A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate the Safety and Immunogenicity of V590 in Healthy Adults
Phase: PHASE1
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04569786 
Document Date: 
17-Feb-2021
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 
Dose-Ranging Trial to Evaluate the Safety and Immunogenicity of 
V590 in Healthy Adults

PRODUCT: V590  
1
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging 
Trial to Evaluate the Safety and Immunogenicity of V590 in Healthy Adults
Protocol Number: 001-03
Compound Number: V590
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
26583
Approval Date: 17 February 2021
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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17-FEB-2021
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 03
17-FEB-2021
Documentation of early study termination
Amendment 02
23-OCT-2020
Inclusion of safety reviews in Part 1
Amendment 01
17-SEP-2020
Modification of doses
Original Protocol
10-SEP-2020
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [001-03]
Overall Rationale for the Amendments:
Rationale for Amendment 001-03:  An evaluation of available Day 28 immunogenicity data, including both ELISA and PRNT, 
indicated that V590 was not predicted to protect against disease caused by SARS-CoV-2. Based on these data the Sponsor made the 
decision not to enroll further participants in the study, to bring the study to a close, and to discontinue development of intramuscularly 
administered V590. V590 was generally well-tolerated, and the decision to discontinue this trial was based solely on the 
immunogenicity data. This amendment is intended to document the termination of the study as permitted under flexible protocol 
language. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1 Protocol Summary 
1.1 Protocol Synopsis 
Updated Estimated Study Duration section
Updated Duration of Participation section
Modified to reflect planned study conduct.
1.3  Schedule of Activities
Added the following in the schedule 
details Notes section:
Amendment 001-03: Study visits on Days 
90, 180, 270, and 365 will not be 
performed. A poststudy visit/phone call 
will be performed, which may be 
combined with the Day 28 visit. .
Modified to reflect planned study conduct.
2 Introduction
2.1 Study Rationale
Updated background to be current.
Updated to reflect current SARS-CoV-2 epidemiology. 
 
 
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Section # and Name
Description of Change 
Brief Rationale 
3 Hypotheses, Objectives, 
and Endpoints
Updated primary endpoints
Updated secondary endpoints
Modified to reflect planned study conduct.
Modified for flexibility for stool shedding assessment. 
4.1 Overall Design
Added the following:
Amendment 001-03: Enrolled participants 
in all parts will be followed through Day 
28 for safety, tolerability, immunogenicity, 
shedding and viremia. A final study 
analysis will be performed on all available 
data through Day 28, in place of an 
Interim Analysis.  
Modified to reflect planned study conduct.
4.2 Scientific Rationale for 
Study Design
Added Rationale for Amendment 001-03
Provides background and rationale for this amendment.
4.2.1.2 Safety Endpoints
Added the following:
Amendment 001-03: Active monitoring of 
AEs, ECIs, and MAAEs will occur 
through Day 28. Spontaneously reported 
SAEs will be collected per protocol (up to 
365 Days for all SAEs, and indefinitely if 
considered related to intervention). 
Modified to reflect planned study conduct.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
5.3.2.1 Caffeine Restrictions
8 Study Assessments and 
Procedures 
8.3 Safety Assessment 
8.11.4 Poststudy
Deleted “(Day 365)” as it relates to the 
poststudy.
Modified to reflect planned study conduct.
8 Study Assessments and 
Procedures 
Added the following:  
Amendment 001-03: Blood will be 
collected through Day 28.
Modified to reflect planned study conduct.
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE, MAAE and Other 
Reportable Safety Event 
Information
Added the following:
Amendment 001-03: All AEs, ECIs, and 
MAAEs must be reported by the 
investigator up to Day 28. Spontaneously 
reported SAEs will be collected per 
protocol (up to 365 Days for all SAEs, and 
indefinitely if considered related to 
intervention). 
Modified to reflect planned study conduct.
8.11.4 Poststudy
Added the following:
Amendment 001-03: A poststudy 
visit/phone call will be performed for 
safety assessment. This may be combined 
with the Day 28 visit. Active monitoring 
of AEs, ECIs, and MAAEs will occur 
through Day 28. Spontaneously reported 
SAEs will be collected per protocol.  
Modified to reflect planned study conduct.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9 Statistical Analysis Plan
9.1 Statistical Analysis Plan 
Summary
Added the following:
For primary safety endpoint: Amendment 
001-03: MAAEs from Day 1 through Day 
28. SAEs from Day 1 through the duration 
of the study until the final database lock.  
For secondary immunogenicity endpoint: 
Amendment 001-03: Immunogenicity 
analyses will include all available data 
through Day 28. 
Amendment 001-03: Active monitoring 
and immunogenicity assessments in the 
study will occur through Day 28. 
Spontaneous safety reporting is permitted 
beyond Day 28 for the protocol specified 
durations. Immunogenicity analyses will 
include all available data through Day 28. 
Safety analyses will include all collected 
safety data through the duration of the 
study until the final database lock. A final 
analysis of study data will occur instead of 
an interim analysis.
Modified to reflect planned study analysis.
9.4.1 Safety Endpoints
Added the following:
Amendment 001-03: MAAEs from Day 1 
post-dose through Day 28.  SAEs from 
Day 1 through the duration of the study 
until the final database lock.
Modified to reflect planned study analysis.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.4.2 Immunogenicity 
Endpoints
Added the following:
Amendment 001-03: Immunogenicity 
analyses will include all available data 
through Day 28.
Modified to reflect planned study analysis.
9.4.3 Viremia and Viral 
Shedding Endpoints
Added the following:
Amendment 001-03: Viremia and viral 
shedding samples will be assayed with the 
intention of testing until negative for 
viremia/viral shedding. Viremia and viral 
shedding analyses will include all 
available data through Day 28.
Modified to reflect planned study analysis.
9.4.4 Efficacy Endpoints
Added the following:
Amendment 001-03: Efficacy analyses 
will include all available data through Day 
28.
Modified to reflect planned study analysis.
9.6.1 Statistical Methods for 
Safety Analyses
Added the following:
Amendment 001-03: MAAEs from Day 1 
post-dose through Day 28. SAEs from Day 
1 through the duration of the study until 
the final database lock.
Modified to reflect planned study analysis.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.6.2 Statistical Methods of
Immunogenicity Analyses
Added the following:
Amendment 001-03: Immunogenicity 
analyses will include all available data 
through Day 28.
Modified to reflect planned study analysis.
9.6.3 Statistical Methods for 
Viremia and Viral Shedding 
Analyses 
Added the following:
Amendment 001-03: Viremia and viral 
shedding samples will be assayed with the 
intention of testing until negative for 
viremia/viral shedding. Viremia and viral 
shedding analyses will include all 
available data through Day 28.
Modified to reflect planned study analysis.
9.6.4 Statistical Methods for 
Efficacy Analyses
Added the following:
Amendment 001-03: Efficacy analyses 
will include all available data through Day 
28.
Modified to reflect planned study analysis.
9.7 Interim Analyses
Added the following:
Amendment 001-03: Participants in all 
parts will be followed through Day 28 for 
safety, tolerability, immunogenicity, 
viremia and viral shedding. A final study 
analysis will be performed on all available 
data through Day 28, in place of an Interim 
Analysis.
Modified to reflect planned study analysis.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
10.8 Appendix 8: 
Approximate Blood Volume 
Table
Added the following:
Amendment 001-03:  Blood will be 
collected through Day 28.  Study visits on 
Days 90, 180, 270, and 365 will not be 
performed.
Modified to reflect planned study conduct.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities...........................................................................................23
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................33
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................40
4.2.1
Rationale for Endpoints ...............................................................................41
4.2.1.1
Efficacy Endpoints.............................................................................41
4.2.1.2
Safety Endpoints................................................................................42
4.2.1.3
Immunogenicity Endpoints................................................................43
4.2.1.4
Viremia and Viral Shedding Endpoints.............................................43
4.2.1.5
Planned Exploratory Biomarker Research.........................................44
4.2.1.5.1
Planned Genetic Analysis ........................................................44
4.2.1.6
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Placebo .................................................................44
4.3
Justification for Dose...........................................................................................45
4.3.1
Starting Dose for This Study........................................................................45
4.3.2
Maximum Dose/Exposure for This Study ...................................................45
4.3.3
Rationale for Dose Interval and Study Design ............................................45
4.4
Beginning and End of Study Definition .............................................................46
4.4.1
Clinical Criteria for Early Study Termination .............................................46
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................47
5.2
Exclusion Criteria................................................................................................49
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
 
 
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5.3.1.1
Diet Restrictions.................................................................................54
5.3.1.2
Fruit Juice Restrictions ......................................................................54
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................55
5.3.2.1
Caffeine Restrictions..........................................................................55
5.3.2.2
Alcohol Restrictions...........................................................................55
5.3.2.3
Tobacco Restrictions..........................................................................55
5.3.3
Activity Restrictions ....................................................................................55
5.3.4
Blood Donation Restrictions........................................................................55
5.3.5
Contraceptive Requirements........................................................................55
5.4
Screen Failures.....................................................................................................55
5.5
Participant Replacement Strategy......................................................................55
6
STUDY INTERVENTION............................................................................................56
6.1
Study Intervention(s) Administered...................................................................56
6.2
Preparation/Handling/Storage/Accountability .................................................58
6.2.1
Dose Preparation..........................................................................................58
6.2.2
Handling, Storage, and Accountability........................................................58
6.3
Measures to Minimize Bias: Randomization and Blinding..............................59
6.3.1
Intervention Assignment..............................................................................59
6.3.2
Stratification.................................................................................................59
6.3.3
Blinding........................................................................................................60
6.4
Study Intervention Compliance..........................................................................60
6.5
Concomitant Therapy..........................................................................................60
6.5.1
Rescue Medications and Supportive Care ...................................................61
6.6
Stopping Rules......................................................................................................62
6.7
Intervention After the End of the Study............................................................62
6.8
Clinical Supplies Disclosure................................................................................62
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................63
7.1
Discontinuation of Study Intervention...............................................................63
7.2
Participant Withdrawal From the Study...........................................................63
7.3
Lost to Follow-up .................................................................................................63
8
STUDY ASSESSMENTS AND PROCEDURES........................................................63
8.1
Administrative and General Procedures ...........................................................65
8.1.1
Informed Consent.........................................................................................65
8.1.1.1
General Informed Consent.................................................................65
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................65
8.1.2
Inclusion/Exclusion Criteria ........................................................................65
 
 
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8.1.3
Participant Identification Card.....................................................................66
8.1.4
Medical History ...........................................................................................66
8.1.5
Prior and Concomitant Medications Review...............................................66
8.1.5.1
Prior Medications...............................................................................66
8.1.5.2
Concomitant Medications..................................................................66
8.1.6
Assignment of Screening Number...............................................................66
8.1.7
Assignment of Treatment/Randomization Number.....................................66
8.1.8
Study Intervention Administration ..............................................................67
8.1.8.1
Timing of Dose Administration.........................................................67
8.1.9
Discontinuation and Withdrawal .................................................................67
8.1.9.1
Withdrawal From Future Biomedical Research ................................68
8.1.10
Participant Blinding/Unblinding..................................................................68
8.1.11
Domiciling ...................................................................................................69
8.1.12
Calibration of Equipment.............................................................................69
8.2
Immunogenicity and Efficacy Assessments.......................................................69
8.2.1
Neutralizing Antibody .................................................................................69
8.2.2
ELISA Antibody Titers................................................................................70
8.2.3
Anti-Nucleocapsid Antibody Assay (Evidence of Infection) ......................70
8.2.4
SARS-CoV-2 RT-PCR (Evidence of Active Infection) ..............................70
8.2.5
Exploratory Immunogenicity Assays...........................................................70
8.3
Safety Assessments...............................................................................................71
8.3.1
Complete Physical Examinations ................................................................71
8.3.2
Symptom Driven Physical Examinations ....................................................71
8.3.3
Targeted Physical Examinations..................................................................71
8.3.4
Height and Weight .......................................................................................71
8.3.5
Oral Temperature Measurements.................................................................72
8.3.6
Heart Rate, Blood Pressure, Respiratory Rate, and Pulse Oximetry ...........72
8.3.7
Electrocardiograms ......................................................................................73
8.3.8
Vaccine Report Card....................................................................................73
8.3.9
Postvaccination Observation Period (4 Hours)............................................74
8.3.10
Monitoring for SARS-CoV-2 Infection.......................................................74
8.3.11
Clinical Safety Laboratory Assessments .....................................................75
8.4
Adverse Events, Serious Adverse Events, Medically-Attended Adverse 
Events and Other Reportable Safety Events.....................................................75
8.4.1
Time Period and Frequency for Collecting AE, SAE, MAAE, and Other 
Reportable Safety Event Information ..........................................................76
8.4.2
Method of Detecting AEs, SAEs, MAAEs, and Other Reportable Safety 
Events...........................................................................................................78
 
 
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8.4.3
Follow-up of AE, SAE, MAAE, and Other Reportable Safety Event 
Information ..................................................................................................78
8.4.4
Regulatory Reporting Requirements for SAE .............................................78
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................78
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................79
8.4.7
Events of Clinical Interest............................................................................79
8.5
Treatment of Overdose........................................................................................79
8.6
Pharmacokinetics.................................................................................................79
8.7
Pharmacodynamics..............................................................................................79
8.8
Biomarkers ...........................................................................................................79
8.8.1
Planned Genetic Analysis Sample Collection..............................................80
8.9
Future Biomedical Research Sample Collection...............................................80
8.10
Health Economics Medical Resource Utilization and Health Economics.......80
8.11
Visit Requirements...............................................................................................81
8.11.1
Screening......................................................................................................81
8.11.2
Vaccination Visit (Admission, Vaccination, and Postdose)........................81
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........81
8.11.4
Poststudy......................................................................................................81
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......82
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................84
9
STATISTICAL ANALYSIS PLAN .............................................................................85
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses.................................................................................88
9.3
Hypotheses/Estimation ........................................................................................88
9.4
Analysis Endpoints...............................................................................................88
9.4.1
Safety Endpoints..........................................................................................88
9.4.2
Immunogenicity Endpoints..........................................................................89
9.4.3
Viremia and Viral Shedding Endpoints.......................................................90
9.4.4
Efficacy Endpoints.......................................................................................90
9.5
Analysis Populations............................................................................................91
9.5.1
Safety Analysis Populations ........................................................................91
9.5.2
Immunogenicity Analysis Populations ........................................................91
9.5.3
Viremia and Viral Shedding Analysis Populations .....................................92
9.5.4
Efficacy Analysis Population.......................................................................92
9.6
Statistical Methods...............................................................................................92
9.6.1
Statistical Methods for Safety Analyses ......................................................92
 
 
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9.6.2
Statistical Methods for Immunogenicity Analyses......................................95
9.6.3
Statistical Methods for Viremia and Viral Shedding Analyses ...................98
9.6.4
Statistical Methods for Efficacy Analyses...................................................98
9.6.5
Demographic and Baseline Characteristics .................................................99
9.7
Interim Analyses ..................................................................................................99
9.8
Multiplicity .........................................................................................................100
9.9
Sample Size and Power Calculations ...............................................................100
9.9.1
Sample Size and Power for Safety Analyses .............................................100
9.9.2
Sample Size and Power for Immunogenicity Analyses.............................101
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................102
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......102
10.1.1
Code of Conduct for Clinical Trials...........................................................102
10.1.2
Financial Disclosure...................................................................................104
10.1.3
Data Protection...........................................................................................104
10.1.3.1
Confidentiality of Data ....................................................................105
10.1.3.2
Confidentiality of Participant Records.............................................105
10.1.3.3
Confidentiality of IRB/IEC Information..........................................105
10.1.4
Committees Structure.................................................................................106
10.1.4.1
Internal Data Monitoring Committee...............................................106
10.1.5
Publication Policy......................................................................................106
10.1.6
Compliance with Study Registration and Results Posting Requirements .106
10.1.7
Compliance with Law, Audit, and Debarment ..........................................107
10.1.8
Data Quality Assurance .............................................................................107
10.1.9
Source Documents .....................................................................................108
10.1.10
Study and Site Closure...............................................................................108
10.2
Appendix 2: Clinical Laboratory Tests............................................................109
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................111
10.3.1
Definition of AE ........................................................................................111
10.3.2
Definition of SAE ......................................................................................112
10.3.3
Additional Events Reported.......................................................................113
10.3.4
Recording AE, SAE, and MAAE ..............................................................114
10.3.5
Reporting of AEs, SAEs, MAAEs, and Other Reportable Safety Events 
to the Sponsor ............................................................................................121
10.4
Appendix 4: Guidance for Assessment and Work-up of Specific 
Postvaccination Adverse Effects.......................................................................123
10.5
Appendix 5: Contraceptive Guidance..............................................................133
10.5.1
Definitions..................................................................................................133
 
 
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10.5.2
Contraception Requirements......................................................................134
10.5.3
Pregnancy Testing (WOCBP)....................................................................135
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................136
10.7
Appendix 7: Country-specific Requirements..................................................141
10.8
Appendix 8: Approximate Blood Volume Table.............................................142
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................144
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...146
10.11 Appendix 11: Abbreviations .............................................................................147
11
REFERENCES.............................................................................................................151
 
 
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LIST OF TABLES
Table 1
Study Design..............................................................................................22
Table 2
Study Interventions....................................................................................57
Table 3
Sample Allocation Schedule......................................................................59
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................77
Table 5
Site Visit Windows ....................................................................................83
Table 6
Sample Collection Windows......................................................................83
Table 7
Analysis Strategy for Safety Parameters....................................................94
Table 8
Analysis Strategy for Immunogenicity Variables......................................97
Table 9
Protocol-required Safety Laboratory Assessments..................................109
Table 10
Injection-Site AE Toxicity Grading Scale ...............................................115
Table 11
Specific Systemic AE Toxicity Grading Scale........................................116
Table 12
Other Systemic AE Toxicity Grading Scale............................................116
Table 13
Vital Sign (Temperature) Toxicity Grading Scale...................................116
Table 14
Laboratory Abnormalities - Serum..........................................................117
Table 15
Laboratory Abnormalities - Hematology.................................................118
Table 16
Laboratory Abnormalities - Urine ...........................................................119
 
 
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LIST OF FIGURES
Figure 1
Study Schematic.........................................................................................38
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging 
Trial to Evaluate the Safety and Immunogenicity of V590 in Healthy Adults
Short Title: Phase 1 Dose Ranging Trial to Assess Safety and Immunogenicity of V590 in 
Healthy Adults
Acronym:
Hypotheses, Objectives, and Endpoints:
Primary Objectives
Primary Endpoints
All Parts:
- To assess the safety and tolerability of 
V590 versus placebo
- Solicited injection site AEs from Day 1 
through Day 5 after study intervention
- Solicited systemic AEs from Day 1 
through Day 28 after study intervention
- Unsolicited AEs from Day 1 through Day 
28 after study intervention
- Medically attended AEs (MAAEs) 
collected from Day 1 through Day 180 
after study intervention 
- SAEs collected from Day 1 through Day 
365 after study intervention 
Amendment 001-03: AEs/MAAEs/SAEs
collected through at least Day 28.
Spontaneous reporting of SAEs after Day 
28 will be recorded through Day 365 for 
unrelated SAEs and indefinitely for SAEs 
considered related to study intervention.
Parts 1 and 2 only:
- To assess the immunogenicity of V590 on 
Day 28
- Hypothesis: At least one well-tolerated dose 
of V590 increases the GMTs of Anti-SARS-
CoV-2 spike serum neutralizing antibody, as 
measured by PRNT, compared to placebo. 
- Anti-SARS-CoV-2 spike serum 
neutralizing antibody responses, as 
measured by plaque reduction 
neutralization test (PRNT), at Day 28
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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17-FEB-2021
Secondary Objectives
Secondary Endpoints
Parts 1 and 2 only:
- To assess the immunogenicity of V590 
using assays to measure immune responses
- Anti-SARS-CoV-2 spike serum 
neutralizing antibody responses, as 
measured by PRNT (all timepoints except 
Day 28)
- Anti-SARS-CoV-2 spike IgG responses, 
as measured by ELISA 
All Parts:
- To assess V590 viral shedding and viremia
- V590 plasma viremia, as measured by 
RT-PCR 
- V590 viral shedding in saliva, urine, and 
stool (if assayed), as measured by RT-PCR
Overall Design:
Study Phase
Phase 1
Primary Purpose
Prevention
Indication
Prevention of COVID-19
Population
Healthy adult participants
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participant
Investigator
Monitor
Estimated Duration of 
Study
The Sponsor estimates that the study will require approximately
13 months from the time the first participant provides 
documented informed consent until the last participant’s last 
study-related contact.
Amendment 001-03: Study duration will be approximately 3.5 
months.
 
 
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PRODUCT: V590  
21
PROTOCOL/AMENDMENT NO.: 001-03 
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17-FEB-2021
Number of Participants:
Approximately 252 participants will be allocated/randomized.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admini-
stration
Vaccination 
Regimen
Use
Part 1 (18 to 54 years old SARS-CoV-2 seronegative)
Panel A
V590
5.00·105 pfu
Single 
Dose
IM
Single IM 
injection on 
Day 1
Experimental 
Treatment
Panel B
V590
2.40·106 pfu
Panel C
V590
1.15·107 pfu
Panel D
V590
5.55·107 pfu
Panels A-D
Placebo
NA
Placebo
Part 2 (≥ 55 years old SARS-CoV-2 seronegative)
Panel E
V590
5.00·105 pfu
Single 
Dose
IM
Single IM 
injection on 
Day 1
Experimental 
Treatment
Panel F
V590
2.40·106 pfu
Panel G
V590
1.15·107 pfu
Panel H
V590
5.55·107 pfu
Panels E-H
Placebo
NA
Placebo
Part 3 (18 to 54 years old SARS-CoV-2 seropositive)
Panel I
V590
5.55·107 pfu
Single 
Dose
IM
Single IM 
injection on 
Day 1
Experimental 
Treatment
Panel I
Placebo
NA
Placebo
Abbreviations: IM: intramuscular
Total 
Number of 
Intervention 
Groups/ 
Arms
252 participants (112 participants in Part 1, 112 participants in Part 2, and 
28 participants in Part 3) will participate in the study that will include a 
total of 4 dose-levels and 9 Panels.
Duration of 
Participation
Each participant will participate in the study for approximately 13 months 
from the time the participant provides documented informed consent
through the final contact.  Each participant will be receiving a single dose 
of study intervention on Day 1. After administration of the study 
intervention, each participant will be followed for 12 months.
Amendment 001-03: Participants will be followed for a minimum of 
approximately 28 days after study intervention.
 
 
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PRODUCT: V590  
22
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 11.
1.2
Schema
The study design is depicted in Table 1.
Table 1
Study Design
Part 1 (18 to 54 years old SARS-CoV-2 seronegative) a, b, c
Panel A
(n = 28)
Panel B
(n = 28)
Panel C
(n = 28)
Panel D
(n = 28)
V590 5.00·105 pfu
or pbo
V590 2.40·106 pfu
or pbo
V590 1.15·107 pfu
or pbo
V590 5.55·107 pfu
or pbo
Part 2 (≥ 55 years old SARS-CoV-2 seronegative) a, b, c
Panel E
(n = 28)
Panel F
(n = 28)
Panel G
(n = 28)
Panel H
(n = 28)
V590 5.00·105 pfu
or pbo
V590 2.40·106 pfu
or pbo
V590 1.15·107 pfu
or pbo
V590 5.55·107 pfu
or pbo
Part 3 (18 to 54 years old SARS-CoV-2 seropositive) a, c
Panel I
(n = 28)
V590 5.55·107 pfu
or pbo
a.
Within each panel of Parts 1, 2, and 3, participants will be randomized to receive V590 or matching Placebo in a 3:1 
ratio according to a computer-generated, permuted-block allocation schedule (i.e., in each panel 21 participants to 
receive V590 and 7 participants to receive matching placebo).
b.
Within Part 1, safety data through Day 7 must be reviewed for at least 6 participants prior to administration of the next 
higher dose level. At least 6 participants from an equal or greater dose level in Part 1 must be dosed with either V590 or 
placebo and safety reviewed through Day 7 prior to dosing in Parts 2 or 3.
c.
The suggested doses may be adjusted downward based on evaluation of safety and tolerability data observed from a 
subset of participants in previous Parts or based upon emerging preclinical data. Part 3 may initiate in parallel with 
Part 2 Panel H. Refer to Section 6.6 (Dose Modification) for the safety data that will be reviewed prior to dosing in 
Parts 2 and 3.
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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17-FEB-2021
1.3
Schedule of Activities
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Administrative Procedures
Informed Consent
X
Sections 8.1.1.1 and 8.11.1
Separate Screening protocol and 
informed consent form may be 
utilized in advance of main 
consent availability to perform 
assessments at Screening.  In this 
event, the main informed consent 
should be obtained on or before
Days -3 to -1. 
Informed Consent for Future 
Biomedical Research
X
Section 8.1.1.2
Participant Identification Card
X
Section 8.1.3
Inclusion/Exclusion Criteria
X
X
Section 5.0
Prior to admission on Days -3 to -
1 and Day 1 randomization, 
confirm participant still meets all 
eligibility criteria (except 
laboratory assessment, which will 
be based on screening)
Medical History
X
X
Section 8.1.4
 
 
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PRODUCT: V590  
24
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
Sections 6.5, 8.1.5 
Including Non-study Vaccination 
Review
Assignment of Screening 
Numbers
X
Section 8.1.6
Assignment of Randomization 
Number
X
Sections 5.5 and 8.1.7
Domiciling (including meals)
  X--------------------------------------------------X
Section 8.1.11
The first day of admission is 
flexible and may be between Days 
-3 and -1 based upon the time 
required to obtain SARS-CoV-2 
testing results to confirm 
eligibility.
Clinical Procedures/ Safety 
Assessment
Full physical examination
X
X
Section 8.3.1
Day 1 predose will be done within 
24 hours prior to dosing.
Symptoms driven physical 
exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.2
Only to be conducted if participant
symptoms warrant an exam or at 
investigator’s discretion.
 
