A Phase 3, Randomized, Double-blind, Active Comparator-controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine-naïve Adults 18 to 64 Years of Age With Increased Risk for Pneumococcal Disease.
Phase: PHASE3
Conditions: Pneumococcal Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05696080 
Document Date: 
24-Oct-2022
A Phase 3, Randomized, Double-blind, Active Comparator-controlled
Clinical Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V116 in Pneumococcal Vaccine-naïve Adults 
18 to 64 years of Age With Increased Risk for Pneumococcal Disease

PRODUCT: V116
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TITLE PAGE
THIS PROTOCOL 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 3, Randomized, Double-blind, Active Comparator-controlled 
Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in 
Pneumococcal Vaccine-naïve Adults 18 to 64 years of Age With Increased Risk for 
Pneumococcal Disease
Protocol Number: 008-00
Compound Number: V116
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):
NCT
Not Applicable
EU CT
2022-501812-32-00
EudraCT
Not Applicable
JAPIC-CT
Not Applicable
WHO
Not Applicable
UTN
U1111-1282-1460
IND
19316
Approval Date: 24 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original Protocol
24-OCT-2022
Not applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Information on Other Study-related Therapy ..............................................22
2.2.2.1
PCV15................................................................................................22
2.2.2.2
PPSV23..............................................................................................22
2.2.2.3
Pneumococcal Vaccination Guidelines..............................................23
2.3
Benefit/Risk Assessment......................................................................................23
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................24
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................26
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Immunogenicity Endpoints................................................................27
4.2.1.2
Safety Endpoints................................................................................27
4.2.1.3
Future Biomedical Research..............................................................28
4.2.2
Rationale for the Use of Comparator/Placebo .............................................28
4.3
Justification for Dose...........................................................................................28
4.4
Beginning and End-of-Study Definition ............................................................29
4.4.1
Clinical Criteria for Early Study Termination .............................................29
5
STUDY POPULATION ................................................................................................29
5.1
Inclusion Criteria.................................................................................................29
5.2
Exclusion Criteria................................................................................................32
5.3
Lifestyle Considerations......................................................................................34
5.4
Screen Failures.....................................................................................................34
5.5
Participant Replacement Strategy......................................................................34
6
STUDY INTERVENTION............................................................................................35
6.1
Study Intervention(s) Administered...................................................................35
6.1.1
Medical Devices...........................................................................................38
6.2
Preparation/Handling/Storage/Accountability .................................................38
6.2.1
Dose Preparation..........................................................................................38
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6.2.2
Handling, Storage, and Accountability........................................................38
6.3
Measures to Minimize Bias: Randomization and Blinding..............................39
6.3.1
Intervention Assignment..............................................................................39
6.3.2
Stratification.................................................................................................39
6.3.3
Blinding........................................................................................................39
6.4
Study Intervention Compliance..........................................................................40
6.5
Concomitant Therapy..........................................................................................40
6.5.1
Rescue Medications and Supportive Care ...................................................41
6.6
Dose Modification ................................................................................................41
6.7
Intervention After the End of the Study............................................................41
6.8
Clinical Supplies Disclosure................................................................................41
6.9
Standard Policies..................................................................................................41
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................42
7.1
Discontinuation of Study Intervention...............................................................42
7.2
Participant Withdrawal From the Study...........................................................42
7.3
Lost to Follow-up .................................................................................................43
8
STUDY ASSESSMENTS AND PROCEDURES........................................................43
8.1
Administrative and General Procedures ...........................................................44
8.1.1
Informed Consent.........................................................................................44
8.1.1.1
General Informed Consent.................................................................44
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................44
8.1.2
Inclusion/Exclusion Criteria ........................................................................45
8.1.3
Participant Identification Card.....................................................................45
8.1.4
Medical History ...........................................................................................45
8.1.5
Prior and Concomitant Medications Review...............................................45
8.1.5.1
Prior Medications...............................................................................45
8.1.5.2
Concomitant Medications..................................................................45
8.1.6
Assignment of Screening Number...............................................................46
8.1.7
Assignment of Randomization Number.......................................................46
8.1.8
