A Phase 1/Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial to Evaluate the Safety, Tolerability and Immunogenicity of V591 (COVID-19 Vaccine) in Healthy Younger and Older Participants
Phase: PHASE1
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04498247 
Document Date: 
19-Feb-2021
A Phase 1/Phase 2, Randomized, Double-Blind, Placebo-
Controlled, Dose-Ranging Trial to Evaluate the Safety, Tolerability
and Immunogenicity of V591 (COVID-19 Vaccine) in Healthy
Younger and Older Participants

PRODUCT: V591  
1
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-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/Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-
Ranging Trial to Evaluate the Safety, Tolerability and Immunogenicity of V591 (COVID-19 
Vaccine) in Healthy Younger and Older Participants
Protocol Number: 001-04
Compound Number: V591
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
24420
EudraCT
2020-003493-46
Approval Date: 19 February 2021
05QFQ7
06DWGN

PRODUCT: V591  
2
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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
 
 
05QFQ7
06DWGN

PRODUCT: V591  
3
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
V591-001-04
19-FEB-2021
The protocol amendment 03 is being amended to document the early study termination as 
permitted under flexible protocol language. Additionally, “plaque reduction neutralization 
test (PRNT)” is changed to “Pseudo-virus Neutralization Assay (PNA)” throughout the 
protocol. This change and other minor clarifications in this protocol amendment are 
unrelated to decision to terminate the study early.
V591-001-03
02-OCT-2020
The protocol amendment 02 is being amended to revise the derived date for the time 
window between the previous vaccine study to the current screening visit in exclusion 
criteria 25 and to revise BMI rounding criteria in order to optimize recruitment of Part 2B 
in the study.
V591-001-02
14-SEP-2020
The protocol amendment 01 is being amended to expand age range for Part 2B (reduce 
lower limit to >55 years old).  Additionally, clarifications to the inclusion/exclusion 
criteria and the criteria that will trigger a study pause, as well corrections of typographical
errors, are included in the amendment.
V591-001-01
13-AUG-2020
The original protocol is being amended to revise several exclusion criteria, add a second 
vaccination of 105 TCID50 on Day 169 for participant receiving the lowest first dose of
104 TCID50 Panel (the new Panel F) and specify sentinel dosing arrangements in Panels 
A, B and Panel E (the highest single dose panel).
Original Protocol
(V591-001-00)
17-JUL-2020
Not applicable
 
 
05QFQ7
06DWGN

PRODUCT: V591  
4
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [04]
Overall Rationale for the Amendments:
An evaluation of available Day 29 immunogenicity data, including both ELISA and a pseudo-neutralization assay, indicated that the 
immune responses elicited by V591 were inferior to those following natural infection and to those reported for other SARS-CoV-
2/COVID-19 vaccines. Thus, V591 was not predicted to protect against disease caused by SARS-CoV-2. Based on these data, the 
Sponsor has decided to terminate the V591-001 study, thereby allowing participants to seek COVID-19 vaccinations outside of the 
study. V591 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. Participants will 
complete activities through at least Day 56, which includes all protocol specified safety laboratory and routine AE assessments. 
Participants will not be actively followed beyond end of trial activities (to occur on or after Day 56); spontaneous reporting of SAEs 
and other protocol-specified events may continue through the protocol specified durations. In place of an Interim Analysis of data, the 
final study analysis will be performed on the collected dataset through at least Day 56.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.3, Schedule of Activities
3, Hypotheses, Objectives, 
and Endpoints
4.1, Overall Design
4.2.1.2 Immunogenicity 
Endpoints
8.2.1, Serum Neutralizing 
Antibodies Measured by PNA
Changed “plaque reduction neutralization 
test (PRNT)” to “Pseudo-virus 
Neutralization Assay (PNA)” throughout
the protocol.
Added PNA in Abbreviation List
Pseudo-virus Neutralization Assay (PNA) will be 
used to measure serum neutralization antibodies 
against SARS-CoV-2 spike protein. Both PNA and 
PRNT test for the same neutralization antibodies and 
report an NT50 titer. There is no impact on data 
report for the assay change.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
5
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Section # and Name
Description of Change 
Brief Rationale 
8.11.5, Critical Procedures 
Based on Study Objectives: 
Timing of Procedure
9, Statistical Analysis Plan
10.8, Appendix 8: Blood 
Volume Table
Appendix 10: Abbreviations
6.7.1, Stopping Rules
8.3.5 Vaccine Report Card
Removed “severe” from “Severe (Grade 3 
or higher) at the beginning of bullets 4 and 
5.
Removed “(severe)” after grade 3 in the 
last sentence in the 2nd paragraph.
Toxicity grade is used for the stopping rule 
assessment. In some case intensity may not match 
toxicity grade.
8.11.4, Poststudy
Added text to clarify required procedures 
at the final post-study visit at least 56 days 
post the last vaccination.
The sponsor has decided to terminate the study based 
on the immunogenicity results. 
This clarification is provisioned by the language as 
indicated in Section 8.11.6 Study 
Design/Dosing/Procedures Modifications Permitted 
Within Protocol Parameters: “Modification of the 
immunogenicity sampling schedule, including 
omitting Timepoints”
 
 
05QFQ7
06DWGN

PRODUCT: V591  
6
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Section # and Name
Description of Change 
Brief Rationale 
10.2, Appendix 2: Clinical 
Laboratory Tests
Changed “HbA1c” to “HbA1c (required at 
screening only)” in the table “Protocol-
required Safety Laboratory Assessments”.
HbA1c measurement is required at screening visit 
only in order to fulfill exclusion criteria #26.
The inclusion of HbA1C in Appendix 2, Table 14 is 
not intended to indicate that it is a Protocol-required 
Safety Laboratory Assessment that must be regularly 
assessed along with hematology and chemistry 
assessments.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
7
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
1.3.1
SoA for 1-Dose Panels.................................................................................20
1.3.2
SoA for 2-Dose Panels (Day 1, Day 57)......................................................25
1.3.3
SoA for 2-Dose Panels (Day 1, Day 169)....................................................30
2
INTRODUCTION..........................................................................................................34
2.1
Study Rationale....................................................................................................34
2.2
Background ..........................................................................................................34
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.3
Benefit/Risk Assessment......................................................................................36
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................37
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Safety Endpoints................................................................................42
4.2.1.2
Immunogenicity Endpoints................................................................43
4.2.1.3
Exploratory Endpoints .......................................................................43
4.2.1.4
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator/Placebo .............................................44
4.2.3
Justification for Dose...................................................................................44
4.2.4
Starting Dose for This Study........................................................................45
4.2.5
Maximum Dose/Exposure for This Study ...................................................47
4.2.6
Rationale for Dose Interval and Study Design ............................................47
4.3
Beginning and End of Study Definition .............................................................48
4.3.1
Clinical Criteria for Early Study Termination .............................................49
5
STUDY POPULATION ................................................................................................49
5.1
Inclusion Criteria.................................................................................................49
5.2
Exclusion Criteria................................................................................................52
5.3
Lifestyle Considerations......................................................................................56
5.3.1
Meals and Dietary Restrictions....................................................................56
 
 
05QFQ7
06DWGN

PRODUCT: V591  
8
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
5.3.1.1
Diet Restrictions.................................................................................56
5.3.1.2
Fruit Juice Restrictions ......................................................................56
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................57
5.3.2.1
Caffeine Restrictions..........................................................................57
5.3.2.2
Alcohol Restrictions...........................................................................57
5.3.2.3
Tobacco Restrictions..........................................................................57
5.3.3
Activity Restrictions ....................................................................................57
5.3.4
Other Restriction..........................................................................................57
5.3.5
Contraceptive Requirements........................................................................57
5.4
Screen Failures.....................................................................................................57
5.5
Participant Replacement Strategy......................................................................57
6
STUDY INTERVENTION............................................................................................58
6.1
Study Intervention(s) Administered...................................................................58
6.2
Preparation/Handling/Storage/Accountability .................................................60
6.2.1
Dose Preparation..........................................................................................60
6.2.2
Handling, Storage, and Accountability........................................................60
6.3
Measures to Minimize Bias: Randomization and Blinding..............................61
6.3.1
Intervention Assignment..............................................................................61
6.3.2
Stratification.................................................................................................62
6.3.3
Blinding........................................................................................................62
6.4
Study Intervention Compliance..........................................................................63
6.5
Management of GMO..........................................................................................63
6.6
Concomitant Therapy..........................................................................................63
6.6.1
Rescue Medications and Supportive Care ...................................................64
6.7
Dose Modification (Escalation/Titration/Other)...............................................64
6.7.1
Stopping Rules.............................................................................................64
6.7.2
Delaying Scheduled Study Vaccinations.....................................................65
6.8
Intervention After the End of the Study............................................................65
6.9
Clinical Supplies Disclosure................................................................................65
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................66
7.1
Discontinuation of Study Intervention...............................................................66
7.2
Participant Withdrawal From the Study...........................................................67
7.3
Lost to Follow-up .................................................................................................67
8
STUDY ASSESSMENTS AND PROCEDURES........................................................68
8.1
Administrative and General Procedures ...........................................................69
8.1.1
Informed Consent.........................................................................................69
8.1.1.1
General Informed Consent.................................................................69
 
 
05QFQ7
06DWGN

PRODUCT: V591  
9
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................69
8.1.2
Inclusion/Exclusion Criteria ........................................................................69
8.1.3
Participant Identification Card.....................................................................70
8.1.4
Medical History ...........................................................................................70
8.1.5
Prior and Concomitant Medications Review...............................................70
8.1.5.1
Prior Medications...............................................................................70
8.1.5.2
Concomitant Medications..................................................................70
8.1.6
Assignment of Screening Number...............................................................70
8.1.7
Assignment of Treatment/Randomization Number.....................................70
8.1.8
Study Intervention Administration ..............................................................71
8.1.8.1
Timing of Dose Administration.........................................................71
8.1.9
Discontinuation and Withdrawal .................................................................71
8.1.9.1
Withdrawal From Future Biomedical Research ................................72
8.1.10
Participant Blinding/Unblinding..................................................................72
8.1.11
Domiciling ...................................................................................................73
8.1.12
Calibration of Equipment.............................................................................73
8.2
Immunogenicity Assessments .............................................................................73
8.2.1
Serum Neutralizing Antibodies Measured by PNA.....................................73
8.2.2
Total Anti-Spike IgG Antibodies Measured by ELISA...............................73
8.2.3
Immune Responses Including Cell-mediated Immunity..............................74
8.2.4
Exploratory Immunogenicity Assays...........................................................74
8.3
Safety Assessments...............................................................................................74
8.3.1
Physical Examinations.................................................................................74
8.3.1.1
Full Physical Examination.................................................................74
8.3.1.2
Symptoms Driven Physical Examination ..........................................75
8.3.1.3
Targeted Physical Examinations........................................................75
8.3.1.4
Height and Weight .............................................................................75
8.3.2
Vital Signs....................................................................................................75
8.3.2.1
Semi-recumbent Heart Rate and Blood Pressure...............................75
8.3.2.2
Body Temperature .............................................................................76
8.3.3
Electrocardiograms ......................................................................................76
8.3.4
Study Intervention Administration ..............................................................77
8.3.5
Vaccine Report Card....................................................................................77
8.3.6
Safety Phone Call Follow Up ......................................................................78
8.3.7
Monitoring for SARS Cov-2 Exposure and COVID-19 Disease ................78
8.3.8
Clinical Safety Laboratory Assessments .....................................................80
 
 
05QFQ7
06DWGN

PRODUCT: V591  
10
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
8.4
Adverse Events, Serious Adverse Events, Medically-Attended Adverse 
Events and Other Reportable Safety Events.....................................................80
8.4.1
Time Period and Frequency for Collecting AE, SAE, MAAE, and Other 
Reportable Safety Event Information ..........................................................81
8.4.2
Method of Detecting AEs, SAEs, MAAEs, and Other Reportable Safety 
Events...........................................................................................................83
8.4.3
Follow-up of AE, SAE, MAAE, and Other Reportable Safety Event 
Information ..................................................................................................83
8.4.4
Regulatory Reporting Requirements for SAE .............................................83
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................83
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................84
8.4.7
Events of Clinical Interest............................................................................84
8.4.8
Adverse Events Reported on the VRC.........................................................85
8.4.8.1
Solicited Adverse Event.....................................................................85
8.4.8.2
Unsolicited Adverse Events...............................................................86
8.5
Treatment of Overdose........................................................................................86
8.6
Pharmacokinetics.................................................................................................86
8.7
Pharmacodynamics..............................................................................................86
8.8
Biomarkers ...........................................................................................................86
8.8.1
Planned Genetic Analysis Sample Collection..............................................86
8.9
Future Biomedical Research Sample Collection...............................................87
8.10
Health Economics Medical Resource Utilization and Health Economics.......87
8.11
Visit Requirements...............................................................................................87
8.11.1
Screening......................................................................................................87
8.11.2
Vaccination Visit .........................................................................................87
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........89
8.11.4
Poststudy......................................................................................................89
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......90
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................92
9
STATISTICAL ANALYSIS PLAN .............................................................................93
9.1
Statistical Analysis Plan Summary.....................................................................93
9.2
Responsibility for Analyses.................................................................................95
9.3
Hypotheses/Estimation ........................................................................................95
9.4
Analysis Endpoints...............................................................................................95
9.4.1
Safety Endpoints..........................................................................................95
9.4.2
Immunogenicity Endpoints..........................................................................96
9.5
Analysis Populations............................................................................................96
 
 
05QFQ7
06DWGN

PRODUCT: V591  
11
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
9.5.1
Safety Analysis Populations ........................................................................96
9.5.2
Immunogenicity Analysis Populations ........................................................96
9.6
Statistical Methods...............................................................................................97
9.6.1
Statistical Methods for Safety Analyses ......................................................97
9.6.2
Statistical Methods for Immunogenicity Analyses......................................99
9.6.3
Demographic and Baseline Characteristics ...............................................100
9.7
Interim Analyses ................................................................................................101
9.8
Multiplicity .........................................................................................................101
9.9
Sample Size and Power Calculations ...............................................................101
9.9.1
Sample Size and Power for Safety Analyses .............................................101
9.9.2
Sample Size and Power for Immunogenicity Analyses.............................102
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................104
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......104
10.1.1
Code of Conduct for Clinical Trials...........................................................104
10.1.2
Financial Disclosure...................................................................................106
10.1.3
Data Protection...........................................................................................106
10.1.3.1
Confidentiality of Data ....................................................................107
10.1.3.2
Confidentiality of Participant Records.............................................107
10.1.3.3
Confidentiality of IRB/IEC Information..........................................107
10.1.4
Committees Structure.................................................................................108
10.1.4.1
Stand Internal Data Monitoring Committee ....................................108
10.1.5
Publication Policy......................................................................................108
10.1.6
Compliance with Study Registration and Results Posting Requirements .108
10.1.7
Compliance with Law, Audit, and Debarment ..........................................109
10.1.8
Data Quality Assurance .............................................................................109
10.1.9
Source Documents .....................................................................................110
10.1.10
Study and Site Closure...............................................................................111
10.2
Appendix 2: Clinical Laboratory Tests............................................................112
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................114
10.3.1
Definition of AE ........................................................................................114
10.3.2
Definition of SAE ......................................................................................116
10.3.3
Additional Events Reported.......................................................................117
10.3.4
Recording AE, SAE, and MAAE ..............................................................117
10.3.5
Reporting of AEs, SAEs, MAAEs, and Other Reportable Safety Events 
to the Sponsor ............................................................................................124
 
 
05QFQ7
06DWGN

PRODUCT: V591  
12
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................125
10.5
Appendix 5: Contraceptive Guidance..............................................................126
10.5.1
Definitions..................................................................................................126
10.5.2
Contraception Requirements......................................................................127
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................128
10.7
Appendix 7: Country-specific Requirements..................................................133
10.8
Appendix 8: Blood Volume Table ....................................................................134
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....136
10.10 Appendix 10: Abbreviations .............................................................................137
11
REFERENCES.............................................................................................................139
 
 
05QFQ7
06DWGN

PRODUCT: V591  
13
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
LIST OF TABLES
Table 1
V591/Placebo Dose Scheme......................................................................19
Table 2
Study Interventions....................................................................................59
Table 3
Sample Allocation Schedule for Part 1 and Part 2A..................................61
Table 4
Sample Allocation Schedule for Part 2B ...................................................62
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................82
Table 6
Solicited Adverse Events for Protocol.......................................................85
Table 7
Two Dose Panels (Panels A-B, F and I-J) Site Visit Windows.................91
Table 8
Single Dose Panels (Panels C-E, G-H) Site Visit Windows......................91
Table 9
Analysis Strategy for Safety Parameters....................................................99
Table 10
Analysis Strategy for Immunogenicity Variables....................................100
Table 11
Differences in Incidence of AE Rates between the 2 Vaccination 
Groups That can be Detected With an ~80% Probability (Assuming 2-
sided 5% Alpha Level With 228 Participants in the V591 Group and 
57 Participants in the Placebo Group) .....................................................102
Table 12
Numbers of Participants Scheduled to Receive Each Study 
Intervention..............................................................................................103
Table 13
95% CIs for Varying Hypothetical GMT/GMC Ratios (V591/Placebo) 
and Varying Standard Deviations............................................................103
Table 14
Protocol-required Safety Laboratory Assessments..................................112
Table 15
Injection-Site AE Toxicity Grading Scale ...............................................118
Table 16
Specific Systemic AE Toxicity Grading Scale........................................119
Table 17
Other Systemic AE Toxicity Grading Scale............................................119
Table 18
Vital Sign (Temperature) Toxicity Grading Scale...................................120
Table 19
Laboratory Abnormalities - Serum..........................................................120
Table 20
Laboratory Abnormalities - Hematology.................................................121
Table 21
Laboratory Abnormalities – Urine...........................................................121
 
 
05QFQ7
06DWGN

PRODUCT: V591  
14
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
LIST OF FIGURES
Figure 1
Study Diagram ...........................................................................................38
 
 
05QFQ7
06DWGN

PRODUCT: V591  
15
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1/Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-
Ranging Trial to Evaluate the Safety, Tolerability and Immunogenicity of V591 (COVID-19 
Vaccine) in Healthy Younger and Older Participants
Short Title: Phase 1/Phase 2 Dose Ranging Trial to Assess Safety, Tolerability, and 
Immunogenicity of V591 (COVID-19 Vaccine) in Healthy Participants
Acronym: NA
Hypotheses, Objectives, and Endpoints:
Healthy male participants and female participants between the ages of 18-55 years (inclusive) 
of age in Parts 1 and 2A (younger adults) and > 55 years of age in Part 2B (older adults)
Primary Objectives
Primary Endpoints
To assess the safety and tolerability 
of V591 compared with placebo
Solicited injection site adverse events from Day 1 
through Day 5 after any study intervention
Solicited systemic adverse events from Day 1 
through Day 14 after any study intervention
Unsolicited adverse events from Day 1 through 
Day 28 after any study intervention
SAEs from Day 1 throughout the duration of study 
Medical attended AEs (MAAEs) collected from 
Day 1 throughout the duration of study
Secondary Objectives
Secondary Endpoints
To compare the humoral 
immunogenicity of V591 with 
placebo at Day 29 (all panels) and 
Day 85 (Panels A, B, I, and J) or 
Day 197 (Panels K and L)
Anti-SARS-CoV-2 spike serum neutralizing 
antibody (nAb) responses, as measured by Pseudo-
virus Neutralization Assay (PNA)
Anti-SARS-CoV-2 spike Immunoglobulin G (IgG) 
responses, as measured by ELISA
To evaluate the humoral 
immunogenicity of V591 at all 
timepoints with serum collection
Anti-SARS-CoV-2 spike serum nAb responses, as 
measured by Pseudo-virus Neutralization Assay 
(PNA)
Anti-SARS-CoV-2 spike IgG responses, as 
measured by ELISA
 
