A Randomized, Observer-Blind, Controlled Study to Assess the Safety, Immunogenicity and Efficacy of the SARS-CoV-2 Self- Amplifying RNA Vaccine ARCT-154 in Adults
Phase: PHASE2
Conditions: COVID-19 Vaccines
Sponsor: Vinbiocare Biotechnology Joint Stock Company

Clinical Study Protocol 
ARCT-154 
Protocol ARCT-154-01 
 
Version 9.0, 07 February 2022 
COVID-19 
 
Confidential 
 
1 
A Randomized, Observer-Blind, Controlled Study to Assess 
the Safety, Immunogenicity and Efficacy of the SARS-CoV-2 
Self-Amplifying RNA Vaccine ARCT-154 in Adults 
 
 
PROTOCOL NO. ARCT-154-01 
Sponsor: 
Vinbiocare Biotechnology Joint Stock Company  
Techno Park building, Vinhomes Ocean Park Residential Area, Da 
Ton ward, Gia Lam District,  
Hanoi, Vietnam 
Version of Protocol: 
9.0 
Date of Protocol: 
07 February 2022 
Previous Version: 
8.0 
Investigational Product(s): 
ARCT-154 
Study Phase: 
1/2/3 
 
Confidentiality Statement 
All financial and nonfinancial support for this study will be provided by Vinbiocare 
Biotechnology Joint Stock Company (the Sponsor). This document contains information that is 
confidential, proprietary, and/or under the control of the Sponsor. The information is only to be 
used in connection with authorized clinical studies of the investigational drug described in the 
protocol provided herewith. You may disclose the contents of this document while acting in the 
capacity of an investigator, potential investigator, or consultant to study personnel under your 
supervision and/or to an applicable Institutional Review Board or Independent Ethics Committee 
who need to know the contents for the aforementioned purpose and who have been advised of 
the confidential nature of the document. You may not disclose any of the information to others 
without written authorization from the Sponsor except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 

Clinical Study Protocol 
ARCT-154 
Protocol ARCT-154-01 
 
Version 9.0, 07 February 2022 
COVID-19 
 
Confidential 
 
2 
SPONSOR’S APPROVAL 
Title 
A Randomized, Observer-Blind, Controlled Study to Assess the Safety, 
Immunogenicity and Efficacy of the SARS-CoV-2 Self-Amplifying RNA Vaccine 
ARCT-154 in Adults 
The ARCT-154 Self-Amplifying RNA Vaccine Study 
Protocol Number 
ARCT-154-01 
Version Number 
9.0 
Version Date 
07 February 2022 
Amendment 
Amendment 8 
 
The design of this study as outlined by this protocol has been reviewed and approved by the 
Sponsor’s responsible personnel. 
 
Protocol accepted and approved on behalf of Sponsor by: 
 
 
 
 
Signature 
 
Date 
 
 
 
Name 
 
Title 
VINBIOCARE BIOTECHNOLOGY JOINT STOCK COMPANY 
Techno Park building, Vinhomes Ocean Park Residential Area, Da Ton ward, Gia Lam 
District,  
Hanoi, Vietnam 
Institution 
 
 
 

Clinical Study Protocol 
ARCT-154 
Protocol ARCT-154-01 
 
Version 9.0, 07 February 2022 
COVID-19 
 
Confidential 
 
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TABLE OF CONTENTS 
SPONSOR’S APPROVAL ............................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................... 3 
LIST OF TABLES ......................................................................................................................... 9 
LIST OF FIGURES ..................................................................................................................... 10 
LIST OF APPENDICES .............................................................................................................. 10 
LIST OF ABBREVIATIONS ...................................................................................................... 11 
1 
SYNOPSIS ....................................................................................................................... 13 
1.1 
Study Schematic............................................................................................................ 36 
2 
INTRODUCTION ........................................................................................................... 38 
2.1 
Background ................................................................................................................... 38 
2.2 
Current Therapies for COVID-19 ................................................................................. 38 
2.3 
Therapeutic Rationale for ARCT-154 in Prevention of COVID-19 ............................. 39 
2.4 
Mechanism of Action .................................................................................................... 40 
2.5 
Nonclinical Experience with ARCT-154 ...................................................................... 41 
2.6 
Clinical Trial Experience with the LUNAR COVID-19 Vaccines (ARCT-021 
and ARCT-154) ............................................................................................................ 42 
2.7 
Rationale for Dose Regimen Selection ......................................................................... 44 
2.8 
Risk: Benefit Assessment ............................................................................................. 44 
2.8.1 
Potential Risks ........................................................................................................... 44 
2.8.2 
Potential Benefits ....................................................................................................... 46 
2.8.3 
Overall Risk: Benefit Assessment ............................................................................. 46 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 47 
3.1 
Phase 1/2/3a Substudy .................................................................................................. 47 
3.1.1 
Phase 1/2/3a Substudy Primary Objectives and Endpoints ....................................... 47 
3.1.2 
Phase 1/2/3a Substudy Secondary Objectives and Endpoints ................................... 49 
3.1.3 
Phase 1/2/3a Substudy Exploratory Objectives and Endpoints ................................. 49 
3.2 
Phase 3b ........................................................................................................................ 52 
3.2.1 
Phase 3b Primary Objectives and Endpoints ............................................................. 52 
3.2.2 
Phase 3b Secondary Objectives and Endpoints ......................................................... 52 
3.2.3 
Phase 3b Exploratory Objectives and Endpoints ....................................................... 53 

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3.3 
Phase 3c Substudy......................................................................................................... 54 
3.3.1 
Phase 3c Substudy Primary Objectives and Endpoints.............................................. 54 
3.3.2 
Phase 3c Substudy Secondary Objectives and Endpoints.......................................... 55 
3.3.3 
Phase 3c Substudy Exploratory Objectives and Endpoints ....................................... 57 
3.4 
Pooled Objectives and Endpoints ................................................................................. 59 
3.4.1 
Pooled Primary Objectives and Endpoints ................................................................ 59 
3.4.2 
Pooled Secondary Objectives and Endpoints ............................................................ 60 
3.4.3 
Pooled Exploratory Objectives and Endpoints .......................................................... 60 
4 
INVESTIGATIONAL PLAN .......................................................................................... 62 
4.1 
Number of Participants ................................................................................................. 62 
4.2 
Number of Sites ............................................................................................................ 62 
4.3 
Duration of Participation............................................................................................... 62 
4.4 
Study Design ................................................................................................................. 62 
4.5 
Study Assessments and Procedures .............................................................................. 66 
4.5.1 
Informed Consent....................................................................................................... 66 
4.5.2 
Randomization and Enrollment ................................................................................. 66 
4.5.3 
Visits .......................................................................................................................... 67 
 
Screening Visit (Up to 10 days prior to Day 1) ...................................................... 69 
 
Vaccine Dose Administration Visits ....................................................................... 69 
 
Follow-up Visit on Day 8 and 36 (Phase 1 only).................................................... 71 
 
Follow-up Visit on Day 57 ..................................................................................... 71 
 
Follow-up Visit on Day 211 (Phase 3c-1 only) ...................................................... 71 
 
Weekly and Monthly Study Calls ........................................................................... 71 
 
Unscheduled Visits ................................................................................................. 72 
 
Final Visit/Early Termination Visit ........................................................................ 74 
4.5.4 
End of Study .............................................................................................................. 74 
4.5.5 
Additional Procedural Specifics ................................................................................ 74 
 
Diary Use to Collect Solicited Adverse Events ...................................................... 74 
 
Collection of Unsolicited Adverse Events and COVID-19 
Exposure/Symptoms ............................................................................................... 75 
 
Blood and SARS-CoV-2 Sampling ........................................................................ 75 
 
Telephone Calls ...................................................................................................... 78 

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Physical Examinations ............................................................................................ 79 
 
Height and Weight .................................................................................................. 79 
 
Vital Signs, Body Temperature, and Pulse Oximetry ............................................. 79 
 
Pregnancy Testing ................................................................................................... 79 
 
Medical History ...................................................................................................... 80 
5 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA ............................... 81 
5.1 
Selection of Study Participants ..................................................................................... 81 
5.1.1 
Inclusion Criteria ....................................................................................................... 81 
5.1.2 
Exclusion Criteria ...................................................................................................... 81 
5.1.3 
Determination of “At Risk” of Severe COVID-19 .................................................... 83 
5.1.4 
Screen Failures ........................................................................................................... 84 
5.1.5 
Switchover/Further Study Vaccine Eligibility Criteria.............................................. 84 
5.2 
Delaying or Discontinuing Study Vaccination and Participant Withdrawal From 
the Study ....................................................................................................................... 85 
5.2.1 
Delay in Study Vaccination ....................................................................................... 85 
5.2.2 
Discontinuation of Study Vaccine (Participant) ........................................................ 86 
5.2.3 
Withdrawal/Discontinuation from the Study ............................................................. 86 
5.2.4 
Discontinuation of Study Dosing (Study-wide) ......................................................... 88 
5.3 
Lost to Follow-Up ......................................................................................................... 88 
5.4 
Replacement of Participants ......................................................................................... 88 
6 
STUDY TREATMENTS ................................................................................................. 89 
6.1 
Method of Assigning Participants to Study Groups ..................................................... 89 
6.2 
Study Vaccine Manufacturer ........................................................................................ 89 
6.3 
Study Vaccine, Dosage, and Route of Administration ................................................. 89 
6.4 
Management of Clinical Supplies ................................................................................. 90 
6.4.1 
Investigational Product Packaging and Storage ......................................................... 90 
6.4.2 
Clinical Supplies for Reconstitution and Administration of Study Vaccine ............. 91 
6.4.3 
Study Vaccine Accountability ................................................................................... 91 
6.4.4 
Other Supplies for Participant Use ............................................................................ 91 
6.5 
Overdose Management ................................................................................................. 91 
6.6 
Blinding......................................................................................................................... 92 
6.6.1 
Breaking the Blind ..................................................................................................... 93 

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6.7 
Compliance With Study Treatment .............................................................................. 93 
6.8 
Concomitant Therapies and Procedures ........................................................................ 93 
6.8.1 
Concomitant Therapy................................................................................................. 93 
 
Concomitant Procedures ......................................................................................... 94 
6.9 
Dose Modification ........................................................................................................ 94 
6.10 
Intervention After the End of the Study ........................................................................ 94 
7 
STUDY ASSESSMENTS ............................................................................................... 95 
7.1 
Efficacy Assessments.................................................................................................... 95 
7.1.1 
Evaluation of Participants With Suspected COVID-19 ............................................. 95 
 
Severe COVID-19 ................................................................................................... 95 
 
Asymptomatic COVID-19 ...................................................................................... 96 
 
Atypical COVID-19 ................................................................................................ 96 
 
Death Attributed to COVID-19 .............................................................................. 96 
7.2 
Immunogenicity Assessments ....................................................................................... 96 
7.3 
Reactogenicity............................................................................................................... 99 
7.4 
Safety Assessments ....................................................................................................... 99 
7.4.1 
Adverse Events .......................................................................................................... 99 
 
Definitions............................................................................................................... 99 
 
Eliciting and Documenting Adverse Events ......................................................... 102 
 
Reporting Adverse Events .................................................................................... 104 
7.4.2 
Physical Examinations ............................................................................................. 106 
7.4.3 
Vital Signs, Body Temperature, and Pulse Oximetry .............................................. 106 
7.5 
Pregnancy .................................................................................................................... 106 
8 
STATISTICAL CONSIDERATIONS........................................................................... 108 
8.1 
Overall Endpoint Testing Strategy.............................................................................. 108 
8.2 
Analysis Sets ............................................................................................................... 109 
8.3 
Statistical Considerations for Phase 3 ......................................................................... 111 
8.3.1 
Estimands and Intercurrent Events for Phase 1/2/3a, Phase 3b and Phase 3c ......... 113 
8.4 
Statistical Hypothesis .................................................................................................. 118 
8.4.1 
Phase 1/2/3a Substudy Statistical Hypothesis.......................................................... 118 
8.4.2 
Phase 3b Statistical Hypothesis ............................................................................... 118 

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8.4.3 
Phase 3c Substudy Statistical Hypotheses ............................................................... 119 
8.4.4 
Pooled Analyses Statistical Hypotheses .................................................................. 120 
8.5 
Sample Size Determination......................................................................................... 120 
8.5.1 
Sample Size for Phase 1/2/3a Substudy ................................................................... 120 
8.5.2 
Sample Size for Phase 3b ......................................................................................... 120 
8.5.3 
Sample Size for Phase 3c Substudy ......................................................................... 121 
8.6 
Description of Additional Subgroups to Be Analyzed ............................................... 121 
8.7 
Statistical Analysis Methodology ............................................................................... 122 
8.7.1 
General Considerations ............................................................................................ 122 
 
General Considerations for Phase 1/2/3a Substudy .............................................. 122 
 
General Considerations for Phase 3b .................................................................... 122 
 
General Considerations for Phase 3c Substudy .................................................... 123 
8.7.2 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity 
Analyses ................................................................................................................... 123 
8.7.3 
Analysis of Primary Endpoints for Phase 1/2/3a, Phase 3b and Phase 3c ............... 128 
 
Main Estimation of Primary Immunogenicity Endpoint for Phase 1/2/3a 
Substudy (Estimand 1) .......................................................................................... 128 
 
Main Estimation of Primary Safety Endpoint for Phase 1/2/3a, 3b, and 3c 
(Estimand 3 & 4)................................................................................................... 129 
 
Supportive Analysis of Primary Safety Endpoints for Phase 1/2/3a, 3b, and 
3c (Estimand 3 & 4) .............................................................................................. 129 
 
Main Estimation of Phase 3b Primary Efficacy Endpoint (Estimand 2) .............. 129 
8.7.4 
Analysis of Secondary Endpoints for Phase 1/2/3a, Phase 3b and Phase 3c ........... 130 
 
Main Estimation of Secondary Immunogenicity Endpoints for Phase 1/2/3a 
and Phase 3c Substudies ....................................................................................... 130 
 
Main Estimation of Secondary Efficacy Endpoints for Phase 3b ......................... 130 
8.7.5 
Analysis of Pooled Efficacy and Safety Endpoints ................................................. 130 
8.7.6 
Analyses of Other Exploratory Endpoints ............................................................... 130 
8.7.7 
Other Analyses ......................................................................................................... 130 
8.7.8 
Analyses of Immunogenicity, Safety and Efficacy Data Post Day 92 (Phase 
1//2/3a, Phase 3b and Pooled Cohorts) .................................................................... 130 
8.8 
Handling of Missing Data ........................................................................................... 131 
8.9 
Primary and Interim Analyses Timepoints ................................................................. 131 

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8.9.1 
Phase 1/2/3a Substudy ............................................................................................. 131 
8.9.2 
Phase 3b ................................................................................................................... 131 
8.9.3 
Phase 3c Substudy.................................................................................................... 131 
8.10 
Monitoring Committees .............................................................................................. 132 
8.10.1 
Blinded Safety Review Committee .......................................................................... 132 
8.10.2 
Blinded Independent Adjudication Committee ....................................................... 132 
8.10.3 
Unblinded Independent Data and Safety Monitoring Board ................................... 132 
9 
DATA QUALITY ASSURANCE ................................................................................. 133 
9.1 
Data Management ....................................................................................................... 133 
9.2 
Data Disclosure ........................................................................................................... 133 
10 
ETHICS.......................................................................................................................... 134 
10.1 
Independent Ethics Committee or Institutional Review Board .................................. 134 
10.2 
Ethical Conduct of the Study ...................................................................................... 134 
10.3 
Participant Information and Consent .......................................................................... 134 
11 
INVESTIGATOR’S OBLIGATIONS ........................................................................... 136 
11.1 
Confidentiality ............................................................................................................ 136 
11.2 
Data Protection............................................................................................................ 136 
11.3 
Financial Disclosure and Obligations ......................................................................... 137 
11.4 
Investigator Documentation ........................................................................................ 137 
11.5 
Study Conduct ............................................................................................................. 137 
11.6 
Adverse Events and Study Report Requirements ....................................................... 137 
11.7 
Investigator’s Final Report ......................................................................................... 137 
11.8 
Records Retention ....................................................................................................... 137 
12 
STUDY MANAGEMENT ............................................................................................ 138 
12.1 
Monitoring .................................................................................................................. 138 
12.1.1 
Monitoring of the Study ........................................................................................... 138 
12.1.2 
Inspection of Records .............................................................................................. 138 
12.2 
Management of Protocol Amendments and Deviations ............................................. 138 
12.2.1 
Modification of the Protocol .................................................................................... 138 
12.2.2 
Protocol Deviations .................................................................................................. 138 
12.3 
Study Termination ...................................................................................................... 139 

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12.4 
Final Report ................................................................................................................ 139 
13 
REFERENCES .............................................................................................................. 140 
14 
APPENDICES ............................................................................................................... 148 
Protocol Amendment 1 (Version 2.0, 27 July 2021): Summary of Major Changes .................. 172 
Protocol Amendment 2 (Version 3.0, 01 August 2021): Summary of Major Changes ............. 174 
Protocol Amendment 3 (Version 4.0, 09 August 2021): Summary of Major Changes ............. 177 
Protocol Amendment 4 (Version 5.0, 24 August 2021): Summary of Major Changes ............. 179 
Protocol Amendment 5 (Version 6.0, 28 October 2021): Summary of Major Changes ........... 181 
Protocol Amendment 5 (Version 6.0, 28 October 2021): Summary of Major Changes ........... 183 
Protocol Amendment 6 (Version 7.0, 28 October 2021): Summary of Major Changes ........... 185 
Protocol Amendment 7 (Version 8.0, 14 December 2021): Summary of Major Changes ........ 187 
Protocol Amendment 8 (Version 9.0, XX February 2022): Summary of Major Changes ........ 191 
 
LIST OF TABLES 
Table 1 
Risk Minimization Measures Included in Clinical Trials of LUNAR 
COVID-19 Vaccines ............................................................................................ 45 
Table 2 
Phase 1/2/3a Substudy Primary Objectives and Endpoints ................................. 48 
Table 3 
Phase 1/2/3a Secondary Objectives and Endpoints ............................................. 49 
Table 4 
Phase 1/2/3a Exploratory Objectives and Endpoints ........................................... 50 
Table 5 
Phase 3b Primary Objectives and Endpoints ....................................................... 52 
Table 6 
Phase 3b Secondary Objectives and Endpoints ................................................... 52 
Table 7 
Phase 3b Exploratory Objectives and Endpoints ................................................. 53 
Table 8 
Phase 3c Substudy Primary Objectives and Endpoints........................................ 55 
Table 9 
Phase 3c Substudy Secondary Objectives and Endpoints.................................... 55 
Table 10 
Phase 3c Substudy Exploratory Objectives and Endpoints ................................. 57 
Table 11 
Pooled Primary Objectives and Endpoints .......................................................... 59 
Table 12 
Pooled Secondary Objectives and Endpoints ...................................................... 60 
Table 13 
Pooled Exploratory Objectives and Endpoints .................................................... 60 
Table 14 
Intercurrent Event Types.................................................................................... 113 
Table 15 
Estimands for Phase 1/2/3a Substudy and Phase 3c Substudy Primary, 
Secondary and Exploratory Immunogenicity Endpoints ................................... 113 
Table 16 
Estimands for Primary, Secondary and Exploratory Efficacy Analyses ........... 115 

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Table 17 
Estimands for Primary Safety Analyses for Phase 1/2/3a, Phase 3b, Phase 
3c and Pooled Cohorts ....................................................................................... 116 
Table 18 
Summary of Statistical Methods, Including Sensitivity Analyses ..................... 124 
Table 19 
Toxicity Grading for Solicited Adverse Events ................................................. 168 
 
LIST OF FIGURES 
Figure 1 
Study Schematic................................................................................................... 37 
Figure 2 
sVNT Antibody Responses to ARCT-154 in Non-Human Primates ................... 41 
Figure 3 
Pseudoneutralization Data from NHPs After Two Doses of ARCT-154 
Vaccine ................................................................................................................ 42 
 
LIST OF APPENDICES 
Appendix 1: 
Schedule of Assessments ................................................................................... 149 
Appendix 2: 
Case Definitions of COVID-19 ......................................................................... 161 
Appendix 3: 
Contraceptive Guidance ..................................................................................... 165 
Appendix 4: 
Toxicity Grading Scales ..................................................................................... 168 
Appendix 5: 
At-risk Medical Conditions................................................................................ 170 
Appendix 6: 
Protocol Amendments ........................................................................................ 172 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
antibody 
AC 
Adjudication Committee 
ACE-2 
angiotensin-converting enzyme 2 
AE 
adverse event 
AESI 
adverse event of special interest 
ARDS 
acute respiratory distress syndrome 
ART 
antiretroviral therapy 
BAb 
binding antibody 
ChAdOx1 
Astra Zeneca COVID_19 vaccine ChAdOx1 nCoV-19 used as comparator 
for Phase 3c 
CFR 
US Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendment 
COVID-19 
Coronavirus disease 2019 
CRO 
clinical research organization 
CSR 
clinical study report 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOS 
end of study 
ET 
early termination 
FDA 
US Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCP 
healthcare provider 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IAS 
immunogenicity analysis set 
IB 
Investigator’s Brochure 
IcEv 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICS 
intracellular cytokine staining 
IEC 
Independent Ethics Committee 
IM 
intramuscular 

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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ISO 
International Organization for Standardization 
LNP 
lipid nanoparticle 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 
mITT 
modified intent-to-treat 
mRNA 
messenger ribonucleic acid 
MOH 
Ministry of Health 
NAAT 
nucleic acid amplification–based test 
NAb 
neutralizing antibody 
NHP 
non-human primate 
nsP 
nonstructural protein 
PCR 
polymerase chain reaction 
PP 
per protocol 
PRNT50 
plaque reduction neutralization test at 50% reduction 
RAS 
reactogenicity analysis set 
RBD 
receptor binding domain 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcriptase-polymerase chain reaction 
S glycoprotein 
spike glycoprotein 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAS 
safety analysis set 
S.C 
subcutaneous 
SC154 
proportion of ARCT-154 participants that seroconvert 
SCChAdOx1 
proportion of ChAdOx1participants that seroconvert 
SCPlacebo 
proportion of placebo participants that seroconvert 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
sVNT 
surrogate virus neutralization 
Tfh 
T follicular helper 
VAERD 
vaccine-associated enhanced respiratory disease 
VE 
vaccine efficacy 
VOC 
variants of concern 
VSV 
vesicular stomatitis virus 
WHO 
World Health Organization 

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1 
SYNOPSIS 
Title 
A Randomized, Observer-Blind, Controlled Study to Assess the Safety, 
Immunogenicity and Efficacy of the SARS-CoV-2 Self-Amplifying RNA 
Vaccine ARCT-154 in Adults 
Short Title 
The ARCT-154 Self-Amplifying RNA Vaccine Study 
Phase 
1/2/3 
Study Design 
This is a Phase 1/2/3, randomized, controlled, observer-blind study designed 
to evaluate the safety, immunogenicity and efficacy of ARCT-154 in adult 
participants to be enrolled in Vietnam.  This study design has been updated 
to include a cohort (Phase 3c) to evaluate the immunogenicity, safety, and 
efficacy of ARCT-154 versus a comparator COVID-19 vaccine.  
The study is divided into five parts: Phase 1, Phase 2, Phase 3a, Phase 3b 
and Phase 3c.  
Participants in Phase 1 and 3b will be randomly assigned to a study group 
that will receive up to 2 vaccination series (4 doses of study vaccine total). 
Each vaccination series comprises two vaccinations at 28-day intervals: an 
initial vaccination series with vaccinations on Day 1 and Day 29 and an 
additional two-dose vaccination series with the opposite vaccine on Day 92 
and Day 120, which is at the 2-month timepoint after the second dose 
(referred to as the “Switchover” vaccination series throughout the protocol). 
Each participant in Phase 1 and 3b is planned to receive a two-dose 
vaccination series of ARCT-154 at a dose of 5 µg and a two-dose 
vaccination series of placebo (saline). Therefore, the study group that 
initially received two doses of ARCT-154 will receive two doses of placebo 
on Switchover and study group that initially received placebo will receive 
two doses of ARCT-154 5 µg on Switchover (Figure 1).  
Participants in Phase 2 and 3a will be randomly assigned to a study group 
that will receive two vaccinations with either ARCT-154 or placebo at a 
28-day interval with vaccinations on Day 1 and Day 29. With protocol 
version 8.0, participants that received ARCT-154 in the initial two-dose 
vaccination series will be further randomized to receive either ARCT-154 or 
placebo (in a 3:1 ratio) at Day 92 (referred to as “Further Study Vaccine” 
throughout the protocol) followed by placebo at Day 120. Participants that 
received Placebo in the initial vaccination series will undergo switch over to 
receive ARCT-154 at Day 92 and Day 120. 
Participants in Phase 3c will be randomized to receive either ARCT-154 or 
Astra Zeneca COVID-19 vaccine (ChAdOx1 nCoV-19; referred to as 
ChAdOx1from here on) which has received authorization for use in 
Vietnam. Participants in Phase 3c will receive a 2-dose priming vaccination 
series of either ARCT-154 5 µg or ChAdOx1, with vaccinations being 
administered on Day 1 and Day 29. Because all participants in Phase 3c will 
receive an active vaccine, no switchover will occur for these participants. 
Phase 1 is a sentinel cohort for assessment of safety. 100 healthy participants 
will be randomly assigned 3:1 to receive ARCT-154 or placebo (75:25) for 
the initial series of vaccinations. The Safety Review Committee (SRC) and 
Vietnam Ministry of Health (MOH) will independently review available 
blinded safety data for Phase 1 participants through at least 7 days post-
second vaccination (Day 36) and, if study vaccination is judged to be 

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adequately tolerated by SRC and the MOH, the study will initiate 
simultaneous enrollment of both Phase 2 and Phase 3a.  
In Phase 2, which expands the safety and immunogenicity characterization 
of the study vaccine in a larger group of participants, 300 participants will be 
randomly assigned 3:1 to receive ARCT-154 or placebo (225:75) for the 
initial series of vaccinations.  
In Phase 3a, which expands the enrollment further to include 600 
participants who will be randomly assigned 3:1 to receive ARCT-154 or 
placebo (450:150) for the initial series of vaccinations. After completion of 
enrollment of Phases 2 and 3a, the SRC and MOH will independently review 
available blinded safety data through at least 7 days (Day 8) post-first 
vaccination and, if study vaccination is judged to be adequately tolerated by 
SRC and the MOH, the study will initiate enrollment of Phase 3b. The 
second dose of study vaccine will not be administered to participants in 
Phase 3b until the SRC has reviewed the Phases 2 and 3a safety data through 
7 days post-second vaccination (Day 36) and judged that study vaccine is 
adequately tolerated. Data from participants in Phase 1, Phase 2, and Phase 
3a will be pooled for a primary analysis of immunogenicity at Day 57. Data 
from this analysis will be submitted to the Vietnamese Ministry of Health 
for evaluation for potential emergency use authorization (EUA). Data from 
Phase 2 and 3a will also be pooled to allow comparison of immunogenicity 
following the 3rd dose (immune responses at Day 120 with that after the 2nd 
dose (immune responses at Day 57). 
In Phase 3b, approximately 16,000 participants will be randomly assigned 
1:1 to receive ARCT-154 or placebo for the initial series of vaccinations. 
Phase 3b constitutes the Exploratory Efficacy Subgroup. Data from this 
subgroup will support regulatory filings along with immunogenicity data 
from Phase 1/2/3a and 3c. Participants in this Phase 3b portion of the study 
will contribute substantially to the safety analyses of ARCT-154. 
Phase 3c will enroll approximately 2,400 participants randomized 1:1 to 
receive ARCT-154 or ChAdOx1. A subset of these enrolled participants (the 
first 1,500 enrolled in Phase 3c) will form an Immunogenicity Noninferiority 
Subgroup (Phase 3c-1). Day 57 data from 800 participants in this Subgroup 
will be used to establish the noninferiority of immunogenicity of ARCT-154 
vaccine as compared to ChAdOx1, a licensed comparator vaccine. These 
data, along with an analysis of safety from participants exposed to ARCT-
154 and followed for a median period of 2 months (60 days) may be 
submitted to health authorities for evaluation for a Marketing Authorization 
or EUA dependent on jurisdiction. 
Phase 1 participants must be <60 years of age. Phase 2, 3a, 3b and Phase 3c 
participants will include elderly (≥60 years) participants as well. Phase 3b 
will enrich for participants at higher risk for COVID-19 by attempting to 
enroll individuals considered at high risk due to their workplace 
environment or living conditions. 
For Phase 2, 3a, 3b and Phase 3c, prior to randomization, participants will be 
stratified by age (< 60 or ≥ 60 years of age) and for participants < 60 years 
of age by risk of severe COVID-19. Participants will be defined as “at risk” 
if they are 60 years of age or older OR have medical history described as 
putting the individual at risk or possibly at risk of severe coronavirus disease 
2019 (COVID-19) (Appendix 5). As the eligibility criteria for Phase 1 

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exclude participants ≥ 60 years of age or otherwise at risk for severe 
COVID-19, stratification will not occur for Phase 1.   
Participants in all study phases will undergo informed consent and screening 
procedures prior to enrollment. After enrollment, participants will be 
randomized to groups. Study vaccines will be given in a supervised medical 
setting. All participants will be evaluated for reactogenicity (solicited 
adverse events) and reporting of unsolicited adverse events and concomitant 
medications through a series of clinic visits and phone calls. Depending on 
the study phase, blood sampling for immunogenicity and testing for COVID-
19 may be performed. See Appendix 1 for an overview of study visits and 
assessments for all phases of the study.  
For participants in Phase 1/2/3a/3b, at the Day 92 visit and prior to receipt of 
further study vaccine, participants will be evaluated by the Investigator 
according to Further Study Vaccine Eligibility criteria (Section 5.1.5). Any 
participant who does not meet these criteria will not receive further 
vaccinations with study vaccine and will be asked to continue in the study 
through Final Visit (Day 394).  
For participants that receive further doses of study vaccine at Day 92 and 
Day 120, this will occur in a blinded fashion in that participants and blinded 
site and Sponsor personnel will remain blinded to treatment assignment until 
End of Study (EOS). 
Participants who choose to receive vaccination with off-study COVID-19 
vaccine will be encouraged to remain in the study, but those that choose to 
leave the study to pursue alternate vaccination will not be unblinded to study 
treatment unless there is an unexpected post study SAE attributed as related 
to study vaccine by the study investigator. 
Data will be collected through a combination of clinic visits and use of 
electronic diaries (and paper diaries in circumstances where electronic 
diaries are not feasible) to capture solicited adverse events and to prompt for 
symptoms of COVID-19 and risk of SARS-CoV-2 exposure, other adverse 
events, and concomitant medications. All participants enrolled in Phase 1 
and Phase 2 must have access to the eDiary to facilitate rapid review of 
safety data by the SRC. 
Exposure to SARS-CoV-2 is defined as a participant who has had close 
contact (within 6 feet [2 meters] to a person with virologically confirmed 
COVID-19 during the active transmission period.  
The active transmission period is:  
1) for a symptomatic COVID-19 case, 3 days before the first 
symptom or 
2) for an asymptomatic COVID-19 case, from 14 days prior to the 
positive COVID-19 test result.   
The close contact definition applies regardless of whether the person with 
COVID-19 or the contact was wearing a mask or whether the contact was 
wearing respiratory personal protective equipment. Individuals with 
suspected COVID-19 symptoms and/or exposures will be evaluated, ideally 
within 72 hours to determine if there is a potential COVID-19 case. 
Participants may also be seen at unscheduled clinic visits if there are any 
safety issues that an investigator wishes to evaluate. 

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Participant data from each of the study phases may be unblinded prior to 
study completion to support regulatory filings. When these unblindings 
occur, unblinded data will only be provided to Sponsor or CRO employees 
not involved in the subsequent conduct of the study; the specific timings of 
these unblindings are defined in Section 8.9. Individual participants, blinded 
study site staff and Sponsor team members involved in overseeing the 
conduct of the study will remain blinded until the end of study for all Phases 
(Phase 1, 2 and 3a/b/c). Sponsor staff and other persons that will become 
unblinded at the various data analysis time points will be specified prior to 
unblinding occurring. 
Phase 1, 2, 3a and 3c-1 participants will be consented to have blood 
collected more frequently for assessment of SARS-CoV-2 neutralizing 
antibody responses and binding antibody responses to the SARS-CoV-2 
spike protein. The study will also include collection of blood samples in all 
participants for potential future exploratory testing of potential correlates of 
protection and vaccine responses to SARS-CoV-2 variants. 
An independent Data and Safety Monitoring Board (DSMB) will perform 
ongoing review of blinded and unblinded data, including both safety and 
confirmed cases of COVID-19 at scheduled data review meetings. At each 
meeting, the DSMB will review the available data and make 
recommendations to the Sponsor to continue, modify, or discontinue study 
enrollment (if the study is enrolling). In addition to the ongoing review of 
safety data, the DSMB will also review available severe COVID-19 case 
data to determine the risk of Vaccine-Associated Enhanced Respiratory 
Disease (VAERD). The DSMB will be constituted prior to commencement 
of Phase 3b. 
An independent blinded adjudication committee will adjudicate all suspected 
COVID-19 cases to determine if they meet the endpoint requirements 
(Appendix 2). 
Rationale 
In January 2020, a novel variant of coronavirus was identified as the cause 
of an outbreak of severe pneumonia in China. This virus, SARS-CoV-2, was 
identified as the causative agent of a broad clinical spectrum of disease 
(from asymptomatic infection to severe or fatal cases of COVID-19). Over 
188 million cases of COVID-19 have been confirmed worldwide and 4.1 
million people have died as of July 2021, and the number of cases continues 
to grow in most countries. While the global incidence of COVID-19 appears 
to be slowing and some vaccines to prevent COVID-19 have been approved 
by health authorities of several countries in recent months, the number of 
cases remains unacceptably high in most countries, and there are significant 
supply limitations for these vaccines. More global access to vaccines to 
prevent COVID-19 is clearly needed. 
Arcturus Therapeutics, Inc (Arcturus) has developed ARCT-154, a self-
replicating ribonucleic acid (RNA) vaccine intended for the prevention of 
COVID-19 caused by SARS-CoV-2. RNA included in this study vaccine 
promotes the synthesis of the SARS-CoV-2 Spike (S) glycoprotein, which is 
the component of SARS-CoV-2 that allows for attachment of the virus to 
host cell angiotensin-converting enzyme 2 receptors.  
The active pharmaceutical ingredient in ARCT-154, mRNA-2105, consists 
of a series of ribonucleotides encoding the replicase and an RNA sequence 
encoding the SARS-CoV-2 S-glycoprotein containing the D614G variant 

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mutation. By promoting expression of this viral S protein in vaccinated 
individuals, ARCT-154 is intended to promote immune responses to 
recognize and prevent SARS-CoV-2 infection. This study will evaluate the 
safety, reactogenicity, immunogenicity, immunogenicity noninferiority 
(compared to ChAdOx1) and (exploratory) efficacy of the ARCT-154 
vaccine in the prevention of COVID-19 in adults, including those adults at 
increased risk of severe COVID-19. 
Target Population 
Eligible participants will be adults without a history of COVID-19 infection, 
immunosuppression, or receipt of another COVID-19 vaccine. Phase 3b and 
3c will be enriched for participants at higher risk for acquiring COVID-19 
infection.  
Number of Participants 
Total of approximately 19,400:  
• 
Phase 1: 100 (75 ARCT-154:25 placebo per study group) 
• 
Phase 2: approximately 300 (225 ARCT-154:75 placebo per study 
group) 
• 
Phase 3a: approximately 600 (450 ARCT-154:150 placebo per 
study group)  
• 
Phase 3b: approximately 16,000 (8,000 per study group) 
• 
Phase 3c: approximately 2,400 (1,200 per study group) 
o 
The first approximately 1,500 participants will be enrolled 
into Phase 3c-1, the group that will have blood drawn for 
immunogenicity assessments. Data from 800 participants 
in this subgroup will be used to establish the noninferiority 
of immunogenicity of ARCT-154 vaccine as compared to 
ChAdOx1 
o 
The remaining ~900 participants will form Phase 3c-2 
Duration of Participation 
The expected duration of participation for an individual participant 
(including the Screening period) is approximately 14 months, 12 months 
after completion of the initial two-dose vaccination series. 
Number of Sites 
Approximately 20 sites in Vietnam 
Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this 
study: 
Consent and Compliance 
1. Individuals or legally authorized representatives must freely 
provide consent to study participation. 
2. Individuals must agree to comply with all study visits and 
procedures (including blood and nasal swab sampling, Diary 
completion, receipt of telephone calls from the site, willingness to 
be available for Unscheduled clinic visits). 
3. Individuals in Phase 1 and Phase 2 must have access to and be 
capable of using an eDiary. 
4. Individuals of childbearing potential who are sexually active must 
be willing to adhere to contraceptive requirements (Appendix 3). 
Type of Participant 
5. Adult males or females of at least 18 years of age at the time of 
signing of the informed consent. 
6. Individuals considered at risk for COVID-19 due to work or living 
environment in the opinion of the Investigator. 

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Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from the 
study: 
Medical Conditions 
1. Significant infection or other acute illness, including body 
temperature >100.4°F (>38.0°C) on the day prior to or Day 1. 
Participants meeting this criterion may be rescheduled within the 
relevant window periods. Afebrile participants with minor illnesses 
can be enrolled at the discretion of the investigator. 
2. Pregnant or breastfeeding. 
3. Known history of COVID-19 (nucleocapsid positive test is not 
exclusionary) or positive nasal swab SARS-CoV-2 by RT-PCR. 
Note: if obtained within 5 days prior to Screening period, do not 
need to repeat RT-PCR at Screening. 
4. Close contact with a person known to be SARS-CoV-2 positive or 
with a clinical diagnosis of COVID-19 within 7 days prior to 
enrollment. Participants meeting this criterion who remain 
asymptomatic for 7 days may be rescheduled for enrollment within 
the relevant windows. 
5. Known history of anaphylaxis, urticaria, or other significant 
adverse reaction to the vaccine or its excipients. See the 
Investigator’s Brochure (IB) for list of vaccine components. 
6. Known history of anaphylaxis to other vaccines. 
7. Bleeding disorder considered a contraindication to intramuscular 
(IM) injection or phlebotomy. 
8. Immunosuppressive or immunodeficient state, asplenia, recurrent 
severe infections, or known to be HIV positive. 
9. An underlying clinically significant acute or chronic medical 
condition or physical examination findings for which, in the 
opinion of the investigator, participation would not be in the best 
interest of the participant (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified 
assessments. 
Prior/Concomitant Therapy 
10. Has previously received investigational or approved MERS-CoV, 
SARS-CoV, SARS-CoV-2 vaccines or who have plans to receive 
off-study COVID-19 vaccines. 
11. Has received a live replicating vaccine within 28 days prior to each 
study vaccination or a licensed inactivated or non-replicating 
vaccine within 14 days prior to first study vaccination.  
12. Has received treatment with immunosuppressive therapy, including 
cytotoxic agents or systemic corticosteroids, eg, for cancer or an 
autoimmune disease, within 6 months prior to Screening, or 
planned receipt throughout the study. If systemic corticosteroids 
have been administered short term (<14 days) for treatment of an 
acute illness, participants should not be enrolled into the study until 
corticosteroid therapy has been discontinued for at least 28 days 
prior to first study vaccine administration. Inhaled/nebulized, intra-
articular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted.  

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13. Has received systemic immunoglobulins or blood products within 
3 months prior to first study vaccine administration or plans to 
receive such products during the study. 
Other Exclusions 
14. Demonstrated inability to comply with the study procedures. 
15. Investigator site staff members, employees of the Sponsor or the 
CRO directly involved in the conduct of the study, or site staff 
members otherwise supervised by the investigator, or immediate 
family members of any of the previously mentioned individuals. 
Additional Exclusion Criteria for Phase 1 Participants Only 
16. Individuals ≥ 60 years of age. 
17. Individuals with clinically significant abnormalities in medical 
history or physical examination, including but not limited to, the 
following: 
a) Respiratory disease (e.g., chronic obstructive pulmonary 
disease [COPD], asthma) requiring daily medications or 
oxygen currently or any treatment of respiratory disease 
exacerbations (e.g., COPD or asthma exacerbation) warranting 
hospitalization or an emergency room visit or supplemental 
oxygen in the last 5 years. 
b) Significant cardiovascular disease (e.g., congestive heart 
failure, cardiomyopathy, ischemic heart disease) or history of 
myocarditis or pericarditis as an adult. 
c) Neurological or neurodevelopmental conditions (e.g., 
migraines, epilepsy, stroke, seizures in the last 3 years, 
encephalopathy, focal neurologic deficits, Guillain-Barré 
syndrome, encephalomyelitis or transverse myelitis). 
d) Significant hematologic abnormalities (e.g., sickle cell disease, 
beta thalassemia, coagulation disorders). 
e) Major surgery within the past 6 months. 
f) 
Individuals with a history of chronic liver disease. 
18. Individuals with the following abnormal Screening laboratory 
results:  
a) Positive nasal swab SARS-CoV-2 by RT-PCR test. Note: if 
obtained within 5 days prior to Screening period, do not need 
to repeat RT-PCR at Screening. 
b) Alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), gamma-glutamyl transferase (GGT), total bilirubin, or 
alkaline phosphatase >1.5 upper limit of normal. 
c) Hemoglobin <9.5 g/dL for females and <10.5 g/dL for males. 
d) Platelet count <100 × 109/L. 
e) Other clinically significant abnormal (according to the 
judgment of the Investigator) Screening laboratory values. 
f) 
Individuals with Type 2 diabetes and Screening hemoglobin 
A1c >8.0%. 

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g) Hepatitis B core antigen (HbsAg), Hepatitis C virus (HCV) 
antibody or human immunodeficiency virus (HIV) positive. 
Additional Exclusion Criteria for Phase 3c Participants Only 
19. No contraindications (as specified in the prescribing information) to 
receiving the ChAdOx1 vaccine. 
Intervention 
For Cohorts 1/2/3a/3b 
Test: ARCT-154 
Reference: Placebo 
For Cohort 3c 
Test: ARCT-154 
Reference: ChAdOx1 
Independent Data Committees 
• 
Unblinded Data and Safety Monitoring Board 
• 
Blinded Adjudication Committee 
Stopping Rules 
All cases of severe COVID-19, SAEs determined to be related to study 
vaccine, or deaths determined to be related to study vaccine will be referred 
to the DSMB (Section 8.10.3) in an expedited fashion.  
In the event of death determined to be related to study vaccine, further 
vaccination will be paused until the relevant safety data has been reviewed 
by DSMB. 
The DSMB, based on their review of the blinded or unblinded safety data 
(including assessment for potential VAERD) will recommend whether the 
study should terminate, proceed unmodified, or proceed but with changes to 
the protocol. 
Analysis Sets 
The following analysis sets are defined for the statistical analyses: 
 
Randomized Set (RS): Includes all participants who are randomly 
assigned in the study regardless of the participants’ vaccination 
status in the study. Participants will be analyzed according to the 
vaccine to which the participant was randomly assigned. RS are 
defined for each Phase of the study as follows: 
o 
Phase 1/2/3a RS: this pools data from Phase 1, 2 and 3a 
participants 
o 
Phase 3b RS 
o 
Phase 3c RS 
o 
Pooled RS: this pools data from all Phases of the study 
 
Intent-to-Treat (ITT) Analysis Set: Includes all participants who 
receive any dose of study vaccine (ARCT-154 or placebo or 
ChAdOx1). Participants will be analyzed according to the vaccine 
to which the participant was randomly assigned. ITT are defined 
for each Phase of the study as follows: 
o 
Phase 1 ITT 
o 
Phase 2/3a ITT: this pools data from Phase 2 and 3a 
participants 
o 
Phase 1/2/3a ITT: this pools data from Phase 1, 2 and 3a 
participants and will include evaluations up to Day 92 
only 
o 
Phase 3b ITT 

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o 
Phase 3c ITT 
o 
Pooled ITT: this pools data from all Phases of the study 
and will include evaluations up to Day 92 only 
 
Safety Analysis Set (SAS): Includes all participants who receive 
any dose of study vaccine (ARCT-154 or placebo or ChAdOx1). 
Participants will be analyzed according to the vaccine received. 
SAS analysis sets are defined for each Phase of the study as 
follows: 
o 
Phase 1 SAS 
o 
Phase 2/3a SAS: this pools data from Phase 2 and Phase 
3a participants 
o 
Phase 1/2/3a SAS: this pools data from Phase 1, Phase 2 
and Phase 3a participants (up to Day 92 only) 
o 
Phase 3b SAS 
o 
Phase 3c SAS 
o 
Pooled SAS: this pools data from Phase 1/2/3a/3b for 
ARCT-154 and placebo, respectively. It will include 
evaluations up to Day 92 only 
 
Reactogenicity Analysis Set (RAS): Includes all participants who 
receive any dose of study vaccine (ARCT-154 or placebo or 
ChAdOx1) and provide at least 1 reactogenicity diary report. 
Participants will be analyzed according to the vaccine received. 
Reactogenicity analysis sets are defined for each Phase of the study 
as follows: 
o 
Phase 1 RAS 
o 
Phase 2/3a RAS: this pools data from Phase 2 and Phase 
3a participants 
o 
Phase 1/2/3a RAS: this pools data from Phase 1, Phase 2 
and Phase 3a participants (up to pre-dose Day 92 only) 
o 
Phase 3b RAS 
o 
Phase 3c RAS 
o 
Pooled RAS: this pools data from Phase 1/2/3a/3b for 
ARCT-154 and placebo, respectively. It will include 
evaluations up to Day 92 only 
 
Modified Intent-to-Treat (mITT) Analysis Set: Includes all 
participants who received all protocol required doses of study 
vaccine (ARCT-154 or placebo or ChAdOx1) up to the evaluation 
timepoint concerned, and who have no evidence of SARS-CoV-2 
infection on Day 1 or up to 7 days after the 2nd study vaccination. 
The mITT analysis set will be analyzed according to vaccine 
assigned. mITT sets are defined for the following Phases of the 
study: 
o 
Phase 3b mITT 
o 
Phase 3c mITT 
o 
Pooled mITT: this pools data from Phases 1/2/3a/3b and 
will include evaluations up to Day 92 only  
 
Per-Protocol (PP) Analysis Set: Includes all eligible randomized 
participants who received all protocol-required doses of study 
vaccine (ARCT-154 or placebo or ChAdOx1) up to the evaluation 
timepoint concerned and within the protocol predefined window, 

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and who have no major protocol deviations expected to affect 
efficacy, immunogenicity, safety or reactogenicity assessments as 
determined by the Sponsor Medical Monitor or designee in a 
blinded manner.  
 