Study Intervention Administration ..............................................................46
8.1.8.1
Timing of Dose Administration.........................................................47
8.1.9
Electronic Vaccination Report Card ............................................................47
8.1.10
Telephone Contact Questionnaire................................................................47
8.1.11
Discontinuation and Withdrawal .................................................................48
8.1.11.1
Withdrawal From Future Biomedical Research ................................48
8.1.12
Participant Blinding/Unblinding..................................................................48
8.1.13
Calibration of Equipment.............................................................................49
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8.2
Immunogenicity Assessments .............................................................................49
8.2.1
Multiplex Opsonophagocytic Assay............................................................49
8.2.2
Pneumococcal Electrochemiluminescence Assay .......................................50
8.3
Safety Assessments...............................................................................................50
8.3.1
Physical Examinations.................................................................................50
8.3.2
Pregnancy Testing........................................................................................51
8.3.3
Body Temperature Measurements ...............................................................51
8.3.4
Postvaccination Observation Period ............................................................51
8.3.5
Clinical Safety Laboratory Assessments .....................................................52
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................52
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................53
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......55
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.4
Regulatory Reporting Requirements for SAE .............................................55
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest............................................................................56
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions......................................................................................56
8.4.9
Adverse Events on the VRC ........................................................................56
8.4.9.1
Solicited Adverse Event.....................................................................56
8.4.9.2
Unsolicited Adverse Events...............................................................57
8.5
Treatment of Overdose........................................................................................57
8.6
Pharmacokinetics.................................................................................................57
8.7
Pharmacodynamics..............................................................................................57
8.8
Biomarkers ...........................................................................................................57
8.9
Future Biomedical Research Sample Collection...............................................57
8.10
Medical Resource Utilization and Health Economics.......................................57
8.11
Visit Requirements...............................................................................................58
8.11.1
Screening......................................................................................................58
8.11.2
Treatment Period/Vaccination Visits...........................................................58
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................58
9
STATISTICAL ANALYSIS PLAN .............................................................................59
9.1
Statistical Analysis Plan Summary.....................................................................59
9.2
Responsibility for Analyses/In-house Blinding .................................................60
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9.3
Hypotheses/Estimation ........................................................................................60
9.4
Analysis Endpoints...............................................................................................60
9.4.1
Immunogenicity Endpoints..........................................................................60
9.4.2
Safety Endpoints..........................................................................................61
9.5
Analysis Populations............................................................................................62
9.5.1
Immunogenicity Analysis Populations ........................................................62
9.5.2
Safety Analysis Populations ........................................................................63
9.6
Statistical Methods...............................................................................................63
9.6.1
Statistical Methods for Immunogenicity Analyses......................................63
9.6.2
Statistical Methods for Safety Analyses ......................................................64
9.6.2.1
Overall Safety Assessment ................................................................64
9.6.3
Demographic and Baseline Characteristics .................................................65
9.7
Interim Analyses ..................................................................................................66
9.8
Multiplicity ...........................................................................................................66
9.9
Sample Size and Power Calculations .................................................................66
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................66
9.9.2
Sample Size and Power for Safety Analyses ...............................................67
9.10
Subgroup Analyses...............................................................................................67
9.11
Compliance (Medication Adherence).................................................................68
9.12
Extent of Exposure...............................................................................................68
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................69
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........69
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................69
10.1.2
Financial Disclosure.....................................................................................73
10.1.3
Data Protection.............................................................................................73
10.1.3.1
Confidentiality of Data ......................................................................73
10.1.3.2
Confidentiality of Participant Records...............................................73
10.1.3.3
Confidentiality of IRB/IEC Information............................................74
10.1.4