 
05QFQ7
06DWGN

PRODUCT: V591  
16
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Overall Design:
Study Phase
Phase 1/Phase 2
Primary Purpose
Prevention
Indication
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
Participants or Subjects
Investigator
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 30 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 260 participants will be allocated/randomized.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
17
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin-
istration
Vaccination 
Regimen
Use
Part 1 (18 to 55 years old) Sentinel Cohort
Panel A
V591
1·105 TCID50
2 doses
IM
IM injection on 
Day 1 and Day 57
Experi-
mental 
Treatment
Panel B
V591
1·106 TCID50
Panels A, B
Placebo
NA
2 doses
IM
IM injection on 
Day 1 and Day 57
Placebo
Part 2A (18 to 55 years old)
Panel C
V591
1·105 TCID50
Single Dose
IM
Single IM 
injection on Day 
1
Experi-
mental 
Treatment
Panel D
V591
1·106 TCID50
Panel E
V591
1·107 TCID50
Panels C-E
Placebo
NA
Single Dose
IM
Single IM 
injection on Day 
1
Placebo
Panels F
V591
1·104 TCID50
/ 1·105
TCID50
2 doses
IM
IM injection on 
Day 1 and Day 
169
Experi-
mental 
Treatment
Panel F
Placebo
NA
2 doses
IM
IM injection on 
Day 1 and Day 
169
Placebo
Part 2B (> 55 years old)
Panel G
V591
1·105 TCID50
Single Dose
IM
Single IM 
injection on Day 
1
Experi-
mental 
Treatment
Panel H
V591
1·106 TCID50
Panes G and 
H
Placebo
NA
Single Dose
IM
Single IM 
injection on Day 
1
Placebo
Panel I
V591
1·105 TCID50
2 doses
IM
IM injection on 
Day 1 and Day 57
Experi-
mental 
Treatment
Panel J
V591
1·106 TCID50
Panels I and 
J
Placebo
NA
2 doses
IM
IM injection on 
Day 1 and Day 57
Placebo
Panel K
V591
1·105 TCID50
2 doses
IM
IM injection on 
Day 1 and Day 
169
Experi-
mental 
Treatment
Panel L
V591
1·106 TCID50
Panels K 
and L
Placebo
NA
2 doses
IM
IM injection on 
Day 1 and Day 
169
Placebo
Abbreviations: IM: intramuscular; NA=not applicable; TCID50=Median tissue culture infectious dose
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: NA
Total 
Number of 
Intervention 
Groups/ 
Arms
260 participants (10 in Part 1 younger sentinel cohort, 100 in Part 2A 
younger cohort and 150 in Part 2B older cohort) will participate in the 
study that will include a total of 4 dose-levels and 12 Panels. Under each 
panel, participants will be randomized to receive V591 or placebo in a 4:1 
ratio.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
18
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Duration of 
Participation
Each participant will participate in the study for approximately 15 to19
months for 2-dose panels and 13 months for 1-dose panels from the time 
the participant provides documented informed consent through the final 
contact. After a screening phase of 28 days, each participant will be 
receiving either 2 doses of assigned intervention (Panels A, B, F, I, J, K and 
L) or 1 dose of assigned intervention (Panels C-E and G-H). After the last 
vaccination, each participant will be followed for 12 months.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Insert Other Oversight 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 10.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
19
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1.2
Schema
The study design is depicted in Table 1 and Figure 1.
Table 1
V591/Placebo Dose Scheme
Part 1 (18 to 55 years old) 
Sentinel Cohort
Part 2A (18 to 55 years old)
Part 2B (> 55 years old)
Sentinel/2-dose 
(Day 1, Day 57)
1-dose
2-dose (Day 1, 
Day 169)
1-dose
2-dose (Day 1, Day 57)
2-dose (Day 1, Day 
169)
Panel A
(n=5)
Panel B
(n=5)
Panel C
(n=25)
Panel D
(n=25)
Panel E
(n=25)
Panel F
(n=25)
Panel G
(n=25)
Panel H
(n=25)
Panel I
(n=25)
Panel J
(n=25)
Panel K
(n=25)
Panel L
(n=25)
105 TCID50
106 TCID50
105
TCID50
106
TCID50
107
TCID50
104 TCID50 / 
105 TCID50
105
TCID50
106
TCID50
105
TCID50
106 TCID50
105
TCID50
106 TCID50
FIH=first in human: n=number of participants; siDMC= Standing Internal Data Monitoring Committee; TCID50=median tissue culture infectious dose
a)
Within each panel, participants will be randomized to receive V591 or Placebo in a 4:1 ratio according to a computer-generated allocation schedule. The suggested doses may 
be adjusted downward based on evaluation of safety or tolerability data observed in previous participants. 
b)
Part 2A and Part 2B may initiate simultaneously based upon siDMC recommendation following review of at least seven days of safety data from n = 5 participants from each 
panel in Part 1 after their Day 1 vaccination. The second vaccination for Panel F and Panels I-L in Part 2B may initiate based upon siDMC recommendation following review 
of at least seven days of safety data from n = 5 participants from each panel in Part 1 after their Day 57 vaccination.
c)
If available, Part 2A and Part 2B may initiate simultaneously based upon siDMC recommendation following review of safety and tolerability data from the COVID-19-101 
study (V591 FIH study sponsored by the Institut Pasteur).
d)
As safety precaution, the enrollment for Panel E, the highest dose panel, will begin Day 1 vaccination with at a minimum five sentinel participants.  
 
 
05QFQ7
06DWGN

PRODUCT: V591  
20
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1.3
Schedule of Activities
1.3.1
SoA for 1-Dose Panels
1-dose Panels C-E and G-H
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening
-28 to -1b
Day 1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 85±3 115±7 211±14 365±14
Section 8.11.5
Details on variance in procedure 
collection times
Administrative Procedures
Informed Consent
X
Section 8.1.1.1
Informed Consent for Future 
Biomedical Research
X
Section 8.1.1.2
Demographics
X
Inclusion/Exclusion Criteria
X
X
Section 5.0
Participant ID Card
X
Section 8.1.3
Medical History & Vaccination 
History
X
Section 8.1.4 
Prior/Concomitant Medication 
Review
X
X
X X
X
X
X
X
X
X
X
X
Sections 6.6, 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
COVID-19 Symptoms Training
X
X
X
X
X
X
X
Section 8.3.7
V591/Placebo Administration
X
Section 8.1.8
Clinical Procedures/ Safety Assessment
Full physical examination
X
X
X
X
Section 8.3.1.1
Symptoms driven physical 
exam
X
X
X
X
X
X
X
Section 8.3.1.2
Only to be conducted if participant 
symptoms warrant an exam or at 
investigator’s discretion
 
 
05QFQ7
06DWGN

PRODUCT: V591  
21
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1-dose Panels C-E and G-H
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening
-28 to -1b
Day 1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 85±3 115±7 211±14 365±14
Section 8.11.5
Details on variance in procedure 
collection times
Targeted physical examination 
of injection site
X
X
X
Section 8.3.1.3
Panel E:  At ~ 8 hours after vaccination 
on Day 1 for the five sentinel 
participants.  
All other panels: At ~1 hour postdose on 
Day 1.
Height
X
Section 8.3.1.4
Weight
X
X
Section 8.3.1.4
Semi-recumbent Vital Signs 
(Blood Pressure [BP] and Heart 
Rate [HR] and Respiratory Rate 
[RR] 
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.2
Day 1 predose measurements will be 
done within ~ 3 hours of dosing. 
Day 1 postdose measurements:
Panel E: At ~ 8 hours after vaccination
on Day 1 for the five sentinel 
participants. 
All other Panels: will be taken minimum 
~ 1 hour after vaccination. 
Body Temperature
X
X
X X X
X
X
X
X
X
X
X
Section 8.3.2.2 (temperature) and 
Section 8.3.5 (VRC)
Days 1 to 14 will be done by participant 
and recorded on the VRC. All other
measurements will be done by clinic 
staff.
12-lead ECG
X
X
Section 8.3.3
Day 1 Predose ECG will be done within 
24 hours of dosing. 
Distribute Paper Vaccination 
Report Card (VRC)
X
Section 8.3.5 (VRC) 
Paper VRC will be provided on Day 1.  
 
 
05QFQ7
06DWGN

PRODUCT: V591  
22
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1-dose Panels C-E and G-H
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening
-28 to -1b
Day 1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 85±3 115±7 211±14 365±14
Section 8.11.5
Details on variance in procedure 
collection times
Participant Record Paper VRC
X X
X
X
Section 8.3.5 (VRC) 
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
Section 8.3.5
Collect Paper VRC From 
Participant
X
Section 8.3.5.
Postvaccination Observation 
Period
X
Section 8.11.2
Panel E: Participants will be observed for 
~ 8 hours postdose on Day 1 for the five 
sentinel participants.
All other panels: Participants will be 
observed for ~ 1 hour postdose on Day 1.
Safety Phone Call Follow-up
X
Section 8.3.6
On non-clinic days the, safety phone calls 
will follow up on AEs, any associated 
medications and vaccinations.
AE Review
X
X X
X
X
X
Sections 8.4 and Appendix 3 
SAE/ECI/MAAE review
X
X X
X
X
X
X
X
X
X
X
Sections 8.4 and Appendix 3 
Nonserious AEs are to be reported from 
Days 1 to 28. SAEs/ECIs/MAAE and 
deaths are to be reported throughout the 
duration of an individual’s study 
participation.
Laboratory Procedures/Assessments
Serum β-hCG or urine 
pregnancy test (WOCBP only)
X
X
X
Appendix 2
Pregnancy test on Day 1 to be performed 
before vaccination.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
23
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1-dose Panels C-E and G-H
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening
-28 to -1b
Day 1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 85±3 115±7 211±14 365±14
Section 8.11.5
Details on variance in procedure 
collection times
Serum FSH - (WONCBP only)
X
Appendix 2 
Confirmatory for WONCBP who are 
postmenopausal or oophorectomized.
HIV, hepatitis B and C screen 
(per site SOP)
X
Appendix 2 
UDS/BDS/Alcohol Breath (per 
site SOP)
X
Any additional UDS/BDS are conducted 
per site SOP
Coagulation: Prothrombin 
time/International Normalized 
Ratio
X
Appendix 2 
Hematology
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Urinalysis
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Chemistry
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Screening and SARS-CoV-2 Test
SARS-CoV-2 PCR
X
Appendix 2
Immunogenicity
Serum Collection for 
Neutralizing Antibodies by 
PNA
X
X
X
X
X
X
X
X
Leftover main study serum samples to be 
stored for FBR
Serum Collection for Total 
Anti-spike IgG and Total Anti-
N IgG Antibodies by ELISA
X
X
X
X
X
X
X
X
Leftover main study serum samples to be 
stored for FBR
Serum collection for 
Immunological Assessments 
(Panels C, D, G, and H only)
X
X
Leftover main study serum samples to be 
stored for FBR
PBMC collection for 
Immunological Assessments
(Panels C, D, G, and H only)
X
X
Leftover main study PBMC samples to 
be stored for FBR
Biomarkers
Blood (DNA) for Future 
Biomedical Research
X
Section 8.9
Collect from enrolled participants only. 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
24
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1-dose Panels C-E and G-H
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, Week, 
etc.
Screening
-28 to -1b
Day 1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 85±3 115±7 211±14 365±14
Section 8.11.5
Details on variance in procedure 
collection times
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; BP=blood pressure; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
ECI=event(s) of clinical interest; ELISA=enzyme-linked immunosorbent assay; FBR=future biomedical research; FSH=follicle stimulating hormone; HIV=human 
immunodeficiency virus; HR=heart rate; ID=identification; IgG=immunoglobulin G; MAAE= Medically Attended Adverse Event; PBMC=peripheral blood mononuclear cells; 
PCR=polymerase chain reaction; PNA=Pseudo-virus Neutralization Assay; RR=respiratory rate; SAE=serious adverse event; SARS-CoV-2=Severe Acute Respiratory Syndrome 
Coronavirus (novel); SOP=standard operating procedure; UDS=Urine Drug Screen; VRC=vaccine report card; WOCBP=women of childbearing potential; WONCP=women of 
nonchildbearing potential
a. Safety calls on Day 2 must occur on the day after Day 1 visit, approximately 18 to 30 hours postdose. 
b. SARS-CoV-2 serology testing will be performed at the screening visit for participants in sentinel Panels A, B and the 5 sentinel participants in panel E only. SARS-CoV-2 
seronegative participants will be enrolled in the sentinel Panels A,B and 5 sentinels participants of panel E. Part 2A (with the exception of the 5 sentinel participants in panel E) 
and Part 2B of the study are not affected by this modification.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
25
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1.3.2
SoA for 2-Dose Panels (Day 1, Day 57)
2-dose Day 1, Day 57-Panels A-B and I-J
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1b
Day 
1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 58a 71±1 85±3 115±7 211±14 422±14
Section 8.11.5
Details on variance in procedure 
collection times
Administrative Procedures
Informed Consent
X
Section 8.1.1.1
Informed Consent for 
Future Biomedical 
Research
X
Section 8.1.1.2
Demographics
X
Inclusion/Exclusion 
Criteria
X
X
X
Section 5.0
Participant ID Card
X
Section 8.1.3
Medical History & 
Vaccination History
X
Section 8.1.4 
Prior/Concomitant 
Medication Review
X
X
X X
X
X
X
X
X
X
X
X
X
X
Sections 6.6, 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
COVID-19 Symptoms 
Training
X
X
X
X
X
X
X
X
Section 8.3.7
V591/Placebo 
Administration
X
X
Section 8.1.8
Clinical Procedures/ Safety Assessment
Full physical examination
X
X
X
X
Section 8.3.1.1
 
 
05QFQ7
06DWGN

PRODUCT: V591  
26
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 57-Panels A-B and I-J
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1b
Day 
1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 58a 71±1 85±3 115±7 211±14 422±14
Section 8.11.5
Details on variance in procedure 
collection times
Symptoms driven physical 
exam
X
X
X
X
X
X
X
X
Section 8.3.1.2
Only to be conducted if participant 
symptoms warrant an exam or at 
investigator’s discretion
Targeted physical 
examination of injection 
site
X
X
X
X
X
Section 8.3.1.3
Panels A and B: ~ 8 hours after 
vaccination on Day 1 and Day 57.
Panels I and J: ~ 1 hour after 
vaccination on Day 1 and Day 57.
Height
X
Section 8.3.1.4
Weight
X
X
X
Section 8.3.1.4
Semi-recumbent Vital 
Signs (Blood Pressure 
[BP] and Heart Rate [HR] 
and Respiratory Rate [RR] 
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.2
Day 1 predose: within ~ 3 hours of 
dosing. 
Panels A and B Postdose: ~ 8 hours 
after vaccination on Day 1 and Day 
57.
Panels I and J Postdose: ~ 1 hour 
after vaccination on Day 1 and Day 
57.
Body Temperature
X
X
X X X
X
X
X
X
X
X
X
X
X
Section 8.3.2.2 (temperature) and
Section 8.3.5 (VRC)
Days 1 to 14 and Days 57 to 70 will 
be done by participant and recorded 
on the VRC. All other measurements 
will be done by clinic staff.
12-lead ECG
X
X
Section 8.3.3
Day 1 predose ECG will be done 
within 24 hours of dosing. 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
27
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 57-Panels A-B and I-J
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1b
Day 
1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 58a 71±1 85±3 115±7 211±14 422±14
Section 8.11.5
Details on variance in procedure 
collection times
Distribute Paper 
Vaccination Report Card 
(VRC)
X
X
Participant Record VRC
X X
X
X
X
X
X
Section 8.3.5 (VRC) 
Paper VRC will be provided on Day 
1 and Day 57.  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
Section 8.3.5
Collect Paper VRC From 
Participant
X
X
Section 8.3.5.
Postvaccination 
Observation Period
X
X
Section 8.11.2
Panels A and B: ~ 8 hours after 
vaccination on Day 1 and Day 57.
Panels I and J:  ~ 1 hour after 
vaccination on Day 1 and Day 57.
Safety Phone Call Follow-
up
X
X
Section 8.3.6
On non-clinic days the, safety phone 
calls will follow up on AEs, any 
associated medications and 
vaccinations.
AE Review
X
X X
X
X
X
X
X
X
X
Sections 8.4 and Appendix 3 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
28
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 57-Panels A-B and I-J
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1b
Day 
1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 58a 71±1 85±3 115±7 211±14 422±14
Section 8.11.5
Details on variance in procedure 
collection times
SAE/ECI/MAAE/ review
X
X X
X
X
X
X
X
X
X
X
X
X
Sections 8.4 and Appendix 3 
Nonserious AEs are to be reported 
from Days 1 to 28 and Days 57 to 84. 
SAEs/ECIs/MAAEs and deaths are 
to be reported throughout the 
duration of an individual’s study 
participation.
Laboratory Procedures/Assessments
Serum β-hCG or urine 
pregnancy test (WOCBP 
only)
X
X
X
X
Appendix 2
Pregnancy test on Day 1 and Day 57 
to be performed before vaccination.
Serum FSH - (WONCBP 
only)
X
Appendix 2 
Confirmatory for WONCBP who are 
postmenopausal or oophorectomized.
HIV, hepatitis B and C 
screen (per site SOP)
X
Appendix 2 
UDS/BDS/Alcohol Breath
(per site SOP)
X
Any additional UDS/BDS are 
conducted per site SOP
Coagulation: Prothrombin 
time/International 
Normalized Ratio
X
Appendix 2 
Hematology
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Urinalysis
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Chemistry
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Screening and SARS-CoV-2 Test
SARS-CoV-2 PCR 
X
Appendix 2
Immunogenicity
Serum Collection for 
Neutralizing Antibodies 
by PNA
X
X
X
X
X
X
X
X
X
Leftover main study serum samples 
to be stored for FBR
 
 
05QFQ7
06DWGN

PRODUCT: V591  
29
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 57-Panels A-B and I-J
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1b
Day 
1 
Pre-
dose
1 2a 8±1 15±1 29±3 57±3 58a 71±1 85±3 115±7 211±14 422±14
Section 8.11.5
Details on variance in procedure 
collection times
Serum Collection for Total 
Anti-spike IgG and Total 
Anti-N IgG Antibodies by 
ELISA
X
X
X
X
X
X
X
X
X
Leftover main study serum samples 
to be stored for FBR
PBMC collection for 
Immunological 
Assessments
X
X
Leftover main study PBMC samples 
to be stored for FBR
Biomarkers
Blood (DNA) for Future 
Biomedical Research
X
Section 8.9
Collect from enrolled participants 
only. 
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; BP=blood pressure; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
ECI=event(s) of clinical interest; ELISA=enzyme-linked immunosorbent assay; FBR=future biomedical research; FSH=follicle stimulating hormone; HIV=human 
immunodeficiency virus; HR=heart rate; ID=identification; IgG=immunoglobulin G; MAAE= Medically Attended Adverse Event; PBMC=peripheral blood mononuclear cells;
PCR=polymerase chain reaction; PNA=Pseudo-virus Neutralization Assay; RR=respiratory rate; SAE=serious adverse event; SARS-CoV-2=Severe Acute Respiratory Syndrome 
Coronavirus (novel); SOP=standard operating procedure; UDS=Urine Drug Screen; VRC=vaccine report card; WOCBP=women of childbearing potential; WONCBP=women of 
nonchildbearing potential
a. Safety calls on Days 2 and 58 must occur on the day after the Day 1 and Day 57 visits, respectively, approximately 18 to 30 hours postdose.
b. SARS-CoV-2 serology testing will be performed at the screening visit for participants in sentinel Panels A, B and the 5 sentinel participants in panel E Only. SARS-CoV-2 
seronegative participants will be enrolled in the sentinel Panels A,B and 5 sentinels participants of panel E. Part 2A (with the exception of the 5 sentinel participants in panel E) 
and Part 2B of the study are not affected by this modification.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
30
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
1.3.3
SoA for 2-Dose Panels (Day 1, Day 169)
2-dose Day 1, Day 169-Panels F and K-L
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1
Day 
1 
Pre-
dose
1
2a
8±1
15±1
29±3
85±3
169±3
170a
197±3
365±7
534±14
Section 8.11.5
Details on variance in procedure 
collection times
Administrative Procedures
Informed Consent
X
Section 8.1.1.1
Informed Consent for 
Future Biomedical 
Research
X
Section 8.1.1.2
Demographics
X
Inclusion/Exclusion 
Criteria
X
X
X
Section 5.0
Participant ID Card
X
Section 8.1.3
Medical History & 
Vaccination History
X
Section 8.1.4 
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Sections 6.6, 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
COVID-19 Symptoms 
Training
X
X
X
X
X
X
X
Section 8.3.7
V591/Placebo 
Administration
X
X
Section 8.1.8
Clinical Procedures/ Safety Assessment
Full physical examination
X
X
X
Section 8.3.1.1
Symptoms driven physical 
exam
X
X
X
X
X
X
X
Section 8.3.1.2
Only to be conducted if participant 
symptoms warrant an exam or at 
investigator’s discretion
Targeted physical 
examination of injection 
site
X
X
X
X
Section 8.3.1.3
At ~ 1 hour postdose on Day 1 and 
Day 169
 
