design of the candidate CoV2 preS dTM antigen selected for this study will promote 
generation of robust neutralizing antibodies over binding but non-neutralizing antibodies, based 
on data generated with other coronavirus vaccine antigens (10) (21). The inclusion of adjuvanted 
formulation is anticipated to further enhance the magnitude of neutralizing antibody responses and 
induce balanced Th1/Th2 cell responses (32) (23). Taken together, these strategies mitigate by 
design the theoretical risks of immune enhancement of viral infection. 
The clinical development plan gives priority to generating data in adults given the higher medical 
and public health need in this population compared to the pediatric population; pediatric studies 
are proposed to be de-linked from the critical path to first authorization/approval. Importantly, the 
Phase II study is designed to be pragmatic to maximize representation of a broader population by 
minimizing exclusionary eligibility criteria and allowing the participation of individuals with a 
range of medical conditions including controlled HIV infection, Hepatitis B, Hepatitis C, and 
conditions associated with an increased risk of severe COVID-19. It is also designed to be 
inclusive of other subpopulations affected by COVID-19, including older adults as well as ethnic 
and racial minorities. 
The clinical development plan for CoV2 preS dTM-AS03 vaccine began with a Phase I/II study 
(VAT00001) in adults with the goal of identifying a formulation, antigen dose, and a dosing 
schedule for further development. In the VAT00001 study, the safety and immunogenicity of a 
low-dose and high-dose antigen formulation corresponding to effective doses of 1.3 µg and 
2.6 µg, respectively, of purified recombinant SARS-CoV-2 S-protein with AF03 and AS03 
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adjuvant administered either as a single injection or 2 injections 21 days apart are being evaluated. 
Interim results of the VAT00001 study support the selection of the AS03 adjuvant system and a 
2-injection schedule but also indicate that further optimization of the antigen formulation and 
dosage is needed. Data from the VAT00001 study have informed the design of this Phase II study 
(VAT00002) aiming at selecting a suitable antigen dose adjuvanted with AS03 in a 2-injection 
schedule for further progression to a Phase III study. 
A Phase II/III study in the pediatric population is planned to be initiated following generation of 
evidence in adults of a favorable benefit-risk of the vaccine. A Phase III study to assess the safety 
and immunogenicity of the vaccine in pregnant women is also planned after availability of a 
nonclinical DART (Developmental and reproductive toxicity) study and interim safety and 
immunogenicity data from the Phase II study in adults. 
2.1 
Study Rationale  
New, highly transmissible SARS-CoV-2 variants of concern have emerged and are spreading 
globally. The UK first identified a variant of concern called Alpha (B.1.1.7) which has been 
shown to be more transmissible and has since been detected in many other countries around the 
world (12) Other variants have emerged first identified in South Africa (Beta [B.1.351] variant), 
Brazil (Gamma [P.1]variant), and India (Delta [B.1.617] variant) and have now been detected in 
other countries. A key question is whether currently approved and available COVID-19 vaccines 
will be able to protect against infection or disease from these variants. Recent preliminary data 
using an adjuvanted protein sub-unit vaccine (Novavax) and the ChAdOx1 nCoV-19 vaccine 
(AZD1222 [Oxford University/AstraZeneca]) showed lower efficacy against mild to moderate 
COVID-19 in South Africa where the Beta (B.1.351) variant predominated compared to the 
efficacy observed for these vaccines in studies conducted in the UK (33) (34) (35). However, data 
from the Ad26CoV2.S vaccine (Johnson & Johnson/Janssen [J&J/Janssen]) showed efficacy 
against symptomatic disease in South Africa suggesting that the prototype vaccines confer 
protection against the Beta (B.1.351) variant. Sera from individuals immunized with prototype 
COVID-19 vaccines show an ability to neutralize the variants but to a lesser extent than the 
prototype strain. This decrease in neutralization is most notable against the Beta (B.1.351) variant 
which has a characteristic E484K mutation in the receptor-binding domain along with other 
mutations in the N-terminal domain of the S protein. These findings have led to the development 
of variant strain vaccines and regulatory guidance for the development of vaccines against the 
variant strains for products that have already demonstrated efficacy with the prototype vaccines 
(17). There has been particular emphasis on developing variant strain vaccines to protect against 
the Beta (B.1.351) variant. Ongoing evolution of SARS-CoV-2 variants, especially in light of the 
growing prevalence of vaccination and the selection pressure that this may exert raises the strong 
public health requirement for SARS-CoV-2 vaccines, including those protective against emergent 
variants of concern. 
This Phase II/III study will assess the safety and immunogenicity of a CoV2 preS dTM-AS03 
vaccine in adults 18 years of age and older. The goal of this study is to select an antigen dose 
adjuvanted with AS03 for further progression to a Phase III study.  
This study will also assess the safety and immunogenicity of the CoV2 preS dTM-AS03 vaccine, 
including monovalent and bivalent formulations, for use as a universal late booster.  
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The data collected during this study will also support future development in other populations. 
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. The virus has been detected in 192 
countries/regions and led to significant morbidity, mortality, and economic impact (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 (also called social distancing) has 
had profound economic consequences. Safe and effective vaccines with sufficient doses would be 
vital to address the significant medical and societal burden caused by the pandemic. 
The CoV2 preS dTM-AS03 vaccines developed by Sanofi Pasteur utilize a recombinant protein 
approach in combination with an oil-in-water adjuvant, AS03 provided by GlaxoSmithKline 
(GSK). The CoV2 preS dTM-AS03 vaccines belong to the pharmacotherapeutic group of “covid-
19 vaccines”. 
The vaccines contain 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 monovalent and bivalent CoV2 preS dTM vaccines and the AS03 adjuvant are 
provided in the respective Investigator’s Brochures (IBs). 
2.2.1 Nonclinical Studies  
Monovalent vaccine with the prefusion S protein from the D614 prototype 
The nonclinical studies provided an assessment of vaccine immunogenicity in mice and in NHPs. 
The studies indicated that the CoV2 preS dTM vaccine formulated with either AF03 or AS03 
induced high S-specific immunoglobulin G (IgG) and SARS-CoV-2 neutralizing responses in 
mice and NHPs, with evidence of a potent adjuvant-effect of AF03 and AS03 as well as a robust 
boost-effect after the second injection. Humoral responses were generally similar or higher than 
levels observed in human convalescent sera. Cell-mediated immune (CMI) responses suggest a 
mixed Th1/Th2 profile, with no evidence of Th17 responses. These studies supported the first-in-
human Phase I/II study. 
Nonclinical safety studies were performed in rabbits to support the first-in-human Phase I/II 
study. A single or repeated dose (3 doses) IM injection(s) of CoV2 preS dTM at an effective 
antigen dose level of 4.2 µg/dose alone or adjuvanted with AS03 or AF03 was well tolerated in 
rabbits. Administration of CoV2 preS dTM with AS03 adjuvant resulted in transient and 
non-adverse changes in hematology, coagulation, and clinical chemistry parameters indicative of a 
transient acute phase response/inflammation. These changes correlated with non-adverse 
histopathology findings of increased severity of acute/subacute to subacute/chronic mixed cell 
inflammation at the injection site and in the overlying skin of animals administered CoV2 
preS dTM with adjuvant. Animals injected on 3 occasions also showed increased lymphoid 
cellularity in the spleen (correlating with increased spleen weights) and lymph nodes. After the 
2-week recovery period (single or repeated doses), the inflammation was still present at the 
injection site(s) but was more chronic in nature as expected with the healing process and was 
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associated with vacuolated macrophages in animals administered CoV2 preS dTM with AS03; 
there was also increased lymphoid cellularity in the iliac and sacral lymph nodes in animals 
administered CoV2 preS dTM with either adjuvant. These changes were expected, being 
consistent with those usually observed following injection of an adjuvanted vaccine. Furthermore, 
a second repeated-dose toxicity study (Study No. 5003591) was conducted with 2 IM injections 
(ie, same number of injections to be administered to humans) 2 weeks apart in NZW rabbits using 
a new product batch to support the bridging between formulations tested in the Phase I/II study 
and formulations more advanced in product development. The study design was similar to that of 
the initial toxicology study. 
Vaccine efficacy studies were also performed in NHPs and hamsters. In one NHP study 
(CoV2-01_NHP), Rhesus macaques immunized twice on D0 and D21 either with 2 antigen-doses 
(5 µg and 15 µg) of CoV2 preS dTM formulated with AS03 or 1 dose of non-adjuvanted CoV2 
preS dTM and challenged 28 days post-dose 2 with 106 PFU of SARS-CoV-2 (D614) by both 
intranasal and intratracheal routes, animals administered both AS03-adjuvanted vaccine 
formulations were protected against viral replication in the lungs and lung pathology (11). In 
another NHP study with Rhesus macaques (CoV2-04_NHP), using a formulation with an effective 
S antigen dose of 4 µg or 12 µg with AS03 adjuvant to assess efficacy against SARS-CoV-2 viral 
challenge was performed. In addition, the ability of the vaccine to elicit cross-neutralizing Abs 
against Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28 or P.1), Delta (B.1.617.2), and Epsilon 
(B.1.429) SARS-CoV-2 virus variants was evaluated in NHP samples using the lentivirus-based 
pseudo-neutralization assay. 
Two vaccine doses conferred robust protection against viral replication in the lower and upper 
airways after a challenge with a virulent viral stock (NR-53780 BEI stock). Strong reduction of 
viral replication was demonstrated on D02 and D04, with a trend for a higher reduction in the high 
dose vaccine group. The pathology and inflammation in the lungs induced by infection 7 days 
post-challenge was clearly reduced in the immunized rhesus macaques, and no increase in 
inflammatory cytokines or chemokines was observed. At both low and high doses, the 
AS03-adjuvanted vaccine elicited high humoral (binding, functional and neutralizing antibodies) 
and cellular (Th1/Th2 balanced S-specific cytokine responses and Tfh cells 2 weeks post-boost) 
responses. The high immunogenicity and efficacy demonstrated in Rhesus macaques using 4 and 
12 µg effective doses (CoV2-04_NHP) supported the Original Phase II Cohort dose-ranging 
clinical trial assessing 5 µg, 10 µg, and 15 µg of CoV2 preS dTM vaccine antigen adjuvanted with 
AS03.  
With regards to the emerging virus variants Alpha (B.1.1.7) and Epsilon (B.1.429), no reduction 
in neutralization Ab titers were observed in the NHP studies with the AS03-adjuvanted CoV2 
preS dTM vaccine. However, a significant decrease was observed in the neutralizing Ab titers 
against the Beta (B.1.351) and Gamma (B.1.1.28 or P.1) variants, with a level of reduction 
consistent with that described for other vaccines (36). The data suggest that the parent D614 
vaccine has the ability to induce antibodies that can neutralize most virus variants circulating in 
Europe and the US including Alpha (B.1.1.7) and Epsilon (B.1.429).  
In addition, vaccine efficacy was evaluated in Golden Syrian hamsters (Mesocricetus auratus), in 
which it was found that AS03-adjuvanted vaccine conferred protection against viral replication in 
the lungs and upper respiratory tract (CoV2-03_Hm). 
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Nonclinical variant booster studies 
Nonclinical studies were performed to document the CoV2 preS dTM-AS03 (D614) and variant 
vaccine formulations (monovalent B.1.351 and bivalent D614 + B.1.351) when used as a booster 
7 months after a primary vaccination with different vaccine platforms (mRNA-primed and 
subunit-primed). The role of AS03 in potentiating the immune response was also evaluated as it is 
unknown if the adjuvant will be necessary in a boosting scenario. In addition, the ability of the 
vaccine  to elicit cross-neutralizing antibodies against Alpha (B.1.1.7), Beta (B.1.351), Gamma 
(B.1.1.28 or P.1), Delta (B.1.617.2), and Epsilon (B.1.429)SARS-CoV-2 virus variants was 
evaluated in NHP serum samples using the lentivirus-based pseudo-neutralization assay.  
In order to address the emergence of variants of concern, vaccine encoding the Beta (B.1.351) 
variant was developed and the immunogenicity of a monovalent vaccine based on the B.1.351 
Spike and a bivalent vaccine (D614 + B.1.351) was evaluated. A third immunization (booster) 
with monovalent (D614), monovalent (B.1.351) or bivalent (D614 + B.1.351) formulations, 7 
months after a priming immunization with messenger ribonucleic acid (mRNA) or subunit 
vaccine, adjuvanted with AS03, was also evaluated (CoV2-07_NHP and CoV2-08_NHP). In 
order to address the risk of lower vaccine efficacy due to variants of concerns, vaccines 
containing the variant CoV2 preS dTM antigen (B.1.351) as a monovalent or bivalent 
(D614 + B.1.351) formulation were evaluated for immunogenicity and efficacy in a primary 
series given to naïve animals, and as a late booster given to NHPs previously vaccinated with 
subunit or mRNA COVID-19 vaccine candidates. 
Booster immunization was evaluated in cynomolgus macaques previously immunized with 
COVID-19 mRNA-LNP candidates developed by Sanofi Pasteur (CoV2-07_NHP) and in Rhesus 
macaques previously immunized with CoV2 preS dTM-AS03 vaccine (CoV2-08_NHP) (37). 
In the CoV2-07_NHP study, Mauritian cynomolgus macaques were immunized with mRNA 
vaccine candidates corresponding to various full-length spike constructs 7 months before the 
booster vaccination. The animals were randomized into 4 groups of 4 macaques based on their 
baseline characteristics, including their neutralizing responses measured 1 month before the 
booster vaccination. Macaques from group 1 were boosted with 5µg of non-adjuvanted CoV2 
preS dTM (B.1.351), group 2 with 5µg of AS03-adjuvanted CoV2 preS dTM (D614), group 3 
with 5µg AS03-adjuvanted CoV2 preS dTM (B.1.351) and group 4 with 5µg AS03-adjuvanted 
CoV2 preS dTM (D614 + B.1.351). 
In the CoV2-08_NHP study, Indian Rhesus macaques were immunized with CoV2 preS dTM-
AS03 (Phase I/II or intermediate Phase III manufacturing process) 7 months before the booster 
vaccination. Prior to the booster, animals were randomized into 5 groups of 4 to 5 macaques based 
on their baseline characteristics, including their neutralizing responses measured 1 month before 
the booster vaccination. The animals from group 1 were vaccinated with 5µg of non-adjuvanted 
CoV2 preS dTM (B.1.351), group 2 with 5µg of AS03-adjuvanted CoV2 preS dTM (D614), 
group 3 with 5µg AS03-adjuvanted CoV2 preS dTM (B.1.351), group 4 with 5µg AS03-
adjuvanted CoV2 preS dTM (D614 + B.1.351) and group 5 with 10µg AS03-adjuvanted CoV2 
preS dTM (D614 + B.1.351). 
Blood samples were collected weekly after the booster vaccination up to D28 for S-binding IgG 
and neutralizing antibody titers on SARS-CoV-2 parental (D614) and variant strains (Alpha, Beta, 
Gamma, and Delta).  
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The nonclinical studies showed that the bivalent CoV2 preS dTM-AS03 (D614 + B.1.351) 
induced strong neutralizing antibody responses against the 4 variants of concern known to date: 
Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Gamma (B.1.1.28 or P.1) in naïve 
macaques. The benefit of a late booster dose with non-adjuvanted CoV2 preS dTM (B.1.351) or 
AS03-adjuvanted CoV2 preS dTM (D614), (B.1.351), or (D614 + B.1.351) was demonstrated in 
mRNA-primed and subunit-primed macaques. The booster vaccine induced very high neutralizing 
antibodies against the 4 variants of concern and robust neutralization of the distant SARS-CoV-1. 
Finally, preliminary data on efficacy in hamsters demonstrated that all AS03-adjuvanted vaccine 
formulations (D614, B.1.351, and D614 + B.1.351) conferred protection against body weight loss 
caused by infection with the Beta (B.1.351) variant (CoV2-03_Hm). 
2.2.2 Previous Experience in Humans  
Monovalent vaccine with the prefusion S protein from the D614 prototype 
The first-in-human study, VAT00001, is a randomized, parallel group, placebo-controlled, 
observer-blind, dose-ranging, multi-center study. The study objectives were to evaluate the safety 
and immunogenicity of the CoV2 preS dTM candidate vaccine (D614) administered alone or in 
combination of either AS03 or AF03 adjuvant by IM route in participants in the US with the goal 
of selecting a formulation, antigen dose, and an injection schedule. The targeted quantities of the 
CoV2 preS dTM antigen per vaccine dose were 5 µg for the low-dose formulation and 15 µg for 
the high-dose formulation. However, the effective dose levels administered in a 0.5 mL vaccine 
dose in this study were 1.3 µg (LD) and 2.6 µg (HD) of functional SARS-CoV-2 preS protein. 
The differences between the targeted and the effective dose levels correspond to an excess HCP 
content in the clinical materials (recalculated HCP content, 3.7 µg and 12.4 µg). 
Two cohorts of participants were enrolled, ie, Cohort 1 receiving one injection at Day (D)01 and 
Cohort 2 receiving 2 injections, the first at D01 and the second at D22. Each cohort was separated 
into 2 age subgroups (18 through 49 years of age and 50 years of age and older). Four hundred 
thirty-nine participants 18 years of age and older (299 adults 18 through 49 years of age and 
140 adults 50 years of age and older) received at least 1 dose of either a low-dose antigen 
formulation [effective dose of antigen 1.3 µg]) with either AF03 or AS03 adjuvant; or a high-dose 
S antigen formulation [effective dose of S antigen 2.6 µg]) with either AF03, AS03, or no 
adjuvant; or placebo and were included in the Safety Analysis Set (SafAS) as shown in Table 2.1 
below. 
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Table 2.1: VAT00001 safety analysis set by injection group 
Participants 18-49 years of age 
Cohort 
Group 
Dose-Level* 
Adjuvant 
N 
Sentinel 
Safety† 
(N=30) 
Total 
(N=299) 
Cohort 1: 
1 injection 
1 
LD 
AF03 
6 
26 
2 
LD 
AS03 
6 
26 
3 
HD 
AF03 
6 
24 
4 
HD 
AS03 
6 
24 
5 
Placebo 
None 
6 
24 
Cohort 2: 
2 injections 
6 
LD 
AF03 
N/A 
16 
7 
LD 
AS03 
N/A 
52 
8 
HD 
AF03 
N/A 
17 
9 
HD 
AS03 
N/A 
54 
10 
HD 
None 
N/A 
18 
11 
Placebo 
None 
N/A 
18 
Participants 50 years of age and older 
Cohort 
Group 
Dose-Level* 
Adjuvant 
N 
(N=140) 
Cohort 1: 
1 injection 
1 
LD 
AF03 
10 
2 
LD 
AS03 
10 
3 
HD 
AF03 
11 
4 
HD 
AS03 
10 
5 
Placebo 
None 
10 
Cohort 2: 
2 injections 
6 
LD 
AF03 
10 
7 
LD 
AS03 
28 
8 
HD 
AF03 
9 
9 
HD 
AS03 
31 
10 
HD 
None 
N/A‡ 
11 
Placebo 
None 
11 
*Antigen Formulation naming for each dose level: CoV2 preS dTM antigen: LD: low dose target antigen dose 5 µg/effective 
dose 1.3 µg, HD: high dose with target antigen dose 15 µg/effective dose 2.6 µg 
† Sentinel Safety Cohort: 6 participants within each dosing group from Cohort 1 (18-49 years of age only) were randomized 
in the Sentinel Safety Cohort. 
‡ As part of risk mitigation for enhanced COVID-19, those in the older age stratification (≥ 50 years) were not allocated to 
this study arm. 
 
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Interim data showed that: 
• A 2-injection schedule of the adjuvanted protein was necessary to induce neutralizing 
antibodies. 
• The low-dose adjuvanted vaccine induced higher titers of neutralizing antibodies 
compared to high-dose unadjuvanted protein-alone vaccine demonstrating the benefit of 
the adjuvant. 
• The CoV2 preS dTM antigen adjuvanted with AS03 induced higher titers of neutralizing 
antibodies compared to both the AF03 adjuvanted group and compared to the 
unadjuvanted groups with a 2-injection schedule. 
• An antigen dose-response effect was observed with higher neutralizing antibody responses 
observed in the high-dose antigen groups compared to the low-dose antigen groups in the 
2-injection schedule adjuvanted arms. 
The high-dose group with AS03 administered in a 2-injection scheduled induced the highest levels 
of neutralizing antibodies. However, even in the best performing vaccine group (2-injection 
schedule of high-dose + AS03), seroconversion rates were below 90% in all adults with lower 
rates in older adults (85% in 50 years and older, 62.5% in 60 years and older). The magnitude of 
neutralizing antibody responses was also lower in adults aged 50 years and older compared to the 
younger age group indicating the need for further optimization of the antigen formulation and 
dose, with doses higher than the effective high dose of 2.6 µg used in this study. In adjuvanted 
groups with the 2-injection schedule, there was no indication of a Th2-profile bias in the cell-
mediated response with a consistent elicitation of Interferon-gamma responses. 
There were no SAEs or AESIs considered related to the vaccine, no AEs leading to 
discontinuation nor immediate related reactions observed in the study at the time of the interim 
analysis. The most frequent injection site reaction in the pooled AS03 group after the second 
injection was pain (90.2%), and the most frequent solicited systemic reactions were malaise 
(75.0%), myalgia (75.8%), and headache (66.7%). The frequency of reactions increased after the 
second dose, was higher in the adjuvanted groups compared to unadjuvanted groups and was 
higher in the younger age-group (18-49 years of age) compared to older adults. Higher than 
expected frequency of Grade 3 solicited reactions were observed after the second injection in the 
adjuvanted groups. All Grade 3 injection site reactions were reported post-injection 2 and the most 
frequent Grade 3 injection site reaction was erythema, reported in 24% and swelling in 13% of 
participants in the high dose + AS03 arm. This reactogenicity was transient, self-limiting, 
non-serious and did not lead to study withdrawal of any participant. The frequency of Grade 3 
systemic reactions was highest in the AS03-adjuvanted vaccine groups after the 2nd injection, 
24% and 25% in the Low Dose and High Dose groups, respectively. The most frequent Grade 3 
systemic reaction was malaise, reported in 17% of participants in each of the AS03-adjuvanted 
arms. Grade 3 fever was reported in 8.3% of participants in the high dose + AS03 arm and 3.8% 
in the low-dose + AS03 arm after the second injection. No Grade 3 systemic reactions were 
considered as serious, and all resolved. This higher than expected reactogenicity is hypothesized 
to be due to higher than targeted content of HCP in the Phase I/II clinical material. The lower than 
expected immunogenicity in combination with the higher than expected reactogenicity observed 
in the Phase I/II study indicates that assessment of optimized antigen formulations (with higher 
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antigen dose and lower HCP content) is necessary to select a formulation to progress to Phase III 
evaluation. 
2.3 
Benefit/Risk Assessment  
Neutralizing antibodies specific for the S protein of other coronaviruses have been shown to be 
associated with protection in humans. In animal models, neutralizing and IgG binding antibodies 
specific to the S protein of SARS-CoV-2 induced by vaccination have been shown to be 
associated with protection against challenge. Specifically, a recent investigation showed that 
adoptive transfer of purified IgG from convalescent macaques protects naïve recipient rhesus 
macaques against SARS-CoV-2 challenge in a dose dependent fashion, with relatively low 
neutralizing antibody titers being sufficient to protect against SARS-CoV-2 in this model (38). 
High neutralizing antibody titers (500 with the assay utilized in the study) achieved full protection 
and low-moderate titers (50 with the assay utilized in the study) attained partial protection in 
macaques. These titers were described by the authors as readily achievable by vaccination in 
humans. These data suggest the sufficiency of neutralizing antibodies for protection in the absence 
of cellular and innate immune responses. Other animal studies provide consistent evidence of the 
primary roles of humoral immune responses in protection against SARS-CoV-2 infection and/or 
disease, including in the evaluation of immunological biomarkers associated with protection in 
rhesus macaques for DNA-based or adenovirus-vectored-based reporting neutralizing antibody 
titers and other functional antibody responses as correlates of protective efficacy (39) (40), as well 
as studies showing that potent RBD-specific monoclonal antibodies can protect against 
SARS-CoV-2 challenge in macaques (41) (42). 
Two COVID-19 mRNA vaccine candidates, BNT162b2 from Pfizer/BioNTech, and mRNA-1273 
from Moderna, which induce neutralizing antibody responses show high levels of efficacy against 
COVID-19 illness and severe disease in their Phase III clinical studies (7) (8). 
Thus, there is a growing body of evidence indicating that the induction of antibodies, particularly 
neutralizing antibodies to the S protein of SARS-CoV-2 may be associated with protection against 
COVID-19 (10) (21). 
However, recent preliminary data have shown a decrease in vaccine efficacy in regions where the 
B.1.351 variant is prevalent. Recent preliminary data using an adjuvanted protein sub-unit vaccine 
(Novavax) and the ChAdOx1-nCoV-19 vaccine (AZD1222 [Oxford University/AstraZeneca]) 
showed lower efficacy against mild to moderate COVID-19 in South Africa where the B.1.351 
predominates compared to efficacy in the UK (33) (34) (35). However, data from the 
Ad26.COV2.S vaccine (J&J/Janssen) show high efficacy against severe disease in South Africa. 
Sera from individuals immunized with COVID-19 vaccines show an ability to neutralize the 
variants but to a lesser extent than the prototype strain. This decrease in neutralization is most 
notable against the South African B.1.351 variant which has a E484K mutation in the receptor-
binding domain of the S protein. Thus, there is a potential reduction in benefit of the D614 
vaccines against newly emergent variants. The development of the bivalent vaccine with the D614 
and B.1.351 variant is expected to provide greater benefit through protection against variants 
particularly in light of data showing improved cross-neutralization of the variants from B.1.351 
convalescent sera compared to cross-neutralization of variants from D614 convalescent sera. 
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Preclinical studies with AS03-adjuvanted CoV2 preS dTM monovalent (D614) vaccine in mice 
and NHPs showed an increase in magnitude of neutralizing antibody response and in NHPs 
protection against SARS-CoV-2 challenge compared to unadjuvanted vaccine along with a 
balanced Th1/Th2 profile. Interim data in humans from the Phase I/II study show that the 
neutralizing Ab titers observed after 2 doses of low dose antigen + AS03 were higher than 
following 2 doses of high-dose antigen without adjuvant demonstrating the benefit of the adjuvant 
in increasing the magnitude of immune response and potential dose-sparing effect. Interim data 
also showed induction of neutralizing and binding antibodies in adjuvanted vaccine groups with 
the highest responses induced following 2 injections of the high-dose + AS03 vaccine. 
A potential theoretical risk with coronavirus vaccines is the ability to potentiate immunopathology 
in vaccinees upon exposure to wild-type virus (28), called VAED. The potential for a coronavirus 
vaccine to exacerbate disease is a theoretical concern that has not been documented in humans to 
date, and hence will be explained as a theoretical risk in the Informed Consent document. The 
frequency and severity of COVID-19 among participants in the study will be actively surveilled 
for study halting rules. 
AS03 is an oil-in-water emulsion containing α-tocopherol and squalene. To support the licensing 
of A/H1N1 pandemic influenza vaccines, Pandemrix® and Arepanrix®, in the elderly large clinical 
studies were carried out in participants aged 61 years and above (43). Additional clinical studies 
were conducted in adults ≥ 18 years of age, children from 6 months to 18 years of age, and older 
adults ≥ 65 years of age as well as post-licensure safety studies (24). All of these studies were 
conducted with vaccine antigens derived from the A/H1N1, H5N1, H7N1, and H9N2 strains. 
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 study evaluated efficacy of AS03-adjuvanted TIV compared 
to unadjuvanted TIV among 43 695 volunteers 65 years of age or older (44). Furthermore, it is 
estimated that approximately 90 million doses of AS03-adjuvanted H1N1 vaccines were 
administered post-licensure in the context of H1N1 pandemic control (24). Taken together, these 
studies and post-licensure data showed that AS03 enhanced antibody and T cell responses and that 
the corresponding AS03-containing vaccines had a clinically acceptable safety profile. 
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 (45) 
(46). 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” (47) (48) (49) (50) (51) (52) (53) (54). 
Based on the theoretical concern that vaccination with an adjuvanted vaccine containing potent 
immunostimulants may interfere with immunological self-tolerance, potential Immune-Mediated 
Diseases (pIMDs) are adverse events of special interest (AESIs) undergoing special safety 
monitoring for vaccines containing Adjuvant Systems. pIMDs are a subset of AEs that include 
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autoimmune diseases and other inflammatory and/or neurological disorders of interest which may 
or may not have an autoimmune etiology (see Table 10.4 for a full list). 
The CoV2 preS dTM-AS03 primary series vaccines offer the potential of protection against 
SARS-CoV-2 infection, COVID-19 disease, and its complications with a potential benefit of 
reduction of the associated burden of disease in the study population over 18 years of age. The 
booster vaccines may prolong and broaden protection. In addition, vaccination has the potential to 
reduce viral burden and viral shedding which may have potential indirect benefit in reduction of 
viral transmission and disease burden in the community. 
The safety and immunogenicity of the candidate vaccine formulations have been established in a 
recent VAT00002 primary series interim analysis (key results for primary safety up to 21 days 
after injection 2 and primary and secondary immunogenicity up to 14 days after injection 2). In 
naïve adults, a high proportion of 2-fold and 4-fold or greater rise in neutralizing antibody titers 
were observed after 2 injections in both younger and older adults with similar proportions 
observed across the different antigen dose groups. The magnitude of neutralizing antibody 
responses was higher in 18 to 59 year old age groups compared to the > 60 year old age group. An 
increase in titers with an increase in antigen dose was observed in the 18 to 59 year old age group. 
A single injection did not generate meaningful neutralizing titers above background consistent 
with previous results in the Phase I/II study.  
In non-naïve adults, a single injection increased neutralizing antibody titers to levels above those 
observed after 2 injections in naïve adults in the overall study population. Based on these results, a 
total dose of ≤ 5 µg of S protein antigen was selected to be evaluated as booster vaccine 
candidates in the Supplemental Cohorts in this study 
More detailed information about the known and expected benefits and risks, reasonably expected 
AEs, the potential risks, and uncertainties of CoV2 preS dTM-AS03 may be found in the 
monovalent and bivalent CoV2 preS dTM IB. 
2.3.1 
Risks from Study Participation  
The potential risks of clinical significance and risk management are summarized in Table 2.2. 
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Table 2.2: 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 (with AS03) 
Anaphylactic reactions 
Class-effect for all vaccines (even 
non-adjuvanted). 
Observation period after 
vaccination for early detection 
and treatment. Risk management 
includes exclusion criterion E04 
(see Section 5.2). 
No anaphylactic reactions were 
observed in the Phase I/II and 
Phase II studies for the candidate 
vaccine. 
Enhanced COVID-19 
A theoretical concern with 
coronavirus vaccines is VAED. This 
is the potential (hypothetical) 
increased disease severity in 
vaccinees upon exposure to wild-
type virus (28). This disease 
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 (29) 
(30) (31). 
During the informed consent 
process, the participants 
enrolling in the study will be 
informed of this potential risk. 
COVID-19 episodes and severity 
of illness will be monitored with 
active and passive surveillances 
for the duration of the study. 
Data from Phase I/II active and 
passive case surveillance and 
data from active surveillance 
from Phase II shows no severe 
COVID-19 cases to date and no 
excess of severe COVID-19 
cases in older participants. 
It is anticipated that the design of 
the candidate CoV2 preS dTM 
antigen selected for this study 
will promote generation of 
robust neutralizing antibodies 
over binding (but non-
neutralizing) antibodies, based 
on data generated with other 
coronavirus vaccine antigens 
(10) (21). 
The adjuvanted formulation is 
anticipated to further enhance 
the magnitude of neutralizing 
antibody responses and induce 
balanced Th1/Th2 cell responses 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Risk Management 
(32) (23). Data from NHP 
studies and interim data from the 
Phase I/II study show induction 
of neutralizing Ab titers after 2 
doses of antigen + AS03 
adjuvant shows no evidence of 
Th2 bias and consistent INFg 
responses. 
Thus, these strategies (antigen 
design and adjuvant) mitigate by 
design the theoretical risks of 
immune enhancement of viral 
infection. 
Available data for mRNA 
COVID-19 vaccines (Moderna, 
Pfizer) and a COVID-19 vaccine 
based on viral vector (Janssen) 
do not indicate a risk of vaccine 
enhanced disease (7) (8) (55). 
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 adjuvanted 
vaccines. 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 over 
the duration of the study. No 
pIMDs were observed to date 
during the Phase I/II and Phase 
II studies for the candidate 
vaccine. 
Refer to CoV2 preS dTM 
IB Section 5 and Section 6 
for more information 
regarding potential risks. 
Refer to the CoV2 preS dTM IB 
Section 5 and Section 6 for more 
information regarding the data from 
previous experience with the 
adjuvants in the investigated vaccine. 
 
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3 
Objectives and Endpoints  
The study objectives and the corresponding endpoints are described in Table 3.1. 
Table 3.1: Objectives and endpoints 
Primary Safety (applicable to Original Phase II Cohort as well as Supplemental Phase III Cohorts) 
To assess the safety profile of all participants in 
each age group and in each study Intervention 
Group. 
• 
Presence of unsolicited systemic AEs reported in the 
30 minutes after each vaccination 
• 
Presence of solicited (pre-listed in the participant’s diary 
card [DC] and [electronic] Case Report Form [CRF]) 
injection site reactions and systemic reactions occurring 
up to 7 days after each vaccination  
• 
Presence of unsolicited AEs reported up to 21 days after 
the last vaccination  
• 
Presence of serious adverse events (SAEs) throughout the 
study 
• 
Presence of AESIs throughout the study 
• 
Presence of MAAEs throughout the study 
Primary Immunogenicity-Original Phase II Cohort 
To assess the neutralizing antibody profile 14 days 
after the last vaccination (D36) in SARS-CoV-2-
naïve adults in each study Intervention Group.  
Neutralizing antibody titers will be measured in SARS-CoV-
2-naïve participants for each study Intervention Group against 
the D614G variant. 
• 
Individual serum neutralizing titer at D01 and D36 
• 
Individual serum neutralization titer fold-rise 
post-vaccination relative to D01 at D36 
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D36 relative to D01 
• 
Responders in SARS-CoV-2 naive, defined as 
participants who had baseline values below lower limit of 
quantification (LLOQ) with quantifiable neutralization 
titer above assay LLOQ at D36  
Primary Immunogenicity-Supplemental Cohort 1  
Co-primary objectives: 
1) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is non-
inferior to the response induced by a two‑dose 
priming series with the CoV2 preS dTM-AS03 
(D614) vaccine in naïve, previously 
unvaccinated individuals. 
2) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is superior to 
that observed immediately before booster.  
Neutralizing antibody titers will be measured for each study 
Intervention Group against the D614G strain. 
• 
Individual serum neutralizing titer at D01 and D15 
(Intervention Group) 
• 
Individual serum neutralizing titer at D36 (Comparator 
Group) 
 
 
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Primary Immunogenicity-Supplemental Cohort 2 
Co-primary objectives: 
3) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine  that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response that is 
non-inferior to the response induced by a 
two-dose priming series with the CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated individuals. 
4) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response that is 
superior to that observed immediately before 
booster.  
• 
Individual serum neutralizing titer at D01 and D15 
against the B.1.351 variant for the CoV2 preS dTM-AS03 
(B.1.351) vaccine and the CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine Intervention Groups. 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain for the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Group. 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Secondary Immunogenicity-Original Phase II Cohort  
1) To assess the neutralizing antibody profile at 
D22, D78, D134, D202, D292, and D387 in 
SARS-CoV-2 naïve adults in each study 
Intervention Group. 
2) To assess the neutralizing antibody profile at 
D01, D22, D36, D78, D134, D202, D292, and 
D387 in each study Intervention Group for 
SARS-CoV-2 non-naïve participants. 
3) To assess the binding antibody profile at D01, 
D22, D36, D78, D134, D202, D292, and D387 
in each study Intervention Group in SARS-
CoV-2 naïve and non-naïve participants.  
Endpoints for secondary immunogenicity objectives #1 and 
#2: 
Neutralizing antibody titers will be measured in participants 
for each study Intervention Group against the D614G variant. 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise 
post-vaccination relative to D01 at each pre-defined time 
point  
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined post-
vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Endpoints for secondary immunogenicity objective #3: 
Binding antibody concentrations will be measured in 
participants for each study Intervention Group against the 
D614G variant. 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold-rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
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vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined post-
vaccination timepoint 
Secondary Immunogenicity-Supplemental Cohort 1 
Conditional secondary objectives: conditional on 
meeting the primary objectives for Supplemental 
Cohort 1: 
1) To demonstrate, in adults 18-55 years of age, 
previously vaccinated with the CoV2 preS 
dTM-AS03 (D614) vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces an immune response that is noninferior 
to the response induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
2) To demonstrate, in adults 18-55 years of age, 
previously vaccinated with CoV2 preS dTM-
AS03 (D614) vaccine, that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
an immune response that is superior to that 
observed immediately before booster.  
Conditional secondary objectives: conditional on 
meeting the conditional secondary objectives (1) 
and (2) for Supplemental Cohort 1: 
3) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces an immune 
response that is non-inferior to the response 
induced by a two-dose priming series with 
CoV2 preS dTM-AS03 (D614) vaccine in 
naïve, previously unvaccinated individuals. 
4) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces an immune 
response that is superior to that observed 
immediately before booster. 
 