 
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PRODUCT: V590  
25
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Targeted physical examination 
of injection site
X
X
X
X
X
Section 8.3.3
Day 1 (post-dose) exam should 
occur ~ 1-2 hours postdose.
Height
X
Section 8.3.4
Weight
X
Section 8.3.4
Semi-recumbent Vital Signs
(Blood Pressure [BP] and Heart 
Rate [HR] and Respiratory 
Rate [RR] and pulse oximetry 
[SaO2])
X
X
X
X
X
X
X
X
X
Section 8.3.6
All measurements of HR and BP 
will be preceded by at least 10 
minutes of quiet semi-recumbent 
rest.
Days 1 predose measurements will 
be done within ~3 hours of dosing. 
Day 1: Post-dose measurements 
will be taken approximately 2 and 
4 hours after vaccination. Days 2 
to 7 measurements will be taken 
around the same time as Day 1 
dosing. 
 
 
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PRODUCT: V590  
26
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Body Temperature
X
X
X
X-------------------------------------------X
Section 8.3.5 and Section 8.3.8
While domiciled, clinic staff will 
observe the participant 
temperature measurement at 
Screening, Day -3 to Day-1, Day 1 
predose and 2-hour postdose to 
done by clinic staff.
Day 1 (4-hour postdose) and daily 
Days 2-28 temperatures are done 
and noted on the VRC by the 
participant.
12-lead ECG
X
X
Section 8.3.7
Predose ECG will be done within 
24 hours of dosing. Postdose ECG 
may be done at the investigator 
discretion (e.g., to further assess 
new symptoms, VS, or PE 
findings).
 
 
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PRODUCT: V590  
27
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Paper Vaccination Report Card 
(VRC)
X-----------------------------------------------------X
Section 8.3.8 
Paper VRC will be provided on 
Day 1.  On the VRC, the 
participant records information, 
including solicited and unsolicited 
(local and systemic) AEs, 
temperature, medications, and 
other complaints.
Review Paper VRC Data with 
Participant
X
X
X
X
X
X
X
X
X
Section 8.3.8
Collect Paper VRC From 
Participant
X
Section 8.3.8
V590/Placebo Administration
X
Section 8.1.8
Postvaccination Observation 
Period
X
Section 8.3.9
Participants will be observed for
~4 hours postdose on Day 1.
AE/ECI Review
X--------------------------------------------X
Sections 8.4 and 10.3
MAAE Review
X-------------------------------------------------------X
Sections 8.4 and 10.3
 
 
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PRODUCT: V590  
28
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
SAE review
X---------------------------------------------------------------------X
Sections 8.4 and 10.3 
Nonserious AEs and ECIs are to 
be reported from Days 1 through 
28 following vaccination. SAEs 
and deaths are to be reported 
throughout the duration of an 
individual’s study participation.
Laboratory Procedures/
Assessments
Serum for VSV Antibodies
X
Test will be read at the central 
laboratory.  Test results not 
required for dosing.
Serum β-hCG or urine 
pregnancy test (WOCBP only)
X
X
X
Sections 10.2 and 10.5.3
Serum FSH – (WONCBP only)
X
Section 10.2 
Confirmatory for WONCP who 
are postmenopausal or 
oophorectomized.
HIV, hepatitis B and C screen 
(per site SOP)
X
Section 10.2 
UDS/BDS (per site SOP)
X
X
Any additional UDS/BDS are 
conducted per site SOP
Hematology / Chemistry / 
Coagulation
X
X
X
X
X
 
 
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PRODUCT: V590  
29
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Urinalysis
X
X
X
X
X
Screening and SARS-CoV-2 
Tests
Swab for SARS-CoV-2 Virus 
by RT-PCR
X
X
Screening and Admission (Days -
3 to -1) tests will be done with the 
Abbott RealTime SARS-CoV-2 
test, supplied by and read at the 
central laboratory.
Alternate tests for active SARS-
CoV-2 (including nasal/oral swabs 
in place of nasopharyngeal swabs, 
and/or antigen tests) at both 
Screening and Admission (Days -
3 to -1) may be permitted with 
agreement by the Sponsor.  
Additional testing may be 
performed based on participant 
symptoms and/or SARS-CoV-2 
exposures, as described in 
Sections 4.2.1.1 and 8.3.10.
Additional testing may be done at 
the discretion of the investigator 
and per site SOP. 
 
 
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PRODUCT: V590  
30
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Serum for Anti-SARS-CoV-2 
Nucleocapsid Antibodies
X
X
X
X
X
X
X
X
X
Tests at all timepoints will be 
done with the Roche Elecsys Anti-
SARS-CoV-2 test, supplied by 
and measured at the central 
laboratory. 
Alternate tests during the Days -3 
to -1 assessment, including anti-
spike antibody tests, may be 
permissible with agreement from 
the Sponsor. 
Post-vaccination samples are only 
collected for Parts 1 and 2 (not 
Part 3).
Immunogenicity and 
Shedding
Serum for Anti-SARS-CoV-2 
Spike Neutralizing Antibodies 
(PRNT)
X
X
X
X
X
X
X
X
Leftover main study serum will be 
stored for FBR.
Serum for Anti-SARS-CoV-2 
Spike IgG (ELISA)
X
X
X
X
X
X
X
X
Leftover main study serum will be 
stored for FBR.
 
 
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PRODUCT: V590  
31
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Plasma for V590 Viremia
X
X
X
X
X
X
X
X
X
Day 1 postdose will be done at ~6 
hours. Other days will be done at 
approximately the same time of 
day as the Day 1 dosing. Leftover 
main study plasma will be stored 
for FBR.
Saliva for V590 Shedding
X
X
X
X
X
X
X
X
X
Day 1 postdose will be done at ~6 
hours. Other days will be done at 
approximately the same time of 
day as the Day 1 dosing. 
Leftover main study saliva will be 
stored for FBR.
Urine for V590 Shedding
X
X
X
X
X
X
X
X
X
Day 1 postdose will be done at ~6 
hours. Other days will be done at 
approximately the same time of 
day as the Day 1 dosing.
Leftover main study urine will be 
stored for FBR.
Stool for V590 Shedding
-----X-----
------X------
Total of 2 stool samples collected 
if produced: one sample on Days 2 
to 4; one sample on Days 5 to 7.
Leftover main study stool will be 
stored for FBR.
 
 
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PRODUCT: V590  
32
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
All Parts/Panels
Study Period:
Screening Study Day
Study Day
Post-
study Notes
Scheduled Hour, Day, Week, 
etc.
Screening
Days 
-3 to -1
Day 
1 
Pre-
dose
1
2
3
4
5
6
7
14
28
90 180 270
365
Section 8.11.5
Details on variance in procedure 
collection times.
Amendment 001-03: Study visits 
on Days 90, 180, 270, and 365 
will not be performed. A 
poststudy visit/phone call will be 
performed, which may be 
combined with the Day 28 visit. 
Serum for Cytokines 
X
X
X
Day 1 postdose will be done at ~6 
hours. Tests at all timepoints will 
be done with a kit to be supplied 
by and measured at the central 
laboratory.
Biomarkers
Blood for Genetic Analysis 
X
Collect predose from enrolled 
participants only. See section 
8.8.1.
Blood (RNA) for Future 
Biomedical Research 
X
X
X
Collect predose from enrolled 
participants only.
Blood for PBMCs and Plasma 
for Future Biomedical 
Research
X
X
PBMCs and plasma will be taken 
at selected sites only.
Serum for Future Biomedical 
Research
X
X
X
X
X
X
X
X
Mucosal Samples for Future 
Biomedical Research 
X
X
X
X
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; ELISA= enzyme-linked immunosorbent assay; FBR=future biomedical research; 
FSH=follicle stimulating hormone; ID=identification; MAAE=medically attended adverse event, SAE=serious adverse event; SOP=standard operating procedure; UDS=Urine 
Drug Screen; PRNT=plaque reduction neutralization test; PBMC=peripheral blood mononuclear cells
 
 
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PRODUCT: V590  
33
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
2
INTRODUCTION
2.1
Study Rationale
SARS-CoV-2 is the virus responsible for the ongoing global COVID-19 pandemic with over 
106 million confirmed cases and 2.3 million deaths as of February 2021
(https://coronavirus.jhu.edu/map.html). There is a pressing global need for safe and effective 
vaccines. V590 is a live recombinant viral vaccine against SARS-CoV-2 that is based upon 
the same platform as ERVEBO, a licensed vaccine against Zaire Ebola virus.
This study is a placebo-controlled dose-ranging trial to evaluate the safety and 
immunogenicity of V590 in healthy younger and older seronegative adults and will 
additionally include a single dose level panel of seropositive younger adults. The primary 
objectives will be safety and tolerability, as well as neutralizing antibodies as measured by 
plaque reduction neutralization test (PRNT) at Day 28. Secondary and Exploratory objectives 
will include vaccine viremia and shedding, anti-Spike antibodies measured by ELISA and 
other immunogenicity endpoints, and serologic evidence of SARS-CoV-2 infection. 
2.2
Background
Refer to the IB for detailed background information on V590.
2.2.1
Pharmaceutical and Therapeutic Background
V590 is a live recombinant viral vaccine consisting of a vesicular stomatitis virus (VSV) in 
which the gene for the VSV envelope glycoprotein (G) has been deleted and replaced with 
coding sequence for the spike glycoprotein of the coronavirus SARS-CoV-2.
This recombinant VSV-vectored replication competent chimeric virus platform technology 
enables delivery of native glycoprotein immunogens in the context of a VSV vaccine 
infection.  VSV-vectored live chimeric virus vaccines exchange the VSV G gene (VSVΔG 
vectors or chimeras) with sequence encoding heterologous glycoproteins from other 
pathogens. The VSV∆G chimera avoids the potential negative associations with the VSV 
glycoprotein including the strong anti-G humoral response and neurotropism in animal 
models.  Benefits of the platform include: 1) fast production of high titers and propagation in 
almost all mammalian cells; 2) lack of reassortment and corresponding potential to undergo 
genetic shift in vivo; 3) inability of the vector’s viral RNA to integrate into the host genome;
4) simple genetic modification with the possibility to accommodate one or multiple antigenic 
inserts; 5) the low anti-VSV seroprevalence in the human population; 6) mild pathogenicity 
in humans; 7) induction of innate, humoral and cellular immune responses irrespective of 
VSV seropositivity [Clarke, D. K., et al 2016].
Preclinical vaccines based on the VSVΔG platform have been developed for diseases 
resulting from coronavirus infection including the 2002 Severe Acute Respiratory Syndrome 
(SARS) agent and Middle Eastern Respiratory Syndrome (MERS) [Kapadia, S. U., et al 
2005] [Kapadia, S. U., et al 2008] [Liu, R., et al 2018]. These SARS and MERS constructs, 
 
 
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PRODUCT: V590  
36
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Objectives
Endpoints
Primary
All Parts:
•
To assess the safety and tolerability 
of V590 versus placebo
•
Solicited injection site AEs from Day 1 
through Day 5 after study intervention
•
Solicited systemic AEs from Day 1 through 
Day 28 after study intervention
•
Unsolicited AEs from Day 1 through Day 28
after study intervention
•
Medically attended AEs (MAAEs) collected 
from Day 1 through Day 180 after study 
intervention
•
SAEs collected from Day 1 through Day 365 
after study intervention
•
Amendment 001-03: AEs/MAAEs/SAEs
collected through at least Day 28.
Spontaneous reporting of SAEs after Day 28
will be recorded through Day 365 for 
unrelated SAEs and indefinitely for SAEs 
considered related to study intervention.
Parts 1 and 2 only:
•
To assess the immunogenicity of 
V590 on Day 28
•
Hypothesis: At least one well-
tolerated dose of V590 
increases the GMTs of Anti-
SARS-CoV-2 spike serum 
neutralizing antibody, as 
measured by PRNT, compared 
to placebo. 
•
Anti-SARS-CoV-2 spike serum neutralizing 
antibody responses, as measured by plaque 
reduction neutralization test (PRNT), at Day 
28
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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Objectives
Endpoints
Secondary
Parts 1 and 2 only:
•
To assess the immunogenicity of 
V590 using assays to measure 
immune responses
•
Anti-SARS-CoV-2 spike serum neutralizing 
antibody responses, as measured by PRNT
(all timepoints except Day 28)
•
Anti-SARS-CoV-2 spike IgG responses, as 
measured by ELISA
All Parts:
•
To assess V590 viral shedding and 
viremia
•
V590 plasma viremia, as measured by RT-
PCR
•
V590 viral shedding in saliva, urine, and 
stool (if assayed), as measured by RT-PCR
Exploratory
Parts 1 and 2 only:
•
To characterize SARS-CoV-2 
seroconversion rates among 
participants
•
Serum anti-SARS-CoV-2 nucleocapsid 
antibodies
Part 3 only:
•
To assess the immunogenicity of 
V590 in seropositive subjects using
assays to measure immune
responses
•
Anti-SARS-CoV-2 spike serum neutralizing 
antibody responses, as measured by PRNT
•
Anti-SARS-CoV-2 spike IgG responses, as 
measured by ELISA
All Parts:
•
To characterize the immune 
response from participants 
vaccinated with V590 or placebo
•
Enzyme-linked immunospot assay 
(ELISPOT) and intracellular cytokine 
staining (ICS) of peripheral blood 
mononuclear cells (PBMCs)
•
Anti-SARS-CoV-2 spike antibodies in 
mucosal samples
•
Serum cytokines/chemokines 
 
 
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PRODUCT: V590  
38
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
Objectives
Endpoints
All Pa rts:
•
To characterize the incidence of 
SARS-CoV-2 infection among 
participants
•
SARS-CoV-2 infection as assessed by PCR
in participants with either symptoms 
potentially consistent with COVID-19 or 
with potential exposures to SARS-CoV-2
All Parts:
•
To explore the relationship between 
genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation 
across the human genome may be 
analyzed for association with 
clinical data collected in the study.
•
Germline genetic variation and association 
to clinical data collected in this study.
4
STUDY DESIGN
4.1
Overall Design
Figure 1
Study Schematic
In this 3-part dose-ranging trial, in Part 1 doses will be ranged in a rolling fashion starting from the lowest dose. 
The arrows indicate review of safety data through Day 7 from n ≥ 6 participants prior to initiation of 
administration of that dose level in Part 2 or 3. There will additionally be a review of safety data from n ≥ 6
participants through Day 7 before initiating dosing of higher dose levels in Part 1. The study design is described 
in detail in the protocol text. 
 
 
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PRODUCT: V590  
39
PROTOCOL/AMENDMENT NO.: 001-03 
V590-001-03 FINAL PROTOCOL
17-FEB-2021
This is a randomized, placebo-controlled, three-part, multi-site, double-blind dose-ranging 
study of V590 in healthy younger and older adult participants to be conducted in 
conformance with Good Clinical Practice. In Parts 1 and 2 (younger and older SARS-CoV-2 
seronegative participants, respectively), four dose levels of V590 will be administered: 
5.00·105 pfu/PBO, 2.40·106 pfu/PBO, 1.15·107 pfu/PBO and 5.55·107 pfu/PBO. Dose-
ranging in Parts 1 and 2 will initiate with the lowest dose level and will be followed by 
administration of the next higher dose level in a rolling fashion. In Part 1 initiation of dosing 
of Panels B, C, and D will follow review of blinded safety data through Day 7 for at least six
participants from the prior panel by the Sponsor safety review team (described further 
below). Higher dose levels may be administered before completion of dosing of lower levels.
Part 2 entails dosing of older participants; 7 days of blinded safety data from at least six 
participants from an equal or higher dose level from the younger participants in Part 1 will be 
reviewed by the Sponsor safety review team (described further below) prior to administration 
in Part 2. Clinical conduct of Parts 1 and 2 may run concurrently provided the formal reviews
of safety data have been performed before initiation of dosing Panels B, C, and D and before
dosing each dose level to the older participants. Part 3 is comprised of SARS-CoV-2 
seropositive participants who will receive a single dose level of 5.55·107 pfu/PBO and may 
start concurrently to the same dose level in Part 2.
In Part 1, approximately 112 seronegative healthy young participants (age 18-54 years
inclusive) will be enrolled. Twenty-eight (28) participants will be randomized in each dose 
level to receive a single IM dose of V590 or placebo in a 3:1 ratio. Dosing of each 
subsequent panels at a higher dose will occur after the Sponsor safety review team (as 
described immediately below) evaluates safety data through Day 7 for at least six participants
from the preceding panel.
In Part 2, approximately 112 seronegative healthy older participants (age ≥ 55 years) will be 
enrolled. Twenty-eight (28) participants will be randomized in each dose level to receive a
single IM dose of V590 or placebo in a 3:1 ratio. Prior to dosing each dose level in Part 2, the 
Sponsor safety review team will evaluate blinded data through Day 7 for at least six 
participants from the corresponding dose level in Part 1. The Sponsor safety review team will 
evaluate these data at formal meetings, and this team consists of a Therapeutic Area Head 
and/or Department Vice President, a Clinical Director, Clinical Scientist(s), Biostatistician, 
as well as input from the Investigator(s). Available blinded safety data from lower doses 
from both Parts 1 and 2 will also be evaluated.   
In Part 3, approximately 28 seropositive healthy participants (age 18-54 years inclusive) will 
be enrolled and randomized to receive a single IM dose (5.55·107 pfu/PBO) of V590 or 
placebo in a 3:1 ratio. Part 3 may initiate based upon review of seven days of safety data 
from n ≥6 participants at this dose level in Part 1 by the Sponsor safety review team (as 
described immediately above) and may initiate simultaneously to administration of this dose 
level in Part 2.
In all parts participants will be domiciled for 7 days from vaccination to facilitate close 
monitoring and specimen acquisition. Participants will have visits as outlined in the SoA over 
the following 12 months to monitor safety and to obtain samples for immunogenicity 
assessments. An Interim Analysis will be performed on safety through at least Day 28 as 
 
 
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well as PRNT and IgG ELISA immunogenicity from Day 1 Predose and Day 28 
postvaccination for participants from Parts 1 and 2, as well as the available data from Part 3 
(Part 3 is not required for this interim analysis, but available data will be included). Upon 
completion of Day 28 by enrolled participants in Parts 1 and 2, analyses will be performed to 
summarize the safety and immunogenicity data in order to inform potential subsequent 
clinical studies.
An siDMC will evaluate safety data and immunogenicity for the Day 28 Interim Analysis 
and will additionally be convened to evaluate available data if stopping rules are met. The 
siDMC is a standing, internal Sponsor committee established to monitor clinical studies. 
Additional details are provided in Section 10.1.4.1 and in the siDMC Charter.
Triggering of Parts 2 and 3 dosing will be based on the Sponsor safety review team’s 
assessment of blinded safety data. 
Because this is a Phase 1 assessment of V590 in humans, the viral dynamics,
immunogenicity, and safety profile of the vaccine are still being elucidated. This protocol is 
therefore written with flexibility to accommodate the inherent dynamic nature of Phase 1 
clinical studies. Refer to Section 8.11.6 for examples of modifications permitted within the 
protocol parameters.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
Amendment 001-03: Enrolled participants in all parts will be followed through Day 28 for 
safety, tolerability, immunogenicity, shedding and viremia. A final study analysis will be 
performed on all available data through Day 28, in place of an Interim Analysis.
4.2
Scientific Rationale for Study Design
This study is being conducted to evaluate the safety, tolerability and immunogenicity in 
healthy younger (18-54 years of age) and older (55 and older) SARS-CoV-2 seronegative 
participants, and in healthy younger (18-54 years of age) seropositive participants. 
This study is designed to ensure participant safety while permitting efficient study conduct in 
the setting of a global pandemic. This accelerated design is supported by past clinical and 
preclinical experience with ERVEBO, which shares a platform technology with V590, as 
well as preclinical data for V590. For each dose level younger participants will be dosed first 
with safety evaluated up to Day 7 before administration of that dose level to older 
participants in Part 2. This is designed to minimize risk to older participants in the context of 
a replication competent chimeric virus, while efficiently obtaining immunogenicity data in 
this older population which is at greatest risk for severe COVID-19 disease. Within Part 1
safety data from at least six individuals through Day 7 from the preceding dose level will be
reviewed prior to administration of the next higher dose level.
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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Parts 1 and 2 will provide safety data for seronegative individuals and will inform on 
immunogenicity of V590. Part 3 will assess safety and immunogenicity in seropositive 
individuals to inform on whether prior exposure to the SARS-CoV-2 spike protein, the 
common antigen shared between V590 and SARS-CoV-2, results in a different safety or 
tolerability profile. 
Clinical conduct will occur in individuals who are not considered to be at high risk for severe 
SARS-CoV-2 disease, with the exception those considered at high risk based solely on age 
(as it is critical to assess immunogenicity in this population). Exclusion criteria are based on 
CDC guidance regarding those at high risk for disease 
(https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-
risk.html) and are further informed by available literature [Petrilli, C. M., et al 2020] 
[Docherty, A. B., et al 2020]. Such risk factors for severe disease include chronic obstructive 
pulmonary disease, immunocompromised state, serious heart conditions (such as heart 
failure, coronary artery disease, cardiomyopathies, and pulmonary hypertension), sickle cell 
disease, obesity and type 2 diabetes mellitus.
Overall, this study aims to obtain safety, tolerability and immunogenicity from a broad age 
range of healthy participants in order to facilitate development of this vaccine.
Rationale for Amendment 001-03: The evaluation of available Day 28 immunogenicity 
data, including both ELISA and PRNT, indicated that V590 was not predicted to protect 
against disease caused by SARS-CoV-2. Based on these data the Sponsor made the decision 
not to enroll further participants in the study, to bring the study to a close, and to discontinue 
development of intramuscularly administered V590. V590 was generally well-tolerated, and 
the decision to discontinue development was based solely on the immunogenicity data. This 
amendment is intended to document the termination of the study as permitted under flexible 
protocol language. Participants will complete activities through Day 28, which includes all 
protocol specified safety laboratory and routine AE assessments. Spontaneous reporting of 
SAEs and other protocol-specified events may continue through the protocol specified 
durations (one year for all SAEs, indefinitely for SAEs considered related to intervention).  
In place of an Interim Analysis of data through Day 28, the final study analysis will be 
performed on the collected dataset through Day 28.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study includes two exploratory efficacy endpoints.
Seroconversion to the SARS-CoV-2 nucleocapsid antigen, a SARS-CoV-2 antigen that is not 
present in V590, will be assessed through 12 months post-vaccination in order to determine 
the rate of SARS-CoV-2 infection (irrespective of symptoms and occurrence of clinical 
COVID-19 disease). 
Additionally, participants with either symptoms potentially consistent with COVID-19, or 
with potential exposures to SARS-CoV-2 (defined by having close contacts with testing 
 
 
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PRODUCT: V590  
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PROTOCOL/AMENDMENT NO.: 001-03 
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17-FEB-2021
positive for acute SARS-CoV-2 [i.e. not an antibody test]), will be tested for SARS-CoV-2 
by RT-PCR. This endpoint will assess the incidence of acute SARS-CoV-2 infection in 
participants during the study.  
As the epidemiology of SARS-CoV-2 is both highly dynamic and geographically 
heterogeneous, it is not possible to make predictions of infection rates during study conduct. 
Given the small sample size it is unlikely that the study will provide sufficient data for 
vaccine efficacy assessment. 
4.2.1.2
Safety Endpoints
As this is the first clinical investigation of V590, safety and tolerability will be primary 
endpoints and will be carefully monitored. It is anticipated that IM administration of V590 at 
the proposed doses will be well-tolerated in humans based on preclinical studies as well as 
previous experience with the VSV-ΔG vector platform from ERVEBO. 
The safety and tolerability of V590 will be monitored by standard means including clinical 
assessments of adverse experiences, physical examinations, monitoring of vital signs (VS), 
and standard laboratory tests (including hematology, chemistry, urinalysis and coagulation). 
Additionally, as this is a replication-competent live attenuated vaccine, viral shedding and 
vaccine strain viremia will be assessed in this study.
Assessments will occur throughout the trial, with time points optimized based on the 
expected timing of local and systemic reactions to vaccination (See Section 8.3). Specific 
safety endpoints to be gathered include:

Solicited local reactogenicity AEs (injection site pain/tenderness, swelling, redness)
will be collected through Day 5. Solicited systemic reactogenicity AEs (muscle pain, 
joint pain, headache, fatigue, rash, nausea, joint swelling, oral lesions, sweating 
more than usual) will be collected through Day 28. These will be recorded by the 
participant in a VRC.

Unsolicited AEs and events of clinical interest (ECIs; overdose, vesicular rashes, 
arthritis) will be collected and analyzed through Day 28 following study 
intervention.

After Day 28, and up to 180 days after study intervention, only SAEs and MAAEs 
will be analyzed.

After Day 180, and up to 365 days after study intervention, only SAEs will be 
analyzed.

Safety laboratory tests will be collected as described in the SoA 
Vital sign measurements and physical exam findings will be collected at scheduled times 
through Day 7 (See Section 1.3)
 
 
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PRODUCT: V590  
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All arthritis and/or vesicular lesions will be followed to resolution (or the end of the study, 
provided stable). Additionally, subjects will be instructed to report any recurrence of 
symptoms corresponding to these events at any time postvaccination through the end of the 
study and any recurrence will also be followed to resolution (or the end of study, if stable).
Evaluations by the investigator and/or by a rheumatologist/dermatologist may be conducted 
as outlined in the separate guidance document covering arthritis, rashes, and oral lesions, 
see Guidance for Assessment and Work-up of Specific Postvaccination Adverse Effects
(Appendix 10.4).
The 2007 Center for Biologics Evaluation and Research (CBER) Guidance Document will 
be used as guidance for the toxicity grading scale for this study (see Appendix 10.3).
Amendment 001-03: Active monitoring of AEs, ECIs, and MAAEs will occur through Day
28. Spontaneously reported SAEs will be collected per protocol (up to 365 Days for all 
SAEs, and indefinitely if considered related to intervention).
4.2.1.3
Immunogenicity Endpoints
Primary, secondary and exploratory endpoints in this trial will address the immunogenicity of 
V590 using assays to measure neutralizing antibodies by PRNT, IgG antibody titers against 
spike protein by ELISA, and exploratory immunogenicity assays.
Serum samples will be collected as outlined in the SoA for:

Serum neutralizing antibodies measured by PRNT 

Total anti-spike IgG antibodies measured by ELISA
Additionally, samples (including serum, PBMCs, nasal swabs and saliva) will be collected 
for exploratory immunogenicity endpoints as outlined in the objectives.
4.2.1.4
Viremia and Viral Shedding Endpoints
As V590 is a replication-competent chimeric virus, secondary objectives will include 
assessing vaccine viremia and viral shedding.
The following samples will be collected as outlined in the SoA at the timepoints through Day 
28 and will be assessed by RT-PCR for the presence of V590:

Blood for V590 viremia

Saliva, urine and stool for shedding
If RT-PCR assays are positive, V590 viremia and shedding samples may additionally be 
measured by plaque assay in order to assess whether replication-competent virus is present.
If samples are positive at Day 28 additional samples may be collected until testing is negative
as a part of the safety evaluation.
 
