A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Immunogenicity of Three Different Potency Levels of V181 (Dengue Quadrivalent Vaccine rDENVΔ30 [Live, Attenuated]) in Healthy Adults
Phase: PHASE2
Conditions: Dengue Disease, Dengue Virus
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05507450 
Document Date: 
14-Jul-2022
A Phase 2, Randomized, Double-Blind, Multicenter Study to 
Evaluate the Safety and Immunogenicity of Three Different Potency 
Levels of V181 (Dengue Quadrivalent Vaccine rDENVΔ30 [live, 
attenuated]) in Healthy Adults

PRODUCT: V181  
1
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Safety and Immunogenicity of Three Different Potency Levels of V181 (Dengue 
Quadrivalent Vaccine rDENVΔ30 [live, attenuated]) in Healthy Adults
Protocol Number: 003-01
Compound Number: V181
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
17780
EudraCT
2020-004501-30
Approval Date: 14 July 2022
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PRODUCT: V181  
2
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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PRODUCT: V181  
3
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
14-JUL-2022
The primary reason for the amendment was to provide the 
potency levels for V181 and to extend the contraception 
requirements from 4 weeks after administration of study 
intervention to 90 days after administration of study 
intervention.
Original Protocol
03-DEC-2020
Not applicable
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PRODUCT: V181  
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PROTOCOL/AMENDMENT NO.: 003-01
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14-JUL-2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The primary reason for the amendment was to provide the potency levels for V181 and to extend the contraception requirements from 
4 weeks after administration of study intervention to 90 days after administration of study intervention.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary Reasons for Amendment
1.1 Synopsis
6.1 Study Intervention(s) 
Administered – Table 1
Added potency levels for each serotype 
being administered for each of the 3 V181 
potency level groups, and deleted footnote 
about potency levels being ‘to be 
determined’.
Added a footnote to indicate that the 
provided potency levels represent the final 
dose strength for the 0.5 mL dose of V181.
Potency levels being administered were previously to 
be determined.
To clarify that the potency levels described represent 
the final dose strength in each 0.5 mL dose of V181.
5.1 Inclusion Criterion No. 3
5.1 Inclusion Criterion No. 4
Extended contraception requirements from 
4 weeks to 90 days.
To reduce the risk of pregnancy in WOCBP who are 
study participants (in accordance to MSD 
specifications for other live virus vaccines, such as 
VARIVAX™) or partners of male study participants (a 
spermatogenesis cycle is approximately 90 days).
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PRODUCT: V181  
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PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Section # and Name
Description of Change 
Brief Rationale 
Additional Changes Made in Amendment
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and updated to the address.
1.1 Synopsis
6.1 Study Intervention(s) 
Administered – Table 1
Changed the intervention name for the 
placebo group from ‘Diluent’ to ‘Placebo’.
In the ‘Use’ column for V181 groups, 
changed ‘Experimental’ to ‘Test Product.’
To reduce confusion around the study intervention 
being administered in the Placebo Group.
To align with EU CTR.
1.3 Schedule of Activities
Added a row for the collection of study-
supplied eVRC devices.
To clarify when eVRC devices will be collected.
2.1 Study Rationale
4.2 Scientific Rationale for 
Study Design
4.3 Justification for Dose
6.2.1 Dose Preparation
Removed placeholder text for the potency 
levels and/or added a cross-reference to the 
study interventions table.
To reflect that potency levels are now known and to 
ensure the ease of finding vaccine potency level 
information.
2.2.1 Dengue Disease and 
V181 Development
Added a description of the risk of ADE for 
dengue vaccines.
To clarify what ADE is and how it may affect the 
study.
4.1 Overall Design
Added a statement about eVRC devices.
To clarify that participants may be provided with an 
eVRC device or may have their personal device 
configured for eVRC.
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PRODUCT: V181  
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Section # and Name
Description of Change 
Brief Rationale 
4.2.2 Rationale for the Use 
of Comparator/Placebo
6 Study Intervention
6.1 Study Intervention(s) 
Administered – Table 1
6.2.1 Dose Preparation
Removed references to ‘diluent,’ including 
removing the footnote in Table 1.
For consistency when referring to placebo and to 
reduce confusion around placebo and diluent.
5 Study Population
Added a statement about the 
confidentiality of collected information.
To align with EU CTR.
5.1 Exclusion Criterion No. 
16
Changed donation requirements from 
6 weeks to 90 days postvaccination.
To reduce the risk of viremic participants donating 
blood, eggs, or sperm.
6.1 Study Intervention(s) 
Administered – Table 1
Deleted footnote about dilution procedures 
for V181.
Revised the column heading and footnote 
for investigational product from 
‘IMP/NIMP’ to ‘IMP or NIMP/AxMP’.
To avoid redundancy in the protocol with the detailed 
information that will be provided in the Pharmacy 
Manual.
To align with EU CTR.
8.1.11.1 Withdrawal From 
Future Biomedical Research
10.6 Appendix 6: Collection 
and Management of 
Specimens for Future 
Biomedical Research
Updated Sponsor email address for clinical 
specimen management.
To align with current email address.
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PRODUCT: V181  
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PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Section # and Name
Description of Change 
Brief Rationale 
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added a statement about investigators 
needing to indicate if an event was 
associated with a medication error, misuse, 
or abuse.
To align with EU CTR.
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Added a subsection to define medication 
error, misuse, and abuse.
To align with EU CTR.
10.3.5 Recording AE and 
SAE – Assessment of 
Intensity
Added 2 rows to the AE Intensity Grading 
table to identify which assessments are 
performed for injection site AEs occurring 
on Days 1 through 5 and those occurring 
on Day 6 or later after vaccination. Added 
a row for ‘Other’ injection-site AEs
occurring on Days 1 through 5, 
reformatted presentation of grading 
criteria, and updated footnotes to align 
with information presented in the table.
Removed induration from list of injection-
site reactions
To align with current reactogenicity guidance for 
vaccine studies.
Induration is not being evaluated as an injection-site 
reaction in this study.
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PRODUCT: V181  
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PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Section # and Name
Description of Change 
Brief Rationale 
Throughout
Minor administrative formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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PRODUCT: V181  
9
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
Dengue Disease and V181 Development ....................................................25
2.2.2
Preclinical Studies........................................................................................27
2.2.3
Completed Clinical Studies..........................................................................27
2.2.3.1
MSD V181 Completed Studies..........................................................27
2.2.3.2
NIH Dengue LATV Completed Studies............................................27
2.2.3.3
Butantan-DV Clinical Studies............................................................27
2.2.4
Information on Other Study-related Therapy ..............................................27
2.3
Benefit/Risk Assessment......................................................................................27
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................32
4.2.1.1
Immunogenicity Endpoints................................................................32
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Other Exploratory Endpoints.............................................................33
4.2.1.4
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End-of-Study Definition ............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.4
Screen Failures.....................................................................................................39
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PRODUCT: V181  
10
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................44
6.5
Management of GMO..........................................................................................44
6.6
Concomitant Therapy..........................................................................................44
6.6.1
Rescue Medications and Supportive Care ...................................................46
6.7
Dose Modification ................................................................................................46
6.7.1
Stopping Rules.............................................................................................46
6.8
Intervention After the End of the Study............................................................46
6.9
Clinical Supplies Disclosure................................................................................46
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................46
7.1
Discontinuation of Study Intervention...............................................................46
7.2
Participant Withdrawal From the Study...........................................................47
7.3
Lost to Follow-up .................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES........................................................47
8.1
Administrative and General Procedures ...........................................................48
8.1.1
Informed Consent.........................................................................................48
8.1.1.1
General Informed Consent.................................................................48
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................49
8.1.2
Assignment of Screening Number...............................................................49
8.1.3
Participant Identification Card.....................................................................49
8.1.4
Inclusion/Exclusion Criteria ........................................................................50
8.1.5
Medical History ...........................................................................................50
8.1.6
Prior and Concomitant Medications Review...............................................50
8.1.6.1
Prior Medications...............................................................................50
8.1.6.2
Concomitant Medications..................................................................50
8.1.7
Pregnancy Test.............................................................................................50
8.1.8
Assignment of Treatment/Randomization Number.....................................51
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6.=