Conditional secondary objectives: conditional on 
meeting the conditional secondary objectives (3) 
and (4) for Supplemental Cohort 1: 
5) To demonstrate, in adults 18-55 years of age 
previously vaccinated with an 
adenovirus-vectored COVID-19 vaccine, that a 
booster dose of CoV2 preS dTM-AS03 (D614) 
vaccine induces an immune response that is 
non-inferior to the response induced by a 
two‑dose priming series with CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated, individuals.  
Endpoints for conditional secondary objectives #1 and #2: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (group primed with CoV2 preS 
dTM-AS03 [D614] vaccine) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
 
Endpoints for conditional secondary objectives #3 and #4: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (groups primed with mRNA 
COVID-19 vaccines) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Endpoints for conditional secondary objectives #5 and #6: 
• 
Individual serum neutralizing titer against the D614G 
strain at D01 and D15 (group primed with 
adenovirus-vectored COVID-19 vaccine) 
• 
Individual serum neutralizing titer against the D614G 
strain at D36 (Comparator Group) 
Endpoints for secondary objectives #7 - #10: 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain, at D15 relative to D01, in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain, at D36 relative to D01 (Comparator Group) 
Endpoints for secondary objectives #11 - #14: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
Endpoints for secondary objective #15: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 to 
B.1.351 variant in the Comparator Group 
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6) To demonstrate, in adults 18-55 years of age 
previously vaccinated with adenovirus-vectored 
COVID-19 vaccines, that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
an immune response that is superior to that 
observed immediately before booster. 
Conditional secondary objective: conditional on 
meeting the conditional secondary objectives (5) 
and (6) for Supplemental Cohort 1, the following 
objectives will be sequentially tested: 
7) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (D614) vaccine induces 
a seroresponse that is non-inferior to the 
seroresponse induced by a two‑dose priming 
series with the CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
8) To demonstrate, in adults 18-55 years of age 
previously vaccinated with the CoV2 preS 
dTM-AS03 (D614) vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine 
induces a seroresponse that is noninferior to the 
seroresponse induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
9) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (D614) vaccine induces a 
seroresponse that is non-inferior to the 
seroresponse induced by a two-dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
10) To demonstrate, in adults 18-55 years of age 
previously vaccinated with an adenovirus-
vectored COVID-19 vaccine, that a booster 
dose of CoV2 preS dTM-AS03 (D614) vaccine 
induces a seroresponse that is noninferior to the 
seroresponse induced by a two‑dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated, 
individuals.  
Secondary objectives: 
11) To describe, in adults 18-55 years of age 
previously vaccinated with the Moderna 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
12) To describe, in adults 18-55 years of age 
previously vaccinated with the 
Endpoints for secondary objective #16: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 
against the D614G strain in the Comparator Group 
Endpoints for secondary objective #17:  
• 
Individual serum neutralizing titer to the D614G strain 
and B.1.351 variant in each Intervention Group at each 
pre-defined timepoint 
• 
Individual serum neutralization titer fold-rise post-
vaccination to the D614G strain and B.1.351 variant at 
each pre-defined timepoint relative to D01 in each 
Intervention Group  
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) to the D614G strain and 
B.1.351 variant at each pre-defined timepoint relative to 
D01 in each study Intervention Group 
Endpoints for secondary objective #18: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objective #19: 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point relative to D01 
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Oxford/AstraZeneca vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (D614) vaccine.  
13) To describe, in adults 18-55 years of age 
previously vaccinated with the J&J/Janssen 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
14) To describe, in adults 18-55 years of age 
previously vaccinated with any COVID-19 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (D614) vaccine. 
15) To compare the neutralizing antibody profile to 
the B.1.351 variant at D01 and D15 in the 
booster groups and at D36 in the Comparator 
group. 
16) To compare the neutralizing antibody profile to 
the B.1.351 variant at D01 and D15 in the 
booster groups and neutralizing antibody 
profile to the D614G strain at D36 in the 
Comparator Group. 
17) To assess the neutralizing antibody profile to 
the D614G strain and to the B.1.351 variant at 
D29, D91, D181, and D366 overall, and by age 
group, by priming platform, and by priming 
vaccine. 
18) To describe the neutralizing antibody profile to 
the B.1.351 variant and to the D614G strain at 
D01 and D15 in adults older than 55 years of 
age in the booster group, overall, by priming 
platform, and by priming vaccine. 
19) To assess the binding antibody profile at D01, 
D15, D29, D91, D181, and D366 after booster 
immunization in adults previously vaccinated 
with COVID-19 vaccines, overall and by age 
group, by priming platform, and by priming 
vaccine. 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined 
post-vaccination timepoint 
Secondary Immunogenicity-Supplemental Cohort 2 
Conditional co-secondary objectives: conditional on 
meeting the primary immunogenicity objectives for 
Supplemental Cohort 2: 
1) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine induces 
an immune response that is non-inferior to the 
response induced by a two-dose priming series 
with CoV2 preS dTM-AS03 (D614) vaccine in 
naïve, previously unvaccinated individuals. 
2) To demonstrate in adults 18-55 years of age 
and previously vaccinated with an mRNA 
COVID-19 vaccine, that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
Endpoints for conditional secondary objectives #1 and #2: 
• 
Individual serum neutralizing titer at D01 and D15 
against the B.1.351 variant for the CoV2 preS dTM-AS03 
(B.1.351) vaccine and the CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine Intervention Groups. 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain for the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Group. 
• 
Individual serum neutralizing titer against the D614 strain 
at D36 (Comparator Group) 
Endpoints for conditional secondary objectives #3: 
• 
Individual serum neutralizing titer at D15 against the 
B.1.351 variant for the CoV2 preS dTM-AS03 (B.1.351) 
vaccine and the CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine Intervention Groups  
• 
Individual serum neutralizing titer at D36 against the 
B.1.351 variant for the Comparator Group 
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vaccine induces an immune response that is 
superior to that observed immediately before 
booster. 
Conditional secondary objective: conditional on 
meeting the primary immunogenicity objectives (1) 
and (2) and the co-secondary objectives for 
Supplemental Cohort 2: 
3) To demonstrate in adults 18-55 years of age 
and previously vaccinated with the 
Pfizer/BioNTech vaccine, that a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces an immune response against 
the B.1.351 variant at D15 that is superior to 
that against the B.1.351 variant at D36 in the 
Comparator Group. 
Conditional secondary objectives: conditional on 
meeting the conditional secondary objective (3) for 
Supplemental Cohort 2, the following objectives 
will be sequentially tested: 
4) To demonstrate in adults 18-55 years of age and 
previously vaccinated with the 
Pfizer/BioNTech vaccine that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine induces a seroresponse that is non-
inferior to the seroresponse induced by a 
two‑dose priming series with the CoV2 preS 
dTM-AS03 (D614) vaccine in naïve, previously 
unvaccinated individuals. 
5) To demonstrate in adults 18-55 years of age and 
previously vaccinated with an mRNA COVID-
19 vaccine, that a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine induces a 
seroresponse that is non-inferior to the 
seroresponse induced by a two-dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
Secondary objectives: 
6) To describe, in adults 18-55 years of age and 
previously vaccinated with an adenovirus-
vectored COVID-19 vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine compared to 
the response induced by a two dose priming 
series with CoV2 preS dTM-AS03 (D614) 
vaccine in naïve, previously unvaccinated 
individuals. 
7) To describe, in adults 18-55 years of age and 
previously vaccinated with an adenovirus-
Endpoints for secondary objectives #4 - #5: 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the B.1.351 variant for the CoV2 preS dTM-
AS03 (B.1.351) vaccine and the CoV2 preS dTM-AS03 
(D614 + B.1.351) vaccine Intervention Groups 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain for the CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine Intervention Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] against the D614G 
strain at D36 relative to D01 (Comparator Group) 
Endpoints for secondary objectives #6 - #11: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain and to the B.1.351 variant in 
each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain and to the B.1.351 variant in each Intervention 
Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain and to the B.1.351 variant in 
each study Intervention Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
D01, against the D614G strain and to the B.1.351 variant 
in each study Intervention Group 
Endpoints for secondary objective #12: 
• 
Individual serum neutralizing titer at D01 and D15 to the 
B.1.351 variant in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 to the 
B.1.351 variant in the Comparator Group 
Endpoints for secondary objective #13: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralizing titer at D01 and D36 
against the D614G strain in the Comparator Group 
Endpoints for secondary objective #14: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [post/pre] at D15 relative to 
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vectored COVID-19 vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine compared to 
that observed immediately before booster. 
8) To describe, in adults 18-55 years of age 
previously vaccinated with the Moderna 
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine. 
9) To describe, in adults 18-55 years of age 
previously vaccinated with the 
Oxford/AstraZeneca vaccine, the immune 
response to a booster dose of CoV2 preS dTM-
AS03 (B.1.351) vaccine or CoV2 preS dTM-
AS03 (D614 + B.1.351) vaccine. 
10) To describe, in adults 18-55 years of age 
previously vaccinated with the J&J/Janssen  
vaccine, the immune response to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine. 
11) To describe, in adults 18-55 years previously 
vaccinated with any COVID-19 vaccine, the 
immune response a booster dose of CoV2 preS 
dTM-AS03 (B.1.351) vaccine or CoV2 preS 
dTM-AS03 (D614 + B.1.351) vaccine. 
12) To compare the neutralizing antibody profile to 
the B.1.351 variant at D15 in each study 
Intervention Group and D36 in the Comparator 
Group, overall, by priming platform, and by 
priming vaccine. 
13) To compare the neutralizing antibody profile 
against the D614G strain at D15 following a 
booster dose of CoV2 preS dTM-AS03 (D614 
+ B.1.351) vaccine and at D36 in the 
Comparator Group. 
14) To describe, among adults previously primed 
with CoV2 preS dTM-AS03 (D614) vaccine, 
the immune response induced by a booster dose 
of  CoV2 preS dTM-AS03 (D614) vaccine or 
CoV2 preS dTM-AS03 (B.1.351) vaccine or 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine, overall, by priming dose, and by age. 
15) To assess the neutralizing antibody profile to 
the D614G strain at D29, D91, D181, and 
D366 in each study Intervention Group, 
overall, by age group, by priming platform, and 
by priming vaccine. 
16) To assess the neutralizing antibody to the 
B.1.351 variant at D29, D91, D181, and D366 
in each study Intervention Group, overall, by 
age group, by priming platform, and by 
priming vaccine. 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objectives #15 and #16: 
neutralizing responses to be evaluated against the D614G 
strain and to the B.1.351 variant 
• 
Individual serum neutralizing titers in each Intervention 
Group at each pre-defined timepoint 
• 
Individual serum neutralization titer fold-rise post-
vaccination at each pre-defined timepoint relative to D01 
in each Intervention Group  
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined 
timepoint relative to D01 in each study Intervention 
Group 
Endpoints for secondary objective #17: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
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17) To describe, in adults over 55 years of age, the 
neutralizing antibody profile to the B.1.351 
variant and to the D614G strain at D01 and 
D15 by Intervention Group, overall, by priming 
platform, and by priming vaccine. 
18) To describe in adults previously vaccinated 
with the Pfizer/BioNTech vaccine the immune 
response (as assessed by pseudovirus 
neutralization assay geometric mean titers and 
geometric mean titer ratios) to a booster dose 
of CoV2 preS dTM-AS03 (B.1.351) vaccine 
exploratory formulations, overall and by age 
stratum. 
19) To assess the binding antibody profile at D01, 
D15, D29, D91, D181, and D366 after booster 
immunization in adults previously vaccinated 
with COVID-19 vaccines, overall and by age 
group, by priming platform, and by priming 
vaccine. 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objective #18: 
• 
Individual serum neutralizing titer at D01 and D15 
against the D614G strain in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 against the D614G 
strain in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
against the D614G strain in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold-or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, against the D614G strain in each study Intervention 
Group 
• 
Individual serum neutralizing titer at D01 and D15 profile 
to the B.1.351 variant in each Intervention Group  
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at D15 profile to the B.1.351 
variant in each Intervention Group 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at D15 relative to D01 
profile to the B.1.351 variant in each study Intervention 
Group 
• 
Seroresponse rate, defined as a 4-fold or greater rise in 
serum neutralization titer [pre/post] at D15 relative to 
D01, profile to the B.1.351 variant in each study 
Intervention Group 
Endpoints for secondary objective #19: 
• 
Individual antibody concentration at each pre-defined 
time point 
• 
Individual antibody fold-rise post-vaccination relative to 
D01 at each pre-defined post-vaccination time point 
• 
2-fold-rise and 4-fold rise (fold-rise in antibody 
concentration [post/pre] ≥ 2 and ≥ 4) at each pre-defined 
post-vaccination time point 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable antibody 
concentration above assay LLOQ at pre-defined post-
vaccination timepoints and participants with baseline 
values above LLOQ with a 4-fold increase in binding 
antibody concentration at each pre-defined post-
vaccination timepoint 
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Secondary Safety-Original Phase II Cohort 
1) To describe the occurrences of laboratory-
confirmed symptomatic COVID-19 in all 
participants in each study Intervention Group. 
2) To describe the occurrences of serologically-
confirmed SARS-CoV-2 infection in each study 
Intervention Group. 
Endpoints for secondary safety objective #1: 
• 
Occurrences of laboratory-confirmed symptomatic 
COVID-19 (based on locally-confirmed or 
protocol-defined NAAT) 
• 
Occurrences of symptomatic COVID-19 episodes 
associated with hospitalization. 
• 
Occurrences of severe symptomatic COVID-19 
• 
Death associated with symptomatic COVID-19 
Endpoints for secondary safety objective #2: 
• 
Occurrences of serologically-confirmed SARS-CoV-2 
infection 
Secondary Safety-Supplemental Cohorts 1 and 2 
To describe the occurrences of laboratory-
confirmed symptomatic COVID-19, overall and in 
each study Intervention Group 
• 
Occurrences of laboratory-confirmed symptomatic 
COVID-19 (based on locally-confirmed or 
protocol-defined NAAT) 
• 
Occurrences of symptomatic COVID-19 episodes 
associated with hospitalization. 
• 
Occurrences of severe symptomatic COVID-19 
• 
Death associated with symptomatic COVID-19 
Exploratory Immunogenicity-Original Phase II Cohort  
1) To describe the ratio between neutralizing 
antibodies and binding antibodies. 
2) To assess the T-cell cytokine profile at D01, 
D22 and D36 in a subset of participants. 
3) To further assess the cellular immune response 
at D01, D22, D36, D134 and D387 in a subset 
of participants. 
4) To assess the mucosal antibody response at 
D01, D22, D36, and D134 in a subset of 
participants. 
5) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains  
Endpoint for exploratory immunogenicity objective #1: 
• 
Ratio between binding antibody (enzyme-linked 
immunosorbent assay [ELISA]) concentration and 
neutralizing antibody titer 
Endpoint for exploratory immunogenicity objective #2: 
• 
T-helper cell (Th)1 and Th2 cytokines measured in whole 
blood following stimulation with full-length S protein at 
D01, D22 and D36. 
Endpoint for exploratory immunogenicity objective #3: 
• 
Other cellular-mediated immunity (CMI) assessments 
may be performed by Intracellular Cytokine Staining 
or/and enzyme-linked immunospot (ELISpot) assays. 
Endpoints for mucosal antibody responses (objective #4) will 
be specified in a supplemental analysis plan. 
Endpoints for exploratory immunogenicity objective #5: 
• 
Neutralizing antibody responses to emergent variant 
strains will be measured in participants for each study 
Intervention Group: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
2-fold-rise and 4-fold-rise in serum neutralization titer 
[post/pre] (fold-rise ≥ 2 and ≥ 4) at each pre-defined post-
vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
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LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Exploratory Immunogenicity-Supplemental Cohorts 
Supplemental Cohorts 1 and 2: 
1) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains 
2) To further describe humoral immune responses 
based on relevant emerging assays, if 
applicable 
Supplemental Cohort 2: 
3) To assess the cellular immune response at D01, 
D15, D29, D91, and D366 in a subset of 
participants. 
4) To assess the mucosal antibody response at 
D01, D15, and D91 in a subset of participants. 
5) To describe the neutralizing antibody response 
to emergent SARS-CoV-2 variant strains 
6) To further describe humoral immune responses 
based on relevant emerging assays, if 
applicable 
Supplemental Cohorts 1 and 2: 
7) To describe the neutralizing antibody response, 
by presence or absence of baseline high-risk 
medical conditions 
 
 
Endpoints for exploratory immunogenicity objective #1 and 
#5: 
Neutralizing antibody responses to emergent variant strains 
will be measured: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] at each pre-defined post-vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
Endpoint for exploratory immunogenicity objective #2 and 
#6: 
• 
Biomarker measurement at baseline and/or post-
vaccination visits 
Endpoint for exploratory immunogenicity objective #3: 
• 
Other CMI assessments may be performed by 
Intracellular Cytokine Staining or/and enzyme-linked 
immunospot (ELISpot) assays. 
Endpoint for mucosal antibody responses (objective #4) will 
be specified in a supplemental analysis plan 
Endpoints for exploratory immunogenicity objective #7: 
Neutralizing antibody responses to D614G and B.1.351 strains 
will be measured: 
• 
Individual serum neutralizing titer at each pre-defined 
time point 
• 
Individual serum neutralization titer fold-rise post-
vaccination relative to D01 at each pre-defined time point 
• 
≥ 2-fold-rise and ≥ 4-fold-rise in serum neutralization titer 
[post/pre] at each pre-defined post-vaccination timepoint 
• 
Responders, defined as participants who had baseline 
values below LLOQ with quantifiable neutralization titer 
above assay LLOQ at each pre-defined post-vaccination 
timepoint and participants with baseline values above 
LLOQ with a 4-fold increase in neutralizing antibody 
titers at each pre-defined post-vaccination timepoint 
 
 
 
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4 
Study Design  
4.1 
Overall Design  
The design of the study is summarized in Table 4.1. 
Table 4.1: Overall design 
Type of design 
Parallel, multi-center 
Phase 
II/III 
Control method (for 
Supplemental Phase III Cohorts 
only) 
active comparator  
(comparator = CoV2 preS dTM-AS03 [D614] administered 
as a 2-injection primary series) 
Study population 
Adults 18 years of age and older 
Level and method of blinding 
Original Phase II Cohort: Modified double-blind 
(observer-blind) 
• Blinding for vaccine group assignment: participants, 
outcome assessors, Investigators, laboratory personnel, 
Sponsor study staff, those administering the study 
intervention if not involved in preparing study 
intervention 
• No blinding for vaccine group assignment: those 
preparing the study interventions  
Supplemental Phase III Cohorts: 
• Supplemental Cohorts Comparator Group will be open-
label. 
• Supplemental Cohort 1 Booster Group will be open-
label. 
• Supplemental Cohort 2 will involve sequential 
randomization to main arms (CoV2 preS dTM-AS03 
[D614], CoV2 preS dTM-AS03 [B.1.351], and CoV2 
preS dTM-AS03 [D614 + B.1.351]) followed by 
randomization to exploratory CoV2 preS dTM-AS03 
(B.1.351) arms after filling the former. Intervention and 
exploratory groups will be modified double-blind 
(observer-blinded) as described 
Study intervention assignment 
method 
Participants will be screened for eligibility criteria at the 
time of inclusion. 
Original Phase II Cohort: 
The randomization was stratified by age groups (18-59 
years of age and 60 years of age and older), baseline SARS-
CoV-2 rapid serodiagnostic test positivity 
(Positive/Negative), and high-risk medical conditions 
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(Yes/No). 
Eligible participants were randomly assigned to one of 
3 study groups in a 1:1:1 ratio, corresponding to one of 3 
formulations of CoV2 preS dTM-AS03 vaccine (with 
different antigen doses). 
Supplemental Phase III Cohorts: 
• Supplemental Cohort 1: previously-vaccinated 
participants will be stratified based on the priming 
vaccine received 4 to < 10 months prior and by age 
group (18-55 years of age and 56 years of age and older) 
and will receive a single booster dose of CoV2 preS 
dTM-AS03 (D614).  
• Supplemental Cohort 2, Main Arms: participants 
previously vaccinated with an mRNA or 
adenovirus-vectored COVID-19 vaccine will be 
stratified based on the vaccine received 4 to 
< 10 months prior and by age group (18-55 years of age 
and 56 years of age and older) and randomly assigned to 
1 of the following booster formulations in a 1:1 ratio: 
o CoV2 preS dTM-AS03 (B.1.351) 
o CoV2 preS dTM-AS03 (D614 + B.1.351) 
Participants previously vaccinated 4 to < 10 months 
prior with the protein-based vaccine in the Original 
Phase II Cohort will be stratified by age group (18-55 
years of age and 56 years of age and older) and 
randomly assigned to 1 of the following booster 
formulations in a 9:1 ratio (D614:B.1.351) for younger 
adults and a 1:1 ratio for older adults:   
o CoV2 preS dTM-AS03 (D614) 
o CoV2 preS dTM-AS03 (B.1.351) 
• Supplemental Cohort 2 Exploratory B.1.351 Arms: 
participants previously vaccinated with the 
Pfizer/BioNTech mRNA vaccine will be enrolled after 
completion of enrollment of the above booster arms in 
Cohort 2 and will be stratified by age group (18-55 
years of age and 56 years of age and older) and 
randomly assigned to receive 1 of the following CoV2 
preS dTM (B.1.351) formulations in a 1:1:1:1 ratio: 
o 2.5 µg antigen with AS03 adjuvant 
o 2.5 µg antigen with half-dosea AS03 adjuvant 
                                                 
a  The half dose of AS03 and the full dose of AS03 contain amounts of tocopherol of 5.93 mg and 11.86 mg, 
respectively 
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o 5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with no adjuvant 
• Supplemental Cohorts Comparator Group: 
SARS-CoV-2-naïve, unvaccinated, adults who are 
18-55 years of age will be given CoV2 preS dTM-AS03 
(D614) as a primary series vaccination of 2 injections 
given 21 days apart.      
• Supplemental Cohort Subsets and Assessment of 
Immunogenicity to Emerging Variants of Concern: A 
randomized subset of 70 participants in Cohort 1 will be 
tested for additional SARS-CoV-2 variants of concern 
including Delta. No additional sample collection, 
procedures, or visits are required for this subset. A 
randomized subset of 82 participants in Cohort 2  
comprised of younger adults (18 to 55 years of age) will 
provide samples for cellular immune response and 
mucosal antibody assessments and will also be tested for 
additional variants of concern including Delta. 
Number of participants 
Original Phase II Cohort: A total of 720 participants are 
planned to be enrolled. After stratification by age-group 
(18-59 years and ≥ 60 years), baseline SARS-CoV-2 rapid 
serodiagnostic test positivity (Positive/Negative [as 
determined at the time of enrollment]) and high-risk 
medical conditions (Yes/No), participants will be randomly 
assigned to the study groups. For all study arms, half of the 
participants will be 18-59 years of age and half of the 
participants will be 60 years or older. Additionally, up to 
20% of participants in each group may be test-positive on 
the rapid serodiagnostic test at enrollment.  
A randomized subset of 112 (40 participants/group) 
participants will provide samples for cellular immune 
response and mucosal antibody assessments. 
See Table 4.2. 
Supplemental Phase III Cohorts: A total of 3660 
participants are planned to be enrolled and will be stratified 
as follows: 
Supplemental Cohort 1: Adults vaccinated 4 to 
< 10 months prior will be stratified by primary vaccine and 
by age to receive a single booster dose of CoV2 preS 
dTM-AS03 (D614):  
• Primed with Pfizer/BioNTech: 
o 18-55 years of age: 215 participants 
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o 56 years of age and older: 50 participants 
• Primed with Moderna: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• Primed with Oxford University/AstraZeneca: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• Primed with J&J/Janssen: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
Supplemental Cohort 2, Main Arms: Adults vaccinated 
4 to < 10 months prior will be stratified by primary vaccine 
and by age and randomized to receive 1 of the following as 
a single booster dose: 
• Primed with Pfizer/BioNTech: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 515 participants 
▪ 56 years of age and older: 50 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 515 participants 
▪ 56 years of age and older: 50 participants 
• Primed with CoV2 preS dTM-AS03 (actual numbers 
will depend on eligibility and consent for Cohort 2 
participation of participants enrolled in the Original 
Phase II Cohort; numbers below are estimates and 
subject to change): 
o CoV2 preS dTM-AS03 (D614): 
▪ 18-55 years of age: 270 participants 
▪ 56 years of age and older: 75 participants 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 30 participants 
▪ 56 years of age and older: 75 participants 
• Primed with Moderna: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
• Primed with Oxford University/AstraZeneca: 
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o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
• Primed with J&J/Janssen: 
o CoV2 preS dTM-AS03 (B.1.351): 
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
o CoV2 preS dTM-AS03 (D614 + B.1.351):  
▪ 18-55 years of age: 75 participants 
▪ 56 years of age and older: 25 participants 
Supplemental Cohort 2 Exploratory B.1.351 Arms: 
Adults vaccinated 4 to < 10 months prior with the 
Pfizer/BioNTech mRNA vaccine will be stratified by age 
and randomized to receive a single booster dose of 1 of the 
following CoV2 preS dTM (B.1.351) formulations: 
• 2.5 µg antigen with full-dose AS03 adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 2.5 µg antigen with half-dose AS03 adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 5 µg antigen with half-dose AS03 adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
• 5 µg antigen with no adjuvant: 
o 18-55 years of age: 75 participants 
o 56 years of age and older: 25 participants 
Supplemental Cohorts Comparator Group: SARS-CoV-
2-naïve, unvaccinated, adults will be enrolled into a parallel, 
non-randomized arm and receive CoV2 preS dTM-AS03 
(D614) as a primary series vaccination of 2 injections given 
21 days apart: 
• 18-55 years of age only: 515 participants 
Supplemental Cohorts Subsets and Assessment of 
Immunogenicity to Emerging Variants of Concern: A 
randomized subset of 70 participants in Cohort 1 will be 
tested for additional SARS-CoV-2 variants of concern 
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including Delta. No additional sample collection, 
procedures, or visits are required for this subset. A 
randomized subset of 82 participants in Cohort 2 comprised 
of younger adults (18 to 55 years of age) will provide 
samples for cellular immune response and mucosal antibody 
assessments and will also be tested for additional variants of 
concern including Delta. See Table 4.5 
Intervention groups 
Original Phase II Cohort:  
Participants will be randomized to receive 2 injections 
21 days apart of one of the 3 different doses of CoV2 preS 
dTM antigen with fixed dose of AS03 adjuvant. 
Supplemental Phase III Cohorts: 
• Supplemental Cohort 1: Previously-vaccinated 
participants will be stratified based on the priming 
vaccine received 4 to < 10 months prior and by age 
group (18-55 years of age and 56 years of age and older) 
and will receive a single booster dose of CoV2 preS 
dTM-AS03 (D614).  
• Supplemental Cohort 2, Main Arms:  
Participants previously vaccinated with an 
authorized/approved mRNA or adenovirus-vectored 
COVID-19 vaccine will be stratified based on the 
vaccine received 4 to < 10 months prior and by age 
group (18-55 years of age and 56 years of age and older) 
and randomly assigned to 1 of the following booster 
formulations in a 1:1 ratio: 
o CoV2 preS dTM-AS03 (B.1.351) 
o CoV2 preS dTM-AS03 (D614 + B.1.351) 
Participants previously vaccinated with CoV2 preS 
dTM-AS03 (D614) as a primary series in the Original 
Phase II Cohort will be stratified by age group 
(18-55 years of age and 56 years of age and older) and 
randomly assigned to 1 of the following booster 
formulations in a 9:1 ratio (D614:B.1.351) for younger 
adults and a 1:1 ratio for older adults:  
o CoV2 preS dTM-AS03 (D614)  
o CoV2 preS dTM-AS03 (B.1.351) 
• Supplemental Cohort 2 Exploratory B.1.351 Arms: 
Participants previously vaccinated with the 
Pfizer/BioNTech mRNA vaccine will be enrolled after 
completion of enrollment of the above booster arms in 
Cohort 2 and will be stratified by age group 
(18-55 years of age and 56 years of age and older) and 
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randomly assigned to receive 1 of the following CoV2 
preS dTM (B.1.351) formulations in a 1:1:1:1 ratio: 
o 2.5 µg antigen with AS03 adjuvant 
o 2.5 µg antigen with half-dosea AS03 adjuvant 
o 5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with no adjuvant 
• Supplemental Cohorts Comparator Group: 
SARS-CoV-2-naïve, unvaccinated, adults who are 
18-55 years of age will be given CoV2 preS dTM-AS03 
(D614) as a primary series vaccination of 2 injections 
given 21 days apart.      
• Supplemental Cohort Subsets and Assessment of 
Immunogenicity to Emerging Variants of Concern: A 
randomized subset of 70 participants in Cohort 1 will be 
tested for additional SARS-CoV-2 variants of concern 
including Delta. No additional sample collection, 
procedures, or visits are required for this subset. A 
randomized subset of 82 participants in Cohort 2 
comprised of younger adults (18 to 55 years of age) will 
provide samples for cellular immune response and 
mucosal antibody assessments and will also be tested for 
additional variants of concern including Delta. 
Total duration of study 
participation 
Original Phase II Cohort: Approximately 365 days post-
last injection (ie, approximately 386 days total) 
Supplemental Cohorts 1 and 2: Approximately 365 days 
post-booster injection (ie, approximately 366 days total) 
Supplemental Cohorts Comparator Group: 
Approximately 365 days post-injection 2 (ie, approximately 
386 days total) 
Countries 
Primary Series: United States, Honduras  
Supplemental Cohorts: to be determined (TBD) 
Use of an independent Data and 
Safety Monitoring Board, Dose 
Escalation Committee, or similar 
review group 
No  
Disclosure Statement: 
Original Phase II Cohort and Supplemental Cohort 2 Intervention Groups: Participants, outcome 
assessors, Investigators, laboratory personnel, Sponsor study staff, and those administering the 
                                                 
a The half dose of AS03 and the full dose of AS03 contain amounts of tocopherol of 5.93 mg and 11.86 mg, 
respectively 
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study intervention if not involved in preparing the study intervention will be blinded to 
Intervention Group; and those preparing the study interventions will be unblinded to vaccine 
assignment group.  
This does not apply to the Supplemental Cohorts Booster Groups and the Supplemental Cohorts 
Comparator Group which will be open-label. 
4.1.1 Intervention Groups and Duration for the Original Phase II Cohort  
Table 4.2: Planned Original Phase II Cohort sample size and approximate size of subsets  
 
Study Intervention Groups 
 
Group 1 
Group 2 
Group 3 
 
CoV2 preS 
dTM-AS03  
(5 µg antigen) 
CoV2 preS 
dTM-AS03 
(10 µg antigen) 
CoV2 preS 
dTM-AS03 
(15 µg antigen) 
Total Overall 
240 
240 
240 
SARS-CoV-2 
serodiagnostic test at 
baseline 
Negative 
At least 192* 
At least 192* 
At least 192* 
Positive 
Up to 48† 
Up to 48† 
Up to 48† 
Age Groups 
Adults (18-59 years) 
120 
120 
120 
Older adults (≥ 60 years) 
120 
120 
120 
Cellular Immunity and Mucosal subset‡ 
40 
(20/age group) 
40 
(20/age group) 
40 
(20/age group) 
* 96 per age group 
† up to 24 per age group 
‡ Participants SARS-CoV-2 serodiagnostic test negative at baseline would be randomized to this subset. 
All participants in the Original Phase II Cohort were to receive 2 vaccine injections given 3 weeks 
apart: the first injection will be at D01 (VAC1) and the second injection will be at D22 (VAC2). 
Blood samples were planned be collected from all participants prior to each injection, 14 days, 
2 months, 4 months, 6 months, 9 months, and 12 months after last injection. Blood samples 
collected from participants will be used for serological assessments in the study. Whole blood, 
PBMCs, and saliva samples were to be collected from a subset of participants to assess cellular 
immune responses and mucosal antibody responses. 
Reactogenicity was assessed by collecting solicited AEs for 7 days after each vaccination, 
unsolicited AEs for 21 days after the last vaccination, and SAEs, MAAEs, and AESIs are being 
assessed for the duration of the study. All participants will be followed for the duration of the 
study to capture occurrences of COVID-19 through passive surveillance wherein participants will 
be instructed to contact the site if they experience symptoms/conditions of a COVID-19-like 
illness at any time during the study. In addition, active surveillance will be undertaken in all 
participants wherein all participants will be contacted once every 2 weeks starting at the D43 
contact to enquire about development of COVID-19-like illness. 
The duration of each Original Phase II Cohort participant’s participation in the study will be 
approximately 365 days post-injection 2 (ie, approximately 386 days total). 
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In the event that the vaccine formulation evaluated in this study is deemed safe and effective by 
regulatory authorities, this authorized/approved vaccine may be offered to eligible participants in 
this study who received a formulation considered less effective to that authorized by the 
regulatory authorities, if permitted by local regulations and in alignment with local 
recommendations. 
If an approved/authorized vaccine is available in the country or region where the study is 
conducted, Investigators will discuss this information with prospective study participants at the 
time of informed consent who will be encouraged to obtain the approved/authorized vaccine if 
applicable to them. Recruitment of eligible participants will proceed only if, despite 
encouragement, the candidate participant expresses no intention to seek an authorized or approved 
vaccine at least until completion of the key follow-up timepoint (D43) for informing progression 
to Phase III and dose selection. 
If the participant is enrolled and seeks vaccination of an authorized/approved vaccine outside of 
the study, he/she will be encouraged to discuss this intention proactively with the study 
Investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved 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. If the visit occurs more than 1 month after the D134 visit, a PBMC sample will also 
be collected if the participant is in the cellular immunity and mucosal subset instead of the D387 
sample. Participants will not receive the second vaccination if they have received the 
authorized/approved vaccine between the first and second scheduled vaccination. 
Interim data from this study will be utilized to inform progression to Phase III and selection of 
antigen dose. This interim analysis will occur after availability of reactogenicity data up to 
21 days post-injection 2 and neutralizing antibody responses at D01 and 14 days post-injection 2 
in all participants.  
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4.1.2 Intervention Groups and Duration for Supplemental Phase III Cohorts  
Table 4.3: Planned sample sizes for Supplemental Cohorts 1 and 2  
 
Cohort 1 
Cohort 2 Main Arms 
Comparator 
 
Booster 
Booster 
Booster 
Booster 
Primary 
Series 
 
CoV2 preS 
dTM-AS03 
(D614) 
 
CoV2 preS 
dTM-AS03 
(B.1.351) 
 
CoV2 preS 
dTM-AS03 
(D614 + 
B.1.351) 
CoV2 preS 
dTM-AS03 
(D614) 
 
CoV2 preS 
dTM-AS03 
(D614) 
 
Total Overall 
565 
970 
865 
345 
515 
SARS-CoV-2-naïve, 
Unvaccinated, Adults (18-55 
years) 
-- 
-- 
-- 
-- 
515 
Pfizer/BioNTech 
Adults (18-
55 years) 
215 
515 
515 
-- 
-- 
Older adults 
(≥ 56 years) 
50 
50 
50 
-- 
-- 
CoV2 preS dTM-
AS03 (Original 
Phase II Cohort) 
Adults (18-
55 years) 
-- 
30 
-- 
270 
-- 
Older adults 
(≥ 56 years) 
-- 
75 
-- 
75 
-- 
Moderna 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
Oxford 
University/ 
AstraZeneca 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
J&J/Janssen 
Adults (18-
55 years) 
75 
75 
75 
-- 
-- 
Older adults 
(≥ 56 years) 
25 
25 
25 
-- 
-- 
  
 
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Table 4.4: Planned sample sizes for Supplemental Cohort 2 Exploratory B.1.351 Arms  
 
CoV2 preS dTM (B.1.351) 
 Treatment Groups 
 
2.5 µg with 
full-dose 
AS03 
5 µg with 
half-dose 
AS03 
5 µg with no 
adjuvant 
2.5 µg with 
half-dose 
AS03 
Total Overall 
100 
100 
100 
100 
Age Groups 
Adults (18-55 years) 
75 
75 
75 
75 
Older adults 
(≥ 56 years) 
25 
25 
25 
25 
Supplemental Cohort 1 and Cohort 2 Booster Arms Only: all participants will receive a single 
booster dose (VAC) at D01. Blood samples will be collected from all participants prior to the 
booster injection, 14 days, 1 month, 3 months, 6 months, and 12 months after the injection. 
Supplemental Cohorts Comparator Group: all participants will receive 2 vaccine injections 
given 3 weeks apart: the first injection will be at D01 (VAC1) and the second injection will be at 
D22 (VAC2). Blood samples will be collected from all participants prior to each injection, 14 
days, 4 months, 6 months, 9 months, and 12 months after last injection. 
Table 4.5: Approximate sample size of Supplemental Cohort subsets for variant testing in 
CMI/Mucosal/Variant Subset for Cohorts 1 and 2 
 