 
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Stool collection is only included during the domiciled portion of this study based on 
operational considerations including requirements for sample collection and preparation.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR research are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
A primary objective of this study is to evaluate the safety and tolerability of V590. A 
placebo-controlled trial will facilitate an unbiased assessment of safety and tolerability. 
Secondary and exploratory endpoints also support the use of placebo, as this serves as a 
negative control for potential environmental exposures to SARS-CoV-2 and provides a 
control for immunologic assays.
 
 
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4.3
Justification for Dose
The methods used in calculating doses and estimated exposures are detailed in Sections 4.3.1 
and 4.3.2.
As this is a Phase 1 assessment of V590 in humans, and the immunogenicity and safety 
profiles of the vaccine are still being evaluated, modifications to the dose or dosing regimen 
may be required to achieve the scientific goals of the study objectives and/or to ensure 
appropriate safety monitoring of the study participants. Details of allowed modifications are 
provided in Section 8.11.6.
4.3.1
Starting Dose for This Study
The starting dose for this study is 5·105 pfu and is based on the non-GLP NHP 
biodistribution study and non-GLP NHP pharmacology study with toxicity endpoints, as well 
as prior preclinical and clinical experience with ERVEBO. The non-GLP NHP pharmacology 
study with toxicity endpoints identified the NOAEL as the highest dose tested (5.94·107
pfu/animal). This is 119-fold higher than the planned clinical starting dose on an absolute 
basis and approximately 742-fold higher than the planned clinical starting dose on a pfu/kg 
basis.
Immunogenicity was observed in the non-GLP NHP pharmacology study with toxicity 
endpoints at 5.94·107 pfu and was not observed at 1.00·105 pfu. Immunogenicity was 
observed in the non-GLP NHP biodistribution study at the single dose level tested of 
5.94·107 pfu.
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose for this study is 5.55·107 pfu, which is similar to the highest dose tested 
in the supporting non-GLP NHP pharmacology study with toxicity endpoints and 
biodistribution study (5.94·107 pfu). There were no adverse V590-related findings observed.
This dose is also similar to the highest dose tested in the ERVEBO clinical program. This is 
approximately 7- to 13-fold lower than the animal exposure on a pfu/kg basis.
4.3.3
Rationale for Dose Interval and Study Design
ERVEBO, which uses the same VSVΔG platform as V590, was studied in multiple Phase 1 
studies in which dose steps of approximately 1 log pfu (i.e. tenfold changes in pfu between 
dose levels) were tested.  Based on the shared platform technology and the safety/tolerability 
profile observed with ERVEBO, dose intervals of up to approximately 1 log pfu would be 
considered reasonable for V590. With a planned starting dose of 5·105 and a highest planned 
dose of 5.55·107 pfu, and with four dose levels total in this study, evenly spaced dose 
intervals on a log scale are planned which results in approximately five-fold differences
between dose levels. 
Based on the clinical and preclinical experience with ERVEBO, and the preclinical 
experience with V590, a dose-ranging design is employed in Parts 1 and 2.
 
 
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant provides documented informed consent. 
The overall study ends when the last participant completes the last study-related contact, 
withdraws from the study, or is lost to follow-up (ie, the participant is unable to be contacted 
by the investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
A primary objective of this early Phase 1 study is to identify the dose that achieves the target 
immune response in humans based on preclinical or early clinical data. Therefore, it is 
possible that not all dose levels specified in the protocol will be evaluated if this objective is 
achieved at lesser dose levels in this study. This would not be defined as early termination of 
the study, but rather an earlier than anticipated achievement of the study objective(s). If a 
finding from another preclinical or clinical study using the study intervention(s), agent of the 
same or similar class, or methodology(ies) used in this study results in the study(ies) or 
program being stopped for nonsafety reasons, this also does not meet the definition of early 
study termination.
5
STUDY POPULATION
Healthy male and female participants between the ages of 18 to 54 years (Parts 1 and 3) or ≥ 
55 years (Part 2) will be enrolled in this study.
The minimum age for Parts 1 and 3 may be adjusted up based upon the legal age of majority 
based upon CRU location (for example, in Nebraska Parts 1 and 3 may enroll from ages 19-
54, based on an age of majority of 19). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
 
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is in overall good health based on medical history, physical examination, and VS 
measurements performed prior to randomization, as assessed by the investigator.
2. Is in overall good health based on laboratory safety tests obtained at the screening visit.
When available, predose safety labs will additionally be reviewed prior to dosing. 
Appendix 2 provides a table of laboratory safety tests to be performed. Appendix 10
provides an algorithm for the assessment of out of range laboratory values.
3. Has a BMI ≤30 kg/m2 inclusive (after rounding to the nearest whole number). See 
Section 8.3.4 for criteria on rounding to the nearest whole number. BMI = weight 
(kg)/height (m)2.
4. Parts 1 and 2 only: Has negative testing for SARS-CoV-2 based on both antibody and 
RT-PCR, at screening and upon start of domiciling.
Part 3 only: Has positive serology (antibody) testing for SARS-CoV-2, also with 
negative SARS CoV-2 RT-PCR testing at screening and upon start of domiciling, and 
without symptoms of respiratory infection for at minimum 3 weeks preceding screening. 
5. Has been practicing social distancing for at least two weeks prior to planned start of 
domiciling and has had no close contacts with known active SARS-CoV-2 infection in 
that time period.
Demographics
6. Is male or female, from 18 years to 54 years of age inclusive (Parts 1 and 3) or ≥ 55 years 
of age (Part 2) at the time of signing the informed consent. 
For Parts 1 and 3, if the age of majority at the location of the CRU is older than 18, this 
legal age of majority must be used as the minimum for enrollment.
7. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 2 months after administration of study intervention.
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
 
 
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•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term 
and persistent basis), as described in Appendix [5] during the intervention period and for 
at least 2 months after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.4.5 and Section 10.5.3.
•
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.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
9. The participant provides written informed consent for the study, including for future 
biomedical research.
 
 
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Additional Categories
10. Is willing to comply with the study restrictions (see Section 5.3 for a complete summary 
of study restrictions), including social distancing between screening and domiciling).
11. Agrees to provide study personnel with a primary telephone number as well as an 
alternate means of contact, if available (such as an alternate telephone number or email) 
for follow-up purposes.
12. Can read, understand, and complete the Vaccination Report Card.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
Is currently known or suspected to be infected with SARS-CoV-2. 
1. Has a known hypersensitivity to any component of V590 or placebo (including Tris, 
rHSA, rice protein, and benzonase).
2. Has any known or suspected active clinically significant autoimmune disease or 
immunosuppressive condition, acquired or congenital, as determined by medical history 
and/or physical examination. (Note that medical history that does not constitute an active 
clinically significant autoimmune/immunosuppressive condition, such as longstanding 
hypothyroidism on stable thyroid hormone replacement, is permitted.) 
3. Has thrombocytopenia or other coagulation disorder contraindicating intramuscular 
vaccination or repeated venipuncture.
4. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4°F 
[≥38.0°C] or axillary or temporal temperature ≥99.4°F [≥37.4°C]) or received antibiotic 
therapy for any acute illness occurring within 7 days before receipt of study vaccine.
5. Has history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study or interfere with the participant’s participation for the 
full duration of the study.
6. Has a history of ongoing liver disease or, at the time of screening, has any one of the 
following: 
-Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × Upper 
Limit of Normal (ULN)
-Alkaline phosphatase and direct bilirubin > ULN. Total bilirubin may be up to 2 × ULN 
as long as direct bilirubin is equal to or below the ULN. 
 
 
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-Prothrombin time (PT) international normalized ratio (INR) > 1.25 
Investigator discretion may be used to determine significance based on local laboratory 
reference ranges.
7. Has a history of asthma or allergic asthma that required systemic corticosteroids in the 
previous year.
8. Has a history of Guillain-Barré syndrome.
9. Has a history of diabetes mellitus, requiring medication at the time of assessment, OR has 
a hemoglobin A1c ≥ 6.5.
10. Has a history of any medical condition that would put the participant at risk for severe 
SARS-CoV-2 disease as judged by the investigator, including uncontrolled hypertension 
(defined as resting systolic ≥140 mmHg and/or diastolic ≥90 mmHg at screening and
allowing stable antihypertensive use), significant ischemic or structural heart disease, 
diabetes, liver disease, chronic pulmonary disease, pulmonary hypertension, sickle cell 
disease, clinically significant thalassemia, is immunocompromised, or anticipates the 
need for immunosuppressive treatment within the next 6 months.
11. Has any ongoing, symptomatic, acute or chronic illness requiring medical or surgical care 
or any condition that is immunosuppressive. Asymptomatic conditions and conditions 
with no evidence of end-organ involvement (e.g., stable hypothyroidism on thyroid 
hormone replacement, dyslipidemia, mild well-controlled hypertension) are not 
exclusionary provided that they are being appropriately managed and are clinically stable 
(i.e., unlikely to result in symptomatic illness within the time-course of this study) in the 
opinion of the Investigator, and are not considered to put the participant at risk for severe 
SARS-CoV-2 disease (with the exception of the age category of over 55). Symptomatic 
osteoarthritis is permitted if surgery and/or intra-articular injections are not anticipated 
during the study, but rheumatoid arthritis and other autoimmune inflammatory arthritides 
such as ankylosing spondylitis, psoriatic arthritis, and lupus are prohibited. Note that 
illnesses or conditions may be exclusionary, even if otherwise stable, due to therapies 
used to treat them, at the discretion of the investigator.  
12. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants with a more 
recent history of situational depression may be enrolled in the study at the discretion of 
the investigator.
13. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
 
 
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opinion of the investigator and with agreement of the Sponsor (e.g., malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
14. Participant has an estimated eGFR ≤60 mL/min/1.73 m2] based on either the MDRD or
the CKD-EPI equation. The selection of equation is at discretion of the investigator.
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creat)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if African American])
At the discretion of the investigator a measured creatinine clearance, as determined by a 24-
hour urine collection, may be used in place of, or in conjunction with, the estimate of the 
eGFR.
Participants who have an eGFR or measured creatinine clearance of up to 10% below of 
either 60 mL/min (for creatinine clearance) or 60 mL/min/1.73m2 (for eGFR) may be 
enrolled in the study at the discretion of the investigator.
OR
CKD-EPI Equation:
eGFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
African American]
At the discretion of the investigator a measured creatinine clearance, as determined by a 24-
hour urine collection, may be used in place of, or in conjunction with, the estimate of the 
eGFR.
Participants who have an eGFR or measured creatinine clearance of up to 10% below of 
either 60 mL/min (for creatinine clearance) or 60 mL/min/1.73m2 (for eGFR) may be 
enrolled in the study at the discretion of the investigator.
15. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic 
allergic reaction) to a vaccine or prescription or non-prescription drugs or food as judged 
by the investigator.
16. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV-1 or 2 antibodies.
Individuals with antibodies to hepatitis C may be enrolled if hepatitis C viral load is 
negative and there is no evidence of or history of liver disease.
17. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
18. A WOCBP who has a positive urine or serum pregnancy test before vaccination.
 
 
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19. A WOCBP who is breastfeeding.
20. Has any unstable chronic medical condition, including one that has resulted in change in 
therapy (medication or other) in the 30 days prior to randomization or hospitalization in 
the previous year or might be predicted to result in hospitalization in the year after 
enrollment. Participants with severe, untreated, or uncontrolled underlying medical 
disease that might either compromise participant safety or affect the ability to assess 
safety of the investigational product are excluded.
Prior/Concomitant Therapy
21. Has received or is expected to receive any SARS-CoV-2 vaccine or other coronavirus
vaccine during the study (except V590), is using investigational agents for prophylaxis of 
SARS-CoV-2 or is taking any systemic antiviral medications.
22. *Has received systemic corticosteroids (equivalent ≥20 mg/day of prednisone for persons 
weighing >10 kg) for ≥14 consecutive days and has not completed intervention at least 
30 days prior to study vaccination.
23. *Has received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) starting from 14 days prior to study 
vaccination. (Note: Topical, ophthalmic, and inhaled/nebulized steroids are permitted
upon joint agreement with the Sponsor.)
24. Has received any intra-articular steroid injections within the 3 months prior to study 
vaccination or is expected to require intra-articular steroid injection during the study.
25. Is receiving immunosuppressive therapy or has received immunosuppressive therapy 
within 6 months of enrollment, including but not limited to chemotherapeutic agents used 
to treat cancer or other conditions, and interventions associated with organ or bone 
marrow transplantation, or autoimmune disease. This exclusion criterion does not include 
corticosteroids, which are covered in separate dedicated exclusion criteria. 
26. *Has received any non-live vaccine starting from 14 days prior to study vaccination or is 
scheduled to receive any non-live vaccine through 30 days following study vaccination. 
Exception: Inactivated influenza vaccine may be administered but must be given at least 
7 days before receipt of study vaccine or at least 15 days after receipt of study vaccine.
27. *Has received any live vaccine starting from 30 days before study vaccination or is 
scheduled to receive any live vaccine through 30 days following study vaccination.
28. Has received a blood transfusion or blood products, including immunoglobulin, in the 3 
months before anticipated study vaccination. Autologous blood transfusions are not 
considered an exclusion criterion.
 
 
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29. Is expected to be receiving or is currently receiving antipyretic or analgesic medication 
on a daily or every other day basis from randomization through Day 7 (a daily dose of 
≤150 mg of aspirin given under the guidance of a physician is not considered 
exclusionary for enrollment). 
30. Is unable to meet the concomitant medication restrictions (see Section 6.5).
Prior/Concurrent Clinical Study Experience
31. Has ever participated in an investigational study of a SARS-CoV-2 vaccine, a 
coronavirus vaccine, or an antiviral or other biologic product intended for the treatment 
of COVID-19. 
32. Has participated in another vaccine study within 3 months prior to screening or has 
participated in an investigational study within 4 weeks prior to the prestudy (screening) 
visit. The window will be derived from the date of the last visit in the previous study. In 
addition, participant cannot participate in another investigational trial up to the post-trial 
visit (approximately 12 months after the study vaccination).   Participation in the separate
screening protocol is not exclusionary.
33. Has ever received a vaccine based on VSV.
Diagnostic Assessments
34. Has a QTcF interval >470 msec (male) or >480 msec (female), has a history of risk 
factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of 
long QT syndrome), has uncorrected hypokalemia or hypomagnesemia.
Other Exclusions
35. Is under the age of legal consent.
36. Is smoking or vaping and/or has a history of chronic smoking or vaping within 
approximately six months prior to planned vaccination.
37. Does not agree to follow the alcohol restrictions (e.g., refrain from consumption of 
alcohol 24 hours prior to each laboratory safety evaluation as well as 24 hours prior to 
treatment vaccination and while domiciled.)
38. Has a tattoo, scar, or other physical finding at the area of the vaccination site that would 
interfere with intramuscular injection or a local tolerability assessment.
39. Is a regular user of any illicit drugs or has a history of drug (including alcohol) abuse 
within approximately 1 year. Smoking of cannabis within approximately six months is 
excluded, but oral consumption of cannabis is not prohibited. Participants must have a 
negative UDS prior to randomization (except for cannabis if non-inhaled per participant 
history).
 
 
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40. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
41. Lives in a nursing home or long-term care facility. (Other age-restricted residences, such 
as over-55 communities, are permissible so long as the participant is capable of 
independently performing their activities of daily living.)
42. Is currently working in an occupation with high risk of exposure to SARS-CoV-2 (e.g., 
health care worker with direct patient contact, emergency response personnel).
43. Has a house-hold contact (HHC) who is immunodeficient, on immunosuppressive 
medications (e.g., parenteral immunosuppressants, >10 mg prednisone equivalent daily), 
human immunodeficiency virus (HIV)-positive with CD4 count <500, pregnant, or has an 
unstable medical condition.
44. Has an HHC 5 years of age or younger or is a childcare worker who has direct contact 
with children 5 years of age or younger.
45. Has direct hands-on job preparing food in the food industry.
46. Has a history of employment in an industry involved in contact with ruminant animals, 
veterinary sciences, or other potential exposure to VSV.
47. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, the Day 1 Visit 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Fasting requirements for study procedures, such as but not limited to laboratory safety 
evaluations are specified in Appendix 2.
Otherwise, dietary restrictions are not required.
5.3.1.2
Fruit Juice Restrictions
Fruit juice restrictions are not required.
 
 
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the screening and poststudy visits and from 12 hours prior to 
and after study intervention.
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to each laboratory safety 
evaluation as well as 24 hours prior to study vaccination and while domiciled.
5.3.2.3
Tobacco Restrictions
Smoking or vaping is not permitted during the study.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (e.g., weight-lifting, 
running, bicycling, etc.) for 48 hours prior to each laboratory safety evaluation.
5.3.4
Blood Donation Restrictions
Blood donation is prohibited during the first 4 months following vaccination due to blood 
volume requirements of this study. Routine blood draws for medical care are acceptable. 
Blood donation is not recommended during the remainder of the study.
5.3.5
Contraceptive Requirements
Participants will follow the contraceptive guidance indicated in Appendix 5.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention OR withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number. The study site should 
contact the Sponsor for the replacement participant’s treatment/randomization number.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies provided by the Sponsor will be packaged to support enrollment and 
replacement participants as required. When a replacement participant is required, the Sponsor 
or designee needs to be contacted prior to dosing the replacement participant. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
 
 
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Table 2
Study Interventions
Panel
Name
Panel Type
Inter-
vention
Name
Intervention 
Type
Dose
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination
Regimen
Use
IMP/
NIMP
Sourcing
Active
Experimental
V590
Biological/
Vaccine
Sterile 
Solution
Titer ≥ 
1E6pfu/ml
5.00X105
pfu/mL
2.40X106
pfu/mL
1.15X107
pfu/mL
5.55X107
pfu/mL
IM
Day 1
Experimental
IMP
Provided 
Centrally by 
the Sponsor
Placebo
Placebo 
Comparator
Placebo
Other
Sterile 
Solution
N/A
N/A
IM
Day 1
Placebo
IMP
Provided 
Centrally by 
the Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European Commission and applies to 
countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
In this protocol, placebo for V590 is diluent (10mM Tris 2.5mg/mL rHSA, 10% w/v Sucrose pH 7.5); diluent is used for blinding purposes and does not contain active ingredients.
 
 
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (e.g., not applicable in 
the case where multiple lots or batches may be required due to the length of the study,).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed in order to administer the 
proper dose to each participant are outlined in a separate document provided by the Sponsor.
The rationale for selection of doses to be used in this study is provided in Section 4.3. V590 
will be prepared by an unblinded pharmacist or medically qualified study personnel (see 
Section 6.3.3 and the Pharmacy Manual). The syringe for IM injection should be prepared 
shortly before administration, per the instructions.
Refer to the Pharmacy Manual for detailed instructions.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
A sample allocation schedule is shown below in Table 3.
Table 3
Sample Allocation Schedule
Part 1 (18 to 54 years old SARS-CoV-2 seronegative) a
Subjects
Per Panel
Panel A
(N = 28)
Panel B
(N = 28)
Panel C
(N = 28)
Panel D
(N = 28)
N = 21
V590 5.00·105
pfu
V590 2.40·106 
pfu
V590 1.15·107 
pfu
V590 5.55·107
pfu
N = 7
Placebo
Placebo
Placebo
Placebo
Part 2 (≥ 55 years old SARS-CoV-2 seronegative) a
Subjects
Per Panel
Panel E
(N = 28)
Panel F
(N = 28)
Panel G
(N = 28)
Panel H
(N = 28)
N = 21
V590 5.00·105
pfu
V590 2.40·106 
pfu
V590 1.15·107 
pfu
V590 5.55·107
pfu
N = 7
Placebo
Placebo
Placebo
Placebo
Part 3 (18 to 54 years old SARS-CoV-2 seropositive) a
Subjects
Per Panel
Panel I
(N = 28)
N = 21
V590 5.55·107
pfu
N = 7
Placebo
a. Within each panel of Parts 1, 2, and 3, participants will be randomized to receive V590 or matching Placebo in a 3:1 
ratio according to a computer-generated, permuted-block allocation schedule (i.e., in each panel 21 participants to 
receive V590 and 7 participants to receive matching placebo).
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
 
 
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6.3.3
Blinding
A double-blinding technique will be used. V590 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
Listed below are specific restrictions for prior/concomitant therapy or vaccination:

Any administration of a nonstudy COVID-19 vaccine is prohibited during the study.

Live and non-live vaccines may only be administered prior to or following the receipt 
of study vaccine according to the time frames specified in Exclusion Criteria (Section 
5.2).
Exception: Inactivated influenza vaccine may be administered but must be given at 
least 7 days before receipt of study intervention or at least 15 days after receipt of 
study intervention.

Participants should not receive systemic corticosteroids (prednisone equivalent of ≥20 
mg/day for ≥14 consecutive days) starting from 30 days prior to vaccination through 
60 days following vaccination.

Participants should not receive systemic corticosteroids exceeding physiologic 
replacement doses (prednisone equivalent dose >5 mg/day) starting from 14 days 
prior to vaccination through 60 days following vaccination. 
 
 
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Note: Topical, ophthalmic, or soft-tissue (e.g., tendon steroid injections) and
inhaled/nebulized steroids are permitted. Intra-articular steroid injections should be 
avoided.

Scheduled antipyretic or analgesic medication on a daily or every other day basis 
from randomization through Day 7 after receiving study vaccination are not 
permitted. 
- A daily dose of ≤150 mg of aspirin given under the guidance of a physician is not
considered exclusionary for enrollment or a contraindication for enrolled participants. 
- For enrolled participants, occasional administration of anti-pyretic or analgesic 
medication to control pain is allowed and not considered a contraindication.
-Antipyretics/analgesics may be administered on an as needed basis following 
vaccination.

Immunoglobulins and/or any blood products within 3 months preceding the study
intervention or at any time during the study.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives through the first 3 months of the study must be 
recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Rescue Medications and Supportive Care
CRUs will be staffed with medically trained personnel with appropriate access to full service 
acute-care hospitals to facilitate rapid institution of medical intervention.
 
 
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6.6
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
If any of the below stopping rules are met, no further enrollment or dosing will occur (unless 
permitted at lower dose levels as specified under criteria #2) until the Sponsor has reviewed 
the totality of data available. This review will include formal assessment by the siDMC. For 
stopping rules #1 and #2 any further dosing will additionally require joint agreement with the 
Sponsor and the investigator at the involved site(s).
1. Any participant experiences a serious adverse event (SAE) considered at least possibly 
related to the vaccine; laryngospasm, bronchospasm, or anaphylaxis after vaccine 
administration considered related to the vaccine; ulceration, abscess, or necrosis at the 
injection site that is considered related to vaccine; or generalized urticaria after vaccine 
administration considered related to the vaccine.
2. Any two or more participants at a given dose level experience the same Grade 3 AE with 
the same Preferred Term based on MedDRA coding and is considered related to vaccine.
If this criterion is met dosing of lower dose panels may continue upon joint agreement 
between the Sponsor and the investigator(s).
3. Any participant has severe COVID-19 as defined in the FDA Guidance on the 
Development and Licensure of Vaccines to Prevent COVID-19 
(https://www.fda.gov/media/139638/download). Severe COVID-19 is defined as 
virologically confirmed SARS-CoV-2 infection with any of the following: a) Clinical 
signs at rest indicative of severe systemic illness (respiratory rate ≥30 per minute, heart 
rate ≥125 per minute, SpO2 ≤93% on room air at sea level or PaO2/FiO2 < 300 mm Hg)
b) Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation or ECMO) c) Evidence of shock (SBP < 90 mm Hg, DBP < 60 
mm Hg, or requiring vasopressors) d) Significant acute renal, hepatic, or neurologic 
dysfunction e) Admission to an ICU or f) Death. If this stopping rule is met, the siDMC 
will evaluate available preclinical data in addition to the clinical data in order to evaluate 
for vaccine-enhanced disease.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
 
 
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•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
Procedures conducted as part of a site generic screening (with an ERC/IRB approved site 
generic screening consent) on potential participants (eg, blood count, vital signs, ECG, 
etc.) and obtained before signing of study ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol specified criteria and were performed 
within the screening window defined in this protocol.
Up to ~627.5 mL of blood may be drawn during the study (up to ~457.5 mL of blood may be 
drawn before Day 90 for safety, viremia or immunologic assessments and up to ~168 mL of 
blood may be drawn from Day 90 to Day 365 for safety, viremia or immunologic 
assessments). The total blood volume withdrawn from any single participant will not exceed 
the maximum allowable volume before and after Day 90. (Appendix 8 or
operations/laboratory manual).
Amendment 001-03: Blood will be collected through Day 28.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant prior to participating in 
a clinical study or future biomedical research. If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or medically 
qualified designee must ensure the appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant must be documented on a consent form. The form 
must include the trial protocol number, trial protocol title, dated signature, andalong with the 
dated signature of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant 
before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the study. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant will be asked to provide documented informed consent.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain documented informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant before performing any procedure related to 
future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
 
 
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Day 1.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 4 weeks before the first dose of study vaccination (see Section 5.2 and Section 6.5 for 
Exclusion Criteria and Study Restrictions pertaining to prior medications and vaccines.)
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. New and/or concomitant medications and nonstudy vaccines taken after 
study vaccination through Day 28 will be recorded with the paper VRC as specified in 
Section 8.3.8.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
 
 
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treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Procedures for handling, preparing, and administering the unblinded vaccines are provided in 
the Pharmacy Manual provided by the Sponsor. Study intervention will be administered into 
the deltoid muscle and witnessed by study staff and recorded in the source documents. The 
deltoid muscle of the non-dominant arm is the preferred site of administration. 
Study site staff will confirm that the participant has received the entire dose of study 
intervention.  On Day 1, the time of V590/Placebo administration is considered Time 0.  Care 
will be taken to maintain the study blinding.
Adequate treatment provision, including epinephrine and equipment for maintaining an 
airway should be available for immediate use should an anaphylactic or anaphylactoid 
reaction occur [Centers for Disease Control and Prevention 2015].
8.1.8.1
Timing of Dose Administration
The first dose of study vaccine will be administered on Day 1, which should be the day of
randomization.
Vaccinations may be administered at any time (although morning administration is suggested 
based upon study design), and without regard to timing of meals.
Each participant's body temperature must be taken before vaccine administration. Individuals
who present with fever (oral ≥100.4°F [≥38.0°C]) may be replaced. 
The predose collection of blood samples must be performed before vaccine administration.
All participants will be observed for at least 4 hours after vaccination for any immediate
reactions. 
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study. If a participant discontinues for any reason at any 
time during the course of the study and/or intervention, the participant may be asked to return 
to the clinic (or be contacted) for a poststudy visit as per the number of days described in
Section 8.11.4 to have the applicable protocol-specified procedures conducted to have the 
 
 
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applicable procedures conducted. However, the investigator may decide to perform the 
poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs prior to the safety follow-up time frame as 
specified in Section 8.4.1, the investigator should perform a follow-up telephone call at the 
end of the follow-up period ( Section 8.4.1) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the toxicity 
grade] of the AEs observed, the relation to study drug, the reason thereof, etc., in the medical 
chart. If it is not possible to record this assessment in the chart prior to the unblinding, the 
unblinding should not be delayed.
 