Committees Structure...................................................................................74
10.1.4.1
Executive Oversight Committee........................................................74
10.1.4.2
External Data Monitoring Committee ...............................................74
10.1.4.3
Scientific Advisory Committee (SAC)..............................................74
10.1.5
Publication Policy........................................................................................75
10.1.6
Compliance with Study Registration and Results Posting Requirements ...75
10.1.7
Compliance with Law, Audit, and Debarment ............................................75
10.1.8
Data Quality Assurance ...............................................................................76
10.1.9
Source Documents .......................................................................................77
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10.1.10
Study and Site Closure.................................................................................77
10.2
Appendix 2: Clinical Laboratory Tests..............................................................78
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................79
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................79
10.3.2
Definition of AE ..........................................................................................79
10.3.3
Definition of SAE ........................................................................................80
10.3.4
Additional Events Reported.........................................................................81
10.3.5
Recording AE and SAE ...............................................................................82
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................88
10.4.1
Definitions....................................................................................................88
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....89
10.5
Appendix 5: Contraceptive Guidance................................................................91
10.5.1
Definitions....................................................................................................91
10.5.2
Contraceptive Requirements........................................................................92
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements....................................................97
10.7.1
Country-specific Requirements for South Korea.........................................97
10.7.2
Country-specific Requirements for Japan....................................................97
10.8
Appendix 8: Abbreviations ...............................................................................100
11
REFERENCES.............................................................................................................104
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LIST OF TABLES
Table 1
Eligibility Based on KDIGO-recommended Stages of GFR and 
Albuminuria.....................................................................................................31
Table 2
Study Interventions..........................................................................................36
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................53
Table 4
Solicited Adverse Events .................................................................................57
Table 5
Analysis Strategy for Immunogenicity Variables............................................64
Table 6
Analysis Strategy for Safety Parameters..........................................................65
Table 7
Within-group 95% CIs for Varying Hypothetical OPA GMTs and Varying 
Standard Deviations.........................................................................................67
Table 8
Protocol-required Safety Laboratory Assessments..........................................78
Table 9
Blood Volumes Collected by Visit ..................................................................78
Table 10
Injection-site AE Overall Intensity Grading Scale ..........................................83
Table 11
Specific Systemic AE Overall Intensity Grading Scale...................................84
Table 12
Other Systemic AE Overall Intensity Grading Scale.......................................84
Table 13
Vital Sign (Temperature) Overall Intensity Grading Scale .............................84
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LIST OF FIGURES
Figure 1
Schema.........................................................................................................15
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind, Active Comparator-controlled 
Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in 
Pneumococcal Vaccine-naïve Adults 18 to 64 years of Age With Increased Risk for 
Pneumococcal Disease
Short Title: Safety and Immunogenicity of V116 in Adults With Increased Risk for 
Pneumococcal Disease
Acronym: STRIDE-8
Hypotheses, Objectives, and Endpoints:
There is no hypothesis testing in this study.
Objectives and endpoints described below will be evaluated in pneumococcal vaccine-naïve 
participants 18 to 64 years of age (inclusive) who are at increased risk for pneumococcal 
disease due to an underlying medical condition.
Primary Objectives
Primary Endpoints
To evaluate the safety and tolerability of 
V116 as assessed by the proportion of 
participants with adverse events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination.
•
Solicited systemic AEs from Day 1 
through Day 5 postvaccination.
•
Vaccine-related Serious Adverse Events 
(SAEs) from Day 1 through the duration 
of participation in the study.
To evaluate the serotype-specific 
opsonophagocytic activity (OPA) geometric 
mean titers (GMTs) postvaccination with 
V116 (30 days postvaccination [Day 30]) 
and PCV15 + PPSV23 (30 days 
postvaccination with the final dose in the 
regimen [Week 12]) within each 
vaccination group separately.
Serotype-specific OPA responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
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Secondary Objectives
Secondary Endpoints
To evaluate the serotype-specific 
Immunoglobulin G (IgG) geometric mean 
concentrations (GMCs) postvaccination 
with V116 (Day 30) and PCV15 + PPSV23 
(Week 12) within each vaccination group 
separately.
Serotype-specific IgG responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
To evaluate the serotype-specific geometric 
mean fold rises (GMFRs) and proportions 
of participants with a ≥4-fold rise from 
baseline (Day 1) to postvaccination with 
V116 (Day 30) and from baseline (Day 1) 
to postvaccination with PCV15 + PPSV23 
(Week 12) for both OPA and IgG responses 
within each vaccination group separately.
Serotype-specific OPA and IgG responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Pneumococcal vaccine-naïve adults 18 to 
64 years of age with increased risk for 
pneumococcal disease.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 14 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.