PRODUCT: V181  
13
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
10.1.7
Compliance with Law, Audit, and Debarment ............................................79
10.1.8
Data Quality Assurance ...............................................................................79
10.1.9
Source Documents .......................................................................................80
10.1.10
Study and Site Closure.................................................................................81
10.2
Appendix 2: Clinical Laboratory Tests..............................................................82
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................83
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................83
10.3.2
Definition of AE ..........................................................................................83
10.3.3
Definition of SAE ........................................................................................85
10.3.4
Additional Events Reported.........................................................................86
10.3.5
Recording AE and SAE ...............................................................................86
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................92
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................94
10.5
Appendix 5: Contraceptive Guidance................................................................95
10.5.1
Definitions....................................................................................................95
10.5.2
Contraception Requirements........................................................................96
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................97
10.7
Appendix 7: Country-specific Requirements..................................................102
10.8
Appendix 8: Abbreviations ...............................................................................103
11
REFERENCES.............................................................................................................105
08MVGC
08SK8Z

PRODUCT: V181  
14
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
LIST OF TABLES
Table 1
Study Interventions..........................................................................................41
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................58
Table 3
Solicited Adverse Events for V181-003 ..........................................................60
Table 4
Analysis Strategy for Immunogenicity Variables............................................68
Table 5
Analysis Strategy for Safety Parameters..........................................................70
Table 6
Differences in Incidence of Adverse Event Rates Between the 2 
Vaccination Groups That Can be Detected With an ~80% Probability 
(Assuming a 2-Sided 5% Alpha Level With 230 Participants in the V181 
High Potency Level Group and 115 Participants in the Placebo Group) ........72
Table 7
Differences in Incidence of Adverse Event Rates Between the 2 
Vaccination Groups That Can be Detected With an ~80% Probability 
(Assuming a 2-Sided 5% Alpha Level With 460 Participants in the V181 
Mid Potency Level or V181 Low Potency Level Group and 115 
Participants in the Placebo Group) ..................................................................73
08MVGC
08SK8Z

PRODUCT: V181  
15
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
LIST OF FIGURES
Figure 1
V181-003 Study Design...................................................................................20
08MVGC
08SK8Z

PRODUCT: V181  
16
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Randomized, Double-Blind, Multicenter Study to Evaluate the 
Safety and Immunogenicity of Three Different Potency Levels of V181 (Dengue 
Quadrivalent Vaccine rDENVΔ30 [live, attenuated]) in Healthy Adults
Short Title: Safety and Immunogenicity of Three V181 Dengue Vaccine Potencies in Adults
Acronym: V181-003
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in healthy male and female 
participants, 18 to 50 years of age (inclusive).
Primary Objectives
Primary Endpoints
- To compare the dengue virus-neutralizing 
antibody geometric mean titers (GMTs) for 
each of the 4 dengue serotypes at Day 28 
postvaccination for participants administered 
the V181 Low Potency Level versus V181 
Mid Potency Level
Hypothesis: V181 Low Potency Level is 
non-inferior to V181 Mid Potency Level for 
each of the 4 dengue serotypes based on 
GMTs at Day 28 postvaccination.
(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 95% 
CI of the GMT ratio [V181 Low Potency 
Level versus V181 Mid Potency Level] be 
greater than 0.67 for each dengue serotype)
- Dengue virus-neutralizing antibody titers 
for each of the 4 dengue serotypes as 
measured by virus reduction neutralization 
test (VRNT)
- To evaluate the safety and tolerability of 3 
different V181 potency levels with respect to 
the proportion of participants experiencing 
SAEs
- Vaccine-related serious adverse events from 
Day 1 through Day 28 postvaccination
08MVGC
08SK8Z

PRODUCT: V181  
17
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Secondary Objectives
Secondary Endpoints
- To evaluate the safety and tolerability of 3 
different V181 potency levels with respect to 
the proportion of participants experiencing 
solicited AEs
- Solicited injection-site adverse events from 
Day 1 through Day 5 postvaccination
- Solicited systemic adverse events from Day 
1 through Day 28 postvaccination
Overall Design:
Study Phase
Phase 2
Primary Purpose
Prevention
Indication
Prevention of dengue disease in toddlers, children, and 
adults in endemic areas, as well as travelers to endemic 
areas
Population
Healthy adults 18 to 50 years of age
Study Type
Interventional
Intervention Model
Parallel
This is a multisite study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Sponsor
Investigator
Participants or Subjects
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 20 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.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
08MVGC
08SK8Z

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09*&
CCI
6.=

PRODUCT: V181  
19
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
08MVGC
08SK8Z

PRODUCT: V181  
20
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V181-003 Study Design
08MVGC
08SK8Z

PRODUCT: V181  
21
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
1.3
Schedule of Activities
Study Period:
Screening/
Randomization/
Intervention
Follow-up
(through Month 12 postvaccination)
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8
Scheduled Day or 
Month:
Day 1
Day 7
Day 12
Day 28
Month 3
Month 6
Month 9
TC
Month 12
For Visit 5, half of 
participants in each 
group will have TC and 
for Visit 6, other half 
will have TC.
Visit Window Permitted:
Pre-
Dose
Dose
Post-
Dose
±2 days
(Days 5 
to 9)
±2 days
(Days 10 
to 14)
+14 days
(Days 28
to 42)
±14 days
(Days 76 
to 104)
±14 days
(Days 166 
to 194)
±14 days
(Days 256 
to 284)
±14 days
(Days 346 
to 374)
Administrative Procedures
Informed Consent
X
Consent must be 
obtained BEFORE any 
study procedures, 
including screening.
Informed Consent for 
FBR
X
Participation in FBR is 
optional. Consent must 
be obtained before 
collection of FBR 
samples.
Assignment of Screening 
Number
X
Participant Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
Medical History
X
Includes medical 
history for 5 years 
before screening.
Prior/Concomitant 
Medication/Vaccines 
Review
X
X
X
X
X
X
X
X
After Visit 4, report only 
concomitant medications
associated with SAEs
and/or receipt of
investigational or 
approved dengue 
vaccine. Sections 5.2 and 
6.6.
08MVGC
08SK8Z

PRODUCT: V181  
22
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Study Period:
Screening/
Randomization/
Intervention
Follow-up
(through Month 12 postvaccination)
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8
Scheduled Day or 
Month:
Day 1
Day 7
Day 12
Day 28
Month 3
Month 6
Month 9
TC
Month 12
For Visit 5, half of 
participants in each 
group will have TC and 
for Visit 6, other half 
will have TC.
Visit Window Permitted:
Pre-
Dose
Dose
Post-
Dose
±2 days
(Days 5 
to 9)
±2 days
(Days 10 
to 14)
+14 days
(Days 28
to 42)
±14 days
(Days 76 
to 104)
±14 days
(Days 166 
to 194)
±14 days
(Days 256 
to 284)
±14 days
(Days 346 
to 374)
Urine Pregnancy Test 
(WOCBP only)
X
Performed by site.
WOCBP must have 
negative result before
vaccination.
Serum hCG 
(WOCBP only)
X
Serum hCG is tested 
only if the urine 
pregnancy test is 
inconclusive. WOCBP 
must have negative 
result before 
vaccination.
Randomization/Vaccination
Assignment of 
Randomization Number
X
V181/Placebo 
Administration
X
Only blinded study 
personnel administer 
study vaccine/placebo. 
See Section 8.1.9.
Distribute eVRC
X
Study-site personnel 
will train participant on
use of eVRC.
Immunogenicity Procedures
Serum samples for 
Dengue Antibody Titers 
(VRNT)
X
X
X
X
X
Day 1 blood sample 
must be collected 
before vaccination. 
See Section 8.2.
For half of 
participants in each of 
the 4 groups at Visits 
5 and 6. See Section 
4.
08MVGC
08SK8Z

PRODUCT: V181  
23
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Study Period:
Screening/
Randomization/
Intervention
Follow-up
(through Month 12 postvaccination)
Notes
Visit Number/Title:
1
2
3
4
5
6
7
8
Scheduled Day or 
Month:
Day 1
Day 7
Day 12
Day 28
Month 3
Month 6
Month 9
TC
Month 12
For Visit 5, half of 
participants in each 
group will have TC and 
for Visit 6, other half 
will have TC.
Visit Window Permitted:
Pre-
Dose
Dose
Post-
Dose
±2 days
(Days 5 
to 9)
±2 days
(Days 10 
to 14)
+14 days
(Days 28
to 42)
±14 days
(Days 76 
to 104)
±14 days
(Days 166 
to 194)
±14 days
(Days 256 
to 284)
±14 days
(Days 346 
to 374)
Safety Procedures
Full Physical 
Examination Including 
Height and Weight
X
Full physical 
examination is required 
to determine study 
eligibility. See Section 
8.3.1.
Vital Signs 
X
See Section 8.3.2.
Postvaccination Safety 
Observation
X
Blinded study personnel 
monitor participant at 
the study site for at least 
30 min for any 
immediate reactions
following vaccination. 
See Section 8.3.3.
AE/SAE Review
X
X
X
X
X
X
X
X
After Visit 4, only 
MAAEs, SAEs, and 
deaths are reported.
Rashes with onset D1 
to D28 
postvaccination 
should be evaluated 
by the investigator 
within 72 hrs of onset 
(Section 8.3.5).
Review of eVRC
X
X
X
Review the eVRC with 
the participant at Visits 
2, 3, and 4.
Collect Electronic 
Device for eVRC
X
For participants who 
received a study-
supplied device.
08MVGC
08SK8Z