The PP analysis set will be analyzed according to which study 
vaccine was received in the event there is a discrepancy. PP 
analysis sets are defined for the following Phases of the study: 
o 
Phase 1 PP set: this excludes any participant that has 
evidence of SARS-CoV-2 infection at baseline or prior to 
the analysis time point concerned (IcEv3) or that receives 
an off-study COVID-19 vaccine prior to the analysis time 
point concerned (IcEv2). 
o 
Phase 2/3a PP set: this pools data from Phase 2 and Phase 
3a participants and excludes any participant that has 
evidence of SARS-CoV-2 infection at baseline or prior to 
the analysis time point concerned (IcEv3) or that receives 
an off-study COVID-19 vaccine prior to the analysis time 
point concerned (IcEv2). 
o 
Phase 1/2/3a PP set: this pools data from Phase 1, 2 and 
Phase 3a participants and excludes any participant that has 
evidence of SARS-CoV-2 infection at baseline or prior to 
the analysis time point concerned (IcEv3) or that receives 
an off-study COVID-19 vaccine prior to the analysis time 
point concerned (IcEv2). This set will include evaluations 
of immunogenicity up to Day 92 only 
o 
Phase 3b PP set: this excludes any participant with 
evidence of SARS-CoV-2 infection on Day 1 or up to 7 
days after the 2nd study vaccination (IcEv3) or that 
receives an off-study COVID-19 vaccine prior to Day 92 
(IcEv2) 
o 
Phase 3c-1 PP set: this includes just the participants 
enrolled in the Phase 3c-1 subset of Phase 3c but excludes 
any participant that has evidence of SARS-CoV-2 
infection at baseline or prior to the analysis time point 
concerned (IcEv3) or that receives an off-study COVID-
19 vaccine prior to the analysis time point concerned 
(IcEv2) 
o 
Phase 3c PP set: this includes all of Phase 3c but excludes 
any participant that has evidence of SARS-CoV-2 
infection at baseline or prior to the analysis time point 
concerned (IcEv3) or that receives an off-study COVID-
19 vaccine prior to the analysis time point concerned 
(IcEv2) 
o 
Pooled PP set: this pools data from Phase 1/2/3a/3b and 
excludes any participant with evidence of 
SARS-CoV-2 infection on Day 1 or up to 7 days after the 
2nd study vaccination (IcEv3) or that receives an off-study 
COVID-19 vaccine prior to Day 92 (IcEv2). This will 
include evaluations up to Day 92 only 
 
Immunogenicity Analysis Set (IAS): Includes all participants who 
received all protocol required doses of study vaccine (ARCT-154 
or placebo or ChAdOx1) up to the evaluation timepoint concerned, 

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who have no evidence of prior SARS-CoV-2 infection at Day 1 
(IcEv3; Section 8.3.1) and who have at least 1 valid post-
vaccination immunogenicity assay result.  Data at timepoints 
following evidence of a SARS-CoV-2 infection (IcEv3), use of 
immune-modifying drugs, blood products or immunogloblins 
(IcEv5) or non-study COVID-19 vaccines (IcEv2), or protocol 
deviations (eg, time windows for doses and blood draws for the 
time period summarized) that may impact immunogenicity as 
determined by the Sponsor Medical Monitor or designee in a 
blinded manner will be excluded. All participants in the IAS will 
be analyzed according to which study vaccine was received. IAS 
are defined for the following Phases of the study: 
o 
Phase 1 IAS 
o 
Phase 2/3a IAS: this pools data from participants in Phase 
2 and 3a 
o 
Phase 1/2/3a IAS: this pools data from Phase 1, 2 and 3a 
participants and will include evaluations of 
immunogenicity up to Day 92 only 
o 
Phase 3b IAS 
o 
Phase 3c-1 IAS 
Objectives and Endpoints 
In interpreting the objectives and endpoints for this study, the following considerations will apply: 
• 
The overall primary efficacy endpoint for the study is vaccine efficacy as evaluated in the Phase 3b 
Modified Intent to Treat (mITT) population 
• 
The overall primary safety endpoints are those evaluated in the Phase 3b Safety Analysis Set (SAS) and 
Phase 3b Reactogenicity Analysis Set (RAS) 
• 
Phase 1/2/3a and subgroups thereof constitute a substudy with separate objectives and endpoints. As 
these constitute a substudy, and there is no evaluation of efficacy for this substudy, no adjustment of 
type 1 error is applied to the overall efficacy primary endpoint 
• 
The Pooled efficacy endpoint is only evaluated as exploratory, so no adjustment of type 1 error is 
applied to the overall efficacy primary endpoint 
• 
Phase 3c and subgroups thereof also constitute a substudy with separate objectives and endpoints. As 
these constitute a substudy, and efficacy for this study is only evaluated as exploratory, no adjustment of 
type 1 error is applied to the overall efficacy primary endpoint. 
 
Phases 1, 2 and 3a Substudy Objectives and Endpoints 
Immunogenicity data from participants in Phases 1, 2 and 3a will be pooled for analysis up to Day 92. With 
implementation of protocol version 8.0, participants in Phase 2 and 3a that received ARCT-154 in the initial 
vaccination series are further randomized to receive a 3rd vaccination of either ARCT-154 or placebo at Day 92 
followed by placebo at Day 120 in order to compare immunogenicity after 3 injections of ARCT-154 with that 
after 2 injections. Therefore, after Day 92 only data from Phase 2/3a will be pooled and will be displayed 
separately from participants in Phase 1. 
Safety data from participants in Phase 2/3a will be pooled for all time points and will be displayed separately to 
safety data from Phase 1.  
Phase 1/2/3a Primary 
Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 
compared to placebo 
Safety will be evaluated in all participants in Phase 1 and Phase 2/3a Safety 
Analysis Sets (SAS, Section 8.2) and will be summarized for each 
vaccination as number and percentage of participants with: 

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Any unsolicited AE starting within 28 days after each study 
vaccine administration, summarized by severity and relationship to 
study vaccine.  
 
Any medically attended adverse event (MAAE), serious adverse 
event (SAE), or AE leading to discontinuation/withdrawal through 
Final Visit/Early Termination (ET) summarized by relationship to 
study vaccine. 
Reactogenicity will be evaluated in participants in the Phase 1 and Phase 
2/3a Reactogenicity Analysis Sets (RAS) and will be summarized following 
each vaccination on Day 1 and Day 29 only in Phase 1 and Day 1, Day 29, 
and Day 92 in Phase 2/3a as the number and percentage of participants with: 
 
Any solicited local or systemic AE starting within 7 days after each 
study vaccine administration by toxicity grade. 
Additional safety analyses in the Phase 1/2/3a SAS may also be performed 
as exploratory. 
2. To assess the neutralizing 
antibody (NAb) responses to 
ARCT-154 by surrogate virus 
neutralization test at Day 57  
Neutralizing antibody (NAb) responses by surrogate virus neutralization test 
(sVNT) will be evaluated at Day 1 (baseline) and Day 57 for assessment of 
seroconversion in all participants in the Phase 1/2/3a Immunogenicity 
Analysis Set (IAS, Section 8.2).  
 
The endpoint is defined as the proportion of participants in each 
study vaccine group that demonstrate seroconversion (defined as: 
4-fold increase in antibody concentration from baseline). 
Data will be summarized according to use of international reference 
standards, if available. 
Phase 1/2/3a Secondary 
Objectives 
Endpoint Description 
1. To assess the neutralizing and 
IgG binding antibody 
responses to ARCT-154 over 
time 
Immunogenicity will be evaluated at the following time points: 
• 
Phase 1 IAS: Day 1 (baseline), Day 29, Day 57, Day 92, Day 394. 
• 
Phase 2/3a IAS: Day 1 (baseline), Day 29, Day 57, Day 92, Day 
120, Day 394 
• 
Phase 1/2/3a IAS: Day 1 (baseline), Day 29, Day 57, Day 92 
The following will be evaluated: 
 
Neutralizing antibody (NAb) by surrogate virus neutralization test 
(sVNT) and IgG antibody binding the full-length SARS-CoV-2 
spike protein (binding antibody [BAb]) responses will be 
evaluated; assessments for both BAb and NAb will include:   
o 
Antibody level: GMC (BAb and NAb)  
o 
Increase in antibody levels from baseline (GMFR or other 
measure, as appropriate for the assay concerned) 
o 
Proportion of participants in each study vaccine group with 
seroconversion at each timepoint. Note: NAb responses at 
Day 57 evaluated as primary. 
Data will be summarized according to use of international reference 
standards, if available. 
Full details will be provided in the statistical analysis plan. 
2. To assess early neutralizing 
antibody responses using a live 
virus assay 
NAb responses by plaque reduction neutralization test at 50% reduction 
(PRNT50) will be evaluated in the subset of the Phase 1/2 IAS (Section 8.2) 

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comprising all participants enrolled in Phase 1 and the first 50 evaluable 
participants in Phase 2 at Day 1 (baseline), Day 29 and Day 57. 
The following endpoints will be assessed: 
 
Geometric mean antibody concentration (GMC)  
 
Increase in antibody levels from baseline (GMFR) 
 
Proportion of participants in each study vaccine group with 
seroconversion. 
Phase 1/2/3a Exploratory 
Objectives 
Endpoint Description 
1. To compare the humoral 
immune responses of ARCT-
154 to those of patients 
recovering from COVID-19  
Day 57 GMT/GMC results following vaccination with ARCT-154 may be 
compared with the test results for convalescent sera from COVID-19 
patients measured on the same assay for the subset of the Phase 1/2/3a IAS 
comprising all participants enrolled in Phase 1 and the first 50 evaluable 
participants in Phase 2. The following assays will be used: 
• 
PRNT50 
• 
MNT 
Immune responses may also be assessed at additional time points and/or in 
additional participants in Phase 2 and Phase 3a. If performed, this will be 
described in the statistical analysis plan (SAP). 
For the MNT assay, data will be summarized according to use of 
international reference standards, if available   
2. To evaluate the efficacy of 
ARCT-154 versus placebo 
for the prevention of 
virologically confirmed 
COVID-19 
Efficacy may be evaluated in participants in the Phase 1/2/3a Modified 
Intent to Treat (mITT) set (Section 8.2). The endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset between Day 36 and Day 92 inclusive. 
Efficacy may also be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series, with no evidence of infection 
prior to vaccination. The endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination 
and up to Day 92. 
3. To assess the neutralizing 
antibody immune responses 
to ARCT-154 to SARS-CoV-
2 variants of concern/variants 
of interest following 2 and 3 
vaccinations with ARCT-154 
Blood samples from post-vaccination timepoints may be evaluated for 
immune responses to SARS-CoV-2 variants of concern/variants of interest 
for the following groups/time points: 
• 
The subset of the Phase 1/2/3a IAS comprising all participants 
enrolled in Phase 1 and the first 50 participants in Phase 2 at Day 1 
(baseline) and Day 57.  
• 
The subset of the Phase 2/3a IAS comprising the first 150 
participants that received ARCT-154 in the initial vaccination series 
in Phase 2; evaluated at Day 1 (baseline), Day 57 and Day 120. 
The following assays may be used: 
• 
PRNT50 
• 
sVNT 
• 
MNT 
 
4. To assess neutralizing 
antibody responses using a 
pseudovirus 
NAb responses by microneutralization test (MNT) will be evaluated for the 
following groups/time points: 

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microneutralization test 
(MNT) following 2 (Day 57) 
and 3 (Day 120) vaccinations 
with ARCT-154 
• 
The subset of the Phase 1/2/3a IAS comprising all participants 
enrolled in Phase 1 and the first 50 evaluable participants in 
Phase 2 at Day 1 (baseline) and Day 57.  
• 
The subset of the Phase 2/3a IAS comprising the first 150 
participants that received ARCT-154 in the initial vaccination series 
in Phase 2; evaluated at Day 1 (baseline), Day 57 and Day 120. 
The following endpoints will be assessed: 
o 
Geometric mean antibody concentration (GMC)  
o 
Increase in antibody levels from baseline (GMFR) 
o 
Proportion of participants in each study vaccine group with 
seroconversion 
Data will be summarized according to use of international reference 
standards, if available. 
5. To assess the neutralizing 
antibody (NAb) responses by 
surrogate virus neutralization 
test to ARCT-154 following 
2 (Day 57) and 3 (Day 120) 
vaccinations with ARCT-154 
in Phase 2/3a Participants 
Neutralizing antibody (NAb) responses by surrogate virus neutralization test 
(sVNT) will be evaluated at Day 1 (baseline), Day 57 and Day 120 for 
assessment of seroconversion in all participants in the Phase 2/3a IAS that 
received ARCT-154 in the initial vaccination series 
 
The endpoint is defined as the proportion of participants that 
demonstrate seroconversion (defined as: 4-fold increase in 
antibody concentration from baseline). 
Data will be summarized according to use of international reference 
standards, if available. 
6. To assess the IgG binding 
antibody responses to 
ARCT-154 following 2 (Day 
57) and 3 (Day 120) 
vaccinations with ARCT-154 
in Phase 2/3a participants 
IgG antibody binding the full-length SARS-CoV-2 spike protein (binding 
antibody [BAb]) responses will be evaluated at Day 1 (baseline), Day 57 and 
Day 120 in all participants in the Phase 2/3a IAS that received ARCT-154 in 
the initial vaccination series. The following endpoints will be assessed: 
 
Geometric mean antibody concentration (GMC)  
 
Increase in antibody levels from baseline (GMFR) 
 
Proportion of participants in each study vaccine group with 
seroconversion 
Data will be summarized according to use of international reference 
standards, if available. 
 
Phase 3b Objectives and Endpoints 
Phase 3b Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 
compared to placebo 
Safety will be evaluated in all participants in the Phase 3b SAS and will be 
summarized for each vaccination as number and percentage of participants 
with: 
 
Any unsolicited AE starting within 28 days after each study 
vaccine administration, summarized by severity and relationship to 
study vaccine.  
 
Any medically attended adverse event (MAAE), serious adverse 
event (SAE), or AE leading to discontinuation/withdrawal through 
Final Visit/Early Termination (ET) summarized by relationship to 
study vaccine. 
Reactogenicity will be evaluated in participants in the Phase 3b RAS and 
will be summarized following vaccinations on Day 1 and Day 29 only as the 
number and percentage of participants with: 

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Phase 3b Exploratory 
Objectives 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
severe COVID-19 at any 
time after first vaccination 
Efficacy may be evaluated in all participants in the Phase 3b mITT who 
have received any dose of study vaccine in the first vaccination series, with 
no evidence of infection prior to vaccination. The endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset at any time after the first study 
vaccination and up to Day 92. 
2. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of death due 
to COVID-19 at any time 
after first vaccination 
Efficacy may be evaluated in all participants in the Phase 3b mITT that have 
received any dose of study vaccine in the first vaccination series. The 
endpoint is as follows: 
 
The occurrence of death attributed to COVID-19 occurring at any 
time after the first study vaccination and up to Day 92. 
 
Any solicited local or systemic AE starting within 7 days after each 
study vaccine administration by toxicity grade. 
2. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 
Efficacy will be evaluated in all participants in the Phase 3b mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset between Day 36 and Day 92 inclusive. 
 
Phase 3b Secondary Objectives 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
severe COVID-19  
Efficacy will be evaluated in all participants in the Phase 3b mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset between Day 36 and Day 92 
inclusive. 
 
2. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 at any time after 
first vaccination 
Efficacy will be evaluated in all participants in the Phase 3b mITT that have 
received any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as follows: 
• 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination 
and up to Day 92 inclusive. 
3. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of death due 
to COVID-19  
Efficacy will be evaluated in all participants in the Phase 3b mITT. The 
endpoint is as follows: 
 
The occurrence of death attributed to COVID-19 disease occurring 
between Day 36 and Day 92 inclusive. 
 
4. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 regardless of 
baseline status for evidence 
of prior SARS-CoV-2 
infection 
Efficacy will be evaluated in all participants in the Phase 3b mITT 
regardless of baseline status for evidence of prior SARS-CoV-2 infection. 
The endpoint to be evaluated is as follows: 
• 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset between Day 36 and Day 92 inclusive. 
 

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Phase 3b Exploratory 
Objectives 
Endpoint Description 
3. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 at any time after 
first vaccination regardless of 
baseline status for evidence 
of prior SARS-CoV-2 
infection 
Efficacy may be evaluated in all participants in the Phase 3b mITT that have 
received any dose of study vaccine in the first vaccination series, regardless 
of baseline status for evidence of prior SARS-CoV-2 infection. The 
endpoints are as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination 
and up to Day 92. 
4. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
SARS-CoV-2 by specific 
strain 
Efficacy will be evaluated in participants in Phase 3b mITT. The endpoint to 
be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2)  
COVID-19 for all participants infected with the same strain of 
SARS-CoV-2, with onset between Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in participants 
under evaluation for COVID-19 will be retained for possible future testing 
to identify the SARS-CoV-2 strain detected in the COVID-19 case. 
5. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
severe SARS-CoV-2 by 
specific strain 
Efficacy will be evaluated in participants in Phase 3b mITT. The endpoint to 
be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 for all participants infected with the same strain 
of SARS-CoV-2, with onset between Day 36 and Day 92 
inclusive. 
A second nasal swab specimen collected contemporaneously in participants 
under evaluation for COVID-19 will be retained for possible future testing 
to identify the SARS-CoV-2 strain detected in the COVID-19 case. 
6. To evaluate an immune 
correlate associated with 
reduced risk of COVID-19 
 
Blood samples drawn at Baseline and Day 57 in all participants 
will be held for potential future testing for evaluation of a correlate 
of protection. 

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Phase 3c Substudy Objectives and Endpoints 
The first approximately 1,500 participants in Phase 3c will be enrolled into Phase 3c-1, the group that will have 
blood drawn for immunogenicity assessments. Data from 800 participants in this subgroup will be used to 
establish the noninferiority of immunogenicity of ARCT-154 vaccine as compared to ChAdOx1. Samples from 
the remaining 700 participants in Phase 3c-1 will be retained for potential future immunological testing, for 
example, against newly emerging variants of concern. Safety evaluations will be based on all participants in 
Phase 3c.  
Phase 3c Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 
and ChAdOx1  
Safety will be evaluated in all participants in the Phase 3c SAS and will be 
summarized for each vaccination as number and percentage of participants 
with: 
 
Any unsolicited AE starting within 28 days after each study 
vaccine administration, summarized by severity and relationship to 
study vaccine.  
 
Any medically attended adverse event (MAAE), serious adverse 
event (SAE), or AE leading to discontinuation/withdrawal through 
Final Visit/Early Termination (ET) summarized by relationship to 
study vaccine. 
Reactogenicity will be evaluated in participants in the Phase 3c RAS and 
will be summarized following vaccinations on Day 1 and Day 29 only as the 
number and percentage of participants with: 
• 
Any solicited local or systemic AE starting within 7 days after each 
study vaccine administration by toxicity grade. 
2. To evaluate noninferiority of 
neutralizing antibody 
geometric mean 
concentration for ARCT-154 
versus ChAdOx1 at Day 57  
Neutralizing antibody (NAb) responses by pseudovirus microneutralization 
test (MNT) will be evaluated at Day 57 for assessment of geometric mean 
concentration in all participants in the Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of the surrogate virus 
neutralization test for ARCT-154 and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Noninferiority will be concluded if the lower bound of the 95% confidence 
interval for the geometric mean ratio of ARCT-154 / ChAdOx1 >0.67. 
Phase 3c Secondary Objectives 
Endpoint Description 
1. To evaluate noninferiority of 
IgG binding antibody 
geometric mean 
concentration for ARCT-154 
versus ChAdOx1 at Day 57  
IgG antibody binding the full-length SARS-CoV-2 spike protein (binding 
antibody [BAb]) responses will be evaluated Day 57 for assessment of 
geometric mean concentration in all participants in the Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of BAb for ARCT- 154 
and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available 
Noninferiority will be concluded if the lower bound of the 95% confidence 
interval for the geometric mean ratio of ARCT-154 / ChAdOx1 >0.67. 
2. To evaluate noninferiority of 
neutralizing antibody 
seroconversion rate for 
Neutralizing antibody (NAb) responses by pseudovirus microneutralization 
test (MNT) will be evaluated at Day 1 (baseline) and Day 57 for assessment 
of seroconversion in all participants in the Phase 3c-1 IAS.  

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ARCT-154 versus ChAdOx1 
at Day 57  
• 
The endpoint is seroconversion rate (defined as: 4-fold increase in 
titer from baseline) for ARCT-154 and ChAdOx1 at Day 57  
Data will be summarized according to use of international reference 
standards, if available  
Noninferiority will be concluded if the lower bound of the 95% confidence 
interval of the difference between neutralizing antibody seroconversion rates 
(ARCT-154 group minus ChAdOx1 nCoV-1 group) excludes the non-
inferiority margin of -10%. 
3. To evaluate noninferiority of 
IgG binding antibody 
seroconversion rate for 
ARCT-154 versus ChAdOx1 
at Day 57  
IgG antibody binding the full-length SARS-CoV-2 spike protein (BAb) 
responses will be evaluated at Day 1 (baseline) and Day 57 for assessment of 
seroconversion in all participants in the Phase 3c-1 IAS.  
• 
The endpoint is seroconversion rate (defined as: 4-fold increase in 
titer from baseline) for ARCT-154 and ChAdOx1 at Day 57  
Data will be summarized according to use of international reference 
standards, if available 
Noninferiority will be concluded if the lower bound of the 95% confidence 
interval of the difference between binding antibody seroconversion rates 
(ARCT-154 group minus ChAdOx1 nCoV-1 group) excludes the non-
inferiority margin of -10%. 
4. To evaluate superiority of 
neutralizing antibody 
geometric mean concentration 
for ARCT-154 versus 
ChAdOx1 at Day 57 
Neutralizing antibody (NAb) responses by pseudovirus microneutralization 
test (MNT) will be evaluated at Day 57 for assessment of geometric mean 
concentration in all participants in the Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of the MNT for ARCT-
154 and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Superiority will be concluded if the lower bound of the 95% confidence 
interval for the geometric mean ratio of ARCT-154 / ChAdOx1 >1.0. 
5. To evaluate superiority of IgG 
binding antibody geometric 
mean concentration for 
ARCT-154 versus ChAdOx1 
at Day 57 
IgG antibody binding the full-length SARS-CoV-2 spike protein (BAb) 
responses will be evaluated at Day 57 for assessment of geometric mean 
concentration in all participants in the Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of BAb for ARCT- 154 
and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Superiority will be concluded if the lower bound of the 95% confidence 
interval for the geometric mean concentration ratio of ARCT-154 / 
ChAdOx1 >1.0. 
6. To assess the neutralizing and 
IgG binding antibody immune 
responses for ARCT-154 and 
ChAdOx1 over time  
Neutralizing antibody (NAb) by pseudovirus microneutralization test (MNT) 
and IgG antibody binding the full-length SARS-CoV-2 spike protein (BAb) 
responses will be evaluated at: Day 1 (baseline), Day 29, Day 57 and Day 
211 for all participants in the Phase 3c-1 IAS. Assessments for both BAb 
and NAb will include:   
• 
Antibody level: GMC 
• 
Increase in antibody levels from baseline (GMFR or other measure, 
as appropriate for the assay concerned) 
• 
Geometric mean ratio (GMR) 
• 
Proportion of participants in each study vaccine group with 
seroconversion at each timepoint  

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Samples will also be collected at Day 394 and may be evaluated in the same 
assays. 
Note: NAb and BAb responses that have been evaluated as other primary 
and secondary endpoints will be included in this endpoint for completeness 
of data presentation across time points. Full details will be provided in the 
statistical analysis plan. 
Phase 3c Exploratory 
Objectives 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 
nCoV-1 for the prevention of 
virologically confirmed 
COVID-19 
Efficacy will be evaluated in all participants in the Phase 3c mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series, with no evidence of infection 
prior to vaccination. The endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination. 
 
2. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 
nCoV-1 for the prevention of 
virologically confirmed 
severe COVID-19  
Efficacy will be evaluated in all participants in the Phase 3c mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series, with no evidence of infection 
prior to vaccination. The endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset at any time after the first study 
vaccination. 
3. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 
nCoV-1 for the prevention of 
death due to COVID-19  
Efficacy will be evaluated in all participants in the Phase 3c mITT. The 
endpoint to be evaluated is as follows: 
 
The occurrence of death attributed to COVID-19 disease occurring 
after Day 35. 
Efficacy may also be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series, with no evidence of infection 
prior to vaccination. The endpoint to be evaluated is as follows: 
• 
The occurrence of death attributed to COVID-19 disease occurring 
at any time after the first study vaccination. 
4. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 
for the prevention of 
virologically confirmed 
COVID-19 regardless of 
baseline status for evidence 
of prior SARS-CoV-2 
infection 
Efficacy will be evaluated in all participants in the Phase 3c mITT regardless 
of baseline status for evidence of prior SARS-CoV-2 infection. The endpoint 
to be evaluated is as follows: 
• 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series. The endpoint is as follows: 
• 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination. 

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5. To evaluate the neutralizing 
antibody responses of 
ARCT-154 and ChAdOx1 
using a surrogate virus 
neutralization test 
Neutralizing antibody (NAb) responses by surrogate virus neutralization test 
(sVNT) may be evaluated at individual time points. The following endpoints 
may be assessed: 
• 
Geometric mean antibody concentration (GMC)  
• 
Increase in antibody levels from baseline (GMFR) 
• 
Proportion of participants in each study vaccine group with 
seroconversion. 
Data will be summarized according to use of international reference 
standards, if available. 
6. To evaluate the neutralizing 
antibody responses of 
ARCT-154 and ChAdOx1 to 
SARS-CoV-2 variants of 
concern/variants of interest 
Neutralizing antibody responses to SARS-CoV-2 variants of concern may be 
evaluated at individual time points in participants in the Phase 3c-1 IAS 
using a pseudovirus microneutralization test (MNT) and/or surrogate virus 
neutralization test (sVNT) for assessment of: 
 
Antibody level: GMC  
 
Increase in antibody levels from baseline (GMFR or other measure, 
as appropriate for the assay concerned) 
 
Geometric mean ratio (GMR) 
 
Proportion of participants in each study vaccine group with 
seroconversion at each timepoint.  
The following assays may be used: 
• 
PRNT50 
• 
sVNT 
• 
MNT 
 
Pooled Objectives and Endpoints 
Pooled Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 
and comparator vaccines 
(placebo, ChAdOx1 nCoV-1)  
Safety data will be evaluated in the Pooled SAS. Data and will be 
summarized for each vaccination as number and percentage of participants 
with: 
 
Any unsolicited AE starting within 28 days after each study 
vaccine administration, summarized by severity and relationship to 
study vaccine.  
 
Any medically attended adverse event (MAAE), serious adverse 
event (SAE), or AE leading to discontinuation/withdrawal through 
Final Visit/Early Termination (ET) summarized by relationship to 
study vaccine. 
Reactogenicity will be evaluated in the Pooled RAS and will be summarized 
following vaccinations on Day 1 and Day 29 only as the number and 
percentage of participants with: 
 
Any solicited local or systemic AE starting within 7 days after each 
study vaccine administration by toxicity grade. 
2. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 
Efficacy will be evaluated in all participants in Pooled mITT. The endpoint 
to be evaluated is as follows: 
• 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset between Day 36 and Day 92 inclusive. 

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Pooled Secondary Objectives 
Endpoint Description 
1.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of
virologically confirmed
severe COVID-19
Efficacy will be evaluated in all participants in the Pooled mITT. The 
endpoint to be evaluated is as follows: 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset between Day 36 and Day 92 
inclusive. 
Severity as scored using the FDA criteria will be the principal 
analysis.  Severity using the WHO criteria will be performed as a 
sensitivity analysis 
2.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of
virologically confirmed
COVID-19 at any time after
first vaccination
Efficacy will be evaluated in participants that have received any dose of 
study vaccine in the first vaccination series, with no evidence of infection 
prior to vaccination. The endpoint is as follows: 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination and up to 
Day 92 inclusive. 
3.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of death due
to COVID-19
Efficacy will be evaluated in all participants in the Pooled mITT The 
endpoint is as follows: 
The occurrence of death attributed to COVID-19 with onset 
between Day 36 and Day 92 inclusive. 
4.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of
virologically confirmed
COVID-19 regardless of
baseline status for evidence
of prior SARS-CoV-2
infection
Efficacy will be evaluated in all participants in the Pooled mITT regardless 
of baseline status for evidence of prior SARS-CoV-2 infection. The endpoint 
to be evaluated is as follows: 
•
The first occurrence of confirmed, protocol-defined (Appendix 2)
COVID-19 with onset between Day 36 and Day 92 inclusive.
Pooled Exploratory Objectives 
Endpoint Description 
1.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of
virologically confirmed
severe COVID-19 at any
time after first vaccination
Efficacy may be evaluated in all participants in the Pooled mITT that have 
received any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as follows: 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 with onset at any time after the first study 
vaccination and up to Day 92. 
2.
To evaluate the efficacy of
ARCT-154 and placebo for
the prevention of death due
to COVID-19 at any time
after first vaccination
Efficacy may be evaluated in all participants in the Pooled mITT that have 
received any dose of study vaccine in the first vaccination series. The 
endpoint is as follows: 
The occurrence of death attributed to COVID-19 disease occurring 
at any time after the first study vaccination and up to Day 92. 

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3. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
COVID-19 at any time after 
first vaccination regardless of 
baseline status for evidence 
of prior SARS-CoV-2 
infection 
Efficacy may be evaluated in all participants in the Pooled mITT that have 
received any dose of study vaccine in the first vaccination series. The 
endpoints are as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination 
and up to Day 92. 
4. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
SARS-CoV-2 by specific 
strain 
Efficacy will be evaluated in participants in Pooled mITT. The endpoint to 
be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 for all participants infected with the same strain of 
SARS-CoV-2, with onset between Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in participants 
under evaluation for COVID-19 will be retained for possible future testing to 
identify the SARS-CoV-2 strain detected in the COVID-19 case. 
5. To evaluate the efficacy of 
ARCT-154 and placebo for 
the prevention of 
virologically confirmed 
severe SARS-CoV-2 by 
specific strain 
Efficacy will be evaluated in participants in Pooled mITT. The endpoint to 
be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
severe COVID-19 for all participants infected with the same strain 
of SARS-CoV-2, with onset between Day 36 and Day 92 
inclusive. 
A second nasal swab specimen collected contemporaneously in participants 
under evaluation for COVID-19 will be retained for possible future testing to 
identify the SARS-CoV-2 strain detected in the COVID-19 case. 
6. To evaluate for an immune 
correlate associated with 
reduced risk of COVID-19 
Blood samples drawn at Baseline and Day 57 in all participants will be held 
for potential future testing for evaluation of a correlate of protection. 
Statistical Considerations 
The design of the study is structured to maintain the integrity of the safety, 
efficacy and immunogenicity noninferiority endpoints for Phase 3b and 3c 
such that these data remain blinded to the blinded Sponsor employees and 
CRO until the analysis of time points for these endpoints whilst earlier 
unblinding of Phases 1/2/3a participants for analysis of Phase 1/2/3a 
immunogenicity and safety may occur earlier to inform filing for EUA.  
Phase 3b Primary Analyses 
The primary Phase 3b safety endpoints will be evaluated in the Phase 3b 
Safety Analysis Set and Phase 3b Reactogenicity Analysis Set (Section 8.2). 
With a sample size ~16,000 participants randomized and with approximately 
8,000 participants randomized in the study to receive ARCT-154 for the 
primary safety analysis, if the incidence rate of an adverse event is 0.1%, the 
probability to detect one event in 8,000 vaccinated participants is >99.9%, 
based upon the following formula: 
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 

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where R = incidence rate and N = sample size 
The primary statistical analyses for vaccine efficacy (VE) will be performed 
using virologically confirmed COVID-19 cases as determined in a blinded 
fashion by an Independent Adjudication Committee according to definitions 
provided in Appendix 2. This analysis of VE will be based on the Phase 3b 
mITT analysis set (Section 8.2). Sensitivity analyses will be performed in 
the Phase 3b PP set and the Pooled mITT set. 
The null hypothesis (H0Efficacy) is as follows: H0Efficacy: VE ≤ 30%  
VE is estimated as 1-HR, where HR is the hazard ratio. The primary efficacy 
objective will be met if the lower limit of the 95% confidence interval (CI) 
for VE exceeds 30%.  
Under the assumptions of proportional hazards over time and a 50% 
reduction in hazard rate (50% VE) and with 1:1 randomization of 
ARCT-154 and placebo, a total of 372 confirmed COVID-19 cases will 
provide approximately 90% power to reject the null hypothesis (H0: VE ≤ 
30%), using a log-rank test statistic with a 1-sided false positive error rate of 
0.025. 
Phase 1/2/3a Substudy 
Data from Phases 1, 2 and 3a will be pooled for the analyses of 
immunogenicity and Safety up to Day 92. The total sample size for Phases 1, 
2 and 3a is primarily driven by the size of safety database required at the 
time of potential EUA application. Safety analyses will be performed in the 
Phase 1/2/3a SAS and Phase 1/2/3a RAS (Section 8.2). With approximately 
750 participants randomized in Phases 1/2/3a to receive ARCT-154 for the 
Phase 1/2/3a primary safety analysis, if the incidence rate of an adverse 
event is 1.0%, the probability to detect one event in 750 vaccinated 
participants is >99%, based upon the following formula:  
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 
where R = incidence rate and N = sample size 
The primary immunogenicity endpoint of Phase 1/2/3a will be evaluated in 
participants in the Phase 1/2/3a Immunogenicity Analysis Set (Section 8.2). 
It is defined as the proportion of participants in each study vaccine group 
that demonstrate seroconversion (defined as: 4-fold increase in titer from 
baseline) by surrogate virus neutralization assay at Day 57.  Sensitivity 
analyses will be performed in the Phase 1/2/3a per protocol (PP) set. 
The null hypothesis (H0Immunogenicity) is that the lower bound of the 95% CI 
for ARCT-154 seroconversion rate (SC154) is ≤ seroconversion rate for 
placebo (SCPlacebo); i.e., H0Immunogenicity: lower bound 95% CI for SC154 ≤ 
SCPlacebo.  A sample size of 750 and 250 participants in the ARCT-154 and 
placebo groups respectively will provide greater than 90% power to exclude 
the null hypothesis with a 1-sided type 1 error rate of 0.025 assuming that 
10% of participants are excluded from the analysis (for example, due to 
baseline seropositivity), and that SC154 >50% and SCPlacebo ≤10%. 
Phase 3c Substudy 
The primary safety endpoints of Phase 3c will be conducted in the Phase 3c 
Safety Analysis Set and Phase 3c Reactogenicity Analysis Set (Section 8.2). 
With a sample size of approximately 2,400 participants randomized and with 
approximately 1,200 participants randomized in the study to receive 
ARCT-154 or ChAdOx1 for the safety analysis, based upon the following 

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1.1 
Study Schematic 
The study schematic is presented in Figure 1. 
formula, if the incidence rate of an adverse event is 0.1%, the probability to 
detect one event in 1,200 vaccinated participants is 69.9% and, if the 
incidence rate is 1.0%, the probability is more than 99%: 
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 
where R = incidence rate and N = sample size 
The primary immunogenicity noninferiority endpoint for Phase 3c is the 
ratio of geometric mean concentrations (geometric mean ratio or GMR) for 
neutralizing antibody (using the pseudovirus microneutralization assay 
[MNT]) concentration and will be evaluated in participants in the Phase 3c-1 
Immunogenicity Analysis Set (Section 8.2). Sensitivity analyses will be 
performed in the Phase 3c PP set. International units (i.e., the WHO/NIBSC 
international reference standard) will be used if available. 
The null hypothesis (H0GMR) for the primary endpoint is as follows: 
H0GMR: R ≤ NIM 
Where R is the ratio of GMC (i.e., GMC for ARCT-154 arm / GMC for the 
ChAdOx1 arm) and NIM is the acceptable noninferiority margin (0.67). The 
null hypothesis will be rejected if the lower bound of the 95% confidence 
interval for GMR is > 0.67.  
Assuming a GMR of ≥0.9 and a coefficient of variation of variation of 4.6, a 
sample size of 800 participants in Phase 3c-1 will provide greater than 90% 
power to exclude a non-inferiority boundary of 0.67 based on the use of a 
one-sided test at the alpha=0.025 level of significance, accounting for a 
dropout rate of approximately 20-25% due to the national COVID-19 
vaccination campaign in Vietnam. 
A sequential/hierarchical testing procedure will be used to control type 1 
error rate over the Phase 3c primary endpoint and the secondary endpoints 
such that the secondary immunogenicity endpoints will only be tested if the 
null hypothesis is rejected for the primary endpoint and Phase 3c secondary 
endpoints numbers 1 through 5 will be tested sequentially using the same 
hierarchical test procedure with each endpoint only being tested if the null 
hypothesis is rejected for the preceding endpoint. 
Missing Data 
How missing data points will be handled will be described in the SAP. 

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Figure 1 
Study Schematic 
 
†Participants in Phase 2 and 3a that are randomized to receive ARCT-154 as the initial vaccination series will be 
further randomized to receive either ARCT-154 or placebo (in a 3:1 ratio) at Day 92 followed by placebo at 
Day 120.  Phase 2 and 3a participants that received placebo initially and Phase 1 and 3b participants switch over to 
the opposite vaccine at Day 92 and will receive this vaccine at both Day 92 and Day 120. 
*Immunogenicity analysis will involve approximately 800 participants enrolled in Phase 3c-1. 
 

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2 
INTRODUCTION 
2.1 
Background 
In January 2020, a novel variant of coronavirus was identified as the cause of an outbreak of 
severe pneumonia in China. This virus, severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2), was identified as the causative agent of a broad clinical spectrum of disease. 
Both symptomatic and asymptomatic infection in humans is caused by the SARS-CoV-2 virus, 
which is a positive strand ribonucleic acid (RNA) virus. A serious manifestation of the infection 
is a viral pneumonia that can progress to acute respiratory distress syndrome (ARDS), respiratory 
failure, and death. Clinical symptoms relating to other organ systems have also been described 
(Zhang 2020; Zaim 2020). Risk factors for more severe disease include age, male sex, 
pregnancy, ethnic minority status, and comorbidity, particularly chronic obstructive pulmonary 
disease, cancer, heart conditions (congestive heart failure, pulmonary hypertension, and coronary 
artery disease), immunocompromise, chronic renal failure, Type 2 diabetes, and obesity (CDC 
2020b; De Lusignan 2020; Williamson 2020; Wu 2021; Yang 2020; Li 2020; Zhou 2020; 
Grasselli 2020). Patients with severe lung disease require ventilatory support and mortality rates 
as high as 25% to >90% have been reported in these patients (Zhou 2020; Richardson 2020; 
Auld 2020; Phua 2020), although more recently mortality rates may be reducing as more is 
known about how best to manage severe disease with treatments such as recently authorized 
targeted monoclonal therapies (etsevimab, casirivimab, and imdevimab) and application of other 
therapeutic agents (remdesivir, tocolizumab, baricitinib, and corticosteroids) (NIH 2021). 
Over 188 million cases of coronavirus disease 2019 (COVID-19) have been confirmed 
worldwide and 4.1 million people have died as of July 2021 (WHO 2021), and the number of 
cases continues to grow in most countries. 
While the global incidence of COVID-19 appears to be slowing and some vaccines to prevent 
COVID-19 have been approved by health authorities of several countries in recent months, the 
number of cases remains unacceptably high in most countries, and there are significant supply 
limitations for these vaccines. More global access to vaccines to prevent COVID-19 is clearly 
needed. 
2.2 
Current Therapies for COVID-19 
COVID-19 is a complicated disease and optimal management is still evolving. As such, a 
comprehensive discussion is beyond the scope of this document. However, a number of 
treatment guidelines exist (WHO 2020; NIH 2020; Bhimraj 2020). Treatment of less severe 
disease involves isolation and largely symptom management. Severe disease requires 
supplemental oxygen ± mechanical ventilation, prevention of thromboembolic complications, 
and treatment of secondary infection. Progress has been made in the development and emergency 
use authorization of targeted monoclonal antibodies directed against SARS-CoV-2 (NIH 2021); 
however, the clinical application of these monoclonal antibodies is limited to non-hospitalized 
patients with mild to moderate symptoms and high risk of progression to severe COVID-19 
disease (NIH 2021; FDA 2021a; FDA 2021b). Application of -anti-inflammatory agents, such as 

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steroids, Interleukin-6 inhibitors, and Janus kinase inhibitors, have improved outcomes in 
hospitalized patients (NIH 2021). 
A critical component to addressing morbidity and mortality due to SARS-CoV-2 is the 
development of vaccines to prevent the spread of infection. In late 2020 and in early 2021, 
multiple companies have shared the results of pivotal trials examining vaccine candidates 
intended to prevent COVID-19 disease. This has led to the emergency use authorization 
approvals of several inactivated SARS-CoV-2 viral (Global Regulatory Partners 2021; Reuters 
2021a; WashingtonPost 2020), SARS-CoV-2 peptide (Turkmenistan Today 2021), SARS-CoV-2 
receptor binding domain (RBD) dimer (RBD dimer), adenoviral vector (EMA 2021a; EMA 
2021b; Reuters 2021b; Burki 2020), and non-self-replicating messenger RNA (mRNA) vaccines 
(FDA 2020b; FDA 2020c; EMA 2021c). While each of these vaccines has demonstrated 
promising early vaccine efficacy and these vaccines have been used in mass vaccination efforts, 
there remains a significant ongoing circulation of SARS-CoV-2, and vaccine rollout campaigns 
will take months or more across the globe. In this current situation of ongoing infection, lack of 
herd immunity, and incomplete vaccine rollout, there exists a new risk of evolutionary selection 
pressure on SARS-CoV-2. 
Ongoing global demand for vaccines is being fueled by the concern that the continued circulation 
of SARS-CoV-2 has led to the development of variants, such as D614G, and may ultimately 
become endemic. With these additional challenges in mind, it will be necessary to characterize 
vaccine durability of response as well as immunogenicity against homologous and heterologous 
SARS-CoV-2 strains, and to continue mass vaccinations to limit morbidity and mortality 
associated with SARS-CoV-2 (Sah 2021). 
2.3 
Therapeutic Rationale for ARCT-154 in Prevention of COVID-19 
SARS-CoV-2 is a novel virus belonging to the β-coronavirus genus. Coronavirus host cell 
infection is mediated by the attachment of the transmembrane spike (S) glycoprotein to host cell 
receptors and subsequent fusion with host cell membranes. The S glycoprotein forms 
homotrimers protruding from the viral surface (Tortorici 2019) and can be divided into 
4 subdomains; S1, S2, transmembrane, and internal domain or endodomain. The S1 domain 
contains the RBD, which allows SARS-CoV-2 to directly bind to the peptidase domain of the 
angiotensin-converting enzyme 2 (ACE-2) receptor expressed on epithelial cells in the lungs, 
heart, kidneys, and gastrointestinal tract. Hence, antibodies to the S glycoprotein, especially the 
RBD, should block viral entry into cells expressing the ACE-2 receptor and thereby prevent 
infection. 
Two conventional mRNA vaccines have established marked vaccine efficacy, and the data from 
the pivotal trials establishing vaccine efficacy has led to the emergency use authorization and/or 
conditional marketing authorizations of these vaccines (see FDA 2020b; FDA 2020c; EMA 
2020; EMA 2021a). However, the ability of post-vaccination serum from these vaccines to 
neutralize the B.1.351 and D614G variants is reduced (Zhou 2021; Wu 2021; Zou 2021), 
resulting in concerns that they may not provide such effective protection against this variant. 
Evaluation of additional mRNA vaccines, the pursuit of an immune correlate of protection, and 
characterization of the vaccine efficacy of these other mRNA vaccines against variants of 
concern remain ongoing at the time of this protocol finalization. 

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2.4 
Mechanism of Action 
Arcturus Therapeutics has developed a series of vaccines intended for the prevention of 
COVID-19 disease based on its mRNA technology. Two of these vaccines are referred to as 
ARCT-154 (the vaccine that will be used in this study) and ARCT-021 (a vaccine that is 
currently under evaluation in other clinical studies). 
ARCT-021 and ARCT-154 each contain Arcturus’ proprietary self-transcribing and -replicating 
RNA (STARR™) technology, an RNA replicon construct based on the alphavirus, Venezuelan 
equine encephalitis virus (VEEV). The replicon for ARCT-021 (mRNA-2002) consists of a 
replicase gene and an RNA sequence encoding the Wuhan strain SARS-CoV-2 S glycoprotein. 
The replicon for ARCT-154 (mRNA-2105) consists of a replicase gene and an RNA sequence 
encoding the SARS-CoV-2 S glycoprotein containing the D614G variant mutation. The final 
drug product for both vaccines includes an RNA replicon formulated with Arcturus’ proprietary 
lipid nanoparticle (LNP) technology (LUNAR®), including 4 different lipid nanoparticles. More 
detail relating to these vaccines is included in the Investigator’s Brochure (IB). 
Alphaviruses are enveloped viruses with a positive strand RNA genome. Upon infection, the 
genomic RNA serves as a template for translation of 4 viral nonstructural proteins that form 
replicase complexes. These complexes synthesize viral genomic and subgenomic RNA, the latter 
of which serves as a template for translation of viral structural proteins, which then assembles 
with genomic RNA into new infectious viral particles. By replacing the RNA coding for 
structural proteins with RNA coding for a protein antigen of interest (in this case the 
SARS-CoV-2 D614G S glycoprotein), the self-replicating machinery of the alphavirus can be 
used to generate sustained expression of the antigen, making such alphavirus replicon constructs 
an attractive tool for vaccines. These replicon RNAs, which do not encode the compliment of 
structural genes necessary for assembly of virus particles and do not contain reverse transcriptase 
that converts the RNA genome into complementary deoxyribonucleic acid (DNA), replicate 
exclusively in the cytoplasm and cannot introduce their genetic material into the cellular genome. 
A more detailed description of the mechanism of mRNA amplification and the biochemical 
functions for each of the nonstructural proteins is described in Rupp 2015. 
On entry into the cytoplasm, the replicase gene, encoding the 4 nonstructural proteins (nsPs) 
(nsP1 to nsP4), is translated from mRNA-2105 producing only the replicase proteins as a single 
polyprotein. The RNA-dependent RNA polymerase, nsP4, is released from the polyprotein and, 
in combination with the remaining nsP123 polyprotein, transcribes the complementary RNA 
strand of the entire mRNA-2105, including the SARS-CoV-2 S glycoprotein RNA and poly A 
tail. The remaining polyprotein is processed into nsP1, nsP2, and nsP3 and, in combination with 
nsP4, transcribes only the 5’-G-methyl capped S glycoprotein mRNA from the 3’-5’ 
complementary strand of mRNA-2105. The multiple copies of S glycoprotein mRNA transcript 
are then translated to produce full-length S glycoprotein, which is the vaccine antigen. Cleavage 
of the nsP123 polyprotein into its component nsPs terminates transcription of the complementary 
RNA (Rupp 2015). Remaining complementary RNA and S glycoprotein mRNA is then degraded 
by intracellular nucleases thereby terminating production of the antigen.  

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During the process of self-replication, a double-stranded RNA intermediate is produced that has 
immunostimulatory properties activating the innate immune system, ultimately enhancing the 
adaptive immune response to the expressed S glycoprotein and thereby behaving as an adjuvant. 
At the injection site, the LNP-formulated RNA is taken up by antigen-presenting cells and 
myocytes, the former of which traffic to regional lymph nodes where they present the vaccine 
antigen to CD4+ T cells and CD8+ T cells, resulting in their activation. Antigen can be detected 
in regional lymph nodes within hours of injection (Liang 2017; Lindsay 2019). 
Interleukin-2 from activated CD4+ T cells is subsequently important in the terminal 
differentiation of the activated, antigen-specific CD8+ T cells (Zhang 2011). Although the 
immunological events leading to antibody responses elicited by RNA vaccines have yet to be 
fully elucidated, T follicular helper (Tfh) cells, which are a subset of CD4+ cells, are required to 
develop germinal center responses and drive immunoglobulin class switch, affinity maturation, 
and long-term B cell memory (Pardi 2018) and strong induction of antigen-specific Tfh cells has 
been demonstrated following vaccination with mRNA vaccines (Lindgren 2017). 
2.5 
Nonclinical Experience with ARCT-154 
Nonclinical studies have characterized the protective effects of vaccination with ARCT-021 and 
the immunogenicity of vaccination with ARCT-021 and ARCT-154 in mouse and non-human 
primate (NHP) models. For full details, please see the IB. 
Immunogenicity data from NHP support that two doses of ARCT-154 lead to high antibody 
titers. As shown below, surrogate virus neutralization (sVNT) Ab responses for four strains of 
SARS-CoV-2, including variants of concern, exceed 87% in all four SARS-CoV-2 strains 
evaluated (Figure 2), and pseudovirus neutralization titers confirm robust responses to VOC, 
including the delta variant (Figure 3).  
 
Figure 2 
sVNT Antibody Responses to ARCT-154 in Non-Human Primates 
 

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Figure 3 
Pseudoneutralization Data from NHPs After Two Doses of ARCT-154 
Vaccine 
 
Results from the Saphire laboratory (La Jolla Institute for Immunology) using VSV pseudotyped with variant 
SARS-CoV-2 spike proteins 
 
Because the principal differences between ARCT-021 and ARCT-154 are primarily limited to the 
SARS-CoV-2 variant spike protein that is expressed, these changes only constitute a change of 
antigen within a platform, consistent with the “platform” approach described in relevant 
regulatory guidances (FDA 2020d; EMA 2021d). As such, nonclinical tissue distribution data, 
Good Laboratory Practices toxicology data, and prior human clinical trial data generated with 
ARCT-021 are used to support clinical development of ARCT-154. Please refer to the IB for a 
description of the results of nonclinical studies conducted with ARCT-021. 
2.6 
Clinical Trial Experience with the LUNAR COVID-19 Vaccines (ARCT-021 and 
ARCT-154) 
At the time of finalization of this protocol (Version 1.0), no clinical trials have been conducted 
with ARCT-154. However, ARCT-154 is based upon the similar LNP-formulated RNA vaccine 
construct, ARCT-021, which has been evaluated in 3 clinical trials. Collectively, ARCT-154 and 
ARCT-021 are referred to as the LUNAR COVID-19 vaccines throughout this protocol.  The 3 
ARCT-021 clinical trials include a Phase 1/2 clinical trial (ARCT-021-01) in healthy adult 
participants in Singapore, which has completed (final report pending); an open-label extension 
trial (ARCT-021-02) following on from ARCT-021-01, which is ongoing, and a Phase 2 trial 
(ARCT-021-04), which is ongoing in the USA and Singapore. The interim analyses of these 
studies, which have enrolled more than 600 participants, is described in detail in the IB.  