Cohort 1* 
Cohort 2* 
 
Variant Testing 
Only 
Participants in the 
Pfizer/BioNTech 
Group 
Participants in the 
CoV2 preS dTM-AS03 
Group (Original Phase 
II Cohort) 
Total Overall 
70 
52 
30 
CoV2 preS dTM-AS03 (D614) 
44 
-- 
27 
CoV2 preS dTM-AS03 (B.1.351) 
-- 
26 
3 
CoV2 preS dTM-AS03 (D614 + 
B.1.351) 
-- 
26 
-- 
Comparator 
26 
-- 
-- 
*All subset participants will be 18-55 years of age only  
Supplemental Cohorts Subsets and Assessment of Immunogenicity to Emerging Variants of 
Concern: A randomized subset of 70 participants in Cohort 1 will be tested for additional 
SARS-CoV-2 variants of concern including Delta. No additional sample collection, procedures, or 
visits are required for this subset. A randomized subset of 82 participants in Cohort 2 comprised 
of younger adults (18 to 55 years of age) will provide samples for cellular immune response and 
mucosal antibody assessments and will also be tested for additional variants of concern including 
Delta. 
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For all cohorts: blood samples collected from all participants will be used for serological 
assessments in the study. Whole blood, PBMCs, and saliva samples will be collected from a 
subset of participants in each cohort to assess cellular immune responses and mucosal antibody 
responses. 
Reactogenicity will be assessed by collecting solicited AEs for 7 days after each vaccination, 
unsolicited AEs for 21 days after the last vaccination, and SAEs, MAAEs, and AESIs for the 
duration of the study. 
All Supplemental Cohort participants will be followed for the duration of the study to capture 
occurrences of COVID-19 through passive surveillance wherein participants will be instructed to 
contact the site if they experience symptoms/conditions of a COVID-19-like illness at any time 
during the study. In addition, active surveillance will be undertaken in all participants wherein all 
participants will be contacted once every 2 weeks starting after the last injection to enquire about 
development of COVID-19-like illness. 
The duration of participation in the study for each participant will be: 
• Supplemental Cohorts 1 and 2: approximately 365 days post-booster injection (ie, 
approximately 366 days total)  
• Supplemental Cohorts Comparator Group: approximately 365 days post-injection 2 (ie, 
approximately 386 days total) 
4.2 
Scientific Rationale for Study Design  
Rationale for Development Approach 
The development approach for the CoV2 preS dTM-AS03 vaccine candidate is undergirded by the 
fact that it is taking place in the setting of a pandemic. The manufacturing platform is the same as 
is used to produce licensed recombinant HA influenza vaccine, commercialized in the US and EU. 
In the context of influenza vaccine development, thousands of younger and older adults have 
received proteins manufactured utilizing the same technology and similar process employed for 
this CoV2 preS dTM-AS03 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 dose to be used in the present study (quadrivalent 
recombinant influenza vaccine contains a total of 180 µg of HA protein; the protein dose of this 
CoV2 preS dTM vaccine is 5-15 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. 
AS03 has been administered to many thousands of individuals (adults and elderly) as part of 
clinical studies of influenza vaccines as well as other vaccines (56). Notably, more than 20 000 
older adults received AS03-adjuvanted influenza vaccine in a large, multi-country efficacy study 
(44). Furthermore, it is estimated that approximately 90 million doses of AS03-adjuvanted H1N1 
vaccines were administered post-licensure in the context of H1N1 pandemic control (24). These 
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studies and post-licensure data showed that AS03 enhanced antibody and T cell responses with an 
acceptable safety profile. 
Recombinant proteins produced in the baculovirus manufacturing platform have been 
administered with AS03. 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. 
Nonclinical studies in multiple animal models with the CoV2 preS dTM vaccine with AS03 
adjuvant have demonstrated induction of immune responses and protection against viral 
challenge. The CoV2 preS dTM vaccine was evaluated with AS03 in the Phase I/II study 
(VAT00001) in healthy adults 18 years of age and older. A low-dose and a high-dose formulation 
corresponding to an effective dose of 1.3 µg and 2.6 µg of antigen were evaluated in the study. No 
related serious adverse events (SAEs) were observed in the study although higher than expected 
Grade 3 reactogenicity was observed after the second injection in the adjuvanted groups. Interim 
immunogenicity data showed that an antigen effective dose of 2.6 µg in a 2-injection schedule 
with the AS03 adjuvant induced the highest titers of neutralizing antibodies across all groups with 
no indication of a Th2 bias in the cell-mediated response with a consistent elicitation of Interferon 
gamma responses (see Section 2.2). 
Rationale for study design 
The VAT00001 study evaluated different formulations of the recombinant protein vaccine 
(antigen concentration and adjuvant) and administration schedules (1 injection versus 2 injections 
21 days apart). During characterization studies performed on the final filled clinical materials 
administered in VAT00001 it was identified that the key polyclonal antibody reagent used for the 
detection of SARS-CoV-2 S protein also detects some HCPs rendering it inappropriate for use in 
the purity and HCP release assays. As a result, the purity and HCP values reported for the Phase 
I/II clinical study materials were inaccurate and the concentration of SARS-CoV-2 S protein 
within the formulated vaccine product is significantly lower than expected. Following 
re-calculation of the SARS-CoV-2 S protein, within a 0.5mL vaccine dose, it has been defined 
that the effective doses administered in VAT00001 are 1.3 µg and 2.6 µg of functional 
SARS-CoV-2 S protein instead of 5 µg and 15 µg, respectively. The differences between the 
targeted and the effective dose levels correspond to an excess HCP content in the clinical 
materials (recalculated HCP content, 3.7 µg and 12.4 µg). 
The neutralizing antibody responses observed in the VAT00001 study were lower than expected 
particularly in the older adults. A dose-response was observed with the high-dose group with 
AS03 inducing higher levels of neutralizing antibodies than the low-dose group with AS03. 
However, even in the best performing vaccine group (2-injection schedule of high-dose + AS03), 
seroconversion rates were below 90% in all adults with lower rates in older adults (85% in 
50 years of age and older, 62.5% in 60 years of age and older). The magnitude of neutralizing 
antibody responses was also lower in adults aged 50 years of age and older compared to the 
younger age group suggesting a need for further dose-optimization with doses higher than the 
effective high dose of 2.6 µg used in this study. Higher than expected reactogenicity was observed 
in the study. Specifically, for the high-dose + AS03 arm, the frequency of Grade 3 (severe) 
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reactions were highest for malaise (17%), followed by myalgia (11%) and headache (7%). 
Overall, 41% of study participants receiving the high-dose + AS03 formulation in a 2-dose 
schedule reported Grade 3 reactions. Although these reactions were not deemed serious and were 
transient and of short duration, a formulation associated with lower reactogenicity is desirable. 
The current hypothesis proposed to explain the observed high reactogenicity is that it may be 
related to the HCP content in the administered product when given with an adjuvant in a 2-dose 
schedule. If this hypothesis is correct, lower content of HCPs in the VAT00002 study product 
should result in lower reactogenicity. 
The lower than expected immunogenicity in combination with the higher than expected 
reactogenicity observed in the Phase I/II study indicate that that assessment of optimized antigen 
formulations (with higher antigen dose and lower HCP content) is necessary to select a 
formulation to progress to Phase III evaluation. 
The Original Cohort enrolled in VAT00002 corresponds to Phase II, randomized, modified 
double-blind, multi-center, dose-finding study to be conducted in adults 18 years of age and older 
to evaluate the safety, reactogenicity, and immunogenicity of 2 injections of CoV2 preS 
dTM-AS03 vaccine administered by IM route. In this study, 3 different antigen doses (effective 
doses of 5 µg, 10 µg, and 15 µg of CoV2 preS dTM monovalent D614 antigen) of the candidate 
vaccine are being evaluated utilizing a 2-injection schedule, as supported by data from the 
VAT00001 study, with doses administered 21 days apart. Interim safety, reactogenicity, and 
immunogenicity data from this Phase II Cohort was used to decide on progression to Phase III and 
for selecting a dose formulation to progress to Phase III. 
As part of an amendment to the original study, Supplemental Phase III Cohorts have been 
incorporated into the study. These will allow the evaluation of the potential use of CoV2 preS 
dTM-AS03 to boost responses in individuals previously vaccinated with other platforms; for this 
purpose, the study will assess the safety and immunogenicity of different formulations of the 
CoV2 preS dTM-AS03 vaccine, including  monovalent and  bivalent formulations, for use as a 
universal late booster.     
Justification for the age range and study population 
Original Phase II Cohort: The study is being conducted in adults 18 years of age and older with 
stratification by 2 age groups: 18-59 years of age and 60 years of age and older. Approximately 
360 adults 18-59 years of age and 360 adults 60 years of age or older were to be enrolled. The 
study is designed to ensure that close to 50% of the study population will be 60 years of age and 
older and stratification of this age-group ensures the benefits of randomization within this age-
stratum. The incidence of disease is higher in adults compared to children, with older adults at 
highest risk of severe disease, hospitalizations, and death compared to younger adults. Moreover, 
interim data from the VAT00001 study showed lower levels of response in older adults indicating 
the need to identify the optimal antigen dose for this older age group. No upper age-range is 
specified in this study, and participants with medical conditions associated with higher risk of 
COVID-19 disease (detailed in Section 5.3) were not excluded from this study cohort. Moreover, 
to ensure evaluation of vaccine performance in high-risk groups, this study cohort allowed 
enrollment of participants with high-risk medical conditions. This is supported by data generated 
in NHPs (Section 2.2) indicating evidence of protection against viral replication in the upper and 
lower respiratory tract and against lung inflammation and pathology with no evidence of vaccine 
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enhanced disease at effective doses similar to the doses targeted in this study (effective doses of 
4 µg and 12 µg of protein were evaluated in such study). The study also indicated robust humoral 
immune responses and a balanced Th1/Th2 cellular response. Participants with well-controlled 
human immunodeficiency virus infection were not excluded from this study cohort. 
Supplemental Phase III Cohorts: For evaluation of booster and variant responses, in accordance 
with the FDA’s updated Emergency Use Authorization (EUA) guidance for vaccine developers 
addressing virus variants (57) and the European Medicines Agency’s (EMA) reflection paper on 
the regulatory requirements for vaccines intended to provide protection against variant strain(s) of 
SARS-CoV-2 (58), the booster and variant priming cohorts will be powered to demonstrate 
non-inferiority of the vaccine candidates in one age group, adults 18-55 years old, with inclusion 
of a proportion of older adults (≥ 56 years old) aimed at enabling extrapolation of results. 
Justification for modified double-blind (observer-blind) and open-label groups 
Original Phase II Cohort: This Cohort corresponds to a modified double blind (observer-blind) 
study. Designated site staff involved in preparing the vaccine was unblinded because the vaccine 
formulation was prepared by mixing the recombinant protein and adjuvant at the study site out of 
sight of the participant. Study staff involved in administering the vaccine may be unblinded to the 
vaccine formulation if they are not involved in preparing the vaccine. The 
Investigator/Sub-investigator/staff involved in the safety assessment and surveillance will remain 
blinded in order to decrease the risk of potential bias in safety and immunogenicity assessments. 
Laboratories performing the assays evaluating immunogenicity and efficacy endpoints remain 
blinded to study intervention. 
Supplemental Phase III Cohorts:  
• Supplemental Cohort 1 Booster Group will be open-label. This group will be initiated as 
soon as possible to generate data on the role of a booster with the CoV2 preS dTM-AS03 
(D614) vaccine. Given the importance of generating data as early as possible to address 
both waning of immune responses and the emergence of variants of concern, the Sponsor 
considers justified to enroll this group in an open-label fashion given that the availability 
of variant-containing candidates will only occur later.  
• Supplemental Cohort 2 Intervention Groups will be blinded to treatment assignment; all 
participants will receive active vaccine, but the formulation administered will remain blind 
(observer-blind for the same reasons explained above).   
Supplemental Cohorts Comparator Group: since this group of naïve, unvaccinated 
individuals overtly differs from the previously vaccinated individuals to be enrolled into 
the booster arms, it will be an open-label arm recruited in geographic locations having 
similar population characteristics as the populations recruited in the booster arms.  
4.3 
Justification for Dose and Dosing Schedule  
Original Phase II Cohort  
The dose of the recombinant protein and dosing schedule chosen for this study cohort were based 
on results from nonclinical studies in animal models, manufacturing capacity limitations, and 
results from the Phase I/II safety and immunogenicity study. Interim data from the Phase I/II 
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study showed that a single injection did not generate meaningful neutralizing titers above 
background and that a 2-injection schedule of the adjuvanted protein was necessary to induce 
neutralizing antibodies. 
The effective dose of antigen administered in the Phase I/II study were 1.3 µg and 2.6 µg of 
functional SARS-CoV-2 S protein. Lower than expected immunogenicity was observed in the 
Phase I/II study, particularly in the older adults, indicating the need for evaluation of higher 
antigen doses. In a nonclinical study (CoV2-04_NHP) in NHPs using an effective dose of 4 µg 
and 12 µg of recombinant protein with AS03 adjuvant to assess efficacy against SARS-CoV-2 
viral challenge, both doses conferred robust protection against viral replication in the lower and 
upper airways after a challenge with a virulent viral stock (NR-53780 BEI stock). Strong 
reduction of viral replication was demonstrated on D02 and D04, with a trend for a higher 
reduction in the high dose vaccine group. The pathology and inflammation in the lungs induced 
by infection 7 days post-challenge was clearly reduced in the immunized rhesus macaques, and no 
increase in inflammatory cytokines or chemokines was observed. At both low and high doses, the 
AS03-adjuvanted vaccine elicited high humoral (binding, functional and neutralizing antibodies) 
and cellular (Th1/Th2 balanced S-specific cytokine responses and Tfh cells 2 weeks post-boost) 
responses. These data provide support to the hypothesis that improved formulation with higher 
antigen doses might improve vaccine performance. 
In addition to the data generated with the vaccine candidate in NHPs and in the clinical Phase I/II 
study, historical data generated with vaccines for pathogens different than SARS-CoV-2 as well 
as other SARS-CoV-2 protein vaccines candidates further informed the desirable dose range to 
assess in this Phase II study cohort: 
• 
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. AS03 adjuvanted arms 
demonstrated robust responses even with the lowest antigen level (59). 
• 
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. In this study, robust humoral immune responses were observed in 
the AS03 adjuvanted arms against homologous and heterologous H7 influenza strains. 
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. 
• 
A recombinant prefusion stabilized SARS-CoV-2 S protein vaccine manufactured in 
baculovirus expression system adjuvanted with Matrix-M1 adjuvant has shown high immune 
responses against SARS-CoV-2, and an adjuvanted protein dose of 5 µg administered in a 
2-injection schedule has advanced to Phase III studies (60). 
• 
A stabilized prefusion form of the SARS-CoV-2 S protein produced by transient expression in 
Nicotiana benthamiana and displayed as a viral-like particle demonstrated promising immune 
responses when administered in a 2-dose regimen with adjuvants in an early clinical study. A 
dose of 3.75 µg adjuvanted with AS03 has advanced to late stage clinical studies (27). 
• 
A protein subunit vaccine candidate composed of a stabilized trimeric form of the S-protein 
produced in CHO cells showed promising responses when administered with adjuvants. A 
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dose of 9 µg adjuvanted with AS03 administered in a 2-injection scheduled has been selected 
to advance to late stage clinical studies (61). 
Taken together, the available evidence supported the dose levels that are being evaluated in this 
study cohort (range between 5 µg and 15 µg of S-protein, administered with AS03 in a 2-injection 
schedule, 21 days apart). 
Supplemental Phase III Cohorts  
The antigen dose levels utilized in the Supplemental Phase III Cohorts are based on the interim 
data obtained from the Original Phase II Cohort in this study.  
The reactogenicity and safety profile was similar across antigen dose groups and therefore the 
choice of antigen dose for the priming cohorts (naïve individuals), is consistent with the dose 
selected for the VAT00008 Phase III efficacy study and is largely informed by the observed 
immunogenicity profile in the naïve adults.  
The neutralizing antibody responses to D614G were generally consistent without clear evidence 
of a dose effect across treatment groups in the overall naive population (18 years of age and 
older). A pattern of higher neutralizing antibody titers with higher antigen doses was observed in 
the younger adults age group, a pattern that was not evident in the older age group.  
The ratio of neutralizing antibody responses in vaccinees compared to human convalescent sera 
has been modeled to correlate with observed vaccine efficacy against the homologous variants. In 
these models, ratios of 1 correlate to vaccine efficacy of ~80-90% and ratios of 0.8 correlate to 
vaccine efficacy of ~70-80% (62) (63). This relationship is modeled for neutralizing antibody 
responses and efficacy against the homologous variants, with the expectation that the predicted 
vaccine efficacy against heterologous variants will be lower for a similar ratio of vaccine-induced 
antibody response to human convalescent sera (HCS).  
In the Original Phase II Cohort in this protocol the geometric mean titers (GMTs) observed in 
naïve individuals at D36 in the overall study population were comparable to GMTs observed in a 
panel of human convalescent sera (GMT 2140; 95% confidence interval [CI]: 1543, 2967; N = 79) 
measured in the same pseudovirus neutralizing assay, laboratory, and time frame. In younger 
adults, the ratio of neutralizing antibody titers to HCS was > 1 (ie, 1.37, 1.85, and 2.25, 
respectively) in the younger naïve adults; and in the older naïve adults, the ratio ranged from 0.7 - 
0.75 across the 3 dosages. Based on these pseudovirus neutralizing ratios (vaccine induced/HCS) 
there is expected to be little difference in vaccine protection between antigen dose levels. 
However, this conclusion is applicable to homologous variants or variants associated with only 
small drifts in neutralizing activity. Based on available preclinical data with the vaccine 
candidates tested in this study and additional data from other vaccines, neutralizing antibody titers 
against the Beta (B.1.351) and Gamma (P.1) variants are likely to be lower. In the context of 
changing epidemiology, selection of 10 µg antigen dose for the D614 monovalent vaccine for the 
Phase III study is expected to mitigate the potential impact of variant circulation as it may provide 
greater cross-reactive antibody titers against variant strains. It is also likely that a higher antigen 
dose would provide greater durability of response and improve the avidity of antibody responses 
over time. The predicted vaccine efficacy curve based on vaccine induced/HCS antibodies begins 
to plateau at ratios close to 2. Increasing the ratio from 1.85 for the 10 µg dose to 2.25 for the 15 
µg dose is only expected to marginally increase vaccine efficacy based on these models. 
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Importantly, in the context of a pandemic, a lower antigen dose would translate into a significant 
increase in vaccine supply.   
These considerations were the basis for selecting a 10 µg dose for the monovalent D614 vaccine  
to be evaluated in Stage 1 of the Phase III efficacy study. This selection mitigates the risk of 
having lower titers against variants.  
For Stage 2 of the Phase III efficacy study with the CoV2 preS dTM-AS03 (D614 + B.1.351) 
vaccine, a 5 µg (D614 component) + 5 µg (B.1.351 component) antigen dose (total amount of S 
antigen of 10 µg) was selected. The 5 µg antigen dose with the D614 vaccine provides 
homologous neutralizing antibody responses comparable to convalescent sera in the overall naïve 
population. It is reasonable to expect that similar homologous responses would be elicited by the 
B.1.351 component of the bivalent vaccine. Thus, by design, the inclusion of the B.1.351 antigen 
with the D614 antigen in the bivalent vaccine mitigates the risk of lower antibody responses 
against circulating variants anticipated with the monovalent D614 vaccine. 
This rationale underpins selection of a total S antigen dose of 10 µg to be evaluated in all study 
arms of the Supplemental Phase III Cohorts of the present study in which previously 
unvaccinated, SARS-CoV-2 naïve individuals will receive a 2-dose primary vaccination series: 
10 µg for CoV2 preS dTM-AS03 (B.1.351) vaccine, and 5 µg (D614 Component) + 5 µg 
(B.1.351 Component) for the CoV2 preS dTM-AS03 (D614 + B.1.351) vaccine, and 10 µg for the 
CoV2 preS dTM-AS03 (D614) (Comparator) for the  Supplemental Cohorts Comparator Group. 
Importantly, the comparator CoV2 preS dTM-AS03 (D614) antigen dosage is the same as that 
which will be evaluated in Stage 1 of VAT00008, serving as a bridge back to the formulation and 
dose for which efficacy will be established. 
Antigen dosage selection for the booster groups is informed by data generated in non-naïve 
individuals in the Original Phase II Cohort of this protocol. As noted in Section 2.3 above across 
all 3 dose levels, the neutralizing antibody GMTs achieved 21 days following a single dose of the 
monovalent (D614) CoV2 preS dTM vaccine in non-naïve participants was greater than the peak 
response at D36 following two doses in naïve participants.  These findings informed selection of  
a single injection of 5 µg of S antigen dose adjuvanted with AS03 in the context of booster 
immunization. A total S antigen dose of 5 µg will therefore be utilized for each of the booster 
arms in the Supplemental Phase III Cohorts in this present study: 5 µg for CoV2 preS dTM-AS03 
(D614) vaccine in Supplemental Cohorts 1 and 2, 5 µg for CoV2 preS dTM-AS03 (B.1.351) 
vaccine in Supplemental Cohort 2, and 2.5 µg (D614 Component) + 2.5 µg (B.1.351 Component) 
for the CoV2 preS dTM-AS03 (D614 + B.1.351) vaccine in Cohort 2. In addition, exploratory 
groups will evaluate a lower dose of 2.5 µg of monovalent (B.1.351) to investigate potential 
alternative doses for use in boosting that could be dose-sparing. 
At present, there is limited evidence as to the durability of efficacy beyond the 2 to 6 months 
following the completion of the primary series of vaccines that have received emergency use 
authorization or conditional approval. While the evidence to define a correlate of risk or correlate 
of protection is not yet fully matured, modelling shows a strong correlation between efficacy and 
peak neutralizing antibody titers (62) (63). Furthermore, extensions of such modelling allow for 
prediction of the effects of waning immunity on efficacy. For mRNA-1273, one authorized 
COVID-19 vaccine for which post-vaccination functional antibody titers up to a half-year have 
been published, neutralizing antibody levels against the prototype strain decline by 4- to 7-fold at 
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6 months from the peak titers achieved post-vaccination (64). Modelling predicts the 
loss-of-efficacy impact would be magnified against variants with larger reductions in neutralizing 
activity compared to the prototype strain, thus implying the need for an earlier booster dose. 
Given these uncertainties, this study will evaluate the administration of booster doses among 
individuals who received a primary series with an authorized COVID-19 vaccine starting 4 to 
10 months previously. 
In lieu of clinical booster vaccination data, responses after the first dose of the monovalent CoV2 
preS dTM-AS03 (D614) vaccine in participants with evidence of prior SARS-CoV-2 infection 
(non-naïve participants) serve as a reasonable proxy from which to draw inferences on the utility 
of a seroresponse co-primary endpoint and success criterion. Below are findings from VAT00002 
participants aged 18-59 who received CoV2 preS dTM-AS03 (D614) at a dose of 5 or 10 µg, the 
primary age group in which the planned booster and variant studies will be performed and the 
antigen dosages that will be used for the booster and comparator priming arms, respectively. 
Non-naïve participants had by definition appreciable pre-existing pseudovirus neutralizing 
antibody titers against S-antigen (D614G)-expressing pseudovirions (Table 4.6). Among 18-59 
year-olds that received 5 and 10 µg of CoV2 preS dTM (D614), seroconversion rates post-dose 1 
(D22) amongst the non-naïve participants were -10% to -18% lower (≥ 2-fold seroconversion) and 
-18% to -20% (≥ 2-fold seroconversion) lower than the corresponding seroconversion rates 
post-dose 2 in naïve participants. This is not unexpected, given that in the context of pre-existing 
responses a proportion of booster recipients will not reach a given level of seroresponse, while 
naïve individuals that have no pre-existing responses are anticipated to mount seroresponses at 
very high frequencies (close to 100%). At the same time, in the corresponding age and dose 
groups, clinically meaningful boosting of pseudovirus neutralizing antibody titers were observed 
after the first vaccine injection in the non-naïve participants, which were 3.3-5.8 fold higher than 
the corresponding responses in non-naïve participants after two vaccine doses. 
We believe that demonstrating a significant benefit from the booster dose in terms of 
improvement of pre-booster antibody levels (by demonstrating superiority of post-booster titers to 
pre-booster titers), complemented by the co-demonstration that such antibody levels are at least 
non-inferior to the comparator group (unvaccinated and SARS-CoV-2 naïve) that receives the 
same lot and schedule of CoV2 preS dTM-AS03 (D614) being used in the Phase III efficacy study 
will allow concluding that there is a clear benefit from the booster dose and that such benefit is 
expected to be reasonably associated with at least the restoration of vaccine protection to levels 
observed in the Phase III efficacy study. 
Table 4.6: GMTs and GMT ratios in non-naïve participants after 1 dose (D22) and naïve 
participants after 2 doses (D36) with the D614G pseudovirus neutralization assay 
(Monogram) in the 18-59 year old age group of VAT00002 (Populations, PPAS Naïve-
D01+D22, PPAS Non-naïve-D01+D22) 
 
 
Group 1 (5 µg + AS03) 
Group 2 (10 µg + AS03) 
Population Time point/ratio 
M 
GMT/GMTR 
(95% CI) 
M 
GMT/GMTR 
(95% CI) 
Naïve† 
D01 
51 
20 
(NC, NC) 
55 
20 
(NC, NC) 
 
D36 
53 
2938 
(2155, 4007) 
58 
3961 
(2795, 5612) 
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Group 1 (5 µg + AS03) 
Group 2 (10 µg + AS03) 
Population Time point/ratio 
M 
GMT/GMTR 
(95% CI) 
M 
GMT/GMTR 
(95% CI) 
Non-naïve‡ 
D01 
10 
316 
(90.8, 1096) 
11 
486 
(112, 2101) 
 
D22 
10 
16962 
(2754, 
104000) 
12 
13039 
(3175, 53540) 
 
D22 (non-naïve) / 
D36 (naïve) 
 
5.77 
 
 
3.29 
 
Note: NC=not calculable. 
† Naïve denotes 18-59-year-old age group in the PPAS Naïve-D01+D22 population 
‡ Non-naïve denotes 18-59-year-old age group in the PPAS Non-naïve-D01+D22 population 
 
Table 4.7: Comparison of ≥ 2-fold and ≥ 4-fold seroconversion rates with the D614G 
pseudovirus neutralization assay (Monogram) in non-naïve participants after 1 dose (D22) 
compared to naïve participants after 2 doses (D36) in the 18-59 year old age group of 
VAT00002 (Populations, PPAS Naïve-D01+D22, PPAS Non-naïve-D01+D22) 
 
 
 
Group 1 (5 µg + AS03) 
Group 2 (10 µg + AS03) 
Population 
Time point 
Fold rise 
n/M 
% 
(95% CI) 
n/M 
% 
(95% CI) 
Naïve† 
D36 
≥ 2 
51/51 
100 
(93.0, 100) 
54/55 
98.2 
(90.3, 100) 
Non-naïve‡ 
D22 
≥ 2 
9/10 
90 
(55.5, 99.7) 
8/10 
80 
(44.4, 97.5) 
Difference (Non-naïve D22 - naïve D36) 
-10 
(-40.4, 0.8) 
 
-18.2 
(-49.2, -1.9) 
Naïve† 
D36 
≥ 4 
51/51 
100 
(93, 100) 
54/55 
98.2 
(90.3, 100) 
Non-naïve‡ 
D22 
≥ 4 
8/10 
80 
(44.4, 97.5) 
8/10 
80 
(44.5, 97.5) 
Difference (Non-naïve D22 - naïve D36) 
-20 
(-51.0, -4.0) 
 
-18.2 
(-49.2, -1.9) 
† Naïve denotes 18-59-year-old age group in the PPAS Naïve-D01+D22 population 
‡ Non-naïve denotes 18-59-year-old age group in the PPAS Non-naïve-D01+D22 population 
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 (CSR) is finalized. 
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5 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. This study is designed to be pragmatic to 
maximize representation of the broader population by minimizing exclusionary eligibility criteria 
and allowing the participation of individuals with a broad range of medical conditions, including 
controlled HIV infection, Hepatitis B and Hepatitis C, and conditions associated with an increased 
risk of severe COVID-19. It is also designed to be inclusive of other subpopulations affected by 
COVID-19, including older adults as well as ethnic and racial minorities. 
If an approved/authorized vaccine is available in the country or region where the study is 
conducted, Investigators will discuss this information with prospective study participants at the 
time of informed consent who will be encouraged to obtain the approved/authorized vaccine if 
applicable to them. Recruitment of eligible participants will proceed only if, despite 
encouragement, the candidate participant expresses no intention to seek an authorized or approved 
vaccine at least until completion of the key follow-up timepoint (D43) for informing progression 
to Phase III and dose selection. 
5.1 
Inclusion Criteria  
Participants are eligible for the study only if all of the following criteria are met: 
I01: 
Aged 18 years or older on the day of inclusiona 
I02: 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
and one of the following conditions applies: 
• Is of non-childbearing potential. To be considered of non-childbearing potential, a female must 
be post-menopausal for at least 1 year or surgically sterile. 
 
OR 
 
• Is of childbearing potential and agrees to use an effective contraceptive method or abstinence 
from at least 4 weeks prior to the first vaccination until at least 12 weeks after the last 
vaccination (ie, second dose of primary series or booster injection). 
• A participant of childbearing potential must have a negative highly sensitive pregnancy test 
(urine or serum as required by local regulation) within 4 hours before any dose of study 
intervention, see Section 8.4.5 (pregnancy testing). 
 
I03: 
Informed consent form has been signed and dated 
I04: 
Able to attend all scheduled visits and to comply with all study procedures 
I05: 
Covered by health insurance, only if required by local, regional, or national 
regulations 
I06: 
SARS-CoV-2 rapid serodiagnostic test performed at the time of enrollment to detect 
presence of SARS-CoV-2 antibodies (Original Phase II Cohort) 
                                                 
a Participants in the Comparator Group for Supplemental Cohorts 1 and 2 must be 18 to 55 years of age.  
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I07: 
For persons living with human immunodeficiency virus (HIV), stable HIV infection 
determined by participant currently on ARVs with CD4 count > 200/mm3 
I08: 
Does not intend to receive an authorized/approved COVID-19 vaccine from first 
vaccination to 3 weeks after the second vaccination (D43) despite encouragement by 
the Investigator to receive the authorized vaccine available to them at the time of 
enrollmenta 
I09: 
Supplemental cohorts: for participants originally enrolled in the Phase II Cohort of the 
study, informed consent has to be signed and dated for transitioning to Supplemental 
Cohort 2  
I10: 
Supplemental Cohorts, Booster Arms: received a complete primary vaccination seriesb 
with an authorized/conditionally approved mRNA COVID-19 vaccine (mRNA-1273 
[Moderna] or BNT162b2 [Pfizer/BioNTech]) or adenovirus-vectored COVID-19 
vaccine (ChAdOx1 nCoV-19 [Oxford University/AstraZeneca] or Ad26.CoV2.S 
[J&J/Janssen]), with the last dose administered a minimum of 4 months prior to 
inclusion but not longer than 10 months prior to inclusion 
5.2 
Exclusion Criteria  
Participants are not eligible for the study if any of the following criteria are met: 
E01: 
Participation at the time of study enrollment (or in the 30 days preceding the first 
study vaccination) or planned participation during the present study period in another 
clinical study investigating a vaccine, drug, medical device, or medical procedure 
E02: 
Receipt of any vaccine in the 30 days preceding or on the day of the first study 
vaccination or planned receipt of any vaccine between the first study vaccination and 
in the 30 days following the second study vaccination except for influenza 
vaccination, which may be received at any time in relation to study intervention. 
E03: 
Applicable to Original Phase II Cohort, Supplemental Cohort 1, Cohort 2 Comparator 
Group: Prior administration of a coronavirus vaccine (severe acute respiratory 
syndrome coronavirus 2 [SARS-CoV-2], SARS-CoV, Middle East Respiratory 
Syndrome [MERS-CoV])c 
                                                 
a While recruitment of eligible participants will proceed only if the candidate participant expresses no intention to 
seek an authorized or approved vaccine at least until completion of the key follow-up timepoint (D43), if the 
participant is enrolled and seeks vaccination of an authorized/approved vaccine outside of the study, he/she will be 
encouraged to discuss this intention proactively with the study Investigator and will be permitted to receive the 
authorized vaccine at any time. If the participant receives the authorized/approved 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 not receive the second vaccination if they have 
received the authorized/approved vaccine between the first and second scheduled vaccination (see Section 7.1.2: 
Definitive Contraindications). 
b To be confirmed either by official written or electronic record 
c Not applicable to booster arms in Supplemental Cohorts 1 and 2 
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E04: 
Known systemic hypersensitivity to any of the vaccine components, or history of a 
life-threatening reaction to a vaccine containing any of the same substancesa 
E05: 
Dementia or any other cognitive condition at a stage that could interfere with 
following the study procedures based on Investigator’s judgment 
E06: 
Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination 
based on Investigator’s judgment 
E07: 
Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, 
contraindicating IM vaccination based on Investigator’s judgment 
E08: 
Deprived of freedom by an administrative or court order, or in an emergency setting, 
or hospitalized involuntarily 
E09: 
Unstable acute or chronic illness that in the opinion of the Investigator or designee 
poses additional risk as a result of participation or that could interfere with the study 
procedures 
E10: 
Receipt of solid-organ or bone marrow transplants in the past 180 days 
E11: 
Receipt of anti-cancer chemotherapy in the last 90 days 
E12: 
Receipt of immunoglobulinsb, blood, or blood-derived products in the past 3 months 
E13: 
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 
E14: 
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 
E15: 
Exclusion criterion for the Supplemental Cohort 1 and Cohort 2 Comparator Group: 
positive rapid diagnostic test for SARS-CoV-2 antibodies at time of enrollment 
E16: 
Exclusion criterion for Supplemental Cohort 2 CoV2 preS dTM-AS03 (D614) primed 
individuals (ie, primed as participant in the Original Phase II Cohort of the present 
study): Receipt of authorized/conditionally approved COVID-19 vaccine after 
enrollment in Original Phase II Cohort    
E17: 
Exclusion criterion for all Booster Groups: Documented virologically-confirmed 
SARS-CoV-2 infection (by NAAT) after first dose of primary immunization 
Depending on country regulations and feasibility, if the participant has a primary physician who is 
not the Investigator, the site may contact this physician with the participant’s consent to inform 
him / her of the participant’s participation in the study. In addition, the site may ask this primary 
physician to verify exclusion criteria including but not limited to previous therapies, such as 
previous vaccines. 
                                                 
a The components of SARS-CoV-2 Recombinant Protein vaccine are listed in Section 6.1 and in the CoV2 preS dTM 
Investigator’s Brochure and the AS03 adjuvant Investigator’s Brochure 
b Including investigational monoclonal antibodies 
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5.3 
High Risk Medical Conditions  
High-risk conditions are conditions considered to be associated with an increased risk of severe 
COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/evidence-
table.html) and include: 
• cancer 
• chronic kidney disease 
• chronic obstructive pulmonary disease (COPD) 
• immunocompromised state from solid organ transplant 
• immunocompromised state from other causes (blood or bone marrow transplant, immune 
deficiencies, HIV, use of corticosteroids, or use of immunosuppressors) 
• obesity (body mass index of 30 or higher) 
• heart conditions such as heart failure 
• coronary artery disease or cardiomyopathies 
• sickle cell disease 
• thalassemia 
• type 1 or type 2 diabetes mellitus 
• moderate-to-severe asthma 
• cerebrovascular disease 
• cystic fibrosis 
• hypertension/high blood pressure 
• neurologic conditions 
• hepatic disease 
• pulmonary fibrosis 
• smoking 
5.4 
Representation of Study Subpopulations  
The study targets representation of specific study subpopulations by capping the number of 
participants in specific subpopulations.  
For the Original Phase II Cohort, participants who are rapid serodiagnostic test positive at baseline 
will be capped to a maximum of approximately 20% of the study population to ensure sufficient 
number of SARS-CoV-2 naïve participants in the study. 
In addition, it may be necessary to cap the number of participants in specific age-groups in 
particular countries based on availability and deployment of an authorized/approved vaccine. 
Prospective study candidates belonging to any of the capped subpopulations may be excluded 
once the cap is reached for the corresponding category. 
5.5 
Lifestyle Considerations  
No other restrictions than the ones listed in the exclusion criteria or in the contraindications for 
subsequent vaccinations are required. 
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5.6 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. Screening information is recorded in 
the source documents. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria not met, capping 
condition reached, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened if the exclusionary condition is considered to be temporary in nature by the 
Investigator. 
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6 
Study Intervention  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
Note: Vaccines or products administered outside of study protocol are not considered as study 
interventions and are reported in the CRF as reportable medications (see Section 6.9). Study 
procedures (eg, blood sampling) are also not considered as study interventions. 
6.1 
Study Interventions Administered  
6.1.1 Original Phase II Cohort Study Interventions  
The study interventions for the Original Phase II Cohort are described in Table 6.1 below. 
Table 6.1: Identity of Original Phase II Cohort study interventions 
CoV2 preS dTM-AS03 
(recombinant, adjuvanted) 
Intervention Names 
COVID-19 vaccine 
(recombinant, 
adjuvanted) or 
CoV2 preS 
dTM-AS03 
(5 µg antigen) 
COVID-19 vaccine 
(recombinant, 
adjuvanted) or 
CoV2 preS 
dTM-AS03 
(10 µg antigen) 
COVID-19 vaccine 
(recombinant, 
adjuvanted) or 
CoV2 preS 
dTM-AS03 
(15 µg antigen) 
Study Group 
Group 1 
Group 2 
Group 3 
Use 
Experimental 
Type 
Vaccine 
Dose Formulation 
Solution and emulsion for injection, mix pre-injection according to 
dose preparation protocol. Final mixed solution and emulsion is in 
a single dose vial. 
CoV2 preS dTM antigen is a sterile, clear, colorless solution (with 
possible presence of endogenous particles) of SARS-CoV-2 
prefusion S proteins for IM injection.  The antigen solution can 
contain endogenous particles. If present, these light-colored 
particles are slow sinking and suspended in solution. 
AS03 adjuvant is a whitish to yellowish homogenous milky liquid 
emulsion. 
Unit Dose Strengths 
Each 0.5 mL dose of Study Intervention will contain the following: 
preS-delta TM 
monovalent: 
prefusion S delta 
TM COVID-19 
antigen,  
low-dose (5 µg) 
preS-delta TM 
monovalent: 
prefusion S delta 
TM COVID-19 
antigen,  
medium-dose 
(10 µg) 
preS-delta TM 
monovalent: 
prefusion S delta 
TM COVID-19 
antigen,  
high-dose (15 µg) 
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AS03 adjuvant is composed of squalene (10.69 milligrams), DL-α-
tocopherol (11.86 milligrams) and polysorbate 80 (4.86 
milligrams). 
Excipients/Diluent 
Excipients: 
Solution vial: 
• Sodium phosphate monobasic monohydrate 
• Sodium phosphate dibasic dodecahydrate 
• Sodium chloride 
• Polysorbate 20 
• Water for injection 
Emulsion vial (AS03): 
• Sodium chloride 
• Disodium hydrogen phosphate 
• Potassium dihydrogen phosphate 
• Potassium chloride 
• Water for injection 
Dosage Level 
0.5 mL per dose 
Number of Doses / Dosing 
Interval 
2 injections / 21 days apart 
Route of Administration 
IM injection 
Site of Administration 
Deltoid muscle in the upper arm 
Sourcing 
CoV2 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 one fixed label containing the dose number. All will be 
labeled in accordance with local Health Authority requirements. 
Batch Number 
TBD 
Storage Conditions 
2 to 8ºC (35°F to 46°F) and protected from light 
 
 
6.1.2 Supplemental Phase III Cohorts Study Interventions  
Study interventions for the Supplemental Cohorts are as follows: 
• Table 6.2: Monovalent (D614)  
• Table 6.3: Monovalent (B.1.351) 
• Table 6.4: Bivalent (D614 + B.1.351)  
 
 
 
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Table 6.2: Identity of Monovalent (D614) study interventions  
Intervention Names 
Monovalent (D614) 
CoV2 preS dTM 
(5 µg antigen) + AS03 (full-dose adjuvant) 
Monovalent (D614) 
CoV2 preS dTM 
(10 µg antigen) + AS03 (full-dose adjuvant) 
Cohort 
Supplemental Cohorts 1 and 2 
Supplemental Cohort 1  
Cohort Group/Arm 
Booster Arms 
Comparator Group and Primary Series 
Use 
Experimental 
IMP and NIMP 
IMP 
Type 
Vaccine 
Dose Form 
Solution and emulsion for injection, mix pre-injection according to dose preparation protocol. The solution 
(Antigen) and emulsion (AS03 Adjuvant), once mixed, form a multi-dose vaccine in a vial. 
CoV2 preS dTM antigen is a sterile, clear, colorless solution (with possible presence of endogenous particles) of 
SARS-CoV-2 prefusion S proteins for IM injection. The antigen solution can contain endogenous particles. If 
present, these light-colored particles are slow sinking and suspended in solution. 
AS03 adjuvant is a whitish to yellowish homogenous milky liquid emulsion. 
After mixing, the vaccine is a whitish to yellowish homogeneous milky liquid emulsion. 
Unit Dose Strengths 
Each 0.5 mL dose of Study Intervention will contain 
the following: 
• preS-delta TM D614: prefusion S delta TM 
D614 COVID-19 antigen, (5 µg) 
• AS03 adjuvant is an oil-in-water emulsion 
containing squalene (10.69 milligrams), DL-α-
tocopherol (11.86 milligrams) and polysorbate 
80 (4.86 milligrams). 
Each 0.5 mL dose of Study Intervention will contain the 
following: 
• preS-delta TM D614: prefusion S delta TM D614 
COVID-19 antigen, (10 µg) 
• AS03 adjuvant is an oil-in-water emulsion 
containing squalene (10.69 milligrams), DL-α-
tocopherol (11.86 milligrams) and polysorbate 80 
(4.86 milligrams). 
Excipients / Diluent 
Excipients: 
Solution vial (Antigen): 
• Sodium phosphate monobasic monohydrate 
• Sodium phosphate dibasic dodecahydrate 
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• Sodium chloride 
• Polysorbate 20 
• Water for injection 
Emulsion vial (AS03): 
• Sodium chloride 
• Disodium hydrogen phosphate 
• Potassium dihydrogen phosphate 
• Potassium chloride 
• Water for injection 
Dosage Level 
0.5 mL per dose 
0.5 mL per dose 
Number of Doses / Dosing 
Interval 
1 injection only (booster) 
2 injections / 21 days apart 
Route of Administration 
IM injection 
Site of Administration 
Deltoid muscle in the upper arm 
Sourcing 
CoV2 preS dTM (D614): 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 one fixed label 
containing the dose number. All will be labeled in accordance with local Health Authority requirements. 
Batch Number 
TBD 
TBD 
Storage Conditions 
2ºC to 8ºC (35°F to 46°F) and protected from light 
IMP: Investigational Medicinal Product; NIMP: Non-Investigational Medicinal Product; TBD: to be determined 
 
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Table 6.3: Identity of Monovalent (B.1.351) study interventions  
Intervention 
Names 
Monovalent (B.1.351) 
CoV2 preS dTM 
(5 µg antigen)  
+ AS03  
(full-dose adjuvant) 
Monovalent (B.1.351) 
CoV2 preS dTM 
(5 µg antigen) 
+ AS03  
(half-dose adjuvant) 
Monovalent (B.1.351) 
CoV2 preS dTM 
(2.5 µg antigen)  
+ AS03  
(half-dose adjuvant) 
Monovalent (B.1.351) 
CoV2 preS dTM  
(2.5 µg antigen)  
+ AS03  
(full-dose adjuvant) 
Monovalent (B.1.351) 
CoV2 preS dTM 
(5 µg antigen)  
(no adjuvant) 
Cohort 
Cohort 2 
Cohort 2 
Cohort 2 
Cohort 2 
Cohort 2 
Cohort Group 
/ Arm 
Booster Group / Main Arm 
 
Booster Group / 
Exploratory Arm 
Booster Group / 
Exploratory Arm 
Booster Group / 
Exploratory Arm 
Booster Group / 
Exploratory Arm 
Use 
Experimental 
IMP and 
NIMP 
IMP 
Type 
Vaccine 
Dose Form 
Solution and emulsion for injection, mix pre-injection according to dose preparation protocol. The solution (Antigen) and emulsion (AS03 
Adjuvant), once mixed, form a multi-dose vaccine in a vial. 
CoV2 preS dTM antigen is a sterile, clear, colorless solution (with possible presence of endogenous particles) of SARS-CoV-2 prefusion S 
proteins for IM injection. The antigen solution can contain endogenous particles. If present, these light-colored particles are slow sinking and 
suspended in solution. 
AS03 adjuvant is a whitish to yellowish homogenous milky liquid emulsion. 
After mixing, the vaccine is a whitish to yellowish homogeneous milky liquid emulsion. 
Unit Dose 
Strengths 
Each 0.5 mL dose of Study 
Intervention will contain 
the following: 
• preS-delta TM B.1.351: 
prefusion S delta TM 
B.1.351 COVID-19 
antigen, (5 µg) 
• AS03 adjuvant (full-
dose) is an oil-in-water 
Each 0.25 mL dose of 
Study Intervention will 
contain the following: 
• preS-delta TM B.1.351: 
prefusion S delta TM 
B.1.351 COVID-19 
antigen, (5 µg) 
• AS03 adjuvant (half-
dose) is an oil-in-water 
Each 0.25 mL dose of 
Study Intervention will 
contain the following: 
• preS-delta TM B.1.351: 
prefusion S delta TM 
B.1.351 COVID-19 
antigen, (2.5 µg) 
• AS03 adjuvant (half-
dose) is an oil-in-water 
Each 0.5 mL dose of Study 
Intervention will contain 
the following: 
• preS-delta TM B.1.351: 
prefusion S delta TM 
B.1.351 COVID-19 
antigen, (2.5 µg) 
• AS03 adjuvant (full-
dose) is an oil-in-water 
Each 0.5 mL dose of 
Study Intervention will 
contain the following: 
• preS-delta TM 
B.1.351: prefusion S 
delta TM B.1.351 
COVID-19 antigen, 
(5 µg) 
• No adjuvant 
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emulsion containing 
squalene (10.69 
milligrams), DL-α-
tocopherol (11.86 
milligrams) and 
polysorbate 80 (4.86 
milligrams). 
emulsion containing 
squalene (5.35 
milligrams), DL-α-
tocopherol (5.93 
milligrams) and 
polysorbate 80 (2.43 
milligrams).   
emulsion containing 
squalene (5.35 
milligrams), DL-α-
tocopherol (5.93 
milligrams) and 
polysorbate 80 
(2.43 milligrams).   
emulsion containing 
squalene (10.69 
milligrams), DL-α-
tocopherol (11.86 
milligrams) and 
polysorbate 80 (4.86 
milligrams). 
 