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09*&
CCI
6.=

PRODUCT: V181  
26
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Dengue disease is caused by 4 virus serotypes: DENV1, DENV2, DENV3, and DENV4.
Infection by any of the 4 serotypes is believed to result in life-long immunity against that 
serotype. Infection with one serotype may provide short-term protection (ie, 6 to 24 months) 
against other serotypes, but does not provide long-term protection. Secondary infections with 
a different viral serotype increase the risk for development of severe disease forms (ie, DHF
and DSS) and death. It has been hypothesized that the increase in severity with secondary 
infection may be immune-mediated through a mechanism termed ADE [Halstead, S. B. 
2007] [Halstead, S. B. 2014] [Guzman, M. G., et al 2013]. According to this hypothesis, 
nonneutralizing, cross-reactive, heterotypic antibodies bind to a heterologous infecting 
serotype and facilitate uptake of the virus into Fc receptor-bearing target cells (such as
monocytes and macrophages), leading to increased viral replication and higher viral and 
viral-antigen NS1 loads that trigger cytokine release that ultimately mediates the plasma 
leakage syndrome observed in DHF. Given this natural history, ADE represents a theoretical 
risk for any dengue vaccine. This risk is considered to be inversely related to efficacy (eg, 
risks in participants where vaccine is not effective or efficacy wanes) [Cassetti, M. C. 2014].
Study participants will be informed in the ICF of the potential risk of ADE after vaccination 
with V181 and ways to protect themselves from exposure to mosquitos if they travel to 
dengue endemic areas.
Based on the above ADE hypothesis, the foremost approach for developing an effective 
dengue vaccine and mitigating the risk of vaccine-induced sensitivity for more severe disease 
is a 4-valent vaccine that will simultaneously and durably protect against disease caused by 
all 4 dengue virus serotypes [Halstead, S. B. and Deen, J. 2002].
V181 is comprised of the attenuated viral strains rDENV1Δ30, rDENV2/4Δ30(ME), 
rDENV3Δ30/31, and rDENV4Δ30 and is intended to prevent disease caused by each of the 4 
dengue serotypes (DENV1, DENV2, DENV3, and DENV4). The parental viruses for V181 
were initially developed by the NIH and in-licensed by the Sponsor. Attenuation of all 4 viral 
components in NIH dengue LATV was achieved by genetic modification (eg, deletion of 30 
nucleotides in the 3’ non-coding region (∆30) of the dengue genome. DENV2 is the only 
serotype that is not a full-length homotypic genome, but is instead a chimeric virus with the 
prM and E protein from DENV2 inserted into an attenuated DENV4 backbone. In addition, 
DENV3 also has an additional 31-nucleotide deletion in the 3 non-coding region (∆30/31). 
The vaccine viral strains are referred to as rDENV1∆30, rDENV2/4∆30(ME), 
rDENV3∆30/31, and rDENV4∆30 for DENV1, 2, 3, and 4 respectively. All of the final 
vaccine strains have been fully characterized and their attenuation confirmed through in vitro 
and in vivo testing.
The overall goal of the V181 program is to demonstrate that a single SC dose of V181 is 
effective in preventing disease from all 4 dengue serotypes in both dengue-naïve and dengue-
experienced individuals.
08MVGC
08SK8Z

PRODUCT: V181  
27
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
2.2.2
Preclinical Studies
Nonclinical studies have been performed on the components of the NIH dengue LATV 
admixture, which supports the V181 clinical program given that the vaccines are similar in 
design. Preclinical information for the NIH dengue LATV is provided in the IB.
2.2.3
Completed Clinical Studies
A brief summary of completed clinical studies are provided below, and details are provided 
in the IB.
2.2.3.1
MSD V181 Completed Studies
Results from the V181-001 Phase 1 study indicated V181 is highly immunogenic through 
6 months postdose 1 and generally safe and well tolerated in flavivirus-naïve and flavivirus-
experienced participants. AEs were generally assessed as mild to moderate in intensity by the 
participants.
2.2.3.2
NIH Dengue LATV Completed Studies
To date, the NIH has administered the dengue LATV monovalent components or tetravalent 
formulations comprising the same parental strains as V181 to more than 1000 participants 
with studies ongoing in the US and Thailand. The NIH monovalent and tetravalent vaccines 
were generally well-tolerated in both nonclinical and human studies conducted by the NIH.
2.2.3.3
Butantan-DV Clinical Studies
V181 and Butantan-DV are derived from the same parental strains originally developed by 
the NIH, are produced using similar methods, have the same antigenic composition and are 
therefore fundamentally the same. Therefore, data from Butantan clinical trials are relevant 
for V181.
Butantan-DV was evaluated in a Phase 2 study of 300 participants (of which 210 received 
Butantan-DV) in Brazil. The vaccine was found to be immunogenic and generally safe and 
well-tolerated in both dengue-naïve and dengue-exposed participants [Kallas, E. G., et al 
2020]. The vaccine is currently being investigated in a large Phase 3 safety and efficacy 
study with approximately 17,000 participants enrolled in Brazil.
2.2.4
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants will directly benefit from study vaccination during 
participation, since this clinical study is being conducted to evaluate the safety and 
immunogenicity of an investigational dengue vaccine.
08MVGC
08SK8Z

PRODUCT: V181  
28
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Data generated to date in V181, NIH dengue LATV, and Butantan-DV clinical studies 
demonstrated that these vaccines are generally safe, well tolerated, and highly immunogenic. 
The frequency, severity, and magnitude of the AEs identified in these studies support a 
favorable benefit-risk analysis for the dengue vaccine in the study population.
Additional details regarding specific benefits and risks for the participants in this clinical 
study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in healthy male and female 
participants, 18 to 50 years of age (inclusive).
Objectives
Endpoints
Primary
•
To compare the dengue virus-
neutralizing antibody geometric mean 
titers (GMTs) for each of the 4 dengue 
serotypes at Day 28 postvaccination for 
participants administered the V181 Low
Potency Level versus V181 Mid Potency 
Level
Hypothesis: V181 Low Potency Level is
non-inferior to V181 Mid Potency Level
for each of the 4 dengue serotypes based 
on GMTs at Day 28 postvaccination.
(The statistical criterion for non-
inferiority requires the lower bound of 
the 2-sided 95% CI of the GMT ratio 
[V181 Low Potency Level versus V181 
Mid Potency Level] be greater than 0.67 
for each dengue serotype)
•
Dengue virus-neutralizing antibody 
titers for each of the 4 dengue serotypes 
as measured by virus reduction 
neutralization test (VRNT)
•
To evaluate the safety and tolerability of 
3 different V181 potency levels with 
respect to the proportion of participants 
experiencing SAEs

Vaccine-related serious adverse events 
from Day 1 through Day 28 
postvaccination
08MVGC
08SK8Z

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CCI
6.=

PRODUCT: V181  
30
PROTOCOL/AMENDMENT NO.: 003-01
V181-003-01 FINAL PROTOCOL
14-JUL-2022
4
STUDY DESIGN
4.1
Overall Design
This is a double-blind with in-house blinding, randomized, placebo-controlled, multicenter, 
study to evaluate the safety and immunogenicity of 3 different potency levels of V181, 
compared with placebo, in healthy adults 18 to 50 years of age. The study will be conducted 
in dengue non-endemic regions. Approximately 1265 participants will be randomized 2:4:4:1
to receive a single dose of 1 of 3 potency levels (high, mid, or low) of V181 or placebo. The 
duration of the study for each participant will be approximately 12 months from the time the 
participant signs the ICF through the final contact.
An unblinded pharmacist or unblinded qualified study site personnel at each site will be
required to manage clinical supplies and prepare the study vaccine/placebo in order to 
maintain the blinding of the clinical material and the study. Once the study vaccine/placebo
has been prepared, it will be provided to a blinded member of the study team for 
administration to the participant. The participant, the investigator, and Sponsor personnel or 
delegate(s) involved in the study intervention administration or clinical evaluation of the 
participants will be blinded to the intervention assignments.
Participants will be screened to document general good health on Day 1. When deemed 
eligible for study participation, participants will be randomized and vaccinated with 1 of 3 
different potency levels of V181 or placebo on the same day (Day 1).
A standardized eVRC will be distributed to all participants for the collection of the following 
data on a daily basis beginning with the day of vaccination (Day 1) through Day 28
postvaccination:

Solicited injection-site AEs of injection-site pain, injection-site erythema, and injection-
site swelling from Day 1 through Day 5 postvaccination

Solicited systemic AEs of rash, headache, fatigue (tiredness), myalgia (muscle pain), and 
arthralgia (joint pain) from Day 1 through Day 28 postvaccination

Unsolicited AEs from Day 1 through Day 28 postvaccination

Oral temperatures from Day 1 through Day 28 postvaccination

Concomitant medications and nonstudy vaccines from Day 1 through Day 28 
postvaccination
All participants will be provided with an electronic device or will have their own electronic 
device configured, if compatible, to complete the eVRC. Study-supplied devices will be 
collected on Day 28.
08MVGC
08SK8Z

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postvaccination immune responses will be assessed for participants to confirm that the 
immune response for the V181 Low Potency Level falls within a predetermined ratio in 
comparison to the V181 Mid (target) Potency Level. The V181 High Potency Level will 
provide an assessment of the safety of V181 at a potency level that is higher than the Mid 
(target) Potency Level.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
A single dose of 1 of 3 potency levels of V181 will be assessed for postvaccination 
neutralizing antibody responses to the 4 vaccine virus serotypes at Day 28 postvaccination 
using the validated VRNT assay. Specimens for the primary endpoints for immunogenicity 
testing will be obtained from the entire study population (N=1265) at Day 28.
The time point of Day 28 was chosen as the primary endpoint based on the immunogenicity 
results observed in the V181-001 study. Among flavivirus-naïve participants, the observed 
seropositivity rates ranged from 70.6% to 97.1% for each of the 4 dengue serotypes. The 
percentage of these flavivirus-naïve participants who achieved quadrivalent or trivalent 
responses was 85.3%. In addition to the evaluation for all participants at Day 28, antibody 
responses will be evaluated for half of the participants in each group at Month 3 and the other 
half at Month 6, and for all participants at Month 12 postvaccination time points in order to 
assess the durability of immune responses.
The above immunogenicity schedule was designed to evaluate the phenomenon of a 3-phase 
immune response in seronegative participants to natural infection or live vaccines. 
Specifically, this refers to (1) a rapid increase in titer (over about 1 month); (2) a rapid decay 
after that peak (over another month); and then (3) a slower decay to a new equilibrium [Alter, 
G. 2020]. Based on these immune kinetics, an alternating immunogenicity visit design is 
planned in order to evaluate immunogenicity at multiple timepoints while minimizing the 
number of blood draws per participant [Food and Drug Administration 2019]. At each of the 
Month 3 and Month 6 visits, half of the participants will have blood draws for 
immunogenicity. Those participants who are assigned for blood draws at Month 3 will have 
telephone calls at Month 6; likewise participants who are assigned to have telephone calls at 
their Month 3 visit will have blood draws at their Month 6 visit. The resulting schema will 
provide immunogenicity data at 4 separate postvaccination time points (Day 28, Month 3, 
Month 6, and Month 12), while only requiring 3 postvaccination blood draws per participant.
As noted above, because the primary endpoint of the study is based on immunogenicity, the 
study will be conducted in participants who are dengue-seronegative at baseline, so a pre-
existing immunity to a dengue serotype/s does not augment the immune response to other 
serotypes and influence the results. A participant is classified as dengue-seronegative if 
VRNT is negative for all four dengue serotypes.
The VRNT is a high-throughput virus neutralization assay, specific for each of the 4 dengue 
serotypes. Serum samples are first diluted and incubated with virus to allow for antibody 
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws, participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Healthy male and female participants between the ages of 18 and 50 years (inclusive) 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 is eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is healthy based on review of medical history and physical examination, according to the 
clinical judgement of the investigator.
Demographics
2. Is male or female, from 18 years to 50 years of age inclusive, at the time of signing the 
informed consent.
Participants Assigned Male Sex at Birth
3.
Male participants are eligible to participate if they agree to the following for at least 90 
days after administration of study intervention (a spermatogenesis cycle is approximately 
90 days):
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
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•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
4. A female participant is eligible to participate if not pregnant or breastfeeding, and at least 
one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), 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 for at least 90 days after administration of study intervention. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (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.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for Future Biomedical 
Research. However, the participant may participate in the main study without 
participating in Future Biomedical Research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
(If a participant meets any of the exclusion criteria marked with an asterisk (*), the Day 1 
visit may be rescheduled for a time when these criteria are no longer met, as long as the study 
is still open to enrollment.)
Medical Conditions
1. Has known history of dengue or zika natural infection.
2. *Has an acute febrile illness (temperature ≥38.0°C [≥100.4°F] oral or equivalent) 
occurring within 72 hours before receipt of study vaccine/placebo.
3. Has a serious or progressive disease according to the investigator, including but not 
limited to cancer; uncontrolled diabetes; severe cardiac, renal, or hepatic insufficiency; or 
systemic autoimmune or neurologic disorder.
4. Has known or suspected impairment of immunological function, including but not limited 
to congenital or acquired immunodeficiency, HIV infection, hematologic malignancy, or 
treatment for autoimmune diseases.
5. Has a condition in which repeated venipuncture or injections pose more than minimal 
risk for the participant, such as hemophilia, thrombocytopenia, other severe coagulation 
disorders, or significantly impaired venous access.
6. Has a known hypersensitivity to any component of the study vaccine/placebo, or history 
of severe allergic reaction (eg, swelling of the mouth and throat, difficulty breathing, 
hypotension or shock) that required medical intervention.
Prior/Concomitant Therapy
7. Has received a dose of any dengue vaccine (investigational or approved) before study 
entry, or plans to receive any dengue vaccine (investigational or approved) for the 
duration of the trial.
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8. * Has received other licensed non-live vaccines within 14 days before receipt of study 
vaccine/placebo or is scheduled to receive any licensed non-live vaccine within 28 days 
following receipt of study vaccine/placebo. Exception: Inactivated influenza vaccine may 
be administered but must be given at least 7 days before receipt of study vaccine/placebo
or at least 28 days after receipt of study vaccine/placebo.
9. * Has received a licensed live vaccine within 28 days before receipt of study 
vaccine/placebo or is scheduled to receive any live vaccine within 28 days after receipt of 
study vaccine/placebo.
10. Has received systemic corticosteroids (equivalent of ≥2 mg/kg/day of prednisone or 
≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days and has not completed 
treatment at least 30 days before study entry or is expected to receive systemic 
corticosteroids at aforementioned dose and duration within 28 days after receipt of study 
vaccine/placebo. (Note: Topical and inhaled/nebulized steroids are permitted.)
11. Has received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) within 14 days before vaccination.
12. Has received immunosuppressive therapies, including chemotherapeutic agents used to 
treat cancer or other conditions, treatments associated with organ or bone marrow 
transplantation, or autoimmune disease, within 6 months before receipt of study 
vaccine/placebo or plans to receive immunosuppressive therapies within 28 days after 
receipt of study vaccine/placebo.
13. Has received a blood transfusion or blood products (including immunoglobulins) within 6 
months before receipt of a study vaccine/placebo or plans to receive a blood transfusion 
or blood products (including immunoglobulins) within 28 days after receipt of study 
vaccine/placebo.
Prior/Concurrent Clinical Study Experience
14. Has participated in another clinical study of an investigational product within 6 months 
before signing the informed consent, or plans to participate in another interventional 
clinical study at any time during the duration of the current clinical study. Participants 
enrolled in observational studies may be included; these will be reviewed on a case-by-
case basis for approval by the Sponsor.
Diagnostic Assessments
Not applicable.
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Other Exclusions
15. Has any other reason that, in the opinion of the investigator, may interfere with the 
evaluation required by the study. Reasons may include, but are not limited to, being 
unable to complete the eVRC, being unable to complete visits including non-office visit 
contacts (eg, telephone), or being unable to comply with study procedures.
16. Has planned donation of blood, eggs, or sperm at any time from signing the informed 
consent through 90 days postvaccination.
17. 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.
5.3
Lifestyle Considerations
No lifestyle restrictions are required for this study.
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 is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
V181 study vaccine will be prepared by reconstitution before administration, as described in 
Section 6.2.1; therefore, clinical supplies will be open-label in this study. The open-label 
clinical supplies will be distributed to unblinded study personnel at the clinical site and 
prepared by an unblinded pharmacist or unblinded qualified study site personnel, as per the 
instructions in the Investigator Study File Binder, which includes the Pharmacy Manual,
provided by the Sponsor. There is no visual difference between the V181 potency level study 
vaccine and placebo in the syringe. Once study vaccine/placebo has been prepared, it will be 
provided to a blinded member of the study team for administration to the participant.
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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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.
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
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 2:4:4:1 ratio to the V181 High 
Potency Level Group, V181 Mid Potency Level Group, V181 Low Potency Level Group, 
and placebo.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. V181 study vaccine 
(3 potency levels) and placebo will be provided open-label. Therefore, an unblinded 
pharmacist or unblinded qualified study site personnel will be responsible for receiving, 
maintaining, and preparing the study vaccine/placebo in accordance with a Pharmacy Manual 
provided by the Sponsor. An unblinded Clinical Research Associate will monitor vaccine 
accountability at the study site.
Once the study vaccine/placebo has been prepared by the unblinded pharmacist or unblinded 
qualified study site personnel, the study vaccine/placebo will be provided to a blinded 
member of the study team for administration to the participant. To avoid bias, contact 
between the unblinded study personnel and participants is strictly prohibited throughout the 
study. Additionally, blinded site personnel will not be present when the study 
vaccine/placebo is prepared. Blinded study-site personnel will be responsible for all safety 
follow-up, and blinded study-site personnel will be responsible for immunogenicity specimen 
collection before/after study vaccine/placebo administration. Laboratory personnel 
responsible for conducting the assays will remain blinded to vaccination group assignments 
throughout the duration of the study.
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The participant, investigator, and study-site personnel directly involved in the clinical 
evaluation of the participants, as well as Sponsor field personnel or delegate(s) involved with 
the conduct of this study will be blinded to the participant-level intervention assignments.
An unblinded statistician and statistical programmer not directly involved in the conduct of 
the study will be responsible for providing unblinded report deliverables to the eDMC. 
Details will be provided in the eDMC charter.
Following Day 28 database lock, most Sponsor Headquarters personnel involved in the 
conduct of the trial will be unblinded to vaccination group assignments for the primary safety 
and immunogenicity analyses. The primary CSR will be authored to present the results from 
Day 1 through Day 28 to support the establishment of the potency release specifications for 
V181. A blinded medical monitoring team will monitor the study after Day 28 through 
Month 12 postvaccination.
Investigators, study site personnel, participants, and Sponsor field personnel or delegate(s)
will remain blinded to treatment group assignments until the final study analyses are 
completed following the Month 12 (final) database lock.
See Section 8.1.12 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Participant study intervention compliance is defined in this study as a participant who 
receives the protocol-specified single dose of V181 or placebo. Any changes in 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
V181 is comprised of 4 genetically modified live viruses. Universal precautions should be 
followed for vaccine preparation and administration. Needles and syringes that have been in 
contact with the study 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 local country regulations for use of a GMO.
6.6
Concomitant Therapy
The following medications/vaccinations are prohibited before and/or during the study:

Any dengue vaccine (investigational or approved) before study entry, or plans to receive 
any dengue vaccine (investigational or approved) for the duration of the trial

Any licensed non-live vaccine 14 days before receipt of study vaccine/placebo or is 
scheduled to receive any licensed non-live vaccine within 28 days after receipt of study 
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vaccine/placebo. Inactivated influenza vaccine may be administered but must be given at 
least 7 days before or 28 days after receipt of study vaccine/placebo.

Any licensed live vaccine within 28 days before or after receipt of study vaccine/placebo.

Systemic corticosteroids (equivalent of ≥2 mg/kg/day of prednisone or ≥20 mg/day for 
persons weighing > 10 kg) for ≥14 consecutive days and has not completed treatment at 
least 30 days before study entry or is expected to receive systemic corticosteroids at 
aforementioned doses and duration within 28 days after receipt of study vaccine/placebo
(topical and inhaled/nebulized steroids are permitted).

Has received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) within 14 days before vaccination.

Has received immunosuppressive therapies, including chemotherapeutic agents used to 
treat cancer or other conditions, treatments associated with organ or bone marrow 
transplantation, or autoimmune disease, within 6 months before receipt of study 
vaccine/placebo or plans to receive immunosuppressive therapies within 28 days after 
receipt of study vaccine/placebo.