 
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In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.11
Domiciling
Participants will report to the CRU between Day -3 and Day -1 prior to the scheduled day of 
study intervention administration on Day 1 and remain in the unit until all procedures have 
been completed on Day 7. At the discretion of the investigator, participants may be requested 
to remain in the CRU longer. Participants may be permitted to leave the unit, for emergency 
situations only, during the domiciling period at the discretion of the investigator after 
discussion with the Sponsor. The decision how to monitor the participant will be at the 
discretion of the investigator after discussion with the Sponsor.
The pre-vaccination domiciling period may be shortened at the discretion of the site provided 
results for the SARS-CoV-2 RT-PCR (or antigen test) and serology tests can be available and 
reviewed by the investigator prior to vaccine administration. 
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity and Efficacy Assessments
8.2.1
Neutralizing Antibody
Neutralizing antibody titers are a measure of antibody levels capable of neutralizing 
infectivity of the vaccine strain V590, which bears the functional SARS-CoV-2 spike protein 
on its surface. This vaccine strain neutralization assay is anticipated to correspond to levels 
antibodies capable of neutralizing wild type SARS-CoV-2 virus. Neutralizing antibody titers 
will be assessed by a plaque reduction neutralization assay (PRNT), which is a standard 
functional assay for quantitating the neutralizing antibody response elicited by the vaccine.
 
 
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8.2.2
ELISA Antibody Titers
ELISA-based analysis will be used to quantify serum total IgG titers to the SARS-CoV-2 
spike protein. This will serve as a measure of the magnitude of the IgG antibody response 
against spike protein.
8.2.3
Anti-Nucleocapsid Antibody Assay (Evidence of Infection)
V590 encodes for SARS-CoV-2 spike protein but does not contain any other SARS-CoV-2 
sequences. Thus, development of an immune response to a SARS-CoV-2 protein other than 
spike is indicative of infection (but does not differentiate between symptomatic and 
asymptomatic infection). Anti-nucleocapsid antibodies will be measured using an assay 
currently available under emergency use authorization (EUA) as outlined in the SoA. This 
will be performed using an EUA authorized qualitative test yielding a positive vs negative 
result for anti-nucleocapsid antibodies. 
8.2.4
SARS-CoV-2 RT-PCR (Evidence of Active Infection)
Participants with symptoms suggestive of potential COVID-19, or with close contacts who 
test positive for active SARS-CoV-2 infection, will be tested for active infection with a 
SARS-CoV-2 RT-PCR assay. The preferred assay is the Abbott RealTime SARS-CoV-2 test
performed on a nasopharyngeal swab and run by the central laboratory. This test is available 
under an EUA and is a dual target assay for SARS-CoV-2 RdRp and N-genes. Other EUA 
approved acute SARS-CoV-2 tests are also acceptable but not preferred; sites should obtain 
the Abbott RealTime SARS-CoV-2 test when possible.
8.2.5
Exploratory Immunogenicity Assays
Exploratory immunogenicity assays will be performed on collected samples in order to 
characterize the immune response elicited by V590. This may include assays performed on 
serum, saliva, and PBMCs (for sites with PBMC-processing capabilities).
These exploratory immunology endpoints may include the following:

ELISPOT assay against spike protein and ICS 

Anti-spike antibodies in mucosal samples

Serum cytokines/chemokines

Wild type SARS-CoV-2 neutralization assays
These exploratory immunology assays, if performed, may be reported in a separate results 
memo outside of the CSR.
Additionally, VSV serologies will be obtained predose for all participants. It is anticipated 
that these serologies will be negative based on exclusion criteria; if positive VSV serologies 
 
 
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are observed the relationship between positive VSV serology and immune response to V590 
may be evaluated.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from screening to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Complete Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at screening and
within a 24-hour window prior to dosing.
8.3.2
Symptom Driven Physical Examinations
A symptom driven physical examination will be conducted only if participant symptoms
warrant an exam or at the investigator’s discretion. The symptom driven physical should be
conducted by an investigator or medically qualified designee (consistent with local
requirements) per institutional standard, specifically targeted any areas for which there are 
symptoms of concern.
8.3.3
Targeted Physical Examinations
A targeted physical examination of the injection site will be conducted by the investigator or
medical qualified designee (consistent with local requirements) per institutional standard at
Day 1 (approximately 1-2 hours after dosing) and as outlined in the SoA Section 1.3. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.4
Height and Weight
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
BMI
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
 
 
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8.3.5
Oral Temperature Measurements
Body temperature should be measured orally and recorded as single measurements per 
timepoint. The same method must be used for all measurements for each individual 
participant and should be the same for all participants. 
Oral temperature will be assessed before study vaccine is administered on Day 1. If the 
participant has a fever (defined as an oral temperature of ≥100.4°F or ≥38.0°C) within the 1-
week period prior to receiving a study vaccination, the participant should not receive the 
study vaccine.
Postvaccination, if an oral temperature indicates a fever (defined as an oral temperature of
≥38.0°C or 100.4°F), then an AE of “fever” must be documented in the eCRF.
Screening, Days -3 to -1, and Day 1 predose and 2 hours postdose will be done by clinic staff 
and noted on the source document.  Screening and admission temperatures will use the 
clinic’s thermometer; the Day 1 predose, the 2 hour postdose, and all later timepoints will use 
the thermometer provided to the participant.  
For measurements to be collected on the VRC on Days 1-28, participants will be provided an 
oral thermometer. The Day 1 postdose measurements will be done approximately 4 hours 
after dosing. The Day 1 to Day 7 temperature will be measured and recorded by the 
participants on the VRC, under observation by the clinic staff (see Section 8.3.8). All the 
other measurements will be done by the participant without supervision.
8.3.6
Heart Rate, Blood Pressure, Respiratory Rate, and Pulse Oximetry
Participants should be resting in a quiet setting without distractions in a semi-recumbent
position for at least 10 minutes prior to having VS measurements obtained. Semi-recumbent 
VS will include HR, systolic and diastolic BP, respiratory rate, and pulse oximetry at 
timepoints indicated in the SoA. The correct size of the BP cuff and the correct positioning 
on the participants' arm is essential to increase the accuracy of BP measurements.
Measurements will be taken with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
The predose (baseline) HR and BP will be triplicate measurements, obtained approximately
1-2 minutes apart] within 3 hours of dosing V590/placebo. The mean of these measurements 
will be used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). Postdose VS measurements will be single measurements.
Participants will be encouraged to rest semi-recumbent from dosing until 4 hours postdose 
except to stand for other study-related procedure; sitting is also permitted during this window 
except as otherwise required (such as at least 10 minutes semi-recumbent prior to VS).
 
 
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8.3.7
Electrocardiograms
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and [QTc] intervals. 
Refer to Appendix 9 for evaluation and withdrawal criteria and additional [QTc] readings 
that may be necessary.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in the semi-recumbent or supine position for at least 10 
minutes prior to each ECG measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin marker pen to ensure reproducible electrode placement.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.3.8
Vaccine Report Card
Participants will be provided with a VRC to fill out on a daily basis from Day 1 (~4 hours 
postdose) to Day 28.  The VRC will be used to collect and grade injection site and systemic 
AEs, using both specific questions for solicited AEs and a space to record unsolicited AEs as 
“other complaints.” The VRC will be reviewed daily with the participants while domiciled 
for the purposes of early detection of safety concerns. 
Participants will use the VRC to document the following information:
• Oral body temperatures measured from Day 1 (~4 hours postdose) to Day 28.
• Solicited injection-site AEs (swelling, redness, pain or tenderness) from Day 1 to Day 5.
• Solicited systemic AEs (muscle pain, joint pain, headache, tiredness, rash, nausea, joint 
swelling, oral lesions, sweating more than usual) from Day 1 to Day 28.
• Any other unsolicited AEs from Day 1 to Day 28 (as “other complaints”).
• Concomitant medications and non-study vaccinations Day 1 to Day 28.
 
 
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On Day 1 and/or as needed, the study staff should review the VRC instructions (including 
AE severity grading) and each page of the VRC carefully with the participant to ensure 
participant comprehension of their requirements.  
During the domiciled period, the study staff should observe and confirm the participant’s 
proper use of the VRC as instructed, including the measurement of temperature and any 
injection site redness or swelling.  On Day 14, the study staff should confirm the participant’s 
proper use of the VRC as instructed.
The VRC entries will be reviewed with the participant at each CRU visit (i.e., Day 14 and 
Day 28) to ensure the instructions were correctly understood and the VRC completed 
properly. Participants will be reminded to complete the VRC daily. As noted above, study 
staff should observe the temperature, swelling, and redness assessments (if any) on Days 1 
through 7. Any AEs recorded in the VRC should be reviewed and fully assessed by the 
investigator as described in Section 8.4 and entered into the Sponsor database in a timely 
manner as per the Data Entry Guidelines.
8.3.9
Postvaccination Observation Period (4 Hours)
All participants will be observed for 4 hours after the vaccination for any immediate 
reactions (injection site and systemic reactions, solicited and unsolicited AEs). If any 
immediate AEs (including allergic reactions) are observed during this period, the time at 
which the event occurred within this timeframe, as well as the event itself, any concomitant 
medications that were administered, and resolution of the event, must be recorded on the 
appropriate eCRF.
8.3.10
Monitoring for SARS-CoV-2 Infection
During the 12 months post-vaccination, participants will be instructed to contact the clinical
site if they either have 1) a close contact who tests positive for SARS-CoV-2 or 2) symptoms 
potentially consistent with SARS-CoV-2 as outlined by the CDC 
(https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html). If 
participants have any emergency warning signs as outlined by the CDC, they should seek
emergent medical care. Clinical sites will solicit participant symptoms and exposure 
histories, and if the investigator considers the participant to meet one of these two conditions 
(or both conditions) the participant will be requested to have SARS-CoV-2 RT-PCR testing 
performed by the clinical site. Central laboratory PCR testing is preferred, but other EUA 
authorized (or, if available, FDA-licensed) PCR tests are permissible. PCR tests are preferred 
over antigen tests, but EUA authorized (or FDA-licensed) antigen tests are also acceptable. 
The CRU will additionally make every effort to follow up on any testing performed that was 
not ordered by the investigator. 
Those with positive tests will be followed up weekly by phone for two weeks or until 
resolution of acute symptoms if present, whichever is longer. These individuals will be 
referred for medical treatment if the investigator considers this medically indicated and will 
additionally be encouraged to follow local public health department guidelines.
 
 
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8.3.11
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events, Serious Adverse Events, Medically-Attended Adverse Events 
and Other Reportable Safety Events
The definitions of an AE, SAE, or MAAE as well as the method of recording, evaluating, and 
assessing causality of AE, SAE, and MAAE and the procedures for completing and 
transmitting AE, SAE, MAAE, and other reportable safety event reports can be found in 
Appendix 3.
Adverse events, SAEs, MAAEs, and other reportable safety events will be reported by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE, SAE or MAAE as well as other reportable safety 
events. Investigators remain responsible for following up AEs, SAEs, MAAEs, and other 
reportable safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE, SAE or MAAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, MAAE, and Other 
Reportable Safety Event Information
AEs, SAEs, MAAEs, and other reportable safety events that occur after the participant 
provides documented informed consent but before intervention allocation, must be reported 
by the investigator for randomized participants only if the event is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo, or a procedure.
From the time of intervention allocation, all AEs and ECIs must be reported by the 
investigator up to Day 28. MAAEs must be reported by the investigator from the time of 
intervention to Day 180. SAEs, and other reportable safety events, must be reported by the 
investigator from the time of intervention allocation to Day 365.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, MAAEs, and other reportable safety events will be 
recorded and reported to the Sponsor or designee within the time frames as indicated in
Table 4.
Amendment 001-03: All AEs, ECIs, and MAAEs must be reported by the investigator up to 
Day 28. Spontaneously reported SAEs will be collected per protocol (up to 365 Days for all 
SAEs, and indefinitely if considered related to intervention).
 
 
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
(Randomized participants 
only)
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the 
Protocol-specified 
Follow-up Period
Time Frame to Report 
Event and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 hours of 
learning of event
MAAE
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 days of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or 
run-in treatment including 
placebo run-in) 
Report all
Previously 
reported – Follow 
to 
completion/termi
nation; report 
outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report all
- require 
regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo run-in 
or other run-in medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, MAAEs, and Other Reportable Safety 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, MAAE, and Other Reportable Safety Event 
Information
After the initial AE/SAE/MAAE report, the investigator is required to proactively follow 
each participant at subsequent visits/contacts. All AEs, SAEs, MAAEs, and other reportable 
safety events, including pregnancy and exposure during breastfeeding, ECIs, cancer, and 
overdose will be followed until resolution, stabilization, until the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). In addition, the 
investigator will make every attempt to follow all nonserious AEs that occur in randomized
participants for outcome. Further information on follow-up procedures is given in Appendix 
3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Rashes assessed as vesicular in nature.
3. Any new or worsening arthritis (i.e., that is not consistent with a participant’s chronic 
osteoarthritis if present). 
Further guidance on the evaluation of these ECIs is provided in the Guidance for Assessment 
and Work-up of Specific Postvaccination Adverse Effects (Appendix 4).
8.5
Treatment of Overdose
In this study, an overdose is defined as a participant receiving either more than 1 dose of 
study vaccine or a higher dose than intended in a 24-hour period. Sponsor does not 
recommend specific treatment for an overdose. Decisions regarding dose interruptions or 
modifications will be made by the investigator in consultation with the Sponsor Clinical 
Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis 
 
 
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8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic 
analysis is not approved, but future biomedical research is approved, this sample will be 
collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
•
RNA for future research  
•
Serum for future research 
•
Mucosal samples for future research
•
PBMCs and Plasma for future research
•
Leftover DNA for future research 
•
Leftover main study serum from anti-SARS-CoV-2 spike neutralizing antibodies (PRNT) 
stored for future research
•
Leftover main study serum from anti-SARS-CoV-2 spike IgG (ELISA) stored for future 
research
•
Leftover main study plasma from V590 viremia stored for future research
•
Leftover main study saliva from V590 shedding stored for future research
•
Leftover main study urine from V590 shedding stored for future research
•
Leftover main study stool from V590 shedding stored for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
 
 
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
The Screening period will be up to 6 weeks before Admission (Day -3 to Day -1 on SoA), 
and at minimum 7 days prior to vaccine administration. A separate Screening Protocol with 
its own informed consent may be utilized by sites in advance of main consent availability to 
perform tests at Screening as indicated on the study SoA.  Screening Protocol assessments/
activities will allow potential participants to be evaluated to determine if they may be eligible 
to enroll in the study based on the requirements described in Section 5; those considered 
potentially eligible may subsequently consider enrolling in this protocol. 
The participant data collected under the Screening Protocol and informed consent will be 
captured on the site study participant source per site SOP.  These participant data may be 
applied for screening in this study after the participant has provided main informed 
consent. The Screening data will be reviewed with the Sponsor.  The Screening data entry 
into the main study database will not be rate-limiting to the study start and the timing and 
procedures of post hoc data entry will be outlined in the supportive data management and 
monitoring documentation.  
All assessments/activities starting at and during Day -3 to Day -1 (beginning with participant 
admission to the clinical unit to begin domiciling) will be performed after the participants 
sign the main study informed consent, per SoA and Section 5.  Data entry will be per study 
process and supporting documentation.  
A screening SARS-CoV-2 RT-PCR and serology test should be performed in the screening
window per SoA.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation/randomization if 
there are Day -1 procedures planned per protocol.
8.11.2
Vaccination Visit (Admission, Vaccination, and Postdose)
Refer to the SoA (Section 1.3) and Administrative General Procedures (Section 8.1).
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
This section is not applicable to this study.
8.11.4
Poststudy
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study. If a participant discontinues for any reason at any 
 
 
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time during the course of the study, the participant may be asked to return to the study site 
(or be contacted) for a post-study visit (approximately 12 months after study vaccination) to 
have the applicable procedures conducted. However, the investigator may decide to perform 
the poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation.
If the poststudy visit occurs less than 12 months after study intervention (and not within 
protocol-specified variance), a subsequent follow-up telephone call should be made at 12 
months postdose of study intervention to determine if any SAEs have occurred since the 
poststudy clinic visit (as well as AEs/ECIs through Day 28 or MAAEs through Day 180, if 
not already collected).
Amendment 001-03: A poststudy visit/phone call will be performed for safety assessment. 
This may be combined with the Day 28 visit. Active monitoring of AEs, ECIs, and MAAEs 
will occur through Day 28. Spontaneously reported SAEs will be collected per protocol.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the timely and accurate collection and recording of AEs, and blood samples 
for immunogenicity (specifically PRNT and ELISA), are the critical procedures.
At any postdose time point, the blood sample for PRNT and ELISA anti-spike titers needs to 
be collected as close to the exact time point as possible. All other procedures should be 
completed as close to the prescribed/scheduled time as possible. Study procedures can be 
performed prior or after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
Site visit windows as outlined in Table 5
•
Samples collection windows as outlined in Table 6
 
 
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Table 5
Site Visit Windows
Site Visit
Visit Window
Day 1
N/A
Day 14
± 2 days
(~ Day 12 to Day 16 postdose)
Day 28
± 2 days
(~ Day 26 to Day 30 postdose)
Day 90
± 7 days
(~ Day 83 to Day 97 postdose)
Day 180
± 7 days
(~ Day 173 to Day 187 postdose)
Day 270
± 14 days
(~ Day 256 to Day 284 postdose)
Day 365
± 14 days
(~ Day 351 to Day 379 postdose)
Table 6
Sample Collection Windows
Sample Collection
Sample Collection Window
0 - <24 hr
1 hour
Days 2-7
2 hours
Days 14 and 28
2 days
Days 90 and 180
7 days
Days 270 and 365
14 days
•
Day 1 postdose will be done at ~6 hours. Other days will be done at approximately the 
same time of day as the Day 1 dosing, flexibly according to site SOP. 
•
Predose standard safety procedures: vital signs (BP, HR, RR, and temperature), and 
laboratory safety tests up to 3 hours before vaccine administration 
•
Predose physical exams up to 24 hours before vaccine administration
•
Postdose standard safety evaluations: vital signs (BP, HR, RR, and temperature), 
laboratory safety tests, and physical exam
-
Day 1 (postdose) procedures may be obtained within approximately 60 minutes of the 
theoretical sampling time
-
Days 2 to 7 evaluations can occur within approximately 2 hours of theoretical 
sampling time 
 
 
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•
Postdose evaluations (other): 
-
For the Roche Elecsys Anti-SARS-CoV-2 (central laboratory) test postdose 
timpoints, samples are only collected for Parts 1 and 2 (not Part 3).
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of V590 in humans, and the viral dynamics, immunogenicity 
and safety profiles of the vaccine are still being elucidated. This protocol is written with 
some flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose of the study intervention administered in any given 
part/panel
•
Interchange of doses between panels
•
Entire panel(s) may be omitted
•
Modification of the viremia/viral shedding/immunogenicity sample collection,
processing, and shipping details based on newly available data
•
Exploratory immunology endpoints may be removed or modified
The viremia/viral shedding/immunogenicity sampling scheme currently outlined in the 
protocol may be modified during the study based on newly available data. If indicated, these 
collected samples may also be assayed in an exploratory manner for additional virologic
and/or immunologic markers.
SARS-CoV-2 serology and RT-PCR testing may be modified based upon evolving 
understanding of the epidemic, development of novel tests, availability of testing, and other 
factors. Local testing may be permissible for serology testing with Sponsor agreement. Anti-
spike serology testing (instead of anti-nucleocapsid testing) may be permitted on Admission 
with Sponsor agreement. Antigen tests may be permitted with Sponsor agreement in place of 
RT-PCR tests; RT-PCR and/or antigen tests which are at present planned to be performed 
with nasopharngyeal swabs may be modified to generally better tolerated collection 
procedures such as those sampling from nasal midturbinate, anterior nares, oral mucosa, or 
saliva. Additional testing per site SOP is permitted. 
Up to ~627.5 mL of blood may be drawn during the study (up to ~457.5 mL of blood may be 
drawn before Day 90 for safety, viremia or immunologic assessments and up to ~168 mL of 
 
 
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blood may be drawn from Day 90 to Day 365 for safety, viremia or immunologic 
assessments). The total blood volume withdrawn from any single participant will not exceed 
the maximum allowable volume before and after Day 90. (Appendix 8).
The timing of procedures for assessment of safety procedures (e.g., vital signs, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
The interim analysis to summarize the safety and immunogenicity data may be performed if 
and when at least 80% of participants from Parts 1 and 2 have the following data available:  
Safety through at least Day 28 and PRNT and ELISA immunogenicity from Day 1 Predose 
and Day 28 postvaccination for participants from Parts 1 and 2 (and will also include as the 
available safety data from Part 3, which is not required for this interim analysis).
An additional interim analysis, using the same analysis plan, may be performed at the 
discretion of the study team when at least 80% of the above described data are available for 
anyone, two or three dose levels of Parts 1 and 2.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with International Council for Harmonisation [ICH] 
Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to unblinding, will be documented in a supplemental 
Statistical Analysis Plan and referenced in the Clinical Study Report (CSR) for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR.
 
 
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9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this study; the 
comprehensive plan is provided in Sections 9.2 through 9.9.
Study Design 
Overview
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, 
Dose-Ranging Trial to Evaluate the Safety and Immunogenicity 
of V590 in Healthy Adults
Intervention 
Assignment
Within each panel of Parts 1, 2, and 3, healthy adult participants 
will be assigned randomly in a 3:1 ratio to receive V590 or 
matching placebo: 
•
Panel A and E: V590 5.00·105 pfu or Placebo
•
Panel B and F: V590 2.40·106 pfu or Placebo
•
Panel C and G: V590 1.15·107 pfu or Placebo
•
Panel D, H, and I: V590 5.55·107 pfu or Placebo
All participants will receive study intervention administered via 
IM injection(s) on Day 1.
Analysis Populations
Safety: All Participants as Treated (APaT)
Viremia and Viral Shedding: All Participants as Treated (APaT)
Immunogenicity: Per-Protocol (PP)
Efficacy: Per-Protocol (PP)
Primary Endpoint
Safety:
•
Solicited injection site AEs from Day 1 through Day 5
•
Solicited systemic AEs from Day 1 through Day 28
•
Unsolicited AEs from Day 1 through Day 28 
•
MAAEs from Day 1 through Day 180
•
SAEs from Day 1 through Day 365
Amendment 001-03: MAAEs from Day 1 through Day 28. SAEs 
from Day 1 through the duration of the study until the final 
database lock.   
Immunogenicity:
•
Anti-SARS-CoV-2 spike serum neutralizing antibody (SNA)
responses, as measured by plaque reduction neutralization test 
(PRNT), at Day 28 (Parts 1 and 2)
 
 
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Key Secondary 
Endpoints
Immunogenicity:
•
Anti-SARS-CoV-2 spike SNA responses, as measured by 
PRNT, at Days 7, 14, 90, 180, 270, and 365 (Parts 1 and 2)
•
Anti-SARS-CoV-2 spike IgG responses, as measured by
enzyme-linked immunosorbent assay (ELISA), at Days 7, 14, 
28, 90, 180, 270, and 365 (Parts 1 and 2)
Amendment 001-03: Immunogenicity analyses will include all 
available data through Day 28.  
Statistical Methods for 
Key Immunogenicity
Analyses
Separately for each primary and secondary immunogenicity 
parameter, the geometric mean titers (GMT) with 95% 
confidence interval (CI), GMT ratios with 90% CI, and the 
hypothesis test (i.e., 2-sided p-value) if applicable, will be 
estimated using a longitudinal data analysis (LDA) method 
utilizing data from all vaccination and combining placebo groups. 
The primary hypothesis that at least one well-tolerated dose level 
of a single dose administration of V590 increases the GMTs of 
anti-SARS-CoV-2 spike SNA, as measured by PRNT, compared 
to placebo, will be tested using a stepwise procedure with an 
assumption that there is an increasing relationship between anti-
SARS-CoV-2 spike SNAs and V590 doses.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. No 
Tier 1 events are defined in this study. For Tier 2 events, 95% CIs
will be provided for between-vaccination group differences in the 
percentage of participants with events; these analyses will be 
performed using the M&N method [Miettinen, O. and Nurminen, 
M. 1985] [Miettinen, O. 1985]. All safety parameters will also be 
summarized via descriptive statistics.
Interim Analyses
An interim analysis of safety and immunogenicity data to inform 
further clinical development will be performed, when at 
minimum 80% participants in Parts 1 and 2 have completed at 
least 28-day follow-up post-vaccination and immunogenicity data 
are available. 
Multiplicity
The study has only 1 primary hypothesis which will be addressed 
using a closed step-wise testing procedure that preserves the 
overall alpha level at 0.05 1-sided (assuming a monotonic dose-
response).
Sample Size and 
Power
Section 9.9 provides information about the ability of this study to
estimate the incidence of AEs in recipients of a dose of V590; 
and the power to demonstrate an increase in anti-SARS-CoV-2 
SNAs elicited by V590, compared to placebo.
 