Excipients / 
Diluent 
Excipients: 
Solution vial (Antigen): 
• Sodium phosphate monobasic monohydrate 
• Sodium phosphate dibasic dodecahydrate 
• Sodium chloride 
• Polysorbate 20 
• Water for injection 
Emulsion vial (AS03): 
• Sodium chloride 
• Disodium hydrogen phosphate 
• Potassium dihydrogen phosphate 
• Potassium chloride 
• Water for injection 
Dosage Level 
0.5 mL per dose 
0.25 mL per dose 
0.25 mL per dose 
0.5 mL per dose 
0.5 mL per dose 
Number of 
Doses / Dosing 
Interval 
1 injection (booster) 
1 injection (booster) 
1 injection (booster) 
1 injection (booster) 
1 injection (booster) 
Route of 
Administration 
IM injection 
Site of 
Administration 
Deltoid muscle in the upper arm 
Sourcing 
CoV2 preS dTM (B.1.351): Provided by the Sponsor 
AS03: Provided by GSK 
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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 one fixed label containing the dose number. All will be labeled in accordance 
with local Health Authority requirements. 
Batch Number 
TBD 
TBD 
TBD 
TBD 
TBD 
Storage 
Conditions 
2ºC to 8ºC (35°F to 46°F) and protected from light 
 
 
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Table 6.4: Identity of Bivalent (D614 + B.1.351) study intervention  
Intervention Name 
Bivalent (D614 + B.1.351) CoV2 preS dTM 
(2.5 µg D614 antigen + 2.5 µg B.1.351 antigen) 
+ AS03 (full-dose adjuvant) 
Cohort 
Supplemental Cohort 2 
Cohort Group / Arm 
Booster Group / mRNA and Adenovirus-vector COVID-19 Vaccine Main Arm 
Use 
Experimental 
IMP and NIMP 
IMP 
Type 
Vaccine 
Dose Form 
Solution and emulsion for injection, mix pre-injection according to dose preparation 
protocol. The solution (bivalent formulated Antigen containing D614 and B.1.351) and 
emulsion (AS03 Adjuvant), once mixed, form a multi-dose vaccine in a vial. 
CoV2 preS dTM bivalent antigen is a sterile, clear, colorless solution (with possible 
presence of endogenous particles) of SARS-CoV-2 prefusion S proteins (D614 and B.1.351) 
for IM injection. The antigen solution can contain endogenous particles. If present, these 
light-colored particles are slow sinking and suspended in solution. 
AS03 adjuvant is a whitish to yellowish homogenous milky liquid emulsion. 
After mixing, the vaccine is a whitish to yellowish homogeneous milky liquid emulsion. 
Unit Dose Strengths 
Each 0.5 mL dose of Study Intervention will contain the following: 
• preS-delta TM D614: prefusion S delta TM D614 COVID-19 antigen, (2.5 µg) 
• preS-delta TM B.1.351: prefusion S delta TM B.1.351 COVID-19 antigen, (2.5 µg) 
• AS03 adjuvant is an oil-in-water emulsion containing squalene (10.69 milligrams), DL-
α-tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams) 
Excipients / Diluent 
Excipients: 
Solution vial (bivalent Antigens): 
• Sodium phosphate monobasic monohydrate 
• Sodium phosphate dibasic dodecahydrate 
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• Sodium chloride 
• Polysorbate 20 
• Water for injection 
Emulsion vial (AS03): 
• Sodium chloride 
• Disodium hydrogen phosphate 
• Potassium dihydrogen phosphate 
• Potassium chloride 
• Water for injection 
Dosage Level 
0.5 mL per dose 
Number of Doses / Dosing Interval 
1 injection only (booster) 
Route of Administration 
IM injection 
Site of Administration 
Deltoid muscle in the upper arm 
Sourcing 
CoV2 preS dTM (D614 + B.1.351): 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 one fixed label containing the dose number. All will be labeled in 
accordance with local Health Authority requirements. 
Batch Number 
TBD 
Storage Conditions 
2ºC to 8ºC (35°F to 46°F) and protected from light 
IMP: Investigational Medicinal Product; NIMP: Non-Investigational Medicinal Product; TBD: to be determined 
 
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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 interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff. 
3) The multidose vial of CoV2 preS dTM antigen, either monovalent or bivalent antigen, will be 
mixed with the multi-dose vial of AS03 adjuvant prior to administration (when applicable). 
Vaccine formulations will be prepared in the CoV2 preS dTM antigen vials by adding an 
equal volume of adjuvant. Further details of the mixing protocol will be provided in the 
Operating Guidelines. 
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  
Original Phase II Cohort:  
On the day of enrollment, participants were tested for presence of SARS-CoV-2 antibodies using 
a rapid serodiagnostic test. All participants who meet the inclusion/exclusion criteria and sign the 
informed consent form (ICF) were randomly assigned to one of the study groups. 
The randomization was stratified by age groups (18-59 years of age and 60 years of age and 
older), baseline SARS-CoV-2 rapid serodiagnostic test positivity (positive/negative), and 
high-risk medical conditions (Yes/No). Up to 20% of participants were allowed to be positive by 
the rapid serodiagnostic test in each group. 
Eligible participants were randomly assigned to one of the 3 study groups in this cohort in a 1:1:1 
ratio, corresponding to one of the 3 formulations of CoV2 preS dTM-AS03 vaccine (with different 
antigen doses).  
A subset of 120 participants (40 participants in each of the 3 dosing group [20 per age group]) 
with negative results of baseline SARS-CoV-2 rapid serodiagnostic test were randomly assigned 
to collect CMI and mucosal samples.  
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Site staff was to connect to the Interactive Response Technology (IRT) system, enter the 
identification and security information, and confirm a minimal amount of data in response to IRT 
prompts. The IRT was to collect information on age-group, high risk medical conditions, 
ethnicity/race, and result of SARS-CoV-2 rapid serodiagnostic test to enable monitoring of 
enrollment and capping of study population groups (see Section 5.4). The IRT was then to provide 
the group assignment. The full detailed procedures for group allocation are described in the 
Operating Guidelines. If the participant was not eligible to participate in the study, then the 
information was to be only be recorded on the participant recruitment log. 
Supplemental Phase III Cohorts 
Supplemental Cohort 1, Booster Groups: 
The Booster Groups in this Cohort will be open-label and not randomly assigned as all 
participants in these groups will receive 1 injection of the CoV2 preS dTM-AS03 (D614) booster 
vaccine candidate. Participants meeting eligibility criteria will be allocated to different groups 
according to 2 stratification variables: age group and priming vaccine. The age criterion will be 
based on 2 age strata: 18-55 years of age and 56 years of age and older. The priming vaccine 
criterion will include 4 strata: Pfizer/BioNTech, Moderna, Oxford University/AstraZeneca, and 
J&J/Janssen. A subset of 10% of participants aged 18-55 years old (~22 participants) in the 
Pfizer/BioNTech-primed CoV2 preS dTM-AS03 (D614) booster vaccine group and a subset of 
10% of participants aged 18-55 years old (~8 participants) each in the other primed (Moderna, 
Oxford University/AstraZeneca, J&J/Janssen) CoV2 preS dTM-AS03 (D614) booster vaccine 
groups will be randomly assigned to variant testing subsets. The number of eligible participants 
allocated to strata defined by age and priming vaccine will be as described in Section 4.1.  
Site staff will connect to the IRT system, enter the identification and security information, and 
confirm a minimal amount of data in response to IRT prompts. The IRT will collect information 
on age-group, priming vaccine, high-risk medical conditions, ethnicity/race (the last 2 for 
monitoring purposes and high-risk medical conditions for potential capping). The IRT will then 
confirm the group assignment within this cohort. The full detailed procedures for group allocation 
are described in the Operating Guidelines. 
Supplemental Cohort 2, Booster Groups: 
The Booster Groups in this cohort will be randomly assigned based on stratification variables. 
Participants meeting eligibility criteria will be stratified according to the following variables: age 
group (2 strata: 18-55 years of age and 56 years of age and older), priming vaccine (5 strata: 
Pfizer/BioNTech, Moderna, Oxford University/Astra Zeneca, J&J/Janssen, and CoV2 preS 
dTM-AS03), exploratory vs. non-exploratory (“main”) arms, and high-risk medical condition 
(Yes/No). 
Eligible participants who have received the Pfizer/BioNTech vaccine will be first assigned to the 
non-exploratory groups (ie, main arms, N = 1130), and will be randomized in a 1:1 ratio to receive 
a single injection of either the CoV2 preS dTM-AS03 (B.1.351) booster vaccine or the CoV2 preS 
dTM-AS03 (D614 + B.1.351) booster vaccine. Randomization will occur by age strata 
(1030 [515 per group] belonging to the 18-55 years of age group, and 100 [50 per group] 
belonging to the 56 years of age and older group). A subset of 5% of participants aged 18-55 years 
old (~26 participants in each of these 2 Booster Groups) will be randomly assigned to collect CMI 
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and mucosal samples plus variant testing. Once enrollment for the main arms has been completed 
for the Pfizer/BioNTech-primed individuals, eligible individuals who have received this vaccine 
will be randomized in a 1:1:1:1 ratio into one of the four Monovalent B.1.351 exploratory groups 
(total N = 400) as described in Section 4.1 No CMI and mucosal samples will be collected in 
these exploratory groups. 
Eligible participants who have received the Moderna (N = 200), Oxford University/Astra Zeneca 
(N = 200), or J&J/Janssen (N = 200) vaccines will be randomized in a 1:1 ratio to receive a single 
injection of either the CoV2 preS dTM-AS03 (B.1.351) booster vaccine or the CoV2 preS 
dTM-AS03 (D614 + B.1.351) booster vaccine. Randomization will occur by age strata (with ¾ of 
participants belonging to the 18-55 years of age group). No CMI and mucosal samples will be 
collected in these groups. 
Eligible participants transitioning from the VAT00002 Original Phase II Cohort who have 
received the CoV2 preS dTM-AS03 (D614) candidate vaccine (targeted N = 450; actual number 
to be determined by number of VAT00002 participants meeting eligibility criteria for transition) 
will be randomized to receive a single injection of either the CoV2 preS dTM-AS03 (D614) or the 
CoV2 preS dTM-AS03 (B.1.351) booster vaccine. Randomization will occur by age strata 
(assumption that about 2/3 of participants will be 18-55 years of age (ie, 300 adults 18-55 years 
old, allocation ratio of 9:1 between CoV2 preS dTM-AS03 [D614] group and the CoV2 preS 
dTM-AS03 [B.1.351] group); the actual number and age distribution will be determined by 
characteristics of those who meet eligibility criteria for transition). A subset of 10% of participants 
aged 18-55 (~30 participants in the 2 Booster Groups combined) will be randomly assigned to 
collect CMI and mucosal samples plus variant testing. 
Site staff will connect to the IRT system, enter the identification and security information, and 
confirm a minimal amount of data in response to IRT prompts. The IRT will collect information 
on age-group, priming vaccine, high-risk medical conditions, and ethnicity/race (the last 2 for 
monitoring purposes and high-risk medical conditions for potential capping). The IRT will then 
provide the group assignment (intervention arm and CMI/mucosal subset [if applicable]). The full 
detailed procedures for group allocation are described in the Operating Guidelines. 
Supplemental Cohorts Comparator Group: 
This Group will be open-label and not randomly assigned as all eligible participants will have 
common baseline characteristics (previously unvaccinated) and all will receive two injections of 
the CoV2 preS dTM-AS03 (D614) candidate vaccine 21 days apart. Eligible participants must be 
18-55 years of age and have a negative baseline SARS-CoV-2 rapid serodiagnostic test to be 
enrolled into this group. A subset of 5% of participants aged 18-55 (~26 participants) will be 
randomly assigned to variant testing subsets. 
Site staff will connect to the IRT system, enter the identification and security information, and 
confirm a minimal amount of data in response to IRT prompts. The IRT will collect information 
on age, documentation of negative baseline SARS-CoV-2 rapid serodiagnostic test, high-risk 
medical conditions, and ethnicity/race (the last 2 for monitoring purposes and high-risk medical 
conditions for potential capping). The IRT will then confirm the assignment to this group. The full 
detailed procedures for group allocation are described in the Operating Guidelines. 
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Applicable to All Cohorts: 
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 consisting of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit participant identifier). The leading number 
of the last 5-digit participant identifier will be designed as the indication of the cellular immunity 
and mucosal subset. Participants from the Original Phase II Cohort who will be transitioning to 
Supplemental Cohort 2 will be assigned a new participant identification number. 
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  
With the exception of the Booster Arms in Supplemental Cohort 1 and the Comparator Arm 
common to Supplemental Cohorts 1 and 2, the study will be performed in a modified double-blind 
(observer-blind) fashion: 
• Investigators and study staff who conduct the safety assessment and monitoring and the 
participant will not know which vaccine is administered in order to decrease the risk of 
potential bias. Study site staff who administer the vaccine may also be blinded if they are 
not involved in preparation of the vaccine. 
• Only the study-site staff who prepare the vaccine and are not involved with the safety 
evaluation will know which vaccine is administered 
• Testing laboratories will be blinded 
At the time of the interim analysis (see Section 9.5) of the Original Phase II Cohort, unblinding at 
the group-level occurred to inform Sponsor decision on dose-selection and progression to Phase 
III. Individual level code will be maintained by the Independent unblinded statistical group till the 
end of the study. In addition to that, Global Clinical Immunology (GCI) and other laboratories 
undertaking assays for the study will be kept blinded until all test results are released. 
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the participant. Code-breaking should be limited to the 
participant(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur 
Responsible Medical Officer (RMO) if a participant’s code was broken. All contact attempts with 
the Sponsor prior to unblinding are to be documented in the source documents, and the code-
breaking CRF is to be completed. 
The Independent Ethics Committee / Institutional Review Board (IEC / IRB) must be notified of 
the code-breaking, in accordance with local regulations. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
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A request for the code to be broken may also be made: 
• by the Global Pharmacovigilance (GPV) Department through an internal system for 
reporting to Health Authorities in the case of an unexpected SAE considered causally 
related, as described in International Council for Harmonisation (ICH)a E2A. In this case, 
the code will be broken only for the participant(s) in question. The information resulting 
from code-breaking (ie, the participant’s study intervention or group assignment) will not 
be communicated to either the Investigator or the immediate team working on the study, 
except for the GPV representative. 
The code-breaking procedures are described in the Operating Guidelines. 
6.4 
Study Intervention Compliance  
The following measures will ensure that the study intervention is administered as planned (see 
Table 6.1), and that any non-compliance is documented so that it can be accounted for in the data 
analyses: 
• All study interventions will be administered by qualified and trained study personnel 
• The person in charge of study intervention management at the site will maintain 
accountability records of study intervention delivery to the study site, study intervention 
inventory at the site, dose(s) given to each participant, and unused or wasted doses 
6.5 
Dose Modifications  
Not applicable 
6.6 
Access to Authorized/Approved vaccine during the study  
If an approved/authorized vaccine is available in the country or region where the study is 
conducted, Investigators will discuss this information with prospective study participants who 
have not yet received an authorized/approved vaccine at the time of informed consent and who 
will be encouraged to obtain the approved/authorized vaccine if applicable to them. Recruitment 
of eligible participants into one of the study cohorts evaluating priming vaccines (Original Phase 
II Cohort and the Supplemental Cohorts Comparator Group) will proceed only if, despite 
encouragement, the candidate participant expresses no intention to seek an authorized or approved 
vaccine at least until completion of the key follow-up timepoint (D43 for the study cohorts 
evaluating priming vaccines) for informing either progression to Phase III and dose selection (for 
Original Phase II Cohort participants) or suitability of variant-containing vaccines for 
authorization/approval (for the Supplemental Cohorts Comparator Group) 
If the participant is enrolled and seeks vaccination of an authorized/approved vaccine outside of 
the study, he/she will be encouraged to discuss this intention proactively with the study 
Investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved vaccine, this information would be collected and the 
                                                 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 
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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 in the cohorts evaluating 
priming vaccines will not receive the second vaccination if they have received the 
authorized/approved vaccine between the first and second scheduled vaccination. 
6.7 
Continued Access to Study Intervention After the End of the Study  
In the event that the vaccine formulation evaluated in this study is deemed safe and effective by 
regulatory authorities, this authorized/approved vaccine may be offered to eligible participants in 
this study who received a formulation considered less effective to that authorized by the 
regulatory authorities, if permitted by local regulations and in alignment with local 
recommendations. 
6.8 
Treatment of Overdose  
Since the study intervention is administered by a health care professional, it is unlikely that 
overdose by injection occurs. 
However, in the event of an overdose, the Investigator should: 
1) Contact the  RMO immediately. 
2) Evaluate the participant to determine, in consultation with the RMO, whether study 
intervention should be interrupted. 
3) Closely monitor the participant for any AE/SAE. 
4) Document the quantity of the excess of the overdose in the source documents. 
6.9 
Concomitant Therapy  
At the time of enrollment, all ongoing medications and other therapies (eg, some vaccines, 
immunoglobulins and monoclonal antibodies) should be recorded in the source document. 
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. 
Reportable medications/vaccinations will be collected in the CRF from the day of each study 
vaccination to the end of the solicited and unsolicited follow-up period after each study 
vaccination in all participants, with the exception of influenza and COVID-19 vaccination which 
will be collected throughout the study in all participants. In addition, any medications used for 
COVID-19 prophylaxis (eg, SARS-CoV-2 antivirals, monoclonal or polyclonal antibodies or 
plasma) will be collected throughout the study in all participants. 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. 
The following 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], 
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anticoagulants, antithrombotics) Note: Topical analgesics should NOT be applied at the 
injection site of study intervention; however, if they are applied inadvertently, they should 
be recorded. 
• Category 2: medications impacting or that may have an impact on the immune response 
(eg, hydroxychloroquine, other vaccines, blood products, immunoglobulins, monoclonal 
antibodies, convalescent plasma, antivirals and antiretrovirals, 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) 
In addition to the above, some therapies or vaccines are to be collected even if they were taken 
before study vaccination or are stopped prior to enrollment, or if they are taken after the solicited 
period and at any time during the study. In this regard, information on use of influenza vaccines in 
the 6 months prior to enrollment is to be collected; information on immunoglobulins, plasma and 
other blood products, monoclonal antibodies, antineoplastics, immunomodulators (including high-
dose corticosteroids utilized for more than 10 days) administered up to 90 days before vaccination 
will be collected. 
Dosage and administration route, homeopathic medication, inhaled steroids, as well as topical 
treatments, ophthalmic and ear treatments will not be recorded (except topical analgesics applied at the 
injection site of study intervention). 
Medications given in response to an AE will be captured in the “Action Taken” section only. 
Medications administered during a COVID-19-like illness episode will be captured in the 
appropriate CRF and will not be considered as concomitant medications. Medications will not be 
coded. No details will be recorded in the concomitant medication Form of the CRF unless the 
medication(s) received belongs to one of the pre-listed categories. 
6.9.1 
Rescue Medicine  
Appropriate medical equipment and emergency medications, including epinephrine (1:1000), 
must be available at the study site in the event of an anaphylactic, vasovagal, or other immediate 
allergic reaction. 
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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
7.1.1 
Temporary Contraindications  
Should a participanta experience one of the conditions listed below, the Investigator will postpone 
further vaccination (if applicable, ie, for groups evaluating priming vaccine candidates) until the 
condition is resolved. 
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) in the 30 days prior to the first 
study vaccination except for influenza vaccine which may be received at any time 
with respect to study intervention 
TCI03: 
Receipt of any vaccine (other than the study vaccine[s]) in the 21 days preceding or on 
the day of the second study vaccination or planned receipt of any vaccine in the 
30 days following the second study vaccination except for influenza vaccine, which 
may be received at any time with respect to study intervention. 
7.1.2 
Definitive Contraindications  
Participants will permanently discontinue (definitive discontinuation) study intervention (if 
applicable, ie, for groups evaluating priming vaccine candidates) for the reasons listed below. 
These participants must not receive any additional dose of study intervention but should continue 
to be followed for safety and other study assessments/procedures. 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 or serum test 
DCI02: 
An anaphylactic or other significant allergic reaction to the previous dose of vaccine 
DCI03: 
AE assessed as related to the study vaccine following the previous dose of vaccine 
which may place the participant at unreasonable or significant risk of injury or illness 
following repeat exposure to study vaccine, based on Investigator’s judgment 
DCI04: 
Positive NAAT at V01 or symptomatic COVID-19 or asymptomatic SARS-CoV-2 
infection confirmed by NAAT after V01 and before V02 
DCI05: 
Receipt of COVID-19 vaccine (other than the study vaccine) or anti-SARS-CoV-2 
monoclonal or polyclonal antibody in the period between the first study vaccination 
and the day corresponding to the second study vaccination. 
                                                 
a Applies to the Primary Series only 
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If the participant is enrolled and seeks vaccination of an authorized/approved vaccine outside of 
the study, he/she will be encouraged to discuss this intention proactively with the study 
Investigator and will be permitted to receive the authorized vaccine at any time. If the participant 
receives the authorized/approved 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 be invited to a visit prior to 
receiving the vaccine and invited to provide a blood sample for immunological assessment. If the 
visit occurs more than 1 month after the D134 visit for the groups evaluating priming vaccine 
candidates (Original Phase II Cohort Arms and the Comparator Arm for the Supplemental 
Cohorts)   or more than 1 month after D91 visit for groups evaluating booster vaccine candidates 
(Booster Arms in Supplemental Cohorts 1 and 2), a PBMC sample will also be collected if the 
participant is in the cellular immunity and mucosal subset instead of the D366 sample. 
Participants will continue to be followed for the duration of the study as per scheduled visits and 
procedures except for receipt of the second vaccination as detailed above. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator or designee for safety, behavioral, 
or compliance reasons. 
• The reason for withdrawal should be clearly documented in the source documents and in the 
CRF: Adverse Event, Lost to Follow-up, Protocol Deviation, or Withdrawal by Participant. 
• The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws consent, he/she may request destruction of any biological samples 
taken (unless local law required not to destroy them), and the Investigator must document this 
in the site study records. 
• Withdrawn participants will not be replaced. 
Follow-up of Discontinuations 
For participants who have prematurely terminated the study, the site should attempt to contact 
them and complete all scheduled safety follow-ups, except if they specified that they do not want 
to be contacted again and it is documented in the source document. 
For participants where the reason for early termination is lost to follow-up, the site will not 
attempt to obtain further safety information.  
For participants from Original Phase II Cohort who terminate the study at D202 if they are 
included in the Supplemental Phase III Cohort 2. 
All participants will be scheduled to attend V08 (or V07 for booster vaccine study participants) 
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 Safety Follow-up 
call to identify the occurrence of any SAEs and AESIs that had not yet been reported. If 
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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. For participants who have 
prematurely terminated the study, the site should attempt to contact them and complete this 12-
month safety follow-up (and all other 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. 
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, text 
messages, or e-mails, and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered lost to follow-
up. 
Discontinuation of specific sites or of the study as a whole are handled as discussed in 
Appendix 10.1. 
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8 
Study Assessments and Procedures  
• Study procedures and their timing are summarized in the SoAs. 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 SoAs, 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. 
Blood and respiratory samples will be collected as described in the SoA tables (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, is not planned to exceed 240 mL (see 
Table 8.1, Table 8.2, and Table 8.3). Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples. 
In addition, for the primary series, if a participant seeks an authorized/approved vaccine, they will 
be invited to a visit prior to receiving the vaccine and invited to provide a blood sample for 
immunological assessment. If the visit occurs more than 1 month after the D134 visit, a PBMC 
sample will also be collected if the participant is in the cellular immunity and mucosal subset 
instead of the D387 sample (D366 for groups receiving booster vaccine). 
Guidance and information for the sample collection, preparation, storage, and shipment are 
provided in the Operating Guidelines. 
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Table 8.1: Original Phase II Cohort: samples collected per visit 
 
D01 
D22 
D36 
D78 
D134 
D202 
D292 
D387 
Vaccination 
X 
X 
 
 
 
BL0001 
BL0002 
BL0003 
BL0004 
BL0005 
BL0006 
BL0007 
BL0008 
SARS CoV2 
Microneutralization assay 
(SP) 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-S IgG ELISA 
X 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Pseudovirus 
Neutralization Assays  
X 
X 
X 
X 
X 
X 
X 
X 
ECLIA Multiplex Assay  
 
 
X 
 
 
 
 
 
Anti-N Immunoassay 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-S Immunoassay 
X 
 
 
 
 
 
 
 
SARS-CoV-2 NAAT on 
nasopharyngeal sample 
X 
X 
 
 
 
 
 
 
SARS-CoV-2 NAAT on 
respiratory sample during a 
COVID-19-like illness 
Illness visit (see Section 8.3.3) 
Rapid SARS-CoV-2 
serodiagnostic Test 
X 
 
 
 
 
 
 
 
Whole Blood TruCulture 
assay 
X 
X 
X 
 
 
 
 
 
Flow Cytometry and 
Intracellular Cytokine 
Staining 
X 
X 
X 
 
X 
 
 
X* 
B-cell memory Fluorospot 
X 
 
 
 
X 
 
 
X* 
Saliva samples 
X 
X 
X 
 
X 
 
 
 
SP, Sanofi Pasteur 
*If a participant seeks an authorized/approved vaccine, they will be invited to a visit prior to receiving the vaccine. If the visit 
occurs more than 1 month after the D134 visit, a PBMC sample will also be collected if the participant is in the cellular immunity 
and mucosal subset instead of the D387 sample. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 8.2:  Participants in Supplemental Groups receiving a single booster dose: Cohort 1, 
Cohort 2 Main Arm, Cohort 2 Exploratory B.1.351 Arm: samples collected per visit 
 
D01 
D15 
D29 
D91 
D181 
D366 
Vaccination 
X 
 
BL0001 
BL0002 
BL0003 
BL0004 
BL0005 
BL0006 
Anti-S IgG ELISA 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Pseudovirus 
Neutralization Assays  
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Pseudovirus 
Neutralization Assays 
Variants of Concern 
X 
X 
X 
 
X 
X 
ECLIA Multiplex Assay 
X 
 
X 
 
 
 
Anti-S Immunoassay 
X 
 
 
 
 
 
SARS-CoV-2 NAAT on 
nasopharyngeal sample 
X 
 
 
 
 
 
SARS-CoV-2 NAAT on 
respiratory sample during a 
COVID-19-like illness 
Illness visit (see Section 8.3.3) 
Flow Cytometry and 
Intracellular Cytokine 
Staining 
X 
 
X 
X 
 
X 
B-cell memory Fluorospot 
X 
 
 
X 
 
X 
Saliva samples 
X 
X 
 
X 
 
 
SP, Sanofi Pasteur 
**PBMC collected only in Cohort 2 
 
 
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Table 8.3: Participants in Supplemental Cohorts Comparator Group receiving 2-dose 
schedule: samples collected per visit 
 
D01 
D22 
D36 
D134 
D202 
D292 
D387 
Vaccination 
X 
X 
 
 
 
BL0001 
BL0002 
BL0003 
BL0004 
BL0005 
BL0006 
BL0007 
Anti-S IgG ELISA 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Pseudovirus 
Neutralization Assays  
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Pseudovirus 
Neutralization Assays Variants 
of Concern 
X 
 
X 
 
X 
 
X 
Anti-S Immunoassay 
X 
 
 
 
 
 
 
SARS-CoV-2 NAAT on 
nasopharyngeal sample 
X 
X 
 
 
 
 
 
SARS-CoV-2 NAAT on 
respiratory sample during a 
COVID-19-like illness 
Illness visit (see Section 8.3.3) 
Rapid SARS-CoV-2 
serodiagnostic Test 
X 
 
 
 
 
 
 
B-cell memory Fluorospot** 
X 
 
 
X 
 
 
X* 
Saliva samples 
X 
X 
X 
X 
 
 
 