Has received a blood transfusion or blood products (including immunoglobulins) within 6 
months before receipt of a study vaccine/placebo or plans to receive a blood transfusion 
or blood products (including immunoglobulins) within 28 days after receipt of study 
vaccine/placebo.
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 in the 
study requires the mutual agreement of the investigator, the Sponsor, and the participant.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives from the time of vaccination through Day 28 
postvaccination must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
After Day 28 postvaccination (Visit 4), only concomitant medications associated with SAEs 
should be reported. The Clinical Director should be contacted if there are any questions 
regarding concomitant or prior therapy.
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6.6.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.7
Dose Modification
No dose modification is allowed in this study.
6.7.1
Stopping Rules
There are no prespecified stopping rules for this study.
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
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/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 8.1.12). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.12 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 studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
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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 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 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
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).
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•
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 used 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.
The approximate total maximum amount of blood volume drawn from each participant is 
50 mL, as detailed in the Investigator Study File Binder.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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) before participating in this clinical study or FBR. 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 their 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.
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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 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 FBR 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 FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
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 before 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 8.10.1.
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.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Inclusion/Exclusion Criteria
Before randomization, 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.
8.1.5
Medical History
A medical history will be obtained by the investigator or qualified designee. The participant’s 
relevant medical history for the 5 years before Visit 1 (Day 1) will be obtained to ensure that 
the participant satisfies the inclusion and exclusion criteria of the study.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication/vaccination use and 
record prior medications/vaccinations taken by the participant within 30 days before 
enrolling in the study in order to assess the study inclusion and exclusion criteria, including 
time windows for medication/vaccination use.
8.1.6.2
Concomitant Medications
At Visit 1 (Day 1) and at Visits 2, 3, and 4 postvaccination, the investigator or qualified 
designee will record medications and nonstudy vaccines, if any, taken by the participant 
through Day 28 postvaccination.
In addition, the participant will use their eVRC (Section 8.1.10) to record new and/or 
concomitant medications and nonstudy vaccines received from Day 1 through Day 28 
postvaccination.
After Day 28 postvaccination, only concomitant medications related to SAEs are reported.
Receipt of any dengue vaccine (investigational or approved) other than study 
vaccine/placebo must also be reported.
8.1.7
Pregnancy Test
A pregnancy test consistent with local requirements (which must be sensitive to detect hCG 
at concentrations of 25 IU/L) must be performed in WOCBP at screening or within 24 hours 
before the first dose of study vaccine/placebo is administered as described in Section 1.3. 
Urine or serum tests may be used, and results must be negative before study vaccine/placebo
is administered. If a urine pregnancy test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required. A negative urine or serum β-hCG pregnancy test 
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must be documented on the day of vaccination before administration of study 
vaccine/placebo. A detailed definition of WOCBP is provided in Appendix 5. Additional 
pregnancy tests may be performed at the discretion of the investigator or as required by local 
regulation at any time during the study.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Study vaccine/placebo 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 is given on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
study vaccine/placebo. Unblinded study personnel should not have contact with participants.
Once the study vaccine/placebo has been prepared by the unblinded pharmacist or unblinded 
qualified study site personnel, the study vaccine/placebo will be provided to a blinded 
member of the study team for administration to the participant. All safety and 
immunogenicity assessments will be conducted by blinded personnel, and the participant will 
be blinded to the study vaccine/placebo received.
Details of each vaccination should be documented on the appropriate eCRF as specified in 
the data entry guidelines. Procedures for handling, preparing, and administering, disposing 
of, and returning the unblinded vaccines are provided in the Investigator Study File Binder, 
which includes the Pharmacy Manual.
8.1.9.1
Timing of Dose Administration
In this study, V181 or placebo will be administered as a 0.5-mL subcutaneous injection at 
Visit 1 (Day 1). The day of the study vaccination is considered Day 1 of the study. Study 
participants will be observed by blinded study-site personnel for at least 30 minutes 
following each vaccination for any immediate AEs; the time period can be extended if 
clinically indicated.
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8.1.10
Electronic Vaccination Report Card (eVRC)
The eVRC was developed to be administered electronically via a hand-held device and is 
used to record AEs during the postvaccination period, as defined in Section 8.4.8. The eVRC 
is structured as recommended in the final US FDA Patient-Reported Outcome Guidance
[U.S. Department of Health and Human Services 2009].
Participants will be provided an electronic device or have their own electronic device 
configured, if compatible, to complete the eVRC. The participant will be trained by the 
investigator or delegate in the use of the eVRC before dispensing it to the participant at Visit 
1 (Day 1). Noncompliance with the eVRC will require retraining by the site as soon as 
possible to ensure accurate and complete data capture.
Daily oral temperatures, injection-site reactions, other complaints or illnesses, and 
concomitant medications/nonstudy vaccines will be recorded on the eVRC from Day 1 
through Day 28 postvaccination (see Section 4.1). Participants will be required to measure 
temperature using a digital thermometer provided by the Sponsor and the size of injection-
site reactions of swelling and redness using a ruler provided by the Sponsor. Refer to Section 
8.4.8 for safety assessments using the eVRC.
For the specific AEs collected via the eVRC, the investigator or delegate will discuss 
information entered into the eVRC with the participant at Day 7, Day 12, and Day 28 
postvaccination (Visit 2, Visit 3, and Visit 4) and apply the appropriate assessment of overall 
intensity grade, as described in Appendix 3.
Any differences between eVRC data and the clinical database must be documented in the 
participant’s source record.
8.1.11
Discontinuation and Withdrawal
Participants in this study will receive a single dose intervention and cannot discontinue study 
intervention.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.11.1
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@MSD.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 
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investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed before 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.
8.1.12
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. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity grade of the AEs observed, the relation to study intervention, the reason thereof, 
etc., in the medical chart. If it is not possible to record this assessment in the medical record
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
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Oral temperatures will be recorded by participants using the eVRC from Day 1 through 
Day 28 postvaccination.
For this study, any temperature ≥100.4°F (≥38.0°C) oral or oral equivalent will be considered 
an AE of fever. All fevers must be reported Day 1 through Day 28 postvaccination unless the 
fever is a symptom of another reported AE.
8.3.3
Postvaccination Safety Observation Period
All participants will be observed, by blinded study-site personnel only, for at least 30 minutes 
following vaccination for any immediate reactions. If any immediate AEs are observed 
during this period, the time at which the event occurred within this timeframe, as well as the 
event itself, any concomitant medications that were administered, any medical intervention 
provided, and resolution of the event must be recorded on the appropriate eCRFs.
8.3.4
Clinical Safety Laboratory Assessments
No clinical safety laboratory assessments are planned for this study.
8.3.5
Assessment of Rash
Rash is a solicited systemic AE and participants who experience rash during the primary 
postvaccination safety period (Day 1 to Day 28 postvaccination) will be asked to record rash 
events on the eVRC. Additionally, participants should be instructed to contact the site 
promptly to ensure that the rash is assessed by the investigator within 72 hours of onset when 
reported from Day 1 to Day 28 postvaccination. If rash assessment cannot occur at a planned 
visit (Visit 2, Visit 3, or Visit 4) within 72 hours of the participant’s rash onset, then the rash 
should be assessed by the investigator at an unscheduled visit. Details of the rash assessment 
should be documented on the appropriate eCRF, as specified in the data entry guidelines.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, 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 or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE 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, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before randomization must be reported by the investigator 
if they cause the participant to be excluded from the study, or are 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 randomization through 28 days following vaccination, all AEs, SAEs, and 
other reportable safety events must be reported by the investigator.
All MAAEs, SAEs, and deaths that occur from the time of randomization through Month 12 
postvaccination (extended safety follow-up period) must be reported by the investigator, 
regardless of whether the events are considered to be vaccine related by the investigator.
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, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 2.
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Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
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.
- any death until 
participant 
completion of study
(Follow ongoing to 
outcome)
Within 24 hours 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/terminati
on; report outcome
Within 24 hours 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 5 calendar days 
of learning of event
NSAE=nonserious adverse event; SAE=serious adverse event
8.4.2
Method of Detecting AEs, SAEs, 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.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, 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 (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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must be reported as 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
Not applicable for this study.
8.4.7
Events of Clinical Interest
There are no specific events of clinical interest for this study.
8.4.8
Adverse Events Reported on the Electronic Vaccination Report Card
Each participant will be provided an eVRC to report solicited and unsolicited AEs (Section 
8.1.10).
8.4.8.1
Solicited Adverse Events
Solicited AEs for this study are summarized in Table 3.
Table 3
Solicited Adverse Events for V181-003
Type of Solicited 
Adverse Event
Predefined Solicited Adverse 
Events
Solicited Time Period
Injection site

Injection-site pain/tenderness

Injection-site erythema/redness

Injection-site swelling
Day 1 through Day 5 
postvaccination
Systemic

Fatigue (tiredness)

Headache

Myalgia (muscle pain)

Rash

Arthralgia (joint pain)
Day 1 through Day 28
postvaccination
All solicited injection-site AEs will be considered related to study intervention. The 
investigator will assess all solicited injection-site AEs for overall intensity grade, and all 
solicited systemic AEs for both overall intensity grade and causality (Appendix 3).
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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?
Investigators are responsible for reviewing, assessing and reporting data entered in the eVRC
on the appropriate eCRF(s) as specified in the data entry guidelines. In addition, solicited 
injection-site AEs and solicited systemic AEs reported by the participant using the eVRC 
will be transferred directly to the Sponsor’s database.
8.4.8.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are either not predefined in Table 3 or 
predefined in Table 3 but reported at any time outside of the solicited time period. 
Unsolicited AEs reported by the participant will be entered by the study site personnel on the 
appropriate eCRF.
As described in Section 8.4, the investigator will assess unsolicited AEs that meet the 
definition of an AE or SAE with respect to seriousness, overall intensity grade, and causality.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than one dose of the investigational V181 
vaccine/placebo.
No specific information is available on the treatment of overdose.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design Overview
A Phase 2, Randomized, Double-Blind, Multicenter 
Study to Evaluate the Safety and Immunogenicity 
of Three Different Potency Levels of V181 
(Dengue Quadrivalent Vaccine rDENVΔ30 [live, 
attenuated]) in Healthy Adults
Treatment Assignment
There are 4 vaccination arms. Participants will be 
assigned randomly in a 2:4:4:1 ratio to the V181 
High Potency Level Group, V181 Mid Potency 
Level Group, V181 Low Potency Level Group, or 
Placebo using an IRT. A double-blind/masking 
technique will be used.
Analysis Populations
Immunogenicity: Per-Protocol Population
Safety: All Participants as Treated (ApaT)
Primary Endpoint(s)
Immunogenicity (Primary):  Dengue virus-
neutralizing antibody GMTs for each of the 4 
dengue serotypes at Day 28 postvaccination as 
measured by 
the VRNT
Safety (Primary): Vaccine-related serious adverse 
events (SAEs) from Day 1 through Day 28 
postvaccination
Key Secondary Endpoints
Safety (Secondary):
Solicited injection-site adverse events (AEs) of 
pain, erythema, and swelling from Day 1 through 
Day 5 postvaccination
Solicited systemic AEs of rash, headache, fatigue 
(tiredness), myalgia (muscle pain), and arthralgia 
(joint pain) from Day 1 through Day 28 
postvaccination
Statistical Methods for Key Immunogenicity
Analyses
To address the primary immunogenicity non-
inferiority objective, the comparison between groups 
will be made based on serotype-specific GMTs for the 
4 dengue serotypes at Day 28 postvaccination. The 
estimation of the GMT ratios and the corresponding 
95% CIs will be calculated using a linear model with
the log-transformed antibody titer as the response and 
a single term for vaccination group.
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Statistical Methods for Key Safety Analyses
The analysis of safety results will follow a tiered 
approach. The tiers differ with respect to the 
analyses that will be performed. Adverse events 
(specific terms as well as SOC terms) are either 
prespecified as “Tier1” endpoints or will be 
classified as belonging to “Tier 2” or “Tier 3” based 
on the number of events observed. There are no 
Tier 1 events for this protocol. Tier 2 parameters 
will be assessed via point estimates with 95% CIs 
provided for differences in the proportion of 
participants with events (Miettinen and Nurminen 
[M&N] method [1985] [Miettinen, O. and 
Nurminen, M. 1985]). 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.
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is needed for this study as 
success is required on all 4 dengue serotypes.
Sample Size and Power 
The overall sample size will be approximately 1265
with 230 participants in the high potency group, 460 
participants in each of the mid and low potency 
groups, and 115 participants in the placebo group. 
The study has an overall power of >95% to establish 
that the V181 Low Potency Level is non-inferior to 
the V181 Mid Potency Level for all four serotypes at 
an overall one-sided, 2.5% alpha-level.
9.2
Responsibility for Analyses/In-house Blinding
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 under in-house blinding procedures.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT. The primary 
safety and immunogenicity evaluation period for this study is defined as the period from Day 
1 through Day 28 postvaccination. A CSR will be produced to present the results for this 
time period in order to inform potency specifications for the V181 vaccine. The official, final 
database for the Day 28 analysis will not be unblinded until medical/scientific review has 
been performed, protocol deviations have been identified, and data have been declared final 
and complete. After the Day 28 postvaccination visit, participants will be followed for safety 
(SAEs and deaths only) and immunogenicity through Month 12 postvaccination. Results 
from the Day 28 through Month 12 postvaccination time period will be presented in a final, 
separate study report.
After database lock for the primary analysis, most Sponsor Headquarters personnel involved 
in the conduct of the trial will be unblinded to vaccination group assignments. A blinded 
08MVGC
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Primary Safety Endpoints