 
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Amendment 001-03: Active monitoring and immunogenicity assessments in the study will 
occur through Day 28. Spontaneous safety reporting is permitted beyond Day 28 for the 
protocol specified durations. Immunogenicity analyses will include all available data through 
Day 28. Safety analyses will include all collected safety data through the duration of the 
study until the final database lock. A final analysis of study data will occur instead of an 
interim analysis. 
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. 
This study will be conducted as a double-blind study. The official, final database will not be 
unblinded until medical/scientific review has been performed, protocol deviations have been 
identified, and data have been declared final and complete. Section 6.3.3 specifies the roles 
and responsibilities of the site and Sponsor personnel who will be unblinded during the 
study. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
Blinding details related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Analysis endpoints of safety, immunogenicity, viremia and viral shredding, and efficacy are 
listed below.
9.4.1
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, postvaccination body temperature measurements, physical examinations, 
laboratory safety tests, and vital signs following any vaccination with V590 or Placebo.
The safety analysis endpoints that address the primary objective include:
•
Solicited injection-site AEs (redness, swelling, and tenderness/pain) from Day 1 post-
dose through Day 5 after study intervention
•
Solicited systemic AEs (muscle pain, joint pain, headache, tiredness, fatigue, rash, 
nausea, joint swelling, oral lesions, sweating more than usual) from Day 1 post-dose 
through Day 28 after study intervention
•
Unsolicited AEs from Day 1 post-dose through Day 28 after study intervention
 
 
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•
The broad AE categories consisting of any AE, vaccine-related AE, ECIs, and 
vaccine-related ECIs from Day 1 post-dose through Day 28 after study intervention
•
The broad AE categories consisting of any MAAE and vaccine related MAAE from 
Day 1 post-dose through Day 180 after study intervention
•
The broad AE categories consisting of any SAE, vaccine related SAEs, and death from 
Day 1 post-dose through the duration of participation in the study after study 
intervention
•
Maximum temperature measurements meeting the Brighton Collaboration cut points 
from Day 1 through Day 28 after study intervention
Additional Safety analysis endpoints include:
•
Safety laboratory results collected at Day 1 predose, Days 3, 7, and 28 
•
Vital signs collected at scheduled (see Section 1.3) and unscheduled visits.
Amendment 001-03: MAAEs from Day 1 post-dose through Day 28. SAEs from Day 1 
through the duration of the study until the final database lock.
9.4.2
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints include:
•
Anti-SARS-CoV-2 spike SNA at Day 28, as measured by plaque reduction 
neutralization test (PRNT), in Parts 1 and 2 participants
The secondary immunogenicity analysis endpoints include:
•
Anti-SARS-CoV-2 spike SNA at Day 1 Predose, Days 7, 14, 90, 180, 270, and 365, as 
measured by PRNT, in Parts 1 and 2 participants
•
Anti-SARS-CoV-2 spike IgG at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 365, 
as measured by enzyme-linked immunosorbent assay (ELISA), in Parts 1 and 2 
participants 
The exploratory immunogenicity analysis endpoints include:
•
Anti-SARS-CoV-2 spike SNA at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 
365, as measured by PRNT, in Part 3 participants
•
Anti-SARS-CoV-2 spike IgG at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 365, 
as measured by ELISA, in Part 3 participants 
 
 
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Additional exploratory immunogenicity analysis endpoints may include:
•
Enzyme-linked immunospot assay (ELISPOT) and intracellular cytokine staining 
(ICS) of peripheral blood mononuclear cells (PBMC)
•
Anti-SARS-CoV-2 spike antibodies in mucosal samples
•
Serum cytokines/chemokines 
Exploratory immunogenicity endpoints may be summarized and reported separately.
Amendment 001-03: Immunogenicity analyses will include all available data through Day 
28.
9.4.3
Viremia and Viral Shedding Endpoints
There is no primary analysis endpoint for V590 viremia and viral shedding.
The secondary V590 viremia and viral shedding analysis endpoints include: 

V590 plasma viremia, as detected by RT-PCR at Day 1 post-dose, Days 2, 3, 4, 5, 6, 7, 
14, and 28 

V590 viral shedding in urine and saliva, as detected by RT-PCR at Day 1 post-dose, 
Days 2, 3, 4, 5, 6, 7, 14, and 28
V590 viral shedding in stool, as detected by RT-PCR at Days 2-4, and 5-7 (if assayed)
Exploratory viremia and viral shedding analysis endpoints include:

V590 plasma viremia, as detected by Plaque Assay

V590 viral shedding in urine, saliva, and stool as detected by Plaque Assay
Amendment 001-03: Viremia and viral shedding samples will be assayed with the intention 
of testing until negative for viremia/viral shedding. Viremia and viral shedding analyses will 
include all available data through Day 28.
9.4.4
Efficacy Endpoints
The exploratory efficacy analysis endpoint includes:

Number and proportion of participants in Parts 1 and 2 experiencing seroconversion, 
which is determined by anti-SARS-CoV-2 nucleocapsid antibody titers at Days 7, 14, 
28, 90, 180, 270, and 365, compared to baseline (Screening).
Amendment 001-03: Efficacy analyses will include all available data through Day 28.
 
 
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9.5
Analysis Populations
The following analysis populations are defined for the analysis and reporting of data.
All Participants as Treated (APaT): The All Participants as Treated population consists of all 
randomized participants who received at least one dose of study vaccination. Participants will 
be included in the vaccination group corresponding to the study intervention they received 
for the analysis using the APaT population. This will be the vaccination group to which they 
are randomized except for participants who receive an incorrect dose of study vaccine or 
placebo; such participants will be included in the vaccination group corresponding to the 
study vaccine actually received.
FAS (Full Analysis Set): The Full Analysis Set population consists of all randomized 
participants who received at least one dose of study vaccination and have at least 1 result of 
the analysis endpoints. Participants will be included in the vaccination group to which they 
are randomized for the analysis using the FAS population.
Per-Protocol (PP): The Per-Protocol population consists of all randomized participants with 
exclusions for important deviations from the protocol that may substantially affect the results 
of the analysis endpoints. Participants will be included in the vaccination group to which they 
are randomized for the analysis using the PP population. 
9.5.1
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least one dose of study 
vaccination.
At least one laboratory, vital sign, or ECG measurement obtained subsequent to at least one 
study treatment is required for inclusion in the analysis of the respective safety parameter.  
To assess change from baseline, a baseline measurement is also required.
9.5.2
Immunogenicity Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of immunogenicity data. The 
PP population consists of all randomized participants with exclusions for important 
deviations from the protocol that may substantially affect the results of the immunogenicity
endpoints. Deviations that may result in the exclusion of a participant from the PP population 
include:

Failure to receive the correct dose of study vaccination at Day 1

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection

Collection of blood sample outside of the pre-specified window
 
 
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The final determination on important protocol deviations, and thereby the composition of the 
Per-Protocol population, will be made by blinded study team members prior to the final 
unblinding of the database. 
A supplementary analysis using the Full Analysis Set (FAS) population will also be 
performed for the primary and secondary immunogenicity endpoints.
Details on the approach to handle missing data are provided in Section 9.6.
9.5.3
Viremia and Viral Shedding Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of viremia 
and viral shedding data. The APaT population consists of all randomized participants who 
received at least one dose of study vaccination. At least one viremia or viral shedding
measurement obtained subsequent to at least one study vaccination is required for inclusion 
in the analysis of the respective parameter.
A supplementary analysis using the Per-Protocol (PP) population may also be performed for 
the viremia and viral shedding endpoints. 
9.5.4
Efficacy Analysis Population
The Per-Protocol (PP) population will be used for the analysis of efficacy data.  The PP 
population consists of all randomized participants with exclusions for important deviations 
from the protocol that may substantially affect the results of the anti-SARS-CoV-2 
nucleocapsid antibody titers.
A supplementary analysis using the Full Analysis Set (FAS) population will also be 
performed for the efficacy endpoint.
9.6
Statistical Methods
Statistical methods for safety, immunogenicity, and viremia and viral shedding analyses are 
described in Section 9.6.1, Section 9.6.2, and Section 9.6.3, respectively. Section 9.6.4
describes how demographic and baseline characteristics will be summarized.
For all analyses, data will be examined for departures from the assumptions of the statistical 
model(s) as appropriate; e.g., heteroscedasticity, non-normality of the error terms. 
Distribution-free methods may be used if a serious departure from the assumptions of the 
models(s) is observed, or suitable data transformations may be applied.
9.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, postvaccination temperatures, laboratory measurements, ECGs, and vital 
signs.
 
 
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The analysis of AEs and postvaccination temperature measurements will follow a tiered 
approach [Table 7]. The tiers differ with respect to the analyses that will be performed. 
Events (specific preferred terms (PT) as well as system organ classes (SOC)) are either pre-
specified as Tier 1 endpoints or will be classified as belonging to Tier 2 or Tier 3 based on 
the number of events observed. 
Laboratory measurements, ECGs, and vital signs will be summarized separately. Summary 
statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or vital signs 
as well as for change from baseline, as deemed clinically appropriate. Depending on the 
safety parameter, the difference from baseline will either be computed on the original scale 
(raw change from baseline) or on the log scale and back-transformed for reporting (percent 
change from baseline). Baseline is defined as the pre-dose measurement.
Tier 1 Events
Safety events or AEs of special interest that are pre-identified constitute Tier 1 safety 
endpoints which will be subject to inferential testing for statistical significance with 95% CIs 
and corresponding p-values provided for the between-treatment differences in the proportion 
of participants with events.
No Tier 1 events are defined for this study.
This study will solicit for predefined injection-site and systemic AEs. However, as this is the 
first clinical study of V590, no data exists around which a comparative, data-driven safety 
hypothesis can be formulated and tested. As a result, the solicited injection-site and systemic 
AE reported in this study will be analyzed as Tier 2 events.
Tier 2 Events
Tier 2 events will be assessed via point estimates and risk differences with 95% CIs provided 
for differences in the proportion of participants with events. Analyses will be performed 
using the Miettinen and Nurminen (M&N) method [Miettinen, O. 1985], an unconditional, 
asymptotic method.
Tier 2 events for this study include solicited injection-site AEs (redness/erythema, swelling, 
and tenderness/pain) from Day 1 through Day 5 postvaccination, solicited systemic AEs 
(muscle pain, joint pain, headache, tiredness, rash, nausea, joint swelling, oral lesions, 
sweating more than usual) from Day 1 through Day 28 postvaccination, and ECIs from Day 1 
through Day 28 postvaccination. In addition, the broad AE categories consisting of the 
percentage of participants with any AE, any vaccine-related AE, any ECI, any vaccine-
related ECI, any MAAE, any vaccine-related MAAE, any SAE, any vaccine-related SAE, 
and death will be considered Tier 2 events. Nonserious AEs will be followed for 28 days 
postvaccination, while MAAEs will be followed through Day 180 and SAEs will be followed 
through the duration of participation in the study. The proportion of participants with 
maximum temperature measurements meeting the Brighton Collaboration [Marcy, S. M., et 
al 2004] cut points (Days 1 to 28) will also be considered Tier 2 endpoints.
 
 
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Adverse events (specific PTs as well as SOCs) will be classified as belonging to Tier 2 if at 
least 4 participants in any vaccination group exhibit the event. The threshold of at least 4 
events was chosen because the 95% CI for the between-group difference in percent incidence 
will always include zero when vaccination groups of equal size each have less than 4 events 
and thus would add little to the interpretation of potentially meaningful differences. Because 
many 95% CIs for Tier 2 events may be provided without adjustment for multiplicity, the CIs 
should be regarded as a descriptive measure supportive of safety review, not a formal method 
assessing the statistical significance of the between-group differences in AEs.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by vaccination group are provided for Tier 3 safety parameters.
Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for Between-
Group Comparison a
Descriptive
Statistics
Tier 2
Injection-site redness/erythema (Days 1 to 5)
X
X
Injection-site swelling (Days 1 to 5)
X
X
Injection-site tenderness/pain (Days 1 to 5)
X
X
Muscle pain/myalgia (Days 1 to 28)
X
X
Joint pain/arthralgia (Days 1 to 28)
X
X
Joint swelling (Days 1 to 28)
X
X
Rash (Days 1 to 28)
X
X
Oral lesion (Days 1 to 28)
X
X
Nausea (Days 1 to 28)
X
X
Headache (Days 1 to 28)
X
X
Tiredness/fatigue (Days 1 to 28)
X
X
Sweating more than usual/abnormal sweating 
(Days 1 to 28)
X
X
Any AEb
X
X
Any Vaccine-Related AEb
X
X
Any ECIb
X
X
Any Vaccine-Related ECIb
X
X
Any MAAEb
X
X
Any Vaccine-Related MAAEb
X
X
Any SAEb
X
X
Any Vaccine-Related SAEb
X
X
Deathb
X
X
Maximum temperature measurements 
meeting the Brighton Collaboration cut 
points (Days 1 to 28) 
X
X
Specific AEs by SOC and PT (incidence ≥4 
participants in at least one of the vaccination 
groups)
X
X
Tier 3
Specific AEs by SOC and PTc (incidence <4 
participants in one of the vaccination groups)
X
 
 
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Safety 
Tier
Safety Endpoint†
95% CI for Between-
Group Comparison a
Descriptive
Statistics
AE = adverse event; CI = confidence interval; MAAE = medically attended adverse event; M&N = Miettinen and 
Nurminen; PT = preferred term; SAE = serious adverse event; SOC = system organ class; X = results will be provided.
a These analyses will be performed using the M&N method [Miettinen, O. and Nurminen, M. 1985].
b These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least 1 AE.
c Includes only those endpoints not prespecified as Tier 2 endpoints.
Amendment 001-03: MAAEs from Day 1 post-dose through Day 28. SAEs from Day 1 
through the duration of the study until the final database lock.
9.6.2
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary, secondary, and 
exploratory immunogenicity objectives. The immunogenicity analyses will be conducted for 
each endpoint separately [Table 8].
Primary Hypothesis
At least one well-tolerated dose level of a single dose administration of V590 increases the 
GMTs of anti-SARS-CoV-2 spike SNA, as measured by PRNT, compared to placebo.
The primary endpoint, anti-SARS-CoV-2 spike SNA GMTs at Day 28 will be assessed via 
the following hypotheses:
H0: GMT1/GMT2 ≤1 versus
H1: GMT1/GMT2 >1,
where GMT1 is the anti-SARS-CoV-2 spike SNA GMT for a V590 dose level and GMT2 is 
the anti-SARS-CoV-2 spike SNA GMT for the placebo. Estimation of the GMT ratio and the 
corresponding 90% CI will be calculated using a LDA model utilizing the log-transformed 
antibody titers as the response.
A Stepwise Procedure
The primary hypothesis will be tested using the following stepwise procedure with an 
assumption that there is an increasing relationship between anti-SARS-CoV-2 spike SNAs
and V590 doses. The primary hypothesis will be supported if the lower limit of the 90% CI
(equivalent to the lower bound of a one-sided 95% CI) for the GMT ratio between the highest 
V590 dose and placebo is >1 (indicating an increase). If the hypothesis is supported in the 
previous step, then the same procedure will be applied to the next lowest dose. The procedure 
continues in this stepwise fashion until the lower limit of the 90% CI at a particular dose is 
≤1. 
 
 
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LDA Model
Separately for each primary and secondary immunogenicity parameter, the GMTs with 95% 
CI, GMT ratios with 90% CI, and the hypothesis test (i.e., 2-sided p-value) if applicable, will 
be estimated using an LDA method utilizing data from all vaccination and placebo groups. 
The response vector consists of the natural log-transformed prevaccination (Day 1) and 
postvaccination (Days 7, 14, 28, 90, 180, 270, and 365) antibody titers. The linear mixed-
effects model will include fixed effects of dose (4 dose levels of V590 and placebo), time
(Days 1, 7, 14, 28, 90, 180, 270, and 365), age stratum (i.e., 18 to 54 years, and ≥55 years), 
the dose-by-time interaction, and age-by-time interaction. The term for time will be treated as 
a categorical variable. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. The Kenward-Roger adjustment will be used with 
REML to make proper statistical inference. This model allows the inclusion of participants 
who are missing either the baseline or postbaseline measurements, thereby increasing 
efficiency.
Exponentiating the least squares means and the lower and upper limits of CIs will yield 
estimates for the population GMTs and corresponding 95% CIs by dose, time, and/or age 
stratum on the original scale. To assess the treatment difference between 1 of the 4 dose 
levels of V590 relative to the placebo, the least squares mean differences (V590 – placebo) 
and 90% CIs from this model will be back-transformed to obtain the GMT ratios
(V590/placebo) and 90% CIs.
Secondary and Exploratory Endpoints
The evaluations of secondary and exploratory objectives will be performed within each
vaccination group separately. Descriptive statistics with point estimates and within-group 
95% CIs will be provided by dose, time, and/or age stratum. For the continuous endpoints, 
the point estimates will be calculated by exponentiating the estimates of the mean of the 
natural log values and the within-group CIs will be derived by exponentiating the bounds of
CIs of the mean of the natural log values based on the t-distribution. For the dichotomous 
endpoints, if any, the within-group CIs will be calculated based on the exact method 
proposed by Clopper and Pearson [Clopper, C. J. 1934].
Additionally, SNA GMTs and IgG GMTs and corresponding 95% CIs may be calculated 
using the same LDA model as for the primary endpoint.
Miscellaneous
The relationship between anti-SARS-CoV-2 spike SNAs and V590 doses will be displayed 
graphically. Reverse Cumulative Distribution Curves for postvaccination SNA GMTs and 
IgG GMTs will be graphically displayed by time points.
For titer measurements that are smaller than the lower bound of the assay detectable range, 
half of the lower bound may be used as the value of the titer.
 
 
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Table 8
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint (H1)
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Day 28
(Parts 1 and 2) 
P
t-distribution with the 
variance estimate from 
an LDA model‡
(estimate, 95% CI, 
p-value)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoint
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Days 7, 14, 90, 180, 
270, and 365
(Parts 1 and 2)
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
GMTs of anti-SARS-CoV-2 spike serum 
IgG, as measured by ELISA, at Days 7, 14, 
28, 90, 180, 270, and 365
(Parts 1 and 2)
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Exploratory Endpoints
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Days 7, 14, 28, 90, 
180, 270, and 365
(Part 3)
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
GMTs of anti-SARS-CoV-2 spike serum 
IgG, as measured by ELISA, at Days 7, 14, 
28, 90, 180, 270, and 365
(Part 3)
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
CI = confidence interval; FAS = Full Analysis Set; GMT = geometric mean titer; H = hypothesis; IgG = Immunoglobulin 
G; SNA = serum neutralizing antibody; PP = Per-Protocol.
†
P = Primary approach using PP population; S = Supportive approach using FAS population.
‡
Estimation of the SNA GMT ratios and computation of the corresponding 95% CIs will be calculated using 
t-distribution with the variance estimate from a constraint longitudinal data model (LDA) utilizing the log-transformed 
antibody titers as the response and a single term for vaccination group. 
Amendment 001-03: Immunogenicity analyses will include all available data through Day 
28.
 
 
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9.6.3
Statistical Methods for Viremia and Viral Shedding Analyses
The viremia and viral shedding analyses will be conducted for each endpoint separately.
Numbers and proportions of participants with positive V590 plasma viremia and positive 
viral shedding in urine, saliva, and stool (if assayed), as detected by RT-PCR, will be 
calculated by dose, time, and/or age stratum. 
GMs with 95% CIs of positive V590 plasma viremia and positive viral shedding in urine,
saliva, and stool (if assayed), will be estimated by dose, time, and/or age stratum. Descriptive 
statistics including n, median, minimum, and maximum will also be provided.
Area under the curve (AUC) of each viremia and viral shedding endpoints between Day 1 
and Day 7 will be calculated and analyzed using a linear model with dose as a fixed 
categorial effect. The mean AUC in each dose group and 95% CIs will be computed based on 
the model. Descriptive statistics of AUC including n, median, minimum, and maximum will 
be provided.
Median, minimum, and maximum durations of positive V590 plasma viremia and viral 
shedding in urine, saliva, and stool (if assayed), will be reported.
The longitudinal patterns of each viremia and viral shedding endpoints after vaccination from 
Day 1 through Day 7 will be displayed graphically by dose group. 
Positive viremia and viral shedding are defined as a detectable RT-PCR results greater than 
or equal to lower limit of detection [≥ LLOD]. Results are deemed quantifiable if the result is 
greater than or equal to the lower limit of quantification [≥ LLOQ].
Amendment 001-03: Viremia and viral shedding samples will be assayed with the intention 
of testing until negative for viremia/viral shedding. Viremia and viral shedding analyses will 
include all available data through Day 28.
9.6.4
Statistical Methods for Efficacy Analyses
The exploratory efficacy analysis will assess the efficacy of V590 to prevent seroconversion 
to anti-SARS-Cov-2 nucleocapsid antibody positivity, an evidence of infection.
GMTs of anti-SARS-CoV-2 nucleocapsid antibody will be calculated by dose, time and/or 
age stratum. Numbers and proportions of participants in the PP population of Parts 1 and 2, 
who meet seroconversion criteria, will be estimated by dose, time, and/or age stratum. 
Corresponding within-group 95% CIs will be calculated based on the exact method proposed 
by Clopper and Pearson [Clopper, C. J. 1934].
Amendment 001-03: Efficacy analyses will include all available data through Day 28.
 
 
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9.6.5
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (e.g., age, race, and gender) and baseline 
characteristics will be summarized by treatment group either by descriptive statistics or 
categorical tables.
9.7
Interim Analyses
An interim analysis of safety and immunogenicity data to inform further clinical 
development will be performed, when at minimum 80% participants in Parts 1 and 2 have 
completed at least 28-day follow-up post-vaccination and immunogenicity data are available. 
All available safety data will be evaluated. Serum samples collected on Day 1 prior to 
vaccination and on Day 28 postvaccination will be assayed for vaccine-induced immune 
responses to V590. Anti-SARS-CoV-2 spike SNA titers measured by PRNT are the primary 
outcome measure. Anti-SARS-CoV-2 spike IgG titers measured using ELISA will be 
analyzed as a secondary objective. The study enrollment, conduct, and ongoing safety 
monitoring will continue.
An additional interim analysis may be conducted earlier at the discretion of the sponsor when 
at minimum 80% participants in one, two, or three dosing levels in Parts 1 and 2 have 
completed at least 28-day follow-up post-vaccination and immunogenicity data are available.
Analyses of immunogenicity data from Day 90, Day 180, and/or 270 may also be conducted 
at the discretion of the sponsor when data are available, to inform future study designs.
siDMC
An unblinded siDMC will receive the unblinded IA safety and immunogenicity data. The 
siDMC will make a recommendation for further clinical development based on review of: (1) 
available safety data through at least Day 28 for all participants enrolled in Parts 1 and 2; (2) 
available immunogenicity data for all evaluable participants enrolled in Parts 1 and 2; and (3) 
any available safety data from Part 3. The primary immunogenicity hypothesis will be 
evaluated to inform the decision.
A description of the structure and function of the siDMC, along with the timing and content 
of the safety review, will be outlined in the siDMC charter. Information regarding the 
composition of the siDMC is provided in Section 10.1.4.1.
 
 
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Blinding
Regardless of the outcome of the IA, blinding to treatment assignment will be maintained at 
all investigational sites. The results of IAs will not be shared with the investigators prior to 
the completion of the study.
For this Phase I study, an internal statistician, statistical programmers, and modelers assigned 
to the protocol will be unblinded throughout the duration of the study to facilitate the interim 
reviews and analyses of the safety and immunogenicity data.
Treatment-level safety and immunogenicity results from the IA will be provided by the 
unblinded statistician to the siDMC. Aggregate safety data and treatment-level 
immunogenicity results will be provided by the unblinded statistician to the sponsor study 
team. The extent to which individuals are unblinded with respect to the results of IAs will be 
documented by the unblinded statistician.
Amendment 001-03: Participants in all parts will be followed through Day 28 for safety, 
tolerability, immunogenicity, viremia and viral shedding. A final study analysis will be 
performed on all available data through Day 28, in place of an Interim Analysis.
9.8
Multiplicity
The study has only 1 primary hypothesis which will be addressed using a closed step-wise
testing procedure that preserves the overall alpha level at 0.05 1-sided (assuming a
monotonic dose-response).
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Safety Analyses
The probability of observing at least one SAE in this study depends on the number of 
participants dosed and the underlying percentage of participants with a SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. 
There is an 90% chance of observing at least 1 SAE among 189 participants receiving V590 
if the underlying incidence of a SAE is 1.2% (1 out of every 84 vaccine recipients). There is 
a 60% chance of observing at least one SAE among 189 participants receiving V590 if the 
underlying incidence of a SAE is 0.5% (1 out of every 189 vaccine recipients). If no SAEs 
are observed in the approximately 189 participants receiving V590, this study provides
97.5% confidence that the true SAE rate is <1.93% (1 out of every 51 vaccine recipients).
 
 
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9.9.2
Sample Size and Power for Immunogenicity Analyses
An estimate of variability was obtained from the available data from V920-009, V920-011, 
and V920-012. The largest variability computed for any PRNT parameter in that studies was 
1.2 (standard deviation on natural log scale). 
The study achieves 90% power at a 1-sided 5% alpha-level to demonstrate V590 increases 
anti-SARS-CoV-2 SNA GMTs, compared to placebo, based on a true GMT ratio of V590 vs. 
placebo ≥2.17, assuming (1) an 85% evaluability rate at Day 28 in Parts 1 and 2 (i.e., 36
evaluable participants out of 42 V590 recipients in each dose level, and 48 evaluable 
participants out of 56 placebo recipients); and (2) a comparable variability as observed in 
V920 (i.e., natural log scale standard deviation to be 1.2).
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
 
 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
 
 
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
 
 
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10.1.4
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the monitoring outlined in this protocol, and in addition to the Sponsor safety 
review team, a separate siDMC will monitor the interim data from this study and will be 
convened if stopping rules are met. The siDMC is comprised of members of Sponsor Senior 
Management, none of whom are directly associated with the conduct of this study. The 
siDMC will monitor the study at the Interim Analysis (Section 9.7) to evaluate available 
safety and immunogenicity data for consideration of further development, as described in the 
detailed monitoring guidelines. The siDMC will review all available relevant data if stopping 
rules are met in this study. 
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
 
 
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
 
 
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Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 9 will be performed by the local laboratory. Additionally, if 
the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 8.1.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose [Indicate if 
fasting, or 
nonfasting]
Calcium
Alkaline 
phosphatase
Creatinine Kinase
(CPK)
C-reactive protein
(CRP) (high-
sensitivity)
Coagulation
Prothrombin 
time/International 
Normalized
Ratio (PT/INR)
Activated Partial 
thromboplastin time 
(aPTT)
Fibrinogen
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
 
 
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Laboratory 
Assessments
Parameters
Other Tests
(per SoA)
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential 
only)
•
Serum β-hCG or urine pregnancy test (as needed in women of childbearing 
potential only)
•
Serum or urine [alcohol and drug screen (specific panel at the site’s discretion, but 
at least including cocaine and opiates)]
•
Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C 
virus antibody)]
•
Hemoglobin A1c
•
All study-required laboratory assessments will be performed by a local laboratory, 
with the exception of SARS-CoV-2 Tests (PCR and antibody tests) that will be 
measured by a Central laboratory (per the SoA)
•
Additional tests may be done per site SOP with Sponsor agreement
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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•
MAAE: defined as adverse events in which medical attention is received during an 
unscheduled, non-routine outpatient visit, such as an emergency room visit, office visit, 
or an urgent care visit with any medical personnel for any reason. Routine visits are not 
considered MAAEs. Examples of routine visits include: physical examinations, wellness 
visits or vaccinations.
•
NOTE: Determination of MAAEs is the responsibility of the investigator or a qualified 
designee. Once identified, MAAEs should be reported to the Sponsor within 5 calendar 
days of learning of the event.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
 
 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
 
 
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10.3.4
Recording AE, SAE, and MAAE
AE, SAE, and MAAE recording

When an AE/SAE/MAAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE/MAAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE/MAAE.