SP, Sanofi Pasteur 
 
8.1 
Baseline Assessments at the Time of Vaccination  
8.1.1 
Demographic Information and Risk Factor Data  
All participants will be asked to provide information on demographic information such as age, 
sex, race, and ethnicity at the time of enrollment. The type of demographic information is 
determined by laws in each country. Race and ethnicity data will be collected from participants as 
these are factors found to be associated with an increased risk of severe COVID-19. 
In addition, information on factors associated with increased risk of exposure to SARS-CoV-2 and 
increased risk of infection will be collected at the time of enrollment (for the Supplemental 
Cohorts Comparator Group only). This may include type of occupation, workplace, type of 
residence, household/residence members, use of public transport, social interactions and known 
history of contact with positive individuals. 
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8.1.2 
Physical Examinations and Vital Signs  
At the time of enrollment, height, weight, vital signs, and a targeted physical examination will be 
performed. For further details on these safety assessments, see Section 8.3.5 and Section 8.3.6. 
8.1.3 
Medical History  
Prior to enrollment, participants will be assessed for pre-existing conditions and illnesses, both 
past and ongoing with specific details regarding medical conditions associated with high risk of 
COVID-19 (Section 5.3). Any such conditions will be documented in the source document 
including the date of diagnosis. 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 repetitive outpatient care will be collected in the CRF. In addition, any prior history of 
COVID-19 will be collected. 
8.1.4 
Clinical Safety Laboratory Assessments  
Urine or serum pregnancy testing will be performed in females of childbearing potential before 
each vaccination. 
8.1.5 
Baseline SARS-CoV-2 Antibody Screening  
A blood sample will be obtained before study enrollment to ascertain evidence of SARS-CoV-2 
antibodies using a SARS-CoV-2 rapid serodiagnostic test that will be done at the site (not 
applicable to Supplemental Cohort 1 or 2). While this serodiagnostic test will be utilized to 
provide real-time information about proportion of participants enrolled who may have been 
previously infected with or immunized against SARS-CoV-2 and therefore critical for study 
capping decisions (for the Original Phase II Cohort), or for restricting enrollment to those 
individuals without evidence of prior exposure based on the test (for the Supplemental Cohorts 
Comparator Group, classification of naïve and non-naïve status will be based on other assays 
(specifically, the combination of information from the N ELECSYS, S ELECSYS, and NAAT at 
baseline for the Original Phase II Cohort, or the combination of information from the S ELECSYS 
and NAAT at baseline for comparator for Supplemental Cohorts 1 and 2) see Section 9.3. 
At the time of enrollment, participants will be directed not to get an antibody test outside the study 
because of the risk of vaccine-induced seropositivity which would make the interpretation of the 
antibody test difficult and raise the potential for unintentional unblinding. 
8.1.5.1 
Healgen COVID-19 IgG/IgM Rapid Test  
The Healgen COVID-19 IgG/IgM Rapid Test Cassette was performed at the clinical site by 
trained personnel for the Original Phase II Cohort only.  
The Rapid Diagnostic Test will be used according to the product insert provided by the 
manufacturer. The COVID-19 IgG/IgM Rapid Test Cassette is a lateral flow 
immunochromatographic assay intended for the qualitative detection and differentiation of IgM 
and IgG antibodies to SARS-CoV-2 in human venous whole blood, plasma from anticoagulated 
blood (Lithium (Li+) heparin, dipotassium ethylenediaminetetraacetic acid (K2EDTA), and 
sodium citrate), or serum. The test uses anti-human IgM antibody, anti-human IgG antibody, and 
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rabbit IgG (control) immobilized on a nitrocellulose strip. The burgundy colored conjugate pad 
contains colloidal gold conjugated to recombinant COVID-19 antigens (SARS-CoV-2 Spike S1 
antigen) conjugated with colloid gold (COVID-19 conjugates). When a specimen followed by 
assay buffer is added to the sample well, IgM and/or IgG antibodies, if present, will bind to 
COVID-19 conjugates forming antigen-antibody complexes. This complex migrates through the 
nitrocellulose membrane by capillary action. When the complex meets the line of the 
corresponding immobilized antibody (anti-human IgM and/or anti-human IgG) the complex is 
trapped forming a burgundy colored band which confirms a reactive test result. The absence of a 
colored band in the test region indicates a non-reactive test result. A colored line must change 
from blue to red in the control line region to be valid, indicating that the proper volume of 
specimen has been added and membrane wicking has occurred. 
The results of this test were to be used for determining the randomization strata and to cap the 
enrollment of SARS-CoV-2 seropositive participants in the Original Phase II Cohort, but not for 
the determination of whether participants are SARS-CoV-2 naïve or non-naïve. This test was to 
inform capping of seropositive participants to a maximum of 20% of enrolled individuals in the 
Original Phase II Cohort. 
8.1.5.2 
 Assure COVID-19 IgG/IgM Rapid Test  
The Assure COVID-19 IgG/IgM Rapid Test will be performed at the clinical site by trained 
personnel for the Supplemental Cohorts Comparator Group.  
The Rapid Diagnostic Test will be used according to the product insert provided by the 
manufacturer. The Assure COVID-19 IgG/IgM Rapid Test Device is a lateral flow 
immunochromatographic assay for the detection of SARS-CoV-2 antibodies in venous whole 
blood, serum, or plasma. This test uses anti-human IgM antibody (test line IgM), anti-human IgG 
(test line IgG) and goat anti-mouse IgG (control line C) immobilized on a nitrocellulose strip. The 
conjugate pad contains recombinant SARS-CoV-2 antigen (antigen is recombinant Nucleocapsid 
Protein and Spike Protein [S1]) conjugated with colloid gold. During testing, the specimen binds 
with SARS-CoV-2 antigen-conjugated gold colloid coated particles in the test cassette. When a 
specimen followed by assay buffer is added to the sample well, IgM and/or IgG antibodies if 
present, will bind to COVID-19 conjugates making antigen antibodies complex. This complex 
migrates through nitrocellulose membrane by capillary action. When the complex meets the line 
of the corresponding immobilized antibody (anti-human IgM and/or anti-human IgG) the complex 
is trapped forming a red line which confirm a reactive test result. Absence of a red line in the test 
region indicates a non-reactive test result. To serve as a procedural control, a red line will always 
appear in the control line region, indicating that the proper volume of specimen has been added 
and membrane wicking has occurred. The presence of a red band(s) on the test region(s) indicates 
a positive result for the particular IgG and/or IgM antibodies, while its absence indicates a 
negative result. A red band at the control region (C) serves as a procedural control, indicating that 
membrane wicking is working.  
The results of this test will be used for determining the SARS-CoV-2 non-naïve individuals for 
inclusion into the Supplemental Cohort 1 Comparator Group. 
While this serodiagnostic test will be utilized to provide real-time information about eligibility for 
enrollment (ie, eligibility requires a negative result in the above mentioned groups in which the 
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test will be applied), classification of naïve and non-naïve status will be based on other assays 
(specifically, the combination of information from the S ELECSYS, and NAAT at baseline). 
At the time of enrollment, participants will be directed not to get an antibody test outside the study 
because of the risk of vaccine-induced seropositivity which would make the interpretation of the 
antibody test difficult and raise the potential for unintentional unblinding. 
8.1.5.3 
ELECSYS Anti-SARS-CoV-2 Anti-N ECLIA  
This test was to be used on D01 and D22 samples to determine naïve and non-naïve status in 
participants in the Original Phase II Cohort. Details were provided in the Operating Guidelines 
and the PPD laboratory manual. Based on data from the Original Phase II Cohort, the performance 
of this test is very similar to that of the ELECSYS Anti-SARS-CoV-2 Anti-S ECLIA described 
below, but the sensitivity of the ELECSYS Anti-SARS-CoV-2 Anti-S ECLIA is marginally 
higher. Therefore, it is considered that the ELECSYS Anti-SARS-CoV-2 Anti-N ECLIA is not 
adding meaningful value beyond the ELECSYS Anti-SARS-CoV-2 Anti-S ECLIA for 
determination of naïve vs. non-naïve status in the priming groups included in the Supplemental 
Cohorts.  
ELECSYS Anti-SARS-CoV-2 is an immunoassay intended for qualitative detection of antibodies 
to SARS-CoV-2 in human serum. The ELECSYS Anti-SARS-CoV-2 assay uses a recombinant 
protein representing the nucleocapsid (N) antigen for the determination of antibodies against 
SARS-CoV-2. Sample, biotinylated SARS-CoV-2 specific recombinant antigen and SARS-CoV-2 
specific recombinant antigen labeled with a ruthenium complex are first incubated and form a 
sandwich complex. After addition of streptavidin-coated microparticles, the complex becomes 
bound to the solid phase via interaction of biotin and streptavidin. The reaction mixture is 
aspirated into the measuring cell where the microparticles are magnetically captured onto the 
surface of the electrode. Unbound substances are then removed with ProCell/ProCell M/ProCell II 
M. Application of a voltage to the electrode then induces chemiluminescent emission which is 
measured by a photomultiplier. Results are determined automatically by the software by 
comparing the electrochemiluminescence signal obtained from the reaction product of the sample 
with the signal of the cutoff value previously obtained by calibration. 
8.1.5.4 
ELECSYS Anti-SARS-CoV2 Anti-S ECLIA  
This test will be used on D01 samples in all participants belonging to any groups evaluating 
priming vaccines (Original Phase II Cohort and the Supplemental Cohorts Comparator Group) to 
determine naïve and non-naïve status. Details will be provided in the Operating Guidelines and 
the PPD laboratory manual. This testing will be performed in all Cohorts.  
ELECSYS Anti-SARS-CoV-2 is an immunoassay intended for qualitative detection of antibodies 
to SARS-CoV-2 in human serum. The ELECSYS Anti-SARS-CoV-2 assay uses a recombinant 
protein representing the S antigen for the determination of antibodies against SARS-CoV-2. 
Sample, biotinylated SARS-CoV-2 specific recombinant antigen and SARS-CoV-2 specific 
recombinant antigen labeled with a ruthenium complex are first incubated and form a sandwich 
complex. After addition of streptavidin-coated microparticles, the complex becomes bound to the 
solid phase via interaction of biotin and streptavidin. The reaction mixture is aspirated into the 
measuring cell where the microparticles are magnetically captured onto the surface of the 
electrode. Unbound substances are then removed with ProCell/ProCell M/ProCell II M. 
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Application of a voltage to the electrode then induces chemiluminescent emission which is 
measured by a photomultiplier. Results are determined automatically by the software by 
comparing the electrochemiluminescence signal obtained from the reaction product of the sample 
with the signal of the cutoff value previously obtained by calibration. 
8.1.6 
NAAT Assessment Prior to Vaccination  
All participants will have a single bilateral nasopharyngeal swab collected at the enrollment visit. 
Participants belonging to groups evaluating primary vaccination (Original Phase II Cohort and the 
Supplemental Cohorts Comparator Group) will also have a single bilateral nasopharyngeal swab 
collected at the second vaccination visit. This will be used for confirmation of SARS-CoV-2 
infection as part of the assessment to determine whether the individual is SARS-CoV-2 naïve or 
non-naïve (see Section 9.3) in previously unvaccinated individuals (ie, priming vaccine groups), 
and to identify acute or recent infection in those previously vaccinated with a COVID-19 vaccine 
(ie, boosting vaccine groups). This testing will be performed in all cohorts. 
8.2 
Immunogenicity Assessments  
8.2.1 
Primary Immunogenicity Assays  
8.2.1.1 
SARS-CoV-2 Pseudovirus Neutralization Assay  
This testing will be performed on all participants at all timepoints. 
The PhenoSense (PS) CoV nAb Assay has been developed by leveraging the proprietary PS assay 
platform that was developed to evaluate antiretroviral drug susceptibility and later adapted to 
evaluate entry inhibitors, neutralizing antibody activity, and co-receptor tropism. The production 
of luciferase is dependent on virus entry and the completion of a single round of virus replication. 
Agents that inhibit pseudovirus entry or replication reduce luciferase activity in a dose-dependent 
manner, providing a quantitative measure of drug and antibody susceptibility. Over time, the PS 
assay platform has been successfully adapted to evaluate vaccines and entry inhibitors that target a 
variety of enveloped viruses including Influenza, RSV, and most recently SARS-CoV-2. 
The measurement of neutralizing antibody activity using the PS SARS-CoV-2 neutralizing 
antibody assay is performed by generating HIV-1 pseudovirions that express the SARS-CoV-2 
S protein. The pseudovirus is prepared by co-transfecting HEK293 producer cells with an HIV-1 
genomic vector and a SARS-CoV-2 envelope expression vector. Neutralizing antibody activity is 
measured by assessing the inhibition of luciferase activity in HEK293 target cells expressing the 
ACE2 receptor following pre-incubation of the pseudovirions with serial dilutions of the serum 
specimen. The expression of luciferase activity in target cells is inhibited in the presence of 
anti-SARS-CoV-2 nAb. Data are displayed by plotting the percent inhibition of luciferase activity 
vs. log10 reciprocal of the serum/plasma dilution and nAb titers are reported as the reciprocal of 
the serum dilution conferring 50% inhibition (ID50) of pseudovirus infection. 
 %Inhibition = 100% – (RLU(Vector+Sample+Diluent) ÷ RLU(Vector+Diluent)) x 100%)  
To ensure that the measured neutralizing antibody activity is SARS-CoV-2 neutralizing antibody 
specific, each test specimen is also assessed using a non-specific pseudovirus (specificity control) 
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that expresses a non-reactive envelope protein of one or more unrelated viruses (eg, avian 
influenza virus).  
This assay will be used to measure neutralizing antibody responses to the prototype strain 
(D614G variant) at all timepoints in all participants (all Cohorts). The neutralizing antibody 
response to the emerging variant B.1.351 will also be performed at D36 in the Original Phase II 
Cohort and all timepoints in Supplemental Cohort 2.     
8.2.2 
Secondary Immunogenicity Assays  
8.2.2.1 
SARS-CoV-2 Neutralizing Antibody Assessment (SP)  
SARS-CoV-2 neutralizing antibodies will be measured using a live virus neutralization assay in 
all participants included in the Original Phase II Cohort at all timepoints. This testing will be 
performed in the Original Phase II Cohort. 
Serum samples are mixed with constant concentration of the SARS-CoV-2 virus. A reduction in 
virus infectivity (viral antigen production) due to neutralization by antibody present in serum 
samples can be detected by ELISA. After washing and fixation, SARS-CoV-2 antigen production 
in cells can be detected by successive incubations with an anti-SARS-CoV-2-specific antibody, 
HRP IgG conjugate, and a chromogenic substrate. The resulting optical density 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. 
8.2.2.2 
Detection of binding antibody levels by ECLIA  
SARS-CoV-2 binding antibodies will be measured using an electrochemiluminescence 
immunoassay (ECLIA) in participants included in the Original Phase II Cohort at D36 and on D01 
and D29 samples in all participants belonging to any groups evaluating priming vaccines (Cohort 
1, Cohort 2 Main Arm, Cohort 2 Exploratory B.1.351 Arm). 
The 4-plex SARS-CoV-2 assay (detecting serum IgG binding to SARS-CoV-2 antigens S Protein 
[S-2P], Receptor Binding Domain [RBD], and Nucleocapsid [N], with a Bovine Serum Albumin 
[BSA] control) is intended for use to aid in identifying volunteers with an immune response to 
SARS-CoV-2 S-2P after vaccination with experimental SARS-CoV-2 vaccines. 
MSD SECTOR® plates are precoated by MSD with SARS-CoV-2 S-2P, RBD protein, N protein, 
and a BSA control in each well in a specific spot-designation for each antigen. The assay will be 
performed with a Beckman Coulter Biomek based automation integration platform including the 
Biotek 405TS Plate Washer. Serum samples will be heat-inactivated for 30 minutes at 56oC prior 
to assay. Plates are blocked for 60 minutes at room temperature (RT) with MSD blocker A 
solution without shaking. Plates are washed and MSD reference standard (calibrator), QC test 
sample (pool of COVID-19 convalescent sera) and human serum test samples are added to the 
precoated wells in duplicates in an 8-point dilution series. Reference standard is added in 
triplicates. MSD Control sera (low, medium, and high) are added undiluted in triplicates as per 
validated assay format. Additional assay controls might be added in triplicates. Samples are 
incubated at RT for 4 hours with shaking on a Titramax Plate shaker (Heidolph) at 1500 rpm. 
SARS-CoV-2 specific antibodies present in the sera or controls bind to the coated antigens. Plates 
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are washed to remove unbound antibodies. Antibodies bound to the SARS-CoV-2 viral proteins 
are detected using an MSD SULFO-TAGTM anti-human IgG detection antibody incubated for 60 
minutes at RT and with shaking. Plates are washed and a read solution (MSD GOLDTM read 
buffer) containing electrochemiluminescence (ECL) substrate is applied to the wells, and the plate 
is entered into the MSD MESO Sector S 600 detection system. An electric current is applied to 
the plates and areas of well surface which form antigen-anti human IgG antibody SULFO-
TAGTM complex will emit light in the presence of the ECL substrate. 
The MSD MESO Sector S 600 detection system quantitates the amount of light emitted and 
reports the ECL unit response as a result for each test sample, control sample and reference 
standard of each plate. Analysis is performed with the MSD Discovery Workbench software, 
Version 4.0. Calculated ECLIA parameters to measure binding antibody activities will include 
interpolated concentrations or assigned international units (IU/mL) read from the standard curve. 
8.2.2.3 
SARS-CoV-2 Spike Protein Antibody Serum IgG ELISA  
SARS-CoV-2 Anti-S protein IgG antibodies will be measured using an ELISA at all timepoints 
and in all participants (all Cohorts). 
Microtiter plates will be coated with SARS-CoV-2 S protein antigen diluted in coating buffer to 
the optimal concentration. 
Plates may be blocked by the addition of a blocking buffer to all wells and incubation for a 
defined period. Following incubation, plates will be washed. All controls, reference, and samples 
will be pre-diluted with dilution buffer. The pre-diluted controls, reference and samples will then 
be further serially diluted in the wells of the coated test plate. 
The plates will be incubated for a defined period. Following incubation, plates will be washed, an 
optimized dilution of goat anti-human IgG enzyme conjugate will be added to all wells, and plates 
will be further incubated. Following this incubation, the plates will be washed, and enzyme 
substrate solution will be added to all wells. Plates will be incubated for a defined period to allow 
the substrate to develop. Substrate development will be stopped by the addition of a stop solution 
to each well. An ELISA microtiter plate reader will be used to read the test plates using assay 
specific SoftMax Pro templates. 
The average OD value for the plate blank will be subtracted from all the ODs within each plate. 
The sample titers will be derived using the measured values of the blanks, controls, and the 
reference standard curve, which will be included on each assay plate within the run. 
8.2.3 
Exploratory Immunogenicity Assays  
8.2.3.1 
TruCulture Whole-Blood Cytokine Profiling  
Th1/Th2 cytokines will be measured in whole blood following stimulation with full-length S 
protein. This will be done in the subset of participants belonging to the cellular immunity and 
mucosal subset of the Original Phase II Cohort at D01, D22, and D36. This testing will be 
performed in the Original Phase II Cohort only. 
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8.2.3.2 
Cellular Immune Assays  
These assays will be done in the subset of participants belonging to the cellular immunity and 
mucosal subset in whom PBMCs will be collected. These subsets will be selected for the Original 
Phase II Cohort and for Supplemental Cohort 2 as described in Table 8.2 and Table 8.3. B cell 
memory responses using a multiplexed B cell FluroSpot assay evaluating IgG and IgA specific B 
cells to S protein will be measured at D01, D134, and D387 in the Original Phase II Cohort and 
D01, D91, and D366 in the Booster Cohort in vaccinees and D01, D134 and D387 in the Booster 
Cohort in naïves.  
Multiparametric flow cytometry will be used to identify antigen-specific CD4+ and CD8+ T-cells 
following stimulation with S protein or S-antigen peptide pools is planned in the subset of 
participants belonging to the cellular immunity and mucosal subset at D01, D22, D36, D134, and 
D387 in the Primary series, D01, D15, D29, D91 and D366 in the Booster Cohort in vaccinees 
and D01, D22, D363, D134 and D387 in the Booster Cohort in naïves. Preparation of blood 
samples and shipping instructions for cellular immunology assays are outlined in the Operating 
Manual. 
Timepoints for these assessments are specified in Table 8.1, Table 8.2, and Table 8.3. 
Preparation of blood samples and shipping instructions for cellular immunology assays are 
outlined in the Operating Manual. 
8.2.3.3 
Mucosal Antibody assays  
The OraSure SARS-CoV-2 Antibody ELISA is intended to be used for detection of total 
antibodies to SARS-CoV-2 in human oral fluid specimens collected with the OraSure Oral 
Antibody Collection Device. This will be done in the subset of participants belonging to the 
cellular immunity and mucosal subset at timepoints as follows: at D01, D22, D36 and D134 in the 
Primary Series and in the Booster Cohort in naïves and at D01, D15 and D91 in the Booster 
Cohort in vaccinees. Details on collection and processing of sample are outlined in the Operating 
Manual. This testing will be performed in all Cohorts 
8.2.3.4 
SARS-CoV-2 Pseudovirus Neutralization Assay (Nexelis)  
The SARS-CoV-2 Pseudovirus Neutralization Assay (Nexelis) evaluates the level of neutralizing 
SARS-CoV-2 pseudovirus antibodies present in the human serum samples. This testing will be 
performed in all Cohorts. 
Pseudotyped virus particles are made from a modified Vesicular Stomatitis Virus (VSVΔG) 
backbone and bear the S glycoprotein of the SARS-CoV-2 from which the last 19 amino acids of 
the cytoplasmic tail were removed. The pseudoparticles contain a Luciferase reporter used for 
detection. Seven 2-fold serial dilutions of heat-inactivated human serum samples are prepared in 
96-well transfer plate(s). The SARS-CoV-2 pseudovirus is added sequentially to the serum 
dilutions at a target working dilution (to obtain approximately 75 000-300 000 relative 
luminescence units [RLU]/well) and incubated at 37°C with 5% CO2 supplementation for 
60 ± 5 minutes. Serum-virus complexes are then transferred onto plates, previously seeded 
overnight with Vero E6 cells, and incubated at 37°C and with 5% CO2 supplementation for 20 ± 2 
hours. Following this incubation, the luciferase substrate is added to the cells in order to assess the 
level of luminescence per well. The plate(s) are then read on a luminescence plate reader and the 
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intensity of the luminescence is quantified in RLUs and is inversely proportional to the level of 
neutralizing antibodies present in the serum. The neutralizing titer of a serum sample is calculated 
as the reciprocal serum dilution corresponding to the 50% neutralization antibody titer (NT50) for 
that sample.   
This assay may be used to assess antibody responses against the parent D614G, Delta (B.1.617) 
variant, and other variant strains (eg, Alpha [B.1.17], Gamma [P1]).     
8.3 
Safety Assessments  
This section presents clinical and safety assessments other than AEs which are presented in 
Section 8.4. 
Planned time points for all safety assessments are provided in the SoA (see Section 1.3). 
8.3.1 
Definitions  
COVID-19-like illness 
Symptoms/conditions of COVID-19-like illness are as listed below, along with an accompanying 
tabulation of terms used in the CRFs versus DC / memory aids (Table 8.4). COVID-19-like illness 
symptoms will be graded by the intensity grade (see Section 10.3.5.1.3). 
New onset or exacerbation of any ONE of the following: 
• Fever (measured temperature ≥ 100.4ºF OR ≥ 38.0ºC) 
• Difficulty breathing or shortness of breath 
• Altered level of consciousness 
• Myocarditis, myocardial infarction 
• Thromboembolic event (blood clots [eg, pulmonary embolism, deep vein thrombosis, 
stroke]) 
• Purpura fulminans 
• Clinical or radiographic evidence of pneumonia 
• Chilblains (COVID-19-toes) 
OR 
New onset or exacerbation of ANY ONE of the following (that persists for a period of at least 
24 hours or reoccurs after a 12-hour period): 
• Cough (dry or productive) 
• Anosmia or partial loss of smell 
• Ageusia or dysgeusia (loss or disturbance of taste) 
OR  
New onset of any TWO of the following symptoms that are present at the same time (both 
symptoms that persist for a period of at least 24 hours or reoccur after a 12-hour period): 
• Pharyngitis 
• Chills 
• Myalgia 
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• Fatigue 
• Malaise 
• Headache 
• Rhinorrhea or nasal congestion 
• Abdominal pain 
• At least one of nausea, diarrhea, vomiting 
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Table 8.4: COVID-19-like illness symptoms/conditions: CRF and Diary Card / Memory Aid 
terms 
CRF term 
Diary Card / Memory Aid term 
Cough 
Cough 
Fever 
Temperature measured as 38.0ºC (100.4ºF) or higher 
Anosmia 
Loss or disturbance of smell 
Ageusia 
Loss or disturbance of taste 
Chilblains  
Pain, redness, sores in your fingers and toes exposed to cold 
Shortness of breath 
Difficulty breathing or feeling short winded 
Altered level of consciousness 
Altered consciousness or altered behavior 
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 
Malaise 
Feeling unwell 
Headache 
Headache 
Rhinorrhea 
Runny nose 
Nasal congestion 
Stuffy nose 
Abdominal Pain 
Belly pain 
Nausea 
Feeling queasy 
Diarrhea 
Loose stools 
Vomiting 
Throwing up 
Fatigue 
Tiredness 
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Laboratory-confirmed SARS-CoV-2 infection 
Laboratory-confirmed SARS-CoV-2 infection is defined as a positive result for SARS-CoV-2 by 
NAAT (done by the central laboratory [Section 8.3.3] or locally) on at least one respiratory 
sample. 
Serologically-confirmed SARS-CoV-2 infection 
Serologically-confirmed SARS-CoV-2 infection is defined as a positive result in a serum sample 
for antibodies specific to the Nucleocapsid of SARS-CoV-2 detected by ECLIA. 
SARS-CoV-2 infection 
SARS-CoV-2 infection is defined as a serologically-confirmed SARS-CoV-2 infection OR 
laboratory-confirmed SARS-CoV-2 infection. 
Symptomatic COVID-19 
Symptomatic COVID-19 is defined as laboratory-confirmed SARS-CoV-2 infection accompanied 
by protocol-defined COVID-19-like illness. 
Asymptomatic SARS-CoV-2 infection 
Asymptomatic SARS-CoV-2 infection is defined as SARS-CoV-2 infection, with no reported 
COVID-19-like illness episodes between enrollment and 14 days after the timepoint at which 
SARS-CoV-2 infection is ascertained. 
Hospitalized COVID-19 
Hospitalized COVID-19 is defined as an episode of Symptomatic COVID-19 that requires 
inpatient hospitalization. 
Severe COVID-19 
Severe COVID-19 is defined as COVID-19 with any one of the following: 
• Any clinical signs of severe illness measured at least on 2 occasions separated by 30 minutes 
(saturation of oxygen [SpO2] ≤ 93% on room air (corrected for altitude), PaO2/FiO2 ˂ 300 
mm Hg, RR ≥ 30 breaths per minute at rest, HR ≥ 125 beats per minute at rest) 
• Supplemental oxygen administration for > 1 hour 
• Use of invasive or non-invasive ventilation or Extracorporeal Membrane Oxygenation 
• Clinical diagnosis of respiratory failure (ie, clinical need for one of the preceding therapies, 
but preceding therapies not able to be administered in setting of resource limitation) 
• Significant acute renal, hepatic, or neurologic dysfunction 
• Shock (defined by systolic blood pressure ˂ 90 mm Hg, or diastolic blood pressure 
˂ 60 mm Hg or requiring vasopressors) 
• Admission to an ICU 
• Death 
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Death associated with COVID-19 
Death associated with COVID-19 is defined as death in a participant with COVID-19 who died 
within 28 days of the first positive specimen date OR died more than 28 days after the first 
specimen date and COVID-19 is mentioned as an immediate or underlying cause of death on the 
death certificate. 
8.3.2 
Schedule of Activities for COVID-19-like Illness  
Surveillance for COVID-19 
Active and passive surveillance will take place as shown below. Presence of COVID-19-like 
illness would result in the site arranging a COVID-19-like illness visit to collect respiratory 
specimens as soon as possible. 
Passive Surveillance: 
All participants will be instructed to contact the site if they experience symptoms/conditions of a 
COVID-19-like illness at any time during the study or if they have a positive COVID-19 test from 
any other source. 
Active Surveillance: 
Following randomization and vaccination, active surveillance will be used to identify potential 
COVID-19 clinical illness cases. 
Participants will be contacted once every 2 weeks starting at D43 (for the Original Phase II Cohort 
and Supplemental Cohorts Comparator Group) and D30 (for Supplemental Cohorts 1 and 2 
Booster Groups) to inquire about the development of symptoms/conditions of COVID-19-like 
illness and to remind participants to contact study staff if they experience symptoms/conditions of 
COVID-19-like illness or if they have a positive COVID-19 test from any other source. Inquiry 
about the development of symptoms/conditions of COVID-19-like illness will also take place at 
scheduled study visits and phone calls occurring at D43 (the Original Phase II Cohort and the 
Supplemental Cohorts Comparator Group) or D29 (for Supplemental Cohorts 1 and 2 Booster 
Groups) or earlier timepoints. 
Schedule of Visits  
During the surveillance for symptoms/conditions of COVID-19-like illness, participants will 
notify Investigators about the onset of COVID-19-like symptoms/conditions or if they had a 
positive COVID-19 test from any other source. Sites will contact participants to verify the 
symptoms/conditions meet the COVID-19-like illness definition. Participants with verified 
COVID-19-like illness will be asked to visit the site as soon as possible for the collection of 
respiratory samples for diagnosis of laboratory-confirmed SARS-CoV-2 infection. Participants 
will be reminded to collect the start date, end date, maximum intensity, health care utilization and 
medication in their diary card during the course of the illness. Participants will also be reminded 
to use the pulse oximeter provided to them at the CLI01 visit to take a pulse oximeter reading 
every day from the CLI01 visit until the results of the NP swab at CLI1 and any other swab 
collected for local NAAT testing at the CLI01 visit are available. Participants will be informed 
that if the readings are repeatedly (on at least 2 readings separated by 5 minutes) below the 
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pre-defined threshold (eg, 93% at sea level or corresponding value adjusted for altitude), they 
should contact the site who may require the participant to visit the site and/or visit their local 
health care provider. Participants will also be informed of the danger signs and 
symptoms/conditions of COVID-19 at the time of the visit. 
In instances in which study participants meet the COVID-19-like illness definition during the 
reactogenicity period based solely on systemic symptoms that overlap with vaccine reactogenicity 
(eg, myalgia, headache, fever, chills, malaise, fatigue, and arthralgia), Investigators should use 
their clinical judgment to decide if a COVID-19-like illness visit is necessary or not. Regardless 
of whether a COVID-19-like illness visit is triggered, the Investigator should report the 
COVID-19-like illness occurrence in the CRF and the nasopharyngeal swab collected at the time 
of vaccination visit will be analyzed by central laboratory NAAT or a local laboratory NAAT to 
ascertain whether the symptoms correspond to a SARS-CoV-2 infection. While either option is 
provided to facilitate testing, the central laboratory NAAT testing is preferred as it would enable 
further evaluation of viral sequence for positive samples. Any study participant reporting any of 
the other COVID-19-like illness definitory symptoms/conditions during the 7-day period after 
each vaccination should be evaluated for COVID-19 with COVID-19-like illness visit and 
procedure completed. 
The start of the illness episode is the date of the first symptom onset corresponding to the 
COVID-19-like illness. The last date of the COVID-19-like illness is the last day of the last 
symptom provided that such date is followed by an asymptomatic period of at least 3 days; if 
symptoms reoccur earlier than the completion of the 3 day asymptomatic period, then the 
reoccurring symptoms are to be considered part of the same illness rather than a new illness. If 
symptoms reoccur after an asymptomatic period of at least 3 days, then those symptoms are to be 
considered a new COVID-19-like illness.   
In the event of an illness with a positive NAAT for SARS-CoV-2, exacerbation/worsening of 
COVID-19-like illness symptoms or occurrence of new symptoms during the ongoing illness will 
be considered part of the ongoing COVID-19 illness episode and a new COVID-19-like illness 
visit and subsequent schedule of events is generally discouraged although it may be triggered at 
the Investigator’s discretion.   
In the event of exacerbation/worsening of COVID-19-like-illness symptoms or occurrences of 
new symptoms during an ongoing COVID-19-like illness which is not associated with a positive 
NAAT for SARS-CoV-2 (missing or negative test), a new COVID-19-like illness visit should be 
generally triggered if the new symptom or exacerbation of symptom occurs more than 7 days from 
the onset of the initial COVID-19-like illness. In these cases, the onset of illness will correspond 
to the date of onset of the new symptom(s) or the date of the worsening of the pre-existing 
symptom(s).  
At the site visit, a bilateral nasopharyngeal swab for central laboratory testing or a respiratory 
specimen as needed for local clinical laboratory testing will be collected from the participant at 
the site. If a participant cannot come to the site for a sample collection and the site has the 
capacity to conduct remote visits, a member of the site staff can collect at the participant’s current 
location. The DC will be reviewed by an appropriate site staff member. Vital signs (respiratory 
rate and heart rate) and SpO2 by pulse oximetry will also be collected to determine severity of 
COVID-19 illness. Participants will be provided with a pulse oximeter for at least twice daily 
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reporting of SpO2 including after exercise and provided instructions on how to use the pulse 
oximeter. Participants will be informed that if the readings are repeatedly (on at least 2 readings 
separated by 5 minutes) below the pre-defined threshold (eg, 93% at sea level or corresponding 
value adjusted for altitude), they should contact the site who may require the participant to visit 
the site and/or visit their local health care provider. 
A respiratory specimen during a COVID-19-like illness will not be collected if the date of 
collection is more than 14 days after resolution of symptoms. 
All participants with symptoms will be informed by Investigators of the local guidance and advice 
for suspected COVID-19 and be advised to follow local health guidelines regarding COVID-19 
prevention (eg, quarantine, avoidance of use of public transportation) until the availability of the 
results of the local or protocol-defined NAAT test.  
The frequency of subsequent contact for medical monitoring is at the discretion of the 
Investigator. 
Reporting of events temporally associated with a COVID-19-like illness 
All participants will be required to record their symptoms, maximum severity of symptoms and 
start and stop date for each symptom for the duration of the illness. 
In addition, information on healthcare utilization events (hospitalizations, emergency room visits, 
and non-routine office visits [including urgent care visits]) occurring within 30 days of the start of 
the illness episode, reason for the health care visit, diagnosis, outcome of the health care visit, and 
prescribed medication including duration of medication (eg, antibiotics, antivirals) will be 
collected. 
In the event of hospitalization or healthcare facility visit (emergency room, urgent care, medical 
office) during the course of illness, detailed information on the course of the illness including 
duration of symptoms, vital signs including peripheral oxygen saturation, oxygen requirements, 
laboratory tests, imaging investigations (eg, Chest x-ray, computerized tomography), use of 
mechanical ventilation and other 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 follow-up 
telephone call 30 days after the onset of symptoms. If symptoms are ongoing at the 30-day 
telephone call, a second telephone call 30 days later will be arranged. 
The intensity scale for the COVID-19-like illness symptoms is presented in Section 10.3.5.1.3. 
Notification of test results  
All participants seen for suspected COVID-19 will be notified of their swab results within 
24 hours of the result becoming available to the Investigator. This will include results of any local 
testing as well as central laboratory NAAT results. 
The first test results, either from the nasopharyngeal swab or local test (if taken), will be notified 
to participants to enable them to follow the local coronavirus guidelines. In individuals who are 
positive, Investigators will inform participants of local guidelines and requirements for 
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COVID-19 cases, provide local health care details, inform participants of the need to continue 
twice daily SpO2 measurement. 
In the event that a participant is diagnosed with laboratory-confirmed SARS-CoV-2 infection, the 
study Investigators will report the result to the local Public Health body as per local guidelines. 
The study Investigator may also inform the primary care provider. 
8.3.3 
Nucleic Acid Amplification Test (NAAT) for Detection of Laboratory-Confirmed 
SARS-CoV-2 infection  
The Abbott RealTime SARS-CoV-2 assay will be used for the detection of laboratory-confirmed 
SARS-CoV-2 infection by the central laboratory; details will be provided in the Operating 
Guidelines and PPD laboratory manual. Testing will be performed on: 
• Nasopharyngeal swabs collected at baseline in all participants 
• Nasopharyngeal swabs collected at D22 in all participants (for the Original Phase II Cohort 
and the Supplemental Cohorts Comparator Group) 
• Nasopharyngeal swab collected at COVID-19-like illness visit 
The Abbott RealTime SARS-CoV-2 assay is a dual target assay for the RNA-dependent RNA 
polymerase (RdRp) and N genes. An RNA sequence that is unrelated to SARS-CoV-2 target 
sequence is introduced into each specimen at the beginning of sample preparation. This unrelated 
RNA sequence is simultaneously amplified by RT-PCR and serves as an internal control (IC) to 
demonstrate that the process has proceeded correctly for each sample. 
The assay detects the SARS-CoV-2 virus and IC target sequences by using target-specific 
fluorescent-labeled oligonucleotide probes. The probes do not generate a signal unless they are 
specifically bound to the amplified product. The 2 SARS-CoV-2-specific probes are labeled with 
the same fluorophore, and the IC-specific probe is labeled with a different fluorophore, thus 
allowing for simultaneous detection of both SARS-CoV-2 and IC amplified products in the same 
reaction well. 
8.3.4 
ELECSYS Anti-SARS-CoV-2 Anti-N ECLIA  
SARS-CoV-2 anti-nucleocapsid antibodies will be measured using the Roche ELECSYS 
Anti-SARS-CoV-2 ECLIA on all blood samples in participants for ascertainment of 
serologically-confirmed SARS-CoV-2 infection in participants belonging to the Original Phase II 
Cohort. In addition, this test will be used on D01 and D22 samples for the Original Phase II 
Cohort in all participants to aid in determination of naïve and non-naïve status (see Section 
8.1.5.3). Details will be provided in the Operating Guidelines and the PPD laboratory manual. 
8.3.5 
Physical Examinations  
At the time of enrollment, height and weight will be collected and a targeted physical examination 
including vital signs based on the participant’s medical history may be performed. At designated 
visits, the Investigator or a designee may 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. 
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8.3.6 
Vital Signs  
Oral pre-vaccination temperature will be systematically collected by the Investigator on the source 
document. Tympanic, skin, and temporal artery thermometers must not be used. Respiratory rate, 
heart rate, and pulse oximetry SpO2 will be recorded by study Investigators at COVID-19-like 
illness visits during a COVID-19-like illness episode. The Investigator may collect other vital 
signs they consider necessary based on medical judgment during any participant visit and record it 
in the source document. 
8.4 
Adverse Events (AEs), Serious Adverse Events, and Other Safety Reporting  
The definitions of an AE, SAE, and the different categories of AEs can be found in 
Appendix 10.3. 
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). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 10.3. 
A dedicated Sponsor’s Safety Team composed of RMOs, Biostatistics, and Pharmacovigilance 
will ensure the safety monitoring by reviewing all SAEs immediately and all safety data at regular 
intervals to identify any new safety signals or safety concerns during the conduct of the study. 
Blinded safety data will be reviewed by the Sponsor’s Safety Team (RMO, Biostatistics, and PV) 
at regular intervals to identify any new safety signals or safety concerns during the conduct of the 
study. SAEs and AESIs will be reviewed immediately by the Sponsor’s Safety Team. A pause 
might be recommended in both recruitment and/or further vaccination while it investigates any 
potential safety signal or concern. The Sponsor has the responsibility to make the decision to 
pause the study. 
For the Original Phase II Cohort, enrollment and further vaccination was to be paused if any of 
the following conditions occur:  
• Any death assessed as related to the vaccine by the Investigator and the Sponsor are reported 
in the study 
• Any SAE assessed as related to the vaccine by the Investigator and the Sponsor are reported in 
the study 
• ≥ 20% participants experiencing Grade 3 systemic reaction (without concurrent infectious 
disease) 
• ≥ 20% participants experiencing Grade 3 solicited injection site pain 
• ≥ 20% participants experiencing Grade 3 unsolicited non serious reactions (reactions not 
explained by any other possible etiology) 
• > 5% of the study population is hospitalized due to SARS-CoV-2 infection 
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• > 10 ICU admissions due to SARS-CoV-2 infection 
• Any other adverse event that, in the opinion of the Investigator, would expose participants to 
unreasonable risk of illness or injury 
If any of these conditions are met, enrollment and further vaccination was to be paused to 
investigate any potential signal or concern. The Sponsor determines continuation or adaptation in 
study design. Case unblinding may be performed if necessary.  
For the Supplemental Phase III Cohorts, similar criteria will apply for further vaccination to be 
paused if any of the following conditions occur: 
• Any death assessed as related to the vaccine by the Investigator and the Sponsor are reported 
in the study 
• Any SAE assessed as related to the vaccine by the Investigator and the Sponsor are reported in 
the study 
• > 5% of the study population is hospitalized due to SARS-CoV-2 infection 
• > 10 ICU admissions due to SARS-CoV-2 infection 
• Any other adverse event that, in the opinion of the Investigator, would expose participants to 
unreasonable risk of illness or injury 
For the Supplemental Phase III Cohorts, reactogenicity criteria will serve as alert threshold rather 
than pause criteria: 
• ≥ 20% participants experiencing Grade 3 systemic reaction (without concurrent infectious 
disease) 
• ≥ 20% participants experiencing Grade 3 solicited injection site pain 
• ≥ 20% participants experiencing Grade 3 unsolicited non serious reactions (reactions not 
explained by any other possible etiology) 
Given the information gained based on interim data from the Original Phase II Cohort for 
reactogenicity events (Grade 3 reactogenicity events being of short duration, non-serious and 
mostly self-limited), it is considered appropriate to monitor the above criteria as alert thresholds 
rather than direct pause triggers. These reactogenicity criteria will be evaluated for individual 
groups (for open-label Arms, ie, Cohort 1 Booster Arm and the Comparator Group for 
Supplemental Cohorts 1 and 2) or as aggregate data (for observer-blind Groups, ie, Supplemental 
Cohort 2 and 3 Groups), as applicable. Upon review of the details of the nature of these 
reactogenicity events, the Sponsor will decide whether or not enrollment and/or further 
vaccination is to be paused or if enrollment and/or further vaccinations can continue.  
Unblinding of the treatment code for a patient may be requested by the Sponsor for regulatory 
reporting purpose (IND safety reports / suspected unexpected serious adverse reactions 
[SUSARs]). 
Further details on the composition and frequency of meetings are provided in the Sponsor’s Safety 
Team charter. 
On the basis of this review, and especially on SAEs assessed as related by Investigator and 
Sponsor, the Sponsor will decide whether further vaccine administration should be temporarily 
halted as a precautionary measure while investigating the potential safety signal.   
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Safety will be evaluated through: 
• Assessment of the reactogenicity profile of each study intervention for participants in each age 
group through 21 days after each vaccination in SARS-CoV-2 naïve and non-naïve subgroups: 
• Presence of solicited (prelisted in the participant’s DC and CRF) injection site reactions 
and systemic reactions occurring up to 7 days after each vaccination 
• Presence of unsolicited AEs reported up to 21 days after the last vaccination 
• Assessment of safety of each study intervention for participants in each age group overall 
(regardless of prior SARS-CoV-2 infection at baseline) and in SARS-CoV-2 naïve and non-
naïve subgroups: 
• Presence of unsolicited systemic AEs reported in the 30 minutes after each vaccination 
• Presence of MAAEs throughout the study 
• Presence of SAEs throughout the study 
• Presence of AESIs throughout the study 
• Presence of SARS-CoV-2 infection and/or symptomatic COVID-19 
• Assessment of frequency of disease in episodes of laboratory-confirmed COVID-19 illness: 
• Occurrences of hospitalized COVID-19 
• Occurrences of severe COVID-19 
• Death associated with COVID-19 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
Immediate Post-vaccination Observation Period 
All 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 the day of vaccination (D01) until 7 days 
after each vaccination (D01 + 7 days). 
Solicited systemic reactions will be collected from the day of vaccination (D01) until 7 days after 
each vaccination (D01 + 7 days).  
The solicited injection site reactions and systemic reactions that are pre-listed in the DCs and 
CRF, together with the intensity scales, are presented in Appendix 10.3.5.1.1. 
Unsolicited Adverse Events 
Unsolicited AEs include unsolicited non-serious AEs and SAEs. The intensity grading scale for 
unsolicited non-serious adverse events is presented in Appendix 10.3.5.1.2. 
Unsolicited non-serious AEs will be collected from the day of vaccination (D01) until 21 days 
after the last vaccination (D01 + 21 days). 
SAEs will be collected and assessed throughout the study, from inclusion until 12 months after the 
last vaccination up to D366 (Supplemental Cohorts 1 and 2 Booster Arms) or D387 (Original 
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Phase II Cohort and Supplemental Cohorts Comparator Group). However, before the first study 
intervention administration, only SAEs related to study procedures are to be collected in the CRF 
(eg, SAEs related to blood sampling). 
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 information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
Medically-Attended Adverse Events (MAAEs) 
MAAEs will be collected throughout the study. 
Adverse Events of Special Interest (AESIs) 
AESIs will be collected throughout the study. 
See Section 8.4.6 for the list of AESIs. 
8.4.2 
Method of Detecting AEs and SAEs  
Individual DCs, specifically designed for this study by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information. These DCs 
will include pre-listed terms and intensity scales as well as areas for free text to capture additional 
safety information or other relevant details. Participants will also be provided with rulers for 
measuring the size of injection site reactions, and with standard digital thermometers for 
measuring daily temperatures. To ensure consistency of reporting, the study sites will instruct 
participants on how to correctly use these tools. 
At specified intervals, the Investigator or a designee will interview the participants to collect the 
information recorded in the DC and will attempt to clarify anything that is incomplete or unclear. 
All clinical study information gathered by the study site will be reported electronically by the 
Investigator or authorized designee using a web-based CRF. Any information that was not 
documented in the DC will first be captured in the source document and then reported 
electronically. 
The 12-month (post-last injection) follow-up will be done by interviewing participants at Visit 7 
(Supplemental Cohorts 1 and 2 Booster Arms) or Visit 8 (Original Phase II Cohort and 
Supplemental Cohorts Comparator Group) (or over the telephone if the visit cannot be performed 
in-person) using a questionnaire to capture SAEs and AESIs, if applicable. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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8.4.3 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts, unless a participant refuses further contact. 
All AEs that are considered by the Investigator as serious, or to be related to the study 
intervention administered or that led to study or vaccination discontinuation, will be followed 
during the conduct of the study until resolution, stabilization, or the participant is lost to follow-up 
(as defined in Section 7.3). For related SAEs ongoing at last study visit, such follow-up may need 
to continue after the end of the study. Further information on follow-up procedures is provided in 
Appendix 10.3 
8.4.4 
Regulatory Reporting Requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB / IEC, and Investigators. 
• Investigator safety reports must be prepared for 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. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
8.4.5 
Pregnancy  
Pregnant women are not eligible to participate in the study and females of childbearing potential 
agree to use an effective contraceptive method during a period starting 4 weeks prior to the first 
vaccination and ending 12 weeks after the last vaccination, as defined in the inclusion criteria. 
However, a participant could potentially become pregnant during her participation. 
If the pregnancy starts during the period of contraception or abstinence: 
• Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the pregnancy outcome.  
• When pregnancy is reported, the Investigator should promptly inform the Sponsor and will 
record pregnancy information together with the contraceptive method on the appropriate form 
and submit it to the Sponsor no later than 1 month of learning of the pregnancy. 
• 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. 
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• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy), any serious event experienced by the pregnant women or by 
the newborn are considered SAEs and will be reported as such. 
• The participant will be followed till the outcome of the pregnancy and the pregnancy outcome 
reported. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure. 
• The offspring will be followed for up to 12 months by the pharmacovigilance department. Any 
data collected after CRF lock will be transmitted to the pharmacovigilance department on the 
paper form. 
If the pregnancy starts after the period of contraception or abstinence:  
• The data collection will be the same during the period of the study. It will end at the last visit 
of the participant. 
• The Investigator should promptly inform the Sponsor and will record pregnancy information 
together with the contraceptive method on the appropriate form and submit it to the Sponsor 
no later than 1 month of learning of the pregnancy. Pregnancy status will be collected, follow-
up of the participant will continue as part of the study, but the participant will not be followed-
up until the pregnancy outcome and the offspring will not be followed. 
• Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. 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. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention until delivery or until delivery and end of lactation. However, 
the participant will be followed for safety assessment (and may be followed for 
immunogenicity assessment, if applicable). 
8.4.6 
Adverse Events of Special Interest  
AESIs will include (see Appendix 10.5): 
• 
Anaphylactic reactions, Generalized convulsion, Thrombocytopenia 
• 
Myocarditis* 
• 
Pericarditis* 
• 
Thrombosis with thrombocytopenia syndrome* 
• 
New onset and worsening of pIMDs (Table 10.4) 
*Due to safety signals detected after the use of other COVID-19 vaccine platforms from other 
manufacturers, Myocarditis, Pericarditis, and Thrombosis with thrombocytopenia syndrome are 
also considered AESIs. 
For case definition, please refer to https://brightoncollaboration.us/category/pubs-tools/case-
definitions/. 
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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 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study. 
8.6 
Pharmacodynamics  
As with most vaccines for active immunization, the mechanism of action consists of the induction 
of immune responses against the antigens contained in the vaccine. Therefore, the 
pharmacodynamic profile of the investigational study intervention is defined by its 
immunogenicity profile. 
8.7 
Genetics  
Genetics are not evaluated in this study. 
8.8 
Biomarkers  
It is possible that as understanding of SARS-CoV-2 virus develops, biomarkers other than those 
specifically described in the immunogenicity assessments section (Section 8.2) may be evaluated 
in this study in exploratory analyses. 
8.9 
Immunogenicity Assessments  
See Section 8.2. 
8.10 Medical Resource Utilization and Health Economics  
Medical Resource Utilization will be collected as part of COVID-19-like illness in this study (see 
Section 8.3.2) as well as for SAE narrative preparation and categorization. In the context of a 
COVID-19-like illness, information on hospital stays, emergency room visits, non-routine medical 
office visits (including urgent care visits), and administered or prescribed antivirals and antibiotics 
will be collected from the participant for the purpose of healthcare utilization assessment 
(regardless of whether or not the medical event, healthcare contact or the use of medications is 
considered to be directly linked to the illness). Data collection will cover the period from the start 
to the end of the COVID-19-like illness. Medically-confirmed data, where available, will be 
considered the primary information source. Routine health care visits for pre-existing conditions, 
routine check-ups, medication prescription renewals, as well are medical office/health care visits 
procedures and hospitalizations planned prior to the start of the respiratory illness will not be 
recorded as part of the assessment of these endpoints. 
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8.11 Leftover Biological Samples and Use of Data  
Any unused part of the serum or respiratory samples collected for this study 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. 
In addition, participants will be asked to indicate in the ICF whether they will permit the future 
use of any unused stored serum samples, by Sanofi Pasteur or one of its research partners, for 
other tests and the corresponding data, unless prohibited by local laws or IRBs/IECs (in such case, 
consent for future use of any unused biological samples will not be included in the site-specific 
ICF). If they refuse permission, the biological samples will not be used for any testing other than 
that directly related to this study. If they agree to this future use, they will not be paid for giving 
permission. Data and samples will be used in compliance with the information provided to 
participants in the ICF Part 2 (future research). 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 and their mechanism of action, the knowledge of infectious diseases, or to 
improve existing tests or develop new tests to assess vaccines, or to help identify new vaccine 
targets or biomarkers that predict participant response to the vaccine. Such research may also 
include, but is not limited to, performing assessments on DNA, RNA, proteins, or metabolites. If 
future research on genetic material is performed, a specific individual consent will be obtained. 
All study participant data and biological samples will be coded such that no direct identifiers will 
be linked to participants. Coded data and biological samples may be transferred to a Sponsor site 
(or a subcontractor site), which may be located outside of the country where the study is 
conducted. The Sponsor adopts safeguards for protecting participant confidentiality and personal 
data (see Section 10.1.4). 
The biological samples will be securely stored at the Sanofi Pasteur laboratory (GCI) or Contract 
Research Laboratory up to 25 years after the end of the study. Unused samples may also be sent to 
another long-term repository at the NIH, BARDA, as well as other US Government-designated 
laboratories. Any samples remaining at the end of retention period will be destroyed. If a 
participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed, and sample related coded data will be anonymized unless otherwise 
required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
Note: The other biological samples collected to qualify the participant for inclusion in the study or 
to monitor his/her health during the study are dedicated for immediate use. If any of these 
biological samples are not completely used up, they will be destroyed at the latest at the end of the 
study or after the time requested by local law. 
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9 
Statistical Considerations  
9.1 
Statistical Hypotheses  
9.1.1 
Original Phase II Cohort  
No hypothesis testing will be performed in this Original Phase II Cohort study. 
9.1.2 
Evaluation of Booster Candidates in Supplemental Cohorts 1 and 2  
For Supplemental Cohorts 1 and 2 in younger adults (18-55 years of age), 3 booster candidates in 
total: CoV2 preS dTM-AS03 (D614) in Supplemental Cohort 1 and CoV2 preS dTM-AS03 
(B.1.351) and CoV2 preS dTM-AS03 (D614 + B.1.351) in Supplemental Cohort 2, share the same 
Comparator Group of SARS-CoV-2-naïve adults, unvaccinated, 18-55 years of age, who will 
receive the CoV2 preS dTM-AS03 (D614) vaccine as a primary series of 2 injections given 21 
days apart, for hypothesis testing. To control for multiple testing, the Bonferroni adjustment will 
be applied to maintain overall type I error at 0.025 one-sided (0.025/3 for each comparison of 
booster candidate). 
For the CoV2 preS dTM-AS03 (D614) booster candidate, there are 2 co-primary endpoints to be 
hypotheses tested with one-sided alpha 0.025/3 in participants primed with the Pfizer/BioNTech  
vaccine. If the primary objectives are met, then 2 conditional secondary endpoints will be 
hypotheses tested with one-sided alpha 0.025/3 applying the sequential testing strategy in 
participants primed with the protein-based vaccine in the Original Phase II Cohort. If the primary 
objectives in the Pfizer/BioNTech vaccine primed and conditional secondary objectives in the 
protein-based vaccine primed are both met, then 2 conditional secondary endpoints will be 
hypotheses tested with one-sided alpha 0.025/3 applying the sequential testing strategy in 
participants primed with an mRNA vaccine. If the primary objectives in the Pfizer/BioNTech 
vaccine primed, conditional secondary objectives in the protein-based vaccine primed, and 
conditional secondary objectives in the mRNA vaccine primed are all met, then 2 conditional 
secondary endpoints will be hypotheses tested with one-sided alpha 0.025/3 applying the 
sequential testing strategy in participants primed with an adenovirus vector vaccine. If the primary 
objectives in the Pfizer/BioNTech vaccine primed and conditional secondary objectives in the 
protein-based vaccine primed, the mRNA vaccine primed, and adenovirus vector vaccine primed 
are all met, then 1 conditional secondary endpoint on seroresponse will be hypotheses tested at 
one-sided alpha 0.025/3 in each Pfizer/BioNTech primed, protein-based primed, mRNA primed, 
and adenovirus vector primed sequentially by applying the sequential testing strategy. 
For the CoV2 preS dTM-AS03 (B.1.351) booster candidate, there are 2 co-primary endpoints to 
be hypotheses tested at 0.025/3 one-sided level in participants primed with the Pfizer/BioNTech 
vaccine. If the primary objectives are met, then 2 conditional secondary endpoints will be 
hypotheses tested at 0.025/3 one-side level in participants primed with an mRNA vaccine 
applying the sequential testing strategy. If primary objectives and conditional secondary 
objectives are both met, then 1 conditional secondary endpoint (GMT) will be hypothesis tested 
with one-sided alpha 0.025/3 in participants primed with the Pfizer/BioNTech vaccine applying 
the sequential testing strategy. If the primary objectives, conditional secondary objectives, and 
conditional secondary objective on GMT are all met, then 1 conditional secondary endpoint on 
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seroresponse will be hypothesis tested at one-sided alpha 0.025/3 in each Pfizer/BioNTech primed 
and mRNA primed sequentially by applying the sequential testing strategy. 
For the bivalent booster candidate, there are 4 co-primary endpoints on both D614G and B.1.351 
variants (if the SARS-CoV-2 D614G variant remains in circulation globally based on reports from 
authorities [eg, WHO]) or 2 co-primary endpoints on the B.1.351 variant to be hypotheses tested 
at 0.025/3 one-sided level in participants primed with the Pfizer/BioNTech vaccine. If the primary 
objectives are met, then 4 conditional secondary endpoints on both D614G and B.1.351 variants 
(if the SARS-CoV-2 D614G variant remains in circulation globally based on reports from 
authorities [eg, WHO]) or 2 conditional secondary endpoints on the B.1.351 variant will be 
hypotheses tested at 0.025/3 one-sided level in participants primed with an mRNA vaccine 
applying the sequential testing strategy. If primary objectives and conditional secondary 
objectives are both met, then 1 conditional secondary endpoint on GMT will be hypothesis tested 
with one-sided alpha 0.025/3 in participants primed with the Pfizer/BioNTech vaccine applying 
the sequential testing strategy. If the primary objectives, conditional secondary objectives, and 
conditional secondary objective on GMT are all met, then 2 conditional secondary endpoints on 
seroresponse for both D614G and B.1.351 variants (if the SARS-CoV-2 D614G variant remains in 
circulation globally based on reports from authorities [eg, WHO]) or 1 conditional secondary 
endpoint on seroresponse for B.1.351 variant will be hypotheses tested at one-sided alpha 0.025/3 
in each Pfizer/BioNTech primed and mRNA primed sequentially by applying the sequential 
testing strategy. 
Figure 9.1: Multiplicity adjustment strategy using Bonferroni and sequential testing method 
in Supplemental Cohort 1 and Supplemental Cohort 2 
 