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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.
Number of Participants:
Approximately 500 participants will be randomized, with approximately 375 participants in 
the V116 group and 125 participants in the PCV15 + PPSV23 group.
Intervention Groups and Duration:
Arm 
Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Vaccination 
Regimen
Use
V116
Pneumococcal 
21-valent 
conjugate 
vaccine
4 µg of each PnPs 
antigen (3, 6A, 7F, 
8, 9N, 10A, 11A, 
12F, 15A, 15C, 
16F, 17F, 19A, 20, 
22F, 23A, 23B, 
24F, 31, 33F, and 
35B)
0.5 mL
IM
Single dose at 
Visit 2 (Day 1)
Test 
Product
V116
Placebo 
(sterile saline)
N/A
0.5 mL
IM
Single dose at 
Visit 5 (Week 8)
Placebo
PCV15 + 
PPSV23
Pneumococcal 
15-valent 
conjugate 
vaccine
2 µg of each PnPs 
antigen (1, 3, 4, 5, 
6A, 7F, 9V, 14, 
18C, 19A, 19F, 
22F, 23F, and 33F) 
and 4 µg of PnPs 
antigen 6B
0.5 mL
IM
Single dose at 
Visit 2 (Day 1)
Comparator
PCV15 + 
PPSV23
Pneumococcal 
vaccine, 
polyvalent 
(23-valent)
25 µg of each PnPs 
antigen (1, 2, 3, 4, 
5, 6B, 7F, 8, 9N, 
9V, 10A, 11A, 
12F, 14, 15B, 17F, 
18C, 19A, 19F, 20, 
22F, 23F, and 33F)
0.5 mL
IM
Single Dose at 
Visit 5 (Week 8)
Comparator
IM=intramuscular; PCV15=pneumococcal 15-valent conjugate vaccine; PnPs=pneumococcal polysaccharide; 
PPSV23=pneumococcal vaccine, polyvalent (23-valent).
Other current or former name(s) or alias(es) for study intervention(s) are as follows: V116, 
polyvalent pneumococcal conjugate vaccine (pPCV).
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Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
for approximately 6 months from the time 
the participant provides documented 
informed consent through the final contact.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Schema
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1.3
Schedule of Activities
Study Period:
Screening
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
8
Visit Type:
Visit
Visit
TC
Visit
Visit
TC
Visit
TC
Study Day:
Screening
Day 1
(Rand.
and 
Vac. 1)
Day 7
(after 
Vac. 1)
Day 30
(after 
Vac. 1)
Week 8
(Vac. 2)
Week 9
(Day 7 
after 
Vac. 2)
Week 12
(Day 30 
after 
Vac. 2)
Month 6
(after 
Vac. 1)
Visits 1 and 2 may 
occur on the same 
day (Section 8.11).
Visit Window:
NA
≤30 
days 
after 
Visit 1
Day 7 to 
Day 10
after 
Visit 2
Day 30 to 
Day 44 
after 
Visit 2
Day 60 to 
Day 74 
after 
Visit 2
Day 7 to 
Day 10 
after 
Visit 5
Day 30 to 
Day 44 
after 
Visit 5
Day 166 to 
Day 194
after
Visit 2
Informed Consent
X
Must be obtained 
before any study 
procedures are 
conducted. 
Informed Consent for 
Optional FBR
X
Must be obtained 
before any sample 
collection.
Assignment of Screening 
Number
X
Participant Identification 
Card
X
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
X
Prior/Concomitant 
Medication and Nonstudy 
Vaccination Review
X
X
X
X
X
X
X
X
Diagnostic Assessments
(if required)
X
Performed only if 
results required for
Inclusion Criterion 1
(Section 5.1) are not 
available.
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Study Period:
Screening
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
8
Visit Type:
Visit
Visit
TC
Visit
Visit
TC
Visit
TC
Study Day:
Screening
Day 1
(Rand.
and 
Vac. 1)
Day 7
(after 
Vac. 1)
Day 30
(after 
Vac. 1)
Week 8
(Vac. 2)
Week 9
(Day 7 
after 
Vac. 2)
Week 12
(Day 30 
after 
Vac. 2)
Month 6
(after 
Vac. 1)
Visits 1 and 2 may 
occur on the same 
day (Section 8.11).