 
05QFQ7
06DWGN

PRODUCT: V591  
31
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 169-Panels F and K-L
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1
Day 
1 
Pre-
dose
1
2a
8±1
15±1
29±3
85±3
169±3
170a
197±3
365±7
534±14
Section 8.11.5
Details on variance in procedure 
collection times
Height
X
Section 8.3.1.4
Weight
X
X
X
Section 8.3.1.4
Semi-recumbent Vital 
Signs (Blood Pressure 
[BP] and Heart Rate [HR] 
and Respiratory Rate [RR] 
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.2
Day 1 predose measurements will 
be done within ~ 3 hours of dosing. 
Day 1 and Day 169: Postdose 
measurements will be taken ~ 1 
hour after vaccination. 
Body Temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.2.2 (temperature) and 
Section 8.3.5 (VRC)
Days 1 to14 and Days 169 to 182
will be done by participant and 
recorded on the VRC. All other 
measurements will be done by 
clinic staff.
12-lead ECG
X
X
Section 8.3.3
Day 1 predose ECG will be done 
within 24 hours of dosing. 
Distribute Paper 
Vaccination Report Card 
(VRC)
X
X
Participant Record VRC
X
X
X
X
X
X
Section 8.3.5 (VRC) 
Paper VRC will be provided on Day 
1 and Day 169.  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
Section 8.3.5
Collect Paper VRC From 
Participant
X
X
Section 8.3.5.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
32
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 169-Panels F and K-L
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1
Day 
1 
Pre-
dose
1
2a
8±1
15±1
29±3
85±3
169±3
170a
197±3
365±7
534±14
Section 8.11.5
Details on variance in procedure 
collection times
Postvaccination 
Observation Period
X
X
Section 8.11.2
Participants will be observed for 
minimum ~ 1 hour postdose on Day 
1 and Day 169.
Safety Phone Call Follow-
up
X
X
Section 8.3.6
On non-clinic days the, safety 
phone calls will follow-up on AEs, 
any associated medications and 
vaccinations.
AE Review
X
X
X
X
X
X
X
X
X
Sections 8.4 and Appendix 3 
SAE/ECI/MAAE review
X
X
X
X
X
X
X
X
X
X
X
X
Sections 8.4 and Appendix 3 
Nonserious AEs are to be reported 
from Days 1 to 28 and Days 169 to 
196. SAEs/ECIs/MAAEs and 
deaths are to be reported throughout 
the duration of an individual’s study 
participation.
Laboratory Procedures/Assessments
Serum β-hCG or urine 
pregnancy test (WONCBP 
only)
X
X
X
X
Appendix 2
Pregnancy test on Day 1 and Day 
169 to be performed before 
vaccination.
Serum FSH - (WOCBP 
only)
X
Appendix 2 
Confirmatory for WONCBP who 
are postmenopausal or 
oophorectomized.
HIV, hepatitis B and C 
screen (per site SOP)
X
Appendix 2 
UDS/BDS/Alcohol Breath 
(per site SOP)
X
Any additional UDS/BDS are 
conducted per site SOP
Coagulation: Prothrombin 
time/International 
Normalized Ratio
X
Appendix 2 
Hematology
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
 
 
05QFQ7
06DWGN

PRODUCT: V591  
33
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2-dose Day 1, Day 169-Panels F and K-L
Screening
Study Day
Post-
Study
Notes
Scheduled Hour, Day, 
Week, etc.
Screening
-28 to -1
Day 
1 
Pre-
dose
1
2a
8±1
15±1
29±3
85±3
169±3
170a
197±3
365±7
534±14
Section 8.11.5
Details on variance in procedure 
collection times
Urinalysis
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Chemistry
X
X
X
X
X
X
X
X
Section 8.3.7 and Appendix 2
Screening and SARS-CoV-2 Test
SARS-CoV-2 PCR 
X
Appendix 2
Immunogenicity
Serum Collection for 
Neutralizing Antibodies 
by PNA
X
X
X
X
X
X
X
X
Leftover main study serum samples 
to be stored for FBR
Serum Collection for 
Total Anti-spike IgG and 
Total Anti-N IgG 
Antibodies by ELISA
X
X
X
X
X
X
X
X
Leftover main study serum samples 
to be stored for FBR
PBMC collection for 
Immunological 
Assessments 
X
X
Leftover main study PBMC 
samples to be stored for FBR
Biomarkers
Blood (DNA) for Future 
Biomedical Research
X
Section 8.9
Collect from enrolled participants 
only. 
AE=adverse event; β-hCG=beta human chorionic gonadotropin; BDS=blood drug screen; BP=blood pressure; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
ECI=event(s) of clinical interest; ELISA=enzyme-linked immunosorbent assay; FBR=future biomedical research; FSH=follicle stimulating hormone; HIV=human 
immunodeficiency virus; HR=heart rate; ID=identification; IgG=immunoglobulin G; MAAE= Medically Attended Adverse Event; PBMC=peripheral blood mononuclear cells; 
PCR=polymerase chain reaction; PNA=Pseudo-virus Neutralization Assay; RR=respiratory rate; SAE=serious adverse event; SARS-CoV-2=Severe Acute Respiratory 
Syndrome Coronavirus (novel); SOP=standard operating procedure; UDS=Urine Drug Screen; VRC=vaccine report card; WOCBP=women of childbearing potential; 
WONCBP=women of nonchildbearing potential
a. Safety calls on Days 2 and 170 must occur on the day after the Day 1 and Day 169 visits, respectively, approximately 18 to 30 hours postdose.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
34
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2
INTRODUCTION
2.1
Study Rationale
Coronaviruses (CoV) are a large family of viruses that can cause illness ranging from the 
common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-
CoV) and Severe Acute Respiratory Syndrome (SARS-CoV). In 2019, an acute respiratory 
syndrome, COVID-19, caused by a novel coronavirus, SARS-CoV-2 was identified
[Harapan, H., et al 2020].  The ongoing outbreak of COVID-19 was declared a pandemic on 
11-MAR-2020 by the World Health Organization (WHO). Community spread has been 
observed in nearly all countries worldwide with over seven million confirmed cases and 
400,000 deaths reported as of June 2020[COVID-19 Treatment Guidelines Panel 2020]
[Dong, E., et al 2020]. More recently a multisystem inflammatory syndrome in children 
(MIS-C) associated with COVID-19 has been observed in pediatric patients, who have 
generally not displayed severe respiratory symptoms[Dufort, E. M., et al 2020].
There is currently no marketed vaccine for SARS-CoV-2 and therapies have demonstrated 
limited efficacy to date. There is a pressing global need for a safe and effective vaccine. 
V591 is a live recombinant viral vaccine against the SARS-CoV-2 Spike protein which is 
based upon an attenuated measles virus measles virus (Schwarz Vaccine strain), commonly 
used in authorized measles vaccines. 
This study is a placebo-controlled dose-ranging trial to evaluate the safety and 
immunogenicity of V591, also designated as TMV-083, in single and two-dose regimens in 
healthy younger and older adults. The primary objectives will be the safety and tolerability of 
the V591 vaccine. Secondary objectives will be to evaluate anti-Spike binding antibody titers 
as well as neutralizing antibody (nAb) titers. Exploratory objectives will include additional 
immunogenicity endpoints of cell mediated immunity, Th1/Th2 polarization, and serologic or 
clinical evidence of SARS-CoV-2 infection.
2.2
Background
Refer to the IB for detailed background information on V591.
2.2.1
Pharmaceutical and Therapeutic Background
V591 is a live attenuated recombinant viral vectored vaccine for the prevention of COVID-
19 disease. The Schwarz measles vaccine strain is used as vector. The measles vaccine is a 
live-attenuated negative-stranded RNA virus, which induces life-long protective immunity 
after a single injection and has dramatically reduced childhood mortality from measles by 
90% since its introduction. Frédéric Tangy and colleagues at the Institut Pasteur introduced 
the live attenuated measles Schwarz strain (MV-Schwarz) as a vector to express heterologous 
viral antigens [Combredet, C., et al 2003]. This technology has been utilized as a platform 
technology for the development of a wide variety of experimental vaccines against different
indications, particularly against emerging infectious diseases. These experimental measles-
vectored vaccines have been shown to be safe, well tolerated and immunogenic in pre-
clinical and clinical studies to date. The most advanced clinical vaccine MV-CHIK has been 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
35
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
demonstrated to be well tolerated and immunogenic through Phase 2 studies. The MV vector 
is thus an appropriate platform for developing an effective COVID-19 vaccine.
The spike protein of SARS-CoV-2 was selected as target antigen to induce the development 
of neutralizing antibodies. Specific mutations were introduced to keep the protein in its pre-
fusion conformation and to avoid cleavage into its subdomains. Nucleotide sequences 
encoding the modified SARS-CoV-2 surface protein Spike (S) were codon-optimized for the 
expression in human cells, chemically synthesized and inserted into the Schwarz vaccine 
strain of measles virus to produce the COVID-19 vaccine candidate on Vero cells. 
The MV vector has been shown to stably express large, heterologous antigens up to 5kb long. 
To date, the vector has been used to generate a number of recombinant MV clones expressing 
heterologous viral antigens including CHIKV [Brandler, S., et al 2013], WNV [Brandler, S., 
et al 2012] [Despres, P., et al 2005], DENV [Brandler, S., et al 2007] [Brandler, S., et al 
2010], HIV [Lorin, C., et al 2004] [Stebbings, R., et al 2012], MERS-CoV [Bodmer, B. S., et 
al 2018] [Malczyk, A. H., et al 2015], SARS-CoV [Escriou, N., et al 2014] and LASV 
[Mateo, M., et al 2019]. The constructs created for the prevention of MERS and SARS are of 
particular interest, because of their high degree of similarity to the COVID-19 vaccine. In 
both cases, the full-length nucleotide sequence encoding the respective MERS and SARS 
Spike genes were inserted into the MV backbone. The resulting constructs were found to 
induce both neutralizing antibodies as well as IFNγ-producing T cells in animal models, 
indicative of a Th1-type immune response [Bodmer, B. S., et al 2018] [Malczyk, A. H., et al 
2015] [Escriou, N., et al 2014].
The Measles Vector platform used for V591 is well suited for the development of a SARS-
CoV-2 vaccine, as both the measles virus itself and MV platform vaccines produce Th1 
polarized responses, which are less likely to predispose to antibody dependent or vaccine 
induced disease enhancement.
Studies of SARS vaccine candidates in animal models suggested that some of them could 
exacerbate disease severity. Immunization with inactivated or subunit vaccine candidates in 
mice followed by challenge with SARS-CoV resulted in immunopathology in the lungs 
despite protection against viremia[Lambert, P. H., et al 2020]. The pathology was identified 
as a Th2-type pathology characterized by heavy eosinophil infiltration. Immunopathology 
was not seen with vaccine formulations known to generate a Th 1-type response, either 
through the use of Th1-polarizing adjuvants or viral vectors [Honda-Okubo, Y., et al 2015]. 
Together, the available results point to the induction of a Th1-type polarized immune 
response as an important safety aspect of a SARS-CoV-2 vaccine candidate[Lambert, P. H., 
et al 2020]. 
The measles vector is a replicating vector which is known to elicit strong and persistent 
humoral and cellular immune response [Plotkin, Stanley A. 2010]. The standard measles 
vaccine elicits a predominantly Th1-type directed immune response [Ovsyannikova, I. G., et 
al 2003] [Howe, R. C., et al 2005] [Moss, W. J. and Griffin, D. E. 2006]. Importantly, for the 
measles vaccine-derived vector, Th1-type directed immune responses have been confirmed 
in preclinical studies for several different vaccine candidates. A MV-based vaccine candidate 
was generated against Lassa fever, a major threat in Western Africa. A single dose of the 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
36
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
vaccine protected NHP against lethal challenge with Lassa virus. Analysis of the immune 
responses showed that complete protection was associated with robust secondary T cell and 
antibody responses against Lassa virus. The T cells response was Th1-driven, largely 
characterized by TNF-a and/or IFN-y positive CD8+ and CD4+ T cells [Mateo, M., et al 
2019]. 
An MV-SARS vaccine candidate expressing the membrane-bound SARS-CoV spike protein 
(analogous to the COVID-19 vaccine candidate) was demonstrated to be efficacious in mice 
against challenge with SARS-CoV. The vaccine candidate elicited high titers of neutralizing 
antibodies as well as a predominantly Th1-type T cell response, as determined by IgG2a over 
IgG1 ratio [Escriou, N., et al 2014].
Collectively, there is strong evidence that vaccine candidates based on the measles vector 
platform induce a Th1-type oriented immune response. Particularly, the prior evidence for an 
MV-SARS preclinical vaccine candidate is highly promising for the development of V591 as 
a SARS-CoV-2 vaccine. 
2.3
Benefit/Risk Assessment
Healthy participants in clinical studies may not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
potential effectiveness of an investigational vaccine.
V591 is intended to induce an immune response against the SARS-CoV-2 virus, and no prior 
clinical studies have been completed with V591 to date. There are no clinical or preclinical 
data to indicate whether this vaccine will induce clinically meaningful protection against 
SARS-CoV-2 disease or infection. The risk of disease enhancement by the vaccine has not 
yet been evaluated preclinically. 
Additional details regarding specific benefits and risks for participants in this clinical study 
can be found in the accompanying IB and informed consent documents.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
37
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Healthy male participants and female participants between the ages of 18-55 years (inclusive) 
of age in Parts 1 and 2A (younger adults) and > 55 years of age in Part 2B (older adults)
Objectives
Endpoints
Primary
To assess the safety and tolerability of
V591 compared with placebo
Solicited injection site adverse events from 
Day 1 through Day 5 after any study 
intervention
Solicited systemic adverse events from Day 
1 through Day 14 after any study 
intervention
Unsolicited adverse events from Day 1 
through Day 28 after any study intervention
SAEs from Day 1 throughout the duration of 
study 
Medical attended AEs (MAAEs) collected 
from Day 1 throughout the duration of study
Secondary
To compare the humoral immunogenicity 
of V591 with placebo at Day 29 (all 
panels) and Day 85 (Panels A, B, I, and J) 
or Day 197 (Panels K and L)
Anti-SARS-CoV-2 spike serum neutralizing 
antibody (nAb) responses, as measured by 
Pseudo-virus Neutralization Assay (PNA)
Anti-SARS-CoV-2 spike Immunoglobulin G 
(IgG) responses, as measured by ELISA
To evaluate the humoral immunogenicity 
of V591 at all timepoints with serum 
collection
Anti-SARS-CoV-2 spike serum nAb 
responses, as measured by Pseudo-virus 
Neutralization Assay (PNA)
Anti-SARS-CoV-2 spike IgG responses, as 
measured by ELISA
Tertiary/Exploratory
To evaluate the immune response to of 
V591, including cell-mediated immunity
PBMCs stimulated with SARS-CoV-2 Spike 
peptides for characterization of cell mediated 
immunity and serum to characterize the 
immune response to V591
 
 
05QFQ7
06DWGN

PRODUCT: V591  
38
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Objectives
Endpoints
To characterize SARS-CoV-2 
seroconversion rates among participants
Anti-SARS-CoV-2 N-protein IgG responses, 
as measured by immunoassay
To document confirmed diagnoses of 
SARS-CoV-2 infection among study 
participants
Laboratory confirmed diagnosis of SARS-
CoV-2 infection reported as an ECI 
To document study participants’ exposures 
to confirmed SARS-CoV-2 cases
Known exposure to a confirmed case of 
active SARS-CoV-2 reported as an ECI
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, two-part, multi-site, double-blind dose-ranging 
study of V591 in healthy younger and older adults to be conducted in conformance with 
Good Clinical Practice in approximately 260 participants as outlined in Figure 1.
Figure 1
Study Diagram
 