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Note:  
i. 
H1, H2 and H3 corresponding to the hypothesis testing of CoV2 preS dTM-AS03 
(D614) in Supplemental Cohort 1, CoV2 preS dTM-AS03 (B.1.351) in Supplemental 
Cohort 2 and CoV2 preS dTM-AS03 (D614 + B.1.351) in Supplemental Cohort 2.  
ii. 
H3 of CoV2 preS dTM-AS03 (D614 + B.1.351) in Supplemental Cohort 2 will include 
hypothesis testing of D614G (H3d, dotted circled ones in Figure 9.1) (if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports from 
authorities [eg, WHO]) and B.1.351 (H3b). 
iii. 
H(=1,2,3b, or 3d)1 corresponding to the hypothesis testing of co-primary endpoints. 
H(=1,2,3b, or 3d)(=2,3,4) corresponding to the hypothesis testing of conditional 
secondary endpoint(s). 
iv. 
H(=2 or 3b)3 corresponding to the hypothesis testing of conditional secondary 
endpoints for superiority claim on B.1.351. 
v. 
H(=1,2,3b, or 3d)(=s1,s2,s3,s4) corresponding to the hypothesis testing of conditional 
secondary endpoint(s) for non-inferiority claim on seroresponse. 
vi. 
H(=1,2,3b, or 3d)(=1,2,3,4)1 corresponding to the hypothesis testing of non-inferiority.  
H(=1,2,3b, or 3d)(=1,2,3,4)2 corresponding to the hypothesis testing of superiority. 
The hypothesis testing strategy of each booster candidate is as follows: 
• Supplemental Cohort 1 – CoV2 preS dTM-AS03 (D614) 
o Overall type 1 error at 0.0.25/3 one-sided level will be maintained  
a) 
2 co-primary endpoints will be hypothesis tested in participants primed with the 
Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha level 
b) A sequential testing strategy will be applied for the 2 conditional co-secondary 
endpoints in participants primed with the protein-based vaccine in the Original 
Phase II Cohort if the 2 co-primary endpoints in participants primed with the 
Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha level is achieved 
c) 
A sequential testing strategy will be applied for the 2 conditional co-secondary 
endpoints in pooled participants primed with an mRNA vaccine if the 2 
co-primary endpoints in participants primed with the Pfizer/BioNTech vaccine 
and 2 conditional co-secondary endpoints in participants primed with the protein-
based vaccine in the Original Phase II Cohort at one-sided 0.025/3 alpha level are 
both achieved 
d) A sequential testing strategy will be applied for the 2 conditional co-secondary 
endpoints in pooled participants primed with an adenovirus vector vaccine if the 2 
co-primary endpoints in participants primed with the Pfizer/BioNTech vaccine, 2 
conditional co-secondary endpoints in participants primed with the protein-based 
vaccine and 2 conditional co-secondary endpoints in pooled participants primed 
with an mRNA vaccine at one-sided 0.025/3 alpha level are all achieved 
e) 
A sequential testing strategy will be applied for the 1 conditional secondary 
endpoint on seroresponse in participants primed with the Pfizer/BioNTech 
vaccine, in participants primed with the protein-based vaccine, in pooled 
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participants primed with an mRNA vaccine, and in pooled participants primed 
with an adenovirus vector vaccine at one-sided 0.025/3 alpha level will be tested 
sequentially if the 2 coprimary endpoints in participants primed with the 
Pfizer/BioNTech vaccine, 2 conditional co-secondary endpoints in participants 
primed with the protein-based vaccine, 2 conditional co-secondary endpoints in 
pooled participants primed with an mRNA vaccine, 2 conditional co-secondary 
endpoints in pooled participants primed with an adenovirus vector vaccine at one-
sided 0.025/3 alpha level are all achieved 
• Supplemental Cohort 2 – CoV2 preS dTM-AS03 (B.1.351) 
o Overall type I error at 0.025/3 one-sided level will be maintained 
a) 
2 co-primary endpoints will be hypothesis tested in participants primed with the 
Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha level 
b) A sequential testing strategy will be applied for the 2 conditional co-secondary 
endpoints in pooled participants primed with an mRNA vaccine if the 
2 co-primary endpoints in participants primed with the Pfizer/BioNTech vaccine 
at one-sided 0.025/3 alpha level is achieved 
c) 
A sequential testing strategy will be applied for the 1 conditional secondary 
endpoint of superiority testing on B.1.351 in participants primed with the 
Pfizer/BioNTech vaccine if the 2 co-primary endpoints in participants primed 
with the Pfizer/BioNTech vaccine and 2 co-secondary endpoints in pooled 
participants primed with an mRNA vaccine at one-sided 0.025/3 alpha level are 
both achieved 
d) A sequential testing strategy will be applied for the 1 conditional secondary 
endpoint on seroresponse in participants primed with the Pfizer/BioNTech vaccine 
at one-sided 0.025/3 alpha level if the 2 co-primary endpoints in participants 
primed with the Pfizer/BioNTech vaccine, 2 conditional co-secondary endpoints 
in pooled participants primed with an mRNA vaccine, and 1 conditional 
secondary endpoint on GMT at one-sided 0.025/3 alpha level are all achieved 
e) 
A sequential testing strategy will be applied for the 1 conditional secondary 
endpoint on seroresponse in pooled participants primed with an mRNA vaccine at 
one-sided 0.025/3 alpha level if the 2 coprimary endpoints in participants primed 
with the Pfizer/BioNTech vaccine, 2 conditional co-secondary endpoints in 
pooled participants primed with an mRNA vaccine, 1 conditional secondary 
endpoint on GMT, and 1 conditional secondary endpoint on seroresponse in 
participants primed with the Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha 
level are all achieved 
• Supplemental Cohort 2 – CoV2 preS dTM-AS03 (D614 + B.1.351) 
o Overall type I error at 0.025/3 one-sided level will be maintained 
o The objectives will be evaluated on the pseudovirus neutralizing titers to the B.1.351 
variant and the pseudovirus neutralizing titers to the D614G variant (if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports from 
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authorities [eg, WHO]). The objective would be considered to be achieved if both 
variants or only B.1.351 variant are met based on the D614G variant circulation 
situation for whether testing on D614G variant is needed or not 
a) 
Two co-primary endpoints for pseudovirus neutralizing titers against B.1.351 and 
2 co-primary endpoints for pseudovirus neutralizing titers against D614G (if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports 
from authorities [eg, WHO]) will be hypothesis tested in participants primed with 
the Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha level 
b) A sequential testing strategy will be applied for the 2 conditional co-secondary 
endpoints for pseudovirus neutralizing titers against B.1.351 and 2 conditional 
co-secondary endpoints for pseudovirus neutralizing titers against D614G (if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports 
from authorities ([eg, WHO]) in pooled participants primed with an mRNA 
vaccine if the 4 co-primary endpoints both on the B.1.351 variant and the D614G 
variant (if the SARS-CoV-2 D614G variant remains in circulation globally based 
on reports from authorities [eg, WHO]) or 2 co-primary endpoints on the B.1.351 
variant in participants primed with the Pfizer/BioNTech vaccine at one-sided 
0.025/3 alpha level are achieved 
c) 
A sequential testing strategy will be applied for the conditional secondary 
endpoint of superiority testing on B.1.351 in participants primed with the 
Pfizer/BioNTech vaccine if the primary objectives in participants primed with the 
Pfizer/BioNTech vaccine and conditional secondary objectives in pooled 
participants primed with an mRNA vaccine at one-sided 0.025/3 alpha level are 
both achieved 
d) A sequential testing strategy will be applied for the 2 conditional secondary 
endpoints on seroresponse for both B.1.351 and D614G variants if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports 
from authorities (eg, WHO) or 1 conditional secondary endpoint on seroresponse 
only for B.1.351 variant in participants primed with the Pfizer/BioNTech vaccine 
at one-sided 0.025/3 alpha level if the primary objectives in participants primed 
with the Pfizer/BioNTech vaccine, conditional secondary objectives in pooled 
participants primed with an mRNA vaccine, and conditional secondary objective 
on GMT in participants primed with the Pfizer/BioNTech vaccine at one-sided  
0.025/3 alpha level are all achieved 
e) 
A sequential testing strategy will be applied for the 2 conditional secondary 
endpoints on seroresponse for both B.1.351 and D614G variants if the SARS-
CoV-2 D614G variant remains in circulation globally based on reports from 
authorities (eg, WHO) or 1 conditional secondary endpoint on seroresponse only 
for the B.1.351 variant in pooled participants primed with an mRNA vaccine at 
one-sided 0.025/3 alpha level if the primary objectives in participants primed with 
the Pfizer/BioNTech vaccine, conditional secondary objectives in pooled 
participants primed with an mRNA vaccine, conditional secondary objective on 
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GMT in participants primed with the Pfizer/BioNTech vaccine, and conditional 
secondary objective on seroresponse in participants primed with the 
Pfizer/BioNTech vaccine at one-sided 0.025/3 alpha level are all achieved. 
9.1.2.1 
A Pooled Primary Series Cohort as Supplemental Cohort 2 Comparator Group  
As the number of authorized and/or approved COVID-19 vaccines increases, promptly enrolling 
the planned 515 naïve participants into the Comparator Group shared by Supplemental Cohorts 1 
and 2 may become unattainable. In order to maintain sufficient target power for Supplemental 
Cohort 2 hypothesis testing, in case of a substantial shortfall in numbers of naïve Comparator 
Group participants, a pooled primary series cohort with a sample size of at least 464 (a 10% 
dropout rate from 515) evaluable participants may be planned to serve as the Comparator Group 
for Supplemental Cohort 2. 
Participants in this pooled primary series cohort will be added from 2 potential sources, in the 
following order: 
1. All SARS-CoV-2-naïve participants contemporaneously enrolled in Supplemental Cohort 
1  
2. Eligible participants from studies involving the same CoV2 preS dTM-AS03 vaccine 
a) Eligible participants in the VAT00002 Original Phase II Cohort 
b) Eligible participants in other studies of this same investigational SARS-CoV-2 vaccine 
program 
Evaluable participants will be pooled in sequence from the above sources. Eligible participants 
will be selected and pooled base on the comparability of population and assessments per clinical 
justification outlined in the SAP. 
An exploratory sensitivity analysis will be performed on the hypothesis testing for Supplemental 
Cohort 2 to test the robustness of the primary analyses by using the pooling primary series as the 
Comparator Group. 
9.1.2.2 
Supplemental Cohort 1  
Hypothesis testing will be conducted for the 2 co-primary immunogenicity endpoints in  
participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine, 2 conditional co-
secondary immunogenicity endpoints in participants, 18-55 years old, primed with the protein-
based vaccine, 2 conditional co-secondary immunogenicity endpoints in participants, 18-55 years 
old, primed with an mRNA vaccine, 2 conditional co-secondary immunogenicity endpoints in  
participants, 18-55 years old, primed with an adenovirus vector vaccine, 1 conditional secondary 
immunogenicity endpoint on seroresponse in participants, 18-55 years old, primed with the 
Pfizer/BioNTech vaccine, the protein-based vaccine, an mRNA vaccine, and an adenovirus vector 
vaccine sequentially. 
Primary objective 1: non-inferiority to the comparator for participants primed with the 
Pfizer/BioNTech vaccine: 
For participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine, 14 days after the 
booster dose (ie, D15) with CoV2 preS dTM-AS03 (D614) and 14 days after the second dose (ie, 
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D36) of the Comparator Group, the GMT against D614G of the Booster Group CoV2 preS dTM-
AS03 (D614), is non-inferior to the GMT against D614G of the Comparator Group. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
The non-inferiority in terms of GMT will be demonstrated if the lower limit of the two-sided 
98.3% CI of the ratio of the GMT is great than (1/1.5). 
Primary objective 2: superiority to the pre-booster for participants primed with the 
Pfizer/BioNTech vaccine: 
For participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine, 14 days after the 
booster dose (ie, D15) with CoV2 preS dTM-AS03 (D614), the serum neutralization titer against 
D614G is superior to the serum neutralization titer against D614G prior to the booster dose at 
D01. 
 Null hypothesis (H0) : Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1) : Ratio (post-booster/pre-booster) > 2 
The superiority will be demonstrated if the lower limit of the two-sided 98.3% CI of the ratio of 
serum neutralization titer is great than 2. 
The primary immunogenicity objective will be demonstrated only if both non-inferiority and 
superiority testing described above are demonstrated. 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine 
is reached, 2 conditional secondary immunogenicity endpoints will be tested for participants 
primed with the protein-based vaccine. 
Conditional secondary objective 1.1: non-inferiority to the comparator for participants primed 
with the protein-based vaccine: 
For participants, 18-55 years old, primed with the protein-based vaccine in the Original Phase II 
Cohort, 14 days after the booster dose (ie, D15) in the CoV2 preS dTM-AS03 (D614) Group and 
after the second dose of the primary vaccination Comparator Group (ie, D36), GMT against 
D614G of the Booster Group, CoV2 preS dTM-AS03 (D614), is non-inferior to the GMT against 
D614G of the primary vaccination Comparator Group in younger adults. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
The non-inferiority in terms of GMT will be demonstrated if the lower limit of the two-sided 
98.3% CI of the ratio of the GMT is great than (1/1.5). 
Conditional secondary objective 1.2: superiority to the pre-booster for participants primed with 
the protein-based vaccine: 
For participants, 18-55 years old, primed with the protein-based vaccine in the Original Phase II 
Cohort, 14 days after the booster dose (ie, D15) with CoV2 preS dTM-AS03 (D614), the serum 
neutralization titer against D614G is superior to the serum neutralization titer against D614G prior 
booster dose at D01 in younger adults. 
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Null hypothesis (H0) : Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1) : Ratio (post-booster/pre-booster) > 2 
The superiority will be demonstrated if the lower limit of the two-sided 98.3% CI of the ratio of 
serum neutralization titer is great than 2. 
The conditional secondary objective will be reached if both non-inferiority and superiority testing 
described above are demonstrated. 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine 
and secondary immunogenicity objective in participants primed with the protein-based vaccine are 
both reached, 2 conditional secondary immunogenicity endpoints will be tested for participants 
primed with an mRNA vaccine. 
Conditional secondary objective 2.1: non-inferiority to the comparator for participants primed 
with an mRNA vaccine: 
For participants, 18-55 years old, primed with an mRNA vaccine, 14 days after the booster dose 
(ie, D15) in the CoV2 preS dTM-AS03 (D614) Group and after the second dose of the primary 
vaccination Comparator Group (ie, D36), GMT against D614G of the Booster Group, CoV2 preS 
dTM-AS03 (D614), is non-inferior to the GMT against D614G of the primary vaccination 
Comparator Group in younger adults. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
The non-inferiority in terms of GMT will be demonstrated if the lower limit of the two-sided 
98.3% CI of the ratio of the GMT is great than (1/1.5). 
Conditional secondary objective 2.2: superiority to the pre-booster for participants primed with 
an mRNA vaccine: 
For participants, 18-55 years old, primed with an mRNA vaccine, 14 days after the booster dose 
(ie, D15) with CoV2 preS dTM-AS03 (D614), the serum neutralization titer against D614G is 
superior to the serum neutralization titer against D614G prior booster dose at D01 in younger 
adults. 
Null hypothesis (H0) : Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1) : Ratio (post-booster/pre-booster) > 2 
The superiority will be demonstrated if the lower limit of the two-sided 98.3% CI of the ratio of 
serum neutralization titer is great than 2. 
The conditional secondary objective will be reached if both non-inferiority and superiority testing 
described above are demonstrated. 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine, 
secondary immunogenicity objective in participants primed with the protein-based vaccine, and 
secondary immunogenicity objective in participants primed with an mRNA are all reached, 2 
conditional secondary immunogenicity endpoints will be tested for participants primed with an 
adenovirus vector vaccine. 
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Conditional secondary objective 3.1: non-inferiority to the comparator for participants primed 
with an adenovirus vector vaccine: 
For participants, 18-55 years old, primed with an adenovirus vector vaccine, 14 days after the 
booster dose (ie, D15) with CoV2 preS dTM-AS03 (D614) and 14 days after the second dose (ie, 
D36) of the Comparator Group, the GMT against D614G of the Booster Group, CoV2 preS dTM-
AS03 (D614), is non-inferior to the GMT against D614G of the Comparator Group. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
The non-inferiority in terms of GMT will be demonstrated if the lower limit of the two-sided 
98.3% CI of the ratio of the GMT is great than (1/1.5). 
Conditional secondary objective 3.2: superiority to the pre-booster for participants primed with 
an adenovirus vector vaccine: 
For participants, 18-55 years old, primed with an adenovirus vector vaccine, 14 days after the 
booster dose (ie, D15) with CoV2 preS dTM-AS03 (D614), the serum neutralization titer against 
D614G is superior to the serum neutralization titer against D614G prior to the booster dose at 
D01. 
Null hypothesis (H0): Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1): Ratio (post-booster/pre-booster) > 2 
The superiority will be demonstrated if the lower limit of the two-sided 98.3% CI of the ratio of 
serum neutralization titer is greater than 2. 
The conditional primary immunogenicity objective will be demonstrated only if both 
non-inferiority and superiority testing described above are demonstrated. 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine, 
conditional secondary immunogenicity objective in participants primed with the protein-based 
vaccine, conditional secondary immunogenicity objective in participants primed with an mRNA 
vaccine, and conditional secondary immunogenicity objective in participants primed with an 
adenovirus vector vaccine are all achieved, 1 conditional secondary immunogenicity endpoint on 
seroresponse for participants primed with the Pfizer/BioNTech vaccine, the protein-based vaccine, 
an mRNA vaccine, and an adenovirus vector vaccine will be tested sequentially. 
Conditional secondary objective 4: non-inferiority in terms of seroresponse rate for participants 
primed with the Pfizer/BioNTech, protein-based, mRNA, or adenovirus vector vaccines: 
For participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine, the protein-based 
vaccine, an mRNA vaccine, or an adenovirus vector vaccine, 14 days after the booster dose (ie, 
D15) with CoV2 preS dTM-AS03 (D614) and 14 days after the second dose (ie, D36) of the 
Comparator Group, the seroresponse rate against D614G of the Booster Group CoV2 preS dTM-
AS03 (D614), is non-inferior to the seroresponse rate against D614G of the Comparator Group. 
Null hypothesis (H0) : p(booster) - p(comparator) ≤ -10%  
Alternative hypothesis (H1) : p(booster) - p(comparator) > -10% 
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The Pfizer/BioNTech vaccine primed, protein-based vaccine primed, mRNA vaccine primed, and 
adenovirus vector vaccine primed will be tested sequentially. The non-inferiority will be 
demonstrated if the lower limit of the two-sided 98.3% CI of the difference between the 
2 proportions is great than -10%.  
9.1.2.3 
Supplemental Cohort 2  
For CoV2 preS dTM-AS03 (B.1.351) (non-exploratory arm only), hypothesis testing will be 
conducted for the 2 co-primary immunogenicity endpoints in participants, 18-55 years of age, 
primed with the Pfizer/BioNTech vaccine, 2 conditional co-secondary immunogenicity endpoints 
in participants, 18-55 years of age, primed with an mRNA vaccine, 1 conditional secondary 
endpoint on GMT in participants, 18-55 years of age, primed with the Pfizer/BioNTech vaccine, 1 
conditional secondary endpoint on seroresponse in participants, 18-55 years of age, primed with 
the Pfizer/BioNTech vaccine and an mRNA vaccine sequentially. 
For CoV2 preS dTM-AS03 (D614 + B.1.351), hypothesis testing will be conducted for the 4 
co-primary immunogenicity endpoints (if the SARS-CoV-2 D614G variant remains in circulation 
globally based on reports from authorities [eg, WHO]) or 2 co-primary immunogenicity endpoints 
on the B.1.351 variant in participants, 18-55 years of age, primed with the Pfizer/BioNTech 
vaccine, 4 conditional co-secondary immunogenicity endpoints on both B.1.351 and D614G 
variants (if the SARS-CoV-2 D614G variant remains in circulation globally based on reports from 
authorities [eg, WHO]), or 2 conditional co-secondary immunogenicity endpoints on the B.1.351 
variant in participants, 18-55 years of age, primed with an mRNA vaccine, 1 conditional 
secondary endpoint on GMT in participants, 18-55 years of age, primed with the Pfizer/BioNTech 
vaccine, 2 conditional endpoints on seroresponse for both B.1.351 and D614G variants (if the 
SARS-CoV-2 D614G variant remains in circulation globally based on reports from authorities 
[eg, WHO]) or 1 conditional endpoint on seroresponse for only the B.1.351 variant in participants, 
18-55 years of age, primed with the Pfizer/BioNTech vaccine and an mRNA vaccine sequentially. 
Primary objective 1: non-inferiority to the comparator for participants primed with the 
Pfizer/BioNTech vaccine: 
For participants, 18-55 years of age, primed with the Pfizer/BioNTech vaccine,  14 days after the 
booster dose (ie, D15) of CoV2 preS dTM-AS03 (B.1.351) (non-exploratory arm only) or CoV2 
preS dTM-AS03 (D614 + B.1.351) and after the second dose of the primary vaccination 
Comparator Group (ie, D36), the GMT against B.1.351 of CoV2 preS dTM-AS03 (B.1.351) or 
GMT against D614G (if the SARS-CoV-2 D614G variant remains in circulation globally based on 
reports from authorities [eg, WHO]) and B.1.351 of CoV2 preS dTM-AS03 (D614 + B.1.351) is 
non-inferior to the GMT against D614G of the Comparator Group. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
Each of the 2 Booster Groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 
+ B.1.351), will be tested separately. The non-inferiority in terms of GMT will be demonstrated 
for either or both Booster Group(s) if the lower limit of the two-sided 98.3% CI of the ratio of the 
GMT is greater than (1/1.5).  
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Primary objective 2: superiority to pre-booster for participants primed with the Pfizer/BioNTech 
vaccine: 
For participants, 18-55 years of age, primed with the Pfizer/BioNTech vaccine, 14 days after the 
booster dose (ie, D15) of CoV2 preS dTM-AS03 (B.1.351) (non-exploratory arm only) or CoV2 
preS dTM-AS03 (D614 + B.1.351) the serum neutralization titer against B.1.351 of CoV2 preS 
dTM-AS03 (B.1.351) or serum neutralization titer against D614G (if the SARS-CoV-2 D614G 
variant remains in circulation globally based on reports from authorities [eg, WHO]) and B.1.351 
of CoV2 preS dTM-AS03 (D614 + B.1.351) is superior to the serum neutralization titer prior to 
the booster dose at D01. 
Null hypothesis (H0) : Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1) : Ratio (post-booster/pre-booster) > 2 
Each of the 2 Booster Groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 
+ B.1.351), will be tested separately. The superiority will be demonstrated for either or both 
Booster Group(s) if the lower limit of the two-sided 98.3% CI of the ratio of serum neutralization 
titer is greater than 2. 
The primary objectives for either or both of the Booster Group(s), CoV2 preS dTM-AS03 
(B.1.351) or CoV2 preS dTM-AS03 (D614 + B.1.351), will be reached if both non-inferiority and 
superiority testing are demonstrated. 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine 
is reached, 2 conditional secondary immunogenicity endpoints will be tested for participants 
primed with an mRNA vaccine for CoV2 preS dTM-AS03 (B.1.351), 4 conditional secondary 
immunogenicity endpoints on both the B.1.351 and D614G variants if the SARS-CoV-2 D614G 
variant remains in circulation globally based on reports from authorities [eg, WHO], or 2 
conditional secondary immunogenicity endpoints on the B.1.351 variant will be tested for CoV2 
preS dTM-AS03 (D614 + B.1.351). 
Conditional secondary objective 1.1: non-inferiority to the comparator in participants primed 
with an mRNA vaccine: 
For participants, 18-55 years of age, primed with an mRNA vaccine, 14 days after the booster 
dose (ie, D15) of CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 + B.1.351) 
and after the second dose of the Comparator Group (ie, D36), the GMT against B.1.351 of CoV2 
preS dTM-AS03 (B.1.351) or GMT against D614G (if the SARS-CoV-2 D614G variant remains 
in circulation globally based on reports from authorities [eg, WHO]) and B.1.351 of CoV2 preS 
dTM-AS03 (D614 + B.1.351) is non-inferior to the GMT against D614G of primary vaccination 
Comparator Group. 
Null hypothesis (H0) : GMT(booster) / GMT(comparator) ≤ (1/1.5) 
Alternative hypothesis (H1) : GMT(booster) / GMT(comparator) > (1/1.5) 
Each of the 2 Booster Groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 
+ B.1.351), will be tested separately. The non-inferiority in terms of GMT will be demonstrated 
for either or both of the Booster Group(s) if the lower limit of the two-sided 98.3% CI of the ratio 
of the GMT is greater than (1/1.5).  
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Conditional secondary objective 1.2: superiority to pre-booster in participants primed with an 
mRNA vaccine: 
For participants, 18-55 years of age, primed with an mRNA vaccine, 14 days after the booster 
dose (ie, D15) of CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 + B.1.351) 
the serum neutralization titer against B.1.351 of CoV2 preS dTM-AS03 (B.1.351) or serum 
neutralization titer against D614G (if the SARS-CoV-2 D614G variant remains in circulation 
globally based on reports from authorities [eg, WHO]) and B.1.351 of CoV2 preS dTM-AS03 
(D614 + B.1.351) is superior to the paired serum neutralization titer prior to booster dose at D01. 
Null hypothesis (H0) : Ratio (post-booster/pre-booster) ≤ 2 
Alternative hypothesis (H1) : Ratio (post-booster/pre-booster) > 2 
Each of the 2 Booster Groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 
+ B.1.351), will be tested separately. The superiority will be demonstrated for either or both of the 
Booster Groups(s) if the lower limit of the two-sided 98.3% CI of the ratio of serum neutralization 
titer is great than 2. 
For each of the Booster Groups, the conditional secondary objective will be reached if  both non-
inferiority and superiority testing described above are demonstrated. For CoV2 preS dTM-AS03 
(D614 + B.1.351), the approach is used across strains (B.1.351 and D614) (if the SARS-CoV-2 
D614G variant remains in circulation globally based on reports from authorities [eg, WHO]) or 
only on the B.1.351 variant.  
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine 
and conditional secondary immunogenicity objectives for participants primed with an mRNA 
vaccine are both achieved, then 1 conditional secondary endpoint on GMT for CoV2 preS dTM-
AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 + B.1.351), will be tested separately. 
Conditional secondary objective 2: superiority to the comparator in terms of GMT against 
B.1.351: 
For participants, 18-55 years of age, primed with the Pfizer/BioNTech vaccine,  14 days after the 
booster dose (ie, D15) of CoV2 preS dTM-AS03 (B.1.351) (non-exploratory arm only) or CoV2 
preS dTM-AS03 (D614 + B.1.351), GMT against B.1.351 of CoV2 preS dTM-AS03 (B.1.351) 
or/and CoV2 preS dTM-AS03 (D614 + B.1.351) is superior to the GMT against B.1.351 of the 
primary vaccination Comparator Group. 
Null hypothesis (H0) : GMT(variant) / GMT(comparator) ≤ 1.5 
Alternative hypothesis (H1) : GMT(variant) / GMT(comparator) > 1.5 
Each of the 2 variant-containing vaccine groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS 
dTM-AS03 (D614 + B.1.351), will be tested separately. The superiority will be demonstrated if 
the lower limit of the two-sided 98.3% CI of the ratio of the GMT is greater than 1.5 for each or 
both variant-containing vaccine group(s). 
If the primary immunogenicity objective in participants primed with the Pfizer/BioNTech vaccine, 
conditional secondary immunogenicity objective in participants primed with an mRNA vaccine, 
and conditional secondary immunogenicity objective on GMT in participants primed with the 
Pfizer/BioNTech vaccine are all achieved. Conditional secondary immunogenicity objective on 
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seroresponse for participants primed with the Pfizer/BioNTech vaccine and an mRNA vaccine 
will be tested sequentially. 
Conditional secondary objective 3: non-inferiority in terms of seroresponse rate for participants 
primed with the Pfizer/BioNTech or mRNA vaccines: 
For participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine or an mRNA vaccine , 
14 days after the booster dose (ie, D15) with CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS 
dTM-AS03 (D614 + B.1.351) and 14 days after the second dose (ie, D36) of the Comparator 
Group, the seroresponse rate against D614G (if the SARS-CoV-2 D614G variant remains in 
circulation globally based on reports from authorities [eg, WHO]) and B.1.351 of the Booster 
Group CoV2 preS dTM-AS03 (D614), is non-inferior to the seroresponse rate against D614G of 
the Comparator Group. 
Null hypothesis (H0) : p(booster) - p(comparator) ≤ -10%  
Alternative hypothesis (H1) : p(booster) - p(comparator) > -10% 
Each of the 2 Booster Groups, CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS dTM-AS03 (D614 
+ B.1.351), will be tested separately. The Pfizer/BioNTech vaccine primed and mRNA vaccine 
primed will be tested sequentially. The non-inferiority will be demonstrated for either or both of 
the Booster Groups(s) if the lower limit of the two-sided 98.3% CI of the difference between the 
2 proportions is great than -10%.  
9.2 
Sample Size Determination  
9.2.1 
Original Phase II Cohort of VAT00002  
A total of 720 participants are planned to be enrolled. The 3 adjuvanted vaccine groups have a 
planned sample size of 240 participants in each group. While formal hypothesis testing will not be 
performed, the targeted sample size is intended to generate sufficient evidence to enable 
comparison of immune responses generated in this study to those generated by efficacious 
vaccines (either in the literature or through testing of historical samples from clinical studies with 
an efficacious vaccine) to inform decisions about progression to and formulation selection for 
further investigation at Phase III. A sample size of 130 evaluable naïve participants per group 
enables detecting a minimum observed GMT ratio of 0.73 assuming GMT ratio of 1 and standard 
deviation of 0.67 (estimated for the Pseudovirus assay) with 95% probability. To generate data in 
SARS-CoV-2 non-naïve participants, up to 20% of participants may be rapid serodiagnostic test 
positive at baseline. 
An attrition rate of roughly 15% is assumed in the study to account for the potential deployment 
and availability of authorized/approved vaccines to study participants. 
9.2.2 
Supplemental Phase III Cohorts 1 and 2  
A Bonferroni adjustment is used to control the overall type I error rate at 0.025 one-sided in 
Supplemental Cohorts 1 and 2, so each comparison of the Booster Group with the Comparator 
Group will be performed at one-sided significance level of 0.00833 (0.025/3). No alpha-splitting 
within hypothesis testing of co-primary endpoints. Assumed attrition rate of Primary Vaccination 
Group is 10% and Booster Group is 3% (it is anticipated that attrition to 14 days post booster will 
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be limited and smaller than the attrition to D36 in the Comparator Group). Other assumptions for 
sample size calculation are as follows: 
• The PsVN Std Dev is around 0.65 for primary vaccination at D36 and around 1.0 for 
booster vaccination at D22 on log10 scale base on immunogenicity data obtained from 
Monogram for the corresponding assay 
o 
Note : The assumption of the standard deviation of the assay is based on the final 
interim data of D614G on the PPAS Naïve-D01+D22 at D36 and FAS NonNaïveD01 
at D22 from VAT0002 Original Phase II Cohort in participants 18-55 years of age.  
• For the primary and secondary objectives in terms of GMT non-inferiority against the 
comparator (using the D614G titers elicited by the comparator as the benchmark), the ratio 
of group GMT margin is 1/1.5, the assumed true ratio of group GMT for D614 containing 
vaccines (comparing D614G titers in both booster vaccine and priming comparator) is 1.5 
(this is informed by preliminary interim data from VAT00002 Original Phase II Cohort, 
indicating titers generally higher in the non-naïve individuals after a single dose, compared 
to the titers in naïve individuals after 2 doses); and the assumed true ratio of group GMT 
for the B1.351 variant-containing vaccines (comparing B.1.351 titers in variant-containing 
vaccines versus D614G titers in the comparator D614 vaccine) is 1 (this is assumed in the 
absence of data). 
• For the primary and secondary objectives in terms of superiority on ratio of serum 
neutralization titer (post-booster compared to pre-booster), the margin of ratio is 2, and the 
assumed true ratio is 5 (this is a conservative assumption informed by interim data from 
VAT00002 Original Phase II Cohort for non-naïve individuals indicating ratio of 
individual serum neutralization titer for D614G post single immunizations compared to 
baseline in the range of 14-16). Std Dev 1.0 difference on log10 scale is assumed for the 
post/pre antibody response. 
• For the conditional secondary objective in Supplemental Cohort 2 on superiority of 
B.1.351 strain (Booster Group versus Comparator Group), the margin of ratio is 1.5, and 
the assumed true ratio is 3 (this is assumed in the absence of data). 
• For the conditional secondary objective on seroresponse (Booster Group at D15 versus 
Comparator Group at D36), the margin of proportion difference is -10%, the assumed true 
seroresponse rate for the Booster Group is around 96.5% (this is assumed in the absence of 
data) and for the Comparator Group is 99%. 
For non-inferiority testing of the difference between 2 means (ratio of group GMT on log10 scale), 
the sample size estimation used a one-sided, two-sample t-test. For superiority by a margin tests 
for paired means, a one-sided t-test was used.  
For the vaccine groups undergoing hypothesis testing, a total of 215 participants, 18-55 years of 
age, are planned to be enrolled in Supplemental Cohort 1 CoV2 preS dTM-AS03 (D614) vaccine 
groups.  
A total of 515 participants, 18-55 years old, primed with the Pfizer/BioNTech vaccine are planned 
to be enrolled in each of the 2 Supplemental Cohort 2 vaccine groups, CoV2 preS dTM-AS03 
(B.1.351) or CoV2 preS dTM-AS03 (D614 + B.1.351).  
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A total of 75 participants 18-55 years of age and 25 participants  56 years of age who have 
received each of the priming vaccines other than those primed with Pfizer/BioNTech, Moderna, 
Oxford University/AstraZeneca, and J&J/Janssen, are planned to be enrolled to receive the CoV2 
preS dTM-AS03 (D614) booster in Supplemental Cohort 1, and the monovalent (B.1.351) booster 
and CoV2 preS dTM-AS03 (D614 + B.1.351) booster in Cohort 2.  
A total of 515 participants, 18-55 years of age, who are SARS-CoV-2 naïve  (no evidence of 
previous infection or vaccination) receiving 2 doses of the CoV2 preS dTM-AS03 (D614) parental 
vaccine will be enrolled as the Comparator Group for both Supplemental Cohorts 1 and 2. 
Additionally, for enabling extrapolation, approximately 50 participants  56 years of age are 
planned to be enrolled in each Supplemental Cohort 1 and Cohort 2 groups primed with the 
Pfizer/BioNTech vaccine (in the non-exploratory arms).  
Approximately 300 participants, 18-55 years of age, primed with the CoV2 PreS dTM-AS03 
vaccine and 150 participants,  56 years of age, primed with the CoV2 PreS dTM-AS03 vaccine 
are assumed to transition from the Original Phase II Cohort into the 2 Supplemental Cohort 2 
vaccine groups, CoV2 preS dTM-AS03 (B.1.351) and CoV2 preS dTM-AS03 (D614); however, 
the actual number of Original Phase II Cohort participants meeting eligibility criteria for transition 
cannot be accurately determined, and as such the actual number of CoV2 PreS dTM-AS03 booster 
participants in Supplemental Cohort 2 may be smaller or larger than assumed. For detailed power 
estimations for Supplemental Cohorts 1 and 2 refer to Table 9.1. 
Table 9.1: Power estimations for Supplemental Cohorts 1 and 2 (18-55 years old) 
Cohort/ 
Objective(s) 
Arm 
Parameters for Non-
inferiority 
Parameters for 
Superiority 
Study Power 
Cohort 1 CoV2 preS dTM-AS03 (D614) Booster Group 
Primary 
Objectives 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(D614) Booster 
Group (N=215) 
 Assumed true ratio of 
group GMT: 1.5 
 Margin: 1/1.5 
 Std Dev (booster): 1.0 
 Std Dev 
(comparator): 0.65 
 Assumed true 
ratio: 5 
 Margin: 2 
 Std 
Dev (booster): 
1.0 
 Non-inferiority: 
98.7% 
 Superiority: 
> 99.9% 
 Overall: 98.7% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
Protein-based 
primed CoV2 preS 
dTM-AS03 (D614) 
Booster Group 
(N~=270) 
 Non-inferiority: 
99.7% 
 Superiority: 
> 99.9% 
 Overall: 99.6% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (D614) 
Booster Group 
(N=290) 
 Non-inferiority: 
99.8% 
 Superiority: 
> 99.9% 
 Overall: 99.8% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
Adenovirus vector 
primed CoV2 preS 
dTM-AS03 (D614) 
Booster Group 
(N=150) 
 Non-inferiority: 
94% 
 Superiority: 
99.1% 
 Overall: 93.2% 
Conditional 
Secondary 
Objective 
Pfizer primed CoV2 
preS dTM-AS03 
Non-inferiority on seroresponse 
95.3% 
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(Type I error: 
0.00833) 
(D614) Booster 
Group (N=215) 
 Assumed true Comparator Group 
seroresponse rate: 99% 
 Assumed actual difference between Booster 
and Comparator Groups: -2.5% 
 Margin: -10% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
Protein-based 
primed CoV2 preS 
dTM-AS03 (D614) 
Booster Group 
(N=270) 
98.9% 
Conditional 
Secondary 
Objective 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (D614) 
Booster Group 
(N=290) 
99.4% 
Conditional 
Secondary 
Objective 
(Type I error: 
0.00833) 
Adenovirus vector 
primed CoV2 preS 
dTM-AS03 (D614) 
Booster Group 
(N=150) 
78.2% 
Cohort 2 CoV2 preS dTM-AS03 (B.1.351) Booster Group 
Primary 
Objectives 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(B.1.351) Booster 
Group (N=515) 
 Assumed true ratio of 
group GMT: 1 
 Margin: 1/1.5 
 Std Dev (booster): 1.0 
 Std Dev 
(comparator): 0.65 
 Assumed true 
ratio: 5 
 Margin: 2  
 Std 
Dev (booster): 
1.0 
 Non-inferiority: 
80.5% 
 Superiority: 
> 99.9% 
 Overall: 80.5% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (B.1.351) 
Booster Group 
(N=590) 
 Non-inferiority: 
84.5% 
 Superiority: 
> 99.9% 
 Overall: 84.5% 
Conditional 
Secondary 
Objective on 
B.1.351 variant 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(B.1.351) booster 
group (N=515) 
Superiority on ratio of group GMT (GMT 
against B.1.351 vs comparator GMT against 
B.1.351) 
 
Assumed true ratio of group GMT: 3 
 
Margin: 1.5 
 
Std Dev (booster): 1.0 
 
Std Dev (comparator): 0.65 
> 99.9% 
Conditional 
Secondary 
Objective on 
seroresponse 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(B.1.351) booster 
group (N=515) 
Non-inferiority on seroresponse 
 Assume true comparator group seroresponse 
rate: 99% 
 Assumed actual difference between booster 
and comparator group: -2.5% 
 Margin: -10% 
> 99.9% 
Conditional 
Secondary 
Objective on 
seroresponse 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (B.1.351) 
booster group 
(N=590) 
> 99.9% 
Cohort 2 CoV2 preS dTM-AS03 (D614 + B.1.351) Booster Group 
Primary 
Objectives 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(D614 + B.1.351) 
Booster Group 
(N=515) 
 
B.1.351 variant: 
 Assumed true ratio of 
group GMT: 1 
 Margin: 1/1.5 
 Std Dev (booster): 1.0 
 Assumed true 
ratio: 5 
 Margin: 2  
 Std 
Dev (booster): 
1.0 
 Non-
inferiority (B.1.35
1 variant): 80.5% 
 Non-inferiority 
(D614G variant):  
> 99.9% 
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 Std Dev 
(comparator): 0.65 
D614 variant: 
 Assumed true ratio of 
group GMT: 1.5 
 Margin: 1/1.5 
 Std Dev (booster): 1.0 
 Std Dev 
(comparator): 0.65 
 Superiority: 
> 99.9% 
 Overall (across 
two strains): 
80.5% 
Conditional 
Secondary 
Objectives 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (D614 + 
B.1.351) Booster 
Group (N=590) 
 
 Non-
inferiority (B.1.35
1 variant): 84.5% 
 Non-inferiority 
(D614 variant): 
> 99.9% 
 Superiority: 
> 99.9% 
 Overall (across 
two strains): 
84.5% 
Conditional 
Secondary 
Objective on 
B.1.351 variant 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(D614 + B.1.351) 
Booster Group 
(N=515) 
Superiority on ratio of group GMT (GMT 
against B.1.351 vs comparator GMT against 
B.1.351) 
 
Assumed true ratio of group GMT: 3 
 
Margin: 1.5 
 
Std Dev (booster): 1.0 
 
Std Dev (comparator): 0.65 
> 99.9% 
Conditional 
Secondary 
Objective on 
seroresponse 
(Type I error: 
0.00833) 
Pfizer primed CoV2 
preS dTM-AS03 
(D614 + B.1.351) 
Booster Group 
(N=515) 
 
Non-inferiority on seroresponse 
 Assumed true Comparator Group 
seroresponse rate: 99% 
 Assumed actual difference between Booster 
and Comparator groups: -2.5% 
 Margin: -10% 
> 99.9% 
Conditional 
Secondary 
Objective on 
seroresponse 
(Type I error: 
0.00833) 
mRNA primed 
CoV2 preS dTM-
AS03 (D614 + 
B.1.351) Booster 
Group (N=590) 
 
> 99.9% 
Note: Std Dev of 0.65 for the comparator at D36, 1.0 for the boosters at D22 were on log10 scale 
and 1.0 for the post/pre booster at D15 relative to D01 was on log10 scale.  
 