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Participant Assessment of Intensity/Severity
•
The study participants will make a self-assessment of intensity/severity for each AE and 
SAE (and other reportable safety event) reported during the study. The study participant 
will assign an intensity or severity of mild, moderate, or severe, as defined in the VRC.  
•
Injection site erythema/redness or swelling from Day 1 (the day of vaccination) through 
Day 5 postvaccination will be evaluated for maximum size by the study participant and 
will not be assigned an intensity/severity rating.  
•
Values self-assessed by the study participants (of intensity/severity and/or daily 
maximum size) should be entered into the database without investigator modification
Investigator Assessment of Toxicity
•
The investigator will make an assessment of toxicity (ie, Grades 1, 2, 3, or 4) for each AE 
and SAE (and other reportable event) reported during the study. A toxicity grade will be 
assigned to injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in Table 10, Table 11, Table 12, and Table 13. The 
laboratory values in Table 14, Table 15, and Table 16 should serve as approximate 
guidelines for defining toxicities due to variations in established normal ranges.  Local 
 
 
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laboratory ranges and investigator discretion should be used for defining [Grade 1] 
toxicities.  Local laboratory ranges and investigator discretion may used for defining 
[Grade 2] toxicities with Sponsor Consultation. The toxicity grading scales used in this 
study are adapted from the “FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007.” 
Table 10
Injection-Site AE Toxicity Grading Scale
Injection Site 
Reaction to Study 
Vaccine/Placeboa
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring Days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative 
dermatitis or 
results in ER 
visit or 
hospitalization
Induration/Swelling
Size measured as 
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER 
visit or 
hospitalization
Other 
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begin on Day 6 following receipt of study vaccine/placebo
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Abbreviations: AE = adverse event; ER = emergency room; VRC = Vaccine Report Card; SAE = serious adverse event
a Based upon information provided by the participant on the VRC and verbally during VRC review. Erythema/Redness and 
Induration/Swelling are specific injection-site AEs with size designations of letters A through E→, based upon a graphic in 
the VRC. Size A is not assigned a toxicity grade; however, injection-site AEs that measure size A should be reported as 
adverse experiences. If the participant has an ER visit or is hospitalized for any injection-site AE, that AE is to be assigned a 
toxicity grade of 4, regardless of the size measured.
 
 
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Table 11
Specific Systemic AE Toxicity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any 
use of narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Abbreviations: ER = emergency room
Table 12
Other Systemic AE Toxicity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical AE 
(as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
ER visit or 
hospitalization
Abbreviations: ER = emergency room; VRC =  Vaccine Report Card; SAE = serious adverse event
a Based upon information provided by the patient on the VRC and verbally during the VRC review during the primary safety 
follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be based upon the initial 
report and/or follow-up of the event.
b AEs resulting in death will be assessed as Grade 4.
Table 13
Vital Sign (Temperature) Toxicity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever 
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements.
b Oral temperature; no recent hot or cold beverages or smoking.
 
 
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Table 14
Laboratory Abnormalities - Serum
Serum *
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening 
(Grade 4)**
Sodium – Hyponatremia mEq/L
132 – 134
130 – 131
125 – 129
< 125
Sodium – Hypernatremia mEq/L
144 – 145
146 – 147
148 – 150
> 150
Potassium – Hyperkalemia mEq/L
5.1 – 5.2
5.3 – 5.4
5.5 – 5.6
> 5.6
Potassium – Hypokalemia mEq/L
3.5 – 3.6
3.3 – 3.4
3.1 – 3.2
< 3.1
Glucose – Hypoglycemia mg/dL
65 – 69
55 – 64
45 – 54
< 45
Glucose –
Hyperglycemia 
Fasting – mg/dL
Random – mg/dL
100 – 110
110 – 125
111 – 125
126 – 200
>125
>200
Insulin 
requirements 
or 
hyperosmolar
coma
Blood Urea Nitrogen
BUN mg/dL
23 – 26
27 – 31
> 31
Requires
dialysis
Creatinine – mg/dL
1.5 – 1.7
1.8 – 2.0
2.1 – 2.5
> 2.5 or 
requires dialysis
Calcium – hypocalcemia mg/dL
8.0 – 8.4
7.5 – 7.9
7.0 – 7.4
< 7.0
Calcium – hypercalcemia mg/dL
10.5 – 11.0
11.1 – 11.5
11.6 – 12.0
> 12.0
Magnesium – hypomagnesemia 
mg/dL
1.3 – 1.5
1.1 – 1.2
0.9 – 1.0
< 0.9
Phosphorous – hypophosphatemia
mg/dL
2.3 – 2.5
2.0 – 2.2
1.6 – 1.9
< 1.6
CPK – mg/dL
1.25 – 1.5 x
ULN***
1.6 – 3.0 x 
ULN
3.1 –10 x ULN
> 10 x ULN
Albumin – Hypoalbuminemia g/dL
2.8 – 3.1
2.5 – 2.7
< 2.5
--
Total Protein – Hypoproteinemia 
g/dL
5.5 – 6.0
5.0 – 5.4
< 5.0
--
Alkaline phosphate –
increase by factor
1.1 – 2.0 x ULN
2.1 – 3.0 x 
ULN
3.1 – 10 x ULN
> 10 x ULN
Liver Function Tests –ALT, AST
increase by factor
1.1 – 2.5 x ULN
2.6 – 5.0 x 
ULN
5.1 – 10 x ULN
> 10 x ULN
Bilirubin – when accompanied by 
any increase in Liver Function Test 
increase by factor
1.1 – 1.25 x ULN 1.26 – 1.5 x 
ULN
1.51 – 1.75 x 
ULN
> 1.75 x ULN
Bilirubin – when Liver Function 
Test is normal; increase by factor
1.1 – 1.5 x ULN
1.6 – 2.0 x 
ULN
2.0 – 3.0 x ULN > 3.0 x ULN
Cholesterol
201 – 210
211 – 225
> 226
---
Pancreatic enzymes – amylase, 
lipase
1.1 – 1.5 x ULN
1.6 – 2.0 x 
ULN
2.1 – 5.0 x ULN > 5.0 x ULN
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example. a low sodium value that falls within 
a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value.
***ULN” is the upper limit of the normal range.
 
 
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Table 15
Laboratory Abnormalities - Hematology
Hematology *
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Hemoglobin (Female) - gm/dL
11.0 – 12.0
9.5 – 10.9
8.0 – 9.4
< 8.0
Hemoglobin (Female)
change from baseline value -
gm/dL
Any decrease – 1.5 1.6 – 2.0
2.1 – 5.0
> 5.0
Hemoglobin (Male) - gm/dL
12.5 – 13.5
10.5 – 12.4
8.5 – 10.4
< 8.5
Hemoglobin (Male)
change from baseline value –
gm/dL
Any decrease – 1.5 1.6 – 2.0
2.1 – 5.0
> 5.0
WBC Increase - cell/mm3
10,800 – 15,000
15,001 –
20,000
20,001 – 25, 000
> 25,000
WBC Decrease - cell/mm3
2,500 – 3,500
1,500 – 2,499
1,000 – 1,499
< 1,000
Lymphocytes Decrease -
cell/mm3
750 – 1,000
500 – 749
250 – 499
< 250
Neutrophils Decrease -
cell/mm3
1,500 – 2,000
1,000 – 1,499
500 – 999
< 500
Eosinophils - cell/mm3
650 – 1500
1501 - 5000
> 5000
Hypereosinophilic
Platelets Decreased - cell/mm3
125,000 – 140,000 100,000 –
124,000
25,000 – 99,000
< 25,000
PT – increase by factor
(prothrombin time)
1.0 – 1.10 x
ULN**
1.11 – 1.20 x 
ULN
1.21 – 1.25 x 
ULN
> 1.25 ULN
PTT – increase by 
factor (partial 
thromboplastin time)
1.0 – 1.2 x ULN
1.21 – 1.4 x 
ULN
1.41 – 1.5 x ULN
> 1.5 x ULN
Fibrinogen increase - mg/dL
400 – 500
501 – 600
> 600
--
Fibrinogen decrease - mg/dL
150 – 200
125 – 149
100 – 124
< 100 or 
associated with 
gross bleeding or 
disseminated 
intravascular
coagulation (DIC)
* The laboratory values provided in the tables serve as guidelines and are dependent upon 
institutional normal parameters. Institutional normal reference ranges should be provided to 
demonstrate that they are appropriate.
** “ULN” is the upper limit of the normal range.
 
 
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Table 16
Laboratory Abnormalities - Urine
Urine *
Mild
(Grade 1)
Moderate 
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Protein
Trace
1+
2+
Hospitalization or
dialysis
Glucose
Trace
1+
2+
Hospitalization for
hyperglycemia
Blood (microscopic) – red 
blood cells per
high power field (rbc/hpf)
1 - 10
11 – 50
> 50 and/or 
gross blood
Hospitalization or packed 
red blood cells (PRBC)
transfusion
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional 
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are 
appropriate.
Assessment of causality
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
 
 
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(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
 
 
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, MAAEs, and Other Reportable Safety Events to the 
Sponsor
AE, SAE, MAAE, and other reportable safety event reporting to Sponsor via electronic 
data collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
 
 
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Guidance for Assessment and Work-up of Specific Postvaccination 
Adverse Effects
The following is the ‘Guidance for Assessment and Work-up of Specific Postvaccination 
Adverse Effects’ that the primary investigator should follow. 
1.
INTRODUCTION
One of the primary objectives of the V590-001 trial is to evaluate the safety of the 
recombinant vesicular stomatitis virus with SARS-CoV spike protein, hereafter referred 
to as V590). V590 shares the same vesicular stomatitis virus vector as the Ebola vaccine 
ERVEBO; in the ERVEBO Phase 1/1b clinical development program some subjects 
reported arthritis and/or peripheral clusters of vesicular lesions.  V590-001 is the first 
study of V590 in humans, and it is unknown whether similar findings might be observed 
with this vaccine. The V590-001 trial will prospectively monitor and assess these events 
in order to characterize the safety profile of the V590 study vaccine.
Subjects who develop AEs potentially suggestive of arthritis, rashes and oral lesions 
(specifically, joint pain, joint swelling, rash and/or oral lesions) will be instructed to 
contact the investigator site immediately for possible evaluation.
This appendix outlines the criteria for subjects to return to the investigator site (if not 
already domiciled) for examination, and the assessments and work-ups that should be 
performed. Briefly, subjects will inform the site if they have joint pain/swelling, rash or 
oral lesions. The investigator will evaluate these complaints; this document provides 
guidance for the evaluation and workup, including potentially referrals to rheumatology 
and/or dermatology for consideration of synovial fluid aspiration and/or skin biopsy, 
respectively. Recommendations are additionally provided to test vesicular fluid and oral 
ulcers for the presence of V590 RNA by RT-PCR. Guidance is provided separately for 
evaluation of arthritis, for rashes/oral lesions, and for vesicular lesions. The rash/oral 
lesion evaluation can direct the investigator to the vesicular lesion section, if the 
rash/oral lesion is vesicular in nature. Of note, if the participant is already domiciled at 
the time of onset the investigator will directly assess promptly through a targeted 
physical exam and history and as outlined in this document.
Additional questions from the investigator or consulting rheumatologist/dermatologist 
that are not addressed in this document should be directed to the site’s Clinical Research 
Associate (CRA) or the Sponsor Clinical team.
 
 
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2.
ADVERSE EVENTS OF ARTHRITIS
What is the definition of arthritis for the purposes of postvaccination AE evaluation in 
this study?
For the purposes of this trial, arthritis is defined as joint pain along with two or more of 
the following symptoms: Joint swelling, stiffness, erythema, warmth, tenderness, 
limitation of range of motion and/or effusions occurring at any time from study 
vaccination through Day 28 postvaccination.
What is the estimated incidence of postvaccination arthritis in this trial?
It is unknown whether arthritis may be observed as an AE with V590. With ERVEBO 
under 5% of subjects reported an AE of arthritis postvaccination. 
When and how should a subject monitor and report AEs of arthritis?
Subjects will be instructed to actively self-assess for events potentially suggestive of 
arthritis (specifically “joint pain” and “joint swelling”) from the time of study 
vaccination through Day 28 postvaccination on a paper Vaccination Report Card (VRC). 
Subjects will be prompted for the events of joint pain and joint swelling in the “Vaccine 
Specific Complaints” section of the study VRC. Subjects will be asked to record the 
onset and stop dates, severity (mild, moderate, or severe), and urgent medical attention 
required (if any). Subjects will also be instructed at the time of enrollment to contact the 
study staff immediately if they experience arthritis/joint swelling/joint pain at any time 
from vaccination through Day 28 postvaccination. Any arthritis that occurs during the 
domiciled period (through Day 7) will be evaluated during the domiciled period, and 
participants may leave domiciling for rheumatology consultation.
When should the subject be brought in for a physical examination and work-up for a
potential AE of arthritis?
Subjects will report symptoms potentially suggestive of arthritis occurring from the time 
of study vaccination through Day 28 postvaccination via phone call to the study site if 
not domiciled at time of onset. The study staff should instruct the subject to return to the 
investigator site for a directed physical examination. If these symptoms develop during 
the domiciled period, joint pain and/or joint swelling will be evaluated as soon as 
possible after onset.
What should the physical examination for potential AEs of arthritis include?
When the subject returns to the study site with an AE potentially consistent with
arthritis, the investigator should conduct a directed physical examination of the affected 
joint(s) and record the findings, as indicated in the Data Entry and Handling Guidelines
(DEGs).
 
 
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What is the threshold for collecting diagnostic specimens after the determination of an
AE of arthritis, and what specimens should be collected by the investigator?
If the subject’s arthritis is not considered to be due to another obvious explanation, then 
the investigator should collect the following specimens for testing:
(1) Blood: To be tested for complete blood count (CBC), blood chemistry, blood  
urea nitrogen (BUN), creatinine, and C-reactive protein (CRP).
(2) Urine: To be tested for urinalysis and microscopy (with analysis of sediment).
These tests do not need to be repeated if they have otherwise been collected as outlined in the 
protocol SoA while these symptoms were present. These labs should be repeated if there is 
significant worsening of these symptoms.
What are the procedures for collection of specimens by the investigator?
The blood and urine specimens should be collected per the site’s local procedures. 
Supplies for the collection and transport of these specimens will be provided by the site.
Where should the specimens collected by the investigator be tested?
The blood and urine specimens collected by the investigator should be tested at the site’s 
local laboratory. Upon receipt, the study staff should manually enter the test results and 
the local lab’s normal ranges into the Supplemental Laboratory (SLAB) eCRF.
When should the subject be referred to the rheumatologist associated with this study 
for additional evaluation?
The subject should be referred to the consulting rheumatologist for further evaluation if:
(1) There are objective findings of arthritis based on the investigator’s directed 
physical examination, and/or
(2) The subject’s blood and/or urine tests return any clinically significant abnormal 
results.
The rheumatologist consultation should occur as soon as possible, but no later than one 
week following the initial assessment by the investigator.
NOTE: The investigator may decide to refer the subject for a rheumatology consultation 
at any time based on clinical judgment and/or the severity of the subject’s clinical 
symptoms.
 
 
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What is the threshold for collecting additional specimens during the rheumatology visit 
and what specimens should be collected by the rheumatologist?
A consulting rheumatologist should conduct a directed physical examination of the 
affected joint(s). A synovial fluid specimen should be collected via arthrocentesis based 
on the following criteria:
(1) Based on evaluation by the consulting rheumatologist, detailed assessment of the 
involved joint(s)indicates that joint aspiration is clinically indicated and likely to 
yield fluid for further analysis, and
(2) When feasible and acceptable to the subject 
Synovial fluid specimens may only be collected once the subject has signed an 
additional consent form for the collection of invasive specimens in accordance with site 
SOPs and the rheumatologist’s standard of practice.
In addition to the standard clinical evaluation by the rheumatologist of this fluid which 
will be the priority, if any additional fluid is available it will be analyzed for the 
presence of V590 RNA by RT-PCR.
What is the guidance for follow-up examinations and repeated specimen collection and 
testing?
After lab tests are collected (and results are pending), the site should continue to follow
the subject through the following tiered approach:
(1) Day 1 to 7 Post-Onset: After the initial examination and collection of lab 
specimens, the site should contact the subject every 1 to 2 days via telephone for 
the first 7 days to check on the status of the symptoms if the subject is not 
domiciled at the time. If domiciled, the participant should be evaluated at least 
daily, as per protocol. If the subject’s lab results return clinically significantly 
abnormal, the investigator should ensure that the consulting rheumatologist is 
aware of the results either in advance of the initial consultation or for follow-up.
(2) Beyond Day 7 Post-Onset: The site should continue to contact the subject every 
7 days via telephone (or via in person visit if scheduled or otherwise indicated, 
allowing for +/- 3 days) until the symptoms have resolved. Repeat lab tests are 
not required at this time. The site should instruct the subject to contact the site 
immediately if the symptoms worsen. Worsening of symptoms (e.g., increase in 
number of joints involved, increase in severity of pain or other symptoms, return 
of swelling/effusion in the joint(s) undergoing arthrocentesis, other new joint 
symptoms consistent with arthritis) should be communicated immediately to the 
consulting rheumatologist for further evaluation.
If the subject’s symptoms have not fully resolved by Day 28 post-onset, then the 
subject should return to the study site for a follow-up examination at ~6-8 weeks
 
 
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post-onset and be referred to the consulting rheumatologist for further evaluation.
The site should continue to follow up with the subject approximately every 2-4 
weeks by telephone until resolution of symptoms.
NOTE: The investigator may decide to conduct repeat assessments and collect repeat 
specimens more frequently if considered clinically indicated. The investigator may also 
refer the subject for a rheumatology consultation at any time based on clinical judgment, 
severity of symptoms, and/or the results of bloodwork/urinalysis testing.
What should be done for reported AEs of arthritis that occur after Day 28 
postvaccination?
New events of arthritis reported after Day 28 postvaccination do not require unscheduled 
follow-up visits, directed physical examinations, or specimen collection. However, if a 
previous event of arthritis initially reported between Days 1 to 28 postvaccination recurs 
after Day 28 postvaccination, then the above-outlined procedures for assessment and 
work-up of arthritis should be followed.
Additionally, all serious adverse events (SAEs) are to be reported at any time during the 
trial (through Day 365).
How long should AEs of arthritis be followed?
All AEs of arthritis should be followed to resolution (or until the end of the study, provided 
stable).
3. ADVERSE EVENTS OF RASH OR ORAL LESION
What is the definition of rash for the purposes of postvaccination AE evaluation in this 
study?
For the purposes of this trial, all rashes (including but not limited to maculopapular, 
petechial, purpuric, localized or disseminated vesicular rashes, etc.) and/or oral lesions 
occurring at any time from study vaccination through Day 28 postvaccination should be 
reported to the study site. This rash will be assessed by the site. If vesicles are present as 
assessed by the investigator, the guidance in Section 4 should be followed on vesicular 
lesions. If there is also a rash or other lesion present (including oral ulceration) in 
addition to vesicles the instructions in this Section should be followed as well.
This approach is designed to ensure that vesicles are assessed and diagnosed by the 
investigator, as they may be difficult for participants to identify (especially if in the oral 
cavity). All rashes will be assessed, and it will be determined whether vesicles are 
present, in which case the vesicle guidance in Section 4 is to be followed. 
 
 
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When and how should a subject monitor and report AEs of rash and/or oral lesion?
Subjects will be instructed to actively self-assess for events of rash of any kind, or oral 
lesions, from the time of study vaccination through Day 28 postvaccination on a paper 
Vaccination Report Card (VRC). Subjects will be prompted for events of rash and oral 
lesions on the VRC. Subjects will be asked to record the onset and stop dates, severity 
(mild, moderate or severe), and urgent medical attention required (if any). Subjects will 
not be expected to characterize the rash; this characterization will be performed by the 
investigator. Subjects will be instructed at the time of enrollment to contact the study 
staff immediately if they develop a rash or oral lesion at any time from vaccination 
through Day 28 postvaccination, during which time the VRC is being utilized.
When should the subject be brought in for a physical examination and work-up for an 
AE of rash or oral lesion?
Subjects will report all AEs of rash and/or oral lesions occurring from the time of study 
vaccination through Day 28 postvaccination via phone call to the study site. The study 
staff should instruct the subject to return to the investigator site for a directed physical 
examination and work-up if:
(1)The rash and/or oral lesion is not due to another obvious explanation.
When the subject returns to the study site with a rash, the investigator should conduct a 
directed physical examination of the affected area(s) and record the findings, as 
indicated in the Data Entry and Handling Guidelines (DEGs).
NOTE: If the subject’s rash/oral lesion is also associated with joint pain and/or swelling 
or includes vesicular lesions, then the procedures for the assessment and work-up of 
arthritis (Section 2) and/or vesicular lesions (Section 4) should also be followed.
What is the threshold for collecting diagnostic specimens for an AE of rash and/or oral 
lesion, and what specimens should be collected by the investigator?
All vesicular lesions should follow the guidance in Section 4, including oral vesicular 
lesions. 
If there is an oral lesion and it is an ulceration, this should be swabbed and submitted for RT-
PCR for V590. 
For lesions that are not vesicular and not oral ulcerations the investigator may decide to 
refer the subject for a dermatology consultation at any time based on clinical judgment 
and/or the severity of the subject’s clinical symptoms. It is expected that disseminated 
rashes, including disseminated vesicles, or otherwise concerning rashes, would merit 
consideration of referral to dermatology and consideration of collection of diagnostic 
specimens. The Sponsor is available to discuss individual cases if/when they arise.
 
 
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If the participant is referred to a dermatologist, what is the threshold for collecting 
additional specimens during the dermatology visit and what specimens should be 
collected by the dermatologist?
The consulting dermatologist should conduct a directed physical examination of the 
rash. One or two tissue specimens should be collected via punch biopsy based on the 
following criteria:
(1) Based on clinical judgment of the consulting dermatologist, the skin lesions are 
maculopapular, petechial, purpuric, or disseminated vesicular in nature, or 
another type of skin lesion of clinical interest (such as a severe or disseminated 
rash), which based on the dermatologist’s clinical judgment would merit biopsy,
and
(2) When feasible and acceptable to the subject 
Tissue biopsy specimens may only be collected once the subject has signed an additional 
consent form for the collection of invasive specimens in accordance with site SOPs and the 
dermatologist’s standard of practice.
In addition to the standard pathological evaluation of this tissue biopsy which will be the 
priority, if any additional tissue is available it will be analyzed for the presence of V590 
RNA by RT-PCR.
4. ADVERSE EVENTS OF VESICULAR LESIONS
What is the definition of vesicular lesions for the purposes of postvaccination AE 
evaluation in this study?
For the purposes of this trial, any rash or oral lesion occurring at any time from study 
vaccination through Day 28 postvaccination should be reported to the study site, as 
described in Section 3. The general approach to non-vesicular rashes is described in 
Section 3. If the investigator assesses the lesion to be a vesicular lesion (including 
vesicles in the mouth), the guidance included in this Section 4 should be followed. 
Please note that disseminated vesicular lesions would generally warrant a separate 
dermatologic consultation in addition to following the instructions in Section 4.
What is the estimated incidence of postvaccination vesicular lesions in this trial?
It is unknown whether vesicular lesions may be observed as an AE with V590. In the 
ERVEBO program under 2% of subjects report an AE of vesicular lesions 
postvaccination. 
When and how should a subject monitor and report AEs of vesicular lesions?
Subjects will be instructed to actively self-assess for rashes and oral lesions from the 
time of study vaccination through Day 28 on a paper Vaccination Report Card (VRC). 
Subjects will also be instructed at the time of enrollment to contact the study staff 
 
 
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immediately if they develop a rash or oral lesion at any time from vaccination through 
Day 28 postvaccination, and this rash/oral lesion will be assessed by the investigator. If it 
is vesicular in nature this will be captured in the investigator assessment as described in 
Section 3.
When should the subject be brought in for a physical examination and work-up for an 
AE of vesicular lesions?
As described in Section 3, subjects will report all AEs of rash or oral lesion occurring 
from the time of study vaccination through Day 28 postvaccination via phone call to the 
study site. The study staff should instruct the subject to return to the investigator site for 
a directed physical examination and work-up if:
(2) The rash is not due to another obvious explanation.
What should the physical examination for potential AEs of vesicular lesions include?
When the subject returns to the study site with an AE of rash or oral lesions, the 
investigator should conduct a directed physical examination of the affected area(s) to 
characterize the lesion and determine whether a vesicular lesion is present, and record 
the findings, as indicated in the Data Entry and Handling Guidelines (DEGs).
NOTE: If the subject’s vesicular lesions are also associated with joint pain, joint 
swelling and/or a rash then the procedures for the assessment and work-up of, arthritis 
(Section 2), and/or rash (Section 3) should also be followed.
What is the threshold for collecting diagnostic specimens for an AE of vesicular lesions 
and what specimens should be collected by the Primary Investigator?
If the subject’s vesicular lesions: (1) Occurred at any time from study vaccination  
through Day 28 postvaccination, and (2) are not considered to be due to another obvious 
explanation, then the investigator should collect the following specimens for testing:
(1) Blood: To be tested for complete blood count (CBC), blood chemistry, blood  
urea nitrogen (BUN), creatinine, and C-reactive protein (CRP).
(2) Urine: To be tested for urinalysis and microscopy (with analysis of sediment).
(3) Swabs of Vesicular Fluid: To be tested for the presence of V590 RNA by RT-
PCR.
The above listed tests do not need to be repeated if they have otherwise been collected as 
outlined in the protocol SoA while these symptoms were present. These labs should be 
repeated if there is significant worsening of these symptoms.
 