 
05QFQ7
06DWGN

PRODUCT: V591  
39
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
In this 2-part Phase 1/2 trial, two Sentinel Panels will be enrolled in Part 1 followed by the
review of safety/tolerability data through 7 days following dose 1 by a standing internal Data 
Monitoring Committee (siDMC) prior to initiation of dosing in Parts 2A and 2B. The siDMC 
will also review the safety/tolerability data from the sentinel Panels through 7 days following 
dose 2 prior to administration of the 2nd dose in Panel F in Part 2A and Panels I-L in Part 2B. 
The study design is described in detail in the protocol text and the SoA.
In Part 1, approximately 10 healthy younger participants (age 18-55 years inclusive) will be 
enrolled in two Sentinel Panels, Panel A and Panel B, and administered two doses of either 
1·105 TCID50 or 1·106 TCID50 V591. Five participants will be randomized into each Panel 
per dose to receive two vaccinations of V591 or placebo 56 days apart in a 4:1 ratio.   
As safety precaution, the study will begin with the Day 1 vaccination of a small group of 
sentinel participants (5 participants from Panel A and 5 participants from Panel B) at one 
investigational site.  
The first and the second participant of sentinel Panel A will receive the Day 1 vaccination 
on the same day, with an interval of at least 3 hours. Twenty-four hours after the injection, 
the participants will be called to collect safety information related to the vaccination. The 
clinical investigator can then decide to move on with the vaccination of the remaining 3
participants in Panel A based on the absence of related severe AEs/SAEs.
The first and the second participant of sentinel Panel B may be enrolled at least seventy-
two hours after the first participant in Panel A has received the first vaccination. The first 
and the second participant in Panel B will receive the Day 1 vaccination on the same day, 
with an interval of at least 3 hours. Twenty-four hours after the injection, the participants will 
be called to collect safety information related to the vaccination. The clinical investigator can 
then decide to move on with the vaccination of the remaining 3 participants in Panel B based 
on the absence of related severe AEs/SAEs.
In Part 2A, approximately 100 healthy younger participants (age 18-55 years inclusive) will 
be enrolled in four Panels, Panel C, Panel, D, Panel E, and Panel F. Participants in Panels C-
E will be administered a single dose of either 1·105 TCID50, 1·106 TCID50, or 1·107 TCID50
of V591, respectively.  Participant in Panel F will be administered 2 doses of V591 or 
placebo: 1 104 TCID50 on Day 1 and 1·105 TCID50 on Day 169.  25 participants will be 
randomized into each Panel per dose to receive a single vaccination of V591 or placebo in a 
4:1 ratio.  Part 2A may initiate based upon siDMC recommendation as outlined below and 
may initiate simultaneously with Part 2B. Panel C, Panel, D, Panel E and Panel F may all be 
enrolled in parallel.  
Panel E in Part 2A: As safety precaution, the enrollment for Panel E, the highest dose panel, 
will begin with the Day 1 vaccination with five sentinel participants at a single 
investigational site.  The first 5 participants in Panel E will be enrolled and receive the Day 1 
vaccination with an interval of at least 3 hours between each participant. Twenty-four hours 
after the injection, the participants will be called to collect safety information related to the 
vaccination. The clinical investigator can then decide to move on with the vaccination of the 
remaining participants in Panel E based on the absence of related severe AEs/SAEs.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
40
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
In Part 2B, approximately 150 healthy older participants (aged > 55 years) will be enrolled in 
six Panels. Two Panels of older participants, Panel G and Panel H, will be administered a 
single dose of either 1·105 TCID50 or 1·106 TCID50 of V591. Two Panels of older 
participants, Panel I and Panel J, will be administered two doses of either 1·105 TCID50 or 
1·106 TCID50 of V591 56 days apart. Two Panels of older participants, Panel K and Panel I,
will be administered two doses of either 1·105 TCID50 or 1·106 TCID50 of V591 168 days 
apart. Twenty-five participants will be randomized into each panel per dosing regimen to
receive IM vaccination of V591 or placebo in a 4:1 ratio. Part 2B may initiate based upon 
siDMC recommendation as outlined below and may initiate simultaneously with Part 2A.
Study participants in Panels I-L may receive their second dose of V591 based upon siDMC 
recommendation as outlined below. Panel G, Panel H, Panel I, and Panel J may be enrolled 
in parallel, while Panel K and Panel L will only commence recruiting study participants after 
Panel G, Panel H, Panel I, and Panel J are full enrolled.
In accordance with the FDA’s “Development and Licensure of Vaccines to Prevent COVID-
19, Guidance for Industry”, the Sponsor will make efforts recruit a representative population 
for this Phase 1/2 study, particularly in the Panels of older adults as this is the only planned 
study in Phase 1 that will include this population. In order to facilitate the enrollment of
diverse study population, particularly those that have been disproportional impacted by 
COVID-19 and historically underrepresented in vaccine trials, older adults in Part 2B will 
only be recruited in the United States. 
The Sponsor’s standing internal Data Monitoring Committee (siDMC) will review safety and 
tolerability data throughout this study, will evaluate safety data for the Safety Reviews 
following the first and second vaccinations in the sentinel Panels, and will be convened to 
evaluate available data if stopping rules are met. The siDMC is a standing, internal Sponsor 
committee established to monitor early phase clinical studies. Additional details are provided 
in Section 10.1.4.1 and in the siDMC charter.
The siDMC will conduct a Safety Review on at least 7 days of safety and tolerability data 
from 5 participants in each Panel of Part 1 after their Day 1 vaccination to decide on
proceeding to Part 2A and Part 2B of the study. 
The siDMC will also conduct a Safety Review on at least 7 days of safety and tolerability 
data from 5 participants in each Panel of Part 1 after their Day 57 vaccination to decide on
proceeding to administer the second V591 dose to Panels F in Part 2A and Panels I-L in Part 
2B of the study. 
V591, also known as TMV-083, is planned to be introduced into a FIH clinical study, 
COVID-19-101, sponsored by the Institut Pasteur.  In COVID-19-101 sentinel cohorts of 
three health young adults each are planned to be vaccinated with a two dose regimen 28 days 
apart at doses of 1·105 TCID50 and 1·106 TCID50 in the middle of August 2020, and it is 
anticipated that at least 7-day safety and tolerability data in three participants at each dose 
level may be available for review by the siDMC before the safety and tolerability data from
the sentinel Panels (Panels A and B) of V591-001.  
 
 
05QFQ7
06DWGN

PRODUCT: V591  
41
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
If safety and tolerability data are available for review from the COVID-19-101 study, it may
be reviewed by the siDMC instead of the V591-001 safety and tolerability data from Panel A 
and Panel B of this study in order to make a decision to proceed to Part 2A and 2B of V591-
001.
At least seven days of safety and tolerability data from the COVID-19-101 sentinel cohorts
following their Day 28 vaccination may be reviewed by the siDMC instead of the V591-001 
safety and tolerability data from Panel A and Panel B in order to make a decision to proceed 
to administer the second dose to Panel F in Part 2A and Panels I-L in Part 2B of the V591-
001 study. 
Up to two interim analyses may be performed on safety and immunogenicity data through at 
least Day 29. In order to trigger the first interim analysis at least 75% of study participants 
per Panel in at least 6 Panels must have completed their Day 29 visit. In order to trigger the 
second interim analysis at least 75% of study participants per Panel in at least 10 Panels must 
have completed their Day 29 visit.  
An interim analysis may be performed on safety and immunogenicity data through at least 
Day 85 for Panels A, B, I, and J. To trigger this interim analysis at least 75% of these Panel’s 
participants must have completed their Day 85 visit. A minimum percentage of participants 
from other study Panels is not required for this interim analysis, though all available data will 
be included.
An interim analysis may be performed on safety and immunogenicity data through at least 
Day 197 for Panels K and L. To trigger this interim analysis at least 75% of these Panel’s 
participants must have completed their Day 197 visit. A minimum percentage of participants 
from other study Panels is not required for this interim analysis, though all available data will 
be included.
These interim immunogenicity analyses will include all available Pseudo-virus 
Neutralization Assay (PNA) data and IgG ELISA data.
Because this is a Phase 1/Phase 2 assessment of V591 in humans, the 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/Phase 2 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.
4.2
Scientific Rationale for Study Design
This study is being conducted to evaluate the safety, tolerability and immunogenicity of 
V591 in healthy younger (18-55 years of age) and older (> 55 and older) adults.  It will 
probably commence shortly after the Institut Pasteur sponsored FIH clinical study of 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
42
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
V591(also known as TMV-083) in healthy young adults, COVID-19-101, plans to begin. 
This study is designed to maximize participant safety while permitting efficient trial conduct 
in the setting of the global COVID-19 pandemic. The design is supported by past clinical and 
preclinical experience with MV-CHIK which uses the same measles virus vector platform as 
V591 and has completed Phase 2 trials, as well as preclinical data for V591. 
The study consists of a placebo controlled, double-blind, dose-ranging design of single or 
two doses regimens of V591. The study incorporates two sentinel cohorts to evaluate safety 
and tolerability of 1·105 TCID50 and 1·106 TCID50 of V591, doses selected as likely to be 
immunogenic and well tolerated, before proceeding to additional Panels.  Based on prior 
experience with MV-CHIK immunogenicity, only doses of V591≥1·104 TCID50 will be 
administered as these are expected to be immunogenic.  They have been selected for clinical 
dosing in order limit the possibility that study participants will being given a sub-
immunogenic dose of V591. 
MV vector shedding has not been observed in prior clinical study with the MV-CHIK. 
Vector shedding will be evaluated by PCR in the FIH COVID-19-101 study, and thus it will 
not be evaluated in this study.
The total sample size was selected to achieve a reasonably sized safety database for the study 
population exposed to V591. In addition, the sample size is considered to be reasonably 
sufficient to achieve adequate precision to evaluate the immunogenicity different doses and 
both single and two regimens of V591.
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.
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
As this is a Phase 1/2 study of V591, safety and tolerability will be primary endpoints and 
will be closely monitored and followed. It is anticipated that IM administration of V591 at 
the proposed doses will be well-tolerated in humans based on preclinical studies as well as 
previous experience with the MV vector platform used for MV-CHIK.
The safety and tolerability of V591 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). 
Assessments will occur throughout the trial, with time points optimized based on the 
expected timing of local and systemic reactions to vaccination (See Section 8.4.1 and 
Appendix 3). Specific safety endpoints to be gathered include:

Solicited injection site AEs (pain/tenderness, swelling, redness) up to 5 days post
each study intervention.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
43
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021

Solicited systemic AEs [ fever (oral temperature), muscle pain, joint pain, headache,
fatigue, rash, nausea] up to 14 days post each study intervention.

Unsolicited AEs up to 28 days post each study intervention.

SAEs, MAAEs and events of clinical interest from Day 1 throughout the duration of 
the study.  Safety laboratory tests as described in the SoA 

Vital sign measurements and physical exam findings as described in the SoA 
The 2007 Center for Biologics Evaluation and Research (CBER) Guidance Document will 
be used as the toxicity grading scale for this study (see Appendix 3).  
4.2.1.2
Immunogenicity Endpoints
As a vaccine trial, secondary and exploratory endpoints in this trial will evaluate the 
immunogenicity of V591 using assays to measure neutralizing antibodies by PNA, IgG 
antibody titers against spike protein by ELISA, cell mediated immune responses, including 
Th1/Th2 polarization, and additional exploratory immunogenicity assays.
For secondary endpoints serum samples will be collected as outlined in the SoA for:

Serum neutralizing antibodies measured by PNA

Total anti-spike IgG antibodies measured by ELISA
For exploratory endpoints PBMCs and serum will be collected as outlined in the SoA for:

PBMCs to be stimulated with SARS-CoV-2 Spike peptides for characterization of 
cell mediated immunity 

Serum for further characterization of the immune response to V591
Additionally, samples including serum and PBMCs will be collected for additional 
exploratory immunogenicity endpoints as outlined in the objectives. 
4.2.1.3
Exploratory Endpoints
In accordance with regulatory guidance, this trial will endeavor to identify potential 
exposures and infections by SARS-CoV-2 amongst study participants. However, this clinical 
trial is not intended to interfere with local health practices and regulations regarding the 
management of confirmed or suspected SARS-CoV-2 infections. Study participants will be
tested as appropriate according to local regulations and will receive any required medical 
care within their existing healthcare systems, please refer to Section 8.3.7 for further details.  
 
 
05QFQ7
06DWGN

PRODUCT: V591  
44
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Additional exploratory endpoints will include the follow assessments to assess the potential 
exposure to and infection by SARS-CoV-2 amongst study participants without potentially 
disrupting medical care:

SARS-CoV-2 N protein specific antibody up to Study Day 534 as assessed by 
immunoassay. As the SARS-CoV-2 N protein is not included in the vaccine, 
infections in study participants seroconversion will identify asymptomatic and pauci-
symptomatic SARS-CoV-2 over the entire course of the study.

Any laboratory confirmed diagnosis of SARS-CoV-2 infection (PCR or antigen 
based) and any resulting clinical sequelae will be reported as an ECI in study 
participants throughout the duration of the study.

Known exposure to a confirmed case of active SARS-CoV-2, defined as individual 
who has had close contact (< 1.5 meters for ≥15 minutes), will be reported as an ECI 
in study participants throughout the duration of the study.
4.2.1.4
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 Comparator/Placebo
A placebo-controlled study will minimize bias during assessment of safety, tolerability, and 
immunogenicity. In addition, placebo serves as a negative control for potential environmental 
exposures to SARS-CoV-2 and provides a control for immunologic assays.
4.2.3
Justification for Dose
The methods and rationale for selecting the proposed doses and estimated exposures of V591 
are detailed in Sections 4.2.4 and 4.2.5.
As this is a Phase 1/Phase 2 assessment of V591 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 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
45
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.2.4
Starting Dose for This Study
The starting V591 doses for this study are 1·105 TCID50 and 1·106 TCID50. These doses of 
have been selected based upon prior clinical safety/tolerability and immunogenicity data with 
the most advanced vaccine using the MV platform, MV-CHIK, along with supportive
preclinical biodistribution and GLP toxicology studies undertaken with MV platform 
vaccines. MV-CHIK has been administered to healthy volunteers in Phase 1 and Phase 2 
studies at doses ranging from 1·104 to 1·106 TCID50 without any significant safety findings.
Clinical safety and tolerability data from Phase 2 studies that administered MV-CHIK at the 
relevant dose levels of 1·105 and/or 1·106 TCID50 are summarized below.
MV-CHIK-202
The immunogenicity and safety of the MV-CHIK vaccine was evaluated in a Phase 2 clinical 
trial, MV-CHIK-202, in 263 study participants[Reisinger, E. C., et al 2019]. Healthy adults 
aged 18-55 years of age were randomly assigned to receive intramuscular injections of either 
5·104 or 5·105 50% tissue culture infectious dose (TCID50) per dose of MV-CHIK or a
Priorix® control in two different administration regimens. Analysis of vaccine safety and 
tolerability during the trial revealed a comparable profile for MV-CHIK as compared to the 
licensed control vaccine Priorix® (Priorix® contains the attenuated vaccine Schwarz strain 
of the measles virus). Adverse events frequencies were similar between groups. with 73.4% 
of MV-CHIK and 70.6% of Priorix® recipients reporting solicited AEs, and 50.7% (116 of 
229) of MV-CHIK and 50.0% (17 of 34) of Priorix® recipient reporting unsolicited AEs. No 
serious AEs related to the vaccine were recorded. 
The most frequent related AEs amongst recipients of MV-CHIK were 52.4% of subjects with 
injection site tenderness, 120 of 229 subjects), 33.2% of subjects with headache (76 of 229 
subjects), 32.8% of subjects with injection site pain (75 of 229 subjects), 22.7% of subjects 
with fatigue (52 of 229 subjects), and 16.2% of subjects with injection site induration (37 of 
229 subjects).
An increased frequency of injection site tenderness (MV-CHIK: 52.4% (120 of 229),
Priorix®: 20.6% (7 of 34) and induration (MV-CHIK: 16.2% (37 of 229), Priorix®: 0% (0 of 
34)) were the only meaningful differences observed between the MV-CHIK and Priorix®
recipients regarding safety and tolerability. The majority of solicited AEs was reported as 
either mild or moderate. However, 10 recipients of MV-CHIK reported at least one solicited 
AE classified as severe: 3 subjects reported injection site pain, 1 reported injection site 
induration, 4 reported fatigue, 2 reported headache, 1 reported flu-like symptoms, and 1 
reported nausea and vomiting. The frequency of severe AEs was not meaningfully different 
between MV-CHIK (4.4% (10 of 229)) and Priorix® (0.0% (0 of 34)) recipients (P=0.3694). 
All solicited AEs reported as severe resolved within one week, and no unsolicited AEs were 
reported as being severe.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
46
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
MV-CHIK-205
MV-CHIK-205 is a Phase 2 trial conducted in healthy adults aged 18-55 years of age in 
Northern Ireland that investigated the immunogenicity, safety and tolerability of MV-CHIK 
after administration of different dose levels in different formulations in five groups of 12 
subjects each: 

Group A: MV-CHIK in a lyophilized formulation, (5·104 TCID50/dose), on day 0 and 
day 28 

Group B: MV-CHIK in liquid frozen formulation, (1·105) TCID50/dose), on day 0 and 
day 28 

Group C: MV-CHIK in liquid SPS® formulation, (1·105 TCID50/dose), on day 0 and 
day 28 

Group D: MV-CHIK in liquid frozen formulation, (1·106 TCID50/dose), on day 0 and 
day 28 

Group E: MV-CHIK in liquid frozen formulation, (1·106 TCID50/dose), on day 0 and 
placebo vaccination on day 28
All dose levels and formulations were generally well tolerated and no serious AEs related to 
the vaccine were recorded. No clinically significant safety laboratory or vital signs 
abnormalities were reported. 
All AEs were of mild or moderate severity, with the exception of one severe solicited AE of 
joint pain in a subject in Group B that was considered by the Investigator to be possibly 
related to the investigational vaccine. Solicited and unsolicited AE were similar across all 
Groups with the exception of Group C, where the percentage of subjects reporting any AE 
was lower (58.3%) than in the other groups (83.3 to 91.7%). For solicited AEs, a lower 
percentage of subjects reported AEs in the low dose groups (Groups A to C, 41.7 to 58.3%) 
than in the high dose groups (Groups D and E, 75.0%). This difference was attributable to 
local AEs, which occurred in 16.7 to 33.3% of subjects in Groups A to C, and in 66.7% of 
subjects in Groups D and E. Systemic solicited AEs, in contrast, were reported in a similar 
percentage of subjects across treatment groups. The most frequently reported local solicited 
AE was injection site tenderness, with the majority of cases in the high dose Groups D and E 
(five [41.7%] subjects each). The most frequent systemic solicited AE was headache in 21 
(35.0%) subjects overall, with a similar frequency across all treatment groups. For 
unsolicited AEs, there were no overall trends with regard to formulation or dose level. 
MV-CHIK has been generally well tolerated in pre-clinical GLP toxicity studies. MV-CHIK 
was well tolerated in a pre-clinical repeated dose toxicity study in NHPs up to 2.5·107
TCID50, the NOAEL. This is 50-fold higher than the planned V591 1·106 TCID50 clinical 
starting dose on an absolute basis and approximately 500-fold higher than the planned 
clinical starting dose on a TCID50/kg basis.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
47
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Single and 2-dose regimens of 1·105 TCID50 and 1·106 TCID50 V591 will also be the only 
dose levels administered to older participants, as they are doses that are most likely to be 
both well tolerated and immunogenic in this population, and it is intended to only administer 
V591 doses that are anticipated to elicit an immune response against SARS-CoV-2 to these 
participants.
4.2.5
Maximum Dose/Exposure for This Study
The maximum dose planned for this study is 1·107 TCID50. This is approximately 50-fold 
lower than the animal exposure on a TCID50/kg basis. This maximum dose will only be 
administered to younger adults in this study.
4.2.6
Rationale for Dose Interval and Study Design
Both single and two dose regimens of V591 will be explored in this study. Prior clinical 
studies with MV-CHIK have demonstrated immunogenicity after a single dose and a boost in
titers following a second vaccination, suggesting that either a single or two dose regimen of 
V591 may induce an effective immune response against SARS-CoV-2.
Doses of 1·105 TCID50 and 1·106 TCID50 will be administered for the initial sentinel Panels 
as they are doses that are most likely to be both well tolerated and immunogenic based on 
prior clinical experience with MV-CHIK, which uses the same measles virus vector platform 
as V591 and has been demonstrated to be immunogenic and well tolerated through Phase 2 
trials. These two dose levels of V591 will also be administered in the clinical study, COVID-
19-101, sponsored by the Institut Pasteur that plans to begin dosing participants in the middle 
of August, 2020. In the COVID-19-101 study doses of 1·105 TCID50 and 1·106 TCID50 will 
be administered as a two dose regimen 4 weeks apart, and 1·106 TCID50 will also be 
administered as a single dose.
As participants in Part 1 of this study will be among the first humans to receive V591, they 
will be monitored closely for serious vaccine reactions and vaccinated in a staggered manner 
as described in Section 4.1, with Panel B following Panel A after an initial safety review by 
the Investigator. As serious acute-onset vaccine associated reactions often manifest within 
minutes and the vast majority occur within 1-4 hours of vaccination[Ruggeberg, J. U., et al 
2007] [McNeil, M. M. 2018], study participants in the sentinel Panels will be conservatively 
monitored for at least 8 hours after both their first and second vaccinations. The first five 
subjects enrolled in Panel E that will be the first to receive 1·107 TCID50 V591, the highest 
planned dose in the study, and will also be enrolled in a staggered approach as described in 
Section 4.1 and conservatively monitored for at least 8 hours after their vaccination. The rest 
of the participants in the study will be monitored for at least 1 hour after vaccination.
As participants in Panel A, Panel B, and the first 5 subjects in Panel E will be amongst the 
first to receive doses of 1·105 TCID50, 1·106 TCID50, and 1·107 TCID50 V591 respectively, 
they will be required to be seronegative for SARS-CoV-2 as an additional precaution. 
Participants in the rest of the study will not be screened by serology for SARS-CoV-2 and 
thus will not be required to be seronegative for enrollment.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
48
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Doses of 1·105 TCID50 and 1·106 TCID50 will also be the only dose levels administered to 
older participants after they have been assessed to be well tolerated in younger adults based 
on data from this study or the COVID-19-101 study as outlined in Section 4.1. These are 
doses that are most likely to be both well tolerated and immunogenic in this population, and 
it is intended to only administer V591 doses that are generally well tolerated and anticipated 
to elicit an immune response against SARS-CoV-2 in older participants. Two dose regimens 
of V591 will be given either 8 or 24 weeks apart in Panels of adults > 55 years of age. As 
older adults have historically demonstrated weaker responses to vaccines[Weinberger, B. 
2012], 2 dose regimens of V591 with wider intervals than the 4 week interval in the COVID-
19-101 study will be evaluated in an effort to identify a regimen of V591 that displays 
enhanced immunogenicity in older adults.  This design will minimize the risks to older 
participants while efficiently obtaining immunogenicity data in this older population that is at 
greatest risk for severe COVID-19 disease. 
In an previous Phase 1 study, MV-CHIK 101, that explored doses ranging from 1.5·10⁴ to 
3·10⁵ TCID50 of MV-CHIK in healthy adults, Doses of 7.5·10⁴ and 3·10⁵ TCID50  MV-
CHIK were generally immunogenic after a single vaccination, while the lower dose of 
1.5·10⁴ TCID50 required 2 doses for comparable immunogenicity.  Based on this clinical 
data, it is anticipated that a single dose of V591 greater than 7.5·10⁴ TCID50 may provide 
adequate immunogenicity after a single dose. Thus a single dose of 1·105 TCID50 will be the 
lowest dose administered as a single dose regimen in this trial.  
Doses of 1·104 TCID50 is the minimum dose level that demonstrated immunogenicity with 
the MV platform in prior clinical studies of MV-CHIK. As noted previously, doses of 
1.5·10⁴ TCID50 MV-CHIK required both a prime and boost regimen in younger adults to 
display comparable immunogenicity to the response of single doses of 7.5·10⁴ and 3·10⁵
TCID50 in the MV-CHIK 101 study. Younger adults administered a dose of 1·10⁴ TCID50
V591 in Panel F will also receive a second dose of 1·105 TCID50 V591 at 169 days.  This 
design will ensure that every study participant will receive at least one dose of 1·105
TCID50V591, the minimum dose anticipated to be immunogenic. The 1·104 TCID50 dose is 
intended to provide a lower margin of immunogenicity to support further clinical 
development of the V591 vaccine. 
The dose of 1·107 TCID50 V591 is the maximum dose level planned in the study and is 
intended to provide a safety margin to support the further development of V591. A single 
dose regimen of 1·107 TCID50 V591 will only be administered to younger adult participants 
after doses of 1·105 TCID50 and 1·106 TCID50 have been assessed to be well tolerated in 
younger adults based on data from this study or the COVID-19-101 study. For added safety 
precaution at this highest planned dose, the enrollment for Panel E, the 1·107 TCID50 Panel, 
will commence with vaccination of a small group of sentinel participants as described above. 
4.3
Beginning and End of Study Definition
The overall study begins when the first participant signs (or their legally acceptable 
representative) provides documented informed consent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent, or is lost to follow-up 
(ie, the participant is unable to be contacted by the investigator).
 