Visit Window:
NA
≤30 
days 
after 
Visit 1
Day 7 to 
Day 10
after 
Visit 2
Day 30 to 
Day 44 
after 
Visit 2
Day 60 to 
Day 74 
after 
Visit 2
Day 7 to 
Day 10 
after 
Visit 5
Day 30 to 
Day 44 
after 
Visit 5
Day 166 to 
Day 194
after
Visit 2
Assignment of 
Randomization Number
X
V116 or PCV15
Administration (blinded)
X
Placebo or PPSV23 
Administration (blinded)
X
Provide Electronic Device 
or Configure Participant’s 
Own Electronic Device for 
eVRC Data Collection
X
Review eVRC Data With 
Participant
X
X
X
X
Collect Electronic Device 
From Participants Who 
Received an Electronic 
Device
X
Complete Telephone 
Contact Questionnaire
X
Safety Procedures
Complete Physical 
Examination
X
Performed by 
investigator or 
medically qualified 
designee before 
vaccination.
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Study Period:
Screening
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
8
Visit Type:
Visit
Visit
TC
Visit
Visit
TC
Visit
TC
Study Day:
Screening
Day 1
(Rand.
and 
Vac. 1)
Day 7
(after 
Vac. 1)
Day 30
(after 
Vac. 1)
Week 8
(Vac. 2)
Week 9
(Day 7 
after 
Vac. 2)
Week 12
(Day 30 
after 
Vac. 2)
Month 6
(after 
Vac. 1)
Visits 1 and 2 may 
occur on the same 
day (Section 8.11).
Visit Window:
NA
≤30 
days 
after 
Visit 1
Day 7 to 
Day 10
after 
Visit 2
Day 30 to 
Day 44 
after 
Visit 2
Day 60 to 
Day 74 
after 
Visit 2
Day 7 to 
Day 10 
after 
Visit 5
Day 30 to 
Day 44 
after 
Visit 5
Day 166 to 
Day 194
after
Visit 2
Directed Physical 
Examination
X
Performed by 
investigator or 
medically qualified 
designee before 
vaccination.
Pregnancy Test
(if applicable)
X
X
POCBP must have a 
negative urine or 
serum test 
(consistent with 
local requirements 
and sensitive to 
≤25 IU hCG) result 
before each 
vaccination.
Prevaccination Body 
Temperature Measurement
X
X
Reschedule if 
participant has 
febrile illness within 
72 hours before 
vaccination.
Postvaccination 
Observation Period
X
X
Observed by blinded 
study-site personnel 
for at least 
30 minutes 
postvaccination.
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Study Period:
Screening
Intervention and Follow-up
Notes
Visit Number:
1
2
3
4
5
6
7
8
Visit Type:
Visit
Visit
TC
Visit
Visit
TC
Visit
TC
Study Day:
Screening
Day 1
(Rand.
and 
Vac. 1)
Day 7
(after 
Vac. 1)
Day 30
(after 
Vac. 1)
Week 8
(Vac. 2)
Week 9
(Day 7 
after 
Vac. 2)
Week 12
(Day 30 
after 
Vac. 2)
Month 6
(after 
Vac. 1)
Visits 1 and 2 may 
occur on the same 
day (Section 8.11).
Visit Window:
NA
≤30 
days 
after 
Visit 1
Day 7 to 
Day 10
after 
Visit 2
Day 30 to 
Day 44 
after 
Visit 2
Day 60 to 
Day 74 
after 
Visit 2
Day 7 to 
Day 10 
after 
Visit 5
Day 30 to 
Day 44 
after 
Visit 5
Day 166 to 
Day 194
after
Visit 2
AE Monitoring
X
X
X
X
X
X
X
X
Nonserious AEs 
collected through 
30 days after each 
vaccination; SAEs 
and deaths collected 
through duration of 
study participation.
Immunogenicity Procedures
Serum for 
Immunogenicity Assays
X
X
X
Visit 2 sample 
should be collected 
before vaccination.