Vaccine-related SAEs from Day 1 through Day 28 postvaccination
Secondary Safety Endpoints

Solicited injection-site AEs of injection-site pain, injection-site erythema, and injection-
site swelling from Day 1 through Day 5 postvaccination

Solicited systemic AEs of rash, headache, fatigue (tiredness), myalgia (muscle pain), and 
arthralgia (joint paint) from Day 1 through Day 28 postvaccination
Additional Safety Endpoints

Unsolicited AEs from Day 1 through Day 28 postvaccination

Elevated temperature (≥100.4°F [38.0°C] oral equivalent) from Day 1 through Day 28 
postvaccination

All MAAEs, SAEs, and deaths through completion of study participation
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol population will serve as the primary population for the analysis of the 
immunogenicity data in this study. The Per-Protocol population excludes participants due to 
deviations from the protocol that may substantially affect the results of the primary 
immunogenicity endpoints. Potential deviations that may result in the exclusion of a 
participant from the PP population for all immunogenicity analyses include:

Prevaccination baseline blood sample test result is seropositive for any of the 4 dengue
serotypes by VRNT. Seropositivity will be defined as having VRNT at or above the 
LLOQ of the assay.

Failure to receive correct clinical material as per randomization schedule

Receipt of prohibited medication or prohibited vaccine before study vaccination or 
though Day 28 postvaccination.

Collection of blood sample at the timepoint for the analysis outside of the pre-specified 
window, as described in Section 1.3
The final determination on protocol deviations, and thereby the composition of the PP
population, will be made before the unblinding of the database and will be documented in a 
separate memo. The key immunogenicity analyses will also be performed using the Full 
Analysis Set (FAS) population, which consists of all randomized participants who receive 
08MVGC
08SK8Z

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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 (Miettinen and Nurminen [M&N] method [1985]
[Miettinen, O. and Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 4 participants in any treatment 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 treatment 
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 helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in AEs.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a vaccine-
related AE, an MAAE, a vaccine-related MAAE, an SAE, a vaccine-related SAE, 
discontinuation due to an AE, and death will be considered Tier 2 endpoints. Solicited 
injection-site AEs (pain, erythema, and swelling) from Day 1 through Day 5 postvaccination, 
solicited systemic AEs (rash, headache, fatigue [tiredness], myalgia [muscle pain], and
arthralgia [joint pain]) from Day 1 through Day 28 postvaccination, and vaccine-related 
SAEs from Day 1 through Day 28 postvaccination will also be considered a Tier 2 endpoint.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
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Table 5
Analysis Strategy for Safety Parameters
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the vaccination groups for each relevant characteristic will be assessed 
by the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed. Demographic variables (eg, age), baseline characteristics, primary and secondary 
Safety 
Tier
Safety Endpointa
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AEa
X
X
Any vaccine-related AEa
X
X
Any MAAEa
X
X
Any vaccine-related MAAEa
X
X
Any SAEa
X
X
Any vaccine-related SAEa
X
X
Discontinuation due to AEa
X
X
Deatha
X
X
Solicited injection-site AEs:  pain, erythema, 
and swelling
X
X
Solicited systemic AEs: rash, headache, fatigue 
(tiredness), myalgia (muscle pain), and 
arthralgia (joint pain)
X
X
Elevated temperature (≥100.4°F [38.0°C] oral 
equivalent) 
X
X
Specific AEs by SOC and PTb (incidence ≥4 
participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOCs and PTb (incidence <4 
participants in all of the vaccination groups)
X
AE = adverse event; CI = confidence interval; MAAE – medically attended adverse event; PT = preferred 
term; SAE = serious adverse event; SOC=system organ class; X = results will be provided
  a 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 one AE. 
  b Includes only those endpoints not already pre-specified as Tier 2 endpoints.
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diagnoses, and prior and concomitant therapies will be summarized by vaccination group 
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned for this study. Participant safety will be monitored by an 
eDMC that will perform periodic reviews of safety data throughout the study (Appendix 1).
An unblinded statistician and statistical programmer not directly involved in the conduct of 
the study will be responsible for providing unblinded report deliverables to the eDMC.
Details will be provided in the eDMC charter.
9.8
Multiplicity
No multiplicity adjustment is needed for this study as success is required on all 4 dengue 
serotypes.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This study will randomize participants in a 2:4:4:1 ratio into the 4 vaccination groups (V181 
High Potency Level Group, V181 Mid Potency Level Group, V181 Low Potency Level 
Group, and Placebo). The overall sample size will be approximately 1265 with 
230 participants in the High Potency Level Group, 460 participants in each of the Mid and 
Low Potency Level Groups, and 115 participants in the placebo group. The study has an 
overall power of >95% to establish that the V181 Low Potency Level is non-inferior to the 
V181 Mid Potency Level for all four serotypes at an overall one-sided, 2.5% alpha-level. The 
power and sample size are based on the following assumptions: 1) an approximately 15% 
non-evaluable rate, 2) the non-inferiority margin of 0.67, 3) the true GMT ratio is assumed to 
be 1, and 4) the standard deviation of the natural-log titers is estimated to be 1.25 for each 
dengue serotype based on previous clinical and assay data. Given these assumptions, using 
the most conservative standard deviation, the lowest estimated GMT ratio that would meet a 
lower bound criterion of 0.67 is approximately 0.78.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 vaccine-related SAE in this study depends on the 
number of participants vaccinated and the underlying percentage of participants with a 
vaccine-related SAE in the study population. If the underlying incidence of a vaccine-related 
SAE is 0.30% (1 of every 333 participants receiving the vaccine), there is a 50% chance of 
observing at least 1 vaccine-related SAE among 230 participants in the V181 High Potency 
Level vaccination group. If the incidence rate is 1 of every 144 recipients (0.69%), there is an 
80% chance of observing at least 1 vaccine-related SAE. If no vaccine-related SAEs are 
observed among the 230 participants in the V181 High Potency Level vaccination group, this 
study will provide 97.5% confidence that the underlying percentage of participants with 
vaccine-related SAE is <1.6% in the V181 High Potency Level vaccination group.
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Table 6 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 AE. These calculations assume 230 participants in the V181 High Potency Level group 
and 115 participants in the Placebo group, and are based on a 2-sided 5% alpha level. The 
calculations are based on an asymptotic method proposed by Farrington and 
Manning[Farrington, C. P. and Manning, G. 1990]; no multiplicity adjustments were made.
Table 6
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups That Can be Detected With an ~80% Probability (Assuming a 2-Sided 5% Alpha 
Level With 230 Participants in the V181 High Potency Level Group and 115 Participants in 
the Placebo Group)
Incidence of an Adverse Event
Risk Difference
V181 High Potency Level Group 
(%)
Placebo (%)
Percentage Points
5.7
0.1
5.6
9.8
2.0
7.8
14.7
5.0
9.7
21.9
10.0
11.9
28.3
15.0
13.3
34.3
20.0
14.3
45.5
30.0
15.5
Incidences presented here are hypothetical and do not represent actual adverse experiences in either 
group. Based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, 
C. P. 1990]
If the underlying incidence of a vaccine-related SAE is 0.15% (1 of every 665 participants 
receiving the vaccine), there is a 50% chance of observing at least 1 vaccine-related SAE
among 460 participants in the V181 Mid Potency Level and V181 Low Potency Level 
Groups. If the incidence rate is 1 of every 287 recipients (0.35%), there is an 80% chance of 
observing at least 1 vaccine-related SAE. If no vaccine-related SAEs are observed among the
460 participants in each of the V181 Mid Potency Level and V181 Low Potency Level 
Groups, this study will provide 97.5% confidence that the underlying percentage of 
participants with vaccine-related SAE is <0.9% in each of the V181 Mid Potency Level and 
V181 Low Potency Level Groups.
Table 7 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 AE. These calculations assume 460 participants in the V181 Mid Potency Level or V181 
Low Potency Level Group and 115 participants in the Placebo group, 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. and Manning, G. 1990]; no multiplicity 
adjustments were made.
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Table 7
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups That Can be Detected With an ~80% Probability (Assuming a 2-Sided 5% Alpha 
Level With 460 Participants in the V181 Mid Potency Level or V181 Low Potency Level 
Group and 115 Participants in the Placebo Group)
Incidence of an Adverse Event
Risk Difference
V181 Mid/Low Potency Level 
Group (%)
Placebo (%)
Percentage Points
5.0
0.1
4.9
9.0
2.0
7.0
13.8
5.0
8.8
20.8
10.0
10.8
27.1
15.0
12.1
33.0
20.0
13.0
44.2
30.0
14.2
Incidences presented here are hypothetical and do not represent actual adverse experiences in either 
group. Based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, 
C. P. 1990]
9.10
Subgroup Analyses
The subgroup analyses will be comprised of descriptive summary statistics for 
immunogenicity by gender and age. Further details of subgroup analyses will be documented 
in the sSAP.
9.11
Compliance (Medication Adherence)
Given that participants will receive only a single dose of 1 of 3 V181 potency levels or 
placebo, compliance will not be calculated. The number and proportion of randomized 
participants receiving each study vaccination will be summarized (see Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered each of the 3 V181 potency levels and randomized participants
administered placebo.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (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. Before trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
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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 
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 before 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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants and recommend to the 
EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
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 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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.
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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
Clinical laboratory tests are not planned for this study.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the poteintial 
to lead to harm to the participant.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
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.
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    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.”
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 before 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 an eVRC and that is 
communicated by a participant who has signed the 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 the 
eVRC.
Definition of MAAE