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ARCT-021 has been administered to more than 500 participants in these clinical trials. The data 
that are shared in this protocol are regarded as draft but inform the characterization of the safety 
and immunogenicity profile and thereby the preferred dose for use in later-phase trials. The data 
from the ARCT-021-04 trial have been shared with the independent DSMB that has endorsed the 
continuation of the study without modification. 
Analysis of the open-label extension study ARCT-021-02 has not yet been conducted.  
At the time of second Interim Analysis, the Phase 2 study (ARCT-021-04) had completed 
enrollment of 426 participants, with no SAEs related to study vaccine, and 8 AEs which led to 
discontinuation.  Across the analyzed clinical trials to date, ARCT-021 has been generally safe 
and well tolerated at doses ≤7.5 µg. 
Most (>90%) ARCT-021-treated participants in each study experienced at least one solicited AE. 
In each study, the majority of solicited events were Grade 1/mild or Grade 2/moderate. A single 
participant reported Grade 4 solicited events (dizziness, fatigue, nausea, chills, headache).  
The most common solicited AEs were injection site pain, injection site tenderness, headache, 
fatigue, myalgia, arthralgia and chills. The majority of solicited events had onset on the day after 
dosing and were no longer reported by the end of 7 days post-dose.  
Solicited AE reporting does not appear to increase with second dose of ARCT-021 and solicited 
AE reporting may be less frequent in older participants  
Unsolicited AE reporting is less frequent following ARCT-021 as compared to solicited AEs. 
The most common unsolicited AEs in both studies include headache, fatigue, injection site 
tenderness, diarrhea, elevated CPK, neutropenia, lymphopenia, urticaria and hematuria (which 
was not confirmed on microscopy).  
Overall, no trends for vaccine-related abnormalities were observed in ECGs (evaluated in the 
ARCT-021-01 study only) or vital signs following vaccination with ARCT-021. Other safety 
laboratory assessments with patterns of interest include declining hemoglobin values (most likely 
due to blood sampling during trial participation), slight shifts in potassium values, and slight 
shifts in lymphocyte and neutrophil count. These laboratory abnormalities have been 
asymptomatic, and the minority have been reported as clinically significant changes.  
Transient, asymptomatic lymphopenia and neutropenia have been observed with other mRNA 
SARS-CoV-2 vaccines (Mulligan 2020; Sah 2021; Sahin 2020; VRBPAC 2020), however, 
lymphopenia is thought to be a normal physiological response (innate immune-stimulation-
related redistribution of lymphocytes into lymphoid tissues) to immune stimulation from the 
vaccine (Sah 2021; Sahin 2020). 
Immunogenicity results following vaccination with ARCT-021 showed a robust IgG immune 
response to the full-length SARS-CoV-2 spike glycoprotein at all doses evaluated. At doses 
≥3 µg, GMT for PRNT50 neutralizing antibody responses tested with a clinical isolate of 
SARS-CoV-2 were within the range of titers observed in convalescent plasma from COVID-19 
patients tested in the same assay at the same laboratory. Spike-specific T-cell responses were 
observed in response to stimulation with peptides from the spike glycoprotein and the CD4+ 
response was Th1-dominant.  

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The evaluation of safety data across the hundreds of participants dosed with ARCT-021 
demonstrates that the vaccine leads to mild to moderate, transient AEs following vaccination for 
the majority of individuals. Overall AE reporting may decrease with second vaccination.  
Taken together, the favorable safety profile and clear signs of immunogenicity to the vaccine 
antigen of ARCT-021, given the fundamental similarities between the ARCT-021 and 
ARCT-154 vaccines and, given the encouraging nonclinical data supporting immune responses 
to SARS-CoV-2 variants, support the continued clinical development of these vaccines intended 
to prevent COVID-19. 
2.7 
Rationale for Dose Regimen Selection 
The dose and schedule of ARCT-154 used in this study are based on the evaluation of both 
preclinical and clinical data arising from the ARCT-021 program. As ARCT-154 includes the 
same lipid nanoparticle formulation and RNA encoding for a replicon and a SARS-CoV-2 spike 
protein (albeit spike proteins with minor differences in amino acid composition), the safety and 
immunogenicity profile is expected to be informed by the experience with ARCT-021. 
The doses selected for the vaccination series in this study are based on data from the following 
sources:  
• Study ARCT-021-01: a Phase 1/2 dose ranging study enrolling younger adults (21 to 
55 years of age) and older adults (56 to 80 years of age). In this study, 2 doses of 5.0 µg 
(separated by 28 days) were well tolerated and immunogenic in younger and older adults. 
• Repeat-dose toxicity studies in rabbits: in these studies, rabbits were given 2 or 3 doses of 
either 20 µg or 40 µg ARCT-021 separated by 14 days. In these dosed animals, 
ARCT-021 was associated with continued increases in anti SARS-CoV-2 IgG levels and 
the NOAEL was assigned at the highest dose evaluated (40 µg) based on the safety 
profile. These data support the administration of up to 3 doses of ARCT-154 (including 
the two priming vaccination doses of 5.0 µg ARCT-154 planned for administration to 
participants in this study). 
Administration of a 3rd dose of ARCT-154 to participants in Phase 2/3a allows the opportunity to 
evaluate the neutralizing antibody of activity of a 3rd (booster) dose of ARCT-154 against 
variants of concern, and in particular the newly identified omicron variant.  Early data indicates 
that neutralizing antibody activity against omicron following two doses of other RNA vaccines 
may be substantially less than against other variant strains, but that activity following a third 
dose is considerably improved (Pfizer 2021).  
Further details on ARCT-021 and ARCT-154 can be found in the Investigator’s Brochure. 
2.8 
Risk: Benefit Assessment 
2.8.1 
Potential Risks 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of the LUNAR COVID-19 vaccines is provided in the IB. The expected benefits and risks 
of ChAdOx1 are summarized in the approved label for this vaccine. This reference material is 

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provided separately.  In addition to the risk mitigation measures incorporated into the study 
design, a summary of the potential risks of treatment with the LUNAR COVID-19 vaccines, 
together with potential mitigation for these risks, is shown in Table 1. 
 
Table 1 
Risk Minimization Measures Included in Clinical Trials of LUNAR 
COVID-19 Vaccines 
Risk 
Mitigation 
Local and Systemic Reactogenicity 
 
Vaccination via the intramuscular route results in a lower 
rate of local reactions than intradermal (I.D.) or 
subcutaneous (S.C.) injection (Zhang 2015).  
 
Local injection site reactions and systemic AEs such as 
headache, fever, myalgia, or arthralgia may be treated with 
acetaminophen (paracetamol), ibuprofen, or other 
non-steroidal anti-inflammatory drugs and/or with topical 
agents (eg, ice or heat); however, administration of these 
agents within 24 hours prior to study vaccine administration 
is prohibited. Allergic AEs may be treated with 
corticosteroids or H1/H2 blockers as indicated and if not 
otherwise contraindicated. 
 
For anaphylaxis or immediate type hypersensitivity 
(≤4 hours after injection) of at least moderate severity 
following the administration of the study vaccine, 
subsequent doses of study vaccine will not be administered. 
VAERD if subsequently infected with 
SARS-CoV-2 
 
Risk minimization measures to date have included ongoing 
characterization of the immune responses in nonclinical and 
clinical studies. These demonstrate that vaccination with 
ARCT-021 leads to reduction in viral replication (NHP and 
mouse data), protection from COVID-19 disease (NHP and 
mouse data), no evidence of lung injury (NHP data), and 
Th1-biased immune response (mouse and human data). 
 
In this study, an independent DSMB or other safety 
committee will assess all cases of severe COVID-19 for 
imbalance in order to assess the risk of VAERD. The 
DSMB will make recommendations concerning modifying 
or stopping the study in order to manage any risk(s) 
identified 
Abbreviations: AE=adverse events; COVID-19=coronavirus disease 2019; DSMB=Data and Safety Monitoring 
Board; H=histamine; I.D.=intradermal; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
S.C.=subcutaneous; Th=T helper; Th1=T helper Type 1; VAERD=vaccine-associated enhanced respiratory 
disease 
Other potential risks of trial participation beyond those associated with study vaccine include 
risks relating to blood sampling and breach of confidentiality. 
Blood sampling may be associated with transient asthenia, risk of fainting, and bruising or 
infection at the blood sampling site. Risk of infection is reduced by cleansing of the skin prior to 
blood withdrawal. Risk of fainting is reduced by performing blood sampling with the participant 
in a seated position. 

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As study participation involves provision of personal health information by the participant to the 
site staff, measures are in place to reduce the risk of sharing of this personal information with 
others. Measures include maintenance of personal information in secure locations (eg, locked file 
cabinets and/or password-protected electronic filing systems). Only personnel involved in the 
conduct, oversight, monitoring, or auditing of this trial will be allowed access to this personal 
information that is collected. All publications from this study will not disclose personal 
information of the participants. Study results disclosed in public locations, such as 
ClinicalTrials.gov, will not include personal information of any enrolled participant. 
There may be other risks, discomforts, or side effects from participation in this study that are 
currently unknown. 
2.8.2 
Potential Benefits 
As the ARCT-154 has not yet been licensed for approval, the benefit of the vaccine has not been 
reviewed and approved by a health authority. Therefore, there is no direct benefit to study 
participants receiving ARCT-154 or placebo beyond a potential benefit to society resulting from 
improved understanding of investigational vaccines to prevent COVID-19 disease. For 
participants enrolled in Phase 3c, the benefit of study participation includes the possibility of 
randomization to an authorized vaccine (ChAdOx1) that may reduce the risk of COVID-19 
disease. However, vaccination with either ARCT-154 or ChAdOx1 may or may not provide 
protection against SARS-CoV-2 infection and COVID-19 disease. Vaccination with placebo is 
not expected to provide protection against SARS-CoV-2 infection. For participants in Phase 1 
and 3b and placebo participants in Phase 2 and Phase 3a, the study design includes a Switchover 
component. This allows participants who remain in the study to receive 2 doses of both study 
vaccines (ARCT-154 and placebo). While it is much preferred that participants forego 
vaccination against COVID-19 with other non-study vaccines during study participation, 
participants will not be denied access to these vaccines. Participants who elect to receive a non-
study COVID-19 vaccine (Section 6.8.1) that is approved for use in Vietnam, recommended for 
their age group/underlying medical condition, and that is made available to them will not be 
allowed to participate in the Switchover portion of the study but will be asked to continue 
study -related procedures (Section 5.2.2). 
2.8.3 
Overall Risk: Benefit Assessment 
Preclinical and clinical studies have been initiated with investigational LUNAR COVID-19 
vaccines intended to prevent COVID-19 disease. This protocol includes measures taken to 
minimize risks to potential study participants. In addition, the available data reflect that the 
LUNAR COVID-19 vaccines are immunogenic and well-tolerated. This favorable risk/benefit 
profile supports further evaluation of ARCT-154 in this Phase 3 clinical study. 

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3 
OBJECTIVES AND ENDPOINTS 
Note, full details of the analysis populations and rules for handling intercurrent events are 
included in Sections 8.2 and 8.3.1, respectively. 
In interpreting the objectives and endpoints for this study, the following considerations will 
apply: 
• 
The overall primary efficacy endpoint for the study is vaccine efficacy (VE) as 
evaluated in the Phase 3b Modified Intent to Treat (mITT) population 
• 
The overall primary safety endpoints are those evaluated in the Phase 3b Safety 
Analysis Set (SAS) and Phase 3b Reactogenicity Analysis Set (RAS) 
• 
Phase 1/2/3a and subgroups thereof constitute a substudy with separate objectives and 
endpoints. As these constitute a substudy, and there is no evaluation of efficacy for 
this substudy, no adjustment of type 1 error is applied to the overall efficacy primary 
endpoint 
• 
The Pooled Efficacy endpoint is only evaluated as exploratory, so no adjustment of 
type 1 error is applied to the overall efficacy primary endpoint 
• 
Phase 3c and subgroups thereof also constitute a substudy with separate objectives 
and endpoints. As these constitute a substudy, and efficacy for this study is only 
evaluated as exploratory, no adjustment of type 1 error is applied to the overall 
efficacy primary endpoint. 
3.1 
Phase 1/2/3a Substudy 
Immunogenicity data from participants in Phases 1, 2 and 3a will be pooled for analysis up to 
Day 92. With implementation of protocol version 8.0, participants in Phase 2 and 3a that 
received ARCT-154 in the initial vaccination series are further randomized to receive a 3rd 
vaccination of either ARCT-154 or placebo at Day 92 followed by placebo at Day 120 in order 
to compare immunogenicity after 3 injections of ARCT-154 with that after 2 injections. 
Therefore, after Day 92 only data from Phase 2/3a will be pooled and will be displayed 
separately from participants in Phase 1. 
Safety data from participants in Phase 2/3a will be pooled for all time points and will be 
displayed separately to safety data from Phase 1.   
3.1.1 
Phase 1/2/3a Substudy Primary Objectives and Endpoints 
The primary objectives and endpoints for Phase 1/2/3a are presented in Table 2.  

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Table 2 
Phase 1/2/3a Substudy Primary Objectives and Endpoints 
Phase 1/2/3a Primary Objectives 
Endpoint Description 
1. To assess the safety and reactogenicity
of ARCT-154 compared to placebo
Safety will be evaluated in all participants in Phase 1 and 
Phase 2/3a Safety Analysis Sets (SAS, Section 8.1) and will be 
summarized for each vaccination as number and percentage of 
participants with: 
Any unsolicited AE starting within 28 days after each 
study vaccine administration, summarized by severity 
and relationship to study vaccine.  
Any medically attended adverse event (MAAE), serious 
adverse event (SAE), or AE leading to 
discontinuation/withdrawal through Final Visit/Early 
Termination (ET) summarized by relationship to study 
vaccine. 
Reactogenicity will be evaluated in in the Phase 1 and Phase 2/3a 
Reactogenicity Analysis Sets (RAS) and will be summarized 
following vaccinations on Day 1 and Day 29 only in Phase 1 and 
Day 1, Day 29, and Day 92 in Phase 2/3a as the number and 
percentage of participants with: 
Any solicited local or systemic AE starting within 7 days 
after each study vaccine administration by toxicity grade. 
Additional safety analyses in the Phase 1/2/3a SAS may also be 
performed as exploratory. 
2. To assess the neutralizing antibody
(NAb) responses to ARCT-154 by
surrogate virus neutralization test at
Day 57
Neutralizing antibody (NAb) responses by surrogate virus 
neutralization test (sVNT) will be evaluated at Day 1 (baseline) 
and Day 57 for assessment of seroconversion in all participants in 
the Phase 1/2/3a Immunogenicity Analysis Set (IAS (Section 8.2). 
The endpoint is defined as the proportion of participants 
in each study vaccine group that demonstrate 
seroconversion (defined as: 4-fold increase in antibody 
concentration from baseline).  
Data will be summarized according to use of international 
reference standards, if available.  
Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; MAAE=medically attended adverse 
event; SAE=serious adverse event; ET=early termination 

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3.1.2 
Phase 1/2/3a Substudy Secondary Objectives and Endpoints 
The secondary objectives and endpoints for Phase 1/2/3a are presented in Table 3. 
Table 3 
Phase 1/2/3a Secondary Objectives and Endpoints 
Phase 1/2/3a Secondary Objectives 
Endpoint Description 
1. To assess the neutralizing and IgG 
binding antibody immune responses to 
ARCT-154 over time 
Immunogenicity will be at the following time points.  
• 
Phase 1 IAS: Day 1 (baseline), Day 29, Day 57, Day 92, 
Day 394. 
• 
Phase 2/3a IAS: Day 1 (baseline), Day 29, Day 57, Day 
92, Day 120, Day 394 
• 
Phase 1/2/3a IAS: Day 1 (baseline), Day 29, Day 57, Day 
92 
The following will be evaluated: 
 
Neutralizing antibody (NAb) by surrogate virus 
neutralization test (sVNT) and IgG antibody binding the 
full-length SARS-CoV-2 spike protein (binding antibody 
[BAb]) responses will be evaluated; assessments for both 
NAb and BAb will include:   
o 
Antibody level: GMC (BAb and NAb)  
o 
Increase in antibody levels from baseline 
(GMFR or other measure, as appropriate for the 
assay concerned) 
o 
Proportion of participants in each study vaccine 
group with seroconversion at each timepoint. 
Note: NAb responses at Day 57 evaluated as 
primary. 
Data will be summarized according to use of international 
reference standards, if available. 
Full details will be provided in the statistical analysis plan. 
2. To assess early neutralizing antibody 
responses using a live virus assay 
NAb responses by plaque reduction neutralization test at 50% 
reduction (PRNT50) will be evaluated in the subset of the 
Phase 1/2 IAS (Section 8.2) comprising all participants enrolled in 
Phase 1 and the first 50 evaluable participants in Phase 2 at Day 1 
(baseline), Day 29 and Day 57. 
The following endpoints will be assessed: 
 
Geometric mean antibody concentration (GMC)  
 
Increase in antibody levels from baseline (GMFR) 
 
Proportion of participants in each study vaccine group 
with seroconversion 
Abbreviations: GMT=geometric mean titer; GMC=geometric mean concentration; GMFR=geometric mean-
fold rise 
3.1.3 
Phase 1/2/3a Substudy Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints for Phase 1/2/3a are presented in Table 4. 

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Table 4 
Phase 1/2/3a Exploratory Objectives and Endpoints 
Phase 1/2/3a Exploratory Objectives 
Endpoint Description 
1. To compare the humoral immune 
responses to ARCT-154 with those 
following COVID-19  
Day 57 GMT/GMC results following vaccination with ARCT-154 
may be compared with the comparable test results for 
convalescent sera from COVID-19 patients measured on the same 
assay for the subset of the Phase 1/2/3a IAS comprising all 
participants enrolled in Phase 1 and the first 50 evaluable 
participants in Phase 2. The following assays will be used: 
• 
PRNT50 
• 
MNT 
Immune responses may also be assessed at additional time points 
and/or in additional participants in Phase 2 and Phase 3a. If 
performed this will be described in the statistical analysis plan 
(SAP). 
For the MNT assay, data will be summarized according to use of 
international reference standards, if available   
2. To evaluate the efficacy of ARCT-154 
versus placebo for the prevention of 
virologically confirmed COVID-19 
Efficacy may be evaluated in all participants in the Phase 1/2/3a 
Modified Intent to Treat (mITT) set (Section 8.1). The endpoint to 
be evaluated is as follows: 
• The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset between Day 36 and Day 
92 inclusive. 
Efficacy may also be evaluated in participants that have received 
any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as 
follows: 
• The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset at any time after the first 
study vaccination and up to Day 92. 
 
3. To assess the neutralizing antibody 
immune responses to ARCT-154 to 
SARS-CoV-2 variants of 
concern/variants of interest following 
2 and 3 vaccinations with ARCT-154 
Blood samples from post-vaccination timepoints may be evaluated 
for immune responses to SARS-CoV-2 variants of 
concern/variants of interest for the following groups/time points: 
• 
The subset of the Phase 1/2/3a IAS comprising all 
participants enrolled in Phase 1 and the first 50 
participants in Phase 2; evaluated at Day 1 (baseline) and 
Day 57.  
• 
The subset of the Phase 2/3a IAS comprising the first 150 
participants that received ARCT-154 in the initial 
vaccination series in Phase 2; evaluated at Day 1 
(baseline), Day 57 and Day 120. 
The following assays may be used: 
• 
PRNT50 
• 
sVNT 
• 
MNT 
 

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Table 4 
Phase 1/2/3a Exploratory Objectives and Endpoints 
4. To assess neutralizing antibody 
responses using a pseudovirus 
microneutralization test (MNT) 
following 2 (Day 57) and 3 (Day 120) 
vaccinations with ARCT-154 
NAb responses by microneutralization test (MNT) will be 
evaluated for the following groups/time points: 
• 
The subset of the Phase 1/2/3a IAS comprising all 
participants enrolled in Phase 1 and the first 50 evaluable 
participants in Phase 2 at Day 1 (baseline) and Day 57.  
• 
The subset of the Phase 2/3a IAS comprising the first 150 
participants that received ARCT-154 in the initial 
vaccination series in Phase 2; evaluated at Day 1 
(baseline), Day 57 and Day 120. 
The following endpoints will be assessed: 
o 
Geometric mean antibody concentration (GMC)  
o 
Increase in antibody levels from baseline 
(GMFR) 
o 
Proportion of participants in each study vaccine 
group with seroconversion. 
Data will be summarized according to use of international 
reference standards, if available. 
5. To assess the neutralizing antibody 
(NAb) responses by surrogate virus 
neutralization test to ARCT-154 
following 2 (Day 57) and 3 (Day 120) 
vaccinations with ARCT-154 in 
Phase 2/3a participants 
Neutralizing antibody (NAb) responses by surrogate virus 
neutralization test (sVNT) will be evaluated at Day 1 (baseline), 
Day 57 and Day 120 for assessment of seroconversion in all 
participants in the Phase 2/3a IAS that received ARCT-154 in the 
initial vaccination series 
 
The endpoint is defined as the proportion of participants 
that demonstrate seroconversion (defined as: 4-fold 
increase in antibody concentration from baseline). 
Data will be summarized according to use of international 
reference standards, if available. 
6. To assess the IgG binding antibody 
responses to ARCT-154 following 2 
(Day 57) and 3 (Day 120) vaccinations 
with ARCT-154 in Phase 2/3a 
participants 
IgG antibody binding the full-length SARS-CoV-2 spike protein 
(binding antibody [BAb]) responses will be evaluated at Day 1 
(baseline), Day 57 and Day 120 in all participants in the Phase 
2/3a IAS that received ARCT-154 in the initial vaccination series. 
The following endpoints will be assessed: 
o 
Geometric mean antibody concentration (GMC)  
o 
Increase in antibody levels from baseline 
(GMFR) 
o 
Proportion of participants in each study vaccine 
group with seroconversion. 
Data will be summarized according to use of international 
reference standards, if available. 
Abbreviations: COVID-19=coronavirus disease 2019 

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3.2 
Phase 3b  
3.2.1 
Phase 3b Primary Objectives and Endpoints 
The primary objectives and endpoints for Phase 3b are presented in Table 5. These form the 
primary objectives and endpoints for the study overall. 
Table 5 
Phase 3b Primary Objectives and Endpoints 
Phase 3b Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 
compared to placebo 
Safety will be evaluated in all participants in the Phase 3b SAS 
and will be summarized for each vaccination as number and 
percentage of participants with: 
 
Any unsolicited AE starting within 28 days after each 
study vaccine administration, summarized by severity 
and relationship to study vaccine.  
 
Any medically attended adverse event (MAAE), serious 
adverse event (SAE), or AE leading to 
discontinuation/withdrawal through Final Visit/Early 
Termination (ET) summarized by relationship to study 
vaccine. 
Reactogenicity will be evaluated in the Phase 3b RAS and will be 
summarized following vaccinations on Day 1 and Day 29 only as 
the number and percentage of participants with: 
 
Any solicited local or systemic AE starting within 7 days 
after each study vaccine administration by toxicity grade. 
2. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of virologically confirmed 
COVID-19 
Efficacy will be evaluated in all participants in the Phase 3b 
mITT. The endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset between Day 36 and 
Day 92 inclusive. 
Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; MAAE=medically attended adverse 
event; SAE=serious adverse event; ET=early termination 
 
3.2.2 
Phase 3b Secondary Objectives and Endpoints 
The exploratory objectives and endpoints for Phase 3b are presented in Table 6. 
Table 6 
Phase 3b Secondary Objectives and Endpoints  
Phase 3b Secondary Objectives 
Endpoint Description 
1. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed severe 
COVID-19  
Efficacy will be evaluated in all participants in the Phase 3b mITT. 
The endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset between 
Day 36 and Day 92 inclusive. 
 

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Table 6 
Phase 3b Secondary Objectives and Endpoints 
Phase 3b Secondary Objectives 
Endpoint Description 
2.
To evaluate the efficacy of
ARCT154 and placebo for the
prevention of virologically
confirmed COVID-19 at any time
after first vaccination
Efficacy will be evaluated in all participants in the Phase 3b mITT 
who have received any dose of study vaccine in the first vaccination 
series, with no evidence of infection prior to vaccination. The 
endpoint is as follows: 
•
The first occurrence of confirmed, protocol-defined
(Appendix 2) COVID-19 with onset at any time after the 
first study vaccination and up to Day 92 inclusive.
3.
To evaluate the efficacy of
ARCT-154 versus placebo for the
prevention of death due to
COVID-19
Efficacy will be evaluated in all participants in the Phase 3b mITT. 
The endpoint is as follows: 
The endpoint is the occurrence of death attributed to 
COVID-19 occurring between Day 36 and Day 92 
inclusive. 
4.
To evaluate the efficacy of ARCT-
154 and placebo for the prevention of
virologically confirmed COVID-19
regardless of baseline status for
evidence of prior SARS-CoV-2
infection
Efficacy will be evaluated in all participants in the Phase 3b mITT. 
The endpoint to be evaluated is as follows: 
•
The first occurrence of confirmed, protocol-defined
(Appendix 2) COVID-19 with onset between Day 36 and
Day 92 inclusive.
Abbreviations: COVID-19=coronavirus disease 2019; SARS-CoV-2=severe acute respiratory syndrome 
coronavirus 2 
3.2.3 
Phase 3b Exploratory Objectives and Endpoints 
The Phase 3b exploratory objectives and endpoints for the study are presented in Table 7. 
Table 7 
Phase 3b Exploratory Objectives and Endpoints 
Phase 3b Exploratory Objectives 
Endpoint Description 
1.
To evaluate the efficacy of
ARCT-154 and placebo for the
prevention of virologically
confirmed severe COVID-19 at any
time after first vaccination
Efficacy may be evaluated in all participants in the Phase 3b mITT 
that have received any dose of study vaccine in the first vaccination 
series, with no evidence of infection prior to vaccination. The 
endpoint is as follows: 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset at any time 
after the first study vaccination and up to Day 92. 
2.
To evaluate the efficacy of ARCT-
154 and placebo for the prevention of
death due to COVID-19 at any time
after first vaccination
Efficacy may be evaluated in all participants in the Phase 3b mITT 
that have received any dose of study vaccine in the first vaccination 
series. The endpoint is as follows: 
The occurrence of death attributed to COVID-19 occurring 
at any time after the first study vaccination and up to Day 
92.

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Table 7 
Phase 3b Exploratory Objectives and Endpoints  
Phase 3b Exploratory Objectives 
Endpoint Description 
3. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed COVID-19 
at any time after first vaccination 
regardless of baseline status for 
evidence of prior SARS-CoV-2 
infection 
Efficacy may be evaluated in all participants in the Phase 3b mITT 
that have received any dose of study vaccine in the first vaccination 
series, regardless of baseline status for evidence of prior SARS-
CoV-2 infection. The endpoints are as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset at any time after the 
first study vaccination and up to Day 92. 
4. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed SARS-CoV-
2 by specific strain 
Efficacy will be evaluated in participants in Phase 3b mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 for all participants infected with 
the same strain of SARS-CoV-2, with onset between 
Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in 
participants under evaluation for COVID-19 will be retained for 
possible future testing to identify the SARS-CoV-2 strain detected in 
the COVID-19 case. 
5. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed severe 
SARS-CoV-2 by specific strain 
Efficacy will be evaluated in participants in Phase 3b mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 for all participants 
infected with the same strain of SARS-CoV-2, with onset 
between Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in 
participants under evaluation for COVID-19 will be retained for 
possible future testing to identify the SARS-CoV-2 strain detected in 
the COVID-19 case. 
6. To evaluate an immune correlate 
associated with reduced risk of 
COVID-19 
 
Blood samples drawn at Baseline and Day 57 in all 
participants will be held for potential future testing for 
evaluation of a correlate of protection. 
 
3.3 
Phase 3c Substudy 
3.3.1 
Phase 3c Substudy Primary Objectives and Endpoints 
The primary objectives and endpoints for Phase 3c are presented in Table 8. The first 
approximately 1,500 participants in Phase 3c will be enrolled into Phase 3c-1, the group that will 
have blood drawn for immunogenicity assessments. Data from 800 participants in this subgroup 
will be used to establish the noninferiority of immunogenicity of ARCT-154 vaccine as 
compared to ChAdOx1. Samples from the remaining 700 participants in Phase 3c-1 will be 
retained for potential future immunological testing, for example against newly emerging variants 
of concern. Safety evaluations will be based on all participants in Phase 3c. 

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Table 8 
Phase 3c Substudy Primary Objectives and Endpoints  
Phase 3c Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 and 
ChAdOx1  
Safety will be evaluated in all participants in the Phase 3c SAS and 
will be summarized for each vaccination as number and percentage 
of participants with: 
 
Any unsolicited AE starting within 28 days after each 
study vaccine administration, summarized by severity and 
relationship to study vaccine.  
 
Any medically attended adverse event (MAAE), serious 
adverse event (SAE), or AE leading to 
discontinuation/withdrawal through Final Visit/Early 
Termination (ET) summarized by relationship to study 
vaccine. 
Reactogenicity will be evaluated in participants in the Phase 3c RAS 
and will be summarized following vaccinations on Day 1 and Day 
29 only as the number and percentage of participants with: 
• 
Any solicited local or systemic AE starting within 7 days 
after each study vaccine administration by toxicity grade. 
2. To evaluate noninferiority of 
neutralizing antibody geometric 
mean concentration for ARCT-154 
versus ChAdOx1 at Day 57  
Neutralizing antibody (NAb) responses by pseudovirus 
microneutralization test (MNT) will be evaluated Day 57 for 
assessment of geometric mean concentration in all participants in the 
Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of the surrogate 
virus neutralization test for ARCT-154 and ChAdOx1 at 
Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Noninferiority will be concluded if the lower bound of the 95% 
confidence interval for the geometric mean ratio of ARCT-154 / 
ChAdOx1 >0.67. 
3.3.2 
Phase 3c Substudy Secondary Objectives and Endpoints 
The secondary objectives and endpoints for Phase 3c are presented in Table 9. 
Table 9 
Phase 3c Substudy Secondary Objectives and Endpoints  
Phase 3c Secondary Objectives 
Endpoint Description 
1. To evaluate noninferiority of IgG 
binding antibody geometric mean 
concentration for ARCT-154 versus 
ChAdOx1 at Day 57  
IgG antibody binding the full-length SARS-CoV-2 spike protein 
(binding antibody [BAb]) responses will be evaluated Day 57 for 
assessment of geometric mean concentration in all participants in the 
Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of BAb for 
ARCT- 154 and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available 
Noninferiority will be concluded if the lower bound of the 95% 
confidence interval for the geometric mean ratio of ARCT-154 / 
ChAdOx1 >0.67 

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Table 9 
Phase 3c Substudy Secondary Objectives and Endpoints  
Phase 3c Secondary Objectives 
Endpoint Description 
2. To evaluate noninferiority of 
neutralizing antibody seroconversion 
rate for ARCT-154 versus ChAdOx1 
at Day 57  
Neutralizing antibody (NAb) responses by pseudovirus 
microneutralization test (MNT) will be evaluated at Day 1 (baseline) 
and Day 57 for assessment of seroconversion in all participants in 
the Phase 3c-1 IAS.  
• 
The endpoint is seroconversion rate (defined as: 4-fold 
increase in titer from baseline) for ARCT-154 and 
ChAdOx1 at Day 57  
Data will be summarized according to use of international reference 
standards, if available.  
Noninferiority will be concluded if the lower bound of the 95% 
confidence interval of the difference between neutralizing antibody 
seroconversion rates (ARCT-154 group minus ChAdOx1 nCoV-1 
group) excludes the noninferiority margin of -10%. 
3. To evaluate noninferiority of IgG 
binding antibody seroconversion rate 
for ARCT-154 versus ChAdOx1 at 
Day 57  
IgG antibody binding the full-length SARS-CoV-2 spike protein 
(BAb) responses will be evaluated at Day 1 (baseline) and Day 57 
for assessment of seroconversion in all participants in the Phase 3c-1 
IAS.  
• 
The endpoint is seroconversion rate (defined as: 4-fold 
increase in titer from baseline) for ARCT-154 and 
ChAdOx1 at Day 57  
Data will be summarized according to use of international reference 
standards, if available. 
Noninferiority will be concluded if the lower bound of the 95% 
confidence interval of the difference between binding antibody 
seroconversion rates (ARCT-154 group minus ChAdOx1 nCoV-1 
group) excludes the noninferiority margin of -10%. 
4. To evaluate superiority of 
neutralizing antibody geometric 
mean concentration for ARCT-154 
versus ChAdOx1 at Day 57 
Neutralizing antibody (NAb) responses by pseudovirus 
microneutralization test (MNT) will be evaluated at Day 57 for 
assessment of geometric mean concentration in all participants in the 
Phase 3c-1 IAS.  
• 
The endpoint is the geometric mean ratio of the MNT for 
ARCT- 154 and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Superiority will be concluded if the 95% confidence interval for the 
geometric mean ratio of ARCT-154 / ChAdOx1 >1.0 
5. To evaluate superiority of IgG 
binding antibody geometric mean 
concentration for ARCT-154 versus 
ChAdOx1 at Day 57 
IgG antibody binding the full-length SARS-CoV-2 spike protein 
(BAb) responses will be evaluated at Day 57 for assessment of 
geometric mean concentration in all participants in the Phase 3c-1 
IAS.  
• 
The endpoint is the geometric mean ratio of BAb for 
ARCT-154 and ChAdOx1 at Day 57 
Data will be summarized according to use of international reference 
standards, if available. 
Superiority will be concluded if the 95% confidence interval for the 
geometric mean ratio of ARCT-154 / ChAdOx1 >1.0. 

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Table 9 
Phase 3c Substudy Secondary Objectives and Endpoints  
Phase 3c Secondary Objectives 
Endpoint Description 
6. To assess the neutralizing and IgG 
binding antibody immune responses 
for ARCT-154 and ChAdOx1 over 
time  
Neutralizing antibody (NAb) by pseudovirus microneutralization 
test (MNT) and IgG antibody binding the full-length SARS-CoV-2 
spike protein (BAb) responses will be evaluated at: Day 1 (baseline), 
Day 29, Day 57 and Day 211 for all participants in the Phase 3c-1 
IAS. Assessments for both BAb and NAb will include:   
• 
Antibody level: GMC 
• 
Increase in antibody levels from baseline (GMFR or other 
measure, as appropriate for the assay concerned) 
• 
Geometric mean ratio (GMR) 
• 
Proportion of participants in each study vaccine group with 
seroconversion at each timepoint.  
Samples will also be collected at Day 394 and may be evaluated in 
the same assays. 
Note: NAb and BAb responses that have been evaluated as other 
primary and secondary endpoints will be included in this endpoint 
for completeness of data presentation across time points. Full details 
will be provided in the statistical analysis plan. 
3.3.3 
Phase 3c Substudy Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints for Phase 3c are presented in Table 10. 
Table 10 
Phase 3c Substudy Exploratory Objectives and Endpoints  
Phase 3c Exploratory Objectives 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 nCoV-1 
for the prevention of virologically 
confirmed COVID-19 
Efficacy will be evaluated in all participants in the Phase 3c mITT. 
The endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received 
any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as 
follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset at any time after the 
first study vaccination. 
2. To evaluate the efficacy of ARCT-
154 and ChAdOx1 nCoV-1 for the 
prevention of virologically 
confirmed severe COVID-19  
Efficacy will be evaluated in all participants in the Phase 3c mITT. 
The endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received 
any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as 
follows: 

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Table 10 
Phase 3c Substudy Exploratory Objectives and Endpoints  
Phase 3c Exploratory Objectives 
Endpoint Description 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset at any time 
after the first study vaccination. 
3. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 nCoV-1 
for the prevention of death due to 
COVID-19  
Efficacy will be evaluated in all participants in the Phase 3c mITT. 
The endpoint to be evaluated is as follows: 
 
The occurrence of death attributed to COVID-19 disease 
occurring after Day 35. 
Efficacy may also be evaluated in participants that have received 
any dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint to be 
evaluated is as follows: 
• 
The occurrence of death attributed to COVID-19 occurring 
at any time after the first study vaccination. 
4. To evaluate the efficacy of 
ARCT-154 and ChAdOx1 for the 
prevention of virologically 
confirmed COVID-19 regardless of 
baseline status for evidence of prior 
SARS-CoV-2 infection 
Efficacy will be evaluated in all participants in the Phase 3c mITT 
regardless of baseline status for evidence of prior SARS-CoV-2 
infection. The endpoint to be evaluated is as follows: 
• 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset after Day 35. 
Efficacy may also be evaluated in participants that have received 
any dose of study vaccine in the first vaccination series. The 
endpoint is as follows: 
• 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset at any time after the 
first study vaccination. 
5. To evaluate the neutralizing antibody 
responses of ARCT-154 and 
ChAdOx1 using a surrogate virus 
neutralization test 
Neutralizing antibody (NAb) responses by surrogate virus 
neutralization test (sVNT) may be evaluated at individual time 
points. The following endpoints may be assessed: 
• 
Geometric mean antibody concentration (GMC)  
• 
Increase in antibody levels from baseline (GMFR) 
• 
Proportion of participants in each study vaccine group with 
seroconversion 
Data will be summarized according to use of international reference 
standards, if available. 
6. To evaluate the neutralizing antibody 
responses of ARCT-154 and 
ChAdOx1 to SARS-CoV-2 variants 
of concern/variants of interest 
Neutralizing antibody responses to SARS-CoV-2 variants of concern 
may be evaluated at individual time points in participants in the 
Phase 3c-1 IAS using a pseudovirus microneutralization test (MNT) 
and/or surrogate virus neutralization test (sVNT) for assessment of: 
 
Antibody level: GMC  
 
Increase in antibody levels from baseline (GMFR or other 
measure, as appropriate for the assay concerned) 
 
Geometric mean ratio (GMR) 
 
Proportion of participants in each study vaccine group with 
seroconversion at each timepoint.  
The following assays may be used: 
• 
PRNT50 

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Table 10 
Phase 3c Substudy Exploratory Objectives and Endpoints  
Phase 3c Exploratory Objectives 
Endpoint Description 
• 
sVNT 
• 
MNT 
3.4 
Pooled Objectives and Endpoints 
3.4.1 
Pooled Primary Objectives and Endpoints 
The pooled primary objectives and endpoints for the study are presented in Table 11. These will 
be evaluated as sensitivity analyses to efficacy and safety endpoints being evaluated in Phase 3b. 
Table 11 
Pooled Primary Objectives and Endpoints  
Pooled Primary Objectives 
Endpoint Description 
1. To assess the safety and 
reactogenicity of ARCT-154 and 
comparator vaccines (placebo, 
ChAdOx1 nCoV-1)  
Safety data will be evaluated in the Pooled SAS and will be 
summarized for each vaccination as number and percentage of 
participants with: 
 
Any unsolicited AE starting within 28 days after each 
study vaccine administration, summarized by severity and 
relationship to study vaccine.  
 
Any medically attended adverse event (MAAE), serious 
adverse event (SAE), or AE leading to 
discontinuation/withdrawal through Final Visit/Early 
Termination (ET) summarized by relationship to study 
vaccine. 
Reactogenicity will be evaluated in the Pooled RAS and will be 
summarized following vaccinations on Day 1 and Day 29 only as the 
number and percentage of participants with: 
 
Any solicited local or systemic AE starting within 7 days 
after each study vaccine administration by toxicity grade. 
2. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of virologically 
confirmed COVID-19 
Efficacy will be evaluated in all participants in Pooled mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset between Day 36 and 
Day 92 inclusive. 

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3.4.2 
Pooled Secondary Objectives and Endpoints 
The pooled secondary objectives and endpoints for the study are presented in Table 12. 
Table 12 
Pooled Secondary Objectives and Endpoints  
Pooled Secondary Objectives 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of virologically 
confirmed severe COVID-19  
Efficacy will be evaluated in all participants in the Pooled mITT. 
The endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset between 
Day 36 and Day 92 inclusive. 
 
Severity as scored using the FDA criteria will be the 
principal analysis.  Severity using the WHO criteria will be 
performed as a sensitivity analysis 
2. To evaluate the efficacy of 
ARCT154 and placebo for the 
prevention of virologically 
confirmed COVID-19 at any time 
after first vaccination 
Efficacy will be evaluated in participants that have received any 
dose of study vaccine in the first vaccination series, with no 
evidence of infection prior to vaccination. The endpoint is as 
follows: 
The first occurrence of confirmed, protocol-defined (Appendix 2) 
COVID-19 with onset at any time after the first study vaccination 
and up to Day 92 inclusive. 
3. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of death due to COVID-
19  
Efficacy will be evaluated in all participants in the Pooled mITT The 
endpoint is as follows: 
 
The occurrence of death attributed to COVID-19 with 
onset between Day 36 and Day 92 inclusive. 
 
4. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of virologically 
confirmed COVID-19 regardless of 
baseline status for evidence of prior 
SARS-CoV-2 infection 
Efficacy will be evaluated in all participants in Pooled mITT 
regardless of baseline status for evidence of prior SARS-CoV-2 
infection. The endpoint to be evaluated is as follows: 
• 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset between Day 36 and 
Day 92 inclusive. 
 
3.4.3 
Pooled Exploratory Objectives and Endpoints 
The Pooled exploratory objectives and endpoints for the study are presented in Table 13. 
Table 13 
Pooled Exploratory Objectives and Endpoints  
Pooled Exploratory Objectives of 
Study 
Endpoint Description 
1. To evaluate the efficacy of 
ARCT-154 and placebo for the 
prevention of virologically 
confirmed severe COVID-19 at any 
time after first vaccination 
Efficacy may be evaluated in all participants in the Pooled mITT 
that have received any dose of study vaccine in the first vaccination 
series, with no evidence of infection prior to vaccination. The 
endpoint is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 with onset at any time 
after the first study vaccination and up to Day 92. 

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Table 13 
Pooled Exploratory Objectives and Endpoints  
Pooled Exploratory Objectives of 
Study 
Endpoint Description 
2. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
death due to COVID-19 at any time 
after first vaccination 
Efficacy may be evaluated in all participants in the Pooled mITT 
that have received any dose of study vaccine in the first vaccination 
series. The endpoint is as follows: 
 
The occurrence of death attributed to COVID-19 occurring 
at any time after the first study vaccination and up to Day 
92. 
3. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed COVID-19 
at any time after first vaccination 
regardless of baseline status for 
evidence of prior SARS-CoV-2 
infection 
Efficacy may be evaluated in all participants in the Pooled mITT 
that have received any dose of study vaccine in the first vaccination 
series, regardless of baseline status for evidence of prior SARS-
CoV-2 infection. The endpoints are as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 with onset at any time after the 
first study vaccination and up to Day 92. 
4. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed SARS-CoV-
2 by specific strain 
Efficacy will be evaluated in participants in the Pooled mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) COVID-19 for all participants infected with 
the same strain of SARS-CoV-2, with onset between 
Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in 
participants under evaluation for COVID-19 will be retained for 
possible future testing to identify the SARS-CoV-2 strain detected in 
the COVID-19 case. 
5. To evaluate the efficacy of ARCT-
154 and placebo for the prevention of 
virologically confirmed severe 
SARS-CoV-2 by specific strain 
Efficacy will be evaluated in participants in Pooled mITT. The 
endpoint to be evaluated is as follows: 
 
The first occurrence of confirmed, protocol-defined 
(Appendix 2) severe COVID-19 for all participants 
infected with the same strain of SARS-CoV-2, with onset 
between Day 36 and Day 92 inclusive. 
A second nasal swab specimen collected contemporaneously in 
participants under evaluation for COVID-19 will be retained for 
possible future testing to identify the SARS-CoV-2 strain detected in 
the COVID-19 case. 
6. To evaluate for an immune correlate 
associated with reduced risk of 
COVID-19 
Blood samples drawn at Baseline and Day 57 in all participants will 
be held for potential future testing for evaluation of a correlate of 
protection. 

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4 
INVESTIGATIONAL PLAN 
Before any study procedures are performed, all potential participants will sign an informed 
consent form (ICF). Additional procedural details related to the ICF are provided in Section 10.3. 
4.1 
Number of Participants 
Enrollment of approximately 19,400 participants across all phases of the study is planned, as 
follows:  
• Phase 1: 100 (75 ARCT-154:25 placebo per study group) 
• Phase 2: approximately 300 (225 ARCT-154:75 placebo per study group) 
• Phase 3a: approximately 600 (450 ARCT-154:150 placebo per study group)  
• Phase 3b: approximately 16,000 (8,000 per study group) 
• Phase 3c: approximately 2,400 (~1,200 per study group) 
o The first approximately 1,500 participants will be enrolled into Phase 3c-1, the 
group that will have blood drawn for immunogenicity assessments. Data from 800 
participants in this subgroup will be used to establish the noninferiority of 
immunogenicity of ARCT-154 vaccine as compared to ChAdOx1 
o The remaining ~900 participants will form Phase 3c-2 
4.2 
Number of Sites 
Approximately 20 sites in Vietnam will participate. 
4.3 
Duration of Participation  
The expected duration of participation for an individual participant (including the Screening 
period) is approximately 14 months, 12 months after completion of the initial two-dose 
vaccination series. 
4.4 
Study Design 
This is a Phase 1/2/3, randomized, controlled, observer-blind study designed to evaluate the 
safety, immunogenicity and efficacy of ARCT-154 in adult participants to be enrolled in 
Vietnam. This study design has been updated to include a cohort (Phase 3c) to evaluate the 
immunogenicity, safety, and efficacy of ARCT-154 versus a comparator COVID-19 vaccine. 
The study is divided into five parts: Phase 1, Phase 2, Phase 3a, Phase 3b and Phase 3c.   
Participants in Phase 1 and 3b will be randomly assigned (Section 4.5.2) to a study group that 
will receive up to 2 vaccination series (4 doses of study vaccine total). Each vaccination series 
comprises two vaccinations at 28-day intervals: an initial vaccination series with vaccinations on 
Day 1 and Day 29 and an additional two-dose vaccination series with the opposite vaccine at the 
6-month timepoint on Day 92 and 120, which is at the 2-months after the second dose (referred 
to as the “Switchover” vaccination series throughout the protocol). Each participant in Phase 1 
and 3b is planned to receive a two-dose vaccination series of ARCT-154 at a dose of 5 µg and a 

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two-dose vaccination series of placebo (saline). Therefore, the study group participants that 
initially received two doses of ARCT-154 will receive two doses of placebo on Switchover and 
study group participants that initially received placebo will receive two doses of ARCT-154 5 µg 
on Switchover (Figure 1).  
Participants in Phase 2 and 3a will be randomly assigned to a study group that will receive two 
vaccinations with either ARCT-154 or placebo at a 28-day interval with vaccinations on Day 1 
and Day 29. With protocol version 8.0, participants that received ARCT-154 in the initial two-
dose vaccination series will be further randomized to receive either ARCT-154 or placebo (in a 
3:1 ratio) at Day 92 (referred to as “Further Study Vaccine” throughout the protocol) followed by 
placebo at Day 120.  Participants that received placebo in the initial vaccination series will 
undergo Switchover to receive ARCT-154 at Day 92 and Day 120. 
Participants in Phase 3c will be randomized to receive either ARCT-154 or Astra Zeneca 
COVID-19 vaccine (ChAdOx1 nCoV-19; referred to as ChAdOx1from here on) which has 
received authorization for use in Vietnam. Participants in Phase 3c will receive a 2-dose priming 
vaccination series of either ARCT-154 5µg or ChAdOx1, with vaccinations being administered 
on Day 1 and Day 29. Because all participants in Phase 3c will receive an active vaccine, no 
switchover will occur for these participants. 
Phase 1 is a sentinel cohort for assessment of safety. 100 healthy participants will be randomly 
assigned 3:1 to receive ARCT-154 or placebo (75:25) for the initial series of vaccinations. The 
Safety Review Committee (SRC) and Vietnam Ministry of Health (MOH) will independently 
review available blinded safety data for Phase 1 participants through at least 7 days post-second 
vaccination (Day 36) and, if study vaccination is judged to be adequately tolerated by SRC and 
the MOH, the study will initiate simultaneous enrollment of both Phase 2 and Phase 3a.  
In Phase 2, which expands the safety and immunogenicity characterization of the study vaccine 
in a larger group of participants, 300 participants will be randomly assigned 3:1 to receive 
ARCT-154 or placebo (225:75) for the initial series of vaccinations.  
In Phase 3a, which expands the enrollment further to include 600 participants, who will be 
randomly assigned 3:1 to receive ARCT-154 or placebo (450:150) for the initial series of 
vaccinations. After completion of enrollment of Phases 2 and 3a, the SRC and MOH will 
independently review available blinded safety data through at least 7 days (Day 8) post-first 
vaccination and, if study vaccination is judged to be adequately tolerated by SRC and the MOH, 
the study will initiate enrollment of Phase 3b. The second dose of study vaccine will not be 
administered to participants in Phase 3b until the SRC has reviewed the Phase 2 and Phase 3a 
safety data through 7 days post-second vaccination (Day 36) and judged that study vaccine is 
adequately tolerated. Data from participants in Phase 1, Phase 2, and Phase 3a will be pooled for 
a primary analysis of immunogenicity at Day 57. Data from this analysis will be submitted to the 
Vietnamese Ministry of Health for evaluation for potential emergency use authorization (EUA). 
Data from Phase 2 and 3a will also be pooled to allow comparison of immunogenicity following 
the 3rd dose (immune responses at Day 120 with that after the 2nd dose (immune responses at Day 
57). 
In Phase 3b, approximately 16,000 participants will be randomly assigned 1:1 to receive 
ARCT-154 or placebo for the initial series of vaccinations. Phase 3b constitutes the Exploratory 

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Efficacy Subgroup. Data from this subgroup will support regulatory filings along with 
immunogenicity data from Phase 1/2/3a and 3c. Participants in this Phase 3b portion of the study 
will contribute substantially to the safety analyses of ARCT-154. 
Phase 3c will enroll approximately 2,400 participants randomized 1:1 to receive ARCT-154 or 
ChAdOx1. A subset of these enrolled participants (the first 1,500 participants enrolled in 
Phase 3c) will form an Immunogenicity Noninferiority Subgroup (Phase 3c-1); the remaining 
~900 participants will form Phase 3c-2. Day 57 data from 800 participants in this Subgroup will 
be used to establish the noninferiority of immunogenicity of ARCT-154 vaccine as compared to 
ChAdOx1, a licensed comparator vaccine. These data, along with an analysis of safety from 
participants exposed to ARCT-154 and followed for a median period of 2 months (60 days) may 
be submitted to health authorities for evaluation for a Marketing Authorization or EUA 
dependent on jurisdiction. 
Phase 1 participants must be <60 years of age. Phase 2, 3a, 3b and 3c participants will include 
elderly (≥60 years) participants as well. Phase 3b and Phase 3c will enrich for participants at 
higher risk for COVID-19 by attempting to enroll individuals considered at high risk due to their 
workplace environment or living conditions. 
For Phases 2, 3a, 3b and 3c, after a 10-day Screening period, prior to randomization, participants 
will be stratified by age (< 60 or ≥ 60 years of age) and for participants < 60 years of age by risk 
of severe COVID-19. Participants will be defined as “at risk” if they are 60 years of age or older 
OR have medical history described as putting the individual at risk or possibly at risk of severe 
coronavirus disease 2019 (COVID-19) (Appendix 5).  As the eligibility criteria for Phase 1 
exclude participants ≥ 60 years of age or otherwise at risk for severe COVID-19, stratification 
will not occur for Phase 1.   
Participants in all study phases will undergo informed consent and screening procedures prior to 
enrollment. After enrollment, participants will be randomized to groups. Study vaccines will be 
given in a supervised medical setting. All participants will be evaluated for reactogenicity 
(solicited adverse events) and reporting of unsolicited adverse events and concomitant 
medications through a series of clinic visits and phone calls. Depending on the study phase, 
blood sampling for immunogenicity and testing for COVID-19 may be performed. See 
Appendix 1 for an overview of study visits by study phase. 
For participants in Phase 1/2/3a/3b, at the Day 92 visit and prior to receipt of further study 
vaccine, participants will be evaluated by the Investigator according to Further Study Vaccine 
eligibility criteria (Section 5.1.5). Any participant who does not meet these criteria will not 
receive further vaccinations with study vaccine and will be asked to continue in the study 
through Final Visit (Day 394).  
For participants that receive further doses of Study Vaccine at Day 92 and Day 120, this will 
occur in a blinded fashion in that participants and blinded site and Sponsor personnel will remain 
blinded to treatment assignment until End of Study (EOS). 
Participants who choose to receive vaccination with off-study COVID-19 vaccine will be 
encouraged to remain in the study, but those that choose to leave the study to pursue alternate 
vaccination will not be unblinded to study treatment unless there is an unexpected post study 
SAE attributed as related to study vaccine by the study investigator. 