A total of 75 participants 18-55 years of age and 25 participants  56 years of age who have been 
primed with the Pfizer/BioNTech vaccine are planned to be enrolled to receive the different 
monovalent (B.1.351) booster formulations in Supplemental Cohort 2. The sample sizes are not 
based on hypothesis to be tested but rather to provide information on potential future adjustments 
of the booster vaccines. 
 
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9.3 
Analysis Sets  
The following subgroup definitions of SARS-CoV-2 Naïve and Non-Naïve at D01 or both D01 
and D22 timepoints are applied for all randomized participants in the Original Phase II Cohort: 
Prior SARS-CoV-2 
infection status (Original 
Phase II Cohort) 
Description 
SARS-CoV-2 Naïve at 
baseline (Naïve-D01) 
• 
Negative by the anti-S immunoassay (Roche Elecsys) on D01 
serum sample 
AND 
• 
Negative by the anti-N immunoassay on D01 serum sample 
AND 
• 
Negative NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 
SARS-CoV-2 Non-Naïve at 
baseline (Non-Naïve-D01) 
• 
Positive by the anti-S immunoassay (Roche Elecsys) on D01 serum 
sample 
OR 
• 
Positive by the anti-N immunoassay on D01 serum sample 
OR 
• 
Positive NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 
SARS-CoV-2 Naïve at 
second injection (Naïve- 
D01+D22) 
• 
Negative by the anti-S immunoassay (Roche Elecsys) on D01 
serum sample 
AND 
• 
Negative by anti-N immunoassay on D01 and D22 serum sample 
AND 
• 
Negative NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 and D22 
SARS-CoV-2 Non-Naïve at 
second injection (Non-Naïve 
-D01/D22) 
• 
Positive by the anti-S immunoassay (Roche Elecsys) on D01 serum 
sample 
OR 
• 
Positive by the anti-N immunoassay on D01 or D22 serum sample 
OR 
• 
Positive NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 or D22 
 
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The following subgroup definitions of SARS-CoV-2 Naïve and Non-Naïve at D01 timepoint are 
applied for all randomized participants in all Supplemental Cohorts: 
Prior SARS-CoV-2 
infection status 
(Supplemental Cohorts) 
Description 
SARS-CoV-2 Naïve at 
baseline (Naïve-D01) 
• 
Negative by the anti-S immunoassay (Roche Elecsys) on D01 
serum sample 
AND 
• 
Negative NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 
SARS-CoV-2 Non-Naïve at 
baseline (Non-Naïve-D01) 
• 
Positive by the anti-S immunoassay (Roche Elecsys) on D01 serum 
sample 
OR 
• 
Positive NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 
The following subgroup definitions of SARS-CoV-2 Naïve and Non-Naïve at both D01 and D22 
timepoints are applied for all randomized participants in the Supplemental Cohorts Comparator 
Group: 
Prior SARS-CoV-2 
infection status 
(Supplemental Cohorts) 
Description 
SARS-CoV-2 Naïve at 
second injection (Naïve- 
D01+D22) 
• 
Negative by the anti-S immunoassay (Roche Elecsys) on D01 
serum sample 
AND 
• 
Negative NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 and D22 
SARS-CoV-2 Non-Naïve at 
second injection (Non-Naïve 
-D01/D22) 
• 
Positive by the anti-S immunoassay (Roche Elecsys) on D01 serum 
sample 
OR 
• 
Positive NAAT for SARS-CoV-2 on respiratory sample collected 
on D01 or D22 
 
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The following populations are defined for analysis: 
Population 
Description 
Screened 
All participants screened for potential study enrollment will be included 
regardless of being enrolled or not being enrolled. The screening 
includes the SARS-CoV-2 rapid serodiagnosis test results, demographic 
information (age, ethnic/racial population, high-risk medical 
conditions), inclusion/exclusion criteria and prior vaccination platform 
for booster vaccination groups. The participants reaching the enrollment 
cap identified in IRT will be excluded from the study enrollment and 
will have no participant ID assigned. 
Randomized 
All participants with a randomized group that have been allocated by 
IRT. 
Safety Analysis Set (SafAS) 
Participants randomized and who have received at least 1 dose of the 
study vaccines. 
All participants will have their safety data analyzed after each dose 
according to the vaccine they truly received, and after any dose 
according to the vaccine received at the first dose. 
Safety data recorded for participants not administered a study 
intervention will be excluded from the analysis (and listed separately). 
Full analysis set (FAS) 
All randomized participants who receive at least 1 study injection. 
Participants will be analyzed according to the intervention to which they 
were randomized. 
Per-protocol analysis set 
(PPAS) 
Subset of the FAS. Participants presenting with at least 1 of the 
following criteria 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 
• 
Participants did not receive both injections for 2 doses primary 
vaccination groups or 1 dose booster injection for booster 
vaccination groups 
• 
Participant received a vaccine other than the one that he / she was 
randomized to receive 
• 
Preparation and / or administration of vaccine was not done as per-
protocol 
• 
Participant did not receive protocol defined vaccine in the proper 
time window 
• 
Participants who did not provide all post-dose blood samples within 
the proper time window or no post-dose blood sample was drawn 
• 
Participant received the second injection (in the primary vaccination 
groups) despite meeting any of the definitive contraindication 
criteria 
• 
Participant receives an authorized/approved COVID-19 vaccine 
prior to D36 for primary vaccination groups or D15 for booster 
vaccination groups 
The definition may be complemented with additional criteria for 
exclusion after the review of protocol deviations reported on site. 
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Cellular Immunity and 
Mucosal analysis set 
(CMIAS) 
Subset of the FAS and randomly assigned to the Cellular Immunity and 
mucosal subset (Original Phase II Cohort, Supplemental Cohort 2 
primed with the Pfizer/BioNTech vaccine in the non-exploratory groups 
and Supplemental Cohort 2 CoV2 preS dTM-AS03 (D614) primary 
series from the Original Phase II Cohort). Participants presenting with at 
least one of the following criteria will be excluded from the CMIAS: 
• 
Participant did not meet all protocol-specified inclusion criteria or 
met at least one of the protocol-specified exclusion criteria 
• 
Participants did not receive both injections in the primary 
vaccination groups or one injection in the booster vaccination 
groups 
• 
Participant received a vaccine other than the one that he / she was 
randomized to receive 
• 
Preparation and / or administration of vaccine was not done as per-
protocol 
• 
Participant did not receive vaccine in the proper time window 
• 
Participants received the second injection (in the primary 
vaccination groups) despite meeting any of the definitive 
contraindication criteria. 
• 
Participant receives an authorized/approved COVID-19 vaccine 
prior to D36 for primary vaccination groups or D15 for booster 
vaccination groups 
The definition may be complemented with additional criteria for 
exclusion after the review of protocol deviations reported on site. 
Variant Testing analysis set 
(VTAS) 
Subset of the FAS and randomly assigned to the Variant Testing subset: 
Supplemental Cohort 1, Supplemental Cohorts 1 and 2 Comparator 
Group, Supplemental Cohort 2 primed with the Pfizer/BioNTech 
vaccine in the non-exploratory groups and Supplemental Cohort 2 
CoV2 preS dTM-AS03 (D614) primary series from the Original Phase 
II Cohort. Participants presenting with at least 1 of the following criteria 
will be excluded from the VTAS: 
• 
Participant did not meet all protocol-specified inclusion criteria or 
met at least one of the protocol-specified exclusion criteria 
• 
Participants did not receive both injections in the primary 
vaccination groups or one injection in the booster vaccination 
groups 
• 
Participant received a vaccine other than the one that he / she was 
randomized to receive 
• 
Preparation and / or administration of vaccine was not done as per 
protocol 
• 
Participant did not receive vaccine in the proper time window 
• 
Participants received the second injection (in the primary 
vaccination groups) despite meeting any of the definitive 
contraindication criteria. 
• 
Participant receives an authorized/approved COVID-19 vaccine 
prior to D36 for primary vaccination groups or D15 for booster 
vaccination groups 
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The definition may be complemented with additional criteria for 
exclusion after the review of protocol deviations reported on site. 
9.4 
Statistical Analyses  
The initial statistical analysis plan (SAP) was finalized prior to the database lock for the interim 
analysis informing progression to Phase III for the Original Phase II Cohort; an amended SAP will 
be finalized prior to the database lock for any interim analysis applicable to the Supplemental 
Phase III Cohorts. Additional SAP amendments may be performed after execution of the interim 
analysis and before any additional analysis that occurs between any such interim analyses and the 
final analysis. The SAP 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. 
The endpoints for safety and immunogenicity are as shown in Table 3.1. 
9.4.1 
General Considerations  
For the Original Phase II Cohort, analyses of safety and immunogenicity objectives will be 
descriptive. For the Supplemental Phase III Cohorts, hypothesis testing will be conducted for the 
primary immunogenicity objectives and conditional secondary objectives as described above. 
Analyses of other secondary objectives and exploratory objectives will be descriptive. Exploratory 
objectives will be included in either the SAP or supplemental SAP.  
9.4.2 
Statistical Considerations  
9.4.2.1 
Original Phase II Cohort  
9.4.2.1.1 
Primary - Safety  
The main parameter will be described for all safety endpoints. The percentage of participants 
(using as denominator the number of participants) will be provided for analysis of solicited AEs, 
unsolicited AEs (including immediate systemic AEs within 30 minutes), SAEs, AESIs and 
MAAEs. The corresponding 95% CIs for the percentages will be calculated based on the 
Clopper-Pearson method. Subgroup analyses will be performed for age group, baseline 
SARS-CoV-2 Naïve status (Naïve at D01 and Non-Naïve at D01) (as defined in Section 9.3), and 
high-risk medical conditions group for the main safety analyses. 
The SafAS population will be used for safety analyses for the following endpoints: 
• Presence, and relationship of unsolicited (immediate) systemic AEs reported in the 
30 minutes after each vaccination. 
• Presence, time of onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (pre-listed in the 
participant’s DC and CRF) injection site reactions and systemic reactions occurring up to 
7 days after each vaccination. 
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• Presence, nature (Medical Dictionary for Regulatory Activities [MedDRA] system organ 
class [SOC] and preferred term [PT]), time of onset, duration, intensity, relationship to 
vaccination and whether the event led to early termination from the study of unsolicited 
AEs reported up to 21 days after the last vaccination. 
• Presence, nature (MedDRA SOC and PT), time of onset, seriousness criteria, relationship 
to vaccination, outcome, and whether the event led to early termination from the study, of 
SAEs. 
• Presence, nature (MedDRA SOC and PT), relationship to vaccination of all 
protocol-specified AESIs from the time of the first study vaccination throughout the study. 
• Presence, nature (MedDRA SOC and PT), relationship to vaccination of MAAEs 
throughout the study. 
9.4.2.1.2 
Primary - Immunogenicity  
The percentage of responders and participants having a 2-fold rise (2FR), 4-fold rise (4FR) will be 
provided against each endpoint with the corresponding 95% CIs using the Clopper-Pearson 
method. Differences of percentages of responders and participants with 2FR, 4FR will be 
provided with 95% CI calculated by the Newcombe-Wilson score method without continuity 
correction for the main immunogenicity analyses (65). GMTs in each injection group and GMT 
ratios between injection groups will be summarized along with their 95% CIs using the normal 
approximation of log-transformed titers. GMTs will be presented in original scale that are 
re-converted from log-transformed titers. GMTRs is defined as geometric mean of individual 
titers ratios (post-vaccination/pre-vaccination for each injection). GMTR will be summarized with 
95% CI (normal approximation) for D36 compared to D01. Reverse Cumulative Distribution 
Curves (RCDC) will be generated for baseline (D01) and post-vaccination immunogenicity. 
Additional parameters may be displayed as appropriate. 
The PPAS Naïve-D01+D22 will be utilized for primary immunogenicity endpoints. Subgroup 
analyses will be performed by age-group (18-59 years old and ≥ 60 years old), and high-risk 
medical conditions groups. The primary immunogenicity endpoints will also be evaluated on 
FAS Naïve-D01 and FAS Naïve-D01+D22. Details of the analysis and any additional analysis 
will be described in the SAP if applicable. 
9.4.2.1.3 
Secondary – Safety  
The occurrences of serologically-confirmed SARS-CoV-2 infection will be described by 
percentages of participants with infection during the analysis period with 95% CI by 
Clopper-Pearson methods. The occurrences of each endpoint related to laboratory-confirmed 
symptomatic COVID-19 will be described by percentages with 95% CI (by Clopper-Pearson 
methods). SafAS population will be utilized for analysis. 
Participants with an active SARS-CoV-2 infection at baseline (as determined by positive NAAT 
at D01) will be listed separately, if applicable. 
If the total number of observed COVID-19 clinical illness cases at the analysis time point is less 
than 5 in all groups, no summary analysis will be performed, and a listing of observed cases will 
be provided. Additional analyses will be described in the SAP. 
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9.4.2.1.4 
Secondary - Immunogenicity  
The same analysis methods stated in Section 9.4.2.1.2 will be applied for both neutralizing 
antibody titers and binding antibody titers in all listed timepoints. Geometric mean value of 
concentrations (GMCs), GMC ratios and geometric mean concentration ratios (GMCRs) will be 
used for notations against binding antibody concentrations instead of GMT, GMT ratios and 
GMTR against neutralizing antibody titers. Analysis of 2FR, 4FR and proportion of responders in 
naïve and non-naive will be estimated as described above. 
The PPAS Naïve-D01+D22 and PPAS Non-Naïve-D01/D22 populations will be utilized for 
secondary immunogenicity endpoints. Analysis will also be performed in FAS Naïve D01+D22, 
FAS Naïve-D01, and FAS Non-Naïve-D01. Details of the analysis and any additional analysis 
will be described in the SAP if applicable. 
9.4.2.1.5 
Exploratory – Immunogenicity  
Details of the exploratory analysis will be described in the SAP or supplemental SAP. 
9.4.2.2 
Supplemental Phase III Cohorts  
9.4.2.2.1 
Primary - Immunogenicity  
Due to the nature of immunogenicity titer, logarithm transformation of the individual data (titers 
or concentrations) (log10(data)) will be calculated and assumed to be normally distributed. The 
statistical inference will be based on the use of the two-sided 98.3% CI (Supplemental Cohorts 1 
and 2) for non-inferiority of difference in means of post-vaccination log10 transformed 
concentrations between the 2 groups with normal approximation. 
The calculation of the CI for the GMT ratio between Booster Arms and the Comparator Group for 
Supplemental Cohorts 1 and 2 will use Welch's t-interval. 
For the geometric mean of individual titer ratios post-boost versus pre-boost for superiority 
testing, the two-sided 98.3% CI (Supplemental Cohorts 1 and 2) of post-booster versus pre-
booster will be calculated using log10-transformed titers assume normal distribution by applying 
paired t-interval. 
The PPAS will be utilized for primary immunogenicity objectives. The primary immunogenicity 
endpoints will also be evaluated in the FAS (Table 9.2). 
Subgroup analyses, where applicable, will be performed by age group (18-55 years old and 
≥ 56 years old) for Intervention Groups, by priming vaccine (Supplemental Cohorts 1 and 2), and 
by priming platform (Supplemental Cohorts 1 and 2), in addition to the Overall Group. 
Table 9.2: Analysis set used in analyses 
Cohort 
Intervention Group(s) 
Comparator Group 
Supplemental Cohort 1 
PPAS, FAS 
PPAS Naïve at D01+D22, FAS 
Naïve at D01, FAS Naïve at 
D01+D22 
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Supplemental Cohort 2 
PPAS, FAS 
PPAS Naïve at D01+D22, FAS 
Naïve at D01, FAS Naïve at 
D01+D22 
9.4.2.2.2 
Primary - Safety  
The main parameter will be described for all safety endpoints. The percentage of participants 
(using as denominator the number of participants) will be provided for analysis of solicited AEs, 
unsolicited AEs (including immediate systemic AEs within 30 minutes), SAEs, AESIs and 
MAAEs. The corresponding 95% CIs for the percentages will be calculated based on the 
Clopper-Pearson method. In the priming vaccine groups (comparator for Cohorts 1 and 2), 
subgroup analyses will be performed by age group (18-55 years old and ≥ 56 years old), high-risk 
medical conditions group, and baseline SARS-CoV-2 naïve status for the main safety analyses. In 
the Booster Groups (in Cohorts 1 and 2), subgroup analyses will be performed by age group (18-
55 years old and ≥ 56 years old), high-risk medical conditions group, priming vaccine platform, 
and individual priming vaccine. Safety endpoints will be analyzed for each of the CoV2 preS 
dTM primary series dosages administered in the Original Phase II Cohort (ie, 5-10-15 µg). The 
SafAS population will be used for safety analyses for the following endpoints: 
• Presence and relationship of unsolicited (immediate) systemic AEs reported in the 
30 minutes after each vaccination. 
• Presence, time of onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (pre-listed in the 
participant’s DC and CRF) injection site reactions and systemic reactions occurring up to 
7 days after each vaccination. 
• Presence, nature (MedDRA SOC and PT), time of onset, duration, intensity, relationship to 
vaccination, and whether the event led to early termination from the study of unsolicited 
AEs reported up to 21 days after the last vaccination. 
• Presence, nature (MedDRA SOC and PT), time of onset, seriousness criteria, relationship 
to vaccination, outcome, and whether the event led to early termination from the study, of 
SAEs. 
• Presence, nature (MedDRA SOC and PT), relationship to vaccination of all 
protocol-specified AESIs from the time of the first study vaccination throughout the study. 
• Presence, nature (MedDRA SOC and PT), relationship to vaccination of MAAEs 
throughout the study. 
9.4.2.2.3 
Secondary - Immunogenicity  
The percentage of responders and participants having 2FR, 4FR will be provided against each 
endpoint with the corresponding 95% CIs using the Clopper-Pearson method. FR is defined as 
fold-rise from post-vaccination relative to pre-vaccination. Differences of percentages of 
responders and participants with 2FR and 4FR will be provided with 95% CI calculated by the 
Newcombe-Wilson score method without continuity correction. GMTs or GMCs in each injection 
group and GMT ratios between injection groups will be summarized along with their 95% CIs 
using the normal approximation of log-transformed titers. GMTs will be presented in original 
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scale that are re-converted from log-transformed titers. GMTRs are defined as the ratio of 
individual geometric mean titer for each injection group. GMTR will be summarized with 95% CI 
(normal approximation). Additional parameters may be displayed as appropriate. 
The same method will be applied for calculating the two-sided CI as in Section 9.4.2.2.1. 
The PPAS will be utilized for secondary immunogenicity objectives. Subgroup analyses will be 
performed but not limited to age group (18-55 years old and ≥ 56 years old) for Intervention 
Groups. The secondary immunogenicity endpoints will also be evaluated on the FAS. 
9.4.2.2.4 
Secondary – Safety  
The occurrences of each endpoint related to laboratory-confirmed symptomatic COVID-19 will be 
described by percentages with 95% CI (by Clopper-Pearson methods). The SafAS population will 
be utilized for analysis. 
Participants with active SARS-CoV-2 infection at baseline (as determined by positive NAAT at 
D01) will be listed separately, if applicable. If the total number of observed COVID-19 clinical 
illness cases at the analysis time point is less than 5 in all groups, no summary analysis will be 
performed, and a listing of observed cases will be provided. Additional analyses will be described 
in the SAP. 
9.4.2.2.5 
Exploratory – Immunogenicity  
The PPAS will be applied for exploratory immunogenicity analyses. These analyses may also be 
performed in the FAS. Details of exploratory analyses will be described in the SAP or 
supplemental SAP. 
9.5 
Interim Analyses  
For the Original Phase II Cohort, the interim analyses were to be performed on data collected for 
primary immunogenicity objectives and on data collected for primary safety objectives up to 
21 days post-injection 2. A partial database lock was conducted for the interim analysis. The 
statistical analyses of this interim analysis were used for dose selection and to support progression 
to Phase III. The study blind was broken at the group level to the Sponsor at that time. 
A second interim analysis for the Original Phase II Cohort will be performed when safety and 
immunogenicity data collected up to D202 are available. The SAP will describe the planned 
interim analyses in greater detail. 
For Supplemental Cohort 1, an interim analysis will be carried out once the following conditions 
apply: 
• Primary immunogenicity data is available up to D15 and primary safety data is available 
up to D22 for the Booster Group in Supplemental Cohort 1 
• Primary immunogenicity data is available up to D36 and primary safety data is available 
up to D43 in the Comparator Group for Supplemental Cohorts 1 and 2  
• Partial database lock is performed 
For Supplemental Cohort 2, an interim analysis may be carried out once the following conditions 
apply: 
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• Primary immunogenicity data is available up to D15 and primary safety data is available 
up to D22 for the Booster Groups in Supplemental Cohort 2  
• Primary immunogenicity data is available up to D36 and primary safety data is available 
up to D43 in the Comparator Group for Supplemental Cohorts 1 and 2   
• Partial database lock is performed 
For Supplemental Cohorts 1 and 2, additional interim analyses may be performed at later 
timepoints. 
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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 (eg, data protection law as General Data Protection 
Regulation [GDPR]) 
• The protocol, protocol amendments, informed consent form (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 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
• The Investigator 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 
• 
Determining whether an incidental finding (as per Sanofi policy) should be returned to a 
participant and, if it meets the appropriate criteria, to ensure the finding is returned (an 
incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
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applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
• 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
• 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
• 
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical study that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical study participants or on the scientific value of the study) prior to their implementation. 
10.1.2 Financial Disclosure  
Information related to financial disclosure is described in the Investigator’s contract. 
10.1.3 Informed Consent Process  
• The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions regarding the study. 
• If an approved/authorized vaccine is available in the country or region where the study is 
conducted, Investigators will discuss this information with the prospective study participant at 
the time of informed consent who will be encouraged to obtain the approved/authorized 
vaccine if applicable to them. Recruitment of eligible participants will proceed only if, despite 
encouragement, the candidate participant expresses no intention to seek an authorized or 
approved vaccine at least until completion of the key follow-up timepoint (D43) for informing 
progression to Phase III and dose selection. Participants will be encouraged to receive the 
authorized/approved vaccine if they are eligible, and the vaccine is available. 
• 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. 
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• 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, unless prohibited by local laws or IRBs/IECs. The Investigator or 
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  
All personal data collected and/or processed in relation to this study will be handled in compliance 
with all applicable Privacy & Data Protection laws and regulations, including the GDPR (General 
Data Protection Regulation). The study Sponsor is the Sanofi company responsible for ensuring 
compliance with this matter, when processing data from any individual who may be included in 
the Sanofi databases, including Investigators, nurses, experts, service providers, Ethics Committee 
members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant, and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
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• Participants race and ethnicity will be collected in this study, if permitted by local (or country) 
regulations, because these data are required by regulatory agencies (35) and specific race and 
ethnicity categories are associated with a higher risk of COVID-19. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only by 
the unique identifier; participant names or any information which would make the participant 
identifiable will not be transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with 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. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this study as well as for the following steps necessary for the 
development of the Investigational Product, including to support negotiations with payers and 
publication of results. 
Protection of data related to professionals involved in the study 
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the study and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) or to 
Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. The 
same rule applies in case the professionals are listed on a regulatory agency’s disqualification 
list. 
• Personal data can be communicated to the following recipients: 
• Personnel within Sanofi or partners or service providers involved in the study 
• Judicial, administrative, and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an adequate 
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level of protection. Those transfers are safeguarded by Sanofi in accordance with the 
requirement of European law including, notably: 
• The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
• Sanofi’s Binding Corporate Rules for intra-group transfers. 
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with any 
competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates in 
the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry (IR) 
project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). Therefore, 
personal data will be securely shared by Sanofi with other pharmaceutical company members 
of the Transcelerate project. This sharing allows Investigators to keep their data up-to-date 
once for all across pharmaceutical companies participating in the project, with the right to 
object to the transfer of the data to the Transcelerate project. 
• Professionals have the right to object to the processing, to request for access to and the 
rectification of their personal data, as well as their erasure (where applicable) by contacting 
the Sanofi Data Protection Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to 
contact Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-
privacy-policy/contact).  
10.1.5 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. 
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10.1.6 Data Quality Assurance  
• Participant data as specified in the protocol 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. 
• Guidance on completion of CRFs will be provided in the CRF completion instructions 
• 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 in a separate study document. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 years after the signature of the final study report unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
10.1.7 Source Documents  
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, screening logs, informed consent forms, telephone contact logs, and worksheets. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
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. 
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Detailed guidance and information are provided in the Operating Guidelines. 
10.1.8 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 or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been either destroyed or returned to the Sponsor, all samples are shipped to the appropriate 
laboratories, the center study-site has all the documents necessary for archiving and a study-site 
closure visit has been performed along with a Site Close Out Form submitted to the IRB, as 
required. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
• Information on the study intervention leads to doubt as to the benefit/risk ratio 
• For site termination: Failure of the Investigator to comply with the protocol, the requirements 
of the IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the Investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.9 Publication Policy  
Information related to publication policy is described in the Investigator’s contract. 
10.2 Appendix: Clinical Laboratory Tests  
A urine or serum human chorionic gonadotropin (hCG) pregnancy test (as needed for females of 
childbearing potential) will be performed before each vaccination. 
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• 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. 
Table 10.1: Protocol-required laboratory tests 
Laboratory 
Tests 
Time period for 
assessment 
Parameters 
Screening 
Tests 
pre-injections 1 and 2 at 
D01 and V02 (D22*), 
respectively 
Highly sensitive urine or serum human chorionic 
gonadotropin (hCG) pregnancy test (as needed for 
females of childbearing potential**) 
D01 
Rapid diagnostic testing for SARS-CoV2 antibody 
screening 
* For SARS-CoV-2-naïve participants only 
** To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or 
surgically sterile 
Participants, outcome assessors, Investigators, laboratory personnel, Sponsor study staff, and 
those administering the study intervention if not involved in preparing the study intervention will 
be blinded to Intervention Group; and those preparing/administering the study interventions will 
be unblinded. 
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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Unsolicited AE/AR 
An unsolicited AE is an observed AE that does not fulfill the conditions of solicited reactions, 
ie, pre-listed in the CRF in terms of diagnosis and onset window post-vaccination. For example, 
varicella or a solicited term such as headache starting after the solicited observation period (eg, 
headache starting on Day 10 post-vaccination in the case where headache occurring between the 
day of vaccination and the next 7 days is pre-listed in the protocol and CRF as a solicited 
reaction). 
An unsolicited AR is an unsolicited AE that is considered related to an IMP. Unsolicited AEs 
includes both serious (SAEs) and non-serious unsolicited AEs. 
All unsolicited AEs occurring at and around the IMP injection/administration site are to be 
considered by default as related to the IMP administered at that site and are therefore referred as 
unsolicited injection/administration site ARs. 
All unsolicited AEs which are not at and around the IMP injection/administration site, are 
referred as systemic unsolicited AE. For each unsolicited systemic AE, the Investigator assesses 
the relationship to the IMP. Systemic AEs assessed as related to IMP are referred as systemic 
ARs. 
Note: any AEs at and around the NIMP injection / administration site regardless of its nature 
and onset is to be reported as unsolicited systemic AE since it does not occur at and around the 
IMP injection/administration site. 
Medically-Attended AE (MAAE) 
An MAAE is a new onset or a worsening of a condition that prompts the participant or 
participant’s parent/guardian 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. 
Adverse Event of Special Interest (AESI): 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s study intervention or program, for which ongoing monitoring 
and rapid communication by the Investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the study Sponsor to other parties (eg, regulators) 
might also be warranted. 
Potential Immune-Mediated Disease (pIMDs): pIMDs constitute a group of AEs that need to 
be recorded and reported as pIMDs and include those listed in Appendix 10.5: Adverse Events 
of Special Interest. 
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10.3.5 Assessment of Intensity  
The Investigator will make an assessment of intensity for each AE reported during the study. An 
intensity grade will be assigned to each AE. The intensity grading scales used in this study are 
adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007”. 
10.3.5.1 Tables for Clinical Abnormalities  
10.3.5.1.1 Solicited AR Intensity Grading Scale  
 
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Table 10.2: Solicited injection site reactions: terminology, definitions, and intensity scales – Adults 
CRF term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site 
erythema 
Injection site swelling  
Diary card term 
Pain 
Redness 
Swelling 
Definition 
Pain either present spontaneously or when the injection site is touched or 
injected limb is mobilized 
Presence of a redness 
including the 
approximate point of 
needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid infiltration 
in tissue or cavity and, depending on the space 
available for the fluid to disperse, swelling may 
be either soft (typically) or firm (less typical) to 
touch and thus can be best described by looking at 
the size of the swelling 
Intensity scale* 
CRF: 
Grade 1: A type of adverse event that is usually transient and may require 
only minimal treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living. 
Grade 2: A type of adverse event that is usually alleviated with additional 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of 
harm to the research participant. 
Grade 3: A type of adverse event that interrupts usual activities of daily 
living, or significantly affects clinical status, or may require intensive 
therapeutic intervention. 
Diary Card: 
Grade 1: No interference with activity 
Grade 2: Some interference with activity 
Grade 3: Significant; prevents daily activity 
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 pain, the scale will be provided in the CRF and the intensity will be transcribed from the diary card. For other injection site reactions (erythema and swelling), the classification as 
Grades 1, 2, or 3 will be applied at the time of statistical analysis; the scale is provided for information purposes only. The actual size of the reaction will be reported in the CRF. 
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Table 10.3: Solicited systemic reactions: terminology, definitions, and intensity scales – Adults 
CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
Diary card 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Joint pain 
Chills 
Definition 
Elevation of 
temperature to ≥°38.0°C 
(≥ 100.4°F) 
Pain or discomfort in 
the head or scalp. Does 
not include migraine. 
General ill feeling. 
Malaise is a generalized 
feeling of discomfort, 
illness, or lack of well-
being that can be 
associated with a 
disease state. It can be 
accompanied by a 
sensation of exhaustion 
or inadequate energy to 
accomplish usual 
activities. 
Muscle aches and pains 
are common and can 
involve more than one 
muscle at the same time. 
Muscle pain can also 
involve the soft tissues 
that surround muscles. 
These structures, which 
are often referred to as 
connective tissues, 
include ligaments, 
tendons, and fascia 
(thick bands of 
tendons). 
Does not apply to 
muscle pain at the 
injection site which 
should be reported as 
injection site pain. 
Pain in a joint or joints  
Sensation of cold  
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CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
Intensity 
scale* 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to 
≤ 101.1°F 
Grade 1: A type of 
adverse event (AE) that 
is usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE 
that is usually transient 
and may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE 
that is usually transient 
and may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
CRF: 
Grade 1: A type of 
adverse event that is 
usually transient and 
may require only 
minimal treatment or 
therapeutic intervention. 
The event does not 
generally interfere with 
usual activities of daily 
living. 
 
Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to 
≤ 102.0°F 
Grade 2: A type of AE 
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 AE 
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 AE 
that is usually alleviated 
with additional 
therapeutic intervention. 
The event interferes 
with usual activities of 
daily living, causing 
discomfort but poses no 
significant or permanent 
risk of harm to the 
research participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
Grade 2: A type of 
adverse event that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual 
activities of daily living, 
causing discomfort but 
poses no significant or 
permanent risk of harm 
to the research 
participant. 
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CRF term 
(MedDRA 
lowest level 
term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Arthralgia 
Chills 
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of AE 
that interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Grade 3: A type of AE 
that interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
Grade 3: A type of AE 
that interrupts usual 
activities of daily living, 
or significantly affects 
clinical status, or may 
require intensive 
therapeutic intervention. 
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 
activity  
Grade 2: Some 
interference with 
activity 
Grade 3: Significant; 
prevents daily activity 
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 
activity  
Grade 2: Some 
interference with 
activity  
Grade 3: Significant; 
prevents daily activity 
DC, Diary Card; MedDRA: Medical Dictionary for Regulatory Activities 
* For all reactions (except fever), the scale will be provided in the CRF and the intensity will be transcribed from the diary card. For fever, the body temperature will be recorded, and 
the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
 
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Important notes for the accurate assessment of temperature: 
Participants are to measure body temperature once per day, preferably always at the same time. 
The optimal time for measurement is the evening, when body temperature is the highest. 
Temperature is also to be measured at the time of any apparent fever. The observed daily 
temperature and the route of measurement are to be recorded in the DC, and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this study is oral. 
10.3.5.1.2 Unsolicited AE Intensity Grading Scale  
For measurable unsolicited AEs that are part of the list of solicited reactions, the corresponding 
scale for solicited reactions will be used (see Section 10.3.5.1.1). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1 
• 
CRF: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• 
DC: No interference with activity. 
• Grade 2 
• 
CRF: A type of AE that is usually alleviated with additional therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant. 
• 
DC: Some interference with activity. 
• Grade 3 
• 
CRF: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• 
DC: Significant; prevents daily activity. 
10.3.5.1.3 COVID-19 Symptoms Intensity and Grading Scale  
COVID-19 symptoms (except for loss of taste and loss of smell) will be classified according to 
the following intensity scale: 
• Grade 1 
• 
CRF: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• 
DC: No interference with usual activities. 
• Grade 2 
• 
CRF: A type of AE that is usually alleviated with additional therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant. 
• 
DC: Some interference with usual activities. 
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• Grade 3 
• 
CRF: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• 
DC: Significant; prevents usual activities. 
For sense of smell and sense of taste, the following grading will apply: 
• Grade 1 – sense of smell/sense of taste is less than usual 
• Grade 2 – no sense of smell/sense of taste 
10.4 Appendix: Collection of Pregnancy Information  
DEFINITIONS: 
Females of Childbearing Potential 
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. 
Females in the following categories are not considered to be of childbearing potential 
1) Premenarchal 
2) Premenopausal female with 1 or more of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3) Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
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COLLECTION OF PREGNANCY INFORMATION 
• The Investigator will collect pregnancy information on all female participants 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 promptly submitted to the Sponsor and no later than 1 month of learning 
of a participant's pregnancy. 
Female Participants who become pregnant 
• If the female participant becomes pregnant during the contraception/abstinence period where 
the participant is requested to be under contraception with 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, the participant will be followed to determine the outcome of the 
pregnancy), the Investigator will collect follow-up information on the participant up to 
delivery and the offspring and the information will be promptly 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. The offspring will be followed 
for up to 12 months. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• If the pregnancy occurs after the contraception/abstinence period, the Investigator should 
promptly inform the Sponsor and will record pregnancy information together with the 
contraceptive method on the appropriate form and submit it to the Sponsor no later than 
1 month of learning of the pregnancy. Pregnancy status will be collected, follow-up of the 
participant will continue as part of the study, but the participant will not be followed-up until 
the pregnancy outcome and the offspring will not be followed. 
• 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 intrauterine demise or 
still birth (occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. 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 she is no longer pregnant (if applicable). However, 
the participant will be followed for safety assessment (and may be followed for 
immunogenicity assessment, if applicable). 
 