 
05QFQ7
06DWGN

PRODUCT: V591  
49
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
4.3.1
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 V591 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.
Early study termination is defined as a permanent discontinuation of the study due to 
unanticipated concerns of safety to the study participants arising from clinical or preclinical 
studies with the study intervention(s), comparator(s), drug(s) of the same class, or 
methodology(ies) used in this study.
5
STUDY POPULATION
Healthy male participants and female participants between the ages of 18-55 years (inclusive)
of age in Parts 1 and 2A (younger adults) and > 55years of age in Part 2B (older adults) will 
be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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, ECG and VS 
measurements performed prior to randomization.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
50
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
2. Is in overall good health based on laboratory safety tests obtained at the screening visit.  
Appendix 2 provides a table of laboratory safety tests to be performed. Appendix 9
provides an algorithm for the assessment of out of range laboratory values.
3. Have a BMI < 30 kg/m2 inclusive. See Section 8.3.1 for criteria on rounding to a single 
decimal place. On this basis a rounded BMI of 29.9 is acceptable to satisfy the inclusion 
criteria. BMI = weight (kg)/height (m)2.
4. Has been practicing social distancing for at least two weeks prior to planned Day 1 
vaccination and has no close contacts with known active SARS-CoV-2 infection in that 
time period.
5.
Sentinel trial participants ONLY (Panel A, Panel B, and the first 5 subjects of Panel E): 
Seronegative for SARS-COV-2.
Demographics
6. Is male or female, from 18 years to 55 years of age (inclusive) (Parts 1 and 2A) or > 55
years of age (Part 2B), at the time of providing documented informed consent.
Male Participants
7.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 6 months after the last dose of study intervention:

Refrain from donating sperm during the intervention period and for at least 6 months 
after the last dose 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
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.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
51
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Female Participants
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 6 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.
o
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.
o
If a urine test cannot be confirmed as negative (eg, 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.
o
Refrain from donating oocyte during the intervention period and for at least 6 
months after the last dose of study intervention.
o
Additional requirements for pregnancy testing during and after study intervention 
are located in Section 8.4.5.
o
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.
o
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 (or legally acceptable representative) has provided documented 
informed consent/assent for the study, including for future biomedical research.
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 randomization).
11. Is willing to abstain from donating whole blood or blood derivatives, tissue or organ all 
along the study.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
52
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
12. 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.
13. 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
1. Is currently actively infected with SARS-CoV-2 (confirmed by PCR). 
2. Has prior medical history of confirmed SARS-CoV-2 infection or known exposure to an 
individual with confirmed COVID-19 disease or SARS-CoV-2 infection within the past 2 
weeks. With the exception of the sentinel participants (Panel A, Panel B, and the first 5 
subjects of Panel E), study participants will not be screened for enrollment by SARS-
CoV-2 serology, allowing those who may have had a prior asymptomatic SARS-CoV-2 
infection to be enrolled.
3. Has a history of severe adverse reactions to vaccine administration, including anaphylaxis 
and related symptoms, such as urticaria, respiratory difficulty, angioedema and 
abdominal pain to vaccines, or history of known or suspected allergic reaction likely to 
be exacerbated by any component of the COVID-19 vaccine.
4. Is currently (or highly suspected to be) immunocompromised, including anticipating the 
need for systemic immunosuppressive treatment within the next 6 months or 12 months 
for 2-dose Day 1 Day 169 panels or has been diagnosed or highly suspected as having a 
congenital or acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic 
lupus erythematosus (SLE), rheumatoid arthritis, juvenile rheumatoid arthritis (JRA),
inflammatory bowel disease, or other autoimmune condition that could impact the 
immune response or the safety of the study vaccine.
5. Has clinically significant thrombocytopenia or other coagulation disorder 
contraindicating intramuscular vaccination or repeated venipuncture.
6. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4°F 
[≥38.0°C] within a week before receiving the first study vaccination.
7. 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.
8. Has a history or presence of clinically significant pulmonary disorders (e.g. COPD, etc.),
or asthma.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
53
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
9. Has a history of confirmed SARS-CoV-1 or MERS.
10. Has a history of or a current clinically significant medical condition that puts or may put
a participant at increased risk for severe SARS-CoV-2 disease. 
These include the following conditions associated with or which might be associated with
increased risk of severe illness from COVID-19 as currently defined by the CDC:
i.
Conditions that are associated with increased risk of severe illness from COVID-
19 (first list by CDC: ‘People with the following conditions are at increased risk 
of severe illness from COVID-19’) 

Cancer

Chronic kidney disease

COPD (chronic obstructive pulmonary disease)

Immunocompromised state (weakened immune system) from solid organ 
transplant

Obesity (BMI of 30 or higher)

Serious heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies

Sickle cell disease

Type 2 diabetes mellitus
ii.
Conditions that might be associated with increased risk of severe illness from 
COVID-19 (second list by CDC: ‘People with the following conditions might be 
at an increased risk for severe illness from COVID-19’). 

Asthma (moderate-to-severe) 

Cerebrovascular disease (affects blood vessels and blood supply to the 
brain)

Cystic fibrosis 

Hypertension or high blood pressure 

Immunocompromised state (weakened immune system) from blood or 
bone marrow transplant, immune deficiencies, HIV, use of corticosteroids, 
or use of other immune weakening medicines 
 
 
05QFQ7
06DWGN

PRODUCT: V591  
54
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021

Neurologic conditions, such as dementia 

Liver disease 

Pregnancy 

Pulmonary fibrosis (having damaged or scarred lung tissues) 

Smoking 

Thalassemia (a type of blood disorder) 

Type 1 diabetes mellitus 
Note: Refer to the most updated risk factors as defined by the CDC for people of any age 
with the following conditions are or might be at increased risk of severe illness from 
COVID-19: (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-
with-medical-conditions.html).
11. Part 2B ONLY: Older adult participants having mild, well controlled hypertension as is
widely characteristic of aging are allowed if their medication regimens have not 
substantively changed for the past 6 months, hypertension has not led to hospitalization 
or currently increased rate of clinic visits over the past year, and hypertension has not 
been confirmed as putting subjects at increased risk of severe illness from COVID-19 by 
the CDC (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-
higher-risk.html).  
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 who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
13. Has a history of any clinically significant major neurological disorders or seizures 
(including Guillain-Barré syndrome), with the exception of febrile seizures during 
childhood.
14. 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 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
15. Has a known or suspected history of significant multiple and/or severe allergies (eg, food, 
drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, 
systemic allergic reaction) to prescription or non-prescription drugs or food.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
55
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
16. Is positive for HBsAg, hepatitis C antibodies or HIV-1 or 2 antibodies. Individuals with 
antibodies to hepatitis C may be enrolled if hepatitis C viral load is undetectable 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.
Prior/Concomitant Therapy
18. Has received immunosuppressive drugs like e.g. systemic corticosteroids (excluding 
topical preparations and inhalers) within 3 months prior to the first vaccination or 6 
months for chemotherapies.
19. *Has received vaccination within 4 weeks prior to first vaccination or is planning to 
receive a licensed vaccine 4 weeks before or after each study vaccination (e.g. Inactivated 
influenza vaccine).
20. *Has received measles-containing vaccine within 3 months prior to the first vaccination.
21. Has received a blood transfusion or blood products, including immunoglobulin, starting 
from 3 months before the first study vaccination or is scheduled to receive a blood 
transfusion or blood product through study completion. Autologous blood transfusions 
are not considered an exclusion criterion.
22. Is unable to meet the concomitant medication restrictions (see Section 6.6).
23. Is using antiviral medications or any investigational agents for prophylaxis of SARS-
CoV-2 within 4 weeks prior to the first vaccination
Prior/Concurrent Clinical Study Experience
24. Has ever participated in an investigational study of a SARS-CoV-2 vaccine, or an 
antiviral or other biologic product intended for the treatment of COVID-19. 
25. Is currently participating in any study of a vaccine or IMP, or has recently completed 
participation in another study of a vaccine or IMP and received a vaccine within 3 
months prior to screening or an IMP within 4 weeks (or 5 half-lives of the IMP, 
whichever is longer) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last study intervention (e.g., receiving a vaccine or IMP) in the 
previous study to the date of the prestudy (screening) visit for this study. In addition, a 
participant cannot participate in another investigational trial up to the post-trial visit of 
this study (approximately 12 months after the last study vaccination).
Diagnostic Assessments
26. Hemoglobin A1C ≥ 6.5% at screening.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
56
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Other Exclusions
27. A history of alcohol, cocaine, or opioid abuse during the previous 3 years.
28. Participants who currently smoke or used nicotine or nicotine-containing products (e.g., 
nicotine patch) within last 3 months. Former smokers that have less than a 10 pack-year 
history of smoking and have not smoker in the last 12 months are eligible to be enrolled.
29. 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.
30. 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.
31. 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 including social distancing and 
mask usage as recommended by local public health authorities, and following 
recommendations regarding mask use and social distancing).
32. Is currently working in occupations with high risk of exposure to SARS-CoV-2 (e.g., 
health care worker with direct patient contact, emergency response personnel), or , at the 
investigator’s discretion to be at increased risk to acquire SARS-CoV-2 for any other 
reason.
33. Individuals who are living and/or working with severely immunocompromised people, 
pregnant women, lactating women, children under 12 months old, or any other individual 
that, in the judgment of the investigator, might be at increased risk.
34. 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
Dietary restrictions are not required.
5.3.1.2
Fruit Juice Restrictions
Fruit juice restrictions are not required.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
57
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) is not permitted during the 
study.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc.) for 48 hours prior to each laboratory safety evaluation. 
5.3.4
Other Restriction
Participants should be advised to avoid contacts with vulnerable individuals as listed in 
exclusion #33 for the duration 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.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
58
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 (Themis Bioscience GmbH) 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.
 
 
05QFQ7
06DWGN

PRODUCT: V591  
59
PROTOCOL/AMENDMENT NO.: 001-04 
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 2
Study Interventions
Arm 
Name
Arm Type
Inter-
vention 
Name
Inter-
vention 
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
V591
Biological/
Vaccine
Sterile 
Solution
0.5 ml
104 
TCID50
105
TCID50
106 
TCID50
107
TCID50
IM
Day 1
Day 1, 
Day 57
Day 1, 
Day 169
Experimental
IMP
Provided 
Centrally by 
the Sponsor
Placebo
Placebo 
Comparator
Placebo
Other
Sterile 
Solution
NA
NA
IM
Day 1
Day 1, 
Day 57
Day 1 
Day 169
Placebo
IMP
Provided 
Centrally by 
the Sponsor or 
sourced 
locally
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
60
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
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 4.2.
V591 and placebo (0.9% sodium chloride, USP or BP sterile saline) 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
61
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 for Part 1 and Part 2A, and Table 4
for Part 2B respectively.
Table 3
Sample Allocation Schedule for Part 1 and Part 2A
Participants
Dosea
Part 1 (18 to 55 years old) Sentinel Cohort
Panel A
n=4
Day 1: 105 TCID50 / Day 57: 105 TCID50
n=1
PBO
Panel B
n=4
Day 1: 106 TCID50 / Day 57: 106 TCID50
n=1
PBO
Part 2A (18 to 55 years old)
Panel C
n=20
Day 1: 105 TCID50
n=5
PBO
Panel D
n=20
Day 1: 106 TCID50
n=5
PBO
Panel E
n=20
Day 1: 107 TCID50
n=5
PBO
Panel F
n=20
Day 1: 104 TCID50 / Day 169: 105 TCID50
n=5
PBO
n=number of participants; PBO=placebo; TCID50=median tissue culture infectious dose
a The suggested doses may be adjusted downward based on evaluation of safety or tolerability 
data observed in previous participants. 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
62
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 4
Sample Allocation Schedule for Part 2B
Participants
Dosea
Part 2B (> 55 years old)
Panel G
n=20
Day 1: 105 TCID50
n=5
PBO
Panel H
n=20
Day 1: 106 TCID50
n=5
PBO
Panel I
n=20
Day 1: 105 TCID50 / Day 57: 105 TCID50
n=5
PBO
Panel J
n=20
Day 1: 106 TCID50 / Day 57: 106 TCID50
n=5
PBO
Panel K
n=20
Day 1: 105 TCID50 / Day 169: 105 TCID50
n=5
PBO
Panel L
n=20
Day 1: 106 TCID50 / Day 169: 106 TCID50
n=5
PBO
n-number; PBO=placebo; TCID50=median tissue culture infectious dose
a The suggested doses may be adjusted downward based on evaluation of safety or tolerability 
data observed in previous participants. 
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study. Based 
on the study design, intervention allocation/randomization will automatically be stratified 
according to participant’s age at time of randomization (18 to 55 and > 55 years of age).
6.3.3
Blinding
A double-blinding technique will be used. V591 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
63
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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
Management of GMO
V591 is a GMO requiring BSL1 standards. Needles and syringes that have been in contact 
with the COVID-19 vaccine, as well as all other potentially contaminated materials, will be 
collected in dedicated containers and will be destroyed in a safe manner. This study will be 
conducted under regulations for contained use of a GMO.
6.6
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.

Any administration of a nonstudy live and non-live vaccines is prohibited within four 
weeks (within 3 months for measles-containing vaccine) prior to or after each study 
vaccination.

Any use of immunosuppressive drugs like corticosteroids (excluding topical 
preparations and inhalers) is prohibited within 3 months prior to the first vaccination 
or 6 months for chemotherapies and throughout the study.

Any scheduled administration of antipyretic or analgesic medication on a daily or 
every other day basis from the day of vaccination through Day 5 after receiving each 
study vaccination is prohibited.

Receipt of blood products or immunoglobulins is prohibited within 3 months prior to 
enrollment or anticipated receipt of any blood product or immunoglobulin before 
completion of study participation (365 days after the last vaccination).
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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
64
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
receiving at the time of enrollment or receives through 28 days after each study vaccination
must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Clinical Director should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.6.1
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.
6.7
Dose Modification (Escalation/Titration/Other)
At least 7 days of safety and tolerability data after the first dose from n = 5 participants from 
each sentinel cohort (Panels A and B) will be reviewed by the siDMC prior to dosing of Parts
2A and 2B, which may initiate simultaneously.  At least 7 days of safety and tolerability data 
after the second dose from n = 5 participants from each sentinel cohort (Panels A and B) will 
be reviewed by the siDMC prior to dosing of Panels F, I-L.  The suggested doses may be 
adjusted downward based on evaluation of safety or tolerability data observed in previous 
participants.
If safety and tolerability data are available for review from the COVID-19-101 study, it may 
be reviewed by the siDMC instead of the V591-001 safety and tolerability data from Panel A 
and Panel B of this study in order to make a decision to proceed to Part 2A and 2B of V591-
001. 
At least seven days of safety and tolerability data from the FIH clinical study sponsored by 
the Institut Pasteur (COVID-19-101) sentinel cohorts following their Day 28 vaccination 
may be reviewed by the siDMC instead of the V591-001 safety and tolerability data from 
Panel A and Panel B in order to make a decision to proceed to administer the second dose to 
Panels F, I-L in Part 2B of the V591-001 study.
6.7.1
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
If any of the following stopping rules are met, the study will be paused and no further dosing 
will occur until the siDMC has reviewed the totality of data available. 
1. Any participant dies or requires ICU admission due to SARS-CoV-2 infection.
2. Any participant experiences a serious adverse (SAE) considered related to the vaccine.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
65
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
3. Any participant experiences any of the following ECIs that are considered as related to 
the vaccine administration: acute respiratory distress syndrome (ARDS), pneumonitis, 
acute cardiac injury, arrhythmias, septic shock-like syndrome, acute kidney injury, 
vasculitis, new onset autoimmune disease, meningitis, atypical measles, encephalitis, or 
encephalopathy.
If any of the following stopping rules are met, dosing will be paused in the affected Panel, 
and any other Panels employing the same or higher dose levels, until the siDMC has 
reviewed the totality of data available.  Dosing may continue in Panels receiving lower dose 
levels while data is reviewed by the siDMC.
4. Grade 3 or higher solicited local AE, considered as related to the vaccine administration 
reported on 2 or more days within the 5 day post-vaccination period in ≥2 participants per 
panel
5. Grade 3 or higher solicited systemic AE, considered as related to the vaccine 
administration reported on 2 or more days within the 14 day post-vaccination period in 
≥2 participants per panel
6. Severe unsolicited AE, considered as related to the vaccine administration within the 28
day post-vaccination period in ≥2 participants per panel
6.7.2
Delaying Scheduled Study Vaccinations
Study vaccination should be delayed for the following reasons:

Clinically significant acute illness at the time of vaccination 

Fever (body temperature ≥38.0°C [100.4°F]) within 24 hours prior to the planned 
time of vaccination.
6.8
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.9
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity . The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
This study is blinded but supplies are provided 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
66
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical trials with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study. In this 
study, participants who receive a single-dose intervention cannot discontinue study 
intervention.
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.1.9, or if available, a protocol clarification letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Sections 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
The participant’s treatment assignment has been unblinded by the investigator, the Sponsor, 
or through the emergency unblinding call center.
The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
The participant has a confirmed positive serum pregnancy test.
Participant who experiences any of the following events assessed to be related to the product 
will not receive further vaccination:
o
Solicited grade 3 adverse event (AE) for more than 24 hours;
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
67
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
o
Unsolicited grade 3 or higher AE;
o
Any grade 4 or higher AE; OR 
o
Serious adverse event (SAE).
For all participants enrolled in 2-dose panels, the inclusion and exclusion criteria should be 
reviewed prior to the second vaccination. Participants who no longer meet inclusion and 
exclusion criteria as specified in Section 5.2 will not receive their second scheduled 
vaccination. If a subject does not receive their second study vaccination, they should still 
continue all scheduled visits for appropriate safety follow up.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.11.3 for those procedures to be completed at each 
specified visit.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
68
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
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.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 288 to 441 mL depending on each panel (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
69
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 (or their legally 
acceptable representative) prior to participating in this 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 or legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) 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 or his/her legally acceptable representative 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 or by the participant’s legally acceptable representative’s dated 
signature.
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, or the participant’s legally acceptable representative, 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
70
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
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.
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 28 days after each study vaccination will be recorded with the 
paper VRC as specified in Section 8.3.5.
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.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
71
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
participant for all procedures occurring after treatment allocation/randomization. Once a 
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.
Study intervention on Day 1 should begin on the day of treatment allocation/randomization 
or as close as possible to the date on which the participant is allocated/assigned.
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. For 2-dose Day 1, Day 57 panels, the second vaccination will be administered 
on Day 57. For 2-dose Day 1, Day 169 panels, the second vaccination will be administered 
on Day 169. Vaccinations may be administered in the morning and without regard to timing 
of meals. 
Each participant's body temperature must be taken before vaccine administration. After 
randomization, the dosing for individuals who present with fever (oral ≥100.4°F [≥38.0°C]) 
may be rescheduled when the fever has resolved. In addition, the second vaccination will be 
administered after predose procedures are executed as per SOA and adherence to study 
restrictions has been confirmed.
The predose collection of blood samples must be performed before vaccine administration. 
As described in section 4.2.6, all participants will be observed for at least 8 hours for sentinel 
panels (Panel A and B) after the first and the second vaccination. At a minimum the first 5
participants enrolled in Panel E that will be conservatively monitored for at least 8 hours 
after their vaccination as well. The rest of the participants in the study will be monitored for 
at least 1 hour after vaccination.
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 and/or intervention. 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 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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
72
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
73
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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
Not applicable for this study.
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 Assessments
8.2.1
Serum Neutralizing Antibodies Measured by PNA
The presence of serum neutralization antibodies against SARS-CoV-2 spike protein will be 
assessed using Pseudo-virus Neutralization Assay using a pseudovirus expressing SARS-
CoV-2 spike protein on a VSV-backbone. This pseudovirus also contains a luciferase-
reporter gene and the amount of luciferase produced after overnight incubation with Vero 
cells is negatively correlated with the amount of spike-protein neutralizing antibodies in 
testing serum samples. This reporter assay reduces the assay time from a typical 2 to 3 days 
plaque assay to overnight. 
Serum sample processing, storage, and shipment specifics will be described in more detail in 
the Study Operations Manual (SOM).
8.2.2
Total Anti-Spike IgG Antibodies Measured by ELISA 
An ELISA for immunoglobulin G (IgG) will be used to quantify the serum antibody 
responses against the S protein. The ELISA will use target antigen a recombinant, purified, 
stabilized extracellular domain (ectodomain) of the S protein, which was trimerized using a 
fold-on motif (ELISA tri- S; Grzelak, preprint). Specificity against circulating coronavirus 
such as 229E, NL63, OC43, and HKU1 will be tested during assay qualification.
Other exploratory assays to characterize the immune response to V591 may be performed 
with excess serum at the discretion of the Sponsor.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
74
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Serum sample processing, storage, and shipment specifics will be described in more detail in 
the Study Operations Manual (SOM).
8.2.3
Immune Responses Including Cell-mediated Immunity
T cell responses, including Th1/Th2 polarization, to V591 may be evaluated by stimulating 
PBMCs with Spike derived peptides and measuring responses by intracellular cytokine
staining and flow cytometry or ELISPOT. Exploratory assays to characterize the immune 
response to the vaccine may be performed with excess PBMCs and serum collected in this 
study.
Detailed instructions on requirements for collection of PBMCs, handling and preparation of 
the samples for analysis, and storage requirements will be provided in the SOM.
8.2.4
Exploratory Immunogenicity Assays
Exploratory immunogenicity assays will be performed on collected samples in order to 
characterize the immune response elicited by V591. This may include assays performed on 
serum, and PBMCs.
These exploratory immunology endpoints may include the following:

PBMCs stimulated with SARS-CoV-2 Spike peptides for characterization of cell 
mediated immunity and serum to characterize the immune response to V591

Anti-SARS-CoV-2 N-protein IgG responses, as measured by immunoassay
These exploratory immunology assays, if performed, may be reported in a separate results 
memo outside of the CSR.
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 (Day 422 or Day 534 for 2-dose panels and Day 365 for 
1-dose panels), 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
Physical Examinations
8.3.1.1
Full Physical Examination
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard and timepoints as 
specified in the SoA. 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
75
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Height and weight will also be measured and recorded per SoA.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Symptoms Driven Physical Examination
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 at the V591/placebo injection 
site (e.g. deltoid) and/or any areas for which there are symptoms of concern.
8.3.1.3
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 on 
vaccination day as outlined in Section 1.3 SoA.
8.3.1.4
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 a single decimal place according to the 
standard convention of 0.01 to 0.04 round down and 0.05 to 0.09 round up.
8.3.2
Vital Signs
Vital signs (i.e. body temperature, pulse or heart rate, respiratory rate, and blood pressure) 
will be assessed.
8.3.2.1
Semi-recumbent Heart Rate and Blood Pressure
Blood pressure and heart rate measurements should be preceded by at least 10 minutes of rest 
for the participant in a quiet setting without distractions. Blood pressure and heart rate 
measurements will be assessed in the semi-recumbent position with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
The correct size of the BP cuff and the correct positioning on the participants' arm is essential 
to increase the accuracy of BP measurements.
All vital signs will be measured and recorded as single measurements.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
76
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
8.3.2.2
Body Temperature
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. The Day 1 vaccination may be rescheduled for a time when fever is resolved. 
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.
For measurements to be collected on the VRC on Days 1-14 and Days 57-70 or Days 169-
182 (2-dose panels only), participants will be provided an oral thermometer.  For sentinel 
panels (Panels A and B), Day 1 and Day 57 postdose measurements will be done 
approximately 8 hours (± 15 min). For Panel E, Day 1 postdose measurements will be done 
approximately 8 hours (± 15 min) for at a minimum the first 5 subjects in the Panel. The rest 
of the participants in panel E will be monitored for at least 1 hour (± 15 min) after 
vaccination. The Day 1, and Day 57 or Day 169 (2-dose panels only) postdose measurement
for all other panels will be done approximately 1 hour (± 15 min). The Day 1, and Day 57 or 
Day 169 (2-dose panels only) postdose measurement will be measured and recorded by the 
participants on the VRC, under observation by the clinic staff.  All the other measurements 
on the VRC and will be done by the participant without supervision. See Section 8.3.5.  
All other temperature measurements listed on the SoA that are not on the VRC will be done 
by clinic staff on the CRU source documents.  
8.3.3
Electrocardiograms
Single 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 HR and measures PR, QRS, QT, and QTc intervals.
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 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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
77
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
Pre-dose ECGs should be obtained on Day 1 within 24 hours prior to dosing V591/placebo. 
All ECG measurements will be single measurements.
Post-dose ECG may be performed if clinically indicated, as a single measurement, according 
to the judgement of the investigator.
8.3.4
Study Intervention Administration
Instructions on how to prepare and administer the proper dose to each participant are outlined 
in a separate document provided by the Sponsor.  Study intervention will be administered 
and witnessed by unblinded study staff and recorded in the source documents. Study site staff 
will confirm that the participant has received the entire dose of study intervention.  On Day 1, 
the time of V591/Placebo administration is considered time= 0.  
8.3.5
Vaccine Report Card
Participants will be provided with a VRC to fill out on a daily basis from Day 1 to Day 28
post each vaccination.  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.” 
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.  The study staff should instruct participants
to inform them if there is a grade 3 event recorded on the VRC as soon as possible.
Participants will use the VRC to document the following information:

AEs as outlined in Section 8.4.8

Concomitant medications and nonstudy vaccinations for the first 28 days after each 
study intervention.
The VRC will be reviewed during the Day 2 and Day 58 or Day 170 (2-dose panels only)
safety phone calls and during the Day 8, Day 15, Day 29, and Day 71, Day 85 or Day 197 
(for 2-dose panels only) in-person visit for the purposes of early detection of safety concerns. 
The safety calls on Day 2 and Day 58 or 170 (for 2-dose panels only) must occur on the day 
after the Day 1, Day 57 or Day 169 visits, respectively, approximately 18 to 30 hours post-
dose.
During the Day 1, Day 8, Day 57 and Day 169 visit, the study staff should observe the 
participant taking their temperature and measuring any injection site redness or swelling in 
order to confirm that the participant is documenting this on the VRC correctly.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
78
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
The VRC will be reviewed with the participant as outlined in the SoA to ensure 
understanding of instructions. Participants will be reminded to complete the VRC at their 
scheduled visits on Day 8, Day 15 and Day 71 (2-dose Day 1 Day 57 panels only) and during 
safety phone calls on Day 2 and Day 58 or Day 170 (2-dose panels only). As noted above, 
study staff should observe the temperature, swelling, and redness assessments (if any) on 
Day 1 and Day 57 or Day 169 (2-dose panels only). Any AEs recorded in the VRC should be 
reviewed by the investigator and entered into the Sponsor database in a timely manner as per 
the Data Entry Guidelines.
8.3.6
Safety Phone Call Follow Up 
Safety follow-up phone calls will be performed at the timepoints indicated in the SoA
(Section 1.3). Safety calls on Days 2 and 58 or 170 must occur after the Day 1, Day 57 or 
Day 169 visits, respectively approximately 18 to 30 hours postdose. 
Safety calls must be done by appropriately trained study site staff. If the initial call is 
unsuccessful, the study site staff should make a total of 3 attempts for each scheduled safety 
call. All attempts to contact the participants will be recorded in the source documents. 
These calls will facilitate the collection of relevant safety information (see Section 8.4). The 
participant will be interviewed to obtain information relating to unsolicited AEs including 
SAEs and other significant medical events. In addition, associated concomitant medications 
and all vaccinations will be recorded. All safety information described by the participant 
must be documented in the source documents.
8.3.7
Monitoring for SARS Cov-2 Exposure and COVID-19 Disease
As outlined in Section 4.2.1.3, this trial intends to identify potential exposures and confirmed 
infections by SARS-CoV-2 amongst study participants. 
Study participants will be educated to recognize and report symptoms that may be related to 
SARS-CoV-2 infection and will be instructed to contact the site via phone in case of 
suspected SARS-CoV-2 infection (if severe symptoms are reported the participant will be 
instructed to seek urgent medical attention). The Investigator will facilitate the study 
participant receiving medical care as appropriate based on their clinical judgement, including 
arranging a nasopharyngeal PCR testing for acute disease. No more than 3 days should 
transpire between the subject contacting the clinical site and the arrangement of a medical 
care visit by the investigator.
Trial participants will be educated at regular intervals during in person visit to recognize and 
report the following potential SARS-CoV-2 symptoms based on current CDC guidance
(https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html). 

Fever or chills

Cough
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
79
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021

Shortness of breath or difficulty breathing

Fatigue

Muscle or body aches

Headache

New loss of taste or smell

Sore throat

Congestion or runny nose

Nausea or vomiting

Diarrhea
The Investigator will endeavor to collect detailed data on confirmed COVID-19 cases 
including the onset of specific symptoms, duration of symptoms, hospitalization (if any), and 
COVID-19 will be classified as severe or non-severe based on the FDA’s “Development and 
Licensure of Vaccines to Prevent COVID-19, Guidance for Industry”
For the purposes of this study, a virologically confirmed SARS-CoV-2 infection is defined as 
any study participant with positive SARS-CoV-2 PCR test.
Severe COVID-19 is defined as: 
Virologically confirmed SARS-CoV-2 infection with any of the following: 
•
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)  
•
Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation or ECMO) 
•
Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring vasopressors) 
•
Significant acute renal, hepatic, or neurologic dysfunction 
•
Admission to an ICU  
•
Death
This clinical trial is not intended to interfere with local health practices and regulations 
regarding the management of confirmed or suspected SARS-CoV-2 infections or COVID-19
disease. The main role of the Investigator to help study participants to receive all appropriate 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
80
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
medical care according to local health practices and regulations. Study participants may be 
tested as appropriate according to local regulations and will receive any required medical 
care within their existing healthcare systems. However if a subject is not administered a 
nasopharyngeal PCR test for SARS-CoV-2 according to local regulations and the 
Investigator feels it is warranted, then they may directly arrange for SARS-CoV-2 PCR 
testing as available by nasopharyngeal swab.
If a subject is suspected/diagnosed with an actual COVID-19 infection they will not receive 
any subsequent study vaccination but should endeavor to perform all visits for safety follow-
up that they are safely able to attend in person as allowed according to local regulations.
Exposure to known SARS CoV-2 infected patients and SARS-CoV-2 infection, and COVID-
19 disease, will be captured as ECIs as documented in Section 8.4.7. 
8.3.8
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
81
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
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 form, but before intervention
allocation/randomization, 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 vaccination all AEs must be reported by the investigator up to 28 days after 
any study vaccination. SAEs, MAAEs, ECIs, arthralgia of any grade and other reportable 
safety events must be reported by the investigator from the time of vaccination through the 
end of study visit.
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 5.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
82
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 5
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
MAAEs
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/termin
ation; 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
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
83
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
84
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
Any laboratory confirmed diagnosis of SARS-CoV-2 infection (virologically confirmed 
by PCR) and any resulting clinical sequelae will be reported as an ECI in study 
participants throughout the duration of the study. See Section 8.3.7 for further details.
3.
Known exposure to a confirmed case of active SARS-CoV-2, defined as individual who 
has had close contact (< 1.5 meters for ≥15 minutes), will be reported as an ECI in 
study participants throughout the duration of the study
4.
AEs≥ Grade 3 reported as a solicited AE on the VRC
5.
Acute respiratory distress syndrome (ARDS)
6.
Pneumonitis
7.
Acute cardiac injury
8.
Arrhythmias
9.
Septic shock-like syndrome
10.
Acute kidney injury
11.
Vasculitis
12.
New onset Autoimmune disease (AID)
13.
Meningitis
14.
Atypical measles
15.
Anosmia
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
85
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
16.
Dysgeusia
17.
Encephalitis
18.
Encephalopathy
19.
Clinically significant arthralgias
The investigator should report all ECIs for the whole period of the study.
8.4.8
Adverse Events Reported on the VRC
Participants will use a VRC to report solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.8.1
Solicited Adverse Event 
Solicited AEs for this study are summarized in Table 6.
Table 6
Solicited Adverse Events for Protocol
Type of Solicited 
Adverse Event
Predefined Solicited
Adverse Events
Solicited Time Period
Injection site
o
Injection-site pain/tenderness
o
Injection-site swelling
o
Injection-site redness/erythema
For the first 5 days after each study 
intervention
o
For 1-dose panels: Day 1 to 
Day 5
o
For 2-dose Day 1 Day 57 
panels: Day 1 to Day 5 and Day 
57 to Day 61
o
For 2-dose Day 1 Day 169 
panels: Day 1 to Day 5 and Day 
169 to Day 173
Systemic
o
Muscle pain/myalgia
o
Joint pain/arthralgia
o
Headache
o
Fatigue/Tiredness
o
Rash
o
Nausea
o
Fever
For the first 14 days after 
each study intervention
o
For 1-dose panels: Day 1 to 
Day 14
o
For 2-dose Day 1 Day 57 
panels: Day 1 to Day 14 and 
Day 57 to Day 71
o
For 2-dose Day 1 Day 169 
panels: Day 1 to Day 14 and 
Day 169 to Day 183
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
86
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
All solicited injection-site AEs will be considered related to study intervention. The 
investigator will assess all solicited injection-site AEs for toxicity, and all solicited systemic 
AEs for both toxicity and causality (Appendix 3).
In addition, the investigator will review all solicited AEs for the following:

Is the event a symptom of another diagnosis?

Is the event ongoing at the end of the solicited period?

Does the event meet serious criteria?
A solicited AE that meets any of the above criteria must also be reported on the appropriate 
eCRF as specified in the data entry guidelines.
8.4.8.2
Unsolicited Adverse Events
Unsolicited AEs will be followed up for 28 days. All adverse events with Grade > 3 will be 
followed up throughout the study.
As detailed in Section 8.4, the investigator will assess unsolicited AEs that meet the 
definition of an AE or SAE with respect to seriousness, intensity/toxicity, and causality.
8.5
Treatment of Overdose
In this study, an overdose is defined as more than 1 dose of study vaccine in a 24-hour period 
or more than 2 doses of study vaccine throughout the study. 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
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.8.1
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
87
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
8.9
Future Biomedical Research Sample Collection
The following specimens will be obtained as part of future biomedical research:

DNA for future research

Leftover main study serum from neutralizing antibodies by PNA stored for future 
research

Leftover main study serum from total anti-spike IgG antibodies by ELISA stored for 
future research

Leftover main study serum from immunological assessments stored for future 
research (Panels C, D, G, and H only)

Leftover main study PBMCs from immunological assessments stored for future 
research
8.10
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR Medical Resource Utilization and Health Economics are not evaluated 
in this study.
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
Within 28 days prior to allocation/randomization, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.
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
Refer to the SoA (Section 1.3) and Administrative General Procedures (Section 8.1).
Day 1
Participants will be randomized and vaccinated at the study site on Day 1, as set forth in the 
SoA and Section 6.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
88
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
If all criteria are fulfilled, no significant change in the participant’s health, participants will 
be assigned a study randomization number to receive V591 or placebo. The assigned study 
intervention (V591 or placebo) will be administered via IM (left or right deltoid) injection. 
The time and the arm (left or right) in which the vaccine was injected will be recorded in the 
participant’s source data and in the eCRF.
After injection, the participants will remain in the clinical sites for medical supervision and 
monitoring as the following:

Panels A and B: for a minimum of 8 hours after the first and the second injection.

Panel E: at a minimum for the first 5 subjects for a minimum of 8 hours post-
injection. The rest of the participants for a minimum of 1 hour post-injection.