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Data will be collected through a combination of clinic visits and use of electronic diaries (and 
paper diaries in circumstances where electronic diaries are not feasible) to capture solicited 
adverse events and to prompt for symptoms of COVID-19 and risk of SARS-CoV-2 exposure, 
other adverse events, and concomitant medications. All participants enrolled in Phase 1 and 
Phase 2 must have access to the eDiary to facilitate rapid review of safety data by the SRC. 
Exposure to SARS-CoV-2 is defined as a participant who has had close contact (within 6 feet 
[2 meters] to a person with virologically confirmed COVID-19 during the active transmission 
period.  
The active transmission period is: 
1) for a symptomatic COVID-19 case, 3 days before the first symptom, or  
2) for an asymptomatic COVID-19 case, from 14 days prior to the positive COVID-19 
test result.  
The close contact definition applies regardless of whether the person with COVID-19 or the 
contact was wearing a mask or whether the contact was wearing respiratory personal protective 
equipment. Individuals with suspected COVID-19 symptoms and/or exposures will be evaluated, 
ideally within 72 hours to determine if there is a potential COVID-19 case. Participants may also 
be seen at unscheduled clinic visits if there are any safety issues that an investigator wishes to 
evaluate. 
Participant data from each of the study phases may be unblinded prior to study completion to 
support regulatory filings. When these unblindings occur, unblinded data will only be provided 
to Sponsor or CRO employees not involved in the subsequent conduct of the study; the specific 
timing of these unblindings is defined in Section 8.9. Individual participants, blinded study site 
staff and Sponsor team members involved in overseeing the conduct of the study will remain 
blinded until the end of study for all Phases (Phases 1, 2, and 3a/b/c). Sponsor staff and other 
persons that will become unblinded at the various data analysis time points will be specified 
prior to unblinding occurring. 
Phase 1, 2, 3a and 3c-1:  participants will be consented to have blood collected more frequently 
for assessment of SARS-CoV-2 neutralizing antibody responses and binding antibody responses 
to the SARS-CoV-2 spike protein. The study will also include collection of blood samples in all 
participants for potential future exploratory testing of potential correlates of protection and 
vaccine responses to SARS-CoV-2 variants. 
An independent Data and Safety Monitoring Board (DSMB) will perform ongoing review of 
blinded and unblinded data, including both safety and confirmed cases of COVID-19 at 
scheduled data review meetings. At each meeting, the DSMB will review the available data and 
make recommendations to the Sponsor to continue, modify, or discontinue study enrollment (if 
the study is enrolling). In addition to the ongoing review of safety data, the DSMB will also 
review available severe COVID-19 case data to determine the risk of Vaccine-Associated 
Enhanced Respiratory Disease (VAERD). The DSMB will be constituted prior to 
commencement of Phase 3b. 
An independent blinded endpoint adjudication committee will adjudicate all suspected 
COVID-19 cases to determine if they meet the primary endpoint requirements (Appendix 2). 

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4.5 
Study Assessments and Procedures 
A schedule of assessments is provided in Appendix 1. 
4.5.1 
Informed Consent 
“Informed consent” is the voluntary agreement of an individual to participate in research. 
Consent must be given with free will of choice and without undue inducement. The individual 
must have sufficient knowledge and understanding of the nature of the proposed research, the 
anticipated risks and potential benefits, and the requirements of the research to be able to make 
an informed decision. 
The process of obtaining informed consent must be documented in the participants source 
documents in addition to maintaining a copy of the signed and dated informed consent. 
Additional specifics regarding the informed consent process are located in Section 10.3. 
If a participant or participant’s legal guardian(s) is/are unable to read, an impartial witness 
should be present during the entire informed consent. An impartial witness is defined as a person 
who is independent from trial conduct, who cannot be unfairly influenced by those involved with 
the trial, who attends the informed consent process if the participant or the participant’s legally 
acceptable representative cannot read, and who reads the informed consent/assent form and any 
other written information supplied to the participant. After the written ICF/assent and any other 
written information to be provided to participants is read and explained to the participant or 
participant’s legal guardian(s), after the participant or participant’s legal guardian(s) has verbally 
consented to the participant’s participation in the trial, and after the participant, if capable of 
doing so, has signed and personally dated the informed consent/assent form, the witness should 
sign and personally date the consent/assent form. By signing the consent form, the witness attests 
that the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the participant or participant’s legal guardian(s) and 
that informed consent was freely given by the participant or participant’s legal guardian(s). 
4.5.2 
Randomization and Enrollment 
Phase 1, 2 and 3a participants will be randomly assigned 3:1 (ARCT-154:placebo), while 
Phase 3b participants will be randomly assigned 1:1 (ARCT-154:placebo).  
• Participants in Phase 1 and 3b will receive two doses of one type of study vaccine on Day 
1 and 29 (ARCT-154 or placebo) and then two doses of the opposite vaccine (placebo or 
ARCT-154) on Day 92 and 120 (referred to as ‘Switchover’).  
• Participants in Phase 2/3a who received ARCT-154 in the initial two-dose vaccination 
series will be further randomized to receive either ARCT-154 or placebo (in a 3:1 ratio) 
at Day 92 followed by placebo at Day 120.  Participants that received placebo in the 
initial vaccination series will undergo Switchover to receive ARCT-154 at Day 92 and 
Day 120. 
Phase 3c participants will be randomized 1:1 to receive ARCT-154 or ChAdOx1; no Switchover 
will occur for Phase 3c participants as all participants in this cohort receive active vaccine. 

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For Phases 2, 3a, 3b and 3c, prior to randomization, participants will be stratified by the 
following 3 stratification factors: 
•
Age < 60 at high risk of severe COVID-19
•
Age < 60 not at high risk of severe COVID-19
•
Age ≥ 60 years of age (considered at risk of severe COVID-19 by default)
Participants will be defined as “at risk” if they are 60 years of age or older OR have medical 
history described as putting an individual at risk or possibly at risk of severe coronavirus 
disease 2019 (COVID-19) (Appendix 5).  
As the eligibility criteria for Phase 1 exclude participants ≥ 60 years of age or otherwise at 
risk for severe COVID-19, stratification will not occur for Phase 1.   
At screening, a Participant Identifier will be assigned by the site via the Interactive Response 
Technology (IRT) system. After the participant has completed screening and is determined to be 
eligible for study participation, the participant will be randomized by the site via the IRT system. 
At randomization, the participant will automatically be assigned to a study group. This 
participant’s randomization must be documented in the Screening and Enrollment Log. 
Randomization in IRT can be performed by the site via the internet by the investigator or site 
personnel (as delegated by the investigator) who are permitted by institutional policy and trained 
to perform this task. 
4.5.3 
Visits 
The number of visits and calls planned for study participants is linked to the study phase into 
which a participant is enrolled and Switchover/Further Study Vaccine status.  
Follow-up visits and Unscheduled visits may be performed by telemedicine visits in combination 
with home health nursing visits or in a hospital setting if warranted by clinical circumstances (eg, 
COVID-19 lockdown in the vicinity) and if permitted by local regulations. 
Phase 1 and 3b Participants Eligible for Switchover: 
•
Phase 1 participants eligible for Switchover have:
o
9 clinic visits, including Screening, Dose 1 (Day 1), Follow-up Visit (Day 8),
Dose 2 (Day 29), Follow-up Visit (Day 36), Follow-up Visit (Day 57),
Switchover Dose 1 (Day 92), Switchover Dose 2 (Day 120), Final Visit (Day
394)/Early Termination (ET) visit (if applicable).
o
25 telephone calls will be made, including: weekly on Days 15, 22, 43, 50, 64, 71,
78, 85, 99, 106, 113, 127, 134, 141, 148, 155, 162, 169, 176 and then monthly
calls on Days 210, 240, 270, 300, 330 and 360.
•
Phase 3b participants eligible for Switchover have:
o
7 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-up
Visit (Day 57), Switchover Dose 1 (Day 92), Switchover Dose 2 (Day 120), Final
Visit (Day 394)/Early Termination (ET) visit (if applicable).

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o 27 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, 99, 106, 113, 127, 134, 141, 148, 155, 162, 169, 176 and then 
monthly calls on Days 210, 240, 270, 300, 330 and 360.  
Participants Ineligible for Switchover: 
• Phase 1 participants ineligible for Switchover have:  
o 8 clinic visits including Screening, Dose 1 (Day 1), Follow-up Visit (Day 8), Dose 
2 (Day 29), Follow-up Visit (Day 36), Follow-up Visit (Day 57), Day 92 
(Switchover ineligible), and Final Visit (Day 394)/ET visit (if applicable).  
o 17 telephone calls will be made, including: weekly calls on Days 15, 22, 43, 50, 
64, 71, 78, 85, and then monthly calls on Days 120, 150, 180, 210, 240, 270, 300, 
330 and 360.  
• Phase 3b participants ineligible for Switchover have:  
o 6 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-
up Visit (Day 57), Day 92 (Switchover ineligible), and Final Visit (Day 394)/ET 
visit (if applicable).  
o 19 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, and then monthly calls on Days 120, 150, 180, 210, 240, 270, 
300, 330 and 360.   
Phase 2 and 3a Participants Eligible for additional study vaccine at Day 92 have: 
o 7 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-up 
Visit (Day 57), Further Dose 1 (Day 92), Further Dose 2 (Day 120), Final Visit 
(Day 394)/Early Termination (ET) visit (if applicable).  
o 27 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, 99, 106, 113, 127, 134, 141, 148, 155, 162, 169, 176 and then 
monthly on Days 210, 240, 270, 300, 330 and 360.  
Phase 2 and 3a Participants NOT Eligible for additional study vaccine at Day 92 have: 
o 6 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-
up Visit (Day 57), Day 92 (further study vaccine ineligible), and Final Visit (Day 
394)/ET visit (if applicable).  
o 19 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, and then monthly calls on Days 120, 150, 180, 210, 240, 270, 
300, 330 and 360.   

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Participants in Cohort 3c will have the following visit/telephone call schedule. In addition, 
participants may have an Early Termination (ET) Visit when relevant, as well as Unscheduled 
Visits. 
• Phase 3c-1 participants:  
o 6 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-
up Visits (Day 57 and Day 211), and Final Visit (Day 394)/ET visit (if 
applicable).  
o 37 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, 162, 169, 176, 
183, 190, 197, 204, 218, 225, 232, 239, 246, 253, 260 then monthly calls on Days 
290, 320 and 350.  
• Phase 3c-2 participants:  
o 5 clinic visits including Screening, Dose 1 (Day 1), Dose 2 (Day 29), Follow-
up Visits (Day 57), and Final Visit (Day 394)/ET visit (if applicable).  
o 38 telephone calls will be made, including: weekly calls on Days 8, 15, 22, 36, 43, 
50, 64, 71, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, 162, 169, 176, 
183, 190, 197, 204, 211, 218, 225, 232, 239, 246, 253, 260 and then monthly calls 
on Days 290, 320 and 350. In addition, participants in all cohorts may have an 
Early Termination (ET) Visit when relevant, as well as Unscheduled Visits. 
 Screening Visit (Up to 10 days prior to Day 1) 
At Screening, individuals willing to participate in the study will undergo informed consent 
followed by an interview to review medical history, current symptoms, COVID-19 exposures, 
AEs, medications, recent vaccinations, and availability for study procedures; will undergo 
complete physical examination, pregnancy testing (if the participant is a woman of childbearing 
potential), vital sign measurements (heart rate, respiratory rate, blood pressure), body 
temperature measurement, as well as height and weight measurements. Blood sampling may be 
performed for pregnancy test (if urine testing is not permitted by site policy), or -follicle 
stimulating hormone (FSH) in women suspected to be menopausal (Appendix 1). Nasal swabs 
for SARS-CoV-2 RT-PCR and blood sampling for screening will be performed as outlined in 
Section 4.5.5.3. The information gathered from this interview and the assessments will be 
evaluated against inclusion/exclusion criteria to determine study eligibility. Prior to 
randomization, participants will undergo determination of “at risk” status for severe COVID-19 
(Appendix 5). 
 Vaccine Dose Administration Visits  
At each vaccine administration visit, participants will undergo an interview for AEs, 
concomitant medications/vaccines, updates to medical history, COVID-19 exposures and/or 
symptoms: pregnancy testing (if the participant is a woman of childbearing potential), complete 
physical examination, vital signs, and body temperature measurement prior to and after receipt 
of study vaccine.  

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Nasal swabs and blood will be collected as outlined in Section 4.5.5.3.  
For participants in Phase 1, additional blood will be collected for safety laboratory assessments 
as outlined in Section 4.5.5.3.    
During all Dose Administration visits (Day 1, Day 29, and (in Cohorts 1, 2, 3a, 3b only) Day 92, 
Day 120), all participants will be trained in how to measure body temperature, ruler use, what 
signs or symptoms of COVID-19 might be (Section 4.5.3.7), whom to call at the site and how 
quickly to call in the event of severe or serious AEs or signs of possible COVID-19. At all later 
points of contact, participants will be reminded of this training. On Day 1 and Day 29, 
participants will also be shown how to report AEs in the Diary (electronic or paper); note diaries 
are not used after the Switchover vaccinations. For participants in Phase 2 and 3a, that are 
receiving additional doses of study vaccine, further training on Diary use will be performed prior 
to vaccination on Day 92. No solicited events will be collected via Diary after vaccination on 
Day 120. 
For Phase 2, 3a, 3b and 3c participants who did not use the eDiary, paper diaries for the first 
injection will be collected at Day 29. For Phase 2 and 3a, participants who did not use the 
eDiary, paper diaries for the third injection will be collected at Day 120.  
The exception to performing these procedures is if the participant is screened and enrolled on the 
same day (Day 1). In this instance, pregnancy testing, screening and safety laboratory 
assessments, physical examination, vital signs, body temperature, AEs and concomitant 
medication collection, and solicitation of potential COVID-19 exposure or symptoms will not be 
repeated. 
After confirmation of eligibility and determination of “at risk” status at Day 1 (for Phases 2, 3a, 
3b and 3c), the participant will be regarded as enrolled, and randomization of the participant in 
the IRT will occur. 
Study vaccine will be administered in an observer-blind fashion as described in Section 6.3. The 
second study vaccination of each series must be at least 28 days after the first study vaccination. 
For Phase 1 and 3b, the first Switchover vaccination (Day 92) must be at least 56 days (+30 
days) after the second vaccination of the initial series.  For Phase 2 and 3a, the 3rd vaccination 
with study vaccine must be at least 56 days (+30 days) after the second vaccination series. 
After receipt of study vaccine in the initial series of vaccinations, the participant will remain 
under observation for at least 3 hours for Phase 1, and 30 minutes for Phase 3b, and until 
clinically stable. For Switchover vaccinations, participants in Phase 1 and Phase 3b will be 
observed for at least 15 minutes and until clinically stable. Participants in Phase 2 and 3a will be 
observed for at least 30 minutes and until clinically stable for vaccinations 1, 2, and 3 (Day 92) 
and for at least 15 minutes and until clinically stable for vaccination 4 (Day 120). During the 
post-vaccination observation period, the participant will undergo assessment of vital signs, body 
temperature, AEs, and concomitant medications prior to discharge from the clinic.  
Should a participant experience a severe AE (including but not limited to hypersensitivity or 
anaphylaxis) immediately following study vaccine administration, the participant should be 
observed until clinically stable, and the Clinical Research Organization (CRO) Medical Monitor 
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discussion between the Medical Monitor and the investigator and subject to Medical Monitor 
approval. 
 Follow-up Visit on Day 8 and 36 (Phase 1 only) 
For Phase 1, follow-up visits on Day 8 and 36 must occur at least 7 days after each vaccination. 
Participants in Phase 1 will undergo the following: an interview for AEs, concomitant 
medications/vaccines, updates to medical history, COVID-19 exposures and/or symptoms, vital 
signs, body temperature, reminder to notify the site of unsolicited AEs and COVID-19 exposures 
and/or symptoms. Physical examination may be performed, if warranted, by the interview.  
Blood will be drawn as outlined in Section 4.5.5.3.  
 Follow-up Visit on Day 57 
The Follow-up visit on Day 57 must occur at least 28 days after the second vaccination. 
Participants will undergo the following: an interview for AEs, concomitant 
medications/vaccines, updates to medical history, COVID-19 exposures and/or symptoms, vital 
signs, body temperature, reminder to notify the site of unsolicited AEs and COVID-19 exposures 
and/or symptoms. Physical examination may be performed, if warranted, by the interview.  
Blood will be drawn as outlined in Section 4.5.5.3.  
For Phase 2, 3a, 3b and 3c participants who did not use the eDiary, paper diaries for the second 
vaccination will be collected.  
 Follow-up Visit on Day 211 (Phase 3c-1 only) 
Participants will undergo the following: an interview for AEs, concomitant 
medications/vaccines, updates to medical history, COVID-19 exposures and/or symptoms, vital 
signs, body temperature, reminder to notify the site of unsolicited AEs and COVID-19 exposures 
and/or symptoms. Physical examination may be performed, if warranted, by the interview.  
Blood will be drawn as outlined in Section 4.5.5.3.  
 Weekly and Monthly Study Calls 
Telephone calls will be performed weekly (when the participant is not otherwise coming in for a 
clinic visit) then monthly as outlined in Section 4.5.3.  
The schedule of the weekly calls (at 7-day intervals) is based on the study day of the prior study 
vaccination. For Phases 2, 3a, 3b and 3c, the weekly call at Day 8 and Day 36 must be at least 
7 days after the prior study vaccination and for participants receiving vaccinations on Days 92 
and 120, the weekly study calls on Day 99 and Day 127 must be at least 7 days after the prior 
study vaccination in order to ensure adequate recording of solicited events.   
Telephone calls will be conducted to evaluate participants for safety (collection of AEs and 
concomitant medications/vaccines, and inquire about COVID-19 exposure and/or symptoms 
(prompting an Unscheduled visit, ideally within 72 hours for evaluation), and arrange evaluation 
in clinic as needed [Section 7.1.1]). 

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 Unscheduled Visits 
 Unscheduled visits should be arranged for the evaluation of reported COVID-19 symptoms, 
exposure to COVID-19, or for the evaluation of safety issues. If a participant experiences these 
symptoms, reports a COVID-19 exposure, or is experiencing a severe or serious safety concern, 
he or she is instructed to contact the site immediately. 
Symptoms of COVID-19 include: 
 Fever 
 Chills 
 Cough 
 Shortness of breath or difficulty breathing 
 Fatigue 
 Muscle or body aches 
 Headache 
 New loss of taste or smell 
 Sore throat 
 Congestion or runny nose 
 Nausea 
 Vomiting  
 
Diarrhea 
Some of these symptoms (fever/chills, fatigue, muscle aches, headache, nausea, diarrhoea, 
vomiting) overlap with solicited event symptoms that may be experienced as a consequence of 
receiving vaccine.  However, based on experience to date, onset of solicited events following 
ARCT-154 is typically within the first 3 days after vaccination and the symptoms have typically 
resolved or improved by 7 days after vaccination. Therefore, it is recommended that: 
 
If any of the following symptoms are observed WITHIN 3 days after vaccination, then 
clinical judgement should be used to determine if COVID-19 is likely. However, if ANY 
ONE or more of these symptoms occur BEYOND 3 days after vaccination or if they 
PERSIST beyond 7 days after vaccination then testing for COVID-19 should be 
performed 
o Fever or chills 
o Fatigue 
o Muscle or body aches 
o Headache 
o Nausea or vomiting 
o Diarrhea 
 
Other symptoms, as listed below, are not typical solicited adverse events, so COVID 
testing should be performed if ANY ONE or more of these symptoms is experienced AT 
ANY time, INCLUDING within the first 3 days after vaccination 
o Cough 

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o Shortness of breath or difficulty breathing 
o New loss of taste or smell 
o Sore throat 
o Congestion or runny nose 
In all participants brought in for Unscheduled Visits, an evaluation of AEs, medical history and 
concomitant medications/vaccines, and collection of nasal swab samples (Section 4.5.5.3) if 
COVID-19 is suspected, will be performed. Note: For Phase 1/2/3a/3b, nasal swabs for RT-PCR 
test do not need to be performed after Day 92. For Phase 3c, nasal swabs should continue to be 
collected until the last study visit (early termination of Day 394). 
Based on local COVID-19 restrictions or clinical considerations, clinic visits may not be 
feasible. If this cannot be arranged, an evaluation of AEs, medical history, concomitant 
medications/vaccines with rapid antigen testing for SARS-CoV-2 may be pursued by 
telemedicine visit or telephone contact. See also Section 4.5.5.3.   
In participants who are able to come to the clinic for evaluation of possible COVID-19, the 
evaluation should include review for symptoms suggestive of COVID-19 as listed in 
Appendix 2, as well as 2 nasal swab samples to be sent to a qualified laboratory. This 
Unscheduled Visit may occur in person, by home visit, by telemedicine visit, or in the hospital 
(if permitted by local policy). If in-person visits are performed, collection of vital signs and body 
temperature, performance of symptom-directed physical examination, and measurement of pulse 
oximetry, are encouraged. 
In some cases, such as when the participant lives remote from the study site, the participant may 
be given two test kits to take home as it may be necessary to perform a rapid antigen test prior to 
bringing the participant to the site for nasal swab RT-PCR testing. In such instances, if the first 
rapid antigen test is negative then a SECOND test should be performed 48 to 72 hours later. 
Participants who are evaluated for COVID-19 outside of the context of an on-site Unscheduled 
Visit should have details of this evaluation captured in the participants’ source documents as an 
Unscheduled Visit (see Section 7.1.1).  
In order to establish virological confirmation of SARS-CoV-2 infection, testing must be 
performed using an FDA-cleared, Clinical Laboratory Improvement Amendment (CLIA)-
certified, International Organization for Standardization (ISO) 15189-accredited, or a 
Vietnamese nationally accredited laboratory at the time that the test was performed. The 
laboratory name, test, and certification must be documented in the source. Failure to document 
the details will result in the exclusion of the participant’s COVID-19 diagnosis from the 
exploratory efficacy endpoint analysis. 
Participants with other severe or AEs warranting an Unscheduled visit should be managed 
according to standard of care, including referral to treating physician, if clinically relevant. 
Beyond this protocol-specified testing, participants should be referred to their treating primary 
care health professional for further evaluation and treatment of potential COVID-19. This may 
include locally run testing to confirm the COVID-19 diagnosis and/or to exclude other potential 
respiratory pathogens. The investigator should continue to follow and report the 
COVID-19 clinical course, including disease severity. 

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For those participants evaluated for suspected COVID-19 symptoms or exposures, the details of 
the clinical evaluation and outcome will be captured in dedicated electronic case report form 
(eCRF) pages. This includes the confirmation or exclusion of SARS-CoV-2 infection. 
  Final Visit/Early Termination Visit 
The Final Visit should be Day 394 for all participants (including if they do not receive study 
vaccinations after the first vaccination). The Final Visit/ET Visit will occur at the participant’s 
last study visit or when the participant withdraws from study participation. ET visits could occur 
at the clinic, by home visit, or in the hospital (if medically unstable). At this visit, participants 
will undergo the following: an interview for AEs, concomitant medications/vaccines, COVID-19 
exposures and/or symptoms, updates to medical history, blood sampling as outlined in Section 
4.5.5.3; a complete physical examination will be performed, and vital signs and body 
temperature will be measured. 
An overview of key study procedures is provided in Figure 1. 
4.5.4 
End of Study 
The EOS is defined as the date on which the last participant completes the last study visit (the 
Final Visit is Day 394; or ET Visit). Any additional long-term follow-up that is required for 
monitoring of the resolution of an AE and any additional exploratory analyses that are not 
conducted after this milestone passes may be appended to the clinical study report. 
4.5.5 
Additional Procedural Specifics 
 Diary Use to Collect Solicited Adverse Events 
A Diary (electronic or paper if electronic is not feasible) will be used to collect solicited AEs 
(i.e., reactogenicity) directly from the participant: 
• Solicited local and systemic AEs will be recorded daily for 7 days starting on the day of 
each study vaccination in the primary vaccination series (Day 1 and 29). For participants in 
Phase 2 and 3a, solicited AEs will also be recorded daily for 7 days following the 3rd 
injection (Day 92). 
- 
Solicited local AEs include injection site erythema, injection site pain, injection 
site induration/swelling, and injection site tenderness. 
- 
Solicited systemic AEs include arthralgia, chills, diarrhea, dizziness, fatigue, fever 
(categorized by measured body temperature), headache, myalgia, and 
nausea/vomiting. 
- 
Also solicited but not categorized as AEs are antipyretic and analgesic use. 
- 
All participants will be trained on what information will be collected from them 
following each vaccination. This includes how to evaluate and score each 
solicited AE. Some solicited AEs are not scored directly by the participant, but 
the values recorded will be analyzed for severity including body temperature and 
visible injection site reactions (erythema or induration/swelling). Body 

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temperature and visible injection site reactions will be measured daily by 
thermometer and ruler, respectively, provided by the site. Participants should be 
trained on how to use the thermometer (including capture of highest body 
temperature if the participant perceives the onset of possible fever) and the ruler. 
Participants should be encouraged to complete the diary at roughly the same time 
of day for the 7 days following vaccination when recording the solicited AEs. 
• An electronic Diary (eDiary) will involve the use of an application on the individual 
participant’s mobile phone or through the use of a loaner mobile phone with the 
application installed. If an eDiary if not feasible, then a paper diary will be used by the 
participant. Training on how to use either the electronic or paper diary will be performed 
at the time of the Day 1 visit. The eDiary will use prompts to encourage the participant to 
enter data, alerts to inform the site and other team members of potential toxicity grade 
solicited AEs (if relevant). Timely follow-up of these alerts is expected. 
 Collection of Unsolicited Adverse Events and COVID-19 Exposure/Symptoms 
Weekly and monthly phone calls and clinic visits (Section 4.5.3) including unscheduled and ET, 
if applicable) will be used to collect unsolicited AEs and COVID-19 exposure/symptoms: 
• Unsolicited AEs will be recorded through Final Visit or ET Visit. For unsolicited AEs 
categorized as AEs leading to discontinuation/withdrawal, medically attended adverse 
events (MAAEs), and serious adverse events (SAEs) documentation will occur through 
365 days after the completion of the initial vaccination series (up to Day 394). 
• Symptoms of COVID-19 (Section 4.5.3.7 and Appendix 2) or exposure to SARS-CoV-2 
will be recorded from first study vaccine administration throughout the entire study (Final 
Visit or ET Visit).  
• Any participant reporting onset of a possible symptom of COVID-19 or a possible 
exposure to SARS-CoV-2 should trigger an Unscheduled Visit (Section 4.5.3.7) for 
further evaluation. This visit should ideally occur within 72 hours of COVID-19 
symptom onset or reported SARS-CoV-2 exposure. Should the participant manifest 
symptoms within the first 4 days after each vaccination, refer to Section 4.5.3.7 for 
further consideration. 
 Blood and SARS-CoV-2 Sampling 
Blood and SARS-CoV-2 sampling will be collected as follows: 
• At Screening: 
In all participants: 
- 
Blood may be drawn for pregnancy testing at sites that do not allow urine 
pregnancy testing. 
- 
Blood may be drawn for FSH measurement in a female to confirm menopausal 
status (Appendix 3). 

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- 
Nasal swab testing for SARS-CoV-2 by RT-PCR. An additional sample will be 
collected and retained in the event of SARS-CoV-2 sequencing for possible 
variant determination. If obtained within 5 days prior to Screening period, nasal 
swab testing does not need to be repeated at Screening. 
In Phase 1 participants: 
- 
Blood will be drawn for additional screening assessments (complete blood count 
[CBC], chemistry panel, and virology [HbsAg, HCV Ab, HIV]). At Screening, in 
addition to sending samples to the central laboratory, a locally processed sample 
can be used for eligibility for enrollment. Samples will be obtained prior to study 
vaccine administration. 
• Day 1: 
In all participants: 
- 
Antibody assessments for SARS-CoV-2 seropositivity for nucleocapsid antigen 
will be performed. 
- 
Blood will be drawn and saved as a baseline sample for a possible future analysis 
of the correlate of protection and possible future analysis for immune responses to 
SARS-CoV-2 variants. 
- 
Nasal swab testing for SARS-CoV-2 by RT-PCR. If Screening test is within 5 
days of Day 1, nasal swab testing does not need to be repeated at Day 1. If 
screening and randomization are being performed on the same day the result of 
the RT-PCR test must be known to be negative prior to randomization. 
In Phase 1/2/3a and Phase 3c-1 participants: 
- 
Blood will be drawn as a baseline sample for testing of SARS-CoV-2 antibody 
responses. 
• Day 8 
In Phase 1 participants: 
- 
Blood will be drawn for safety laboratory assessments (CBC and chemistry 
panel). 
• Day 29 
In Phase 1 participants: 
- 
Blood will be drawn for safety laboratory assessments (CBC and chemistry 
panel), prior to study vaccine administration. 
In all participants: 
- 
Antibody assessments for SARS-CoV-2 seropositivity for nucleocapsid antigen 
will be performed. 
In Phase 1/2/3aand Phase 3c-1 participants: 

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- 
Blood will be drawn for testing of SARS-CoV-2 antibody responses. An archive 
sample will also be drawn for potential future analysis for immune responses to 
SARS-CoV-2 variants. 
• Day 36 
In Phase 1 participants: 
- 
Blood will be drawn for safety laboratory assessments (CBC and chemistry 
panel). 
• Day 57: 
In Phase 1 participants: 
- 
Blood will be drawn for safety laboratory assessments (CBC and chemistry 
panel). 
In all participants: 
- 
Blood will be drawn and saved for a possible future analysis of a correlate of 
protection and possible future analysis for immune responses to SARS-CoV-2 
variants. 
In Phase 1/2/3a and the Phase 3c-1 participants: 
- 
Blood will be drawn for testing of SARS-CoV-2 antibody responses, including 
anti-nucleocapsid antibody responses. 
• Day 92 (Cohorts 1/2/3a and 3b only): 
In Phase 1/2/3a participants: 
- 
Blood will be drawn for testing of SARS-CoV-2 antibody responses, including 
anti-nucleocapsid antibody responses. An archive sample will also be drawn for 
potential future analysis for immune responses to SARS-CoV-2 variants. 
• Day 120 (Cohorts 1/2/3a and 3b only): 
In Phase 2/3a participants: 
- 
Blood will be drawn for testing of SARS-CoV-2 antibody responses, including 
anti-nucleocapsid antibody responses. An archive sample will also be drawn for 
potential future analysis for immune responses to SARS-CoV-2 variants. 
• Day 211 (Cohort 3c-1 only) 
- 
Blood will be drawn for testing of SARS-CoV-2 antibody responses, including 
anti-nucleocapsid antibody responses. An archive sample will also be drawn for 
potential future analysis for immune responses to SARS-CoV-2 variants. 

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• Unscheduled Visits: 
In all participants that have COVID-19 symptoms and/or COVID-19 exposure, the 
participant is asked to contact the site as soon as feasible to make arrangements for 
testing.  
The preferred assessment is to evaluate for SARS-CoV-2 via nasal swab. Testing of the 
nasal swab will be performed as follows:  
- 
To measure SARS-CoV-2 by reverse transcriptase-polymerase chain reaction 
(RT-PCR). 
- 
An additional sample will be collected and retained in the event of 
SARS-CoV-2 sequencing for possible variant determination. 
- 
In some cases, such as when the participant lives remote from the study site, the 
participant may be given two test kits to take home as it may be necessary to 
perform a rapid antigen test prior to bringing the participant to the site for nasal 
swab RT-PCR testing. In such instances, if the first rapid antigen test is negative 
then a SECOND test should be performed 48 to 72 hours later. 
- 
Note: For Phase 1/2/3a/3b, nasal swabs for RT-PCR test do not need to be 
performed after Day 92. For Phase 3c, nasal swabs should continue to be 
collected until the last study visit (early termination of Day 394). 
• Day 394 (Final Visit); or ET: 
In the Immunogenicity Subgroup Participants: 
Blood will be drawn for testing of SARS-CoV-2 antibody responses, including anti-
nucleocapsid antibody responses. An archive sample will also be drawn for potential 
future analysis for immune responses to SARS-CoV-2 variants. 
 Telephone Calls 
Telephone calls will be performed at intervals specified in Section 4.5.3 and the schedule of 
assessments (Appendix 1) for the following reasons: 
• To determine if any solicited AEs are persisting longer than 7 days after each study 
vaccination 
• To evaluate for unsolicited AEs (including MAAEs, SAEs, AEs leading to 
discontinuation/withdrawal) 
• To collect information for concomitant medication/vaccines 
• To evaluate for symptoms of COVID-19 disease and risks of exposure to COVID-19. 
Solicitation of symptoms and risks of exposure to COVID-19 will follow a scripted 
interview provided in the Investigator Site File 
Calls to the participant will be performed by a trained site team member designated by the 
investigator. However, in the event the participant reports any change in health status or change 
in medications, a qualified health care practitioner will need to complete the safety assessment. 

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 Physical Examinations 
For participants in Phase 1, complete physical examination will be performed at Screening, 
Days 1, 8 29, 36, 92 and 120, and Final Visit (or ET). For Phase 2, 3a and 3b complete physical 
examination will be performed at Screening, Days 1 and 29, 92 and 120, and Final Visit (or ET). 
For participants in Phase 3c complete physical examination will be performed at Screening, Days 
1 and 29, and Final Visit (or ET).  Symptom-directed examination (if any symptoms) may be 
performed at other timepoints as indicated to assess changes from Screening.  
• A complete physical examination will include, at a minimum, assessments of the general 
status of the participant, the skin of the intended study vaccine administration site, 
superficial lymph nodes, cardiovascular, respiratory, gastrointestinal, and neurological 
systems.  
• A directed physical examination will include, at a minimum, assessments of the skin of 
the intended/actual study vaccine administration site, and/or any organ systems relevant 
to symptoms or AEs reported by the participant. Investigators should pay special 
attention to clinical signs related to previous serious illnesses. 
Physical examination is to be performed by a qualified health care practitioner designated by the 
investigator. 
 Height and Weight 
At Screening, height and weight will be measured and recorded using calibrated instruments. 
Body mass index for “at risk” determination will be calculated using these values.  
 Vital Signs, Body Temperature, and Pulse Oximetry 
Vital signs will be obtained at each clinic visit. Vital signs will be measured in a semi-supine 
position after 5 minutes of rest and will include systolic and diastolic blood pressure, heart rate, 
and respiratory rate.  
Body temperature will be measured according to standard of care and thermometer instructions. 
If body temperature is taken orally, the participant should not have consumed hot or cold 
beverages or smoked within 15 minutes prior to measurement.  
Pulse oximetry will be performed at Unscheduled Visits, if warranted, to evaluate symptoms of 
COVID-19. Vital sign measurements are to be performed by a qualified health care practitioner 
designated by the investigator. 
 Pregnancy Testing 
For women of childbearing potential (refer to Appendix 3 for definition), urine pregnancy testing 
(“dipstick” test) will be performed at the sites, if available and permissible by local policy, prior 
to each vaccination dose. The site may perform serum testing of beta human chorionic 
gonadotropin if this is required by policy. The test may be performed at the local laboratory or 
central laboratory. The results of the pregnancy test must be read before each dose of study 
vaccine, and the result must be recorded in the source documents.  

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 Medical History 
At Screening, medical history will also be collected including, but not limited to, any medical 
history that may be relevant to participant eligibility for study participation such as prior 
vaccinations, concomitant medications/vaccines, and previous and ongoing illnesses or injuries. 
Relevant medical history can also include any medical history that contributes to the 
understanding of an AE that occurs during study participation if it represents an exacerbation of 
an underlying disease/pre-existing problem. Medical history and vaccination history should be 
obtained for a minimum of, but not limited to, the 2-month period prior to enrollment.  
Vaccination history specifically for COVID-19, SARS-CoV, or Middle East respiratory 
syndrome (MERS) must include any known exposure to these investigational or authorized 
vaccines.  
Should review of on-study AEs or concomitant medications determine that there was a pre-
existing medical condition present but not captured at Screening, this medical condition should 
be added to the Medical History. 
 

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5 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
5.1 
Selection of Study Participants 
Study sites may be selected based on SARS-CoV-2 infection risk of the local population. 
Participants will be assigned to study treatment only if they meet all the inclusion criteria and 
none of the exclusion criteria. 
Participants who withdraw from the study after randomization will not be replaced. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the eligibility criteria as specified in the protocol is essential. 
5.1.1 
Inclusion Criteria 
Each participant must meet all the following criteria to be enrolled in this study: 
Consent and Compliance 
1. Individuals or legally authorized representatives must freely provide consent to study 
participation. 
2. Individuals must agree to comply with all study visits and procedures (including blood 
and nasal swab sampling, Diary completion, receipt of telephone calls from the site, 
willingness to be available for Unscheduled clinic visits). 
3. Individuals in Phase 1 and Phase 2 must have access to and be capable of using an 
eDiary. 
4. Individuals of childbearing potential who are sexually active must be willing to adhere to 
contraceptive requirements (Appendix 3). 
Type of Participant 
5. Adult males or females of at least 18 years of age at the time of signing of the informed 
consent. 
6. Individuals considered at risk for COVID-19 due to work or living environment in the 
opinion of the Investigator. 
5.1.2 
Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from the study: 
Medical Conditions 
1. Significant infection or other acute illness, including body temperature >100.4°F 
(>38.0°C) on the day prior to or Day 1. Participants meeting this criterion may be 
rescheduled within the relevant window periods (Section 5.2.1). Afebrile participants 
with minor illnesses can be enrolled at the discretion of the investigator. 
2. Pregnant or breastfeeding. 

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3. Known history of COVID-19 (nucleocapsid positive test is not exclusionary) or positive 
nasal swab SARS-CoV-2 by RT-PCR test. Note: if obtained within 5 days prior to 
Screening period, do not need to repeat RT-PCR at Screening. 
4. Close contact with a person known to be SARS-CoV-2 positive or with a clinical 
diagnosis of COVID-19 within 7 days prior to enrollment. Participants meeting this 
criterion who remain asymptomatic for 7 days may be rescheduled for enrollment within 
the relevant window periods (Section 5.2.1). 
5. Known history of anaphylaxis, urticaria, or other significant adverse reaction to the 
vaccine or its excipients. See the Investigator’s Brochure for list of vaccine components. 
6. Known history of anaphylaxis to other vaccines. 
7. Bleeding disorder considered a contraindication to intramuscular (IM) injection or 
phlebotomy. 
8. Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections, or 
known to be HIV positive. 
9. An underlying clinically significant acute or chronic medical condition or physical 
examination findings for which, in the opinion of the investigator, participation would not 
be in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments. 
Prior/Concomitant Therapy 
10. Has previously received investigational or approved MERS-CoV, SARS-CoV, 
SARS-CoV-2 vaccines or who have plans to receive off-study COVID-19 vaccines. 
11. Has received a live replicating vaccine within 28 days prior to each study vaccination or a 
licensed inactivated or non-replicating vaccine within 14 days prior to first study 
vaccination. 
12. Has received treatment with immunosuppressive therapy, including cytotoxic agents or 
systemic corticosteroids, eg, for cancer or an autoimmune disease, within 6 months prior 
to Screening, or planned receipt throughout the study. If systemic corticosteroids have 
been administered short term (<14 days) for treatment of an acute illness, participants 
should not be enrolled into the study until corticosteroid therapy has been discontinued 
for at least 28 days prior to first study vaccine administration. Inhaled/nebulized, intra-
articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.  
13. Has received systemic immunoglobulins or blood products within 3 months prior to first 
study vaccine administration or plans to receive such products during the study. 
Other Exclusions 
14. Demonstrated inability to comply with the study procedures. 
15. Investigator site staff members, employees of the Sponsor or the CRO directly involved 
in the conduct of the study, or site staff members otherwise supervised by the 
investigator, or immediate family members of any of the previously mentioned 
individuals. 

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Additional Exclusion Criteria for Phase 1 Participants Only 
16. Individuals ≥ 60 years of age. 
17. Individuals with clinically significant abnormalities in medical history or physical 
examination, including but not limited to, the following: 
a) Respiratory disease (e.g., chronic obstructive pulmonary disease [COPD], asthma) 
requiring daily medications or oxygen currently or any treatment of respiratory 
disease exacerbations (e.g., COPD or asthma exacerbation) warranting hospitalization 
or an emergency room visit or supplemental oxygen in the last 5 years. 
b) Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, 
ischemic heart disease) or history of myocarditis or pericarditis as an adult. 
c) Neurological or neurodevelopmental conditions (e.g., migraines, epilepsy, stroke, 
seizures in the last 3 years, encephalopathy, focal neurologic deficits, Guillain-Barré 
syndrome, encephalomyelitis or transverse myelitis). 
d) Significant hematologic abnormalities (e.g., sickle cell disease, beta thalassemia, 
coagulation disorders). 
e) Major surgery within the past 6 months. 
f) Individuals with a history of chronic liver disease. 
18. Individuals with the following abnormal Screening laboratory results:  
a) Positive nasal swab SARS-CoV-2 by RT-PCR test. Note: if obtained within 5 days 
prior to Screening period, do not need to repeat RT-PCR at Screening. 
b) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (GGT), total bilirubin, or alkaline phosphatase >1.5 upper limit of normal. 
c) Hemoglobin <9.5 g/dL for females and <10.5 g/dL for males. 
d) Platelet count <100 × 109/L. 
e) Other clinically significant abnormal (according to the judgment of the Investigator) 
Screening laboratory values. 
f) Individuals with Type 2 diabetes and Screening hemoglobin A1c >8.0%. 
g) Hepatitis B core antigen (HbsAg), Hepatitis C virus (HCV) antibody or HIV positive. 
Additional Exclusion Criteria for Phase 3c Participants Only 
19. No contraindications (as specified in the prescribing information) to receiving the 
ChAdOx1 vaccine. 
5.1.3 
Determination of “At Risk” of Severe COVID-19 
Prior to randomization, the medical history of the participant will be reviewed. In Phases 2, 3a, 
Phase 3b and 3c, participants identified as being either 60 years of age or older OR who have 

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any of the medical conditions provided in Appendix 5 will be categorized as “at risk” of severe 
COVID-19 
Each of the medical conditions provided in Appendix 5 is currently regarded as a known or 
suspected medical condition affiliated with risk of severe COVID-19 (CDC 2021). 
At time of randomization, participants in Phases 2, 3a, 3b and 3c will be stratified by age (< 60 
or ≥ 60 years of age) and for participants < 60 years of age by risk of severe COVID-19; a total 
of 3 stratification factors. 
5.1.4 
Screen Failures 
Screen failures are individuals who fail to meet all inclusion criteria or who meet at least 1 of the 
exclusion criteria. Rescreening will not be permitted but enrollment may be delayed if the entry 
criterion is specific to a time window; see Section 5.2.1. Reasons for screen failure will be 
collected and entered in the electronic data capture (EDC) system. 
5.1.5 
Switchover/Further Study Vaccine Eligibility Criteria 
At Day 92, all participants in Phase 1, 2, 3a and 3b will be reviewed for eligibility to receive 
further study vaccine based on meeting any of the following exclusionary criteria on Day 92. 
Participants meeting any of the following criteria will be excluded from receiving further study 
vaccine administration: 
• Significant infection or other acute illness, including body temperature >100.4°F 
(>38.0°C) on the day prior to or day of planned Switchover/Further Study Vaccine 
vaccine administration (see Section 5.2.1). 
• Pregnant or breastfeeding. 
• Persistence of symptoms from COVID-19 disease (recovered COVID-19, asymptomatic 
SARS-CoV-2 infection and/or nucleocapsid positive test is not exclusionary). 
• Receipt of an off-study COVID-19 vaccine since study enrollment.  
• Demonstrated inability to comply with the study procedures since study enrollment. 
• Development of new severe allergy to vaccine components since study enrollment. See 
the IB for list of vaccine components. 
• New onset of bleeding disorder considered a contraindication to IM injection or 
phlebotomy. 
• New onset of immunosuppressive or immunodeficient state, asplenia, or recurrent severe 
infections.  
• Has received a live replicating vaccine within 28 days prior to intended 
Switchover/Further Study Vaccine vaccine administration or an inactivated or non-
replicating vaccine within 14 days prior to intended Switchover/Further Study Vaccine 
vaccine administration. Please see Section 5.2.1 for guidance on deferral of study 
vaccination.  