 
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When should the subject be referred to the dermatologist associated with this study for 
additional evaluation?
Provided that the subject’s vesicular lesions are isolated in nature (not disseminated) and 
are not associated with other dermatologic lesions, then a referral to the consulting 
dermatologist for further evaluation is not necessary. If the subject’s vesicular lesions 
are associated with a rash, referral to a dermatologist should be considered by the 
investigator. If the vesicular lesions are widely disseminated over a large area then 
dermatologist evaluation is recommended.
What is the guidance for follow-up evaluations and repeat specimen collection and 
testing?
After lab tests are collected (and results are pending), the site should continue to follow 
the subject through the following tiered approach:
(1) Day 1 to 7 Post-Onset: After the initial examination and collection of lab 
specimens, the site should contact the subject every 1 to 2 days via telephone for 
the first 7 days to check on the status of the symptoms. If domiciled, the 
participant should be evaluated at least daily as per protocol. If the subject’s lab 
results come back clinically significantly abnormal, the investigator should refer 
the subject to a consulting dermatologist for further evaluation.
(2) Beyond Day 7 Post-Onset: The site should continue to contact the subject every 7 
days via telephone (or via in person visit if scheduled or otherwise indicated, 
allowing for +/- 3 days) until the symptoms have resolved. Repeat lab tests are 
not required at this time. The site should instruct the subject to contact the site 
immediately if the symptoms worsen. An increase in number of vesicles should 
prompt increased frequency of follow-up to every 1 to 2 days via telephone
for the first week following worsening, as well as a prompt in person visit to re-
sample for the presence of V590 by RT-PCR. The follow-up may then decrease 
to every 7 days in frequency. Clinically significant worsening of symptoms (e.g., 
excessive or persistent weeping from lesions, evidence of infection, or evidence 
of dissemination) should be evaluated in person as soon as possible, and referred 
to the consulting dermatologist as appropriate.
If the subject’s symptoms have not fully resolved by Day 28 post-onset, then the 
subject should return to the study site for a follow-up examination at ~6-8 weeks 
and be referred to the consulting dermatologist for further evaluation if still 
present. The site should continue to follow up with the subject approximately 
every 2-4 weeks by telephone until resolution of symptoms. 
Additional information regarding the subject’s symptoms collected during follow-up 
phone calls should be entered, as indicated in the Data Entry and Handling Guidelines
(DEGs).
 
 
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NOTE: The investigator may decide to conduct repeat assessments and collect repeat 
specimens more frequently if considered clinically indicated in the investigator’s 
judgement. The investigator also reserves the right to refer the subject for a 
dermatologist consultation at any time based on clinical judgment, severity of symptoms, 
and/or the results of bloodwork/urinalysis testing.
What should be done for reported AEs of vesicular lesions that occur after Day 28 
postvaccination?
New events of vesicular lesions reported after Day 28 postvaccination do not require 
unscheduled follow-up visits, directed physical examinations, or specimen collection. 
However, if a previous event of vesicular lesions initially reported between Days 1 to 28 
postvaccination recurs after Day 28 postvaccination, then the above-outlined procedures 
for assessment and work-up of vesicular lesions should be followed. New events of 
vesicular lesions reported after Day 28 may be further evaluated by the investigator 
based on the investigator’s judgement.
Additionally, all serious adverse events (SAEs) are to be reported at any time during the 
trial (through Day 365).
How long should AEs of vesicular lesions be followed?
All AEs of vesicular lesions should be followed to resolution (or until the end of the 
study, provided stable).
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Females
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
• Oral
• Intravaginal
• Transdermal
• Injectable
•
Progestogen-only hormonal contraceptionc,d
• Oral
• Injectable
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.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only 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
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
[If hormonal contraception efficacy for a female participant is potentially decreased due to interaction(s) with 
study intervention(s), add the following footnote. If hormonal contraception is prohibited, or if hormonal 
contraception efficacy is NOT decreased due to interaction with study intervention(s), delete the following 
footnote:]
c Male condoms must be used in addition to female participant hormonal contraception.
d If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation. 
e IUS is a progestin releasing IUD.
f A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male and female condom should not be used together (due to risk of failure with friction).
 
 
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Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following terms during the protocol defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and LAM.
•
Male and female condom cannot be used together.
-
A combination of male condom with either cap, diaphragm, or sponge with 
spermicide are considered acceptable, but not highly effective, birth control methods.
10.5.3
Pregnancy Testing (WOCBP)
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. This test should be repeated within 24 hours 
before the first vaccination administration (after start of domiciling).
Following administration of treatment, additional pregnancy testing will be performed at Day 
28 following dosing of study intervention, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
 
 
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
This appendix is not applicable to this study.
 
 
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10.8
Appendix 8: Approximate Blood Volume Table
Parts 1, 2, and 3
Screening
Days
-3 to -1
Vaccination 
Period (Day 1 
to Day 270)
Poststudy
(Day 365)
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety 
Tests
1
1
3
0
5
8.5
42.5
Hemoglobin A1c
1
0
0
0
1
1
1
Coagulation
1
1
3
0
5
3.5
17.5
HIV/Hepatitis 
Screen (at the 
discretion of the 
investigator)
1
0
0
0
1
3.5
3.5
Blood for Drug 
Screen
1
1
0
0
2
10
20
FSH (WONCBP 
only)
1
0
0
0
1
3.5
3.5
Serum Pregnancy 
Test (WOCBP only)
1
1
1
0
2
3.5
10.5
Serum for VSV 
antibodies
0
1
0
0
1
3
3
Serum for anti-
SARS-CoV-2 
nucleocapsid 
antibodies
1
1
6 (Parts 1 and 2 
only)
1 (Parts 1 
and 2 only)
9
3
27
Serum for anti-
SARS-CoV-2 spike 
neutralizing 
antibodies (PRNT)
0
0
7
1
8
10
80
Serum for anti-
SARS-CoV-2 spike 
IgG (ELISA)
0
0
7
1
8
10
80
Plasma for V590 
viremia
0
0
9
0
9
6
54
Blood for PBMCs 
and Plasma for 
Future Biomedical 
Research (selected 
sites only)
0
0
2
0
2
50
100
Serum for Cytokines
0
0
3
0
3
3
9
Blood for Genetic 
Analysis
0
0
1
0
1
8.5
8.5
Blood (RNA) for 
Future Biomedical 
Research
0
0
3
0
3
2.5
7.5
Serum for Future 
Biomedical 
Research
0
0
7
1
8
20
160
Total Blood Volume per Female Participants
Parts 1 and 2a 
627.5 mL
Parts 1 and 2a without PBMC
527.5 mL
Parts 1 and 2 Total Blood Volume up to Day 90 
457.5 mL
Parts 1 and 2 Total Blood Volume from Days 90 to 365
168 mL
Part 3a 
610.5 mL
Part 3a without PBMC
510.5 mL
Parts 3 Total Blood Volume up to Day 90
450.5 mL
Parts 3 Total Blood Volume from Days 90 to 365
160 mL
 
 
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Parts 1, 2, and 3
Screening
Days
-3 to -1
Vaccination 
Period (Day 1 
to Day 270)
Poststudy
(Day 365)
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Total Blood Volume per Male Participants
Parts 1 and 2a 
613.5 mL
Parts 1 and 2a without PBMC
515.5 mL
Parts 1 and 2 Total Blood Volume up to Day 90 
447.5 mL
Parts 1 and 2 Total Blood Volume from Days 90 to 365
168 mL
Part 3a 
598.5 mL
Part 3a without PBMC
498.5 mL
Parts 3 Total Blood Volume up to Day 90 
4438.5 mL
Parts 3 Total Blood Volume from Days 90 to 365
160 mL
a
If additional immunogenicity and/or safety analysis is necessary, additional blood (up to 50mL) may be 
obtained. Note: never to exceed 50 mL
Amendment 001-03:  Blood will be collected through Day 28.  Study visits on Days 90, 
180, 270, and 365 will not be performed.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR <40 bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior Hemiblock 
(LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior Hemiblock 
(LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 ms; 
or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as Defined 
Above
New Onset RBBB (Not Including 
Rate-related)
Incomplete Right BBB (ICRBBB) 
(QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intra-Ventricular Conduction 
Delay
QRS 130 ms
QRS 130 ms + Increase of 10 ms
QTcF
Male
QTc 470 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or P 
Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus Strain 
Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of Myocardial 
Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
 
 
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at screening visit and/or admission day and/or predose 
evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1.
The participant may be excluded from the study;
2.
The participant may be included in the study if the abnormal value(s) is NCS 
(the investigator must annotate the laboratory value “NCS” on the laboratory 
safety test source document).
3.
The participant may be included in the study if the abnormality is consistent 
with a pre-existing medical condition which is not excluded per protocol (e.g., 
elevated eosinophil count in a participant with asthma or seasonal allergies),
the medical condition should be annotated on the laboratory report.
OR
4.
The abnormal test may be repeated (refer items a. and b. below for 
continuation of algorithm for repeated values).
a. If the repeat test value is within the normal range, the participant may 
enter the study.
b. If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
 
 
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ACCP
American College of Chest Physicians
ADA
anti-drug antibodies
ADL
activities of daily living  
AE
adverse event 
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti-retroviral therapy
ATD
accelerated titration design
ATP
adenosine triphosphate
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BICR
blinded independent central review
BID
twice daily
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CBER
Center for Biologics Evaluation and Research 
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DAIDS
Division of AIDS
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
 
 
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Abbreviation
Expanded Term
ECMO
Extracorporeal membrane oxygenation
ELISA
enzyme-linked immunosorbent assay
ELISPOT
Enzyme-linked immunospot assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic patient-reported outcomes
EQ-5D
EuroQoL-5D
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle stimulating hormone 
FVC
forced vital capacity
G
glycooprotein
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GLP
Good Laboratory Practice
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HHC
house-hold contact
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
iCRO
imaging CRO
ICU
Intensive Care Unit
ID
identification 
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
Investigational medicinal product
IND
Investigational New Drug 
IO
immunooncology
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
 
 
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Abbreviation
Expanded Term
IVRS
interactive voice response system
IWRS
integrated web response system
KPS
Karnofsky performance status
LAM
lactational amenorrhoea method
LCQ
Leicester Cough Questionnaire
MAAE
Medically-attended adverse event
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MERS
Middle Eastern Respiratory Syndrome
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
non-eosinophilic bronchitis
NIMP
Non-investigational medicinal product
NHP
non-human primate
NSCLC
non-small cell lung cancer
NDA
New Drug Application 
NP
nasopharyngeal
NOAEL
no observed adverse effect level 
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over-the-counter
PBMC
peripheral blood mononuclear cells
PBPK
physiologically-based PK
PCR
polymerase chain reaction
PD-1
programmed cell-death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PO
orally
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRNT
plaque reduction neutralization test
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
QOL
quality of life
QP2
department of quantitative pharmacology and pharmacometrics
RCC
refractory chronic cough
 
 
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Abbreviation
Expanded Term
rHSA
Recombinant human serum albumin
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SARS
Severe Acute Respiratory Syndrome
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual
SNA
Serum neutralizing antibody
SoA
schedule of activities
SOP
standard operating procedure
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TMDD
target-mediated drug disposition
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
URTI
upper respiratory tract infection
V 
volume of distribution
VAS
Visual Analog Scale
VE
Vaccine efficacy
VS
vital sign
VSV
vesicular stomatitis virus
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
ZEBOV
Zaire ebolavirus
 
 
05QCTS
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V590-001-03 FINAL PROTOCOL
17-FEB-2021
11
REFERENCES
[Camacho, A., et al 
2015]
Camacho A, Carroll MW, Dean NE, Doumbia M, 
Edmunds WJ, Egger M, et al. The ring vaccination 
trial: a novel cluster randomised controlled trial 
design to evaluate vaccine efficacy and 
effectiveness during outbreaks, with special 
reference to Ebola. BMJ. 2015 Jul 27;351:h3740.
[05JHRV]
[Centers for Disease 
Control and 
Prevention 2015]
Centers for Disease Control and Prevention. 
Epidemiology and prevention of vaccine-
preventable diseases. 13th ed. Hamborsky J, Kroger 
A, Wolfe S, editors. Washington (DC): Department 
of Health and Human Services (HHS); c2015. 
Chapter 6, Vaccine administration; p. 79-106.
[0508PV]
[Clarke, D. K., et al 
2016]
Clarke DK, Hendry RM, Singh V, Rose JK, 
Seligman SJ, Klug B, et al. Live virus vaccines 
based on a vesicular stomatitis virus (VSV) 
backbone: Standardized template with key 
considerations for a risk/benefit assessment. 
Vaccine. Forthcoming 2016.
[04JHYJ]
[Clopper, C. J. 1934]
Clopper CJ, Pearson ES. The use of confidence or 
fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
[03Y75Y]
[Docherty, A. B., et 
al 2020]
Docherty AB, Harrison EM, Green CA, Hardwick 
HE, Pius R, Norman L, et al. Features of 20133 UK 
patients in hospital with covid-19 using the ISARIC 
WHO Clinical Characterisation Protocol: 
prospective observational cohort study. BMJ. 
2020;369:m1985.
[05JQSM]
[Henao-Restrepo, A. 
M., et al 2015]
Henao-Restrepo AM, Longini IM, Egger M, Dean 
NE, Edmunds WJ, Camacho A, et al. Efficacy and 
effectiveness of an rVSV-vectored vaccine 
expressing Ebola surface glycoprotein: interim 
results from the Guinea ring vaccination cluster-
randomised trial. Lancet. 2015 Aug 29;386:857-66.
[055B0S]
[Henao-Restrepo, A. 
M., et al 2017]
Henao-Restrepo AM, Camacho A, Longini IM, 
Watson CH, Edmunds WJ, Egger M, et al. Efficacy 
and effectiveness of an rVSV-vectored vaccine in 
preventing Ebola virus disease: final results from 
the Guinea ring vaccination, open-label, cluster-
randomised trial (Ebola Ca Suffit!) (including 
supplement appendix). Lancet. 2017 Feb 
4;389(10068):505-18.
[04T4FX]
 
 
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PROTOCOL/AMENDMENT NO.:  001-03  
V590-001-03 FINAL PROTOCOL
17-FEB-2021
[Kapadia, S. U., et al 
2005]
Kapadia SU, Rose JK, Lamirande E, Vogel L, 
Subbarao K, Roberts A. Long-term protection from 
SARS coronavirus infection conferred by a single 
immunization with an attenuated VSV-based 
vaccine. Virology. 2005;340:174-82.
[05JHSJ]
[Kapadia, S. U., et al 
2008]
Kapadia SU, Simon ID, Rose JK. SARS vaccine 
based on a replication-defective recombinant 
vesicular stomatitis virus is more potent than one 
based on a replication-competent vector. Virology.
2008;376:165-72.
[05JHSK]
[Liu, R., et al 2018]
Liu R, Wang J, Shao Y, Wang X, Zhang H, Shuai 
L, et al. A recombinant VSV-vectored MERS-CoV 
vaccine induces neutralizing antibody and T cell 
responses in rhesus monkeys after single dose 
immunization. Antiviral Res. 2018;150:30-8.
[05JHSL]
[Marcy, S. M., et al 
2004]
Marcy SM, Kohl KS, Dagan R, Nalin D, Blum M, 
Jones MC, et al. Fever as an adverse event 
following immunization: case definition and 
guidelines of data collection, analysis, and 
presentation. Vaccine 2004;22:551-6.
[03QPWY]
[Miettinen, O. 1985]
Miettinen O, Nurminen M. Comparative analysis of 
two rates. Stat Med. 1985 Apr-Jun;4(2):213-26.
[04J96G]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative Analysis 
of Two Rates. Stat Med 1985;4:213-26.
[03QCDT]
[Petrilli, C. M., et al 
2020]
Petrilli CM, Jones SA, Yang J, Rajagopalan H, 
O'Donnell L, Chernyak Y, et al. Factors associated 
with hospital admission and critical illness among 
5279 people with coronavirus disease 2019 in New 
York City: prospective cohort study. BMJ. 
2020;369:m1966.
[05JQG8]
[Regules, J. A., et al 
2017]
Regules JA, Beigel JH, Paolino KM, Voell J, 
Castellano AR, Hu Z, et al. A recombinant 
vesicular stomatitis virus ebola vaccine. N Engl J 
Med. 2017 Jan 26;376(4):330-41. Supplemental 
material; 16 p.
[05D22Z]
 
 
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Supplemental Statistical Analysis Plan (sSAP)
1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.
2
SUMMARY OF CHANGES 
A summary of changes is provided in the table below:
Section 
Description of Change
Rationale
Section 3.4.2 
Immunogenicity 
Endpoints
Added details for the additional 
exploratory immunogenicity analysis 
endpoints ICS and serum cytokine: 
“SARS-CoV-2 Specific CD4+ and 
CD8+ T Cell Responses (IFN-γ, IL-2, 
IL-4, IL-13, and TNF-α) at Day 1 
Predose and Day 28, as measured by 
intracellular cytokine staining (ICS) of 
PBMC.”
“Serum cytokines (IFN-γ, IL-1β, IL-2, 
IL-4, IL-6, IL-8, IL-10, IL12p70, IL-13, 
and TNF-α) at Day 1 Predose, Day 1 
post-dose, and Day 4, as measured by 
electrochemiluminescence (ECL) 
assay.”
Revisions made for clarity.
Section 3.4.4 
Efficacy Endpoints
Updated analysis period from “data 
through Day 28” to “data through the 
duration of the study until final database 
lock”. 
Revisions made to provide 
all available data for 
transparency.
Section 3.5 Analysis 
Populations
Section 3.5.2 
Immunogenicity 
Analysis 
Populations
Section 3.5.4
Efficacy Analysis 
Populations
Added details and clarifications for Per-
Protocol (PP) populations used for 
different endpoints, including Per-
Protocol Immunogenicity (PPI)
population for Parts 1 and 2: “all 
randomized participants who were 
seronegative to anti-SARS-CoV-2 
nucleocapsid antibody through Day 28 
with exclusions for important 
deviations”; PPI population for Part 3; 
PPI population for supplementary 
Revisions made for clarity
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
sensitivity analysis: “PPI population 
with exclusions of participants who had 
Day 1 predose values >2LLOQ (Lower 
Limit of Quantification) for anti-SARS-
CoV-2 spike serum IgG measured by 
ELISA or SNA measured by PRNT”; 
and Per-Protocol Efficacy (PPE) 
population.
Section 3.6.1
Removed a sentence “MAAEs will be 
followed through Day 180” to be 
consistent with the amended protocol 
and avoid confusion.
Revisions made for clarity 
and consistency
Section 3.6.2 
Statistical Methods 
for Immunogenicity 
Analyses
Removed (Days 7, 14, 28, 90, 180, 270, 
and 365) from LDA Model to be 
consistent with the amended protocol 
and avoid confusion.
Updated analysis populations from “PP” 
to “PPI” in Table 8. 
Revisions made for clarity 
and consistency
Section 3.6.3
Statistical Methods 
for Viremia and
Viral Shedding 
Analyses
Removed the area under the curve 
(AUC) and duration analyses.
Viremia and viral shedding 
samples are not assayed for 
all time points. Instead, 
samples are assayed with 
the intention of testing until 
negative.  Analyses are not 
applicable due to data 
changes.
Section 3.6.3 
Statistical Methods 
for Viremia and 
Viral Shedding 
Analyses
Added a sentence: “ For sample titers 
above LLOD and below LLOQ, ½ of 
the LLOQ value is used for analysis.”
Revisions made for clarity.
Section 3.6.4 
Statistical Methods 
for Efficacy 
Analyses
Removed analyses inapplicable: GMTs 
of anti-SARS-CoV2 nucleocapsid; and 
within group 95% CIs.
Result is categorical and 
GMT is inapplicable. 95% 
CI is inapplicable due to 
small # of occurrence in 
each treatment group.
3.6.5 Statistical 
Methods for 
Analyses of SARS-
CoV-2 Specific 
CD4+ and CD8+ T 
Cell Responses
Added a paragraph to specify the 
statistical methods for analyses.
Revisions made for clarity.
3.6.6 Statistical 
Methods for Serum 
Cytokines
Added a paragraph to specify the 
statistical methods for analyses.
Revisions made for clarity.
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
3
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other 
non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding/final database lock, will be documented in a supplemental SAP (sSAP) and 
referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will 
be clearly identified in the CSR.
3.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this study; the
comprehensive plan is provided in Sections 3.2 through 3.9.
Study Design 
Overview
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose-
Ranging Trial to Evaluate the Safety and Immunogenicity of V590 
in Healthy Adults
Intervention 
Assignment
Within each panel of Parts 1, 2, and 3, healthy adult participants 
will be assigned randomly in a 3:1 ratio to receive V590 or 
matching placebo: 
•
Panel A and E: V590 5.00·105 pfu or Placebo
•
Panel B and F: V590 2.40·106 pfu or Placebo
•
Panel C and G: V590 1.15·107 pfu or Placebo
•
Panel D, H, and I: V590 5.55·107 pfu or Placebo
All participants will receive study intervention administered via 
IM injection(s) on Day 1.
Analysis Populations
Safety: All Participants as Treated (APaT)
Viremia and Viral Shedding: All Participants as Treated (APaT)
Immunogenicity: Per-Protocol (PP)
Efficacy: Per-Protocol (PP)
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Primary Endpoint
Safety:
•
Solicited injection site AEs from Day 1 through Day 5
•
Solicited systemic AEs from Day 1 through Day 28
•
Unsolicited AEs from Day 1 through Day 28 
•
MAAEs from Day 1 through Day 180
•
SAEs from Day 1 through Day 365
Amendment 001-03: MAAEs from Day 1 through Day 28. SAEs 
from Day 1 through the duration of the study until final database 
lock.  
Immunogenicity:
•
Anti-SARS-CoV-2 spike serum neutralizing antibody (SNA) 
responses, as measured by plaque reduction neutralization test 
(PRNT), at Day 28 (Parts 1 and 2)
Key Secondary 
Endpoints
Immunogenicity:
•
Anti-SARS-CoV-2 spike SNA responses, as measured by 
PRNT, at Days 7, 14, 90, 180, 270, and 365 (Parts 1 and 2)
•
Anti-SARS-CoV-2 spike IgG responses, as measured by 
enzyme-linked immunosorbent assay (ELISA), at Days 7, 14, 
28, 90, 180, 270, and 365 (Parts 1 and 2)
Amendment 001-03: Immunogenicity analyses will include all 
available data through Day 28.  
Statistical Methods for 
Key Immunogenicity 
Analyses
Separately for each primary and secondary immunogenicity 
parameter, the geometric mean titers (GMT) with 95% confidence 
interval (CI), GMT ratios with 90% CI, and the hypothesis test 
(i.e., 2-sided p-value) if applicable, will be estimated using a 
longitudinal data analysis (LDA) method utilizing data from all 
vaccination and combining placebo groups. The primary 
hypothesis that at least one well-tolerated dose level of a single 
dose administration of V590 increases the GMTs of anti-SARS-
CoV-2 spike SNA, as measured by PRNT, compared to placebo, 
will be tested using a stepwise procedure with an assumption that 
there is an increasing relationship between anti-SARS-CoV-2 
spike SNAs and V590 doses.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. No 
Tier 1 events are defined in this study. For Tier 2 events, 95% CIs 
will be provided for between-vaccination group differences in the 
percentage of participants with events; these analyses will be 
performed using the M&N method [Miettinen, O. and Nurminen, 
M. 1985] {04J96G}. All safety parameters will also be 
summarized via descriptive statistics.
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Interim Analyses
An interim analysis of safety and immunogenicity data to inform 
further clinical development will be performed, when at minimum 
80% participants in Parts 1 and 2 have completed at least 28-day 
follow-up post-vaccination and immunogenicity data are available. 
Multiplicity
The study has only 1 primary hypothesis which will be addressed 
using a closed step-wise testing procedure that preserves the 
overall alpha level at 0.05 1-sided (assuming a monotonic dose-
response).
Sample Size and 
Power
Section 3.9 provides information about the ability of this study to 
estimate the incidence of AEs in recipients of a dose of V590; and 
the power to demonstrate an increase in anti-SARS-CoV-2 SNAs 
elicited by V590, compared to placebo. 
Amendment 001-03: Active monitoring and immunogenicity assessments in the study will 
occur through Day 28. Spontaneous safety reporting is permitted beyond Day 28 for the protocol 
specified durations. Immunogenicity analyses will include all available data through Day 28. 
Safety analyses will include all collected safety data through the duration of the study until final 
database lock. A final analysis of study data will occur instead of an interim analysis. 
  