All other panels: for a minimum of 1 hour post-injection.
Post vaccination safety assessments (VS and local reaction of the injection site and general 
reaction) on Day 1 will be performed as set forth in the SoA.
Participant will be provided with a VRC, a ruler and a thermometer and they will receive 
instructions on how to measure temperature and record adverse events during the subsequent 
28 days after the injection. The VRC will be returned on the next visit at the clinical sites.
Subject will be given an emergency card with a phone number to call in case of questions or 
upon occurrence of any AE.
At the end of the visit, which lasts approximately 9 hours in Panels A, B and for the sentinel 
participants of panel E, and approximately 2 hours in other panels and remaining participants 
of panel E, once the study physician has determined that a participant is fit to be released, the 
participant will be discharged from the clinical site. The appointment for the phone call (24 
hours ± 6 hours) and for the next clinical visit will be scheduled and confirmed with the 
participant.
Day 57 (the second vaccination for 2-dose Day 1, Day 57 panels)
On Day 57 of the study, participants in the 2-dose Day 1, Day 57 panels (Panels A, B, I and
J) will receive the second intramuscular injection of V591 or placebo into the deltoid muscle
accordingly to protocol randomization schedule. Predose and post vaccination safety and 
immunogenicity assessments will be performed as set forth in the SoA. After injection, the 
participants will remain in the clinical sites for medical supervision and monitoring for a 
minimum of 8 hours after injection. (Panels A and B) and for a minimum of 1 hour after 
injection (Panels I and J).
Participant will be provided with a new VRC for the 28 following days. At the end of the 
visit, which lasts approximately 9 hours in Panels A and B , 2 hours for Panels I and J, once 
the study physician has determined that participant is fit to be released, the participant will be 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
89
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
discharged from the clinical site. The appointment for the phone call (24 hours ±6 hours) and 
for the next clinical visit will be scheduled and confirmed with the participant.
Day 169 (the second vaccination for 2-dose Day 1, Day 169 panels)
On Day 169 of the study participants in the 2-dose Day 1, Day 169 panels (Panels F, K and 
L) will receive the second intramuscular injection of V591 or placebo into the deltoid muscle 
accordingly to protocol randomization schedule. Predose and post vaccination safety and 
immunogenicity assessments will be performed as set forth in the SoA. After injection, the 
participants will remain in the clinical sites for medical supervision and monitoring for a 
minimum of 1 hour after injection.
Participant will be provided with a new VRC for the 28 following days. At the end of the 
visit, which lasts approximately 2 hours, once the study physician has determined that 
participant is fit to be released, the participant will be discharged from the clinical site. The 
appointment for the phone call (24 hours ± 6 hours) and for the next clinical visit will be 
scheduled and confirmed with the participant.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, study procedures specified in the SoA may be completed at the discretion of the 
investigator and with Sponsor agreement. The subset of study procedures completed will be 
communicated in a PCL.
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 
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 365 days after the last vaccination) to 
have the applicable procedures conducted. However, the investigator may decide to perform 
the post-study procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs less than 365 days after the last study 
intervention, a subsequent follow-up telephone call should be made at 365 days or after 
(within the protocol-specified variance) of the last study intervention to determine if any 
SAEs, ECIs or MAAEs have occurred since the poststudy clinic visit (as well as AEs through 
Day 28 if not already collected).
Amendment 04:
The sponsor has decided to terminate the study based on the immunogenicity results. All 
participants should be asked to return to the study site (or be contacted by phone) for a final 
post-study visit at least 56 days post the last vaccination to have the applicable procedures 
conducted. The post-study procedures as outlined Section 1.3.1, 1.3.2 and 1.3.3 (Schedule of 
Activities for all panels) should be followed for the final post-study visit, except for the 
serum sample collection for immunogenicity assessments. Serum sample for neutralizing 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
90
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
antibodies and serum sample for total anti-spike IgG and total anti-N IgG antibodies will not 
be collected.
8.11.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the timely and accurate collection and recording of AEs, along with blood 
samples for anti-SARS-CoV-2 spike serum neutralizing antibody titers (PNA) and anti-
SARS-CoV-2 spike IgG titers (ELISA) are the critical procedures.
At any postdose time point, the blood sample for PNA and ELISA 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.
Vaccination Day Postdose procedure of panels A and B may be obtained within 
approximately 8 hours [±15 min] for Day 1 and Day 57. Vaccination Day Postdose 
procedure for the sentinel participants in Panel E may be obtained within approximately 8 
hours [±15 min] for Day 1. Vaccination day (D1, D57, D169) postdose procedure may be 
obtained within approximately 1 hour [±15 min] for all other panels and remaining 
participants of panel E. Day 2, Day 58 and Day 170 (for 2-dose panels only) evaluations can 
occur any time the day after dosing (approximately 18 to 30 hours post-dose)
Day 8 evaluations can occur ± 24 hours (approximately Day 7 to Day 9 postdose)
Site visit windows as outlined for Two dose Panels in Table 7 and Single dose Panels 
Table 8.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
91
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 7
Two Dose Panels (Panels A-B, F and I-J) Site Visit Windows
Site Visit
Visit Window
Day 1
No variance
Day 2 
On the day after Day 1 visit
Day 8
± 1 day
Day 15
± 1 day
Day 29 
± 3 days
Day 57/Day 169
± 3 days
Day 58, Day 170
On the day after Day 57 or Day 169
Day 71
± 1 day
Day 85, Day 197
± 3 days
Day 115, Day 365
± 7 days
Day 211
± 14 days
Day 422, Day 534
± 14 days
Table 8
Single Dose Panels (Panels C-E, G-H) Site Visit Windows
Site Visit
Visit Window
Day 1
No variance
Day 2 
On the day after Day 1 visit
Day 8
± 1 day
Day 15
± 1 day
Day 29 
± 3 days
Day 57
± 3 days
Day 85
± 3 days
Day 115
± 7 days
Day 211
± 14 days
Day 365
± 14 days
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
92
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
8.11.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1/Phase 2 assessment of V591 in humans, and the safety profile of the 
vaccine is still being elucidated. This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of early phase 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 doses may not exceed those currently outlined in the protocol.

Repeat of or decrease in the dose of the study intervention administered in any given 
panel

Interchange of doses between panels

Entire panel(s) may be omitted, or the number of participants in each panel may be 
decreased

Modification of the vaccination interval between the 1st and 2nd vaccination (for 2-
dose panels only)

Modification of the sample processing and shipping details based on newly available 
data

Modification of the immunogenicity sampling schedule, including omitting 
timepoints

Addition of a siDMC review

Addition of Safety Phone Call Follow-ups

Clinic in-person visit may be replaced by telephone, video or home visit using a site 
staff or a nursing service if circumstance do not support an in-person site visit.
The safety and 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 metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety and/or immunogenicity analyses. 
The total blood volume withdrawn from any single participant will not exceed the maximum 
allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
93
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
It is understood that the current study may employ some or none of the alterations described 
above. Any non-substantial 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.  All substantial changes to the protocol will be submitted to the regulatory 
authorities and ethics committees accordingly for evaluation and approval before 
implementation. .
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 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 SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.9.
Study Design Overview
A Phase 1/Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-
Ranging Trial to Evaluate the Safety, Tolerability and Immunogenicity of 
V591 in Healthy Younger and Older Participants
Treatment Assignment
260 participants (10 in Part 1 younger sentinel cohort, 100 in Part 2A younger 
cohort and 150 in Part 2B older cohort) will participate in the study that will 
include a total of 4 dose-levels and 12 Panels. Under each panel, participants 
will be randomized to receive V591 or placebo in a 4:1 ratio.
Analysis Populations
Safety: All Participants as Treated (APaT)
Immunogenicity: Per-Protocol (PP)
Primary Endpoint(s)

Solicited injection site AEs from Day 1 through Day 5 after any study 
intervention

Solicited systemic AEs from Day 1 through Day 14 after any study 
intervention

Unsolicited AEs from Day 1 through Day 28 after any study intervention

SAEs and MAAEs from Day 1 throughout the duration of study 
Key Secondary Endpoints

Anti-SARS-CoV-2 spike serum nAb as measured by PNA

Anti-SARS-CoV-2 spike IgG as measured by ELISA
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
94
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Statistical Methods for 
Key Safety Analyses
For the Tier 2 endpoints, 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events; these analyses will 
be performed using the Miettinen and Nurminen method (1985) [Miettinen, 
O. and Nurminen, M. 1985]. 
Statistical Methods for 
Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The geometric mean ratios and 95% CIs of the anti-SARS-CoV-2 spike 
serum nAb GMTs will be calculated using a cLDA method proposed by 
Liang and Zeger (2000) [Liang, K-Y and Zeger, S. L. 2000]. In this model, 
the response vector consists of the log-transformed prevaccination and 
postvaccination antibody titers. The repeated measures model will include 
terms for time, the interaction of time-by-vaccination group (with a 
restriction of the same baseline mean across groups). The treatment 
difference in terms of a geometric mean ratio at a given post-vaccination 
time point will be estimated and tested from this model. 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. This 
model allows the inclusion of participants who are missing either the 
baseline or postbaseline measurements, thereby increasing efficiency.
A similar statistical approach will be used to evaluate the anti-SARS-CoV-2 
spike IgG responses.
Interim Analyses
Up to two interim analyses may be performed on safety and immunogenicity 
data through at least Day 29. In order to trigger the first interim analysis at 
least 75% of study participants per Panel in at least 6 Panels must have 
completed their Day 29 visit.  In order to trigger the second interim analysis at 
least 75% of study participants per Panel in at least 10 Panels must have 
completed their Day 29 visit.
An interim analysis may be performed on safety and immunogenicity data 
through at least Day 85 for Panels A, B, I, and J. To trigger this interim 
analysis at least 75% of these Panel’s participants must have completed their 
Day 85 visit. A minimum percentage of participants from other study Panels 
is not required for this interim analysis, though all available data will be 
included.
An interim analysis may be performed on safety and immunogenicity data 
through at least Day 197 for Panels K and L. To trigger this interim analysis at 
least 75% of these Panel’s participants must have completed their Day 197 
visit. A minimum percentage of participants from other study Panels is not 
required for this interim analysis, though all available data will be included.
These interim immunogenicity analyses will include all available nAb PNA
and IgG ELISA data.
Results of the interim analysis will be provided to the unblinded siDMC.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Safety:
Section 9.9.1 provides information about the ability of this study to estimate 
the incidence of AEs within the V591 group as well as differences between 
V591 and Placebo.
Immunogenicity:
This is a descriptive study and there are no hypotheses to be evaluated. This 
study will randomize approximately a total of 208 participants into 4 different 
dose-levels of the V591 group and 52 participants into the placebo group. 
Section 9.9.2 provides information about the expected variability of the GMT 
ratios given the sample size.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
95
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 and immunogenicity are listed below.
9.4.1
Safety Endpoints
The safety analysis endpoints include:
Solicited injection-site AEs from Day 1 through Day 5 after study intervention
Solicited systemic AEs from Day 1 through Day 14 after study intervention
Unsolicited AEs from Day 1 through Day 28 after study intervention
The broad AE categories consisting of any AE and any vaccine-related AE from Day 1 
through Day 28 after study intervention
The broad AE categories consisting of any SAE, any vaccine related SAEs, and death 
from Day 1 through the duration of participation in the study
The broad AE categories consisting of any MAAE and any ECI (event of clinical 
interest) from Day 1 throughout the duration of the study.  
Maximum temperature measurements meeting the Brighton Collaboration cut points 
from Day 1 through Day 14 after study intervention
Safety laboratory results, vital signs, and physical exam findings as described in the 
SoA
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
96
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
9.4.2
Immunogenicity Endpoints
The immunogenicity analysis endpoints include:
Anti-SARS-CoV-2 spike serum nAb as measured by PNA
Anti-SARS-CoV-2 spike IgG as measured by ELISA
PBMCs stimulated with SARS-CoV-2 Spike peptides for characterization of cell 
mediated immunity and serum to characterize the immune response to V591
Anti-SARS-CoV-2 N-protein IgG responses as measured by immunoassay
9.5
Analysis Populations
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 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they received for the analysis of safety data using the APaT population. This 
will be the treatment 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 
treatment group corresponding to the study treatment actually received. In the 2-dose panels, 
safety parameters for cross-treated participants (ie, those who received vaccinations of both 
V591 and Placebo) will be summarized separately.
9.5.2
Immunogenicity Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of immunogenicity data in this 
study. The PP population consists of all randomized participants without deviations from the 
protocol that may substantially affect the results of the immunogenicity endpoint. Potential 
deviations that may result in the exclusion of a participant from the PP population for all 
immunogenicity analyses include:

Failure to receive any study vaccine at Day 1

Failure to receive the correct dose of study vaccine at Day 1

Receipt of prohibited medication or prohibited vaccine prior to the Day 1 blood 
sample collection
Additional deviations that may result in the exclusion of a participant from the PP population 
for specific immunogenicity analyses at a particular timepoint include:

Collection of blood sample outside of the pre-specified window (as described in 
Section 1.3)
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
97
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021

Receipt of prohibited medication or prohibited vaccine prior to a blood sample
collection

Failure to receive the second dose of V591 or placebo according to vaccination 
schedule (for 2-dose panels only)
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population. Determinations on protocol deviations will be 
made by blinded study team members prior to the planned interim analyses (Section 9.7) and 
prior to the final unblinding of the database. Participants will be included in the vaccination 
group to which they are randomized for the analysis of immunogenicity data using the PP 
population.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the key secondary immunogenicity analysis endpoints. The FAS population consists of all 
randomized participants who received at least 1 vaccination and have at least 1 serology 
result. Participants will be included in the vaccination group to which they are randomized 
for the analysis of immunogenicity data using the FAS population.
9.6
Statistical Methods
Statistical testing and inference for safety and immunogenicity analyses are described in
Section 9.6.1 and Section 9.6.2, respectively. Section 9.6.3 describes how demographic and
baseline characteristics will be summarized.
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. For the 2-dose panels, summary of safety parameters following each dose separately
will also be provided.
The analysis of AEs and postvaccination temperature measurements will follow a tiered 
approach (Table 9). The tiers differ with respect to the analyses that will be performed. 
Events (specific preferred terms as well as system organ classes) 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. 
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
98
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-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 V591, 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 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method 
(1985) [Miettinen, O. and Nurminen, M. 1985].
Tier 2 events for this study include solicited injection-site AEs from Day 1 through Day 5
postvaccination, solicited systemic AEs from Day 1 through Day 14 postvaccination (Section 
8.4.8.1). In addition, the broad AE categories consisting of the percentage of participants 
with any AE, any vaccine-related AE, any SAE, any vaccine-related SAE, any MAAEs, any 
ECI, 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 cut points (Days 1 to 14) 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% confidence interval 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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
99
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Between-Group 
Comparison a
Descriptive
Statistics
Tier 2
Solicited injection site AE (Days 1 to 5 after study intervention)
X
X
Solicited systemic AE (Days 1 to 14 after study intervention)
X
X
Any AEb
X
X
Any Vaccine-Related AEb
X
X
Any SAEb
X
X
Any Vaccine-Related SAE
X
X
Any MAAE
X
X
Any ECI
X
X
Deathb
X
X
Maximum temperature measurements meeting the Brighton 
Collaboration cut points (Days 1 to 14 after study intervention)
X
X
Specific AEs by SOC or 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; 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.
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.
9.6.2
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the secondary immunogenicity 
objectives. Methods related to exploratory objectives will be further described in the 
supplemental statistical analysis plan.
The geometric mean ratios and 95% CIs of the anti-SARS-CoV-2 spike serum nAb GMTs 
will be calculated using a cLDA method proposed by Liang and Zeger (2000) [Liang, K-Y 
and Zeger, S. L. 2000]. In this model, the response vector consists of the log-transformed 
prevaccination and postvaccination antibody titers. The repeated measures model will 
include terms for time, the interaction of time-by-vaccination group (with a restriction of the 
same baseline mean across groups). The treatment difference in terms of a geometric mean 
ratio at a given postvaccination time point will be estimated and tested from this model. 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. This model allows the 
inclusion of participants who are missing either the baseline or postbaseline measurements, 
thereby increasing efficiency. 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
100
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
The observed nAb GMTs at each timepoint with serum collection and GMFRs from 
prevaccination to postvaccination will be performed within each vaccination group 
separately. Descriptive statistics with point estimates and within-group 95% CIs will be 
provided. 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.
A similar statistical approach will be used to evaluate the anti-SARS-CoV-2 spike serum IgG 
responses.
For responses smaller than the lower limit of quantitation (LLOQ), half of the LLOQ will be
used for analysis when calculating the nAb GMTs and IgG GMCs.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 10.
Table 10
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Secondary Endpoint
nAb GMT ratio and IgG GMC ratio 
at Day 29 (all panels) and Day 85 (2-
dose panels only)
P/S
cLDA modelb
(estimate and 95% CI)
PP/FAS
Model-based
nAb GMT and IgG GMC at all 
timepoint with serum collection
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
GMFR from baseline to 
postvaccination for nAb and IgG
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
CI = confidence interval; FAS = Full Analysis Set; GMC = geometric mean concentration; GMFR=geometric mean 
foldrise; GMT = geometric mean titer; IgG = Immunoglobulin G; nAb = neutralizing antibody; PP = Per-Protocol.
a
P = Primary approach; S = Supportive approach.
b
Estimation of the 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 (cLDA) utilizing the log-transformed antibody 
titers as the response and a single term for vaccination group. 
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by using summary tables. 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), baseline characteristics, and 
prior and concomitant therapies will be summarized by treatment group either by descriptive 
statistics or categorical tables.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
101
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
9.7
Interim Analyses
Up to two interim analyses may be performed on safety and immunogenicity data through at 
least Day 29. In order to trigger the first interim analysis at least 75% of study participants 
per Panel in at least 6 Panels must have completed their Day 29 visit.  In order to trigger the 
second interim analysis at least 75% of study participants per Panel in at least 10 Panels must 
have completed their Day 29 visit.
An interim analysis may be performed on safety and immunogenicity data through at least 
Day 85 for Panels A, B, I, and J. To trigger this interim analysis at least 75% of these Panel’s 
participants must have completed their Day 85 visit. A minimum percentage of participants 
from other study Panels is not required for this interim analysis, though all available data will 
be included.
An interim analysis may be performed on safety and immunogenicity data through at least 
Day 197 for Panels K and L. To trigger this interim analysis at least 75% of these Panel’s 
participants must have completed their Day 197 visit. A minimum percentage of participants 
from other study Panels is not required for this interim analysis, though all available data will 
be included.
These interim immunogenicity analyses will include all available nAb PNA and IgG ELISA 
data.
For this early phase study, an internal statistician, statistical programmer, 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. Analyses of 
immunogenicity data may also be conducted at the discretion of the sponsor when data are 
available.
Results of the interim analysis will be provided to the unblinded siDMC. The siDMC will 
make a recommendation for further clinical development. Group summaries will be reviewed 
by the Sponsor’s study team. Sponsor’s study team (except for the unblinded statistician and 
programmer) will be blinded to the V591 treatment information at the participant level.
9.8
Multiplicity
No adjustment will be made for multiplicity.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence 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 80% chance of observing at least 1 SAE among 
228 participants receive a vaccination of V591 if the underlying incidence of a SAE is 0.70% 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
102
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
(1 of every 143 participants receiving the vaccine). There is a 50% chance of observing at 
least 1 SAE among 228 participants receive a vaccination of V591 if the underlying 
incidence of a SAE is 0.30% (1 of every 329 participants receiving the vaccine). If no SAEs 
are observed among the 228 participants receive a vaccination of V591, this study will 
provide 97.5% confidence that the underlying percentage of participants with a SAE is 
<1.61% (1 in every 63 participants) in the V591 group.
Table 11 summarizes the percentage point differences between the 2 vaccination groups that 
could be detected with 80% probability for a variety of hypothetical underlying incidences of 
an adverse event. These calculations assume 228 participants receive a vaccination of V591 
and 57 participants receive placebo and are based on a 2-sided 5% alpha level. The 
calculations are based on an asymptotic method proposed by Farrington and Manning (1990) 
[Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 11
Differences in Incidence of AE Rates between the 2 Vaccination Groups That can 
be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level With 228
Participants in the V591 Group and 57 Participants in the Placebo Group)
Incidence of Adverse Event
Risk Difference
V591 (%)
Placebo (%)
Percentage Points
6.0
0.1
5.9
11.2
2
9.2
16.9
5
11.9
24.9
10
14.9
31.8
15
16.8
38.2
20
18.2
49.9
30
19.9
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method [Farrington, C. P. 1990]
9.9.2
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study and there are no hypotheses to be evaluated. This study will 
randomize approximately a total of 228 participants into 4 different dose-levels of the V591 
group and 57 participants into the placebo group. Table 12 displays the numbers of 
participants scheduled to receive each study intervention.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
103
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 12
Numbers of Participants Scheduled to Receive Each Study Intervention
Treatment Group
Number of Participants
Day 1 (Dose 1 for all 
panels)
Day 57 (Dose 2 for 
Panels A, B, I, and J)
Day 169 (Dose 2 for 
Panels F†, K, and L)
V591-104/105 TCID50
20
0
20
V591-105 TCID50
84
24
20
V591-106 TCID50
84
24
20
V591-107 TCID50
20
0
0
125-fold dilution of 
V591-107 TCID50
20
0
0
Placebo
57
12
15
TCID50=median tissue culture infectious dose
†Participant in Panel F will be administered V591-104 TCID50 or placebo on Day 1, and V591-105 TCID50 or 
placebo on Day 169.
The width of the 95% CIs for the GMT/GMC ratios depend on the sample size, variability of 
the natural log concentrations, and the magnitude of the ratio. In Table 13, 95% CIs for 
various hypothetical GMT/GMC ratios at Day 29 and various hypothetical standard deviation 
estimates for the natural log titers are displayed. It is assumed that approximately 85% 
participants will be evaluable for immunogenicity analyses based on PP population at Day 
29.
Table 13
95% CIs for Varying Hypothetical GMT/GMC Ratios (V591/Placebo) and 
Varying Standard Deviations
Standard Deviation 
of Natural Log 
Titers/Concentration
GMT/GMC Ratios (V591/Placebo)
1.5
2.0
2.5
3.0
1.0
(1.04, 2.17)
(1.38, 2.90)
(1.73, 3.62)
(2.07, 4.34)
1.5
(0.86, 2.61)
(1.15, 3.48)
(1.44, 4.36)
(1.72, 5.23)
2.0
(0.72, 3.14)
(0.95, 4.19)
(1.19, 5.24)
(1.43, 6.29)
CI=confidence interval; GMC=geometric mean concentration; GMT= geometric mean titer.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
104
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
105
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
106
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
107
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
108
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.1.4
Committees Structure
10.1.4.1
Stand Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate siDMC will 
monitor the interim data from this study. 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 an appropriate frequency for evidence of adverse 
effects of study intervention. The siDMC will determine whether the study should continue 
(or other modifications, prespecified or otherwise, should be made) according to the protocol, 
considering the overall risk and benefit to study participants. The siDMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both participant 
safety and the continued ethical integrity of the 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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
109
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
110
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
111
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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).
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
112
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 14 will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2 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 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
MCHC
Reticulocytes
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
HbA1c (required at screening 
only)
Coagulation
Prothrombin time/International Normalized Ratio (PT/INR)
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
ULN)
Albumin
LDH
GGT
Serum Ferritin
Creatinine
Sodium
ALT/SGPT
Total Protein
CPK
Alkaline phosphatase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte by dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
Other Screening 
Tests
FSH (as needed in WONCBP only)
Alcohol breath test and drug screen (to include at minimum: cocaine and opiates), sample to be 
determined by site SOP
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
SARS-CoV-2 serology testing: at the screening visit for participants in sentinel Panels A, B and 
the 5 sentinel participants in panel E Only. 
COVID-19 PCR test
Additional tests may be done per site SOP with Sponsor agreement.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CPK=creatine 
phosphokinase; FSH=follicle-stimulating hormone; GGT= gamma-glutamyl transpeptidase; HBsAg=hepatitis B surface 
antigen; hCG=human chorionic gonadotropin; HIV= human immunodeficiency virus; LDH=lactate dehydrogenase; 
MCH=mean corpuscular hemoglobin; MCHC=mean cell hemoglobin concentration; MCV=mean corpuscular volume; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
SOP=standard operating procedure; ULN=upper limit of normal; WBC=white blood cell; WOCBP=women of 
childbearing potential; WONCBP=women of nonchildbearing potential
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
113
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
114
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.”
o
Any new cancer or progression of existing cancer.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
115
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
o
Medically Attended Adverse Events (MAAEs): 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.
o
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.
Definition of Unsolicited and Solicited AE