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• Has received immunosuppressive therapy, including cytotoxic agents or has initiated 
systemic corticosteroid therapy. If systemic corticosteroids have been administered short 
term (<14 days) for treatment of an acute illness, see Section 5.2.1 for additional 
guidance. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) 
corticosteroids are permitted.  
• Has received systemic immunoglobulins or blood products within the past 3 months.  
• Has newly identified that they are investigator site staff members, employees of the 
Sponsor or the CRO directly involved in the conduct of the study, or site staff members 
otherwise supervised by the investigator or immediate family members of any of the 
previously mentioned individuals. 
• Has a clinically significant acute or chronic medical condition or physical examination 
findings for which, in the opinion of the investigator, further study vaccine administration 
would not be in the best interest of the participant (eg, compromise the well-being) or that 
could prevent, limit, or confound the protocol-specified assessments. 
5.2 
Delaying or Discontinuing Study Vaccination and Participant Withdrawal From the 
Study 
5.2.1 
Delay in Study Vaccination 
Body temperature must be measured and the participant asked about recent concomitant 
medication/vaccine receipt prior to each administration of study vaccine. 
The following events constitute criteria for delay of study vaccination and the window of delay 
specified forthwith: 
• On planned Day 1, close contact with a person known to be SARS-CoV-2 positive or 
with a clinical diagnosis of COVID-19 within 7 days prior to enrollment.  
o Participants meeting this criterion who remain asymptomatic for 7 days may be 
rescheduled for vaccination. 
• Acute moderate or severe infection with or without fever at the time of dosing (delay: 
until afebrile for 48 hours and clinically improved according to investigator judgment) 
o Participants with minor illness and without fever may be vaccinated if deemed 
appropriate according to investigator judgment. 
• Fever without signs of acute illness, defined as body temperature 100.4°F (≥38.0°C) 
(delay: until afebrile for 48 hours). 
• Use of antipyretics or analgesics within 24 hours. 
• Receipt of vaccines or specified steroid doses close to the time of intended study 
vaccination. 
o Vaccination will be deferred to confirm 28 days since receipt of a live replicating 
vaccine. 

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o Vaccination will be deferred to confirm 14 days since receipt of an inactivated or 
non-replicating vaccine. 
o Vaccination will be deferred to confirm at least 28 days since receipt of systemic 
steroid therapy. 
• Participants who are confirmed to be RT-PCR positive for SARS-CoV-2 after the first 
study vaccine administration, should still receive the second study vaccine administration 
if deemed appropriate by the Investigator. However, the second vaccine administration 
should be at least 28 days after the date of the positive RT-PCR result, and at the time of 
vaccination the participant must not meet any other criteria for delay in study vaccination 
(as outlined above). 
Vaccination may be performed once these criteria are no longer met. For the first vaccination this 
will not constitute a protocol deviation as long as the vaccine is administered within 28 days after 
signing the informed consent. If greater than 28 days, then participants must be rescreened.  
If vaccination is delayed for any of the reasons described above, subsequent study visits will be 
based on calendar days after the receipt of the study vaccine.  
5.2.2 
Discontinuation of Study Vaccine (Participant)  
A participant may not receive additional study vaccine administrations for any of the reasons 
outlined in Section 5.1.5.  
Additional reasons for discontinuation of study vaccine for a participant would include: 
• Participant request to discontinue study vaccinations. 
• Participant is lost to follow-up. 
• New information becomes available that makes further participation unsafe. 
• Termination of the trial study vaccinations. 
Should study vaccine administration be discontinued, the participant will be encouraged to 
continue study participation for study evaluations through Day 394 (Final Visit). 
5.2.3 
Withdrawal/Discontinuation from the Study 
Participants are free to withdraw from participation in the study at any time upon request, 
without prejudice to further treatment the participant may need to receive. The investigator will 
request that the study participant complete all study procedures pending at the time of 
withdrawal. 
A participant will be recorded as a screen failure for the study if any of the following occur prior 
to first administration of study vaccine:  
• Eligibility criteria are not met. 
• The participant requests to discontinue study participation. 

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If, after randomization, a participant withdraws from the study, an EOS eCRF will be completed 
and information related to the withdrawal will be documented in the eCRF. The investigator will 
document whether the decision to withdraw a participant from the study was made by the 
participant or by the investigator, as well as which of the following possible reasons was 
responsible for withdrawal: 
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
• AE or SAE (specify) 
• Participant request (specify) 
• Protocol deviation (specify) 
• Physician/Investigator decision (specify) 
• Pregnancy 
• Other (specify) 
The investigator must capture the reason for withdrawal from the study in the eCRF for all 
participants that withdraw. 
If, after enrollment, a participant desires to withdraw from the study because of an AE, the 
investigator will try to obtain agreement to follow-up with the participant until the event is 
considered resolved or stable and will then complete the EOS eCRF. 
If a participant approaches the site requesting to receive off-study COVID-19 vaccine, the 
participant should be counseled and reminded of the Switchover study design (for Phase 1, 2, 3a 
and 3b cohorts) or the comparison with another active vaccine (for Cohort 3c) whereby all 
participants will receive active investigational vaccine. The participant should be encouraged to 
demonstrate evidence of a scheduled appointment to receive off-study COVID-19 vaccine. If, 
after counseling and confirmation of the appointment, a study participant maintains his/her 
interest in receiving off-study vaccine, he/she will be advised to preferably schedule off-study 
vaccine at least 28 days after last dose of study vaccine, the participant will not be eligible to 
receive Switchover/Further Study Vaccine vaccine (if the Switchover/Further Study Vaccine day 
has not passed) and the participant is asked to continue study procedures through Final Visit 
(Day 394).  
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the site 
study records and notify the Sponsor or CRO accordingly. 
If a participant withdraws consent and specifies no further contact with him/her or persons 
previously authorized by the participant to provide this information, this should be documented 
by the investigator in the study source documents. If vital status (whether the participant is alive 
or dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law. 

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5.2.4 
Discontinuation of Study Dosing (Study-wide) 
All cases of severe COVID-19, SAEs determined to be related to study vaccine or deaths 
determined to be related to study vaccine will be referred to the DSMB (Section 8.10.3) in an 
expedited fashion.  
In the event of death determined to be related to study vaccine, further vaccination will be 
paused until the relevant safety data has been reviewed by DSMB. 
The DSMB, based on their review of the blinded or unblinded safety data (including assessment 
for potential vaccine-associated enhanced respiratory disease [VAERD]) will recommend 
whether the study should terminate, proceed unmodified, or proceed but with changes to the 
protocol. 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons. 
5.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
or is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 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 the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record. 
If the participant continues to be unreachable, he/she will be considered to have withdrawn from 
the study at the date of last study contact. 
5.4 
Replacement of Participants 
Participants who withdraw from the study after randomization will not be replaced. 

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6 
STUDY TREATMENTS 
6.1 
Method of Assigning Participants to Study Groups  
Assignment of participants to Study Groups will proceed using an IRT system. The site 
personnel (study coordinator or specified designee) will be required to enter or select information 
including but not limited to the password, the protocol number, participant age and the 
participant code (a unique number identifying the participant), and participant’s relevant 
underlying health conditions that will be used to determine “at risk” status prior to 
randomization. The site personnel will then be provided with a vaccine assignment. The IRT 
system will provide an unblinded confirmation report containing the participant code and study 
intervention allocation assigned. The confirmation report must be stored in the site’s unblinded 
files away from the view of blinded site staff.  
Participants will then be randomly assigned and stratified as described in Section 4.5.2. 
Treatment designation will be assigned in the IRT. 
Confirmation of a participant’s eligibility to receive additional study vaccine must be entered 
into the IRT prior to dispensing the assigned vaccination on Day 92. 
6.2 
Study Vaccine Manufacturer 
For Phase 1, 2, 3a and 3b ARCT-154 and placebo (0.9% sterile saline) constitute the study 
vaccine. 
For Phase 3c ARCT 154 and the Astra Zeneca vaccine ChAdOx1 constitute the study vaccines. 
Arcturus Therapeutics, Inc. (10578 Science Center Drive, Suite 150, San Diego, CA 92121 
USA), as owner of the drug product, is the designated manufacturer of ARCT-154.  Arcturus 
contracts manufacture of ARCT-154 as follows: 
• 
 
 
• 
 
 
• 
 
 
0.9% saline and ChAdOx1 are sourced from commercial supply and emergency use supply (in 
Vietnam), respectively and manufacturer details can be found in the prescribing information. 
6.3 
Study Vaccine, Dosage, and Route of Administration 
The ARCT-154 study vaccine is a lipid-nanoparticle-formulated RNA product. The RNA 
comprises a replicon based upon an alphavirus in which RNA coding for the virus structural 
proteins has been replaced with RNA coding for the SARS-CoV-2 S glycoprotein containing the 
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The nanoparticle composition includes 4 lipid excipients (ionizable cationic lipid, Arcturus 
proprietary lipid; neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine; cholesterol; and 
polyethylene glycol-lipid conjugate). 
ARCT-154 is provided as a lyophilized formulation in a 12-mL-size glass vial presentation that 
allows for multiple 5.0-µg doses of ARCT-154 after reconstitution. The diluent for reconstitution 
consists of sterile 0.9% sodium chloride for injection, that is USP, BP or equivalent grade, and is 
preservative-free.  
The comparator (placebo) for Phase 1, 2, 3a and 3b is sterile 0.9% sodium chloride for injection 
that is United States Pharmacopeia (USP), British Pharmacopeia (BP) or equivalent grade, and is 
preservative-free. 
The comparator for Phase 3c is the Astra Zeneca vaccine ChAdOx1, which is already authorized 
for use in Vietnam. ChAdOx1 active substance is a chimpanzee Adenovirus encoding the 
SARS-CoV-2 Spike glycoprotein. Further details can be found in the prescribing information for 
ChAdOx1. 
The study vaccines will be prepared by an unblinded trained site staff member in accordance 
with the Pharmacy Manual, and outside of the view of blinded team members.  Study vaccines 
will be matched for volume (0.5 mL) and appearance (1-mL syringe) prior to administration. 
Study vaccine will be administered by IM injection to the deltoid muscle by an unblinded health 
care provider who will not be involved in assessments of any study endpoints.  
Study vaccine preparation and administration should be performed in an area outside of the view 
of blinded team members. All documents containing unblinded information must also be kept out 
of view of the blinded team members and the study participants. Unblinded team members will 
not otherwise participate in other study-related procedures or assessments of the participant. 
The IM injection of the study vaccine will be into the lateral aspect of the deltoid muscle of the 
non-dominant arm, where possible. 
Epinephrine for subcutaneous (S.C.) injection, diphenhydramine for intravenous injection, and 
any other medications and resuscitation equipment for the emergency management of 
anaphylactic reactions must be available in close proximity to the room where the vaccination is 
administered. 
See Section 4.5.3.2 for additional guidance on procedures during the Dose Administration visit. 
6.4 
Management of Clinical Supplies 
6.4.1 
Investigational Product Packaging and Storage 
The Sponsor or designee will provide the Investigator with: 
• packaged ARCT-154 containers labeled in accordance with specific country regulatory 
requirements.  
• sodium chloride intended for use as diluent and placebo will be provided  
• ChAdOx1 vaccine 

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See the Pharmacy Manual for additional guidance study vaccine packaging and study vaccine 
storage requirements. 
The study staff is required to document the receipt, dispensing, and return/destruction of 
ARCT-154 and ChAdOx1 supplies provided by the Sponsor or designee. The study center must 
destroy or return for destruction all unused frozen vials of ARCT-154/ ChAdOx1 to the Sponsor 
or designee. Vials of ARCT-154/ ChAdOx1 should be destroyed by the study center or delegate 
only after drug accountability has been done by the unblinded study monitor. Destruction or 
return of study vaccine must be documented. 
6.4.2 
Clinical Supplies for Reconstitution and Administration of Study Vaccine 
Syringes, needles and filters will be supplied by the Sponsor or designee. See the Pharmacy 
Manual for guidance on the use of ancillary supplies for vaccinations. 
6.4.3 
Study Vaccine Accountability 
The investigator will maintain accurate records of receipt of all study vaccines (ARCT-154, 
placebo/diluent, ChAdOx1), including dates of receipt. In addition, accurate records will be kept 
regarding when and how much study vaccine is administered to each participant in the study. 
Only participants enrolled in the study may receive any study vaccine and only authorized site 
personnel may supply or administer the study vaccine. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all study vaccines will be reconciled and destroyed 
according to applicable regulations. Further guidance and information for the final disposition of 
unused study vaccines are provided in the Pharmacy Manual. 
6.4.4 
Other Supplies for Participant Use 
Study sites will distribute sponsor-provided thermometers (for body temperature measurement) 
and rulers to measure injection site erythema and induration/swelling reactions, respectively. The 
measurements will be captured in the Diary provided by the site. Electronic Diaries will be used 
wherever possible and, if a participant does not have his/her own smart phone devices for eDiary 
use, the site will provide an electronic alternative or a paper diary. 
If the participant should have suspected or confirmed COVID-19 and cannot come into the clinic 
for evaluation, the participant may undergo a telemedicine or Home Visit.  
6.5 
Overdose Management 
Study vaccine (ARCT-154, placebo or ChAdOx1) errors (including overdose, underdose, and 
administration error) must be documented as protocol deviations. A brief description should be 
provided of the deviation, including whether the participant was symptomatic (list symptoms) or 
asymptomatic, and whether the event was accidental or intentional. 
Dosing details should be captured on the Dosing eCRF.  
An overdose is the accidental or intentional administration of a vaccine in an amount higher than 
the dose being studied. An overdose or incorrect administration of study vaccine is not itself an 
AE, but it may result in an AE. If the participant receives a dose of study vaccine (ARCT-154, 

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placebo or ChAdOx1) that exceeds protocol specifications and the participant is symptomatic, 
the symptom(s) should be documented as an AE. 
Should an overdose occur, the investigator or designee should contact the CRO medical monitor 
or designee within 24 hours. 
There are no known treatments for potential overdose of study vaccine. In the event of an 
overdose, the individual should be monitored and provided with symptomatic treatment as 
appropriate. 
Unless there is a user error leading to failure to administer any volume of study vaccine, “catch-
up” vaccine administrations will not be performed. 
6.6 
Blinding  
The study vaccines will be administered in an observer-blind fashion. 
Each of the study vaccines will be prepared by an unblinded trained team member and in 
accordance with the Pharmacy Manual. 
Unblinded personnel (of limited number) will be assigned to vaccine accountability procedures 
and will prepare study vaccine for all participants. These personnel will have no study functions 
other than study vaccine management, documentation, accountability, preparation, and 
administration. They will not be involved in participant evaluations and will not reveal the 
identity of study vaccine to either the participant or the blinded study site personnel involved in 
the conduct of the study unless this information is necessary in the case of an emergency. 
• Unblinded health care providers will administer the study vaccine. They will not be 
involved in assessments of any study endpoints. 
• All documents containing unblinded information must also be kept out of view of the 
blinded team members and the study participants. 
• Unblinded site monitors not involved in other aspects of monitoring will be assigned as 
the study vaccine accountability monitors. They will have responsibilities to ensure that 
sites are following all proper study vaccine accountability, preparation, and 
administration procedures. 
• An unblinded DSMB will perform the ongoing review of safety data from enrolled 
participants to determine if there are any unexpected risks that warrant modification or 
termination of the study. The DSMB will provide recommendations to the Sponsor 
following each data review. 
In order to maintain an observer-blind design, investigators, site staff, participants, and CRO 
staff with oversight of study conduct will remain blinded to vaccine assignments for the study 
duration. The Sponsor representatives with direct oversight of the study will remain blinded to 
individual participant vaccine assignments until the time of study unblinding at the final analysis. 
The Switchover/Further Study Vaccine will occur in a blinded fashion and participants and 
blinded site and Sponsor personnel will remain blinded to treatment assignment until End of 
Study (EOS).  

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Additional members of the Sponsor team that are not involved in direct oversight of the study 
may receive unblinded study data but will not share any unblinded information with the Sponsor 
team overseeing the study. Sponsor staff and other persons that will become unblinded at the 
various data analysis time points will be specified in a written unblinding plan prior to 
unblinding occurring. 
The dosing assignment will be concealed by having the unblinded personnel prepare the study 
vaccine in a secure location not accessible or visible to blinded study staff members. Only 
delegated unblinded site staff will perform the injection of prepared study vaccine. Once the 
injection is completed, only the blinded study staff will perform further assessments and interact 
with the participants. Access to the randomization code will be strictly controlled at the 
pharmacy. All other site staff performing study-related assessments will be blinded for the 
duration of the study. 
6.6.1 
Breaking the Blind 
An individual participant’s study vaccine assignment will not be unblinded to the investigator or 
other blinded study site staff until the EOS unless awareness of the vaccine assignment is 
relevant to the care of the study participant. If the blind needs to be broken because of a medical 
emergency, the investigator may unblind an individual participant’s treatment allocation.  
To the extent possible before unblinding, the investigator should contact the medical monitor to 
discuss the medical emergency and the reason for revealing the actual treatment received by that 
participant. The study vaccine assignment will be unblinded through IRT. Reasons for 
unblinding must be clearly explained and justified in the eCRF. The date on which the code was 
broken together with the identity of the person responsible must also be documented. 
Participants who choose to receive vaccination with licensed COVID-19 vaccine will be 
encouraged to remain in the study, but those that choose to leave the study to pursue alternate 
vaccination will not be unblinded to study treatment unless there is an unexpected post study 
SAE attributed as related to study vaccine by the study investigator. 
6.7 
Compliance With Study Treatment  
When participants are dosed at the site, they will receive the study vaccine directly from the 
Investigator or designee under medical supervision. The date and time of each dose administered 
in the clinic will be recorded in the source documents and recorded in the eCRF. The receipt of 
study vaccine and study participant identification will be confirmed at the time of dosing by a 
member of the study site personnel other than the person administering the study vaccine. 
6.8 
Concomitant Therapies and Procedures 
6.8.1 
Concomitant Therapy 
Study site staff must question the participant regarding any medications taken (including 
herbal/homeopathic substances) and vaccinations received by the participant. The following 
information will be recorded in the eCRF: 

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• All non-study vaccinations administered within the period starting 28 days before the first 
dose of study vaccine and for the duration of study participation. 
• All concomitant medications and non-study vaccinations taken through 28 days after 
each study vaccination.  
• Any concomitant medications/vaccines used to prevent or treat COVID-19. 
• Any concomitant medications/vaccines relevant to or for the treatment of a solicited or 
unsolicited AE, an SAE, an MAAE, or an AE leading to discontinuation/withdrawal. 
• Participants will be asked prior to vaccination and will be asked for 7 days after each 
vaccination of the initial series in the Diary if they have taken any antipyretic or 
analgesics to prevent or treat vaccine-associated side effects (AEs). For participants in 
Phase 2/3a, the diary will also be completed for 7 days after the 3rd dose of study vaccine 
(Day 92). 
All medications and interventions necessary for the appropriate care of the study participant, 
particularly to treat COVID-19, should be administered and appropriately documented along 
with the AE. 
All concomitant medications/vaccines must be recorded in the eCRF until 28 days after each 
dose of study vaccine. Thereafter, only vaccines and concomitant medications associated with an 
SAE, MAAE, or AEs leading to discontinuation/withdrawal will be entered in the eCRF. 
Prohibited Concomitant Vaccines 
Receipt of off-study COVID-19 vaccine is actively discouraged for enrolled participants. Any 
participant who receives an off-study COVID-19 vaccine will not receive further study 
vaccinations. All participants should remain in the study until the Final Visit (Day 394). If the 
off-study vaccine becomes known to the site prior to Switchover/Further Study Vaccine, the 
participant will not receive Switchover/Further Study Vaccine vaccinations and will be requested 
to stay in the study through Final Visit (Day 394).  
 Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical therapy) 
or diagnostic assessment (eg, blood gas measurement, bacterial cultures) performed between 
signing of the informed consent and the participant’s last protocol-specified study visit. 
All concomitant procedures must be recorded in the eCRF until 28 days after each study vaccine. 
Thereafter, only concomitant procedures associated with an SAE, MAAE, or evaluation of 
COVID-19 cases will be entered in the eCRF. 
6.9 
Dose Modification 
No dose modifications will be allowed. 
6.10 
Intervention After the End of the Study 
No intervention will be provided to study participants after the EOS. 

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7 
STUDY ASSESSMENTS 
Technical considerations for study assessments are described throughout Section 4 of the 
protocol.  
The schedule of study assessments is provided in Appendix 1. 
7.1 
Efficacy Assessments 
7.1.1 
Evaluation of Participants With Suspected COVID-19 
Participants with suspected COVID-19 will be evaluated for the presence of potential symptoms 
and clinical findings of COVID-19 as tabulated in Appendix 2. 
To be considered as a protocol-defined COVID-19 case, virological confirmation (by RT-PCR) 
of SARS-CoV-2 and demonstration of at least one of the symptoms or clinical findings listed in 
Appendix 2 are required. This criterion may be met by any of the following tests: 
RT-PCR test or other equivalent nucleic acid amplification–based test (NAAT). Results from lab 
test will only be considered acceptable if it was obtained using: 
• An assay accredited by the Vietnamese MOH; 
• Additional accreditation of the assay by FDA is also preferred; 
• OR an assay performed in a laboratory that is currently CLIA-certified;  
• OR an assay performed by a laboratory accredited according to the ISO 15189 standard. 
Note: For Phase 1/2/3a/3b, nasal swabs for RT-PCR test do not need to be performed after Day 
92. For Phase 3c, nasal swabs should continue to be collected until the last study visit (early 
termination of Day 394). 
Case definitions for the evaluation of COVID-19 and severe COVID-19 are provided in 
Appendix 2. All suspected COVID-19 cases will undergo tiered review:  
• All SARS-CoV-2-confirmed cases are reviewed by a blinded, independent adjudication 
committee (AC) against the symptoms and scales provided in Appendix 2. The AC will 
determine if the severity of symptoms of COVID-19 accompanying SARS-CoV-2 
virological confirmation aligns with protocol-defined COVID-19 case definitions, 
asymptomatic SARS-CoV-2 infection, or atypical COVID-19 case presentations. 
COVID-19 cases (protocol-confirmed and atypical) will also be evaluated by severity 
using FDA and World Health Organization (WHO) criteria. 
 Severe COVID-19 
Two definitions will be used to define severe COVID-19: FDA and WHO (Appendix 2). 
Confirmed COVID-19 must meet the protocol-defined COVID-19 case definition and either the 
FDA or the WHO criteria for severe COVID-19 in order to be considered an event of Severe 
COVID-19 for evaluation of this endpoint. These criteria are summarized in Appendix 2. 

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 Asymptomatic COVID-19 
Asymptomatic SARS-CoV-2 infection is defined as a participant with a positive NAAT test for 
SARS-CoV-2 without the presence of protocol-specified COVID-19 (Appendix 2) or atypical 
COVID-19 symptoms. These cases will be collected as disease events but not analyzed towards 
COVID-19 cases. 
 Atypical COVID-19 
Atypical COVID-19 is defined as a participant with a positive NAAT test for SARS-CoV-2 virus 
and contemporaneous symptoms that are not those listed in Appendix 2 but nevertheless 
clinically suspected to represent a manifestation of COVID-19. These cases will be used for 
exploratory analyses of COVID-19 cases only. 
 Death Attributed to COVID-19 
Any participant who dies during study participation will be evaluated for suspected/confirmed 
causes of death. Autopsy results and histopathology results, as available, will be requested. Any 
death attributed to confirmed COVID-19 will be evaluated for the death endpoint. For cases of 
clinical suspicion of COVID-19 as the cause of the death, these cases will be subject to review 
by the blinded AC for confirmation of whether these meet the ‘Death Attributed to COVID-19’ 
endpoint. 
7.2 
Immunogenicity Assessments 
For Phase 1, Phase 2, Phase 3a and Phase 3c-1 participants, blood samples for immunogenicity 
assessments will be collected at the time points indicated in Section 4.5.5.3 and the Schedule of 
Assessments (Appendix 1). On Days 1, 29, and 92, blood samples for immunogenicity 
assessment will be collected before administration of each study vaccine. The following analytes 
will be measured: 
1) Assays run at National Institute of Hygiene and Epidemiology, Department of Virology, 
Vietnam  
a) Serum NAb titer against SARS-CoV-2: 
i. Genscript SARS-CoV-2 surrogate virus neutralization test (sVNT):  This sVNT 
assay is a functional Enzyme-Linked Immunosorbent Assay (ELISA) intended 
for qualitative or semi-quantitative detection of total neutralizing antibodies in 
human serum, K2-EDTA plasma, peripheral blood and blood plasma that block 
the binding of SARS-CoV-2 to the human ACE2 receptor of host cells. This 
binding assay has been shown to correlate well with cell-based neutralizing 
antibody assays. When run with an appropriate reference standard, the data can 
be converted to international units using the WHO reference standard 
conversion. The assay will be performed on samples from participants in 
Phase 1/2/3a. It may also be performed on samples from participants in 
Phase 3c-1. 
ii. Plaque reduction neutralization test [PRNT]: This live virus assay is performed 
in a biosafety level 3 (BSL3) laboratory using a Wuhan reference standard 

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strain and delta variant strain isolated at the Department of Virology, National 
Institute of Hygiene and Epidemiology. Neutralizing antibody titers are 
calculated as the highest serum dilution that results in 50% reduction in the 
number of virus plaques (PRNT50). This assay will be performed on samples 
from all participants in Phase 1 and the first 50 participants in Phase 2. It may 
also be performed on samples from additional participants in Phase 2/3a and/or 
3c-1.  
iii. Genscript SARS-CoV-2 pseudovirus neutralization (MNT) assay kit Luc 
reporter: this kit provides a cell-based functional assay for measuring the 
potency of candidate drugs in neutralizing SARS-CoV-2 S protein. The S 
protein described in this kit is located on the surface of the lentivirus-based 
pseudovirus particles, so the pseudovirus can bind to the ACE2 receptor 
overexpressed on the target cells, simulating the fusion process of the 
coronavirus-cell and cell-cell membrane. After infection, the pseudovirus can 
express the luciferase gene in the target cell. By measuring the bioluminescence 
signal, the extent of pseudovirus infection can be determined. When a candidate 
drug that is able to neutralize SARS-CoV-2 binds to the S protein, the 
interaction of ACE2 and S proteins on the pseudovirus is blocked, preventing 
the pseudovirus infection and resulting in a decrease in the bioluminescence 
signal. Therefore, the sample potential for neutralizing SARS-CoV-2 can be 
determined from the signal reduction. This assay may be performed on samples 
from participants in Phase 3c-1 and on samples from participants in 
Phase 1/2/3a. 
b) Serum IgG antibodies binding the SARS-CoV-2 spike protein 
i. Siemens ADVIA Centaur XP/XPT system: this is a fully automated 2-step 
antigen sandwich immunoassay using acridinium ester chemiluminescent 
technology. The solid phase contains a preformed complex of streptavidin-
coated microparticles and biotinylated SARS-CoV-2 recombinant antigens. This 
reagent complex is used to capture full-length SARS-CoV-2 S protein-specific 
antibodies in the patient samples. This assay will be performed on samples from 
participants in Phase 1/2/3a and 3c-1. 
2) Assays run at PPD BioA Labs in Richmond, VA, USA  
a) Serum NAb titer against SARS-CoV-2 
i. Pseudovirus microneutralization test (MNT; (Wuhan-Hu-1 [D614G strain])): 
The SARS CoV-2 MNT is a cell-based assay that is designed to determine the 
ability of anti-SARS CoV-2 Spike neutralizing antibodies to inhibit the 
infection of 293T-ACE2 cells by D614G strain-specific SARS CoV-2 Spike 
Reporter Virus Particles (RVP) which express green fluorescent protein (GFP). 
Results can be converted to IU/mL using a WHO reference standard calibration 
factor. This assay will be performed on samples from all participants in Phase 1 
and the first 150 participants who received ARCT-154 in the initial vaccination 

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series in Phase 2. This assay may also be performed on samples from additional 
participants in Phase 1/2/3a and/or participants in Phase 3c-1.  
ii. ACE2 receptor binding inhibition sVNT assay: The V-PLEX COVID-19 
Coronavirus (ACE2) Kit is a multiplex neutralization assay that measures the 
antibodies capable of blocking the binding of angiotensin-converting enzyme 2 
(ACE2) to the SARS-CoV-2 Spike and RBD antigens. The Panel serves as a 
high-throughput alternative to traditional neutralization assays. The Panel 13 
(IgG) Kit is a multiplex serology assay for antibodies to ten Spike antigens from 
variants of SARS-CoV-2, including the Alpha, Beta, Gamma, Delta, and several 
emerging variants. Panel 13 has Spike antigens from the following lineages: A 
(WT), (B.1.1.7), (B.1.351), (B.1.526.1), (B.1.617), (B.1.617.1), (B.1.617.2), 
(B.1.617.3), (P.1), and (P.2). This assay will be performed on samples from all 
participants in Phase 1 and the first 150 participants who received ARCT-154 in 
the initial vaccination series in Phase 2. This assay may also be performed on 
samples from additional participants in Phase 1/2/3a and/or participants in 
Phase 3c-1.  
iii. Delta virus MNT: This is a cell-based assay designed to determine the ability of 
anti-SARS CoV-2 Spike neutralizing antibodies to inhibit the infection of 293T-
ACE2 cells by Delta strain-specific SARS CoV-2 Spike Reporter Virus 
Particles (RVP) which express green fluorescent protein (GFP). The readout is 
ID50. This assay will be performed on samples from all participants in Phase 1 
and the first 150 participants who received ARCT-154 in the initial vaccination 
series in Phase 2. This assay may also be performed on samples from additional 
participants in Phase 1/2/3a and/or participants in Phase 3c-1.  
b) Serum IgG antibodies binding the SARS-CoV-2 spike 
i. Mesoscale Discovery (MSD) multiplex assay. MSD multiplex indirect binding 
ECL is a quantitative electrochemiluminescence (ECL) assay designed to detect 
antibodies to total immunoglobulin G (IgG) against the full-length spike, RBD, 
and N antigens of the Wuhan strain SARS-CoV-2. Results can be converted to 
BAU/mL using WHO reference standard calibration factors provided by MSD. 
This assay may be performed on samples from participants in Phase 1/2/3a 
and/or Phase 3c-1. 
Additional testing may also be performed using other assays. 
Immunogenicity laboratory results will only be considered acceptable if obtained using an assay 
accepted by the Vietnamese MOH. 
Sample aliquots will be designed to ensure that backup samples are available and that adequate 
vial volumes may allow for further testing. The actual time and date of each sample collected 
will be recorded in the eCRF, and unique sample identification will be used to maintain the blind 
at the laboratory at all times and to allow for automated sample tracking and storage. Handling 
and preparation of the samples for analysis, as well as shipping and storage requirements, will be 
provided in a separate study manual.  

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7.3 
Reactogenicity 
Reactogenicity will be evaluated in all participants enrolled in the study (Section 7.4.1.1.1.1). 
Reactogenicity will be evaluated following receipt of each vaccination of the initial series and 
evaluated in those participants who provide at least 1 response to the Diary. Further details on 
the reactogenicity analysis set are provided in Section 8.2. 
Participants will complete a Diary collecting solicited AEs for 7 days following each vaccine 
administration of the initial series. 
7.4 
Safety Assessments 
Safety assessments will include monitoring and recording of solicited and unsolicited AEs, 
MAAEs, AEs leading to discontinuation of the study vaccine/study withdrawal, SAEs, vital 
signs, body temperature and (in participants who are evaluated for suspected COVID-19) pulse 
oximetry. 
For Phase 1 participants, safety blood sampling will include CBC, chemistry panel. Virology 
testing (HbsAg, HCV Ab, and HIV) will also be performed at Screening. Procedures for 
collection, handling, and storage of blood collected for safety assessments will be detailed in the 
Laboratory Manual. 
7.4.1 
Adverse Events 
In this study, AEs include subcategories of AEs collected by solicitation of participants as to 
types of signs and symptoms observed following vaccination (reactogenicity), referred to as 
“solicited AEs”, and a general category of unsolicited AEs that includes any spontaneously 
reported or observed AE occurring after the signing of informed consent.   
 Definitions 
7.4.1.1.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the study vaccine or their clinical significance. AE 
collection will begin after the signing of informed consent; however, AEs that occur prior to the 
administration of first dose of study vaccine (ie, non-treatment-emergent AEs) will be listed 
separately in the clinical study report. 
An AE is defined as an untoward medical occurrence associated with the use of a medicinal 
product in humans, whether or not considered related to the medicinal product. 
An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study vaccine, whether or not 
considered related to the study vaccine 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition)  

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• Recurrence of an intermittent medical condition (eg, headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (eg, electrocardiogram, 
X-ray) that is associated with symptoms or leads to discontinuation from the study vaccine 
7.4.1.1.1.1 
Solicited adverse events 
The term “reactogenicity” refers to selected signs and symptoms (“reactions”) occurring in the 
hours and days following a vaccination. These signs and symptoms are collected as solicited AEs 
from participants by use of the Diary for 7 consecutive days following each of the first 2 study 
vaccine administrations.  
• The following solicited AEs are included in the Diary:  
- 
Solicited local AEs: injection site erythema, injection site pain, injection site 
induration/swelling, and injection site tenderness 
- 
Solicited systemic AEs: arthralgia, chills, diarrhea, dizziness, fatigue, fever 
(categorized by measured body temperature), headache, myalgia, and 
nausea/vomiting 
The occurrence of each of these solicited AEs is regarded as a vaccine-related AE. 
Also solicited from participants but not categorized as an AE is the use of antipyretics and 
analgesics to prevent or treat solicited AEs. 
Solicited AEs are graded for severity according to scales defined in the Center for Biologics 
Evaluation and Research’s Guidance: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (DHHS 2007), Appendix 4. 
Solicited AEs may also lead to circumstances that warrant collection of the events as unsolicited 
AEs. This includes any solicited AE that leads to: 
• a medically attended visit 
• an SAE 
• a discontinuation of study vaccine 
• a withdrawal from the study 
• or any solicited AE that persists beyond 7 days after the first study vaccine 
administration. 
Furthermore, should the site determine that the participant experienced and failed to enter a 
Grade 3 or Grade 4 solicited AE in the Diary during the time when the Diary was accepting data 
entry, this Grade 3 or Grade 4 solicited AE should be entered as an unsolicited AE in the CRFs.   
7.4.1.1.1.2 
Unsolicited adverse events 
Unsolicited AEs are defined as any spontaneously reported or discovered AE. 
Unsolicited AEs will be collected in all participants who receive at least 1 dose of study vaccine 
and are classified according to the following: 

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• mild, moderate, or severe 
• whether or not the AE was categorized as an SAE, an MAAE, and/or an AE leading to 
discontinuation/withdrawal 
• whether or not the AE was related to study vaccine or study procedure in the judgment of 
the investigator 
7.4.1.1.2 
Serious Adverse Events 
An SAE is defined as any event that: 
• results in death 
• is immediately life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect arising from a pregnancy conceived after receipt of 
study vaccine 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the participant or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
7.4.1.1.3 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is any SAE wherein a causal 
relationship to study vaccine is at least reasonably possible and wherein the nature or severity of 
the AE is not consistent with the Reference Safety Information in the IB. 
7.4.1.1.4 
Medically Attended Adverse Events 
An MAAE is an AE that leads to an unscheduled visit (including a telemedicine visit) with a 
healthcare provider (HCP, eg, nurse, nurse practitioner, physician’s assistant, physician). This 
would include visits to a study site for unscheduled assessments (eg, rash assessment, possible 
COVID-19 symptoms, and visits to HCPs external to the study site for acute changes in health 
(eg, urgent care, primary care physician). Investigators will review unsolicited and solicited AEs 
for the occurrence of any MAAEs. If a solicited AE leads to an unplanned HCP visit for 
evaluation of the symptoms, this will be entered as an unsolicited AE (also marked as an MAAE) 
in addition to the solicited AE captured. The following considerations of MAAEs also apply:  
• Routine study visits will not be considered medically attended visits.  
• AEs observed in the immediate 30-minute post-vaccination observation period will be 
regarded as an MAAE if: 

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- 
Treatment of the AE is required prior to discharge OR 
- 
Extension of observation is required due to clinical concerns or unstable clinical 
findings 
7.4.1.1.5 
Adverse Events Leading to Discontinuation/Withdrawal  
Any AE that leads to discontinuation of the vaccine (Section 5.2.2) and/or withdrawal from the 
study (Section 5.2.3) will be regarded as an AE leading to discontinuation/withdrawal. 
Investigators will review reasons for discontinuation/withdrawal and report this on the 
appropriate eCRF page (AE eCRF for AEs leading to withdrawal of the study vaccine and Study 
Termination eCRF for reason for study discontinuation). 
7.4.1.1.6 
Adverse Event of Special Interest 
No AESIs are specified for this study. 
7.4.1.1.7 
Cases of COVID-19 or Asymptomatic SARS-CoV-2 Infection 
Onset of symptoms (eg, respiratory tract infection) suggestive of COVID-19 may first be 
reported by sites as an AE or SAE. As reflected in other sections of the protocol, symptoms 
suggestive of COVID-19 should be evaluated promptly for virological confirmation of 
SARS-CoV-2 virus. In addition, should further evaluation of the clinical case determine that the 
case is virologically confirmed COVID-19 or asymptomatic SARS-CoV-2, these infections must 
be reported to the Sponsor within 24 hours.  
All events that meet the definition of an SAE will be captured as SAEs, regardless of whether 
they are regarded as COVID-19-related events. 
 Eliciting and Documenting Adverse Events 
AEs will be assessed from the time the participant signs the ICF until exit from the study. Any 
ongoing disease/condition (eg, intercurrent illness) that a participant is experiencing at the time 
of signing informed consent and during Screening should be captured as medical history.  
Solicited AEs will be solicited by Diary for 7 days after each of the vaccinations in the initial 
series in all participants.  
At every clinic visit and on weekly/monthly phone calls, participants will be asked a standard 
nonleading question to elicit any medically related changes in their well-being. Any and all new 
changes to the participant’s health (including exacerbation of underlying disease) is regarded as 
an unsolicited AE.  
In addition to participant observations, AEs identified from any study data (eg, physical 
examination findings, vital signs, or pulse oximetry) or identified from review of other 
documents (eg, participant Diary) that are relevant to participant safety will be documented on 
the AE page in the eCRF. 
All solicited AEs through 7 days after each vaccination of the initial series will be collected. 
Continuing solicited AEs persisting beyond 7 days after each vaccination or that meet the 

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definition of a SAE or MAAE will be captured as unsolicited AEs, categorized accordingly and 
followed until stabilization/resolution.  
All unsolicited AEs through 28 days after study vaccine administration will be collected. 
Unsolicited AEs that meet the protocol definition of MAAE, SAE, or AEs leading to 
withdrawal/discontinuation will be captured for the duration of study participation. 
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 
vaccine or study participation, the investigator must promptly notify the Sponsor. 
7.4.1.2.1 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the participant’s 
daily activities. Changes in the severity of an AE should be documented to allow an assessment 
of the duration of the event at each level of intensity. AEs characterized as intermittent do not 
require documentation of onset and duration of each episode. 
Unsolicited AEs: The intensity of unsolicited AEs will be rated as mild, moderate, or severe 
using the following criteria: 
Mild: 
These events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
OR 
An event usually transient in nature and generally not interfering with normal activities. 
Moderate: 
These events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with normal functioning. 
OR 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
These events interrupt a participant’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
OR 
An AE that is incapacitating and prevents normal activities. 
Solicited AEs: The intensity of solicited AEs will be graded for severity as Grade 0, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening). 
Further details on the toxicity grading scales are provided in Appendix 4. 
7.4.1.2.2 
Assessment of Causality 
The investigator’s assessment of an unsolicited AE’s relationship to the study vaccine is part of 
the documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 

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The relationship or association of the study vaccine in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Related: 
There is a ‘reasonable possibility’ that the reported adverse event was caused by the study 
vaccine. ‘Reasonable possibility’ means that there is evidence to suggest a causal 
relationship between the event and the study vaccine. 
Unrelated: 
There is not a ‘reasonable possibility’ that the adverse event was caused by the study 
vaccine. 
Solicited AEs are, by definition, regarded as related to study vaccine. Therefore, causality is not 
assessed. 
 Reporting Adverse Events 
Non-serious unsolicited AEs are recorded through 28 days after study vaccine administration, 
unless they meet the protocol definition of MAAE, SAE, or AEs leading to 
withdrawal/discontinuation, which will be recorded and reported for the duration of study 
participation. 
All unsolicited AEs reported or observed during the study will be recorded on the AE page in the 
eCRF. Information to be collected includes the following: 
• event term 
• date of onset 
• date of resolution/stabilization 
• for AEs occurring within 24 hours of the vaccination only: time of onset 
• investigator-specified assessment of severity and relationship to the study vaccine or 
study procedure 
• for AEs initiating and resolving within 24 hours of the vaccination only: time of 
resolution of the event 
• seriousness 
• any required treatment or evaluations 
• outcome 
• whether the AE met the protocol definition of MAAE 
• whether the AE led to study vaccine withdrawal 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported. All AEs (solicited 
and unsolicited) will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary will be used to code all unsolicited AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should be reported as medical history rather than as an AE. However, if this medical 
condition deteriorates at any time during the study, it should be recorded as an AE. 

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7.4.1.3.1 
Reporting Serious Adverse Events 
Any AE (solicited or unsolicited) that meets SAE criteria (Section 7.4.1.1.2) must be reported to 
the CRO immediately (i.e., within 24 hours) after site personnel first learn of the event. 
Reporting instructions for SAE reports, including the fax number and/or email address for 
submitting paper forms, can be found in the investigator site file for the study. 
7.4.1.3.2 
Regulatory Reporting Requirements for SAEs Including Suspected Unexpected 
Serious Adverse Reactions 
The Sponsor is required to notify national regulatory agencies and (in conjunction with the 
investigator) local regulatory authorities about the safety of a study vaccine under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, institutional review board (IRB)/Independent Ethics 
Committee (IEC), and investigators. The Sponsor or designee will promptly evaluate all 
SUSARs against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, applicable IRBs/IECs, and health authorities based 
on applicable legislation. 
To determine reporting requirements for SUSAR cases, the Sponsor or designee will assess the 
expectedness of these events using the reference safety information contained in the IB. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information from the Sponsor or designee will review and then file it as appropriate and 
will notify the IRB/IEC, if appropriate according to local requirements.  
7.4.1.3.3 
Follow-up of Participants Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, the event is considered to be stable, or the participant is lost to follow-up. 
All confirmed cases of COVID-19 meeting the definition of severe COVID-19 (as defined in 
Appendix 2) will be shared with the DSMB within 48 hours of confirmation. 
7.4.1.3.4 
Laboratory Test Abnormalities 
For participants in Phase 1, clinically significant abnormal laboratory test results, in the opinion 
of the Investigator, may constitute or be associated with an AE. Examples of these include 
abnormal laboratory results that are associated with symptoms or require treatment, e.g., 
bleeding due to thrombocytopenia, tetany due to hypocalcemia, or cardiac arrhythmias due to 
hyperkalemia. Whenever possible, the underlying diagnosis should be listed in preference to 
abnormal laboratory values as AEs. Severity grading of abnormal test results should follow the 
grading of unsolicited AEs when the event is deemed clinically significant by the Investigator 
(Section 7.4.1.1.1.2). Clinically significant abnormalities will be monitored by the Investigator 
until the parameter returns to its baseline value or until agreement is reached between the 
Investigator and Sponsor Medical Monitor (or designee) that further follow-up is not required. 
Laboratory abnormalities deemed NCS by the Investigator should not be reported as AEs. 
Similarly, laboratory abnormalities reported as AEs by the Investigator should not be deemed 

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NCS on the laboratory sheet. Where relevant, safety laboratory assessments will be analyzed by 
toxicity grade at the time of interim and final analysis. 
The Investigator is responsible for reviewing and signing all laboratory reports. The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
7.4.2 
Physical Examinations 
Any clinically significant change in physical examination should be evaluated for underlying 
cause and the associated AE reported. If no known cause is determined, the clinically 
significantly abnormal parameter may be reported as an AE. 
7.4.3 
Vital Signs, Body Temperature, and Pulse Oximetry 
Vital signs, body temperature, and pulse oximetry will be evaluated for clinical significance. Any 
clinically significant change in vital signs, body temperature or pulse oximetry should be 
evaluated for underlying cause and the associated AE reported. If no known cause is determined, 
the clinically significantly abnormal parameter may be reported as an AE. 
7.5 
Pregnancy 
If a participant becomes pregnant or a pregnancy is suspected, or if a male participant believes 
his sexual partner has become pregnant during the study participation, the study center staff must 
be informed immediately. The pregnancy will be reported using a paper Pregnancy Notification 
Form and collected in the safety database. The Pregnancy Notification Form should be faxed or 
emailed to the Sponsor or designee. Follow-up information, including delivery or termination, 
should be reported within 24 hours. Pregnancy reporting instructions, including the fax number 
and email address for submitting paper forms can be found in the investigator site file for the 
study. 
Female participants: If a suspected pregnancy occurs while on the study in a female participant 
who has received study vaccine, a pregnancy test will be performed. If the pregnancy test is 
positive, the participant will be encouraged to complete all study procedures. Regardless of 
continued study participation, the study physician will assist the participant in getting obstetrical 
care and the progress of the pregnancy will be followed until the outcome of the pregnancy is 
known (ie, delivery, elective termination, or spontaneous abortion). The vaccine assignment of 
the participant may be unblinded according to the judgment of the investigator, provided 
unblinding informs a decision relating to pursuit of additional care or vaccination. If the 
pregnancy results in the birth of a child, the Study Center and Sponsor may require access to the 
mother’s and infant’s medical records to obtain additional information relevant to the pregnancy 
progress and outcome. A longer follow-up may be required if a newborn child experiences a 
medical condition. Follow-up will be performed to the extent permitted by the applicable 
regulations and privacy considerations, for example, a pregnancy ICF may be required. 
Male participants: If the female partner of a male participant who has received study 
vaccine becomes pregnant, the progress of the pregnancy of the male participant’s partner should 
be followed until the outcome of the pregnancy is known (ie, delivery, elective termination, or 

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spontaneous abortion). If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may follow-up with the mother and may request access to the mother and infant’s 
medical records to obtain additional information relevant to the pregnancy progress and 
outcome. A longer follow-up may be required if a newborn child experiences a medical 
condition. Follow-up will be performed to the extent permitted by the applicable regulations and 
privacy considerations, for example, partner ICF may be required. 