3.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. 
This study will be conducted as a double-blind study. The official, final database will not be 
unblinded until medical/scientific review has been performed, protocol deviations have been 
identified, and data have been declared final and complete. Section 6.3.3 specifies the roles and 
responsibilities of the site and Sponsor personnel who will be unblinded during the study. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
Blinding details related to the planned interim analyses are described in Section 3.7.
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
3.4
Analysis Endpoints
Analysis endpoints of safety, immunogenicity, viremia and viral shredding, and efficacy are 
listed below.
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
3.4.1
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, including 
AEs, postvaccination body temperature measurements, physical examinations, laboratory safety 
tests, and vital signs following any vaccination with V590 or Placebo.
The safety analysis endpoints that address the primary objective include:
•
Solicited injection-site AEs (redness, swelling, and tenderness/pain) from Day 1 post-dose 
through Day 5 after study intervention
•
Solicited systemic AEs (muscle pain, joint pain, headache, tiredness, fatigue, rash, nausea, 
joint swelling, oral lesions, sweating more than usual) from Day 1 post-dose through 
Day 28 after study intervention
•
Unsolicited AEs from Day 1 post-dose through Day 28 after study intervention
•
The broad AE categories consisting of any AE, vaccine-related AE, ECIs, and vaccine-
related ECIs from Day 1 post-dose through Day 28 after study intervention
•
The broad AE categories consisting of any MAAE and vaccine related MAAE from Day 1 
post-dose through Day 180 after study intervention
•
The broad AE categories consisting of any SAE, vaccine related SAEs, and death from 
Day 1 post-dose through the duration of participation in the study after study intervention
•
Maximum temperature measurements meeting the Brighton Collaboration cut points from 
Day 1 through Day 28 after study intervention
Additional Safety analysis endpoints include:
•
Safety laboratory results collected at Day 1 predose, Days 3, 7, and 28 
•
Vital signs collected at scheduled (see Section 1.3) and unscheduled visits.
Amendment 001-03: MAAEs from Day 1 post-dose through Day 28. SAEs from Day 1 through 
the duration of the study until final database lock.
3.4.2
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints include:
•
Anti-SARS-CoV-2 spike SNA at Day 28, as measured by plaque reduction neutralization 
test (PRNT), in Parts 1 and 2 participants
The secondary immunogenicity analysis endpoints include:
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
•
Anti-SARS-CoV-2 spike SNA at Day 1 Predose, Days 7, 14, 90, 180, 270, and 365, as 
measured by PRNT, in Parts 1 and 2 participants
•
Anti-SARS-CoV-2 spike IgG at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 365, as 
measured by enzyme-linked immunosorbent assay (ELISA), in Parts 1 and 2 participants 
The exploratory immunogenicity analysis endpoints include:
•
Anti-SARS-CoV-2 spike SNA at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 365, as 
measured by PRNT, in Part 3 participants
•
Anti-SARS-CoV-2 spike IgG at Day 1 Predose, Days 7, 14, 28, 90, 180, 270, and 365, as 
measured by ELISA, in Part 3 participants 
Additional exploratory immunogenicity analysis endpoints may include:
•
Enzyme-linked immunospot assay (ELISPOT) of peripheral blood mononuclear cells 
(PBMC)
•
SARS-CoV-2 Specific CD4+ and CD8+ T Cell Responses (IFN-γ, IL-2, IL-4, IL-13, and 
TNF-α) at Day 1 Predose and Day 28, as measured by intracellular cytokine staining (ICS) 
of PBMC
•
Anti-SARS-CoV-2 spike antibodies in mucosal samples
•
Serum cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL12p70, IL-13, and TNF-α)
at Day 1 Predose, Day 1 post-dose, and Day 4, as measured by electrochemiluminescence 
(ECL) assay
Exploratory immunogenicity endpoints may be summarized and reported separately.
Amendment 001-03: Immunogenicity analyses will include all available data through Day 28.
3.4.3
Viremia and Viral Shedding Endpoints
There is no primary analysis endpoint for V590 viremia and viral shedding.
The secondary V590 viremia and viral shedding analysis endpoints include: 

V590 plasma viremia, as detected by RT-PCR at Day 1 post-dose, Days 2, 3, 4, 5, 6, 7, 14, 
and 28 

V590 viral shedding in urine and saliva, as detected by RT-PCR at Day 1 post-dose, Days 
2, 3, 4, 5, 6, 7, 14, and 28

V590 viral shedding in stool, as detected by RT-PCR at Days 2-4, and 5-7
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Exploratory viremia and viral shedding analysis endpoints include:

V590 plasma viremia, as detected by Plaque Assay

V590 viral shedding in urine, saliva, and stool as detected by Plaque Assay
Amendment 001-03: Viremia and viral shedding samples will be assayed with the intention of 
testing until negative for viremia/viral shedding. Viremia and viral shedding analyses will 
include all available data through Day 28.
3.4.4
Efficacy Endpoints
The exploratory efficacy analysis endpoint includes:

Number and proportion of participants in Parts 1 and 2 experiencing seroconversion, 
which is determined by anti-SARS-CoV-2 nucleocapsid antibody titers at Days 7, 14, 28, 
90, 180, 270, and 365, compared to baseline (Screening).
Amendment 001-03: Efficacy analyses will include all available data through the duration of the 
study until final database lock.
3.5
Analysis Populations
The following analysis populations are defined for the analysis and reporting of data.
All Participants as Treated (APaT): The All Participants as Treated population consists of all 
randomized participants who received at least one dose of study vaccination. Participants will be 
included in the vaccination group corresponding to the study intervention they received for the 
analysis using the APaT population. This will be the vaccination group to which they are 
randomized except for participants who receive an incorrect dose of study vaccine or placebo; 
such participants will be included in the vaccination group corresponding to the study vaccine
actually received.
FAS (Full Analysis Set): The Full Analysis Set population consists of all randomized participants 
who received at least one dose of study vaccination and have at least 1 result of the analysis 
endpoints. Participants will be included in the vaccination group to which they are randomized 
for the analysis using the FAS population.
Per-Protocol (PP): The Per-Protocol population consists of all randomized participants with 
exclusions for important deviations from the protocol that may substantially affect the results of 
the analysis endpoints. Participants will be included in the vaccination group to which they are 
randomized for the analysis using the PP population. The Per-Protocol Immunogenicity (PPI)
population and Per-Protocol Efficacy (PPE) population are defined in Sections 3.5.2 and 3.5.4.
3.5.1
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, which 
consists of all randomized participants who received at least one dose of study vaccination.
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
At least one laboratory, vital sign, or ECG measurement obtained subsequent to at least one 
study treatment is required for inclusion in the analysis of the respective safety parameter.  To 
assess change from baseline, a baseline measurement is also required.
3.5.2
Immunogenicity Analysis Populations
The Per-Protocol Immunogenicity (PPI) population will be used for the analysis of 
immunogenicity data, SARS-CoV-2 Specific CD4+ and CD8+ T Cell Responses, and serum 
cytokines. 
The PPI population for Parts 1 and 2 consists of all randomized participants who were 
seronegative to anti-SARS-CoV-2 nucleocapsid antibody through Day 28 with exclusions for 
important deviations from the protocol that may substantially affect the results of the 
immunogenicity endpoints. The PPI population for Part 3 consists of all randomized participants 
with exclusions for important deviations from the protocol that may substantially affect the 
results of the immunogenicity endpoints. 
Deviations that may result in the exclusion of a participant from the PP population include:

Failure to receive the correct dose of study vaccination at Day 1

Receipt of prohibited medication or prohibited vaccine prior to a blood sample collection

Collection of blood sample outside of the pre-specified window (Day 14 visit: -2/+7 
days, Day 28 visit: -2/+14 days)
The final determination on important protocol deviations, and thereby the composition of the 
Per-Protocol population, will be made by blinded study team members prior to the final 
unblinding of the database. 
A supplementary sensitivity analysis using the PPI population with exclusions of participants 
who had Day 1 predose values >2LLOQ (Lower Limit of Quantification) for anti-SARS-CoV-2 
spike serum IgG measured by ELISA or SNA measured by PRNT will be performed for the 
primary and secondary immunogenicity endpoints.
A supplementary analysis using the Full Analysis Set (FAS) population will also be performed 
for the primary and secondary immunogenicity endpoints.
Details on the approach to handle missing data are provided in Section 3.6.
3.5.3
Viremia and Viral Shedding Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of viremia and 
viral shedding data. The APaT population consists of all randomized participants who received at 
least one dose of study vaccination. At least one viremia or viral shedding measurement obtained 
subsequent to at least one study vaccination is required for inclusion in the analysis of the 
respective parameter.
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
A supplementary analysis using the Per-Protocol (PP) population may also be performed for the 
viremia and viral shedding endpoints. 
3.5.4
Efficacy Analysis Populations
The Per-Protocol Efficacy (PPE) population will be used for the analysis of efficacy data.  The 
PPE population consists of all randomized participants with exclusions for important deviations 
from the protocol that may substantially affect the results of the anti-SARS-CoV-2 nucleocapsid 
antibody titers.
A supplementary analysis using the Full Analysis Set (FAS) population will also be performed 
for the efficacy endpoint.
3.6
Statistical Methods
Statistical methods for safety, immunogenicity, and viremia and viral shedding analyses are 
described in Section 3.6.1, Section 3.6.2, and Section 3.6.3, respectively. Section 3.6.4 describes 
how demographic and baseline characteristics will be summarized.
For all analyses, data will be examined for departures from the assumptions of the statistical 
model(s) as appropriate; e.g., heteroscedasticity, non-normality of the error terms. Distribution-
free methods may be used if a serious departure from the assumptions of the models(s) is 
observed, or suitable data transformations may be applied.
3.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, including 
AEs, postvaccination temperatures, laboratory measurements, ECGs, and vital signs.
The analysis of AEs and postvaccination temperature measurements will follow a tiered 
approach [Table 1]. The tiers differ with respect to the analyses that will be performed. Events 
(specific preferred terms (PT) as well as system organ classes (SOC)) are either pre-specified as 
Tier 1 endpoints or will be classified as belonging to Tier 2 or Tier 3 based on the number of 
events observed. 
Laboratory measurements, ECGs, and vital signs will be summarized separately. Summary 
statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or vital signs as 
well as for change from baseline, as deemed clinically appropriate. Depending on the safety 
parameter, the difference from baseline will either be computed on the original scale (raw change 
from baseline) or on the log scale and back-transformed for reporting (percent change from 
baseline). Baseline is defined as the pre-dose measurement.
Tier 1 Events
Safety events or AEs of special interest that are pre-identified constitute Tier 1 safety endpoints 
which will be subject to inferential testing for statistical significance with 95% CIs and 
corresponding p-values provided for the between-treatment differences in the proportion of 
participants with events.
06FCX3

V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
No Tier 1 events are defined for this study.
This study will solicit for predefined injection-site and systemic AEs. However, as this is the first 
clinical study of V590, no data exists around which a comparative, data-driven safety hypothesis 
can be formulated and tested. As a result, the solicited injection-site and systemic AE reported in 
this study will be analyzed as Tier 2 events.
Tier 2 Events
Tier 2 events will be assessed via point estimates and risk differences with 95% CIs provided for 
differences in the proportion of participants with events. Analyses will be performed using the 
Miettinen and Nurminen (M&N) method {04J96G}, an unconditional, asymptotic method. 
Tier 2 events for this study include solicited injection-site AEs (redness/erythema, swelling, and 
tenderness/pain) from Day 1 through Day 5 postvaccination, solicited systemic AEs (muscle 
pain, joint pain, headache, tiredness, rash, nausea, joint swelling, oral lesions, sweating more 
than usual) from Day 1 through Day 28 postvaccination, and ECIs from Day 1 through Day 28 
postvaccination. In addition, the broad AE categories consisting of the percentage of participants 
with any AE, any vaccine-related AE, any ECI, any vaccine-related ECI, any MAAE, any 
vaccine-related MAAE, any SAE, any vaccine-related SAE, and death will be considered Tier 2 
events. Nonserious AEs will be followed for 28 days postvaccination, while SAEs will be 
followed through the duration of participation in the study. The proportion of participants with 
maximum temperature measurements meeting the Brighton Collaboration {03QPWY} cut points 
(Days 1 to 28) will also be considered Tier 2 endpoints.
Adverse events (specific PTs as well as SOCs) will be classified as belonging to Tier 2 if at least 
4 participants in any vaccination group exhibit the event. The threshold of at least 4 events was 
chosen because the 95% CI for the between-group difference in percent incidence will always 
include zero when vaccination groups of equal size each have less than 4 events and thus would 
add little to the interpretation of potentially meaningful differences. Because many 95% CIs for 
Tier 2 events may be provided without adjustment for multiplicity, the CIs should be regarded as 
a descriptive measure supportive of safety review, not a formal method assessing the statistical 
significance of the between-group differences in AEs.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by vaccination group are provided for Tier 3 safety parameters.
Table 1
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for Between-
Group Comparison a
Descriptive
Statistics
Tier 2
Injection-site redness/erythema (Days 1 to 5)
X
X
Injection-site swelling (Days 1 to 5)
X
X
Injection-site tenderness/pain (Days 1 to 5)
X
X
Muscle pain/myalgia (Days 1 to 28)
X
X
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Safety 
Tier
Safety Endpoint†
95% CI for Between-
Group Comparison a
Descriptive
Statistics
Joint pain/arthralgia (Days 1 to 28)
X
X
Joint swelling (Days 1 to 28)
X
X
Rash (Days 1 to 28)
X
X
Oral lesion (Days 1 to 28)
X
X
Nausea (Days 1 to 28)
X
X
Headache (Days 1 to 28)
X
X
Tiredness/fatigue (Days 1 to 28)
X
X
Sweating more than usual/abnormal sweating (Days
1 to 28)
X
X
Any AEb
X
X
Any Vaccine-Related AEb
X
X
Any ECIb
X
X
Any Vaccine-Related ECIb
X
X
Any MAAEb
X
X
Any Vaccine-Related MAAEb
X
X
Any SAEb
X
X
Any Vaccine-Related SAEb
X
X
Deathb
X
X
Maximum temperature measurements meeting 
the Brighton Collaboration cut points (Days 1 
to 28) 
X
X
Specific AEs by SOC and PT (incidence ≥4 
participants in at least one of the vaccination 
groups)
X
X
Tier 3
Specific AEs by SOC and PTc (incidence <4 
participants in one of the vaccination groups)
X
AE = adverse event; CI = confidence interval; MAAE = medically attended adverse event; M&N = Miettinen and 
Nurminen; PT = preferred term; SAE = serious adverse event; SOC = system organ class; X = results will be provided.
a These analyses will be performed using the M&N method {03QCDT}.
b These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least 1 AE.
c Includes only those endpoints not prespecified as Tier 2 endpoints.
Amendment 001-03: MAAEs from Day 1 post-dose through Day 28. SAEs from Day 1 through 
the duration of the study until final database lock.
3.6.2
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary, secondary, and 
exploratory immunogenicity objectives. The immunogenicity analyses will be conducted for 
each endpoint separately [Table 2].
Primary Hypothesis
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
At least one well-tolerated dose level of a single dose administration of V590 increases the 
GMTs of anti-SARS-CoV-2 spike SNA, as measured by PRNT, compared to placebo. 
The primary endpoint, anti-SARS-CoV-2 spike SNA GMTs at Day 28 will be assessed via the 
following hypotheses:
H0: GMT1/GMT2 ≤1 versus
H1: GMT1/GMT2 >1,
where GMT1 is the anti-SARS-CoV-2 spike SNA GMT for a V590 dose level and GMT2 is the 
anti-SARS-CoV-2 spike SNA GMT for the placebo. Estimation of the GMT ratio and the 
corresponding 90% CI will be calculated using an LDA model utilizing the log-transformed 
antibody titers as the response.
A Stepwise Procedure
The primary hypothesis will be tested using the following stepwise procedure with an 
assumption that there is an increasing relationship between anti-SARS-CoV-2 spike SNAs and 
V590 doses. The primary hypothesis will be supported if the lower limit of the 90% CI 
(equivalent to the lower bound of a one-sided 95% CI) for the GMT ratio between the highest 
V590 dose and placebo is >1 (indicating an increase). If the hypothesis is supported in the 
previous step, then the same procedure will be applied to the next lowest dose. The procedure 
continues in this stepwise fashion until the lower limit of the 90% CI at a particular dose is ≤1. 
LDA Model
Separately for each primary immunogenicity parameter, the GMTs with 95% CI, GMT ratios 
with 90% CI, and the hypothesis test (i.e., 2-sided p-value) if applicable, will be estimated using 
an LDA method utilizing data from all vaccination and placebo groups. The response vector 
consists of the natural log-transformed prevaccination (Day 1) and postvaccination antibody 
titers. The linear mixed-effects model will include fixed effects of dose (4 dose levels of V590 
and placebo), time, age stratum (i.e., 18 to 54 years, and ≥55 years), the dose-by-time 
interaction, and age-by-time interaction. The term for time will be treated as a categorical 
variable. An unstructured covariance matrix will be used to model the correlation among 
repeated measurements. The Kenward-Roger adjustment will be used with REML to make 
proper statistical inference. This model allows the inclusion of participants who are missing 
either the baseline or postbaseline measurements, thereby increasing efficiency.
Exponentiating the least squares means and the lower and upper limits of CIs will yield estimates 
for the population GMTs and corresponding 95% CIs by dose, time, and/or age stratum on the 
original scale. To assess the treatment difference between 1 of the 4 dose levels of V590 relative 
to the placebo, the least squares mean differences (V590 – placebo) and 90% CIs from this 
model will be back-transformed to obtain the GMT ratios (V590/placebo) and 90% CIs.
Secondary and Exploratory Endpoints
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
The evaluations of secondary and exploratory objectives will be performed within each
vaccination group separately. Descriptive statistics with point estimates and within-group 95% 
CIs will be provided by dose, time, and/or age stratum. For the continuous endpoints, the point 
estimates will be calculated by exponentiating the estimates of the mean of the natural log values 
and the within-group CIs will be derived by exponentiating the bounds of CIs of the mean of the 
natural log values based on the t-distribution. For the dichotomous endpoints, if any, the 
within-group CIs will be calculated based on the exact method proposed by Clopper and Pearson
{03Y75Y}.
Additionally, SNA GMTs and IgG GMTs and corresponding 95% CIs may be calculated using 
the same LDA model as for the primary endpoint.
Miscellaneous
The relationship between anti-SARS-CoV-2 spike SNAs and V590 doses will be displayed 
graphically. Reverse Cumulative Distribution Curves for postvaccination SNA GMTs and IgG 
GMTs will be graphically displayed by time points.
For titer measurements that are smaller than the lower bound of the assay detectable range, half 
of the lower bound may be used as the value of the titer.
Table 2
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint (H1)
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Day 28
(Parts 1 and 2) 
P
t-distribution with the 
variance estimate from 
an LDA model‡
(estimate, 95% CI, 
p-value)
PPI
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoint
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Days 7, 14, 90, 180, 
270, and 365
(Parts 1 and 2)
P
Descriptive Statistics
(estimate, 95% CI)
PPI
Missing data 
will not be 
imputed
S
FAS
GMTs of anti-SARS-CoV-2 spike serum 
IgG, as measured by ELISA, at Days 7, 14, 
28, 90, 180, 270, and 365
(Parts 1 and 2)
P
Descriptive Statistics
(estimate, 95% CI)
PPI
Missing data 
will not be 
imputed
S
FAS
Exploratory Endpoints
P
Descriptive Statistics
(estimate, 95% CI)
PPI
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
GMTs of anti-SARS-CoV-2 spike SNA, as 
measured by PRNT, at Days 7, 14, 28, 90, 
180, 270, and 365
(Part 3)
S
FAS
Missing data 
will not be 
imputed
GMTs of anti-SARS-CoV-2 spike serum 
IgG, as measured by ELISA, at Days 7, 14, 
28, 90, 180, 270, and 365
(Part 3)
P
Descriptive Statistics
(estimate, 95% CI)
PPI
Missing data 
will not be 
imputed
S
FAS
CI = confidence interval; FAS = Full Analysis Set; GMT = geometric mean titer; H = hypothesis; IgG = Immunoglobulin G; 
SNA = serum neutralizing antibody; PP = Per-Protocol.
† P = Primary approach using PP population; S = Supportive approach using FAS population.
‡ Estimation of the SNA GMT ratios and computation of the corresponding 90% CIs will be calculated using t-distribution 
with the variance estimate from a longitudinal data model (LDA) utilizing the log-transformed antibody titers as the response 
and a single term for vaccination group. 
Amendment 001-03: Immunogenicity analyses will include all available data through Day 28.
3.6.3
Statistical Methods for Viremia and Viral Shedding Analyses
The viremia and viral shedding analyses will be conducted for each endpoint separately.
Numbers and proportions of participants with positive V590 plasma viremia and positive viral 
shedding in urine, saliva, and stool, as detected by RT-PCR, will be calculated by dose, time, 
and/or age stratum. 
GMs with 95% CIs of positive V590 plasma viremia and positive viral shedding in urine, saliva,
and stool will be estimated by dose, time, and/or age stratum. Descriptive statistics including n, 
median, minimum, and maximum will also be provided.
Positive viremia and viral shedding are defined as a detectable RT-PCR results greater than or 
equal to lower limit of detection [≥ LLOD]. Results are deemed quantifiable if the result is 
greater than or equal to the lower limit of quantification [≥ LLOQ]. For sample titers above 
LLOD and below LLOQ, ½ of the LLOQ value is used for analysis.
Amendment 001-03: Viremia and viral shedding samples will be assayed with the intention of 
testing until negative for viremia/viral shedding. Viremia and viral shedding analyses will 
include all available data through Day 28.
3.6.4
Statistical Methods for Efficacy Analyses
The exploratory efficacy analysis will assess the efficacy of V590 to prevent seroconversion to 
anti-SARS-Cov-2 nucleocapsid antibody positivity, an evidence of infection.
Numbers and proportions of participants in the PP population of Parts 1 and 2, who meet 
seroconversion criteria, will be estimated by dose, time, and/or age stratum. 
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
Amendment 001-03: Efficacy analyses will include all available data through the duration of the 
study until final database lock.
3.6.5
Statistical Methods for Analyses of SARS-CoV-2 Specific CD4+ and CD8+ T Cell 
Responses
GMs with 95% CIs for each endpoint will be estimated by dose, time, and/or age stratum. 
Descriptive statistics including n, median, minimum, and maximum will also be provided.
Boxplots of each endpoint will be provided by dose, time, and/or age stratum.
3.6.6
Statistical Methods for Serum Cytokines
GMs with 95% CIs for each endpoint will be estimated by dose, time, and/or age stratum. 
Descriptive statistics including n, median, minimum, and maximum will also be provided.
Boxplots of each endpoint will be provided by dose, time, and/or age stratum.
3.6.7
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants screened 
and randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (e.g., age, race, and gender) and baseline characteristics will 
be summarized by treatment group either by descriptive statistics or categorical tables.
3.7
Interim Analyses
An interim analysis of safety and immunogenicity data to inform further clinical development 
will be performed, when at minimum 80% participants in Parts 1 and 2 have completed at least 
28-day follow-up post-vaccination and immunogenicity data are available. All available safety 
data will be evaluated. Serum samples collected on Day 1 prior to vaccination and on Day 28
postvaccination will be assayed for vaccine-induced immune responses to V590. Anti-SARS-
CoV-2 spike SNA titers measured by PRNT are the primary outcome measure. Anti-SARS-
CoV-2 spike IgG titers measured using ELISA will be analyzed as a secondary objective. The 
study enrollment, conduct, and ongoing safety monitoring will continue.
An additional interim analysis may be conducted earlier at the discretion of the sponsor when at 
minimum 80% participants in one, two, or three dosing levels in Parts 1 and 2 have completed at 
least 28-day follow-up post-vaccination and immunogenicity data are available. 
Analyses of immunogenicity data from Day 90, Day 180, and/or 270 may also be conducted at 
the discretion of the sponsor when data are available, to inform future study designs.
siDMC
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
An unblinded siDMC will receive the unblinded IA safety and immunogenicity data. The siDMC 
will make a recommendation for further clinical development based on review of: (1) available 
safety data through at least Day 28 for all participants enrolled in Parts 1 and 2; (2) available 
immunogenicity data for all evaluable participants enrolled in Parts 1 and 2; and (3) any 
available safety data from Part 3. The primary immunogenicity hypothesis will be evaluated to 
inform the decision.
A description of the structure and function of the siDMC, along with the timing and content of 
the safety review, will be outlined in the siDMC charter. Information regarding the composition 
of the siDMC is provided in Section 10.1.4.1.
Blinding
Regardless of the outcome of the IA, blinding to treatment assignment will be maintained at all 
investigational sites. The results of IAs will not be shared with the investigators prior to the 
completion of the study.
For this Phase I study, an internal statistician, statistical programmers, and modelers assigned to 
the protocol will be unblinded throughout the duration of the study to facilitate the interim 
reviews and analyses of the safety and immunogenicity data.
Treatment-level safety and immunogenicity results from the IA will be provided by the 
unblinded statistician to the siDMC. Aggregate safety data and treatment-level immunogenicity 
results will be provided by the unblinded statistician to the sponsor study team. The extent to 
which individuals are unblinded with respect to the results of IAs will be documented by the 
unblinded statistician.
Amendment 001-03: Participants in all parts will be actively followed through Day 28 for 
safety, tolerability, immunogenicity, viremia and viral shedding. A final study analysis will be 
performed on all available data through Day 28, in place of an Interim Analysis.
3.8
Multiplicity
The study has only 1 primary hypothesis which will be addressed using a closed step-wise
testing procedure that preserves the overall alpha level at 0.05 1-sided (assuming a monotonic 
dose-response).
3.9
Sample Size and Power Calculations
3.9.1
Sample Size and Power for Safety Analyses
The probability of observing at least one SAE in this study depends on the number of 
participants dosed and the underlying percentage of participants with a SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. 
There is an 90% chance of observing at least 1 SAE among 189 participants receiving V590 if 
the underlying incidence of a SAE is 1.2% (1 out of every 84 vaccine recipients). There is a 60% 
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V590-001                                                                                                   PROTOCOL NO 001-03
Supplemental SAP                                                                                                         8 APR 2021
chance of observing at least one SAE among 189 participants receiving V590 if the underlying 
incidence of a SAE is 0.5% (1 out of every 189 vaccine recipients). If no SAEs are observed in
the approximately 189 participants receiving V590, this study provides 97.5% confidence that 
the true SAE rate is <1.93% (1 out of every 51 vaccine recipients).
3.9.2
Sample Size and Power for Immunogenicity Analyses
An estimate of variability was obtained from the available data from V920-009, V920-011, and 
V920-012. The largest variability computed for any PRNT parameter in that studies was 1.2 
(standard deviation on natural log scale). 
The study achieves 90% power at a 1-sided 5% alpha-level to demonstrate V590 increases anti-
SARS-CoV-2 SNA GMTs, compared to placebo, based on a true GMT ratio of V590 vs. placebo 
≥ 2.17, assuming (1) an 85% evaluability rate at Day 28 in Parts 1 and 2 (i.e., 36 evaluable 
participants out of 42 V590 recipients in each dose level, and 48 evaluable participants out of 56 
placebo recipients); and (2) a comparable variability as observed in V920 (i.e., natural log scale 
standard deviation to be 1.2).
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