 
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10.5 Appendix: Adverse Events of Special Interest (AESIs)  
AESIs considered potentially applicable to coronavirus vaccine 
• Anaphylactic reactions 
• Generalized convulsion 
• Thrombocytopenia 
• Thrombosis with thrombocytopenia syndrome 
• Myocarditis 
• Pericarditis 
Events potentially associated with the adjuvant use (AS03) and/or coronavirus vaccine 
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 10.4. 
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 10.4, 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 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 participant, the Investigator (or 
designate) must complete, date, and sign an electronic Expedited Adverse Events Report. 
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Table 10.4: List of potential immune-mediated diseases (version: January-2022) 
Blood disorders and 
coagulopathies 
Cardio-pulmonary inflammatory 
disorders 
Endocrine disorders 
- Antiphospholipid syndrome 
- Autoimmune aplastic anemia 
- Autoimmune hemolytic 
anemia, including: 
o Warm antibody hemolytic 
anemia 
o Cold antibody hemolytic 
anemia 
- Autoimmune 
lymphoproliferative syndrome 
(ALPS) 
- Autoimmune neutropenia  
- Autoimmune pancytopenia 
- Autoimmune 
thrombocytopenia* 
o Frequently used related terms 
include: “autoimmune 
thrombocytopenic purpura”, 
“idiopathic thrombocytopenic 
purpura (ITP)”, “idiopathic 
immune thrombocytopenia”, 
“primary immune 
thrombocytopenia”. 
- Evans syndrome 
- Pernicious anemia 
- Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
- Thrombotic thrombocytopenic 
purpura 
o Also known as 
“Moschcowitz-syndrome” or 
“microangiopathic hemolytic 
anemia” 
- Idiopathic Myocarditis/Pericarditis, 
including: 
o Autoimmune / Immune-mediated 
myocarditis 
o Autoimmune / Immune-mediated 
pericarditis 
o Giant cell myocarditis 
- Idiopathic pulmonary fibrosis, 
including: 
o Idiopathic interstitial pneumonia 
(Interstitial lung disease, 
Pulmonary fibrosis, Immune-
mediated pneumonitis) 
o Pleuroparenchymal fibroelastosis 
(PPFE) 
- Pulmonary alveolar proteinosis 
(PAP) 
o Frequently used related terms 
include: “pulmonary alveolar 
lipoproteinosis”, 
“phospholipidosis” 
- Addison’s disease 
- Autoimmune / Immune-mediated 
thyroiditis, including: 
o Hashimoto thyroiditis 
(autoimmune hypothyroidism, 
lymphocytic thyroiditis) 
o Atrophic thyroiditis  
o Silent thyroiditis  
o Thyrotoxicosis 
- Autoimmune diseases of the 
testis and ovary, including: 
o Autoimmune oophoritis 
o Autoimmune ovarian failure 
o Autoimmune orchitis 
- Autoimmune hyperlipidemia 
- Autoimmune hypophysitis 
- Diabetes mellitus type I 
- Grave's or Basedow’s disease, 
including: 
o Marine Lenhart syndrome 
o Graves' ophthalmopathy, also 
known as thyroid eye disease 
(TED) or endocrine 
ophthalmopathy 
- Insulin autoimmune syndrome 
- Polyglandular autoimmune 
syndrome, including: 
o Polyglandular autoimmune 
syndrome type I, II and III 
Eye disorders 
Gastrointestinal disorders 
Hepatobiliary disorders 
- Ocular Autoimmune / Immune-
mediated disorders, including: 
o Acute macular 
neuroretinopathy (also known 
- Autoimmune / Immune-mediated 
pancreatitis 
- Celiac disease 
- Autoimmune cholangitis 
- Autoimmune hepatitis 
- Primary biliary cirrhosis 
- Primary sclerosing cholangitis 
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as acute macular outer 
retinopathy) 
o Autoimmune / Immune-
mediated retinopathy  
o Autoimmune / Immune-
mediated uveitis, including 
idiopathic uveitis and 
sympathetic ophthalmia  
o Cogan's syndrome: an oculo-
audiovestibular disease 
o Ocular pemphigoid 
o Ulcerative keratitis 
o Vogt-Koyanagi-Harada 
disease 
- Inflammatory Bowel disease, 
including: 
o Crohn’s disease  
o Microscopic colitis  
o Terminal ileitis 
o Ulcerative colitis  
o Ulcerative proctitis 
Musculoskeletal and connective 
tissue disorders 
Neuroinflammatory/neuromuscular 
disorders 
Renal disorders 
- Gout, including: 
o Gouty arthritis 
- Idiopathic inflammatory 
myopathies, including: 
o Dermatomyositis 
o Inclusion body myositis 
o Immune-mediated necrotizing 
myopathy 
o Polymyositis 
- Mixed connective tissue 
disorder 
- Polymyalgia rheumatica (PMR) 
- Psoriatic arthritis (PsA) 
- Relapsing polychondritis 
- Rheumatoid arthritis, including: 
o Rheumatoid arthritis 
associated conditions 
o Juvenile idiopathic arthritis 
o Palindromic rheumatism 
o Still's disease 
o Felty’s syndrome 
- Sjögren’s syndrome 
- Spondyloarthritis, including: 
o Ankylosing spondylitis 
o Juvenile spondyloarthritis 
o Keratoderma blenorrhagica 
o Psoriatic spondylitis  
- Acute disseminated 
encephalomyelitis (ADEM)* and 
other inflammatory-demyelinating 
variants, including:  
o Acute necrotising myelitis 
o Bickerstaff's brainstem 
encephalitis  
o Disseminated necrotizing 
leukoencephalopathy (also known 
as Weston-Hurst syndrome, acute 
hemorrhagic leuko-encephalitis, 
or acute necrotizing hemorrhagic 
encephalomyelitis)  
o Myelin oligodendrocyte 
glycoprotein antibody-associated 
disease 
o Neuromyelitis optica (also known 
as Devic’s disease) 
o Noninfective encephalitis / 
encephalomyelitis / myelitis 
o Postimmunization 
encephalomyelitis 
- Guillain-Barré syndrome (GBS)*, 
including: 
o Variants such as Miller Fisher 
syndrome and the acute motor 
- Autoimmune / Immune-mediated 
glomerulonephritis, including: 
o IgA nephropathy 
o IgM nephropathy 
o C1q nephropathy 
o Fibrillary glomerulonephritis 
o Glomerulonephritis rapidly 
progressive 
o Membranoproliferative 
glomerulonephritis 
o Membranous 
glomerulonephritis 
o Mesangioproliferative 
glomerulonephritis 
o Tubulointerstitial nephritis and 
uveitis syndrome 
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o Reactive Arthritis (Reiter's 
Syndrome) 
o Undifferentiated 
spondyloarthritis 
- Systemic Lupus Erythematosus, 
including: 
o Lupus associated conditions 
(e.g. Cutaneous lupus 
erythematosus, Lupus 
nephritis, etc.) 
o Complications such as 
shrinking lung syndrome 
(SLS) 
- Systemic Scleroderma 
(Systemic Sclerosis), including: 
o Reynolds syndrome (RS) 
o Systemic sclerosis with 
diffuse scleroderma 
o Systemic sclerosis with 
limited scleroderma (also 
known as CREST syndrome) 
and sensory axonal neuropathy 
(AMSAN) 
- Idiopathic cranial nerve 
palsies/paresis and inflammations 
(neuritis), including: 
o Cranial nerve neuritis (e.g. Optic 
neuritis) 
o Idiopathic nerve palsies/paresis 
(e.g. Bell’s palsy) 
o Melkersson-Rosenthal syndrome 
o Multiple cranial nerve 
palsies/paresis 
- Multiple Sclerosis (MS), including: 
o Clinically isolated syndrome 
(CIS)  
o Malignant MS (the Marburg type 
of MS)  
o Primary-progressive MS (PPMS) 
o Radiologically isolated syndrome 
(RIS) 
o Relapsing-remitting MS (RRMS) 
o Secondary-progressive MS 
(SPMS) 
o Uhthoff's phenomenon 
- Myasthenia gravis, including: 
o Ocular myasthenia 
o Lambert-Eaton myasthenic 
syndrome 
- Narcolepsy* (with or without 
presence of unambiguous 
cataplexy) 
- Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies, including 
o Acute Brachial Radiculitis (also 
known as Parsonage-Turner 
Syndrome or neuralgic 
amyotrophy) 
o Antibody-mediated 
demyelinating neuropathy 
o Chronic idiopathic axonal 
polyneuropathy (CIAP) 
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o Chronic Inflammatory 
Demyelinating 
Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants 
(e.g. multifocal acquired 
demyelinating sensory and motor 
neuropathy also known as Lewis-
Sumner syndrome) 
o Multifocal motor neuropathy 
(MMN) 
- Transverse myelitis (TM), 
including: 
o Acute partial transverse myelitis 
(APTM) 
o Acute complete transverse 
myelitis (ACTM) 
Skin and subcutaneous tissue 
disorders 
Vasculitis 
Other (including multisystemic) 
- Alopecia areata 
- Autoimmune / Immune-
mediated blistering dermatoses, 
including: 
o Bullous Dermatitis 
o Bullous Pemphigoid  
o Dermatitis herpetiformis  
o Epidermolysis bullosa 
acquisita (EBA)  
o Linear IgA-mediated bullous 
dermatosis (LABD), also 
known as Linear IgA disease 
o Pemphigus 
- Erythema multiforme 
- Erythema nodosum 
- Lichen planus, including: 
o Liquen planopilaris 
- Localised Scleroderma 
(Morphoea) 
o Eosinophilic fasciitis (also 
called Shulman syndrome) 
- Psoriasis 
- Pyoderma gangrenosum 
- Reactive granulomatous 
dermatitis, including : 
- Large vessels vasculitis*, 
including: 
o Arteritic anterior ischemic optic 
neuropathy (AAION or arteritic 
AION) 
o Giant cell arteritis (also called 
temporal arteritis)  
o Takayasu's arteritis 
- Medium sized and/or small vessels 
vasculitis*, including: 
o Anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified)  
o Behcet's syndrome  
o Buerger’s disease 
(thromboangiitis obliterans) 
o Churg–Strauss syndrome (allergic 
granulomatous angiitis)  
o Erythema induratum (also known 
as nodular vasculitis) 
o Henoch-Schonlein purpura (also 
known as IgA vasculitis) 
o Microscopic polyangiitis 
o Necrotizing vasculitis 
o Polyarteritis nodosa 
- Anti-synthetase syndrome 
- Capillary leak syndrome 
o Frequently used related terms 
include : “systemic capillary 
leak syndrome (SCLS)” or 
“Clarkson's Syndrome” 
- Goodpasture syndrome 
o Frequently used related terms 
include: “pulmonary renal 
syndrome” and “anti-
Glomerular Basement 
Membrane disease (anti-GBM 
disease)” 
- Immune-mediated enhancement 
of disease, including: 
o Vaccine associated enhanced 
disease (VAED and VAERD). 
Frequently used related terms 
include “vaccine-mediated 
enhanced disease (VMED)”, 
“enhanced respiratory disease 
(ERD)”, “vaccine-induced 
enhancement of infection”, 
“disease enhancement”, 
“immune enhancement”, and 
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o Interstitial granulomatous 
dermatitis 
o Palisaded neutrophilic 
granulomatous dermatitis 
- Stevens-Johnson Syndrome 
(SJS), including: 
o Toxic Epidermal Necrolysis 
(TEN)  
o SJS-TEN overlap 
- Sweet’s syndrome, including: 
o Acute febrile neutrophilic 
dermatosis 
- Vitiligo 
o Single organ cutaneous vasculitis, 
including leukocytoclastic 
vasculitis, hypersensitivity 
vasculitis and acute hemorrhagic 
edema of infancy (AHEI) 
o Wegener's granulomatosis 
“antibody-dependent 
enhancement (ADE) 
- Immunoglobulin G4 related 
disease 
- Langerhans' cell histiocytosis 
- Multisystem inflammatory 
syndromes, including: 
o Kawasaki’s disease 
o Multisystem inflammatory 
syndrome in adults (MIS-A) 
o Multisystem inflammatory 
syndrome in children (MIS-C) 
- Overlap syndrome 
- Raynaud’s phenomenon 
- Sarcoidosis, including: 
o Loefgren syndrome 
- Susac's syndrome 
*Adverse events of special interest (AESI) considered potentially applicable to COVID-19 vaccines as defined by 
the Safety Platform for Emergency Vaccines (SPEAC), based on known association with vaccination in general 
(see https://brightoncollaboration.us/wp-content/uploads/2021/01/SO2_D2.1.2_V1.2_COVID-19_AESI-update-
23Dec2020-review_final.pdf). SPEAC list extended with additional potential immune-mediated diseases.   
 
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  
AC 
 
 
Adjudication Committee 
AE 
 
 
adverse event 
AESI  
 
adverse event of special interest 
AR 
 
 
adverse reactions 
ccIAS  
 
Case-cohort immunogenicity analysis set 
CDC  
 
Centers for Disease Control and Prevention 
CI 
 
 
confidence interval 
CMI 
 
 
cellular-mediated immunity 
CMIAS 
 
Cellular-Mediated Immunity analysis set 
CoV2 preS dTM 
SARS-CoV2 prefusion Spike delta TM 
COVPN 
 
COVID-19 Prevention Trials Network 
CRF 
 
 
(electronic) case report form 
CSR 
 
 
clinical study report 
DC 
 
 
diary card 
DMC  
 
Data Monitoring Committee 
DSMB  
 
Data and Safety Monitoring Board 
ECMO  
 
Extracorporeal membrane oxygenation 
ELISA  
 
enzyme-linked immunosorbent assay 
ELISpot 
 
enzyme-linked immunospot 
EMA  
 
European Medicines Agency 
EU 
 
 
European Union 
EUA  
 
Emergency Use Authorization 
 
FAS 
 
 
Full analysis set 
GCI 
 
 
Global Clinical Immunology 
GCP  
 
Good Clinical Practice 
GMC  
 
geometric mean concentration 
GMT  
 
geometric mean titer 
GMTR  
 
geometric mean titer ratio 
GPV  
 
Global Pharmacovigilance 
HA 
 
 
hemagglutinin 
HCP  
 
Host-Cell Protein 
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HR 
 
 
heart rate 
HRT  
 
Hormonal replacement therapy 
IB 
 
 
Investigator’s Brochure 
IC 
 
 
internal control 
ICF 
 
 
informed consent form 
ICH 
 
 
International Council for Harmonisation 
IEC 
 
 
Independent Ethics Committees 
IM 
 
 
intramuscular 
IMP 
 
 
Investigational Medicinal Product 
INN 
 
 
International non-proprietary name 
IRB 
 
 
Institutional Review Boards 
IRT 
 
 
Interactive Response Technology 
LB 
 
 
lower bound 
LLOQ  
 
lower limit of quantification 
MAAE 
 
medically-attended adverse event 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mFAS-PD2 
 
Modified full analysis set post-dose 2 
mRNA  
 
messenger ribonucleic acid 
NAAT  
 
Nucleic Acid Amplification Test 
NHP  
 
non-human primate 
NIH 
 
 
National Institutes of Health 
NIMP  
 
Non- Investigational Medicinal Product 
OG 
 
 
Oversight Group 
PBMC  
 
peripheral blood mononuclear cell 
PCR 
 
 
polymerase chain reaction 
pIMD  
 
potential immune-mediated disease 
PPAS  
 
Per-protocol analysis set 
PS 
 
 
PhenoSense 
PT 
 
 
preferred term 
PV 
 
 
pharmacovigilance 
rIAS 
 
 
Random immunogenicity analysis set 
rapIAS  
 
Rapid immunogenicity analysis set 
RMO  
 
Responsible Medical Officer 
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RNA  
 
ribonucleic acid 
RP2 
 
 
Respiratory Panel 2 
RR 
 
 
respiratory rate 
S 
 
 
Spike 
SA 
 
 
saliva sample 
SAE 
 
 
serious adverse event 
SafAS  
 
Safety Analysis Set 
SAP 
 
 
Statistical analysis plan 
SARS-CoV-2  
severe acute respiratory syndrome coronavirus 2 
SoA 
 
 
Schedule of Activities 
SP 
 
 
Sanofi Pasteur 
SUSAR 
 
suspected unexpected serious adverse reaction 
TBD  
 
to be determined 
Th 
 
 
T-helper 
US 
 
 
United States 
USG  
 
United States Government 
VAED  
 
vaccine associated enhanced disease 
 
 
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10.8 Appendix: Protocol Amendment/Update History  
The Protocol Amendment rationale for the current change in versions (from Version 9.0 to 
Version 10.0) is located directly before the Table of Contents. 
Protocol Version 2.0, dated 15 January 2021 
The major protocol revisions and rationale for revisions from Version 1.0 to Version 2.0 are as 
shown below: 
Revision 
Rationale 
The study design changed to a 
Phase II dose-finding study 
evaluating safety and 
immunogenicity of 3 different doses 
of recombinant protein antigen with 
a fixed dose of AS03 adjuvant to 
generate data to decide on 
progression to Phase III and dose- 
selection. 
The safety and immunogenicity of the CoV2 preS dTM-AS03 
adjuvanted vaccine was evaluated in the Phase I/II study in 
healthy adults 18 years of age and older. The objective of the 
Phase I/II study was to inform progression to a Phase III study, 
dose selection, formulation choice, and injection schedule 
selection. A low-dose and a high-dose antigen formulation 
corresponding to an effective dose of 1.3 µg and 2.6 µg of CoV2 
preS dTM antigen were evaluated in the study in combination 
with a fixed dose of either AS03 or AF03 adjuvants. Interim 
data from the study indicated that a 2-injection schedule of the 
adjuvanted vaccine was necessary to induce neutralizing 
antibody responses and that the AS03 adjuvanted vaccine 
attained higher immune responses than the AF03 adjuvanted 
vaccine. Interim data from the study showed lower than 
expected immunogenicity, particularly in older adults, in 
combination with higher than expected reactogenicity indicating 
that assessment of optimized antigen formulations (with higher 
antigen dose and lower host-cell protein content) is necessary to 
select a formulation to progress to Phase III evaluation. 
Therefore, the study design is revised as a Phase II study to 
determine progression to Phase III and selection of an optimized 
formulation for the Phase III. 
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Protocol Version 3.0, dated 04 February 2021 
The major protocol revisions and rationale for revisions from Version 2.0 to Version 3.0 are as 
shown below: 
Revision 
Rationale 
Data Safety Monitoring Board / 
Oversight Group / Protocol Safety 
Review Team text removed 
throughout 
As the funding structure for this study has changed, the common 
DSMB under the US government funded COVID-19 programs 
and the OG have been removed for the Phase II administrative 
structure. 
Table 6.1 (Identity of Study 
Interventions): 
 
Dose Formulation Row: Added: 
CoV2 preS dTM vaccine is a sterile, 
clear, colorless solution (with 
possible presence of endogenous 
particles) of SARS-CoV-2 prefusion 
S proteins for IM injection. 
Endogenous particles, if present, 
would be seen as light in color 
flocculates that are slow sinking and 
suspended in solution. 
New product appearance information received since previous 
protocol update. 
Any mention of “OWS” for 
Operation Warp Speed has been 
changed to “USG” for US 
Government 
Due to change in funding and administrative structure after shift 
from Phase III and II/III to Phase II as well as the new name 
provided to the US Government funded COVID-19 effort. 
Besides deletion of DSMB/PSRT 
text, revised text to state that the 
Sponsor may recommend a pause 
and determines 
continuation/adaptation of study 
design. 
Revisions due to decision made for administrative structure and 
safety monitoring after the study changed to Phase II. 
Section 9.3: 
Per-protocol analysis set bullet 
below revised: 
“Participant receives an 
authorized/approved COVID-19 
vaccine prior to D43 D36” 
Correction, as D36 is the key BL collection date. 
Section 9.4.2.1 / Section 9.4.2.3 : 
Biostats assessments revisions 
It is planned to maintain the standard format for safety reporting 
using proportion of participants rather than person-time as this is 
Phase II study. 
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Protocol Version 4.0, dated 08 April 2021 
The major protocol revisions and rationale for revisions from Version 3.0 to Version 4.0 are as 
shown below: 
Revision 
Rationale 
Major revision 
Section 8.2.1.2 (old) / Section 8.2.2.1 (new): 
The SARS-CoV-2 Neutralizing Antibody assay 
has been moved to a secondary immunogenicity 
assay. The only assay identified for the primary 
immunogenicity assay is the SARS-CoV-2 
Pseudovirus Neutralization assay.  
Safety, reactogenicity, and immunogenicity data 
from this Phase II study will be used to determine 
progression to a Phase III and inform dose 
selection. To clarify that neutralizing antibody 
responses to the D614 strain measured by the 
pseudovirus neutralization assay will be the 
primary immunogenicity data to support this 
decision making, one assay is designated as the 
primary immunogenicity assay. 
Section 8.3.2  
Added the following text: 
The start of the illness episode is the date of the 
first symptom onset corresponding to the COVID-
19-like-illness. The last date of the COVID-19-
like-illness is the last day of the last symptom 
provided that such date is followed by an 
asymptomatic period of at least 3 days; if 
symptoms reoccur earlier than the completion of 
the 3 day asymptomatic period, then the 
reoccurring symptoms are to be considered part of 
the same illness rather than a new illness. If 
symptoms reoccur after an asymptomatic period 
of at least 3 days, then those symptoms are to be 
considered a new COVID-19-like-illness.   
In the event of an illness with a positive NAAT 
for SARS-CoV-2, exacerbation/worsening of 
COVID-19-like-illness symptoms or occurrence 
of new symptoms during the ongoing illness will 
be considered part of the ongoing COVID-19 
illness episode and a new COVID-19-like-illness 
visit and subsequent schedule of events is 
generally discouraged although it may be 
triggered at the Investigator’s discretion.   
In the event of exacerbation/worsening of 
COVID-19-like-illness symptoms or occurrences 
of new symptoms during an ongoing COVID-19-
like-illness which is not associated with a positive 
NAAT for SARS-CoV-2 (missing or negative 
test), a new COVID-19-like-illness visit should be 
generally triggered if the new symptom or 
Revised text to clarify the onset of COVID-like-
illness and define schedule of events if ongoing. 
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exacerbation of symptom occurs more than 7 days 
from the onset of the initial COVID-19-like-
illness. In these cases, the onset of illness will 
correspond to the date of onset of the new 
symptom(s) or the date of the worsening of the 
pre-existing symptom(s).  
Section 8.4: Added the following halting rule: 
“Any other adverse event that, in the opinion of 
the Investigator, would expose participants to 
unreasonable risk of illness or injury.” 
Halting rule added per CBER non-hold comment. 
Minor revisions 
Primary and Secondary Immunogenicity 
Endpoints 
Added the following text for clarification  
Neutralizing antibody titers will be measured in SARS-
CoV-2-naïve participants for each study Intervention 
Group against the D614G variant.  
Added “D614G” to clarify in the primary and 
secondary immmunogenicty endpoints that the 
neutralizing antibody responses will be measured 
against the parental D614G strain. 
Synopsis: Overall Design / Table 4.1 
Countries: 
Changed “TBD” to “and Honduras” 
Added actual country study population which 
includes United States and Honduras. 
Table 1.1: Schedule of Activities: 
Added “End of phase participation record” row, 
with “X” in columns at D43 and D202 
End of phase D43 / End of Phase D202 added in 
the Schedule of Activities to be consistent with the 
planned interim locks. 
Table 2.2: Potential risks 
Anaphylactic reactions” row / “Risk 
management” column: 
“Observation period after vaccination for early 
detection and treatment. Risk management 
includes also exclusion criterion E06 E04 (see…” 
Administrative revision to correct the exclusion 
criterion number referenced. 
“Enhanced COVID-19” row / “Risk management” 
column: 
Added text and reference citation for Janssen: 
"Available data for mRNA COVID-19 vaccines 
(Moderna, Pfizer) and a COVID-19 vaccine based 
on viral vector (Janssen) do not indicate a risk of 
vaccine enhanced disease” 
Janssen vaccine has received authorization since 
the previous protocol version (protocol version 
3.0). Mention of Janssen product and literature 
reference added. 
Table 6.1: Identity of study interventions 
- 
Revised text for product appearance  
Text added/revised for clarity at the site level. 
Storage conditions clarified, in line with important 
information in the Investigator’s Brochure. 
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- 
Added protected from light for storage 
conditions 
Table 8.1: Samples collected per visit 
B-cell memory Flurospot row: deleted timepoints 
at D22 and D36 
Administrative revision to correct error. Timepoints 
now align with text in Section 8.2.3.2. 
Section 8.2.1.1 
SARS-CoV-2 Pseudovirus Neutralization Assay 
revised for new PhenoSense Assay text and to add 
text on assay timepoints and emergent variants. 
Updated test procedure due to change in laboratory 
for USG assay. 
Section 8.2.2.1 (old) / Section 8.2.3.4 (new): 
SARS-CoV-2 Virus Neutralization Assays (USG) 
section moved from secondary immunogenicity 
assay subsection (8.2.2.1) to exploratory 
immunogenicity assay subsection (8.2.3.4). 
Updated test scope due to change in assay strategy. 
Section 8.2.2.2 
Deleted “USG” from the title. 
Added text as below: 
SARS-CoV-2 binding antibodies will be 
measured using an electrochemiluminescence 
immunoassay (ECLIA) in all participants at all 
timepoints. 
Clarification that this assay will be performed in all 
participants at all timepoints. Updated that this 
assay will be undertaken at a laboratory that is not a 
USG laboratory. This assay transferred from the 
US Government designated laboratory. 
Section 8.2.3.4 (old): 
Section deleted and text added as part of 
Section 8.2.1.1 text. 
Deleted as separate section and added to 
Section 8.2.1.1 to be more precise on the testing 
plan.  Due to global spread of variants of concern, 
updated test scope to reflect increased importance 
of generating data in SARS-CoV-2 variants. 
Section 8.2.3.5: 
New “SARS-CoV-2 Pseudovirus Neutralization 
Assay” section added. 
Assays at Nexelis added as an exploratory endpoint 
as a backup to cover the eventuality of the 
Monogram PSV assay not being available 
Section 8.4: 
Halting Rules Bullet #1 (Death/SAE): split into 2 
separate bullets: one for Death and one for SAEs 
Added the following halting rule: 
“Any other adverse event that, in the opinion of 
the Investigator, would expose participants to 
unreasonable risk of illness or injury.” 
- 
First halting bullet split to distinguish for both 
situations. 
- 
Halting rule added per CBER non-hold 
comment. 
Section 8.4.5: 
Text revised for clarity. 
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Pregnancy Text updated for reporting of 
pregnancy period starting before period of 
contraception or abstinence and also as after 
period of contraception or abstinence. 
Section 9.2: 
Sample size determination text revised as below: 
“A sample size of 160 130 evaluable naïve 
participants per group enables detecting a 
minimum observed GMT ratio of 0.71 0.73 
assuming GMT ratio of 1 and standard deviation 
of 0.67 (estimated for the Pseudovirus assay) with 
95% probability.” 
Revised to clarify how the calculation is done with 
the number of evaluable participants emphasized 
and to provide a more accurate number from the 
calculation. 
Section 9.3 
Text on the analysis for population revised for 
clarification 
The following subgroup definitions of SARS-
CoV-2 Naïve and Non-Naïve at D01 or both D01 
and D22 timepoints participants are applied for all 
randomized participants. 
Revised to clarify that the for each analysis set, the 
following subgroups of naive and non-naive as 
defined by the table will be used in the analysis.   
Section 10.3.5.1.3 
COVID-19 symptoms (except for loss of taste and 
loss of smell) will be classified according to the 
following intensity scale, except for loss of taste, 
loss of smell, shortness of breath, where presence 
at rest or on exercise will be used for defining 
severity: 
Changes made to reflect that the usual Grading 
Scale (Grade 1/2/3) will be applied for “shortness 
of breath”. 
Section 10.3.5.1.3 
For sense of smell and sense of taste, the 
following grading will apply: 
• 
Grade 0  sense of smell/sense of taste is the 
same as usual 
• 
Grade 1 – sense of smell/sense of taste is less 
than usual 
Grade 2 – no sense of smell/sense of taste 
This line will not be completed by Investigators as 
participants will not notify them that they have the 
usual sense of smell/sense of taste. 
 
 
 
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Protocol Version 5.0, dated 10 June 2021 
The main reason for updating the protocol from Version 4.0 to Version 5.0 was to add 
Supplemental Phase III Cohorts for Booster Study 1. 
Revision 
Rationale 
The study design changed to add a 
Supplemental Phase III Cohorts 
(Booster Study 1)  
Booster Study 1 consists of Supplemental Phase III Cohorts and 
will test different formulations for specific variants and to 
develop a universal booster vaccine 
Phase change 
From Phase II to Phase II/III 
Study name changed to add 
Supplemental Phase III Cohorts 
The original Phase II in this protocol is now called “Original 
Phase II Cohort” 
The added study is called “Supplemental Phase III Cohorts” 
Titles changed to add Supplemental 
Phase III Cohorts 
Full title: “Immunogenicity and Safety of SARS-CoV-2 
Recombinant Protein Vaccines with AS03 Adjuvant in Adults 
18 Years of Age and Older as a Primary Series and 
Immunogenicity and Safety of a Booster Dose of SARS-CoV-2 
Adjuvanted Recombinant Protein Vaccines (two Monovalent 
and one Bivalent)” 
Brief title: “Study of Recombinant Protein Vaccines with 
Adjuvant as a Primary Series and as a Booster Dose against 
COVID-19 in Adults 18 Years of Age and Older” 
New formulations added for the 
Supplemental Phase III Cohorts  
These formulations have been added to the Phase III study: 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, 
monovalent D614 (CoV2 preS dTM-AS03 [D614]): monovalent 
vaccine with the Spike (S) protein sequence from the D614 
variant 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, 
monovalent B.1.351 (CoV2 preS dTM-AS03 [B.1.351]): 
monovalent vaccine with the S protein sequence from the 
B.1.351 variant 
SARS-CoV2 prefusion Spike delta TM, monovalent B.1.351 
(Monovalent [B.1.351]): monovalent vaccine with the S protein 
sequence from the B.1.351 variant 
SARS-CoV2 prefusion Spike delta TM with AS03 adjuvant, 
bivalent D614/B.1.351 (CoV2 preS dTM-AS03 [D614 + 
B.1.351]): bivalent vaccine with the S protein sequence from the 
D614 variant and the B.1.351 variant 
Study Design changed to add the 
Supplemental Phase III Cohorts 
• Supplemental Cohort 1: adults 18 years of age and older 
who were vaccinated 4 to < 10 months prior with an 
authorized/approved mRNA or adenovirus-vectored 
COVID-19 vaccine will be given Monovalent (D614) CoV2 
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preS dTM-AS03 (CoV2 preS dTM-AS03 [D614]) as a 
single booster injection.     
• Supplemental Cohort 2, Main Arms: adults 18 years of 
age and older who were vaccinated 4 to < 10 months prior 
with an authorized/approved mRNA or adenovirus-vectored 
COVID-19 vaccine, or who received the protein-based 
vaccine in the Original Phase II Cohort will be randomized 
to receive a single booster injection of one of the following: 
o Monovalent (B.1.351) CoV2 preS dTM-AS03 
(CoV2 preS dTM-AS03 [B.1.351]) 
o Bivalent (D614 + B.1.351) CoV2 preS dTM-AS03 
(CoV2 preS dTM-AS03 [D614 + B.1.351]) 
o CoV2 preS dTM-AS03 (D614)  
Note: Original Phase II Cohort participants will be 
randomized across all 3 vaccines, while participants who 
received authorized/approved mRNA or adenovirus-
vectored COVID-19 vaccines will be randomized across the 
B.1.351-containing vaccines only. 
• Supplemental Cohort 2 Exploratory B.1.351 Arms: in 
these arms, different antigen doses of CoV2 preS dTM, 
monovalent B.1.351 (Monovalent [B.1.351]) with and 
without adjuvants will be evaluated. Adults 18 years of age 
and older who received the Pfizer/BioNTech mRNA vaccine 
4 to < 10 months prior will be randomized to receive a 
single booster injection of one of the following Monovalent 
(B.1.351) formulations: 
o 2.5 µg antigen with AS03 adjuvant 
o 2.5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with half-dose AS03 adjuvant 
o 5 µg antigen with no adjuvant 
• Supplemental Cohorts 1 and 2 Comparator Group: 
SARS-CoV-2 naïve, unvaccinated, adults who are 18-55 
years of age will be given CoV2 preS dTM-AS03 (D614) as 
a primary series vaccination of 2 injections given 21 days 
apart.      
• Supplemental Variant Prime Cohort 3: SARS-CoV-
2naïve, unvaccinated, adults who are 18 years of age and 
older will be randomized to receive one of the following as a 
primary series vaccination of 2 injections given 21 days 
apart: 
o CoV2 preS dTM-AS03 (B.1.351) 
o CoV2 preS dTM-AS03 (D614 + B.1.351) 
o Monovalent (D614)AS03 (Comparator Group) 
• Supplemental Cohorts Subsets and Assessment of 
Immunogenicity to Emerging Variants of Concern: A 
randomized subset of 70 participants in Cohort 1 will be 
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tested for additional SARS-CoV-2 variants of concern. No 
additional sample collection, procedures, or visits are 
required for this subset. A randomized subset of 
112 participants in Cohort 2 and 87 participants in Cohort 3 
comprised of younger adults (18 to 55 years of age) will 
provide samples for cellular immune response and mucosal 
antibody assessments and will also be tested for additional 
variants of concern 
Objectives and Endpoints added for 
the Supplemental Phase III Cohorts 
All objectives and endpoints have been added as pertains to the 
Supplemental Phase III Cohorts (Booster Study 1) added to this 
protocol 
Schemas added for the Supplemental 
Phase III Cohorts 
Schemas added for the Supplemental Phase III Cohorts:  
• 
Figure 1.2 Booster arms for Supplemental Cohorts 1 
and 2  
• 
Figure 1.3: Supplemental Variant Prime Cohort 3 and 
Comparator Groups  
• 
Figure 1.4: Design for COVID-19-like illness follow-
up for the Original Series and all Supplemental Cohorts  
Schedule of Activities added for the 
Supplemental Phase III Cohorts 
Schedule of Activities tables added for the Supplemental Phase 
III Cohorts: 
• 
Table 1.2 presents the overall study SoA for the booster 
arms of Supplemental Cohorts 1 and 2. 
• 
Table 1.3 presents the overall study SoA for 
Supplemental Variant Prime Cohort 3 and both 
Comparator Group arms.  
• 
Table 1.4 presents the SoA for the follow-up of 
COVID-19like illness for the Original Phase II Cohort 
and Supplemental Cohorts. 
Section 2 Introduction:  
Section 2.1 Rationale / Section 2.2 
Background / Section 2.3 
Benefit/Risk Assessment 
Section 4 Study Design: 
Section 4.2 Scientific Rationale for 
Study Design / Section 4.3 
Justification for Dose and Dosing 
Schedules  
Text added: information on SARS-CoV-2 variants, Phase II 
interim analysis results, justification for dosing in the 
Supplemental Phase III Cohorts, updated literature information 
regarding evolving understanding of SARS-CoV-2 informing 
the Phase III trial design 
Section 4 Study Design: 
Section 4.1.2 Intervention Groups 
and Duration for Supplemental 
Cohorts 
Subsections added for Intervention Groups and Duration 
for Supplemental Phase III Cohorts: Cohorts 1, 2 and 3 
arms, participant numbers, duration of study involvement 
 
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Section 5 Study Population: 
Section 5.1 Inclusion Criteria / 
Section 5.2 Exclusion Criteria 
Inclusion criteria, exclusion criteria updated to add list items for 
Supplemental Phase III Cohorts 
Section 6 Study Intervention 
(through entire section)  
Subsection 6.1.2 Supplemental 
Phase III Cohorts Study 
Interventions  
Text added throughout to add the information for the 
Supplemental Phase III Cohort study interventions  
Subsection 6.1.2 added to include tables of all study 
formulations for the Supplemental Phase III Cohorts 
Section 7 Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal /  
Section 8 Study Assessments and 
Procedures 
Text added throughout each section specific to the additional  
Supplemental Phase III Cohorts 
Section 9 Statistical Considerations 
(through entire section)  
Subsection 9.1.2 / Subsection 9.1.3 / 
Subsection 9.2.2 / Subsection 9.2.3 / 
Text added throughout to add the statistics information for the 
Supplemental Phase III Cohorts  
Subsections added to include statistical considerations specific 
to the Supplemental Phase III Cohorts 
Section 9.5 Interim Analyses 
Text added for interim analyses specific to the Supplemental 
Phase III Cohorts 
Section 10 Supporting 
Documentation and Operational 
Considerations 
Section 11 References 
Text added throughout each section specific to the additional  
Supplemental Phase III Cohorts 
References updated for additional references 
 
 
 
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Protocol Version 7.0, dated 31 August 2021 
Protocol updated from Version 5.0 to Version 6.0 to add conditional co-primary objectives for 
Supplemental Cohort 1 and relevant nonclinical non-human primate (NHP) study results. Version 
6.0 was not submitted to Health Authorities. The protocol was updated from Version 6.0 to 
Version 7.0 with minor changes to inclusion and exclusion criteria.  
Revision 
Rationale 
Throughout: 
Shortened names of vaccine candidates changed: 
• 
CoV2 preS dTM-AS03 (D614) 
• 
CoV2 preS dTM-AS03 (B.1.351) 
• 
CoV2 preS dTM-AS03 (D614 + B.1.351) 
Changed to align with study intervention 
naming conventions across all documents in the 
program. 
Throughout: 
Greek letter names for the virus variants have been 
added, ie Alpha (B.1.1.7), Beta (B.1.351), Delta 
(B.1.617) 
In early June 2021, the World Health 
Organization issued new naming conventions 
for each SARS-CoV-2 virus variant. Variants 
will now be named by Greek alphabet letters; 
protocol updated to reflect this change. 
Synopsis: Rationale / Section 2.2 / Section 4.2: 
Added text “the virus has been detected in 192 
countries/regions and led to significant morbidity, 
mortality, and economic impact”  
Text added to replace pandemic scope text in 
previous versions. 
Synopsis: Rationale / Section 2.2: 
Nonclinical studies text added for monovalent and 
bivalent vaccine data. 
Additional data added at time of this protocol 
update, in line with text in the Investigator’s 
Brochure update. 
Objectives and Endpoints table in Synopsis Rationale 
and Section 3: 
Objectives added for Supplemental Cohort 1: 
“Conditional Co-Primary Objectives: Conditional on 
meeting the primary objectives for Supplemental 
Cohort 1:” 
#1: “To demonstrate, in adults 18-55 years of age 
previously vaccinated with an adenovirus-vectored 
COVID-19 vaccine, that a booster dose of CoV2 
preS dTM-AS03 (D614) vaccine induces an 
immune response  that is non-inferior to the 
response induced by a two‑dose priming series 
with CoV2 preS dTM-AS03 (D614) vaccine in 
naïve, previously unvaccinated, individuals.”  
#2: “To demonstrate, in adults 18-55 years of age 
previously vaccinated with adenovirus-vectored 
COVID-19 vaccines, that a booster dose of CoV2 
preS dTM-AS03 (D614) induces an immune 
response that is superior to that observed 
immediately before booster.” 
Additional objectives for Supplemental Cohort 
1 added to further assess the immune response 
of a booster dose of CoV2 preS dTM-AS03 
(D614) vaccine in participants previously 
vaccinated with adenovirus-vectored COVID-19 
vaccines. 
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Objectives and Endpoints table in Synopsis Rationale 
and Section 3: 
Objective and corresponding endpoint text added for 
Supplemental Cohort 2: 
“Conditional Secondary Objective: Conditional on 
meeting the Primary Immunogenicity Objectives and 
the Co-Secondary Objectives for Supplemental Cohort 
2:” 
#1: “To demonstrate in adults 18-55 years of age and 
previously vaccinated with the Pfizer/BioNTech 
mRNA COVID-19 vaccine, that a booster dose of 
CoV2 preS dTM-AS03 (B.1.351) or CoV2 preS 
dTM-AS03 (D614 + B.1.351) induces an immune 
response against the B.1.351 variant at D15 that is 
superior to that against the B.1.351 variant at D36 
in the Comparator Group.” 
 
#15: “To describe, in adults over 55 years of age, the 
neutralizing antibody profile to the B.1.351 variant 
and to the D614G strain at D01 and D15 by 
Intervention Group, overall, by priming platform, 
and by priming vaccine.” 
Additional objectives for Supplemental Cohort 
2 added to further assess the immune response 
of a booster dose of CoV2 preS dTM-AS03 
(B.1.351) or CoV2 preS dTM-AS03 (D614 + 
B.1.351) against the B.1.351 variant.  
Throughout document, at all mentions of Supplemental 
Cohort subsets, modified participant numbers for 
Cohort 3 subset to 87 participants (previously 88).  
Changed to clarify number of participants in the 
subset. 
Figure 1.4 / Table 1.4 / Section 8.3.2 
Pulse oximeter text updated to explain participants will 
receive it at the CLI01 visit rather than enrollment 
Changed to clarify when participants will 
receive their pulse oximeter. 
Table 6.1 / Table 6.2 / Table 6.3 / Table 6.4 
Dose formulation text updated 
Text updated for clarity. 
Section 6.2: 
List item #3 text added “…either monovalent or 
bivalent antigen…”  
Text added to clarify both monovalent and 
bivalent antigens are included. 
Section 5.1 Inclusion Criteria:  
Text modified : 
“I02: Is of childbearing potential and agrees to use an 
effective contraceptive method or abstinence from at 
least 4 weeks prior to the first vaccination until at least 
12 weeks after the second last vaccination (ie, second 
dose of primary series or booster injection).” 
Text modified to be applicable to both primary 
series and booster vaccination.  
Section 5.2 Exclusion Criteria: 
Text modified: 
“E12:  Receipt of immunoglobulinsa, blood, or blood-
derived products in the past 3 months” 
Footnote added for clarity regarding 
investigational monoclonal antibodies. 
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Footnote added: “Including investigational monoclonal 
antibodies.” 
Table 8.1 / Section 8.2.3.4 
Removed text for SARS-CoV-2 Virus Neutralization 
Assays 
Text removed as assay will not be done. 
Section 9 
Statistics text added/modified throughout the section 
corresponding to the updates in the Objectives and 
Endpoints table. 
 
 
 
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Protocol Version 8.0, dated 12 October 2021 
The major protocol revisions and rationale for revisions from Version 7.0 to Version 8.0 are as 
shown below: 
Revision 
Rationale 
Throughout:  
For protein-primed dosing groups only: 
• 
Participants who were primed with the 
protein-based vaccine candidate in the 
Original Phase II Cohort will receive one 
of the 2 monovalent booster formulations 
and will not receive a booster dose of the 
bivalent vaccine candidate CoV2 preS 
dTM-AS03 (D614 + B.1.351). 
• 
Added hypothesis testing of monovalent 
D614 booster responses. 
• 
Added descriptive analyses for 
monovalent Beta variant responses. 
• 
Changed to 9:1 enrollment allocation in 
younger adults (D614:Beta), and 1:1 for 
older adults. 
To more fully characterize the response of CoV2 preS 
dTM-AS03-primed individuals to a homologous 
booster, and thereby address the requirement for pre-
specified testing of homologous booster responses, the 
protocol has been modified to generate data to support 
a homologous prime boost vaccination with our 
recombinant vaccine platform.  
Eligible CoV2 preS dTM-AS03-primed individuals 
from the Original Phase II Cohort will be randomly 
assigned in Supplemental Cohort 2 to receive a 
booster dose of one of the two monovalent booster 
formulations (CoV2 preS dTM-AS03 [D614]) OR 
CoV2 preS dTM-AS03 [B.1.351]). The bivalent 
booster formulation will not be evaluated. 
Randomization will be weighted in the 18 to 55 year-
old age stratum to ensure adequate power to perform 
hypothesis testing for the D614 (parental) strain 
booster formulation. The booster response overall 
following any priming dose will be assessed. The 
hypothesis will be specified as for the other powered 
arms in Cohort 2. Responses to the B.1.351 variant 
booster formulation will be descriptively analyzed. 
Throughout: 
Seroresponse to be included as conditional 
secondary endpoint for powered comparisons 
Owing to uncertainties of the interpretation of titre 
values and of a 4-fold rise in the setting of pre-
existing antibody responses, hypothesis testing to 
evaluate 4-fold seroresponse will be performed as a 
secondary endpoint. 
Throughout: 
AESIs: include myocarditis and pericarditis 
To address CBER request 
Throughout: 
Specify that Delta variant is to be evaluated 
To address CBER request 
Section 9.1 Statistical Hypotheses 
New subsection added: Section 9.1.2.1 A Pooled 
Primary Series Cohort as Supplemental Cohorts 
1 and 2 Comparator Group 
Section added to address the possibility of a pooled 
primary series cohort with a sample size of at least 
515 evaluable SARS-CoV-2 naïve participants could 
be planned to serve as the Comparator Group for 
Supplemental Cohorts 1 and 2. 
 
 
 
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Protocol Version 9.0, dated 12 November 2021 
The major protocol revisions and rationale for revisions from Version 8.0 to Version 9.0 are as 
shown below: 
Revision 
Rationale 
Throughout: 
Removed bivalent vaccine candidate arm from Variant 
Prime Cohort 3  
1) Operational feasibility of recruiting SARS-
CoV-2 naive, unvaccinated participants has 
become significantly more challenging 
2) Initiation of other studies to support 
evaluation of the bivalent vaccine 
Throughout: 
• Participant numbers change in remaining 2 main 
monovalent arms as follows: 
o 
Monovalent (B.1.351), 18-55 years of age: 239 
participants (was 294) 
o 
Monovalent (D614), 18-55 years of age: 239 
participants (was 294) 
• Participant numbers change in monovalent arms for 
variant testing CMI/Mucosal subset groups as 
follows: 
o 
Monovalent (B.1.351), 18-55 years of age: 24 
participants (was 29) 
o 
Monovalent (D614), 18-55 years of age: 24 
participants (was 29) 
• Total participant numbers change in remaining 2 
monovalent arms (main + subset) as follows: 
o 
Monovalent (B.1.351), 18-55 years of age: 289 
participants (was 344) 
o 
Monovalent (D614), 18-55 years of age: 289 
participants (was 344) 
Recalculation of required sample size due to 
removal of bivalent vaccine arm from Variant 
Prime Cohort 3. 
Throughout:  
Total participant numbers changed to 4238 (was 4692) 
Total changed due to no bivalent arm in Variant 
Prime Cohort 3 and participant numbers change 
in remaining monovalent arms. 
Section 6.1.2, Table 6.4, removed bivalent vaccine 
candidate formulation 
Bivalent formulation no longer tested in Variant 
Prime Cohort 3. 
Section 8.3.1 Definitions; under COVID-19-like 
illness, in the definition for “Fever” temperature 
measurement, symbol changed as follows: 
Previous text: 
• Fever (measured temperature > 100.4ºF OR 
38.0ºC) 
Revised text: 
• Fever (measured temperature ≥ 100.4ºF OR ≥ 
38.0ºC) 
Revised to “≥” to align with measurement used 
in the Case Report Forms and intensity grading 
scales 
Sections 9.1.3 and 9.2.3 Variant Prime Cohort 3 
statistical analysis updated 
Statistical analysis sections for Variant Prime 
Cohort 3 updated to remove bivalent vaccine 
candidate arm. 
 
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