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8 
STATISTICAL CONSIDERATIONS  
This section summarizes the planned statistical analysis strategy and procedures for the study. 
The details of statistical analysis will be provided in the SAP, which will be finalized before 
database lock for each study analysis. If after the study has begun, but prior to any unblinding, 
material changes are made to primary and/or key secondary objectives/hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with International Council for Harmonisation [ICH] Guideline E9). Changes to other secondary 
or exploratory analyses made after the protocol has been finalized, along with an explanation as 
to when and why they occurred, will be listed in the SAP or clinical study report (CSR) for the 
study. Ad hoc exploratory analyses, if any, will be clearly identified in the CSR. 
The design of the study is structured to maintain the integrity of the safety, efficacy and 
immunogenicity noninferiority endpoints for Phase 3b and 3c such that these data remain blinded 
to the blinded Sponsor employees and CRO until the analysis of time points for these endpoints 
whilst earlier unblinding of Phase 1/2/3a participants for analysis of Phase 1/2/3a 
immunogenicity and safety may occur earlier to inform filing for EUA. 
8.1 
Overall Endpoint Testing Strategy 
The overall primary efficacy objective for the study is determination of vaccine efficacy (VE) as 
evaluated in the Phase 3b Modified Intent to Treat (mITT) population (Section 8.2). Hence the 
study will be regarded to have met the primary objective if the null hypothesis, as described in 
Section 8.4.1, is rejected. Hence the primary efficacy objective will be met, and the study overall 
declared to be positive, if the lower limit of the 95% confidence interval (CI) for VE exceeds 
30%. VE is defined as the percent reduction in the hazard of the primary endpoint (ARCT-154 
versus placebo).  
The overall key secondary objectives for the study are Phase 3b Secondary Endpoints 1 and 2 
(Section 3.2.2). These endpoints will be evaluated in a hierarchical fashion such that Pooled 
Secondary Endpoint 1 will only be evaluated in a hypothesis testing fashion if the overall 
primary objective of the study has been met and Pooled Secondary Endpoint 2 will only be 
evaluated in a hypothesis testing fashion if the null hypothesis for Pooled Secondary Endpoint 1 
has been rejected. 
Phase 3b secondary endpoints 3 and 4 will be evaluated in a hypothesis generating fashion with 
any statistical significance being nominal.  
For the Pooled analyses, endpoints are nominally declared as primary/secondary/exploratory, but 
all endpoints are evaluated as sensitivity analyses to the equivalent endpoints being assessed in 
the Phase 3b populations.  
Phase 1/2/3a and subgroups thereof constitute a distinct substudy with its own distinct objectives 
and endpoints. There is no testing procedure for controlling type 1 error for Phase 1/2/3a 
substudy primary or secondary endpoints. As this is a substudy, and there is no evaluation of 
efficacy for this substudy, no adjustment of type 1 error is applied to the overall efficacy primary 
endpoint 

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Phase 3c and subgroups thereof constitutes a distinct substudy with its own distinct objectves and 
endpoints and testing strategy. A sequential/hierarchical testing procedure will be used to control 
type 1 error rate over the Phase 3c primary immunogenicity noninferiority endpoint and the 
secondary endpoints such that the Phase 3c secondary immunogenicity endpoints will only be 
tested if the null hypothesis is rejected for the primary endpoint and Phase 3c secondary 
endpoints numbers 1 through 5 will be tested sequentially using the same hierarchical test 
procedure with each endpoint only being tested if the null hypothesis is rejected for the 
preceding endpoint. As this constitutes a substudy, and efficacy for this study is only evaluated 
as exploratory, no adjustment of type 1 error is applied to the overall efficacy primary endpoint. 
8.2 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
Randomized Set: Includes all participants who are randomly assigned in the study regardless of 
the participants’ vaccination status in the study. Participants will be analyzed according to the 
vaccine to which the participant was randomly assigned. RS are defined for each Phase of the 
study as follows: 
o Phase 1/2/3a RS: this pools data from Phase 1, 2 and 3a participants 
o Phase 3b RS 
o Phase 3c RS 
o Pooled RS: this pools data from all Phases of the Study 
Intent-to-Treat (ITT) Analysis Set: Includes all participants who receive any dose of study 
vaccine (ARCT-154 or placebo or ChAdOx1). Participants will be analyzed according to the 
vaccine to which the participant was randomly assigned. ITT are defined for each Phase of the 
study as follows: 
o Phase 1 ITT 
o Phase 2/3a ITT: this pools data from Phase 2 and 3a participants 
o Phase 1/2/3a ITT: this pools data from Phase 1, 2 and 3a participants and will 
include evaluations up to Day 92 only 
o Phase 3b ITT 
o Phase 3c ITT 
o Pooled ITT: this pools data from all Phases of the Study and will include 
evaluations up to Day 92 only 
Safety Analysis Set (SAS): Includes all participants who receive any dose of study vaccine 
(ARCT-154 or placebo or ChAdOx1). Participants will be analyzed according to the study 
vaccine received. SAS analysis sets are defined for each Phase of the study as follows: 
o Phase 1 SAS 
o Phase 2/3a SAS: this pools data from Phase 2 and Phase 3a participants 
o Phase 1/2/3a SAS: this pools data from Phase 1, Phase 2 and Phase 3a 
participants (up to Day 92 only) 
o Phase 3b SAS 

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o Phase 3c SAS 
o Pooled SAS: this pools data from Phase 1/2/3a/3b for ARCT-154 and placebo, 
respectively. It will include evaluations up to Day 92 only 
Reactogenicity Analysis Set (RAS): Includes all participants who receive any dose of study 
vaccine (ARCT-154 or placebo or ChAdOx1) and provide at least 1 reactogenicity diary report. 
Participants will be analyzed according to the vaccine received. Reactogenicity analysis sets are 
defined for each Phase of the study as follows: 
o Phase 1 RAS 
o Phase 2/3a RAS: this pools data from Phase 2 and Phase 3a participants 
o Phase 1/2/3a RAS: this pools data from Phase 1, Phase 2 and Phase 3a 
participants (up to pre-dose Day 92 only) 
o Phase 3b RAS 
o Phase 3c RAS 
o Pooled RAS: this pools data from Phase 1/2/3a/3b for ARCT-154 and placebo, 
respectively. It will include evaluations up to Day 92 only 
Modified Intent-to-Treat (mITT) Analysis Set: Includes all participants who received all 
protocol-required doses of study vaccine (ARCT-154 or placebo or ChAdOx1) up to the 
evaluation timepoint concerned, and who have no evidence of SARS-CoV-2 infection on Day 1 
or up to 7 days after the 2nd study vaccination. The mITT analysis set will be analyzed according 
to vaccine assigned. mITT sets are defined for the following Phases of the study: 
o Phase 3b mITT 
o Phase 3c mITT 
o Pooled mITT: this pools data from Phases 1/2/3a/3b and will include evaluations 
up to Day 92 only 
Per-Protocol (PP) analysis Set: Includes all eligible randomized participants who received all 
protocol-required doses of study vaccine (ARCT-154 or placebo or ChAdOx1) up to the 
evaluation timepoint concerned and within the protocol predefined window, and who have no 
major protocol deviations expected to affect efficacy, immunogenicity, safety or reactogenicity 
assessments as determined by the Sponsor Medical Monitor or designee in a blinded manner. 
The PP analysis set will be analyzed according to which study vaccine was received, in the event 
there is a discrepancy. PP analysis sets are defined for the following Phases of the study: 
o Phase 1 PP set: this excludes any participant that has evidence of SARS-CoV-2 
infection at baseline or prior to the analysis time point concerned (IcEv3) or that 
receives an off-study COVID-19 vaccine prior to the analysis time point 
concerned (IcEv2). 
o Phase 2/3a PP set: this pools data from Phase 2 and Phase 3a participants and 
excludes any participant that has evidence of SARS-CoV-2 infection at baseline 
or prior to the analysis time point concerned (IcEv3) or that receives an off-study 
COVID-19 vaccine prior to the analysis time point concerned (IcEv2). 
o Phase 1/2/3a PP set: this pools data from Phase 1, 2 and Phase 3a participants and 
excludes any participant that has evidence of SARS-CoV-2 infection at baseline 

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or prior to the analysis time point concerned (IcEv3) or that receives an off-study 
COVID-19 vaccine prior to the analysis time point concerned (IcEv2). This set 
will include evaluations of immunogenicity up to Day 92 only. 
o Phase 3b PP set: this excludes any participant with evidence of 
SARS-CoV-2 infection on Day 1 or up to 7 days after the 2nd study vaccination 
(IcEv3) or that receives an off-study COVID-19 vaccine prior to Day 92 (IcEv2) 
o Phase 3c-1 PP set: this includes just the participants enrolled in the Phase 3c-1 
subset of Phase 3c but excludes any participant that has evidence of SARS-CoV-
2 infection at baseline or prior to the analysis time point concerned (IcEv3) or that 
receives an off-study COVID-19 vaccine prior to the analysis time point 
concerned (IcEv2). 
o Phase 3c PP set: this includes all of Phase 3c but excludes any participant that has 
evidence of SARS-CoV-2 infection at baseline or prior to the analysis time point 
concerned (IcEv3) or that receives an off-study COVID-19 vaccine prior to the 
analysis time point concerned (IcEv2). 
o Pooled PP set: this pools data from Phase 1/2/3a/3b and excludes any participant 
with evidence of SARS-CoV-2 infection on Day 1 or up to 7 days after the 2nd 
study vaccination (IcEv3) or that receives an off-study COVID-19 vaccine prior 
to Day 92 (IcEv2). This will include evaluations up to Day 92 only. 
Immunogenicity Analysis Set (IAS): Includes all participants who received all 
protocol-required doses of study vaccine (ARCT-154 or placebo or ChAdOx1) up to the 
evaluation timepoint concerned, who have no evidence of prior SARS-CoV-2 infection at Day 1 
(IcEv3; Section 8.3.1) and who have at least 1 valid post-vaccination immunogenicity assay 
result.  Data at timepoints following evidence of a SARSCoV2 infection (IcEv3), use of 
immune-modifying drugs, blood products or immunogloblins (IcEv5) or non-study COVID-19 
vaccines (IcEv2), or protocol deviations (eg, time windows for doses and blood draws for the 
time period summarized) that may impact immunogenicity as determined by the Sponsor 
Medical Monitor or designee in a blinded manner will be excluded. All participants in the IAS 
will be analyzed according to which study vaccine was received. IAS are defined for the 
following Phases of the study: 
o Phase 1 IAS 
o Phase 2/3a IAS: this pools data from participants in Phase 2 and 3a 
o Phase 1/2/3a IAS: this pools data from Phase 1, 2 and 3a participants and will 
include evaluations of immunogenicity up to Day 92 only 
o Phase 3b IAS 
o Phase 3c-1 IAS 
8.3 
Statistical Considerations for Phase 3 
The overall primary efficacy and safety objectives for the study will be evaluated in the Phase 3b 
mITT and Phase 3b SAS/RAS, respectively. 

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Participants in Phases 1, 2 and 3a constitute the Immunogenicity Substudy group and data from 
these participants will be pooled up to Day 92 for the analysis of safety and immunogenicity for 
Phase 1/2/3a. A subset of participants in Phase 2 and 3a receive a third (booster) vaccination at 
Day 92 and their data will be pooled at all immunogenicity assessment timepoints.  
Data from Phases 1, 2, 3a and 3b will be pooled up to Day 92 for sensitivity analysis of efficacy 
and safety (the ‘Pooled Analyses’).  
Unblinding of data from individual cohorts may occur over time as shown in Section 8.9, in 
order to support regulatory filings in Vietnam. At these time points, unblinded data will only be 
provided to Sponsor and CRO employees that are designated as unblinded and these employees 
will have no further active role in the conduct of the study after the point at which they become 
unblinded. Individual participants, blinded study site staff and Sponsor team members involved 
in overseeing the conduct of the study will remain blinded until the end of study for all phases of 
the study. 
Estimand 1 in Section 8.3.1 relates to the immunogenicity and immunogenicity noninferiority 
primary, secondary and exploratory endpoints for the Phase 1/2/3a and Phase 3c substudies. 
Estimand 2 relates to the primary, secondary and exploratory efficacy endpoints. Estimands 3 
and 4 relate to the safety endpoints of Phase 1/2/3a, Phase 3b, Phase 3c and the Pooled Analysis 
(Phases 1/2/3a/3b) safety endpoints.  
The exploratory efficacy endpoints will be descriptive, and 95% CIs will be provided whenever 
applicable. 
 
 

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8.3.1 
Estimands and Intercurrent Events for Phase 1/2/3a, Phase 3b and Phase 3c 
Possible intercurrent events (IcEvs) are presented in Table 14. 
Table 14 
Intercurrent Event Types 
Label 
Intercurrent Event Type 
IcEv1 (Death not due to 
COVID-19) 
Death due to any cause other than COVID-19 associated. 
IcEv2 (Non-study COVID-19 
vaccine) 
Use of non-study COVID-19 vaccine. 
IcEv3 (Early infection) 
Positive RT-PCR test or seropositivity for antinucleocapsid antibody or 
neutralizing antibody (as assessed by sVNT for Phase 1/2/3a and MNT for Phase 
3c) indicating exposure to SARS-CoV-2 prior to vaccination or SARS-CoV-2 
infection prior to 7 days (inclusive) after the second study vaccination dose (Day 
35). 
Note: for immunogenicity endpoints, Day 57 is the watershed for early infection. 
IcEv4 (Study infection) 
Develops virologically confirmed SARS-CoV-2 infection, with or without 
COVID-19 symptoms more than 7 days after second study vaccine dose (≥Day 
36). 
IcEv5 (Confounding On-
study Medications) 
Receives any of the following concomitant medications/vaccines prior to the 
time point for which the analysis is being performed: 
• 
Live vaccines within 28 days before or after any study vaccination 
• 
Systemic (oral, intravenous, intramuscular or subcutaneous) 
corticosteroids given at any study time point prior to the timepoint at 
which the analysis is being performed 
• 
Blood products or immunoglobulins given at any study time point prior 
to the timepoint at which the analysis is being performed 
• 
Immunosupressive medications, including cytotoxic medication for 
cancer or autoimmune disease, given at any study time point prior to the 
timepoint at which the analysis is being performed 
Abbreviations: COVID-19=coronavirus disease 2019; IcEv=intercurrent event; SARS-CoV-2=severe acute 
respiratory syndrome coronavirus 2 
Attributes for the principal safety and immunogenicity estimands for Phase 1/2/3a, 3b and 3c 
with strategies for IcEvs are presented in the tables below. 
Table 15 
Estimands for Phase 1/2/3a Substudy and Phase 3c Substudy Primary, 
Secondary and Exploratory Immunogenicity Endpoints 
Estimand Label 
Estimand 1 (immunogenicity) 
Estimand Description 
NAb by surrogate virus neutralization test (primary for Phase 1/2/3a), NAb 
by PRNT50 (secondary for Phase 1 and 2 only), NAb by pseudovirus 
microneutralization test (MNT; secondary for Phase 3c) and BAb 
(secondary for Phase 1/2/3a and Phase 3c) responses at defined time points 
following vaccination (as defined in Sections 3.1.1, 3.1.2 and 3.3.2) with 
ARCT-154 or placebo. These endpoints will be assessed based on responses 
at Day 57.  International units (i.e., the WHO/NIBSC international reference 
standard) will be used if available. 

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Table 15 
Estimands for Phase 1/2/3a Substudy and Phase 3c Substudy Primary, 
Secondary and Exploratory Immunogenicity Endpoints 
Target Population 
Vaccinated participants (as defined by eligibility criteria) in Phases 1, 2, 3a 
and 3c (Phase 3c-1 participants only). The population includes participants 
without evidence of COVID-19, SARS-CoV-2 infection, or nucleocapsid 
antibody positivity on or prior to Day 57. 
Endpoint 
Phase 1/2/3a: NAb and BAb responses as defined in Sections 3.2.1 and 3.2.2 
Phase 3c: NAb and BAb responses as defined in Section 3.3.2 
Treatment Conditions 
Phase 1, 2 and 3a: ARCT-154 dose 5 µg or placebo administered on Day 1 
and Day 29. 
Phase 3c: ARCT-154 dose 5 µg or ChAdOx1 administered on Day 1 and 
Day 29. 
Population-Level Summary 
The following will be assessed 
 
Geometric mean concentrations for NAb and BAb 
 
The geometric mean ratio (ARCT-154 /Placebo and ARCT-154 / 
ChAdOx1) for NAb and BAb concentrations 
 
Proportion of participants in each study vaccine group that 
demonstrate seroconversion (as defined by 4-fold increase in 
antibody concentration [based on international units, if available] 
from baseline). 
 
Geometric mean fold rise (GMFR) for NAb and BAb 
Intercurrent Event (IcEv) Strategy  
 
   IcEv1 (Death not due to 
COVID-19) 
Hypothetical strategy 
   IcEv2 (Non-study COVID-19 
vaccine) 
Treatment policy strategy  
   IcEv3 (Early infection) 
Principal stratum strategy 
   IcEv4 (Study infection) 
Principal stratum strategy 
   IcEv5 (Confounding On-study 
Medications) 
Treatment policy strategy 
Rationale for Strategies 
IcEv 2 and IcEv5 could be potentially confounding to the analysis of the 
endpoint and result in censoring of the participant for all endpoint 
assessments after the time of the IcEv treatment policy). IcEv4 and IcEv5 
could also be potentially confounding but it is more difficult to determine 
the precise timing of these events, so a principal stratum strategy is used to 
exclude these participants from immunogenicity analyses. 
Abbreviations: NAb=neutralizing antibody; BAb=binding antibody; PRNT50=plaque reduction neutralization 
test at 50% reduction; COVID-19=coronavirus disease 2019; IcEv=intercurrent event; SARS-CoV-2=severe 
acute respiratory syndrome coronavirus 2 
 

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Table 16 
Estimands for Primary, Secondary and Exploratory Efficacy Analyses 
Estimand Label 
Estimand 2 (Vaccine Efficacy) 
Estimand Description 
•
The proportion of participants (and 95% confidence interval) with 
virologically confirmed COVID-19 (Appendix 2) detected after 7 days 
post the second study vaccine dose.
•
Proportion of participants (and 95% confidence interval) with 
virologically confirmed COVID-19 (Appendix 2) detected at any time 
after first vaccine dose
Target Population 
Eligible participants who have received both doses of study vaccine in the 
initial series. The population includes participants without evidence of 
COVID-19, SARS-CoV-2 infection, or nucleocapsid antibody positivity on 
or prior to Day 35. 
Endpoint 
Incidence of COVID-19/severe COVID 19/death due to COVID-19 
(dependent on the endpoint concerned (Section 3)) detected after 7 days post 
the second study vaccine dose and based upon virologically confirmed 
COVID-19 (Appendix 2) 
Additional endpoints will include proportion of participants with 
virologically confirmed COVID-19 (Appendix 2) detected at any time after 
first vaccine dose. 
Treatment Conditions 
Phase 1, 2, 3a and 3b: ARCT-154 dose 5 µg or placebo administered on Day 
1 and Day 29. 
Phase 3c: ARCT-154 dose 5 µg or ChAdOx1 administered on Day 1 and 
Day 29. 
Population-Level Summary 
The proportion of participants (and 95% confidence interval) with 
virologically confirmed COVID-19 cases (Appendix 2) detected after 7 days 
post the second study vaccine dose. 
Additional exploratory endpoints will include proportion of participants 
with virologically confirmed COVID-19 (Appendix 2) detected at any time 
after first vaccine dose. 
Intercurrent Event (IcEv) Strategy 
   IcEv1 (Death not due to 
COVID-19) 
Hypothetical strategy 
   IcEv2 (Non-study COVID-19 
vaccine)  
Hypothetical strategy 
   IcEv3 (Early infection) 
Principal stratum strategy 
   IcEv4 (Study infection) 
Composite strategy 
IcEv5 (Confounding On-study 
Medications) 
Hypothetical strategy 
Rationale for Strategies 
Early infection (IcEv3) results in complete exclusion from analyses because 
prior to Day 36, the vaccine may not have achieved full efficacy. Additional 
exploratory analyses are performed where participants with early infection 
occurring after Day 1 but before Day 36 are included. 

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Table 17 
Estimands for Primary Safety Analyses for Phase 1/2/3a, Phase 3b, Phase 
3c and Pooled Cohorts 
Estimand Label 
Estimand 3 (Safety – Unsolicited AEs/AEs leading to discontinuation or 
withdrawal/MAAE/SAE) 
Estimand Description 
Count and percentage of vaccinated participants who would develop 
unsolicited AEs, AEs leading to discontinuation/withdrawal, MAAEs, and 
SAEs. 
These will be evaluated with each dose of study vaccine, ARCT-154 or 
placebo.  
Target Population 
The population who are enrolled in the study and receive any dose of study 
vaccine (Phase 1, 2, 3a, 3b, 3c-1, and 3c-2 participants) 
Endpoint 
Occurrence of unsolicited AEs will be analyzed up to 28 days after each 
study vaccine administration.  
Occurrence of AEs leading to discontinuation/withdrawal, MAAEs, or 
SAEs will be analyzed up to Day of Switchover/Further Study Vaccine, 
receipt of non-study vaccine, early withdrawal, or last on-study assessment 
visit, whichever comes first.  
Occurrence of AEs leading to discontinuation/withdrawal, MAAEs and 
SAEs after the Switchover/Further Study Vaccine will be recorded and 
summarized for the interval from the switchover/Further Study Vaccine up 
to Day 394 (Phase 1/2/3a and Phase 3b only). 
For Phase 1/2/3a and 3b, AEs in participants who do not undergo 
Switchover/Further Study Vaccine will be recorded for the interval from 
Day 92 up to Day 394 
Treatment Conditions 
Phase 1/2/3a and 3b: ARCT-154 dose 5 µg or placebo administered on Day 
1, Day 29, or at Switchover/Further Study Vaccine (Day 92 and Day 120) 
Phase 3c: ARCT-154 dose 5 µg or ChAdOx1 administered on Day 1 and 
Day 29. 
Population-Level Summary 
Percentage of vaccinated participants who develop each type of AE 
Intercurrent Event (IcEv) Strategy 
 
   IcEv1 (Death not due to 
COVID-19) 
Composite strategy 
   IcEv2 (Non-study vaccine) 
Treatment policy strategy 
   IcEv3 (Early infection) 
Composite strategy 
   IcEv4 (Study infection) 
Composite strategy 
…IcEv5 (Confounding On-study 
Medications) 
Composite strategy 
Rationale for Strategies 
Events occurring after IcEv2 could contribute spurious safety data so a 
treatment policy is used for these events and events occurring after this 
IcEv’s will be summarized separately. Sensitivity analyses will be 
conducted in the ITT population where these events will be included 
(composite strategy).  

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Table 17 
Estimands for Primary Safety Analyses for Phase 1/2/3a, Phase 3b, Phase 
3c and Pooled Cohorts 
 
Estimand Label 
Estimand 4 (Reactogenicity – Solicited AEs) 
Estimand Description 
Count and percentage of vaccinated participants who would develop 
solicited AEs. 
These will be evaluated after vaccination on Day 1 and Day 29, ARCT-154 
or placebo.  
Target Population 
Vaccinated adults providing at least 1 Diary assessment, including reported 
absence of solicited events. 
Endpoint 
Occurrence of solicited AEs: 
Solicited AEs within 7 days after study vaccination on Day 1 and Day 29, 
by Toxicity Grade (Appendix 4) 
Treatment Conditions 
Placebo or ARCT-154 at dose 5 µg administered on Day 1 and Day 29. 
Population-Level Summary 
Percentage of vaccinated participants who provide at least 1 safety 
assessment. 
Intercurrent Event (IcEv) Strategy  
 
   IcEv1 (Death not due to 
COVID-19) 
Composite strategy 
   IcEv2 (Non-study vaccine) 
Treatment policy strategy 
   IcEv3 (Early infection) 
Treatment policy strategy 
   IcEv4 (Study infection) 
Composite strategy 
…IcEv5 (Confounding 
Concomitant Medications) 
Treatment policy strategy 
Rationale for Strategies 
Events occurring after IcEv2, IcEv3 and IcEv5 could contribute spurious 
reactogenicity data so a treatment policy is used for these events and events 
occurring after these IcEv’s will be summarized separately.  
Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; IcEv=intercurrent event; 
MAAE=medically attended adverse event; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory 
syndrome coronavirus 2. 
 
 

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8.4 
Statistical Hypothesis 
8.4.1 
Phase 1/2/3a Substudy Statistical Hypothesis 
For the seroconversion rate primary immunogenicity objective, the null hypothesis 
(H0Immunogenicity) is that the lower bound of the 95% CI for ARCT-154 seroconversion rate (SC154) 
is ≤ seroconversion rate for placebo (SCPlacebo); i.e., H0Immunogenicity: lower bound 95% CI for 
SC154 ≤ SCPlacebo. Hence the Phase 1/2/3a part of the study will be considered to meet the primary 
immunogenicity objective if the lower bound of the 95%CI for SC154 > SCPlacebo.   
There is no hypothesis testing for safety data analysis. Where statistical methods are applied, the 
emphasis will be on estimation with 95% CIs. 
8.4.2 
Phase 3b Statistical Hypothesis 
The overall primary endpoints for the study are evaluated in the Phase 3b population as follows: 
• The overall primary efficacy endpoint for the study is vaccine efficacy as evaluated in 
the Phase 3b Modified Intent to Treat (mITT) population 
• The overall primary safety endpoints are those evaluated in the Phase 3b Safety 
Analysis Set (SAS) and Phase 3b Reactogenicity Analysis Set (RAS) 
There is no hypothesis testing for safety data analysis. Where statistical methods are applied, the 
emphasis will be on estimation with 95% CIs. 
The primary statistical analyses for VE will be performed using virologically confirmed 
COVID-19 cases as adjudicated in a blinded fashion by the Independent Adjudication 
Committee according to definitions provided in Appendix 2. This analysis of the VE will be 
based on the Phase 3b mITT analysis set (Section 8.2). Sensitivity analyses will be performed in 
the Phase 3b PP set. 
The null hypothesis (H0Efficacy) as follows: H0Efficacy: VE ≤ 30%  
VE is estimated as 1-HR, where HR is the hazard ratio, and will be presented together with 95% 
CIs. The primary efficacy objective will be met if the lower limit of the 95% CI for VE exceeds 
30%.  
Under the assumptions of proportional hazards over time and a 50% reduction in hazard rate 
(50% VE) and with 1:1 randomization of ARCT-154 and placebo, a total of 372 confirmed 
COVID-19 cases will provide approximately 90% power to reject the null hypothesis (H0: 
VE ≤ 30%), using a log-rank test statistic with a 1-sided false positive error rate of 0.025. 

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8.4.3 
Phase 3c Substudy Statistical Hypotheses 
There is no hypothesis testing for primary Phase 3c safety objective. Where statistical methods 
are applied, the emphasis will be on estimation with 95% CIs. 
For the primary Phase 3c immunogenicity noninferiority objective the null hypothesis is as 
follows: 
H0GMR: R ≤ NIM 
Where R is the ratio of GMC (i.e., GMC for ARCT-154 arm / GMC for the ChAdOx1 arm) and 
NIM is the acceptable noninferiority margin (0.67). The null hypothesis will be rejected if the 
lower bound of the 95% confidence interval for GMR is > 0.67. 
A sequential/hierarchical testing procedure will be used to control type 1 error rate over the 
Phase 3c primary immunogenicity noninferiority endpoint and the secondary endpoints such that 
the Phase 3c secondary immunogenicity endpoints will only be tested if the null hypothesis is 
rejected for the primary endpoint and Phase 3c secondary endpoints numbers 1 through 5 will be 
tested sequentially using the same hierarchical test procedure with each endpoint only being 
tested if the null hypothesis is rejected for the preceding endpoint. 
For secondary endpoints based on the ratio of GMC (i.e., GMR; secondary endpoints 1, 4, 5): 
• The null hypothesis for noninferiority and the grounds for rejecting the null hypothesis is 
as stated for the primary Phase 3c endpoint. 
• The null hypothesis for superiority of ARCT-154 to ChAdOx1 arm (ie, GMC of 
ARCT-154 statistically significantly higher than ChAdOx1) is as follows: 
H0GMR: R ≤ 1 
The null hypothesis will be rejected if the lower bound of the 95% confidence interval for 
GMR is > 1.0 
For secondary endpoints based on seroconversion rate (Secondary endpoints 2 and 3): 
• The null hypothesis for noninferiority of the ARCT-154 arm to the ChAdOx1 arm 
(H0Seroconversion) is as follows:  
H0Seroconversion: SC154 - SCChAdOx1 ≤ D0 
Where SC154 is the proportion seroconverting in the ARCT-154 group, SCChAdOx1 is the 
proportion seroconverting in the ChAdOx1 group and D0 is the acceptable noninferiority 
margin (-10.0%). Seroconversion is defined as: 4-fold increase in concentration from 
baseline. The 95% confidence interval of the difference between two proportions will be 
calculated using the method of Miettinen-Nurminen (Miettinen 1985). International units 
(i.e., the WHO/NIBSC international reference standard) will be used if available. 
The null hypothesis will be rejected if the lower bound of the 95% confidence interval 
(CI) of the difference between neutralizing antibody seroconversion rates (ARCT-154 
group minus ChAdOx1 group) excludes the non-inferiority margin of -10%. 

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8.4.4 
Pooled Analyses Statistical Hypotheses 
Pooled analyses are performed as sensitivity analyses to the Phase 3b safety and efficacy primary 
endpoints. As such, Pooled analyses of efficacy and safety are nominally declared as primary, 
secondary, and exploratory to align with the equivalent endpoints in the Phase 3b population, but 
any statistical analysis performed will be nominal. The pooled endpoints will be evaluated in the 
same fashion as the equivalent analyses in the Phase 3b populations.  
8.5 
Sample Size Determination 
The sample size for the study overall is driven by the sum of the sample size assumptions for the 
individual phases of the study, as outlined in the subsections below.  
8.5.1 
Sample Size for Phase 1/2/3a Substudy 
Data from Phases 1, 2 and 3a will be pooled up to Day 92 for safety analyses, which will be 
performed in the Phase 1/2/3a SAS and Phase 1/2/3a RAS (Section 8.2). The total sample size 
for Phase 1/2/3a is primarily driven by the size of safety database required at the time of 
potential EUA application. With approximately 750 participants randomized in Phases 1, 2 and 
3a to receive ARCT-154 for the Phase 1/2/3a primary safety analysis, if the incidence rate of an 
adverse event is 1.0%, the probability to detect one event in 750 vaccinated participants is >99%, 
based upon the following formula:  
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 
where R = incidence rate and N = sample size 
Data from Phases 1, 2 and 3a will be pooled up to Day 92 for immunogenicity analyses, which 
will be performed in the Phase 1/2/3a IAS (Section 8.2).The primary immunogenicity endpoint is 
defined as the proportion of participants in each study vaccine group that demonstrate 
seroconversion (defined as: 4-fold increase in titer from baseline) by surrogate virus NAb assay 
at Day 57. Sensitivity analyses will be performed in the Phase 1/2/3a per protocol (PP) set. 
The null hypothesis is H0Immunogenicity: lower bound 95% CI for SC154 ≤ SCPlacebo.  A sample size 
of 750 and 250 participants in the ARCT-154 and placebo groups respectively will provide 
greater than 90% power to exclude the null hypothesis with a 1-sided type 1 error rate of 0.025 
assuming that 10% of participants are excluded from the analysis (for example due to baseline 
seropositivity), and that SC154 >50% and SCPlacebo ≤10%. 
8.5.2 
Sample Size for Phase 3b 
The primary safety endpoints will be evaluated in the Phase 3b SAS and the Phase 3b RAS 
(Section 8.2). With a sample size of ~16,000 participants randomized and with approximately 
8,000 participants randomized in the study to receive ARCT-154 for the primary safety analysis, 
if the incidence rate of an adverse event is 0.1%, the probability to detect one event in 8,000 
vaccinated participants is >99.9%, based upon the following formula: 
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 
where R = incidence rate and N = sample size 

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For the overall primary efficacy objective of the study, the null hypothesis is that the VE of 
ARCT-154 to prevent first occurrence of polymerase chain reaction (PCR)-confirmed 
COVID-19 is ≤30% (ie, H0efficacy: VE ≤0.3). 
The primary efficacy objective will be met if the lower limit of the 95% CI for VE exceeds 30%. 
VE is defined as the percent reduction in the hazard of the primary endpoint (ARCT-154 versus 
placebo). Equivalently, the null hypothesis is as follows: 
• H0efficacy: HR >0.7 (equivalently, proportional hazards VE ≤0.3) 
A Cox proportional hazard model will be used to assess the magnitude of the study group 
difference (ie, HR) between ARCT-154 and placebo at a 1-sided 0.025 significance level. Data 
will be presented overall and by the stratification factors described in Section 8.6. 
Under the assumption of proportional hazards over time and with 1:1 randomization of 
ARCT-154 and placebo, a total of 372 COVID-19 cases will provide approximately 90% power 
to detect a 50% reduction in hazard rate (50% VE), rejecting the null hypothesis with a 1-sided 
false positive error rate of 0.025.  
The study will be considered positive at the primary analysis if the one-sided p-value for 
rejecting HR ≥ 0.7 is less than or equal to 0.025.  
8.5.3 
Sample Size for Phase 3c Substudy 
Immunogenicity endpoints will be evaluated in participants in the Phase 3c-1 IAS (Section 8.2). 
Sensitivity analyses will be performed in the Phase 3c PP set. For the primary immunogenicity 
noninferiority endpoint of neutralizing antibody (using the pseudovirus microneutralization assay 
[MNT]) geometric mean ratio (GMR), assuming a GMR of ≥0.9 and a coefficient of variation of 
variation of 4.6, a sample size of 800 participants in Phase 3c-1will provide greater than 90% 
power to exclude a non-inferiority boundary of 0.67 based on the use of a one-sided test at the 
alpha=0.025 level of significance, accounting for a dropout rate of approximately 20-25% due to 
the national COVID-19 vaccination campaign in Vietnam. 
The primary safety endpoints of Phase 3c will be conducted in the Phase 3c Safety Analysis Set 
and Phase 3c Reactogenicity Analysis Set (Section 8.2). With a sample size of approximately 
2,400 participants randomized and with approximately 1,200 participants randomized in the 
study to receive ARCT-154 or ChAdOx1 for the safety analysis, based upon the following 
formula, if the incidence rate of an adverse event is 0.1%, the probability to detect one event in 
1,200 vaccinated participants is 69.9% and if the incidence rate is 1.0% the probability is more 
than 99%: 
𝑝𝑝 = 1 – (1 – 𝑅𝑅)N 
where R = incidence rate and N = sample size 
8.6 
Description of Additional Subgroups to Be Analyzed 
To determine consistency of immunogenicity across various subgroups in Phase 1/2/3a and 
Phase 3c, the immunogenicity and the 95% CIs may be estimated using similar methods to the 
primary analyses for groups stratified by the following classification variables, if feasible: 

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• Seropositive or seronegative by SARS-CoV-2 nucleocapsid antibody test on or prior to 
Day 29  
• Age groups: ≥18 to <60 years and ≥60 years 
• Age and health risk for severe disease: ≥18 to <60 years and “healthy,” ≥18 and 
<60 years and “at risk,” and ≥60 years 
• Sex (female, male) 
• Race/ethnicity  
• Receipt of a live non-COVID-19 vaccine within 28 days before or after any study 
vaccination 
These subgroup analyses may also be performed for the exploratory analyses of vaccine efficacy 
if there are sufficient COVID-19 events to make such subgroup analyses feasible. 
Safety may also be evaluated by Age group, Age and health risk for severe disease and Sex.  
8.7 
Statistical Analysis Methodology 
Details of the statistical analyses, methods, and data conventions are described in the SAP. 
Statistical analysis will be performed using SAS® software version 9.4 or later. Continuous 
variables will be summarized using the mean, standard deviation, median, minimum value, and 
maximum value. Categorical variables will be summarized using frequency counts and 
percentages. Data will be listed in data listings. 
8.7.1 
General Considerations 
 General Considerations for Phase 1/2/3a Substudy 
For Phase 1/2/3a, immunogenicity data analysis will be considered to meet the primary 
immunogenicity objective if the lower bound of the 95%CI for SC154 > SCPlacebo.  This analysis 
will be based on the Phase 1/2/3a IAS (Section 8.1). Sensitivity analyses will be performed in the 
per protocol (PP) set. 
Statistical analysis of safety data will be descriptive, and 95% CIs will be provided whenever 
applicable. It will be based on the Phase 1/2/3a and Phase 2/3a SAS and reactogenicity analysis 
set (RAS). Sensitivity analysis of unsolicited events will also be performed in the Phase 1/2/3a 
ITT and Phase 2/3a ITT analysis sets. 
 General Considerations for Phase 3b 
Statistical analysis of safety data will be descriptive, and 95% CIs will be provided whenever 
applicable. It will be based on the Phase 3b safety analysis set (SAS) and Phase 3b reactogenicity 
analysis set (RAS). Sensitivity analysis of unsolicited events will also be performed in the Phase 
3b ITT analysis set and in the Pooled SAS. Sensitivity analysis of solicited events will be 
performed in the Pooled RAS. 

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The primary efficacy analysis will be conducted in the Phase 3b mITT and will be considered to 
meet the primary endpoint if the lower limit of the 95% CI for VE exceeds 30%. Sensitivity 
analyses will be performed in the Phase 3b per protocol (PP) set and the Pooled mITT.  
 General Considerations for Phase 3c Substudy 
Phase 3c-1 immunogenicity noninferiority data will be considered to meet the primary 
immunogenicity noninferiority endpoint if the lower bound of the 95% confidence interval for 
the geometric mean ratio of ARCT-154 / ChAdOx1 excludes 0.67.  Geometric mean 
concentrations will be displayed in international units (i.e., using the WHO/NIBSC reference 
standard) if available. 
A sequential/hierarchical testing procedure will be used to control type 1 error rate over the 
Phase 3c primary endpoint and the secondary endpoints such that the secondary immunogenicity 
endpoints will only be tested if the null hypothesis is rejected for the primary endpoint and the 
secondary endpoints numbers 1 through 5 will be tested sequentially using the same hierarchical 
test procedure with each endpoint only being tested if the null hypothesis is rejected for the 
preceding endpoint. 
8.7.2 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity 
Analyses 
A summary of the statistical methods and sensitivity analyses is presented in Table 18.  
 
 

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Table 18 
Summary of Statistical Methods, Including Sensitivity Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 1 
NAb by surrogate virus 
neutralization test (primary for 
Phase 1/2/3a, NAb by PRNT50 
and Bab (secondary for Phase 1 
and 2 only), NAb by pseudovirus 
microneutralization test (MNT; 
secondary for Phase 3c) and BAb 
(secondary for Phase 1/2/3a and 
Phase 3c) responses at defined 
time points following vaccination 
(as defined in Sections 3.1.1, 
3.1.2, and 3.3.2) with ARCT-154 
or placebo. The primary 
immunogenicity endpoint (Phase 
1/2/3a) and secondary 
immunogenicity noninferiority 
endpoints (Phase 3c) will be 
measured based on responses at 
Day 57. 
Phase 1/2/3a 
IAS 
Phase 3c-1 
IAS 
For deaths unrelated 
to COVID-19, censor 
at date of death. For 
participants who 
undergo 
Switchover/Further 
Study Vaccine or 
receive a non-
study vaccine, censor 
at date of 
Switchover/Further 
Study Vaccine or 
non-study 
vaccination. 
Participants with 
early infection (prior 
to Day 57) are 
excluded from the 
analysis.  
Proportion of participants in 
each study vaccine group that 
demonstrate seroconversion (as 
defined by 4-fold increase in 
antibody concentration from 
baseline). International units 
(i.e., the WHO/NIBSC 
international reference 
standard) will be used if 
available.) 
NAb and BAb geometric mean 
antibody titers/concentrations  
Sensitivity: the same 
analysis will be 
performed in the Phase 
1/2/3a and Phase 3c-1 PP 
analysis sets. 

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Table 18 
Summary of Statistical Methods, Including Sensitivity Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Estimand 2  
• The proportion of 
participants (and 95% 
confidence interval) with 
virologically confirmed 
COVID-19 (Appendix 2) 
detected after 7 days post the 
second study vaccine dose.  
• Proportion of participants 
(and 95% confidence 
interval) with virologically 
confirmed COVID-19 
detected at any time after first 
vaccine dose 
Phase 3b 
mITT 
(primary) 
Phase 3c 
mITT 
(exploratory) 
 
For deaths unrelated 
to COVID-19, censor 
at date of death. For 
participants who 
undergo 
Switchover/Further 
Study Vaccine or 
receive a non-study 
COVID-19 vaccine, 
censor at date of 
Switchover or 
non-study 
vaccination. 
The proportion of participants 
with virologically confirmed 
COVID-19 (Appendix 2) in 
each vaccine group will be 
displayed together with 95% 
CI.  
Sensitivity: the same 
analysis will be 
performed in the Pooled 
mITT and Phase 3b PP 
analysis sets. 

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Estimand 3  
Percentage of vaccinated 
participants who would develop 
unsolicited AEs, AEs leading to 
discontinuation/withdrawal, 
MAAEs, and SAEs within 
timeframe up to the earlier of 
Day 92/Switchover/Further Study 
Vaccine or receipt of non-study 
COVID-19 vaccine. 
A treatment policy strategy is 
used for assessing safety 
irrespective of a current (or prior) 
SARS-CoV-2 infection at time of 
the study vaccination. See 
Table 17 for full definition. 
Events occurring before and after 
Switchover/Further Study 
Vaccine will be analyzed 
separately. 
Phase 1/2/3a 
SAS 
Phase 2/3a 
SAS 
Phase 3b 
SAS 
Phase 3c SAS 
Pooled SAS 
 
SARS-CoV-2  
infections and death 
due to COVID-19 (if 
they meet the AE and 
time window criteria) 
are included in the 
endpoint (composite 
strategy). 
Summaries of number of 
participants (%) with 
unsolicited AEs (including 
summary by severity and 
relatedness to study vaccine), 
AEs leading to 
discontinuation/withdrawal, 
MAAEs, and SAEs will be 
presented. The Clopper-
Pearson 95% CIs will be 
presented for the incidence rate 
of these events. See 
Section 8.7.3.2 and the SAP for 
further details. 
Sensitivity analyses will 
also be performed in the  
Phase 1/2/3a ITT 
Phase 2/3a ITT 
Phase 3b ITT 
Phase 3c ITT 
Pooled ITT 
 
Supportive: Analysis will 
be performed for different 
time intervals, 
specifically:  
All MAAEs, AE/SAEs, 
AEs leading to 
discontinuation/ 
withdrawal up to Day 29, 
Day 57, Day 92, and Day 
394 or Final Visit/Early 
Termination Visit/receipt 
of non-study COVID-19 
vaccine after the first 
vaccination will be 
summarized accordingly.  
AEs occurring after the 
Day 92 will be recorded 
and summarized for the 
interval Day 92 up to Day 
394 (Phase 1/2/3a and 
Phase 3b only).  
For Phase 1/2/3a and 3b, 
AEs in participants that 
do not receive additional 
study vaccine at Day 92 
will be recorded 
separately for the interval 

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Table 18 
Summary of Statistical Methods, Including Sensitivity Analyses 
Estimand 
Label 
Estimand Description 
Main Estimation 
Sensitivity Analysis 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
from Day 92 up to Day 
394 
All AEs including those 
occurring after receipt of 
a non-study COVID-19 
vaccination will be 
summarized separately as 
supportive analyses, if 
applicable. 
Estimand 4  
Percentage of vaccinated 
participants who would provide 
reactogenicity information within 
timeframe. 
A treatment policy strategy is 
used for assessing safety 
irrespective of a current (or prior) 
SARS-CoV-2 infection at time of 
the study vaccination. See 
Table 17 for full definition. 
Phase 1/2/3a 
RAS 
Phase 2/3a 
RAS 
Phase 3b 
RAS 
Phase 3c 
RAS 
Pooled RAS 
  
Events are only 
recorded for the 
initial vaccination 
series. SARS-CoV-2 
infections and death 
due to COVID-19 (if 
they meet the AE and 
time window criteria) 
are included in the 
endpoint (composite 
strategy). 
Summaries of number of 
participants (%) with solicited 
AEs (by toxicity grade) will be 
presented. The Clopper-
Pearson 95% Cis will be 
presented for the incidence rate 
of these events. See Section 
8.7.3.2 and the SAP for further 
details. 
 
Abbreviations: NAb=neutralizing antibody; Bab=binding antibody; PRNT50=plaque reduction neutralization test at 50% reduction; GMT=geometric mean 
titer; GMC=geometric mean concentration; AE=adverse event; CI=confidence interval; COVID-19=coronavirus disease 2019; HR=hazard ratio; 
MAAE=medically attended adverse event; mITT=modified intent-to-treat; PP=per protocol; RAS=reactogenicity analysis set; SAE=serious adverse event; 
SAP=statistical analysis plan; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SAS=statistical analysis set 

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8.7.3 
Analysis of Primary Endpoints for Phase 1/2/3a, Phase 3b and Phase 3c  
 Main Estimation of Primary Immunogenicity Endpoint for Phase 1/2/3a Substudy 
(Estimand 1) 
The primary immunogenicity endpoint for Phase 1/2/3a and the primary immunogenicity 
noninferiority endpoint for Phase 3c-1 will be evaluated in the Phase 1/2/3a IAS and Phase 3c-1 
IAS respectively.  
• For Phase 1/2/3a it is defined as the proportion of participants in each study vaccine 
group that demonstrate seroconversion (defined as: 4-fold increase in titer from baseline) 
by surrogate virus NAb assay at Day 57.  The lower bound of the 95% CI for SC154 will 
be used for evaluation of ARCT-154- vs placebo-treated participants (Section 8.3.1).  
• For Phase 3c it is defined as the geometric mean ratio (i.e., the ratio of geometric mean 
concentration for ARCT-154 / ChAdOx1 nCoV-1) by pseudovirus microneutralization 
test at Day 57. 
• International units (i.e., the WHO/NIBSC international reference standard) will be used if 
available. 
Seroconversion is defined as at least 4-fold increase of post-study intervention antibody titers 
from the baseline titer or from half of the LLOQ if undetectable at baseline. GMT ratio is defined 
as geometric mean of fold increase of post-study intervention titers over the baseline titers. 
Geometric mean concentration (GMC) is the geometric mean of the antibody concentrations of 
all participants in each treatment arm; geometric mean ratio (GMR) is the ratio of geometric 
mean concentrations for the two study vaccines being compared, and geometric mean fold rise is 
the geometric mean of the proportional rise in GMC from baseline. These will be calculated as 
follows: 
GMC = ln−1(
∑
𝑙𝑙𝑙𝑙𝑙𝑙
𝑛𝑛
𝑖𝑖=1
𝑛𝑛
), where X: antibody titer 
GMR = 
𝐺𝐺𝐺𝐺𝐺𝐺𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 1
𝐺𝐺𝐺𝐺𝐺𝐺𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑖𝑖𝑛𝑛𝑛𝑛 2  
GMFR = ln−1 ቆ
∑
ln (𝑋𝑋2
𝑋𝑋1)
𝑛𝑛
𝑖𝑖=1
𝑛𝑛
ቇ, where X2 is the antibody concentration at time point 
of evaluation and X1 is the antibody concentration at the reference time point (for 
example baseline) 
For SCR, chi-square or Fisher’s exact test will be used to perform comparison of the two 
treatment arms. 95% CI of the SCR will also be presented. Pearson’s Chi-square test will be used 
except for the case of small cell count (less than 5). 
Definition and handling of intercurrent events is described in Section 8.3.1.  

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 Main Estimation of Primary Safety Endpoint for Phase 1/2/3a, 3b, and 3c (Estimand 3 
& 4) 
Summaries of the number of participants (%) with solicited AEs, unsolicited AEs, MAAEs, 
SAEs, and AEs leading to discontinuation/withdrawal will be presented. Unsolicited events will 
be presented overall and with a focus on those related to vaccine administration. All summaries 
will be evaluated by study group.  
As summarized in Table 18, the Clopper-Pearson 95% CIs will be presented for the incidence 
rate of solicited AEs, unsolicited AEs, SAEs, MAAEs, and AEs leading to 
discontinuation/withdrawal, as well as those that are considered related (possibly, probably, or 
definitely) to study vaccine. 
Solicited AEs will be analyzed in the RAS and unsolicited AEs, MAAEs, AE/SAEs will be 
summarized in the SAS relevant to the Phase of the study being evaluated (Section 8.2). 
 Supportive Analysis of Primary Safety Endpoints for Phase 1/2/3a, 3b, and 3c 
(Estimand 3 & 4) 
Analysis of safety, as described Section 8.7.3.2 and Table 18 will be performed for a number of 
different time intervals. Evaluation may also be performed by the stratification factors described 
in Section 8.6. 
The number and percentage of participants with any solicited AEs (local injection site and 
systemic events) before and after each vaccination will be reported, including summaries by 
grade (Appendix 4). The number and percentage of participants with unsolicited AEs will be 
reported, including summaries by severity (mild/moderate/severe). The number and percentage 
of SAEs and MAAEs will be summarized by incidence. The incidence rate of these events will 
be presented with 2-sided 95% CIs using the Clopper-Pearson method. 
Solicited AE will be analyzed in the RAS and unsolicited AEs, MAAEs, AEs leading to 
discontinuation/withdrawal, SAEs will be summarized in the SAS relevant to the Phase of the 
study being evaluated (Section 8.2).  
Adverse events after to any non-study vaccination will be analyzed accordingly as a supportive 
analysis.  
 Main Estimation of Phase 3b Primary Efficacy Endpoint (Estimand 2) 
This endpoint is the incidence rate of virologically confirmed COVID-19. The main analysis on 
this endpoint will be carried out in the Phase 3b mITT and the sensitivity analysis will be 
performed in the Phase 3b PP analysis set. Incidence rate in each arm will be displayed together 
with 95% CI. 
The statistical hypothesis for this analysis is described in Section 8.4.2. 
Definition and handling of intercurrent events is described in Section 8.3.1.  

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8.7.4 
Analysis of Secondary Endpoints for Phase 1/2/3a, Phase 3b and Phase 3c 
 Main Estimation of Secondary Immunogenicity Endpoints for Phase 1/2/3a and Phase 
3c Substudies 
Secondary endpoints will be evaluated in participants in Phases 1, 2 and 3a (the Immunogenicity 
Subgroup) and Phase 3c-1 (the Immunogenicity Noninferiority Subgroup) who have no evidence 
of early infection (Section 8.3.1) and have received two doses of study vaccine (ARCT-154 or 
placebo for Phase 1/2/3a; ARCT-154 or ChAdOx1 for Phase 3c) in the initial vaccination series. 
International units (i.e., the WHO/NIBSC international reference standard) will be used if 
available, and comparisons will be based on lower bound of the 95% CI. 
Definition and handling of intercurrent events is described in Section 8.3.1.  
 Main Estimation of Secondary Efficacy Endpoints for Phase 3b 
These will be evaluated in the Phase 3b mITT using the same testing methods as for the Phase 3b 
primary efficacy endpoint 
8.7.5 
Analysis of Pooled Efficacy and Safety Endpoints 
The pooled safety primary endpoints include the number of participants (%) with solicited AEs, 
unsolicited AEs, MAAEs, SAEs, and AEs leading to discontinuation/withdrawal and will be 
evaluated in the Pooled SAS and the Pooled RAS.  
The pooled efficacy primary endpoint is the incidence rate of virologically confirmed COVID-
19. This analysis will be conducted as a sensitivity analysis to the Phase 3b primary endpoint for 
the study and will be carried out in the Pooled mITT. 
The analysis will be conducted using the same methods as described for the Phase 3b primary 
efficacy analysis (Section 8.7.3.4) and Phase 3b primary safety analysis (Section 8.7.3.2). 
Definition and handling of intercurrent events is described in Section 8.3.1.  
8.7.6 
Analyses of Other Exploratory Endpoints 
The analysis of other exploratory endpoints will be described in the SAP. 
8.7.7 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, physical 
examination, social history, and risk factor variables at baseline, as well as vital signs, clinical 
laboratory tests, etc. 
8.7.8 
Analyses of Immunogenicity, Safety and Efficacy Data Post Day 92 (Phase 
1//2/3a, Phase 3b and Pooled Cohorts) 
Participants in Phase 1/2/3a and Phase 3b receive additional study drug (after the initial two-dose 
vaccination series) at Day 92 (Section 4.5.2). Immunogenicity data before and after Day 92 will 
be presented separately for these participants.  