An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant who has provided documented informed consent. Unsolicited AEs 
include serious and nonserious AEs.

Solicited AEs are predefined local (at the injection site) and systemic events for which 
the participant is specifically questioned, and which are noted by the participant in their 
VRC.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
116
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
117
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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
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, SAE 
and MAAE (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.  
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
118
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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,
SAE, and MAAE (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 15 through Table 18. The laboratory values in 
Table 19, Table 20 and Table 21 should serve as approximate guidelines for defining 
toxicities due to variations in established normal ranges.  Local laboratory ranges and 
investigator discretion should be used for defining [Grade 1] toxicities.  Local laboratory 
ranges and investigator discretion may be used for defining [Grade 2] toxicities with Sponsor 
Consultation. the following tables. 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 15
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
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
119
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Injection Site 
Reaction to Study 
Vaccine/Placeboa
Grade 1
Grade 2
Grade 3
Grade 4
Any injection-site reaction that begins ≥6 days after 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.
Table 16
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 17
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
120
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 18
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.
Table 19
Laboratory Abnormalities - Serum
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
121
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Table 20
Laboratory Abnormalities - Hematology
Table 21
Laboratory Abnormalities – Urine
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 initial
document must be retained for the required regulatory time frame. The criteria below are 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
122
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(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.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
123
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
Follow-up of AE, SAE and MAAE

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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
124
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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).
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).
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
125
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
This appendix is not applicable to this study.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
126
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
127
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.5.2
Contraception Requirements
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 progesterone-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.
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
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
128
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
129
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
130
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
131
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
132
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
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/
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
133
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.7
Appendix 7: Country-specific Requirements
As noted in Section 4, Study Design, older adults in Part 2B will only be recruited in the 
United States in order to facilitate the enrollment of minority groups that have been 
disproportional impacted by COVID-19 and historical underrepresented in vaccine trials.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
134
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.8
Appendix 8: Blood Volume Table
Panels C-E and G-H
(1-dose Panels)
Screening
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/ 
Test
Laboratory Safety Tests
1
5
1
7
12.5
87.5
Blood for HIV/Hepatitis screen (at 
the discretion of the investigator)
1
1
9
9
Blood (DNA) for Future 
Biomedical Research
1
1
8.5
8.5
Blood for Drug Screen
1
1
10
10
Prothrombin Time
1
1
3
3
Serum β-hCG pregnancy test 
(Females only)
1
1
2
3.5
7
FSH (Females only)
1
1
3.5
3.5
Serum Collection for PNA and 
ELISA Assays
7
1
8
20
160
Serum collection for 
Immunological Assessments 
(Panels C, D, G, and H only)
2
2
5
10
Blood for PBMCs Assays (for 
Panels C, D, G and H only)
2
2
60
120
Total Blood Volume per Male Participant for Panels C, D, G and Ha 408 mL
Total Blood Volume per Female Participant for Panels C, D, G and Ha 418.5 
mL
Total Blood Volume per Male Participant for Panels Ea 288 mL
Total Blood Volume per Female Participant for Panels Ea 298.5 
mL
a
If additional immunogenicity assessments and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained. Note: never to exceed 50 mL.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
135
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Panels A, B, I and J
(2-dose Day 1, Day 57 panels)
Screening
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests
1
6
1
8
12.5
100
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
1
9
9
Blood (DNA) for Future 
Biomedical Research
1
1
8.5
8.5
Blood for Drug Screen
1
1
10
10
Prothrombin Time
1
1
3
3
Serum β-hCG pregnancy test 
(Females only)
1
1
2
3.5
7
FSH (Females only)
1
1
3.5
3.5
Serum Collection for PNA and 
ELISA Assays
8
1
9
20
180
Blood for PBMCs Assays 
2
2
60
120
Total Blood Volume per Male Participanta 430.5 mL
Total Blood Volume per Female Participanta 441 mL
a
If additional immunogenicity assessments and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained. Note: never to exceed 50 mL.
Panels F, K and L
(2-dose Day 1, Day 169 panels)
Screening
Treatment 
Periods
Poststudy
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests
1
6
1
8
12.5
100
HIV/Hepatitis Screen (at the 
discretion of the investigator)
1
1
9
9
Blood (DNA) for Future 
Biomedical Research
1
1
8.5
8.5
Blood for Drug Screen
1
1
10
10
Prothrombin Time
1
1
3
3
Serum β-hCG pregnancy test 
(Females only)
1
1
2
3.5
7
FSH (Females only)
1
1
3.5
3.5
Serum Collection for PNA and 
ELISA Assays
7
1
8
20
160
Blood for PBMCs Assays
2
2
60
120
Total Blood Volume per Male Participanta 410.5 mL
Total Blood Volume per Female Participanta 421 mL
a
If additional immunogenicity assessments and/or safety analysis is necessary, additional blood (up to 50 mL) may be 
obtained. Note: never to exceed 50 mL.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
136
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit 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 (eg, 
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.
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
137
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
All-Participants-as-Treated
AR
adverse reaction
BMI
body mass index
BP
blood pressure
BSL 1
Biosafety Level 1
CHIKV
Chikungunqa virus 
CI
confidence interval
COPD
chronic obstructive pulmonary disease
CoV
coronaviruses
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
DENV
Dengue virus
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FIH
first in human
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GI
gastrointestinal
GLP
Good Laboratory Practice
GMO
genetically-modified organism
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
IFNγ
interferon gamma
IND
Investigational New Drug 
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhoea method
LASV
Lassa Fever virus
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
138
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
Abbreviation
Expanded Term
LLOQ
lower limit of quantitation
MAAE
Medically-attended adverse event
MERS
Middle Eastern Respiratory Syndrome
MERS-CoV
Middle East Respiratory Syndrome Coronavirus
MIS-C
Multisystem Inflammatory Syndrome in Children
MV
Measles virus
MV-CHIK
Measles vector-Chikungunya
MV-SARS
Measles vector-Severe Acute Respiratory Syndrome
nAb
neutralizing antibody
NCS
not clinically significant
NOAEL
no observed adverse effect level 
PK
pharmacokinetic
PP
per-protocol
PNA
Pseudo-virus Neutralization Assay
PRNT
plaque reduction neutralization test
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV
Severe Acute Respiratory Syndrome Coronavirus
siDMC
Standing Internal Data Monitoring Committee
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
TNF-a
tumor necrosis factor alpha
UDS
urine drug screen
USP
United States Pharmacopeia
VRC
vaccination report card
VS
vital sign
WHO
World Health Organization
WNV
West Nile virus
WOCBP
woman/women of childbearing potential 
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
139
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
11
REFERENCES
[Bodmer, B. S., et 
al 2018]
Bodmer BS, Fiedler AH, Hanauer JRH, Prufer S, 
Muhlebach MD. Live-attenuated bivalent measles 
virus-derived vaccines targeting Middle East 
respiratory syndrome coronavirus induce robust and 
multifunctional T cell responses against both viruses 
in an appropriate mouse model. Virology. 
2018;521:99-107.
[05JQ9M]
[Brandler, S., et al 
2007]
Brandler S, Lucas-Hourani M, Moris A, Frenkiel 
MP, Combredet C, Fevrier M, et al. Pediatric 
measles vaccine expressing a dengue antigen 
induces durable serotype-specific neutralizing 
antibodies to dengue virus. PLoS Negl Trop Dis. 
2007 Dec 12;1(3):e96
[05JQ9T]
[Brandler, S., et al 
2010]
Brandler S, Ruffie C, Najburg V, Frenkiel MP, 
Bedouelle H, Despres P, et al. Pediatric measles 
vaccine expressing a dengue tetravalent antigen 
elicits neutralizing antibodies against all four dengue 
viruses. Vaccine. 2010;28:6730-9.
[05JQ9G]
[Brandler, S., et al 
2012]
Brandler S, Marianneau P, Loth P, Lacote S, 
Combredet C, Frenkiel MP, et al. Measles vaccine 
expressing the secreted form of West Nile virus 
envelope glycoprotein induces protective immunity 
in squirrel monkeys, a new model of West Nile virus 
infection. JID. 2012 Jul 15;206:212-9.
[05JQ9R]
[Brandler, S., et al 
2013]
Brandler S, Ruffie C, Combredet C, Brault JB, 
Najburg V, Prevost MC, et al. A recombinant 
measles vaccine expressing chikungunya virus-like 
particles is strongly immunogenic and protects mice 
from lethal challenge with chikungunya virus. 
Vaccine. 2013;31:3718-25.
[05JQ9Q]
[Combredet, C., et 
al 2003]
Combredet C, Labrousse V, Mollet L, Lorin C, 
Delebecque F, Hurtrel B, et al. A molecularly cloned 
Schwarz strain of measles virus vaccine induces 
strong immune responses in macaques and 
transgenic mice. J Virol. 2003 Nov;77(21):11546-
54.
[05JQ9P]
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
140
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
[COVID-19 
Treatment 
Guidelines Panel 
2020]
COVID-19 Treatment Guidelines Panel. 
Coronavirus disease 2019 (COVID-19) treatment 
guidelines. Bethesda (MD): National Institutes of 
Health (NIH); 2020. 146 p.
[05JQGC]
[Despres, P., et al 
2005]
Despres P, Combredet C, Frenkiel MP, Lorin C, 
Brahic M, Tangy F. Live measles vaccine 
expressing the secreted form of the West Nile virus 
envelope glycoprotein protects against West Nile 
virus encephalitis. J Infect Dis. 2005 Jan 
15;191:207-14.
[05JQ9S]
[Dong, E., et al 
2020]
Dong E, Du H, Gardner L. An interactive web-based 
dashboard to track COVID-19 in real time 
[correspondence]. Lancet Infect Dis. In press 2020.
[05GCDV]
[Dufort, E. M., et al 
2020]
Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, 
Muse A, Rowlands J, et al. Multisystem 
inflammatory syndrome in children in New York 
State. N Engl J Med. In press 2020.
[05JRTC]
[Escriou, N., et al 
2014]
Escriou N, Callendret B, Lorin V, Combredet C, 
Marianneau P, Fevrier M, et al. Protection from 
SARS coronavirus conferred by live measles 
vaccine expressing the spike glycoprotein. Virology. 
2014;452-453:32-41.
[05JQF2]
[Farrington, C. P. 
1990]
Farrington CP, Manning G. Test Statistics and 
Sample Size Formulae for Comparative Binomial 
Trials with Null Hypothesis of Non-Zero Risk 
Difference or Non-Unity Relative Risk. Stat Med 
Vol. 9,1447-1454 (1990)
[04FS6L]
[Harapan, H., et al 
2020]
Harapan H, Itoh N, Yufika A, Winardi W, Keam S, 
Te H, et al. Coronavirus disease 2019 (COVID-19): 
a literature review. J Infect Public Health. 
2020;13:667-73.
[05J8DV]
[Honda-Okubo, Y., 
et al 2015]
Honda-Okubo Y, Barnard D, Ong CH, Peng BH, 
Tseng CTK, Petrovsky N. Severe acute respiratory 
syndrome-associated coronavirus vaccines 
formulated with delta inulin adjuvants provide 
enhanced protection while ameliorating lung 
eosinophilic immunopathology. J Virol. 2015 
Mar;89(6):2995-3007.
[05JSLN]
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
141
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
[Howe, R. C., et al 
2005]
Howe RC, Dhiman N, Ovsyannikova IG, Poland 
GA. Induction of CD4 T cell proliferation and in 
vitro Th1-like cytokine responses to measles virus. 
Clin Exp Immunol. 2005;140:333-42.
[05JSLM]
[Lambert, P. H., et 
al 2020]
Lambert PH, Ambrosino DM, Andersen SR, Baric 
RS, Black SB, Chen RT, et al. Consensus summary 
report for CEPI/BC March 12-13, 2020 meeting: 
assessment of risk of disease enhancement with 
COVID-19 vaccines. Vaccine. 2020;38:4783-91.
[05JPLX]
[Liang, K-Y and 
Zeger, S. L. 2000]
Liang K-Y, Zeger SL. Longitudinal data analysis of 
continuous and discrete responses for pre-post 
designs. Sankyha: The Indian Journal of Statistics 
2000;62(Series B, Part 1):134-48.
[00V5V6]
[Lorin, C., et al 
2004]
Lorin C, Mollet L, Delebecque F, Combredet C, 
Hurtrel B, Charneau P, et al. A single injection of 
recombinant measles virus vaccines expressing 
human immunodeficiency virus (HIV) type 1 clade 
B envelope glycoproteins induces neutralizing 
antibodies and cellular immune responses to HIV. J 
Virol. 2004 Jan;78(1):146-57.
[05JQ9J]
[Malczyk, A. H., et 
al 2015]
Malczyk AH, Kupke A, Prufer S, Scheuplein VA, 
Hutzler S, Kreuz D, et al. A highly immunogenic 
and protective Middle East respiratory syndrome 
coronavirus vaccine based on a recombinant measles 
virus vaccine platform. J Virol. 2015 
Nov;89(22):11654-67.
[05JQ9N]
[Mateo, M., et al 
2019]
Mateo M, Reynard S, Carnec X, Journeaux A, 
Baillet N, Schaeffer J, et al. Vaccines inducing 
immunity to Lassa virus glycoprotein and 
nucleoprotein protect macaques after a single shot. 
Sci Transl Med. 2019 Oct 2;11(512):eaaw3163.
[05JQF3]
[McNeil, M. M. 
2018]
McNeil MM, DeStefano F. Vaccine-associated 
hypersensitivity. J Allergy Clin Immunol. 2018 
Feb;141:463-72.
[05JVGH]
[Miettinen, O. and 
Nurminen, M. 
1985]
Miettinen O, Nurminen M. Comparative Analysis of 
Two Rates. Stat Med 1985;4:213-26.
[03QCDT]
 
 
05QFQ7
06DWGN

PRODUCT:  V591  
142
PROTOCOL/AMENDMENT NO.:  001-04  
V591-001-04 FINAL PROTOCOL
19-FEB-2021
[Moss, W. J. and 
Griffin, D. E. 2006]
Moss WJ, Griffin DE. Global measles elimination. 
Nat Rev Micro 2006;4:900-8.
[03QXLW]
[Ovsyannikova, I. 
G., et al 2003]
Ovsyannikova IG, Dhiman N, Jacobson RM, 
Vierkant RA, Poland GA. Frequency of measles 
virus-specific CD4(+) and CD8(+) T cells in 
subjects seronegative or highly seropositive for 
measles vaccine. Clin Diagn Lab Immunol. 2003 
May;10(3):411-6.
[05JSLL]
[Plotkin, Stanley A. 
2010]
Plotkin SA. Correlates of Protection Induced by 
Vaccination. Clinical and Vaccine Immunology 
2010;17(7):1055-65.
[03RTVJ]
[Reisinger, E. C., et 
al 2019]
Reisinger EC, Tschismarov R, Beubler E, 
Wiedermann U, Firbas C, Loebermann M, et al. 
Immunogenicity, safety, and tolerability of the 
measles-vectored chikungunya virus vaccine MV-
CHIK: a double-blind, randomised, placebo-
controlled and active-controlled phase 2 trial. 
Lancet. 2019 Dec 22-29;392:2718-27.
[05JQG3]
[Ruggeberg, J. U., 
et al 2007]
Ruggeberg JU, Gold MS, Bayas JM, Blum MD, 
Bonhoeffer J, Friedlander S, et al. Anaphylaxis: case 
definition and guidelines for data collection, 
analysis, and presentation of immunization safety 
data. Vaccine. 2007;25:5675-84.
[04VSH4]
[Stebbings, R., et al 
2012]
Stebbings R, Fevrier M, Li B, Lorin C, Koutsoukos 
M, Mee E, et al. Immunogenicity of a recombinant 
measles-HIV-1 clade B candidate vaccine. PLoS 
One. 2012 Nov;7(11):e50397.
[05JQ9L]
[Weinberger, B. 
2012]
Weinberger B, Grubeck-Loebenstein B. Vaccines 
for the elderly. Clin Microbiol Infect. 2012 
Oct;18(suppl 5):100-8.
[05D0PN]
 
 
05QFQ7
06DWGN