AEs 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 with any medical 
personnel for any reason. Routine visits are not considered MAAEs. Examples of routine 
visits include physical examination, wellness visit, or vaccinations.
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Note:  Determination of MAAEs is the responsibility of the investigator or qualified 
designee. Once identified, MAAEs should be reported to the Sponsor per the timeline for 
reporting AEs/SAEs.
10.3.3
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 before 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.
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f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
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
10.3.5
Recording AE and SAE
AE and SAE recording
    When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
    The investigator will record all relevant AE/SAE 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.
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    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.
Assessment of intensity
    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.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
•
The investigator will make an assessment of overall intensity grade for each AE and SAE 
(and other reportable event) reported during the study. An overall intensity grade will be 
assigned to injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The overall intensity grading scales 
used in this study follow the “FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
September 2007.”
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Injection Site AE Overall Intensity Grading Scale
Injection-Site 
Reaction to Study 
Vaccine/Placeboa
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening
(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
≤5 cm (size 
measured as A or
B)
5.1 to 10 cm (size 
measured as C or 
D)
>10 cm (size 
measured as E→)
Necrosis or 
exfoliative 
dermatitis or 
results in ER visit 
or hospitalization
Swelling
≤5 cm (size
measured as A or 
B)
5.1 to 10 cm (size
measured as C or 
D)
>10 cm (size
measured as E→)
Necrosis or ER 
visit or 
hospitalization
Other
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Any injection-site reaction that begins ≥6 days after receipt of study vaccine/placebo
Pain/Tenderness
Erythema/Redness
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
AE=adverse event; ER=emergency room; eVRC=electronic Vaccination Report Card
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a Based upon information provided by the participant on the eVRC and verbally during VRC review. Erythema/Redness
and Swelling are specific injection-site AEs with size designations of letters A (<2.5 cm), B (2.5 to 5 cm), C (5.1 to 
7.4 cm), D (7.5 to 10 cm), and E (>10 cm), based upon a graphic in the eVRC. If the participant has an ER visit or is 
hospitalized for any injection-site AE, that AE is to be assigned an intensity grade of 4, regardless of the size 
measured.
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Specific Systemic AE Overall Intensity 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
Arthralgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Rash
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
ER=emergency room
Other Systemic AE Overall Intensity 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
ER=emergency room; eVRC=electronic Vaccination Report Card; SAE=serious adverse event
a Based upon information provided by the patient on the eVRC and verbally during the eVRC 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.
Vital Sign (Temperature) Overall Intensity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life Threatening
(Grade 4)
Fever 
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements.
b Oral temperature; no recent hot or cold beverages or smoking.
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
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.
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
    The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
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include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
    New or updated information will be recorded in the CRF.
    The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, 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.
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    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
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 subdermal contraceptive implantc,d
•
IUSc
•
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 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 Dependenta
Failure rate of <1% per year when used consistently and correctly.
• Combined (estrogen- and progestogen- containing) hormonal contraceptionb,c
- Oral
- Intravaginal
- Transdermal
- Injectable
• Progestogen-only hormonal contraceptionb,c
- 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   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
c   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
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).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues 
that is a sign of a normal or abnormal process or of a condition or disease. A 
biomarker may be used to see how well the body responds to a treatment for a 
disease or condition.1
b.   Pharmacogenomics: The investigation of variations of DNA and RNA 
characteristics as related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8
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.
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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.
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.
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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.
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 the 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@MSD.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 before 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.
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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 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.
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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@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data 
and Sample Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-
pharmacogenetics-genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the 
Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: 
A Guide for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. 
Available at http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
Adverse event 
ADE
Antibody-dependent enhancement
ApaT
All-Participants-as-Treated
hCG
human chorionic gonadotropin
Butantan-DV
Butantan-Dengue Vaccine
CI
Confidence interval
CRF
Case report form 
CSR
Clinical study report
CTFG
Clinical Trials Facilitation Group
DENV
Dengue virus
DHF
Dengue hemorrhagic fever
DNA
Deoxyribonucleic acid
DSS
Dengue shock syndrome
DMC
Data Monitoring Committee
ECI
Event of clinical interest
eCRF
Electronic case report form
EDC
Electronic data capture
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
eVRC
Electronic Vaccination Report Card
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice
GMO
genetically modified organism
GMT
Geometric mean titer
HEENT
Head, eyes, ears, nose, and throat
HIV
Human Immunodeficiency Virus
HRT
Hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Intervention randomization system
IUD
Intrauterine device
IUS
Intrauterine system
LAM
Lactational amenorrhea method
LATV
Live-attenuated tetravalent vaccine
LLOQ
Lower limit of quantification
MAAE
Medically attended adverse event
NA
Not applicable
NIH
National Institute of Health
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08SK8Z

PRODUCT:  V181  
104
PROTOCOL/AMENDMENT NO.:  003-01  
V181-003-01 FINAL PROTOCOL
14-JUL-2022
Abbreviation
Expanded Term
NIMP
Non-Investigational Medicinal Product
NSAE
Nonserious adverse event
PFU
Plaque-forming unit
PP
Per Protocol
PT
Preferred term
RNA
Ribonucleic acid
RT-PCR
Reverse transcriptase polymerase chain reaction
SAE
Serious adverse event 
SC
Subcutaneous
SoA
Schedule of activities
SOC
System organ class
sSAP
Supplemental statistical analysis plan
SUSAR
Serious unexpected serious adverse reaction
TBD
To-be determined
US
United States
VRNT
Virus Reduction Neutralization Test
WOCBP
Woman/women of childbearing potential 
WT
Wild-type
08MVGC
08SK8Z

PRODUCT:  V181  
105
PROTOCOL/AMENDMENT NO.:  003-01  
V181-003-01 FINAL PROTOCOL
14-JUL-2022
11
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08MVGC
08SK8Z

PRODUCT:  V181  
106
PROTOCOL/AMENDMENT NO.:  003-01  
V181-003-01 FINAL PROTOCOL
14-JUL-2022
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08MVGC
08SK8Z

PRODUCT:  V181  
107
PROTOCOL/AMENDMENT NO.:  003-01  
V181-003-01 FINAL PROTOCOL
14-JUL-2022
[Kallas, E. G., et al 2020]
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[04VZYM]
08MVGC
08SK8Z

PRODUCT:  V181  
108
PROTOCOL/AMENDMENT NO.:  003-01  
V181-003-01 FINAL PROTOCOL
14-JUL-2022
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[03RK0R]
08MVGC
08SK8Z