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All safety data collected post Day 92 will be presented separately, using the same methods 
described in Estimand 2 or 3. Safety data collected post Day 92 include solicited AEs (Phase 
2/3a participants only), unsolicited AEs, MAAEs, AEs leading to discontinuation/withdrawal, 
and SAEs. 
Efficacy data after Day 92 will only be collected for Phase 3c participants and will be presented 
up to Day 394. Rate and 95% CI of the confirmed infection will be calculated using Poisson 
distribution. 
8.8 
Handling of Missing Data 
Details regarding handling of missing Diary data for the evaluation of solicited AEs and missing 
immunogenicity assessments will be described in the SAP. 
8.9 
Primary and Interim Analyses Timepoints 
8.9.1 
Phase 1/2/3a Substudy 
The primary immunogenicity analysis for Phase 1/2/3a will be performed after all participants in 
this cohort reach the Day 57 timepoint. 
The primary Phase 1/2/3a analysis of safety will be performed when all participants in this 
cohort have reached Day 92. Subsequent analyses of safety will be exploratory.  
Interim analysis of safety data through at least Day 57 may be performed for Phase 1/2/3a at the 
time of analysis of the primary immunogenicity endpoint of Phase 1/2/3a to support application 
for emergency use authorization. Participants that are further randomized to receive ARCT-154 
or placebo at Day 92 may be unblinded again at Day 120 for evaluation of safety and 
immunogenicity following the third dose. Sponsor and CRO staff responsible for day-to-day 
conduct of the study will remain blinded until the final unblinding of data at the end of study 
occurs in order that safety assessments can continue in an unbiased fashion. 
8.9.2 
Phase 3b 
The primary Phase 3b analysis of safety and efficacy will be performed when all participants in 
Phase 3b that are evaluable for the primary efficacy analysis have reached Day 92 and all 
potential COVID-19 events in these participants up to Day 92 have been adjudicated by the 
blinded Independent Adjudication Committee. 
Subsequent analyses of safety will be exploratory. However, Sponsor and CRO staff responsible 
for day-to-day conduct of the study will remain blinded until the final unblinding of data at the 
end of study occurs in order that safety assessments can continue in an unbiased fashion. 
8.9.3 
Phase 3c Substudy 
The primary Phase 3c analysis of safety will be performed when all participants have reached the 
last study visit (Day 394). 
The primary immunogenicity non-inferiority analysis for Phase 3c-1 will be performed after all 
participants in this cohort reach the Day 57 timepoint. 

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Interim analysis of safety data through at least Day 57 may be performed for Phase 3c at the time 
of analysis of the primary immunogenicity non-inferiority endpoint of Phase 3c-1 to support 
regulatory submission.  
8.10 
Monitoring Committees 
8.10.1 
Blinded Safety Review Committee 
A blinded Safety Review Committee (SRC) composed of the medical monitoring team from the 
Sponsor and the CRO will perform ongoing medical review of the blinded safety data of enrolled 
participants throughout the study.  
The SRC will review all available blinded safety data for the 100 participants in Phase 1 through 
at least 7 days post-second vaccination (Day 36) and, if study vaccination is judged to be 
adequately tolerated, the study will initiate simultaneous enrollment of both Phase 2 and 
Phase 3a. After completion of enrollment of Phases 2 and 3a, the SRC will review all available 
blinded safety data through at least 7 days (Day 8) post-first vaccination and, if study vaccination 
is judged to be adequately tolerated, the study will initiate enrollment of Phase 3b. The second 
dose of study vaccine will not be administered to participants in Phase 3b until the SRC has 
reviewed the Phase 2 and Phase 3a safety data through 7 days post-second vaccination (Day 36) 
and judged that study vaccine is adequately tolerated. This committee may request an ad hoc 
meeting of the DSMB in the event of safety concerns. 
8.10.2 
Blinded Independent Adjudication Committee 
A blinded independent AC will be assembled for the purpose of reviewing potential cases of 
COVID-19 to determine if the criteria for the primary and secondary endpoints have been met. 
The AC will remain blinded to treatment assignment. The AC composition, its remit, and 
frequency of data review will be further defined in a charter.  
8.10.3 
Unblinded Independent Data and Safety Monitoring Board 
An independent DSMB, which will be guided by a signed charter, will perform ongoing review 
of blinded and unblinded data, including both safety and confirmed cases of COVID-19 at 
scheduled data review meetings. 
At each analysis, the DSMB will review the available data and make recommendations to the 
Sponsor to continue, modify, or discontinue study enrollment (if the study is enrolling). In 
addition to the ongoing review of safety data, the DSMB will also review available severe 
COVID-19 case data to determine the risk of VAERD. Prespecified harm rules will determine if 
stopping boundaries for risk of VAERD have been exceeded. The DSMB will be constituted 
prior to commencement of enrollment of Phase 3b. 

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9 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6(R2) risk and quality processes described 
in the applicable procedural documents. The quality management approach to be implemented in 
this study will be documented and will comply with the current ICH guidance on quality and risk 
management (ICH Q9). The Sponsor assumes accountability for actions delegated to other 
individuals (eg, CROs). 
9.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include laboratory reports and hospital 
records. 
All CRF information is to be filled in. If an item is not available or is not applicable, this fact 
should be indicated. Blank spaces should not be present unless otherwise directed.  
For eCRFs, investigative site personnel will enter participant data into the electronic data capture 
(EDC) system. The analysis data sets will be a combination of these data and data from other 
sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable CRO standards and 
data cleaning procedures to ensure the integrity of the data (eg, removing errors and 
inconsistencies in the data). AE terms will be coded using MedDRA, an internal validated 
medical dictionary, and concomitant medications/vaccines will be coded using the WHO Drug 
Dictionary. 
9.2 
Data Disclosure 
The Sponsor or designee will publicly disclose clinical study results through posting the results 
of studies on www.clinicaltrials.gov (ClinicalTrials.gov 2020) and other public registries in 
accordance with applicable local laws/regulations.  
In all cases, study results will be reported in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study or the country in which the study 
was conducted. 

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10 
ETHICS 
10.1 
Independent Ethics Committee or Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before human participants participate in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study participants, and any 
other written information regarding this study to be provided to the participant or the 
participant’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonized tripartite guideline E6(R2): 
Good Clinical Practice (GCP) will be maintained by the site and will be available for review by 
the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The investigator 
must promptly supply the Sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to participants. 
10.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that originated from the 
Declaration of Helsinki, ICH GCP, and all applicable regulations. 
10.3 
Participant Information and Consent 
A written informed consent in compliance with regulatory authority regulations or US Title 
21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each participant before 
entering the study or performing any unusual or nonroutine procedure that involves risk to the 
participant. An informed consent template may be provided by the Sponsor to investigative sites. 
If any institution-specific modifications to study-related procedures are proposed or made by the 
site, the consent should be reviewed by the Sponsor or its designee or both before IRB/IEC 
submission. Once reviewed, the consent will be submitted by the investigator to his or her 
IRB/IEC for review and approval before the start of the study. If the ICF is revised during the 
course of the study, all active participants must be reconsented by signing the revised form, if 
required by IRB/IEC. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian will 
be given a full explanation of the study, allowed to read the approved ICF, and allowed to have 
any questions answered. Once the investigator is assured that the participant/legal guardian 
understands the implications of participating in the study, the participant/legal guardian will be 
asked to give consent to participate in the study by signing the ICF. The authorized person 
obtaining the informed consent will also sign the ICF. 

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The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research (if applicable) and explain/address the exploratory research 
portion of the study. Participant medical records need to state that written informed consent was 
obtained.  
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
ICF(s) to the participant or legal guardian. 

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11 
INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
11.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legal guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the FDA, or the IRB/IEC. 
The investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
11.2 
Data Protection 
All personal data collected related to participants, investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in accordance with 
local data protection law, including laws regarding implementation of technical measures to 
ensure 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. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access. The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster. In the event 
of a potential personal data breach, the study site will be responsible for determining whether a 
personal data breach has in fact occurred and, if so, providing breach notifications as required by 
law. 
To protect the rights and freedoms of participants with regard to the processing of personal data, 
participants will be assigned a single, participant-specific numerical code (participant code). Any 
participant records or data sets that are transferred to the Sponsor will contain the participant 
code; participant names must not be transferred. All other identifiable data transferred to the 
Sponsor will be identified by this participant code. The study site will maintain a confidential list 
of participants who participated in the study, linking each participant code to his or her actual 
identity and medical record identification. In case of data transfer, the Sponsor will protect the 
confidentiality of participants’ personal data consistent with the clinical study agreement and 
applicable privacy laws. 

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11.3 
Financial Disclosure and Obligations 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Neither the Sponsor nor the CRO is financially responsible for further testing or treatment of any 
medical condition that may be detected during the Screening process. In addition, in the absence 
of specific arrangements, neither the Sponsor nor the CRO is financially responsible for further 
treatment of the participant’s disease. 
11.4 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 9.2 by providing all essential documents. 
11.5 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be posted 
on publicly available clinical trial registers before enrollment of participants begins. 
11.6 
Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the Sponsor and/or IRB/IEC according to 
the timeline and method outlined in the protocol. In addition, the investigator agrees to submit 
reports according to local reporting requirements to the study site IRB/IEC as appropriate. 
11.7 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the institution; 
the investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authority(ies) with any reports required. 
11.8 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study vaccine. These documents should be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. It is the responsibility of the Sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. No records may be transferred to another location 
or party without written notification to the Sponsor. 

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12 
STUDY MANAGEMENT 
The study administrative structure will include an SRC, an independent DSMB, CRO, third party 
vendors, and laboratories. 
12.1 
Monitoring 
12.1.1 
Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the objectives, 
purpose, design, and complexity of the study. Site monitoring is conducted to ensure that the 
rights of human participants are protected, that the study is implemented in accordance with the 
protocol and/or other operating procedures, and that the study uses high quality data collection 
processes. The monitor will evaluate study processes based on ICH E6(R2) and all applicable, 
regulatory guidelines. The investigator will allocate adequate time for all monitoring visits and 
between visits to facilitate the requirements of the study and study timelines. The investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
direct access to all study-related documents and study-related facilities (eg, pharmacy and 
diagnostic laboratory), phone, fax, and internet and has adequate space to conduct the monitoring 
visit (if the monitoring visit is conducted in person). If the COVID-19 outbreak does not allow 
direct access to the site by the monitor, the investigator will make every effort to provide access 
to source documents in a remote fashion. This includes anticipation of medical release forms to 
be signed by the participant at the time of study enrollment. 
12.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency access to all study records. 
The investigator should promptly notify the Sponsor and CRO of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the Sponsor. 
12.2 
Management of Protocol Amendments and Deviations 
12.2.1 
Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the participant, must be reviewed and approved by the 
Sponsor or designee. Amendments to the protocol (including emergency changes) must be 
submitted in writing to the investigator’s IRB/IEC, along with any applicable changes to the ICF, 
for approval before participants can be enrolled into an amended protocol. 
12.2.2 
Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/IEC and agreed to by the investigator. A 
significant deviation occurs when there is non-adherence to the protocol or to local regulations or 

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ICH GCP guidelines that may or may not result in a significant, additional risk to the participant 
or impacts the integrity of study data. 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from or a change of the protocol to eliminate an immediate hazard/safety risk to study 
participants without prior IRB/IEC approval. As soon as possible, after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval and to the Sponsor for agreement 
and regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the investigator and relevant site 
personnel will be trained in all aspects of study conduct by the Sponsor/Sponsor’s representative. 
This training will occur either as part of the investigator meeting or site initiation. Ongoing 
training may also be performed throughout the study during routine site monitoring activities. 
As this Phase 3 study is planned for execution during a global health emergency 
(COVID-19 pandemic), there may be local restrictions that prevent or modify the performance of 
certain study-related procedures (eg, clinic visits and blood sampling). For protocol deviations 
attributed to COVID-19 interruptions, relevant details leading to the protocol deviation will be 
captured in the source documents and EDC system in accordance with relevant guidances (for 
example FDA guidance (FDA 2020a) or any applicable country-specific guidance). 
12.3 
Study Termination 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons. 
The EOS is defined as the date on which the last participant completes the last visit (includes 
Follow-up Visit). 
If the study is prematurely terminated or suspended, the Sponsor or Sponsor representative shall 
promptly inform the investigators, IRBs/IECs, regulatory authorities, and any contract research 
organization(s) used in the study of the reason(s) 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. 
12.4 
Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the final 
data are summarized and provided to the regulatory agency(ies) as required by the applicable 
regulatory requirement(s). The Sponsor will also ensure that any CSRs in marketing applications 
(as applicable) meet the standards of the ICH harmonized tripartite guideline E3: Structure and 
content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 

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Food and Drug Administration. Frequently asked questions on the emergency use authorization 
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020-01626-9. 
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Lindsay KE, Bhosle SM, Zurla C, et al. Visualization of early events in mRNA vaccine delivery 
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14 
APPENDICES 

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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS  
INITIAL VACCINATIONS AT DAY 1 AND DAY 29 FOR PHASE 1 PARTICIPANTS 
Visit Name 
Screening 
Dose 1 
Follow-up 
Visit 
Weekly 
Study Call 
Dose 2 
Follow-up 
Visit 
Weekly 
Study Call 
Follow-up 
Visit 
Weekly Study Call 
Unscheduled 
Visitb 
ET Visit 
Visit Typea 
Clinic 
Clinic 
Clinic 
TC 
Clinic 
Clinic 
TC 
Clinic 
TC 
Clinic 
Clinic 
Study Day 
-10 to 1 
(pre-
dose)c 
1 
8 
15, 22 
29 
36 
43, 50  
57 
64, 71, 78, 85,  
N/A 
N/A 
Visit Window (days): 
0 
0 
+2 
+2 
+2 
+2 
±2 
+2 
±2 
N/A 
N/A 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
Xc 
X 
 
X 
X 
 
 
 
X 
X 
Vital signs and body 
temperaturee  
X 
Xc 
X 
 
X 
X 
 
X 
 
X 
X 
Pulse oximetry 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
Xc 
 
 
X 
 
 
 
 
 
 
Blood samplingg 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
Nasal swab for RT-PCR 
SARS-CoV-2h 
X 
X 
 
 
 
 
 
 
 
X 
 
Review of Medical 
history 
X 
Xc 
X 
 
X 
X 
 
X 
 
X 
X 
Review of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Study vaccine 
administrationi 
 
X 
 
 
X 
 
 
 
 
 
 
Post-vaccination 
observationj 
 
X 
 
 
X 
 
 
 
 
 
 
Review for COVID-19 
symptoms and risksk 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsl 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccines 
collection 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect paper diary m 
 
 
X 
 
 
X 
 
 
 
 
 

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Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
RT-PCR=reverse transcription polymerase chain reaction; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
TC=telephone call 
a 
Clinic Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits may be performed in the clinic, by 
home visit, by hospital visit (if allowed by local policy), or via telemedicine/telephone visit. Required procedures at these visits include AE and 
concomitant medication collection. For participants evaluated for COVID-19, samples should be collected for SARS-CoV-2 testing. Should the visit 
occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry, and symptom-directed physical examination.  
c 
Screening procedures may be performed on Day 1, if feasible. All Screening procedures must be performed prior to determination of eligibility and 
enrollment of the participant in the trial. If all Screening procedures are completed on Day 1, the following Screening assessments do not need to be 
repeated prior to dosing: physical examination, vital signs, body temperature, pregnancy testing, review of COVID-19 symptoms and risks, and 
collection of AEs and concomitant medications. 
d 
Complete physical examination will be performed at Screening, Days 1, 8, 29, 36, 92 and 120 (Switchover/Further Study Vaccine vaccinations), and 
Final Visit (or ET); symptom-directed examination (if any symptoms) may be performed at other timepoints as indicated to assess changes from 
Screening. 
e 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
f 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
g 
Screening blood sampling may be performed if warranted to confirm pregnancy (if urine dipstick not permitted), and menopausal status (as clinically 
relevant). Collection of blood is outlined in Section 4.5.5.3.  Phase 1 participants will have additional blood collected for screening and safety laboratory 
assessments at Screening, Day 8, 29, 36 and 57. These blood samples will be sent to the central laboratory. Screening samples may be processed at the 
site or at the central laboratory if the test is not available.  
h 
Collection of nasal samples is outlined in Section 4.5.5.3. Use of provided nasal swab test kits (including 2 collection containers) to be sent to the central 
laboratory is strongly preferred. Approved alternate measures of virological confirmation of SARS-CoV-2 may be performed if use of provided kits is 
not feasible.  
i 
Study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle. Injection into the nondominant arm is 
recommended. Study vaccine will be administered in an observer-blind fashion at Day 1 and Day 29. At Switchover/Further Study Vaccine (if the 
participant meets eligibility criteria for Switchover/Further Study Vaccine), vaccine will be administered at Day 92 and Day 120. 
j 
Vaccinated participants in Phase 1 will be observed at the site for at least 3 hours following vaccine administration (if performed) and until clinically 
stable. During the post-vaccination observation period, the participant will undergo assessment of vital signs, body temperature, AEs, and concomitant 
medications prior to discharge from the clinic 
k 
Review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for 
symptoms of COVID-19 (Appendix 2). If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is 
identified during the TC with the participant, an Unscheduled visit should be arranged. 
l 
Review of AEs will include surveillance for Solicited AEs within 7 days of each vaccination for the initial series (collected by eDiary or paper diary). 
Unsolicited AEs will be collected for 28 days after each vaccination in all participants. SAEs, MAAEs, and AEs leading to discontinuation/withdrawal 
will be collected throughout study from signing of informed consent in all participants. 
m 
For participants who do not use the eDiary, collect paper diary at Day 8 and 36 Visit. The paper diary must be retained as a source document. 

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INITIAL VACCINATIONS AT DAY 1 AND DAY 29 FOR PHASE 2, PHASE 3A AND 3B PARTICIPANTS 
Visit Name 
Screening 
Dose 1 
Weekly 
Study Call 
Dose 2 
Weekly 
Study Call 
Follow-up 
Visit 
Weekly Study 
Call 
Unscheduled 
Visitb 
ET Visit 
Visit Typea 
Clinic 
Clinic 
TC 
Clinic 
TC 
Clinic 
TC 
Clinic 
Clinic 
Study Day 
-10 to 1 
(pre-dose)c 
1 
8, 15, 22 
29 
36, 43, 50  
57 
64, 71, 78, 85  
N/A 
N/A 
Visit Window (days): 
0 
0 
+2 
+2 
+2 
+2 
±2 
N/A 
N/A 
Informed consent 
X 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
Xc 
 
X 
 
 
 
X 
X 
Vital signs and body 
temperaturee  
X 
Xc 
 
X 
 
X 
 
X 
X 
Pulse oximetry 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
Xc 
 
X 
 
 
 
 
 
Blood samplingg 
X 
X 
 
X 
 
X 
 
 
X 
Nasal swab for RT-PCR 
SARS-CoV-2h 
 
X 
 
 
 
 
 
X 
 
Review of Medical history 
X 
Xc 
 
X 
 
X 
 
X 
X 
Review of 
inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Determination of “at risk” 
statusi 
 
X 
 
 
 
 
 
 
 
Study vaccine 
administrationj 
 
X 
 
X 
 
 
 
 
 
Post-vaccination 
observationk 
 
X 
 
X 
 
 
 
 
 
Review for COVID-19 
symptoms and risksl 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsm 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccines 
collection 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
Collect paper diary n 
 
 
 
X 
 
X 
 
 
 

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Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
RT-PCR=reverse transcription polymerase chain reaction; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
TC=telephone call 
a 
Clinic Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits may be performed in the clinic, by 
home visit, by hospital visit (if allowed by local policy), or via telemedicine/telephone visit. Required procedures at these visits include AE and 
concomitant medication collection. For participants evaluated for COVID-19, samples should be collected for SARS-CoV-2 testing. Should the visit 
occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry, and symptom-directed physical examination.  
c 
Screening procedures may be performed on Day 1, if feasible. All Screening procedures must be performed prior to determination of eligibility and 
enrollment of the participant in the trial. If all Screening procedures are completed on Day 1, the following Screening assessments do not need to be 
repeated prior to dosing: physical examination, vital signs, body temperature, pregnancy testing, review of COVID-19 symptoms and risks, and 
collection of AEs and concomitant medications. 
d 
Complete physical examination will be performed at Screening, Days 1 and 29, 92 and 120 (Switchover/Further Study Vaccine vaccinations), and Final 
Visit (or ET); symptom-directed examination (if any symptoms) may be performed at other timepoints as indicated to assess changes from Screening. 
e 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
f 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
g 
Screening blood sampling may be performed if warranted to confirm pregnancy (if urine dipstick not permitted), and menopausal status (as clinically 
relevant). Collection of blood is outlined in Section 4.5.5.3. Phase 1, Phase 2 and Phase 3a participants (the Immunogenicity Subgroup) will have blood 
collected more frequently for assessment of antibody responses to the SARS-CoV-2 spike protein. These blood samples will be sent to the central 
laboratory. Screening samples may be processed at the site or at the central laboratory if the test is not available.  
h 
Collection of nasal samples is outlined in Section 4.5.5.3. Use of provided nasal swab test kits (including 2 collection containers) to be sent to the central 
laboratory is strongly preferred. Approved alternate measures of virological confirmation of SARS-CoV-2 may be performed if use of provided kits is 
not feasible (Section 7.1.1).  
i 
Determination of a participant’s health status will be performed prior to randomization only (Day 1, prior to study vaccine administration). 
j 
Study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle. Injection into the nondominant arm is 
recommended. Study vaccine will be administered in an observer-blind fashion at Day 1 and Day 29. At Switchover/Further Study Vaccine (if the 
participant meets eligibility criteria for Switchover/Further Study Vaccine), vaccine will be administered at Day 92 and Day 120. 
k 
Vaccinated participants in Phases 2, 3a and 3b will be observed at the site for at least 30 minutes following vaccine administration (if performed) and 
until clinically stable. During the post-vaccination observation period, the participant will undergo assessment of vital signs, body temperature, AEs, and 
concomitant medications prior to discharge from the clinic 
l 
Review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for 
symptoms of COVID-19 (Appendix 2). If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is 
identified during the TC with the participant, an Unscheduled visit must be arranged unless clinically unstable. 
m 
Review of AEs will include surveillance for Solicited AEs within 7 days of each vaccination for the initial series (collected by eDiary or paper diary). 
Unsolicited AEs will be collected for 28 days after each vaccination in all participants. SAEs, MAAEs, and AEs leading to discontinuation/withdrawal 
will be collected throughout study from signing of informed consent to Final Visit in all participants. 

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n 
For Phase 2, 3a and 3b participants who do not use the eDiary, collect paper diary at Day 29 and 57 Visit. The paper diary must be retained as a source 
document. 
 
 
 

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INITIAL VACCINATIONS AT DAY 1 AND DAY 29 FOR PHASE 3C PARTICIPANTS 
Visit Name 
Screening 
Dose 1 
Weekly 
Study Call 
Dose 2 
Weekly 
Study Call 
Weekly 
Study Call 
Follow-up 
Visit 
Weekly 
Study Call 
Unscheduled 
Visitb 
ET Visit 
Visit Typea 
Clinic 
Clinic 
TC 
Clinic 
TC 
TC 
Clinic 
TC 
Clinic 
Clinic 
Study Day 
-10 to 1 
(pre-
dose)c 
1 
8, 15, 22 
29 
36 
 50 
57 
64, 71, 78, 
85  
N/A 
N/A 
Visit Window (days): 
0 
0 
+2 
+2 
+2 
+2 
+2 
±2 
N/A 
N/A 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
Xc 
 
X 
 
 
 
 
X 
X 
Vital signs and body 
temperaturee  
X 
Xc 
 
X 
 
 
X 
 
X 
X 
Pulse oximetry 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
Xc 
 
X 
 
 
 
 
 
 
Blood samplingg 
X 
X 
 
X 
 
 
X 
 
 
X 
Nasal swab for RT-PCR 
SARS-CoV-2h 
 
X 
 
 
 
 
 
 
X 
 
Review of Medical 
history 
X 
Xc 
 
X 
 
 
X 
 
X 
X 
Review of 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Determination of “at 
risk” statusi 
 
X 
 
 
 
 
 
 
 
 
Study vaccine 
administrationj 
 
X 
 
X 
 
 
 
 
 
 
Post-vaccination 
observationk 
 
X 
 
X 
 
 
 
 
 
 
Review for COVID-19 
symptoms and risksl 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsm 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccines 
collection 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
Collect paper diary n 
 
 
 
X 
 
 
X 
 
 
 

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Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
RT-PCR=reverse transcription polymerase chain reaction; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
TC=telephone call 
a 
Clinic Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits may be performed in the clinic, by 
home visit, by hospital visit (if allowed by local policy), or via telemedicine/telephone visit. Required procedures at these visits include AE and 
concomitant medication collection. For participants evaluated for COVID-19, samples should be collected for SARS-CoV-2 testing. Should the visit 
occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry, and symptom-directed physical examination.  
c 
Screening procedures may be performed on Day 1, if feasible. All Screening procedures must be performed prior to determination of eligibility and 
enrollment of the participant in the trial. If all Screening procedures are completed on Day 1, the following Screening assessments do not need to be 
repeated prior to dosing: physical examination, vital signs, body temperature, pregnancy testing, review of COVID-19 symptoms and risks, and 
collection of AEs and concomitant medications. 
d 
Complete physical examination will be performed at Screening, Days 1 and 29, and Final Visit (or ET); symptom-directed examination (if any 
symptoms) may be performed at other timepoints as indicated to assess changes from Screening. 
e 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
f 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
g 
Screening blood sampling may be performed if warranted to confirm pregnancy (if urine dipstick not permitted), and menopausal status (as clinically 
relevant). Collection of blood is outlined in Section 4.5.5.3. Collection of blood samples is outlined in Section 4.5.5.3. The first 1,500 participants in 
Phase 3c (the Immunogenicity Noninferiority Subgroup, Phase 3c-1) will have additional blood collected at Day 211 for assessment of antibody 
responses to the SARS-CoV-2 spike protein. These blood samples will be sent to the central laboratory.  The last ~900 participants enrolled (Phase 3c-2) 
will have phone visits Day 211. 
h 
Collection of nasal samples is outlined in Section 4.5.5.3. Use of provided nasal swab test kits (including 2 collection containers) to be sent to the central 
laboratory is strongly preferred. Approved alternate measures of virological confirmation of SARS-CoV-2 may be performed if use of provided kits is 
not feasible (Section 7.1.1).  
i 
Determination of a participant’s health status will be performed prior to randomization only (Day 1, prior to study vaccine administration). 
j 
Study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle. Injection into the nondominant arm is 
recommended. Study vaccine will be administered in an observer-blind fashion at Day 1 and Day 29.  
k 
Vaccinated participants in Phases 3c will be observed at the site for at least 30 minutes following vaccine administration (if performed) and until 
clinically stable. During the post-vaccination observation period, the participant will undergo assessment of vital signs, body temperature, AEs, and 
concomitant medications prior to discharge from the clinic 
l 
Review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for 
symptoms of COVID-19 (Appendix 2). If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is 
identified during the TC with the participant, an Unscheduled visit must be arranged unless clinically unstable. 
m 
Review of AEs will include surveillance for Solicited AEs within 7 days of each vaccination for the initial series (collected by eDiary or paper diary). 
Unsolicited AEs will be collected for 28 days after each vaccination in all participants. SAEs, MAAEs, and AEs leading to discontinuation/withdrawal 
will be collected throughout study from signing of informed consent to Final Visit in all participants. 
n 
For Phase 3c participants who do not use the eDiary, collect paper diary at Day 29 and 57 Visit.. The paper diary must be retained as a source document. 

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DAY 92 TO END OF STUDY VISIT FOR PHASE 1, PHASE 2, PHASE 3A AND PHASE 3B PARTICIPANTS 
Visit Name 
Further 
Dose 1n 
Weekly Study 
Call o 
Further 
Dose 2o 
Weekly Study Call o 
Monthly Study Call 
Final Visit 
Unscheduled Visit b 
ET Visit 
Visit Typea 
Clinic  
TC 
Clinic  
TC 
TC  
Clinic 
Clinic  
Clinic 
Study Day: 
92 
99. 106, 113 
120 o 
127, 134, 141, 148, 
155, 162, 169, 176 
210, 240, 270, 300, 
330 and 360 
394 
N/A 
N/A 
Visit Window (days): 
+30 or 
+14n 
+2 
+2 
+2 
±2 
+14 
N/A 
N/A 
Physical examinationc 
X 
 
X 
 
 
X 
X 
X 
Vital signs and body 
temperatured 
X 
 
X 
 
 
X 
X 
X 
Pulse oximetry 
 
 
 
 
 
 
X 
 
Pregnancy teste 
X 
 
X 
 
 
 
 
 
Blood sampling f 
X 
 
X 
 
 
X 
 
X 
Nasal swab sample for 
RT-PCR SARS-CoV-2 
g 
 
 
 
 
 
 
X 
 
Review of Medical 
History 
X 
 
X 
 
 
X 
X 
X 
Review of eligibility 
criteria for 
Switchover/Further 
Study Vaccine h, i 
X 
 
 
 
 
 
 
 
Study vaccine 
administration i 
X 
 
X 
 
 
 
 
 
Post-vaccination 
observation j 
X 
 
X 
 
 
 
 
 
Review for COVID-19 
symptoms and risks k 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events l 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication/vaccines 
collection 
X 
X 
X 
X 
X 
X 
X 
X 
Collect paper diarym 
 
 
X 
 
 
 
 
 

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Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
RT-PCR=reverse transcription polymerase chain reaction; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
TC=telephone call 
a  
Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits may be performed in the clinic, by 
home visit, by hospital visit (if allowed by local policy), or via telemedicine/telephone visit. Required procedures at these visits include AE and 
concomitant medication collection. For participants evaluated for COVID-19, samples should be collected for SARS-CoV-2 testing. Should the visit 
occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry, and symptom-directed physical examination. 
c 
Complete physical examination will be performed at Switchover/Further Study Vaccine vaccinations on Day 92 and Day 120, and Final Visit (or ET); 
symptom-directed examination (if any symptoms) may be performed at other timepoints as indicated to assess changes from Screening. 
d 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
e 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
f 
Collection of blood samples is outlined in Section 4.5.5.3. Phase 1, Phase 2 and Phase 3a participants (the Immunogenicity Subgroup) will have blood 
collected more frequently for assessment of antibody responses to the SARS-CoV-2 spike protein. These blood samples will be sent to the central 
laboratory. 
g 
Collection of nasal swab samples is outlined in Section 4.5.5.3. Use of provided nasal swab test kits (including 2 collection containers) to be sent to the 
central laboratory is strongly preferred. Approved alternate measures of virological confirmation of SARS-CoV-2 may be performed if use of provided 
kits is not feasible. Note: For Phase 1/2/3a/3b, nasal swabs for RT-PCR test do not need to be performed after Day 92. 
h 
Confirm Switchover/Further Study Vaccine eligibility criteria (Section 5.1.5) prior to Switchover/Further Study Vaccine vaccine administration.  
i 
Study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle of the nondominant arm. Study vaccine will 
be administered in an observer-blind fashion at Day 92 and Day 120 (if the participant meets eligibility criteria for Switchover/Further Study Vaccine). 
For participants who do not meet eligibility criteria for Switchover/Further Study Vaccine, study vaccination will not be performed. 
j 
For Switchover vaccinations, participants in Phase 1 and Phase 3b will be observed for at least 15 minutes and until clinically stable. Participants in 
Phase 2 and 3a will be observed for at least 30 minutes and until clinically stable for vaccinations 1, 2, and 3 (Day 92) and for at least 15 minutes and 
until clinically stable for vaccination 4 (Day 120). 
k 
Review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for 
symptoms of COVID-19 (Appendix 2). If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is 
identified during the TC with the participant, an Unscheduled visit should be arranged. 
l 
Review of AEs will include surveillance for solicited (only after Day 92 vaccination and only for Phase 2 and 3a) and unsolicited AEs, SAEs, MAAEs, 
and AEs leading to discontinuation/withdrawal; Solicited AE data will be gathered by Diary for Day 1 through Day 7 for all participants after each of 
the initial vaccination series only; Unsolicited AE data will be gathered by interview at clinic visits and telephone contacts through Screening and 28 
days after each vaccination. SAEs, MAAEs, and AEs leading to discontinuation/withdrawal will be collected at all timepoints after signing of the 
informed consent. 
m 
Only participants in Phase 2 and 3a complete a diary after vaccination on Day 92; no diary is completed after vaccination on Day 120. Participants in 
Phase 1 and 3b do not complete a diary after vaccination on either Day 92 or Day 120.  
n 
For participants in Phase 1 and Phase 3b, the visit window at Day 92 is +30 days. For participants in Phase 2 and Phase 3a, the visit window at Day 92 is 
+14 days. 

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o 
Participants ineligible for additional doses (Section 5.1.5) do not have a clinic visit at Day 120 and will not have weekly telephone visits on Day 99 to 
Day 113 and Days 127 to Day 176 but will have monthly telephone visits instead on Days 120, 150, and 180.  
 
  
 

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DAY 92 TO END OF STUDY VISIT FOR PHASE 3C PARTICIPANTS 
Visit Name 
Weekly Study 
Call 
Follow-up Visit 
Weekly Study 
Call 
Monthly Study 
Call 
Final Visit  
Unscheduled Visit b 
ET Visit 
Visit Typea 
TC 
Clinic  
TC  
TC  
Clinic 
Clinic  
Clinic 
Study Day: 
92, 99, 106, 
113, 120, 127, 
134, 141, 148, 
155, 162, 169, 
176, 183, 190, 
197, 204 
211 
218, 225, 232, 
239, 246, 253, 
260 
290, 320, 350 
394 
N/A 
N/A 
Visit Window (days): 
±2 
+30 
±2 
±2 
+14 
N/A 
N/A 
Physical examinationc 
 
X 
 
 
X 
X 
X 
Vital signs and body temperatured 
 
X 
 
 
X 
X 
X 
Pulse oximetry 
 
 
 
 
 
X 
 
Blood sampling e 
 
X 
 
 
X 
 
X 
Nasal swab sample for RT-PCR 
SARS-CoV-2 f 
 
 
 
 
 
X 
 
Review of Medical History 
 
X 
 
 
X 
X 
X 
Review for COVID-19 symptoms and 
risks g 
X 
X 
X 
X 
X 
X 
X 
Adverse events h 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication/vaccines 
collection 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
RT-PCR=reverse transcription polymerase chain reaction; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; 
TC=telephone call 
a  
Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits may be performed in the clinic, by 
home visit, by hospital visit (if allowed by local policy), or via telemedicine/telephone visit. Required procedures at these visits include AE and 
concomitant medication collection. For participants evaluated for COVID-19, samples should be collected for SARS-CoV-2 testing. Should the visit 
occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry, and symptom-directed physical examination. 
c 
Complete physical examination will be performed at the Final Visit (or ET); symptom-directed examination (if any symptoms) may be performed at 
other timepoints as indicated to assess changes from Screening. 
d 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 

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e 
Collection of blood samples is outlined in Section 4.5.5.3. The first 1,500 participants in Phase 3c  (the Immunogenicity Noninferiority Subgroup, Phase 
3c-1) will also have blood collected at Day 211 for assessment of antibody responses to the SARS-CoV-2 spike protein. These blood samples will be 
sent to the central laboratory.  The last ~900 participants enrolled (Phase 3c-2) will have a phone visit on Day 211. 
f 
Collection of nasal swab samples is outlined in Section 4.5.5.3. Use of provided nasal swab test kits (including 2 collection containers) to be sent to the 
central laboratory is strongly preferred. Approved alternate measures of virological confirmation of SARS-CoV-2 may be performed if use of provided 
kits is not feasible. Note: For Phase 3c, nasal swabs should continue to be collected until the last study visit (early termination of Day 394). 
g 
Review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for 
symptoms of COVID-19 (Appendix 2). If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is 
identified during the TC with the participant, an Unscheduled visit should be arranged. 
h 
Review of AEs will include surveillance for unsolicited AEs, SAEs, MAAEs, and AEs leading to discontinuation/withdrawal; Solicited AE data will be 
gathered by Diary for Day 1 through Day 7 for all participants after each of the initial vaccination series only; Unsolicited AE data will be gathered by 
interview at clinic visits and telephone contacts through Screening and 28 days after each vaccination. SAEs, MAAEs, and AEs leading to 
discontinuation/withdrawal will be collected at all timepoints after signing of the informed consent. 
 

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APPENDIX 2: 
CASE DEFINITIONS OF COVID-19 
Primary Case Definition (Based on FDA recommendation (DHHS 2020)) 
Case Definition  
Laboratory Finding* 
Clinical Status 
Symptoms 
Other Clinical Parameters 
Uninfected 
No positive SARS-CoV-
2 test 
None 
None relevant 
Asymptomatic 
SARS-CoV-2 Infection 
Positive SARS-CoV-2 
test 
None 
None relevant 
Protocol-defined 
COVID-19 
Positive SARS-CoV-2 
test 
At least one of the following that is 
a NEW or WORSENING finding:  
 
Fever or chills 
 
Cough 
 
Shortness of breath or 
difficulty breathing 
 
Fatigue 
 
Muscle or body aches 
 
Headache 
 
New loss of taste or smell 
 
Sore throat 
 
Congestion or runny nose 
 
Nausea or vomiting 
 
Diarrhea 
None relevant 
Atypical COVID-19 
Positive SARS-CoV-2 
test 
Clinical findings suggestive of 
COVID-19 but not included in the 
row above 
None relevant 
Severe COVID-19 
Positive SARS-CoV-2 
test 
As above for protocol-defined 
COVID-19 
Any of the following: 
 
Clinical signs at rest indicative of severe systemic 
illness: 
- 
Respiratory rate ≥30 per minute, 

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Case Definition  
Laboratory Finding* 
Clinical Status 
Symptoms 
Other Clinical Parameters 
- 
Heart rate ≥125 per minute, 
- 
SpO2 ≤93% on room air at sea level or PO2/FiO2 
<300 mm Hg 
 
Respiratory failure (defined as needing high flow 
oxygen, noninvasive ventilation, mechanical ventilation 
or ECMO) 
 
Evidence of shock: 
- 
SBP <90 mm Hg, or 
- 
DBP <60 mm Hg,  
- 
or requiring vasopressors 
 
Significant acute renal, hepatic, or neurologic 
dysfunction 
 
Admission to an ICU 
 
Death 
Abbreviations: COVID-19=coronavirus disease 2019; DBP=diastolic blood pressure; ECMO=extracorporeal membrane oxygenation; FiO2=fraction of 
inspired oxygen; ICU=intensive care unit; pO2=partial pressure of oxygen; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SBP=systolic 
blood pressure; SpO2=oxygen saturation  

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Alternate Case Definition for Grading of Severity of SARS-CoV-2 Infection/COVID-19 (Based on World Health Organization 
WHO 2020) 
Case Definition 
Lab Finding* 
Clinical Status 
Other Clinical Parameters 
Score 
Uninfected 
No positive SARS-CoV-2 test 
N/A 
N/A 
0 
Mild Disease 
Positive SARS-CoV-2 test 
Ambulatory 
Asymptomatic 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Moderate Disease 
Positive SARS-CoV-2 test 
Hospitalized 
No oxygen therapy  
NOTE: If hospitalized for isolation only, 
record status as for ambulatory patient 
4 
Oxygen by mask or nasal prongs 
5 
Severe Disease 
Positive SARS-CoV-2 test 
Hospitalized 
Oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation,  
pO2/FiO2≥150 or  
SpO2/FiO2≥200 
7 
Mechanical ventilation, 
pO2/FiO2<150 or  
SpO2/FiO2<200 or 
vasopressors 
8 
Mechanical ventilation, 
pO2/FiO2<150 and vasopressors, dialysis 
or ECMO 
9 
Dead 
Positive SARS-CoV-2 test 
Dead 
N/A 
10 
Abbreviations: ECMO=extracorporeal membrane oxygenation; FiO2=fraction of inspired oxygen; N/A=not applicable; NIV=noninvasive ventilation; 
pO2=partial pressure of oxygen; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SpO2=oxygen saturation 

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*Laboratory Confirmation of SARS-CoV-2 Infection 
SARS-CoV-2 viral infection as measured by either reverse transcriptase-polymerase chain reaction (RT-PCR) test, other equivalent 
nucleic acid amplification–based test (ie, NAAT), or rapid antigen test. Results from the central laboratory (preferred) or from local 
laboratory will be used; however, if local tests are used, the lab test will be considered acceptable if it was obtained using 
• A Food and Drug Administration (FDA)-cleared assay 
• OR an assay performed in a laboratory that is currently Clinical Laboratory Improvement Amendment (CLIA-certified) 
• OR an assay performed by a laboratory accredited according to the International Organization for Standardization (ISO) 15189 
standard  
• OR an assay accredited by a national or regional authority in the country concerned 
 

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APPENDIX 3: 
CONTRACEPTIVE GUIDANCE 
Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during the 
intervention period and for at least 60 days after administration of study vaccine, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s): 
• Refrain from donating sperm. 
PLUS, either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to 
remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for passage 
of ejaculate to another person. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in women of childbearing potential (WOCBP) partners of male participants (refer 
to the list of highly effective methods below). 
Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
• Is not a WOCBP (see definitions below) 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described below during 
the intervention period (for a minimum of 60 days after administration of study vaccine). The 
investigator should evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
Woman 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 the first dose of study intervention, additional evaluation should be considered, 
including follicle-stimulating hormone (FSH) test. 
Women in the following categories are not considered WOCBP 
• Premenopausal female with 1 of the following: 

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- 
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 for any of the above categories can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview. The 
method of documentation should be recorded in the participant’s medical record for the study. 
• Postmenopausal defined as follows: 
- 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
- 
A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or hormone replacement therapy (HRT). 
- 
A female participant on HRT and whose menopausal status is in doubt will be 
required to use one of the nonestrogen 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. 
Contraception Methods Inclusion Criteria 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
Acceptable contraception methods include the following:  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner: 
- 
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. The spermatogenesis cycle is 
approximately 90 days. 

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• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
Oral 
- 
Intravaginal 
- 
Transdermal 
- 
Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral 
- 
Injectable 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 
• Sexual abstinence: 
- 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
The following methods of birth control are not regarded as highly reliable methods and are 
therefore discouraged as a single method only for contraception:  
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action 
• Male or female condom with or without spermicide 
• Cervical cap, diaphragm, or sponge with spermicide 
 
 

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APPENDIX 4: 
TOXICITY GRADING SCALES 
 
Table 19 
Toxicity Grading for Solicited Adverse Events  
Solicited Local Adverse 
Events 
Grade 0 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
Injection Site Erythema * 
<2.5 cm 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Emergency 
Room (ER) 
visit, 
hospitalization 
or  
necrosis or 
exfoliative 
dermatitis 
Injection Site 
Induration/Swelling ** 
<2.5 cm 
2.5-5 cm 
5.1-10 cm 
>10 cm 
ER visit or 
hospitalization 
or necrosis 
Injection Site Pain 
None 
Present but 
does not 
interfere with 
daily activity 
Interferes with 
daily activity 
or leads to use 
of non-
narcotic pain 
reliever for 
>24 hours 
Prevents daily 
activity or 
leads to use of 
narcotic pain 
reliever 
ER visit or 
hospitalization 
Injection Site Tenderness 
None 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Solicited Systemic 
Adverse Events 
 
 
 
 
 
Fever (°C) *** 
(°F) *** 
<38.0 
<100.4 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40 
102.1-104 
>40 
>104 
Nausea/vomiting 
None 
1-2 
episodes/24 
hours 
>2 episodes/2
4 hours 
without 
seeking 
medical 
attention 
Requires 
outpatient 
intravenous 
hydration 
ER visit or 
hospitalization 
for 
hypotensive 
shock 
Diarrhea 
<2 loose 
stools/24 
hours 
2-3 loose 
stools/24 
hours 
4-5 stools/24 
hours 
6 or more 
loose or 
watery 
stools/24 
hours or 
requires 
outpatient 
intravenous 
hydration 
ER visit or 
hospitalization 

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Table 19 
Toxicity Grading for Solicited Adverse Events  
Solicited Local Adverse 
Events 
Grade 0 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
Headache 
None 
Present but 
without 
interference 
with daily 
activity 
Interferes with 
daily activity 
or leads to use 
of non- 
narcotic pain 
reliever for 
>24 hours 
Prevents daily 
activity or 
leads to use of 
narcotic pain 
reliever 
ER visit or 
hospitalization 
Fatigue 
None 
Present but 
without 
interference 
with daily 
activity 
Interferes with 
daily activity 
Prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
None 
Present but 
without 
interference 
with daily 
activity 
Interferes with 
daily activity 
Prevents daily 
activity 
ER visit or 
hospitalization 
Arthralgia, chills, and 
dizziness 
None 
Present but 
without 
interference 
with daily 
activity 
Interferes with 
daily activity 
Prevents daily 
activity  
ER visit or 
hospitalization 
 
Abbreviation: ER=emergency room 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
*** If temperature taken orally, no recent hot or cold beverages or smoking. 
Adapted from Source: DHHS 2007 
 
 

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APPENDIX 5: 
AT-RISK MEDICAL CONDITIONS  
Ongoing surveillance of the spread and complications of severe acute respiratory syndrome 
coronavirus 2 infection has identified a set of conditions that are associated with increased risk of 
severe, life-threatening coronavirus disease 2019 (COVID-19). 
COVID-19 has demonstrated both high attacks and elevated mortality rates in older individuals. 
As such, individuals older than 60 years are currently prioritized for immunization in several 
countries with COVID-19 vaccines available for distribution.  
Each of the medical conditions described below has been named as probably or possibly 
associated with increased risk of severe complications of COVID-19 (CDC 2021).  
For the purposes of determining which participants will be managed as “at risk,” some relevant 
clinical definitions for each of these findings is provided. The information shared below should 
be evaluated against the participant’s medical records for confirmation of risk.  
• Cancer: Includes any individual with a history of malignancy EXCEPT 
o Malignancy with low potential risk for recurrence after curative treatment (eg, history 
of childhood leukemia) or metastasis in the opinion of the investigator 
o Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of 
disease 
o Adequately treated uterine cervical carcinoma in situ without evidence of disease 
o Localized prostate cancer 
• Chronic kidney disease: Stage 3 (eg, estimated glomerular filtration rate 
<60 mL/min/1.73 m2) or worse within the past year 
• Chronic obstructive pulmonary disease such as chronic bronchitis or emphysema 
• Cystic fibrosis 
• Pulmonary fibrosis 
• Down syndrome 
• Cardiovascular conditions: Includes any participant with any of the following: 
o Hypertension that is regarded as uncontrolled for age according to the Eighth Joint 
National Committee guidelines (James 2014) 
o Congestive heart failure by New York Heart Association classification ≥2 
(Dolgin 1994) 
o Recent (within 6 months prior to first study vaccination) exacerbation of coronary 
artery disease as manifested by cardiac intervention, addition of new cardiac 
medications for control of symptoms, or unstable angina 
o Cardiomyopathy 
o Pulmonary hypertension 

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• Obesity (body mass index of 30 kg/m2 or higher measured at Screening) 
• Sickle cell disease or other hemoglobinopathies such as thalassemia 
• Current or former smoker defined as someone who has smoked more than 100 cigarettes 
in a lifetime (CDC 2017)  
• Type 1 or type 2 diabetes mellitus  
• Asthma (moderate-to-severe) 
• Cerebrovascular disease (eg, stroke, transient ischemic attack, aneurysms, and vascular 
malformations) 
• Dementia or Alzheimer’s 
• Current or recent substances abuse disorder (alcohol, opioid, cocaine) 
• Liver disease such as follows:  
o alcohol-related liver disease 
o nonalcoholic fatty liver disease 
o cirrhosis 
 

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APPENDIX 6: 
PROTOCOL AMENDMENTS 
Protocol Amendment 1 
The purpose of this amendment is to address the study design recommendations from the 
Vietnam Ministry of Health. The Phase 3a/b study was revised to a Phase 1/2/3 study design, 
with SRC review of safety data from one phase prior to enrollment of the next. In addition to the 
changes listed below, this amendment includes administrative changes for consistency of 
language and changes to the Synopsis for consistency with the changes to the main body outlined 
below, as well as correction of minor typographical and referencing errors. 
Protocol Amendment 1 (Version 2.0, 27 July 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 1.1 
Study schematic updated to 
the current design 
To align with the new study design and 
accurately reflect the Phases and timepoints 
Section 3.1 and subsections 
Objectives and Endpoints 
revised  
To align with the new study design 
Section 4.1 
Updated participant 
enrollment numbers 
To align with the new study design 
Section 4.4 
Revised text to reflect the 
new study design, including 
Phase 1, 2, and 3a/b, with 
safety reviews between 
phases. The immunogenicity 
subgroup is described as 
Phase 2 and 3a participants, 
and immunogenicity data at 
Day 57 will be pooled for the 
primary analysis.   
To align with the new study design 
Section 4.5.3.3 
Deleted reference to only 
collecting blood in Phase 3a 
Blood being collected in all Phases of study 
Section 4.5.3.5 
Corrected blood sample to 
nasal swab 
Correction of an error in original protocol 
Section 4.5.5.2 
Removed description of 
blood volumes to be 
collected. These will be 
described in the Lab Manual 
Blood volumes will be described in the Lab 
Manual 
Section 8 
Added language to describe 
how data integrity will be 
maintained 
To align with the new study design 
Section 8.1,  
Added language to include 
the additional study phases 
To align with the new study design 

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Protocol Amendment 1 (Version 2.0, 27 July 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 8.3.1 
Added language to include 
the additional study phases 
and the Immunogenicity 
Subgroup 
To align with the new study design 
Section 8.3.2 
Clarified where decision 
rules for sample size 
evaluation will be described 
Clarification 
Section 8.6.3 
Additional detail added 
concerning the analysis 
population 
Consistency with stated objectives and 
endpoints 
Section 8.9.1 
Added additional detail 
concerning time points for 
SRC review of safety data 
To align with the new study design 
Section 8.9.3 
Timing of constitution of 
DSMB updated 
To align with the new study design 
Section 14, Appendix 1 
Title updated to reflect that 
the Schedule of Assessments 
applies to all (Phases 1, 2 
and 3) participants. 
 
Footnote updated to clarify 
and emphasize the 
Immunogenicity Subgroup 
(Phases 2 and 3a) will have 
more frequent blood 
collection. 
To align with the new study design 
 
 
 
 
To align with the new study design 

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Protocol Amendment 2 
The purpose of this amendment is to address the study design recommendations from the 
Vietnam Ethics Committee. The size of the Phase 1 part was increased and participants in 
Phase 1 have been incorporated into the Immunogenicity Subgroup. Assessment of safety 
laboratory testing had also been added for Phase 2 participants.  In addition to the changes listed 
below, this amendment includes administrative changes for consistency of language and changes 
to the Synopsis for consistency with the changes to the main body outlined below, as well as 
correction of minor typographical and referencing errors. 
Protocol Amendment 2 (Version 3.0, 01 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title of Study 
Reactogenicity removed from title 
Request by Ethics Committee. 
3.1 
Updated description of Immunogenicity 
Subgroup and clarified the participants that 
each type of neutralizing antibody test will 
be performed in 
To align with new study design. 
4.1 
Updated enrollment numbers for Phase 1 
and Phase 2 
To align with new study design. 
4.4 
Revised text for Phase 1 to be 3:1 
randomization, no stratification for Phase 1, 
and added Phase 1 to immunogenicity 
subgroup. Added that Phase 1 participants 
must be <60 years of age 
To align with new study design. 
4.4 
Specified that tolerability criteria will be 
agreed with  
Request by Ethics Committee. 
4.5.2 
Updated enrollment to be 3:1 
(ARCT-154:placebo) for Phase 1. Clarified 
that no stratification will occur for Phase 1 
participants 
To align with new study design. 
4.5.3 
Updated number of visits for Phase 1 
participants to have additional visits on Day 
8 and 36. 
To align with new study design. 
4.5.3.1 
Added nasal swab and blood sampling for 
screening and safety laboratories at 
screening for Phase 1. 
To align with new study design. 
4.5.3.2 
For 3a and 3b, added collection of paper 
diaries, if applicable, at Day 29. 
To correct an omission from 
previous version. 
 
Added observation for at least 3 hours for 
Phase 1 initial series of vaccinations. 
Longer observation in Phase 1 for 
the initial series of vaccine 
administrations. 
4.5.3.3 
Added Follow-up Visits on Day 8 and 36, 
including blood sampling for safety 
laboratories 
To align with new study design. 

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Protocol Amendment 2 (Version 3.0, 01 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
4.5.3.4 
For Phase 3a and 3b, added collection of 
paper diaries, if applicable, at Day 57. 
To correct an omission from 
previous version. 
4.5.5.2 
Added screening and safety laboratories at 
Screening for Phase 1. 
 
Added safety laboratories at Day 8, 29, 36 
and 57 for Phase 1 participants. 
 
Added Phase 1 to Immunogenicity 
subgroup. 
 
Added PRNT50 laboratory test at Day 29 
and 57. 
To align with new study design. 
5.1.2 
For Phase 1, added exclusions for clinically 
significant medical conditions and abnormal 
screening laboratory values. 
 
Added exclusion of ≥ 60 years of age.  
To align with new study design. 
5.1.3 
Clarified that all Phases except Phase 1 will 
be stratified for at-risk participants. 
To align with new study design. 
5.2.1 
Revised language to clarify that participants 
must be rescreened if delay in vaccination is 
> 28 days after signing the informed 
consent. 
Corrected language to align delay in 
study vaccination with Screening 
period. 
6.1 
Clarified that all Phases except Phase 1 will 
be stratified for at-risk participants. 
To align with new study design. 
6.2 
New section describing contract 
organizations responsible for manufacturing 
ARCT-154. Following Section 6 
subsections renumbered accordingly 
Request by Ethics Committee. 
7.3  
Added safety blood sampling for Phase 1 to 
safety assessments. 
To align with new study design. 
7.3.1.2 
Revised language from ongoing AE to 
ongoing disease/condition and clarified that 
conditions from signing informed consent 
and during screening period will be reported 
as medical history. 
Clarified process for eliciting and 
documenting AEs. 
7.3.1.3.4 
Added new Subsection for laboratory test 
abnormalities 
To align with new study design, 
which included adding safety 
laboratories for Phase 1 at 
Screening, Day 29 and Day 57. 
8.1 
Updated description of Immunogenicity 
Subgroup. Clarified in Table 9 that 
immunogenicity analysis target population 
To align with new study design. 

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Protocol Amendment 2 (Version 3.0, 01 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
is only Phase 1, 2 and 3a participants and 
also clarified which neutralization tests will 
be performed as primary and secondary 
8.3.1 
Amended the number of ARCT-154 
participants in Phase 3a analysis of safety 
and clarified that the primary Nab test will 
be a pseudovirus assay 
To align with new study design. 
8.4 
Clarified that Immunogenicity Analysis Set 
comprises participants in Phases 1, 2 and 3a 
Clarification to align with new 
study design. 
8.6.2 
In Table 13 clarified which neutralization 
tests are primary and secondary 
Clarification to align with new 
study design. 
8.6.3 
Clarified that Phase 3a immunogenicity 
analysis will be conducted in participants in 
Phases 1, 2 and 3a and that the primary Nab 
test will be a pseudovirus assay 
Clarification to align with new 
study design. 
8.9.1 
Updated the enrollment number for Phase 1 
to 100 participants. 
To align with new study design. 
Section 14, Appendix 1 
Added Phase 1 Schedule of Assessments 
Table, with additional visits on Days 8 and 
36. 
To align with new study design 
 
For Phase 2, 3a and 3b, added collection of 
paper diaries at Day 29 and 57. 
To correct omission from previous 
version. 
 
Added Phase 1 to Immunogenicity 
Subgroup blood collection schedule. 
To align with new study design. 

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Protocol Amendment 3 
The primary purpose of this amendment is to address inconsistencies and errors in Protocol 
Version 3.0. In addition to the changes listed below, this amendment includes administrative 
changes for consistency of language and changes to the Synopsis for consistency with the 
changes to the main body outlined below, as well as correction of minor typographical and 
referencing errors.  
Protocol Amendment 3 (Version 4.0, 09 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title 
Removed Phase 1/2/3 
Request from Ethics Committee 
Section 2.6 
Revised to reflect ARCT-021 safety data as 
of Interim Analysis #2. 
Provides a more accurate 
representation of available safety 
data. 
Section 3.1.1 
Corrected the NAb assay from a 
pseudovirus assay to a surrogate virus 
neutralization test 
Correct an error 
Section 3.1.2 
Corrected the NAb assay from a 
pseudovirus assay to a surrogate virus 
neutralization test. Made PRNT50 a 
separate secondary endpoint 
Correct errors 
Section 4.1 
Clarified that the number of participants in 
Phase 1 will be 75 ARCT-154 and 25 
placebo-treated. 
Provides clarification. 
Section 4.5.3 
Revised telephone calls to Day 216, 223, 
230, 244, 251, 258, 265. 
Corrects a miscalculation of study 
calls occurring at 7-day intervals. 
Section 4.5.3.2 
Added language that the second study 
vaccination must be at least 28 days after 
the first vaccination, and the Switchover 
must be at least 180 days after the second 
vaccination of the initial series. 
Provides clarification for the 
minimum interval between 
vaccinations.  
Section 4.5.3.3 
Added language to clarify that visits on Day 
8 and 36 must be at least 7 days after prior 
vaccination. 
Ensures minimum time interval for 
safety evaluations. 
Section 4.5.3.4 
Added clarification that Day 57 visit must 
occur at least 28 days after second 
vaccination. 
Ensures minimum time interval for 
safety evaluations. 
Section 4.5.3.5 
Added clarification that timing of the 
weekly phone calls is based on the prior 
study vaccination, and for Day 8 and 36, 
must be at least 7 days after vaccination.  
Ensures minimum time interval for 
safety evaluations. 
Section 4.5.3.7 
Added clarification that the Final Visit 
should be Day 394 for all participants. 
 
Removed that Final Visit and ET Visit 
could occur by telemedicine. 
Provides clarification for intent of 
protocol design. 
 
Ensures that in person visit will 
occur to collect necessary safety 
assessments. 

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Protocol Amendment 3 (Version 4.0, 09 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 4.5.5.2 
Added for Day 29 that all participants will 
have nucleocapsid Ab testing performed. 
Provides necessary lab testing for 
proper analysis of the primary 
endpoint, to identify participants 
who have had prior COVID-19. 
Section 5.1.1 
Added link to Appendix 3 to Inclusion 4 
 
Added to Inclusion 6 “in the opinion of the 
Investigator” 
Provides a link to the contraceptive 
guidance. 
Provides guidance to Investigators 
to use judgement in determining 
this. 
Section 7.2 
Added laboratory requirements for 
immunogenicity laboratory tests 
Ensures laboratory assessments are 
completed properly and ensures 
integrity of efficacy data. 
Section 8.1.1 and 8.6.2 
Corrected the NAb assay from a 
pseudovirus assay to a surrogate virus 
neutralization test in Table 9 and Table 13 
Correct an error 
Section 8.6.3.1 
Corrected the NAb assay from a 
pseudovirus assay to a surrogate virus 
neutralization test 
Correct an error 
Section 11.6 
Revised to “according to local reporting 
requirements.” 
Updated because IRB reporting 
requirements may not be annual. 
Appendix 1 
Revised windows for study calls to +2 at 
Day 8, 15, 22, 43 and 50, and ±2 for all 
other study calls. 
 
Revised windows for clinic visits to +2 days 
at Day 29, 36, and 57. 
 
 
Revised footnote l to clarify Unscheduled 
visit must be arranged unless participant is 
clinically unstable. 
 
Revised table name to ‘Day 209 to End of 
Study Visit for All Participants’ 
 
 
Revised study calls to Day 216, 223, 230, 
244, 251, 258 and 265. 
Ensures a minimum safety follow-
up of at least 7 days for key 
timepoints, while simplifying the 
study design. 
Ensures a minimum safety follow-
up for key timepoints while 
simplifying the study design.  
 
Ensures appropriate data is 
collected by conducting 
Unscheduled Visits. 
 
More accurately reflects table 
because not all participants will 
have Switchover vaccinations. 
 
Corrects a miscalculation of study 
calls occurring at 7-day intervals.  
Summary of Changes for 
Protocol Amendment 2 
Clarified that PRNT50 performed for Days 
1, 29 and 57 by deleting erroneous 
reference to Days 209 and 394 
Correction of an error 
 

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Protocol Amendment 4 
The primary purpose of this amendment is to change to allow Phase 3a to be initiated at the same 
time as Phase 2 and to change the randomization ratio for Phases 2 and 3a to 3:1 ARCT-154 to 
placebo.  In addition to the changes listed below, this amendment includes administrative 
changes for consistency of language and changes to the Synopsis for consistency with the 
changes to the main body outlined below, as well as correction of minor typographical and 
referencing errors.  
Protocol Amendment 4 (Version 5.0, 24 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Figure 1 
Study schematic updated 
Updated to reflect the current study 
design in this amendment. 
Section 3.1 and subsections 
and tables 
Section 8.1.1 
Section 8.2.1 
Section 8.3.1 
Section 8.6.1.1 
Section 8.6.3 and 
subsections 
Section 8.8 
Revised titles/text to reflect that objectives 
and endpoints relate to Phases 1, 2 and 3a 
Provides a more accurate 
description. 
Sections 4.4 and 8.9.1 
Revised text that Phases 2 and 3a will start 
simultaneously after review of safety data 
from Phase 1 through Day 36. 
Due to the rapidly increasing rate of 
COVID cases in Vietnam, more 
rapid transition through the early 
phases is desirable in order to get to 
Phase 3 initiation as soon as 
possible. 
Section 4.1 
Randomization revised to 3:1 for Phases 2 
and 3a. 
Updated to align with study plan. 
Section 4.2 
The number of sites revised to 
approximately 20. 
Updated to align with study plan. 
Section 4.4 
Revised text that the SRC will review safety 
data for Phase 1 participants instead of 
referring to them as a sentinel cohort. 
Language revised to be more 
accurate since all of Phase 1 
participants will be enrolled and 
safety data reviewed by the SRC. 
Section 4.4 
Revised the text such that Phases 2 and 3a 
start simultaneously after review of Phase 1 
safety data through Day 56. 
 
Updated text to be consistent with 3:1 
randomization for Phases 2 and 3a. 
Updated to align with study plan. 
Section 4.5.2 
Updated text to be consistent with 3:1 
randomization for Phases 2 and 3a. 
Updated to align with study plan. 
Section 4.5.3.1 
Updated text to reflect nasal swabs for 
SARS-CoV-2 RT-PCR will be performed in 
Updated to align with study plan. 
Rapid results observed in Phase 1 

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Protocol Amendment 4 (Version 5.0, 24 August 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
all participants at Screening, not only 
Phase 1 participants.  
will permit testing of all participants 
in later Phases.   
Section 4.5.3.2 
Revised to include Phase 2 participants who 
did not use eDiary to provide paper diaries 
at Day 29 Visit. 
Correction to address omission. 
Section 4.5.3.4 
Revised to include Phase 2 participants who 
did not use eDiary to provide paper diaries 
at Day 57 Visit. 
Correction to address omission. 
Section 5.1.2 
Revised exclusion criteria #3 to exclude 
participants with a positive nasal swab 
SARS-CoV-2 RT-PCR test at Screening. 
The exclusion will now apply to all 
participants, not only Phase 1 participants. 
Due to the availability of rapid RT-
PCR testing available to study sites, 
and the quick identification of these 
participants in Phase 1, rapid 
screening and exclusion of these 
participants has been expanded to 
Phase 2, 3a and 3b.  
Section 8.3.1 
Updated sample size of Phase 1/2/3a 
ARCT-154-treated participants to 750 
Updated to align with study plan. 
Section 8.9.3 
Revised to say that DSMB will be 
constituted prior to initiation of Phase 3b 
(previously Phase 3a and Phase 3b) 
Initiation of Phase 3a now moved 
up to be in parallel with Phase 2 
rather than in parallel with Phase 3b 
Appendix 5 
Revised to create several sub-bullets. 
Removed HIV. 
Correction of formatting errors. 
HIV is exclusionary, so no longer 
relevant as an At-Risk condition. 
 
 

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Protocol Amendment 5 
The primary purpose of this amendment to add an additional Cohort (Phase 3c) in which 
participants are randomized to either ARCT-154 or the Astra Zeneca COVID-19 vaccine 
ChAdOx1 nCoV-19. This cohort will compare the two active vaccines for noninferiority based 
on immunogenicity endpoints. This amendment also reduces the period of observation prior to 
Switchover from 6 months to 2 months after the second dose of study vaccine (due to the 
aggressive government roll out of authorized vaccines it has become unethical to keep 
participants on placebo for a prolonged period) and moves the efficacy endpoints for Phase 3b 
from primary to exploratory (the shortened follow-up period prior to Switchover coupled with 
falling COVID-19 rates in Vietnam mean that it is unlikely that sufficient COVID-19 events will 
accrue for statistical analysis of efficacy). In addition to the changes listed below, reference to 
Cohort 3c has been added to multiple sections and this amendment includes administrative 
changes for consistency of language and changes to the Synopsis for consistency with the 
changes to the main body outlined below, as well as correction of minor typographical and 
referencing errors. 
Protocol Amendment 5 (Version 6.0, 28 October 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title pages 
Protocol version and dates updated and 
sponsor name changed from Vinbiocare to 
Vinbiotech 
Sponsor company changed its name 
Figure 1 
Study schematic updated 
Updated to reflect the current study 
design in this amendment. 
Section 3 and subsections 
Objectives and endpoints changed to reflect 
the new study design/objectives and Phase 
3c objectives and endpoints added. A 
combined exploratory safety endpoint 
added that pools data from all phases of 
study 
Updated to reflect study design 
changes. 
Section 4.1 
Number of participants in Phase 3b 
amended and Phase 3c added 
Updated to reflect the current study 
design in this amendment. 
Section 4.4 
Changes made throughout this section to 
reflect new study design 
Updated to reflect the current study 
design in this amendment. 
Section 4.5.2 
Phase 3c added 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3 
Visit schedule amended to move 
Switchover visits to Day 92 and Day 120. 
Telephone visits monthly after Switchover 
for Phase 1/2/3a/3b. Phase 3c schedule 
added 
Updated to reflect the current study 
design in this amendment. 
 
Section 4.5.3.2 
Amended Switchover visit days. Added 
clarifying text on training regarding AEs 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.4 
Added Day 43 visit for Cohort 3c 
 
Updated to reflect the current study 
design in this amendment 

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Protocol Amendment 5 (Version 6.0, 28 October 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 4.5.3.5 
Clarified that Phase 3c paper diaries may be 
collected at Day 57 visit 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.6 
Added Day 211 visit for Cohort 3c 
 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.7 
Updated to reflect revised telephone call 
schedule 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.8 
Clarified the instructions for COVID-19 
testing to include language from Protocol 
Clarification Memo #6 
Clarification of protocol procedures 
Section 4.5.5.2 
Added clarification text for nasal swab 
sampling based on Protocol Clarification 
Memo #2 
Added Phase 3c visits 
Amended timing of Switchover Visits 
Clarification of protocol procedures 
and updates to reflect the current 
study design in this amendment 
Section 4.5.5.4 
Clarified the schedule of full physical 
exams for each cohort 
Clarification of protocol procedures 
 
Section 5.1.2 
Added an exclusion criterion specific to 
participants in Phase 3c 
Updated to reflect the current study 
design in this amendment 
Section 5.2.1 
Added instruction from Protocol 
Clarification Memo # 4for delay in second 
vaccination in the event of an intercurrent 
SARS-CoV-2 infection 
Clarification of protocol procedures 
 
Sections 6.2, 6.3 and 6.4, 
6.4.3, 6.5 
Updated to include Astra Zeneca vaccine  
Updated to reflect the current study 
design in this amendment 
Section 6.5 
Added additional instruction for overdose 
Clarification of protocol procedures 
 
Section 7.2 
Clarified which assays used for antibody 
testing 
Updated to reflect the current study 
design in this amendment 
Section 8 and Subsections 
Major revisions to endpoints and Estimand 
descriptions made to align with new study 
design 
Updated to reflect the current study 
design in this amendment 
 

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Protocol Amendment 5 
The primary purpose of this amendment to add an additional Cohort (Phase 3c) in which 
participants are randomized to either ARCT-154 or the Astra Zeneca COVID-19 vaccine 
ChAdOx1 nCoV-19. This cohort will compare the two active vaccines for noninferiority based 
on immunogenicity endpoints. This amendment also reduces the period of observation prior to 
Switchover from 6 months to 2 months after the second dose of study vaccine (due to the 
aggressive government rollout of authorized vaccines, it has become unethical to keep 
participants on placebo for a prolonged period) and moves the efficacy endpoints for Phase 3b 
from primary to exploratory (the shortened follow-up period prior to Switchover coupled with 
falling COVID-19 rates in Vietnam mean that it is unlikely that sufficient COVID-19 events will 
accrue for statistical analysis of efficacy). In addition to the changes listed below, reference to 
Cohort 3c has been added to multiple sections and this amendment includes administrative 
changes for consistency of language and changes to the Synopsis for consistency with the 
changes to the main body outlined below, as well as correction of minor typographical and 
referencing errors. 
Protocol Amendment 5 (Version 6.0, 28 October 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title pages 
Protocol version and dates updated and 
sponsor name changed from Vinbiocare to 
Vinbiotech 
Sponsor company changed its name 
Figure 1 
Study schematic updated 
Updated to reflect the current study 
design in this amendment. 
Section 3 and subsections 
Objectives and endpoints changed to reflect 
the new study design/objectives and Phase 
3c objectives and endpoints added. A 
combined exploratory safety endpoint 
added that pools data from all phases of 
study 
Updated to reflect study design 
changes. 
Section 4.1 
Number of participants in Phase 3b 
amended and Phase 3c added 
Updated to reflect the current study 
design in this amendment. 
Section 4.4 
Changes made throughout this section to 
reflect new study design 
Updated to reflect the current study 
design in this amendment. 
Section 4.5.2 
Phase 3c added 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3 
Visit schedule amended to move 
Switchover visits to Day 92 and Day 120. 
Telephone visits monthly after Switchover 
for Phase 1/2/3a/3b. Phase 3c schedule 
added 
Updated to reflect the current study 
design in this amendment. 
 
Section 4.5.3.2 
Amended Switchover visit days. Added 
clarifying text on training regarding AEs 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.4 
Added Day 43 visit for Cohort 3c 
 
Updated to reflect the current study 
design in this amendment 

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Section Number 
Description of Change 
Brief Rationale 
Section 4.5.3.5 
Clarified that Phase 3c paper diaries may be 
collected at Day 57 visit 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.6 
Added Day 211 visit for Cohort 3c 
 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.7 
Updated to reflect revised telephone call 
schedule 
Updated to reflect the current study 
design in this amendment 
Section 4.5.3.8 
Clarified the instructions for COVID-19 
testing to include language from Protocol 
Clarification Memo #6 
Clarification of protocol procedures 
Section 4.5.5.2 
Added clarification text for nasal swab 
sampling based on Protocol Clarification 
Memo #2 
Added Phase 3c visits 
Amended timing of Switchover Visits 
Clarification of protocol procedures 
and updates to reflect the current 
study design in this amendment 
Section 4.5.5.4 
Clarified the schedule of full physical 
exams for each cohort 
Clarification of protocol procedures 
 
Section 5.1.2 
Added an exclusion criterion specific to 
participants in Phase 3c 
Updated to reflect the current study 
design in this amendment 
Section 5.2.1 
Added instruction from Protocol 
Clarification Memo # 4for delay in second 
vaccination in the event of an intercurrent 
SARS-CoV-2 infection 
Clarification of protocol procedures 
 
Sections 6.2, 6.3 and 6.4, 
6.4.3, 6.5 
Updated to include Astra Zeneca vaccine  
Updated to reflect the current study 
design in this amendment 
Section 6.5 
Added additional instruction for overdose 
Clarification of protocol procedures 
 
Section 7.2 
Clarified which assays used for antibody 
testing 
Updated to reflect the current study 
design in this amendment 
Section 8 and Subsections 
Major revisions to endpoints and Estimand 
descriptions made to align with new study 
design 
Updated to reflect the current study 
design in this amendment 
 
 

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Protocol Amendment 6 
The primary purpose of this amendment to correct the size of Cohorts Phase 3b and Phase 3c. 
The sample size agreed with the Vietnam Ministry of Health for Phase 3c was 4,000, with 1,500 
to be included for immunogenicity noninferiority endpoints, Protocol Version 6.0 incorrectly 
specified the size of this cohort as 1,500 participants. This error has been corrected by increasing 
the size of Phase 3c and reducing the size of Phase 3b accordingly. The other major change was 
returning the Phase 3b efficacy endpoint from Exploratory to Secondary, which was requested by 
the Ethics Committee (in Protocol Version 6.0 it had been moved from primary to exploratory). 
In addition to the changes listed below, the revised sample sizes for Phase 3b and Phase 3c are 
reflected in multiple sections and this amendment includes administrative changes for 
consistency of language and changes to the Synopsis for consistency with the changes to the 
main body outlined below, as well as correction of minor typographical and referencing errors. 
Protocol Amendment 6 (Version 7.0, 28 October 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title 
Remove “Placebo” in title 
The study control groups are no 
longer limited to placebo and 
include ChAdOx1 vaccine in Phase 
3c. 
Synopsis: Study Design 
and Protocol Section 4.4 
Clarification of primary purpose of each 
phase of study, addition of text plaining the 
study procedures overview. 
To explain the rationale for each of 
the different phases of study 
Synopsis: Study Objectives 
and Protocol Sections 
3.1.3, 3.2.2, and 3.2.2 
Text added to indicate that the exploratory 
objective analyzing COVID-19 
convalescent sera. The immunogenicity 
assessment(s) will be performed on the 
same assay(s) as that is/are used for 
assessing study vaccine immunogenicity. 
To clarify specifications for the 
analysis of the COVID-19 
convalescent sera. 
 
Text added to indicate that COVID-19 cases 
will be analyzed in Phase 1, 2, 3a 
participants as an exploratory objective 
To clarify the handling of COVID-
19 cases as a study objective in 
these phases of the study. 
 
An exploratory immunogenicity objective 
evaluating variants of concern was added 
If assays are available to test 
immune responses against variants 
of concern, testing of vaccinated 
participants may be performed. 
Synopsis:  Statistical 
Considerations 
Sample size calculations for participants in 
Phase 3c-1 and 3c-2 added  
To elaborate on the study’s power 
to evaluate safety data in Phase 3c. 
Figure 1 
Figure updated to add asterisk 
This change maps out the difference 
between Phase 3c-1 and Phase 3c-2 
participants for immunogenicity 
assessments. 
Section 2.8 
Addition of benefits and risks of ChAdOx1 
vaccine added 
This information is relevant to 
participants enrolling into Phase 3c, 
where the Astra Zeneca vaccine will 
be used as a comparator vaccine. 

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Protocol Amendment 6 (Version 7.0, 28 October 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 3.1.3 
Evaluation of sera for antibody responses to 
variants of concern added as an exploratory 
endpoint 
This is required per sponsor 
conversations with Vietnam 
Ministry of Health 
Section 3.2,2 
Vaccine efficacy moved from exploratory 
(Section 3.2) to a secondary endpoint 
Request by Ethics Committee 
Section 4.5.3 
Study visits numbers and types updated for 
each Phase 
Improved protocol comprehension 
Section 4.5.3.8 and Section 
4.5.5.2 
Clarification of wording to allow for home 
testing for COVID-19 if clinically 
appropriate 
Improved protocol compliance 
Section 8.0 
Clarification text added  
Clarification 
Section 8.1 subsections 
Clarification text added to tables 
Clarification 
Section 8.2.2 
Statistic hypothesis for vaccine efficacy 
added 
Vaccine efficacy moved from 
exploratory to secondary endpoint 
Section 8.3.3 
Text describing sensitivity of sample size 
for detection of adverse events in Phase 3c 
added 
Safety is a key endpoint of Phase 3c 
Section 8.6.3 
Formulae corrected and additional formula 
for GMFR added. Additional clarification 
added to text 
Corrections and clarifications 
Section 8.6.5 
Title corrected 
Error correction 
Section 8.6.6  
Section added to describe analysis of Phase 
3b exploratory efficacy endpoints. 
Subsequent sections renumbered 
accordingly 
Additional description of endpoints 
Section 8.8 
Timing of interim analyses further clarified 
Clarification  
Section 11.4 
Text referring to the Code of Federal 
Regulations removed 
These regulations cannot be applied 
outside of the US 

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Protocol Amendment 7 
The primary purpose of this amendment is to add to the design that participants in Phase 2 and 3a 
who received ARCT-154 in the initial vaccination series will be further randomized to receive a 
3rd vaccination of either ARCT-154 or placebo at Day 92 followed by placebo at Day 120 in 
order to compare immunogenicity after 3 injections of ARCT-154 with that after 2 injections. 
Administration of a 3rd dose of ARCT-154 to participants in Phase 2/3a allows the opportunity to 
evaluate the neutralizing antibody of activity of a 3rd (booster) dose of ARCT-154 against 
variants of concern, and in particular the newly identified omicron variant.  Early data indicates 
that neutralizing antibody activity against omicron following two doses of other RNA vaccines 
may be substantially less than against other variant strains, but that activity following a third 
dose is considerably improved.  
In addition, the principal analysis of Efficacy was changed to be performed as a secondary 
analysis in the pooled participant populations from Phase 1/2/3a/3b in order to increase statistical 
power of this analysis. Additionally, enrollment of Phase 3c was terminated at request of 
Vietnam Ministry of Health after enrollment of ~2,400 of the originally planned 4,000 since 
4,000 participants are not needed for assessment of the principal immunogenicity endpoints. 
Therefore, this amendment updates the number of participants in Phase 3c and clarifies that 
Phase 3c immunogenicity assessments will be performed in 800 participants in subgroup 
Phase 3c-1. This amendment also includes administrative changes for consistency of language 
and changes to the Synopsis for consistency with the changes to the main body outlined below, 
as well as correction of minor typographical and referencing errors. 
Protocol Amendment 7 (Version 8.0, 14 December 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Cover page 
Name of sponsor company updated  
Company name change 
Section 1.1 
Study schematic (Figure 1) updated to 
reflect new study design 
Updated to reflect the current study 
design in this amendment 
Section 2.7 
Added rationale for the 3rd dose for cohorts 
2/3a 
Updated to reflect the current study 
design in this amendment 
Section 3.0 and subsections 
Updated objectives and endpoints to reflect 
the new study design 
Wording of other objectives and endpoints 
amended for greater specificity/clarity 
Updated to reflect the current study 
design in this amendment 
Clarification changes 
Section 3.3.2 
Deleted visit at Day 43. Made processing of 
samples at Day 394 optional for Phase 3c-1 
secondary endpoint #6 
The principal noninferiority time 
point is Day 57 and inclusion of a 
visit at Day 43 as well adds 
unnecessary burden to participants. 
The Day 394 time point is not 
critical for the noninferiority 
comparison or characterization of 
long-term immunogenicity as the 
later time point is being evaluated in 
Phase 1/2/3a 

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Protocol Amendment 7 (Version 8.0, 14 December 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 3.4 
Section deleted 
Redundant with the other changes 
made to the objectives and 
endpoints 
Section 4.1 
Updated to reflect number of participants 
enrolled in Phase 3c at time of termination 
of enrollment. Added additional information 
on constitution of 3c-1 and 3c-2. Clarified 
that immunogenicity assessments will be 
performed on 800 participants in 3c-1. 
Updated to reflect the current study 
design in this amendment 
Clarification changes 
Section 4.4 
Updated to include the revised study design 
elements and to include some additional 
clarifications. Clarified that 
immunogenicity assessments will be 
performed on 800 participants in 3c-1. 
Updated to reflect the current study 
design in this amendment  
Clarification changes 
Section 4.5.2 
Updated to include the revised study design 
elements and to include some additional 
clarifications 
Updated to reflect the current study 
design in this amendment  
Clarification changes 
Section 4.5.3 and 
subsections 
Updated to include the revised study design 
elements and to include some additional 
clarifications 
Updated to reflect the current study 
design in this amendment  
Clarification changes 
Section 4.5.3.2 
Reduced the period of post vaccine 
observation at Day 92 and Day 120 from 30 
to 15 minutes to be consistent with 
observation period following other mRNA 
vaccines 
Sufficient safety information has 
been accrued on study to reduce this 
observation period 
Section 4.5.3.4 
Deleted this section as was for Day 43 visit 
which has been removed for cohort 3c-1 
 
Section 4.5.5.1 and 4.5.5.2 
Updated to include the revised study design 
elements. Included some of the original 
Section 4.5.5.1 language under a new 
section 4.5.5.2 for clarity. Renumbering of 
subsequent sections 
Updated to reflect the current study 
design in this amendment  
Clarification changes 
Section 4.5.5.3 
Deleted Day 43 visit for cohort 3c-1 
Updated to reflect the current study 
design in this amendment 
Section 5.1.3 
Section header and section text amended for 
clarity 
Clarification changes 
Section 5.1.5 
Section header and section text amended to 
align with new study design elements 
Updated to reflect the current study 
design in this amendment  
Section 5.2.3 
Removed ‘study vaccine not administered’ 
as a screen fail criterion 
Correction of error 
Section 6.1 
Amended to reflect new study design 
elements 
Updated to reflect the current study 
design in this amendment 
Section 6.8.1 
Amended to reflect new study design 
elements 
Updated to reflect the current study 
design in this amendment 

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Protocol Amendment 7 (Version 8.0, 14 December 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 7.2 
Additional details added on 
immunogenicity assays to be used in each 
stage of study 
Additional detail for clarification 
Section 7.2.1 
Amended level 3 heading of 7.2.1 to a level 
2 heading of 7.3 and subsequent sections 
renumbered 
Correction of error 
Section 8.0 
Text revised to reflect changes in sequence 
of unblinding implemented with this 
amendment  
Updated to reflect the current study 
design in this amendment 
Section 8.1 and 8.4 
Section 8.4 moved up to become section 
8.1. Provided more detailed description of 
the analysis sets 
To place description of the analysis 
sets at the beginning of stats section 
for context, and to add further 
clarifications to this section 
Section 8.2 
Amended to reflect new study design 
elements 
Updated to reflect the current study 
design in this amendment 
Section 8.2.1 
Added seropositivity neutralizing antibody 
(as assessed by sVNT for Phase 1/2/3a/3b 
and MNT for Phase 3c) to the criteria 
defining early infection 
Additional intercurrent event (IcEv5) of 
‘Confounding on-study Medications’ added 
Text in tables amended for better clarity. 
Estimand handling corrected in Table 15 
Further clarification of IcEVs  
Clarification changes and correction 
of errors 
Section 8.3.2 
Removed the requirement for at least 50 
events before statistical testing of vaccine 
efficacy. Moved vaccine efficacy in Phase 
3b to be an exploratory endpoint. 
Due to reduced opportunity to 
collect COVID events brought 
about by changes included in 
protocol version 6.0, the principal 
analysis of efficacy will now be 
performed in an analysis set that 
pools data from Phase 1,2,3a and 3b 
to maximize the number of events 
included in the analysis. 
Section 8.3.3 
Corrected equation for the null hypothesis 
for the primary endpoint and more clearly 
specified the secondary endpoints to be 
tested in a hierarchical fashion. Changed the 
terminology used for the NIM from decimal 
(-0.1) to percentage (-10.0%) 
Correction of error 
Additional information 
Section 8.3.4 
Section added to describe statistical 
hypothesis for the pooled analyses 
Additional information added to 
reflect new study design 
Section 8.4 and subsections 
Additional text added for clarifications 
Clarification 
Section 8.4.4 
Section added to describe sample size 
considerations for the pooled safety analysis 
Updated to include additional 
information relevant to study 
endpoints 

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Protocol Amendment 7 (Version 8.0, 14 December 2021): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 8.5 
Amended Day 15 to Day 29 as no antibody 
testing being performed on Day 15 
Clarification of language 
Correction of errors and 
clarification changes 
Section 8.6.1 and 
subsections 
Additional clarifying text added  
Align with revisions to the 
statistical analyses included in this 
amendment 
Section 8.6.2 
Clarifying text added to Table 16 
Align with revisions to the 
statistical analyses included in this 
amendment 
Section 8.6.3 and 
subsections 
Clarifying text added. Text that was 
repetitive of other sections deleted and 
those sections cross-referenced instead to 
minimize chances of inconsistencies within 
the protocol 
Error in formula for GMFR corrected 
LOD corrected to LLOQ 
Align with revisions to the 
statistical analyses included in this 
amendment 
Correction of errors 
Sections 8.6.4.1, 8.6.5 and 
8.6.6 
Clarifying text added. Text that was 
repetitive of other sections deleted and 
those sections cross-referenced instead to 
minimize chances of inconsistencies within 
the protocol 
Align with revisions to the 
statistical analyses included in this 
amendment 
Section 8.6.7 
Section added to describe to pooled 
assessments 
Align with revisions to the 
statistical analyses included in this 
amendment 
Section 8.6.10 
Section header and section body text 
amended to align with revisions to 
statistical analysis included in this 
amendment 
Align with revisions to the 
statistical analyses included in this 
amendment 
Section 8.8 
Section header and section content 
amended, including addition of level 3 
subheadings, to reflect both primary and 
interim analysis time points 
Due to the complexities of analysis 
time points across all of the cohorts, 
having a section where all analysis 
time points are described aids 
interpretation of the study design 
Appendix 1 
Schedule of assessments amended to reflect 
study design changes and to correct minor 
errors 
Additional information added to 
reflect new study design 
Correction of errors 

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Protocol Amendment 8 
The primary purpose of this amendment is to declare the Phase 3b Efficacy and Safety analyses 
to be the overall primary endpoints for this study. 
In the original version of the protocol (Version 1.0), vaccine efficacy in Phase 3b was the 
primary endpoint of the study. However, with protocol version 6.0, the period of placebo-
controlled observation for collection of COVID events was shortened from 6 months to 2 months 
after last vaccination due to ethical concerns about maintaining participants on placebo for a 
prolonged period.  This change coincided with a sharp reduction in the incidence of COVID in 
the Vietnamese population due to lockdown measures introduced by the Vietnamese 
government. Because of the combined impact of reduced placebo-controlled observation period 
together with reduced incidence of COVID in Vietnam, Sponsor had significant concerns about 
the ability to collect a sufficient number of COVID events to evaluate vaccine efficacy in a 
hypothesis testing fashion. Therefore, with protocol version 6, vaccine efficacy was demoted 
from being the primary endpoint. However, since that time, the incidence of COVID has 
increased substantially in Vietnam and at the time of writing of this amendment, there are over 
400 PCR-confirmed COVID cases undergoing evaluation by the blinded event adjudication 
committee, which is sufficient to exclude 30% vaccine efficacy at lower bound of the 95% 
confidence interval if true vaccine efficacy is ≥50%. Sponsor therefore believes that it is 
appropriate to test vaccine efficacy as the primary endpoint.  
This amendment also includes administrative changes for consistency of language and changes 
to the Synopsis for consistency with the changes to the main body outlined below, as well as 
correction of minor typographical and referencing errors. 
Protocol Amendment 8 (Version 9.0, 07 February 2022): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Title pages and headers 
Updated version number and date 
Align with new version number and 
date 
Throughout the protocol 
Amended ‘Switchover’ to 
‘Switchover/Further Study Vaccine’ 
This is a correction and aligns with 
the design changes introduced in 
protocol version 8.0  
Section 3 
Text added to clarify that the Phase 3b 
primary endpoints are the overall primary 
endpoints for the study, that Phase 1/2/3a 
and Phase 3c are substudies and that no 
adjustment of type 1 error is made as a 
consequence of endpoints evaluated in the 
Phase 1/2/3a or Phase 3c substudies.   
Clarification of endpoints  
Section 3.1 
Made it clear in the title that Phase 1/2/3a is 
a substudy 
Clarification 
Section 3.2 and subsections 
The first Phase 3b secondary efficacy 
endpoint was moved to be the Phase 3b 
efficacy primary endpoint. 
Phase 3b exploratory endpoints promoted to 
secondary endpoints as follows: 
Phase 3b primary analyses are 
declared as the overall primary 
efficacy and safety analyses for the 
study, so original Phase 3b efficacy 
secondary efficacy endpoint 

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Section Number 
Description of Change 
Brief Rationale 
• 2nd and 3rd Phase 3b exploratory 
efficacy endpoints moved to be 1st 
and 3rd Phase 3b secondary 
endpoints 
• 4th Phase 3b exploratory endpoint 
moved to be 4th Phase 3b secondary 
endpoint  
The optional analyses of participants that 
have received any dose of study vaccine in 
the first vaccination series that were 
contained in the Phase 3b exploratory 
efficacy endpoints 1, 2, 3 and 4 remain as 
Phase 3b secondary endpoint 2, and Phase 
3b exploratory endpoints 1, 2 and 3 
Additional exploratory analyses 4 and 5 
added to evaluate efficacy by specific strain, 
to explore the effect of emerging variant 
strains on efficacy. Original exploratory 
endpoint 6 deleted as now replaced by strain 
specific exploratory endpoints 4 and 5 
Original exploratory endpoint 5 becomes 
exploratory endpoint 6 
promoted to a primary efficacy 
endpoint., The Phase 3b exploratory 
efficacy endpoints were also 
promoted to secondary to reflect the 
fact that the Phase3b mITT is now 
the principal cohort for efficacy 
analyses.  
Explore the effect of emerging 
variant strains on efficacy 
Section 3.4 and subsections 
Clarified that Pooled analyses are conducted 
as sensitivity analyses. 
The first pooled secondary efficacy 
endpoint was moved to be the Pooled 
efficacy primary endpoint. 
Pooled exploratory endpoints promoted to 
secondary endpoints as follows: 
• 2nd and 3rd Pooled exploratory 
efficacy endpoints moved to be 1st 
and 3rd Phase 3b secondary 
endpoints 
• 1st Pooled exploratory endpoint 
moved to be 2nd pooled secondary 
endpoint 
• 4th Pooled exploratory endpoint 
moved to be 4th Pooled secondary 
endpoint  
The optional analyses of participants that 
have received any dose of study vaccine in 
the first vaccination series that were 
contained in the Pooled exploratory efficacy 
endpoints 2, 3 and 4 remain as Pooled 
exploratory endpoints 1, 2 and 3 
Additional exploratory analyses 4 and 5 
added to evaluate efficacy by specific strain, 
Changes made to align with the 
Phase 3b efficacy endpoints as the 
pooled efficacy endpoints will be 
evaluated as sensitivity analyses to 
the Phase 3b efficacy analyses 

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Protocol Amendment 8 (Version 9.0, 07 February 2022): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
to explore the effect of emerging variant 
strains on efficacy 
Sections 4.5.3, 4.5.5, 7.1.1 
and Appendix 1 
Clarified that for Phase 1/2/3a/3b, nasal 
swabs for RT-PCR test do not need to be 
performed after Day 92. For Phase 3c, nasal 
swabs should continue to be collected until 
the last study visit (early termination of Day 
394) 
Clarification 
Section 5.1.5 
Amended title to ‘Switchover/Further Study 
Vaccine Eligibility Criteria’ 
More correctly reflects what the 
section applies to 
Section 8.1 
New section added to describe the endpoint 
testing strategy. 
Subsequent sections renumbered 
accordingly 
Clarification of endpoint testing 
strategy 
Section 8.2 
Pooled SAS and RAS amended to only pool 
data from Phases 1, 2, 3a and 3b (ie, 3c 
removed) 
This prevents unblinding of 3c 
participants prior to the final 
analysis of Phase 3c endpoints 
Section 8.3 
Removed language relating to the risk of 
not having sufficient COVID events for 
analysis as at time of this amendment there 
are over 372 cases of symptomatic, PCR 
positive COVID in the EDC. 
Additional clarifications relating to 
evaluations added 
Pooled analyses amended to only pool data 
from Phases 1, 2, 3a and 3b (ie, 3c 
removed) 
Correction 
Align with vaccine efficacy being 
evaluated as primary endpoint 
Prevents unblinding of 3c 
participants prior to the final 
analysis of Phase 3c endpoints 
Section 8.3.1 
Correction of IcEv 3 in Table 14 
Clarified in tables that Phase 1/2/3a and 
Phase 3c are substudies 
Removed evaluation of vaccine efficacy 
based on confirmation antigen tests from 
Table 16 as these were removed from the 
endpoints with Protocol Amendment 7. 
Correction/clarification 
Section 8.4.1 
Made it clear in the title that Phase 1/2/3a is 
a substudy 
Clarification 
Section 8.4.2 
Added more detail to the Phase 3b statistical 
hypotheses as these are now primary 
endpoints 
Align with changes in endpoint 
primacy introduced with this 
amendment 
Section 8.4.3 
Made it clear in the title that Phase 3c is a 
substudy  
Clarification and align with changes 
in endpoint primacy introduced with 
this amendment  

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Protocol Amendment 8 (Version 9.0, 07 February 2022): Summary of Major Changes 
Section Number 
Description of Change 
Brief Rationale 
Section 8.4.4 
Removed detailed description of statistical 
hypothesis for the pooled analyses as these 
are now sensitivity analyses. 
Align with changes in endpoint 
primacy introduced with this 
amendment 
Section 8.5 
Added a description of how overall sample 
size for the study was determined 
Clarification 
Section 8.5.1 
Made it clear in the title that Phase 1/2/3a is 
a substudy 
Clarification 
8.5.2 
Added more detailed description of sample 
size evaluation for Phase 3b 
Align with changes in endpoint 
primacy introduced with this 
amendment 
Section 8.5.3 
Made it clear in the title that Phase 3c is a 
substudy  
Clarification and align with changes 
in endpoint primacy introduced with 
this amendment  
Section 8.5.4 
This section on sample size considerations 
for the pooled analyses was deleted 
Pooled analyses are no longer the 
overall primary endpoints for the 
study 
Section 8.7.1.1 
Made it clear in the title that Phase 1/2/3a is 
a substudy 
Clarification 
Section 8.7.1.2 
Added more description to the Phase 3b 
statistical considerations 
Clarification and align with changes 
in endpoint primacy introduced with 
this amendment 
Section 8.7.1.3 
Made it clear in the title that Phase3c is a 
substudy 
Clarification and align with changes 
in endpoint primacy introduced with 
this amendment 
Section 8.7.2 
Added geometric mean antibody 
concentrations to the analysis method in 
Table 18.  
Clarified that primary efficacy analysis will 
be conducted in Phase 3b mITT 
Efficacy analyses based on antigen test 
removed from Table 18 as these no longer 
being performed as of Protocol Version 8.0 
 
Correction of erroneous omission 
Correction of error 
Align with changes in endpoint 
primacy introduced with this 
amendment 
Section 8.7.3.1 
Made clear in title that Phase 1/2/3a is a 
substudy.  
Correction of error in GMFR equation 
Clarification 
Correction of error 
Section 8.7.3.4 
Added section on Phase 3b primary efficacy 
endpoint 
Align with changes in endpoint 
primacy introduced with this 
amendment 
Section 8.7.4.1 
Made it clear that Phase 1/2/3a and Phase 
3c are substudies 
Clarification 
Section 8.7.4.2 
Section added 
Clarification 

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Section Number 
Description of Change 
Brief Rationale 
Section 8.7.5 
Added additional details on pooled efficacy 
and safety analysis 
Clarification 
Section 8.7.6 
Deleted original Section 8.6.6 as redundant 
with the new section 8.7.4.2 
Deletion of duplication 
Section 8.7.7 
Clarified that efficacy data after Day 92 will 
only be collected for Phase 3c participants 
Clarification 
Section 8.7.8 
Clarified that efficacy data after Day 92 will 
only be collected for Phase 3c participants 
and will be presented up to Day 394. 
Clarification 
Section 8.9.1 
Made it clear in the title that Phase 1/2/3a is 
a substudy. Added further clarification 
concerning timing of the safety analysis 
Clarification 
Section 8.9.2 
Clarified timing of evaluation of Phase 3b 
endpoints 
This change aligns description with 
what is actually happening 
Section 8.9.3 
Made it clear in the title that Phase 3c is a 
substudy 
Clarification 
Appendix 1, Table ‘DAY 
92 TO END OF STUDY 
VISIT FOR PHASE 1, 
PHASE 2, PHASE 3A 
AND PHASE 3B 
PARTICIPANTS’ 
Corrected footnote ‘j’ to clarify the different 
post-dose observation periods for the 3rd 
dose for Phase 1/3b and Phase 2/3a 
participants 
Correction of error