Future Biomedical Research
Blood (DNA) for FBR
X
For participants who 
provided FBR 
consent, sample 
should be collected 
before vaccination 
at Visit 2, or at a 
later date as long as 
FBR consent is 
obtained before 
collection.
AE=adverse event; DNA=deoxyribonucleic acid; eVRC=electronic vaccination report card; FBR=future biomedical research; hCG=human chorionic gonadotropin; 
IU=international units; NA=not applicable; PCV15=pneumococcal 15-valent conjugate vaccine; POCBP= participants of childbearing potential; PPSV23=pneumococcal 
vaccine, polyvalent (23-valent); SAE=serious adverse event; Rand.=randomization; TC=telephone contact; Vac.=vaccination.
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2
INTRODUCTION
The Sponsor is developing an investigational polyvalent pneumococcal 21 valent conjugate 
vaccine (V116) for the prevention of pneumococcal disease caused by the serotypes in the 
vaccine.
2.1
Study Rationale
Streptococcus pneumoniae is a major cause of vaccine-preventable disease worldwide. It is 
associated with considerable morbidity and mortality, with the highest burden in children 
<5 years and adults >70 years of age [Troeger, C., et al 2018]. Vaccines directed against 
S pneumoniae have reduced the incidence of disease caused by vaccine serotypes in the age 
groups being vaccinated (primarily children <5 years of age in most countries), and have 
reduced vaccine-type disease in other age groups, called an indirect effect.
An unmet medical need exists as there remains a substantial burden of disease in adults due 
to serotypes not currently included in licensed pneumococcal vaccines. V116 is an 
investigational PCV designed to address this unmet need and includes S pneumoniae
serotypes not included in licensed pneumococcal vaccines, accounting for the majority of 
IPD currently observed in adults.
Vaccination guidelines generally categorize individuals as having increased risk or high risk
for pneumococcal disease. The category of increased risk refers to those individuals with 
underlying chronic conditions such as diabetes, heart disease, kidney disease, liver disease, 
lung disease (including COPD and asthma), smoking, and heavy alcohol consumption. These 
individuals are at increased risk for pneumococcal disease and its complications; the 
incidence rates of IPD are 2- to 8-fold higher in persons with chronic illnesses relative to
healthy individuals, and rates increase with the number of conditions present [Kyaw, M. H., 
et al 2005] [Weycker, D., et al 2016] [Curcio, D., et al 2015] [Morton, J. B., et al 2017] 
[Torres, A., et al 2015]. The concern for this population is underscored by the high 
prevalence of several of these conditions in the adult population, with heart disease, lung 
disease, and diabetes ranked as some of the top causes of death and disability globally [GBD 
2019 Diseases and Injuries Collaborators 2020] [Ward, B. W., et al 2014] [Centers for 
Medicare and Medicaid Services 2022].
Recommendations for vaccination can vary for each risk condition, and can also vary by 
country/region. In the most recent updates to recommendations (October 2021), the US ACIP 
recommends pneumococcal vaccination either with a sequential regimen of PCV15 followed 
by PPSV23 or with a single dose of PCV20 for adults 19 to 64 years of age with chronic 
medical conditions or immunocompromising conditions that confer an increased risk of 
pneumococcal disease [Kobayashi, M., et al 2022]. Many other countries and regions follow 
similar recommendations (sequential regimen of PCV13 followed by PPSV23 or PPSV23 
alone) for adults with certain conditions at increased risk of pneumococcal disease [Castiglia 
P. 2014] [Bonnave, C., et al 2019].
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Adults at increased risk for pneumococcal disease due to underlying conditions may benefit 
from receiving V116, as V116 has broader protection against pneumococcal disease
compared with currently licensed pneumococcal vaccines.
This clinical study is designed to evaluate the safety, tolerability, and immunogenicity of a 
single dose of V116 in pneumococcal vaccine-naïve individuals at increased risk for 
pneumococcal disease due to diabetes mellitus, chronic heart disease, chronic kidney disease, 
chronic liver disease, and chronic lung disease.
2.2
Background
To date, a Phase 1/2 study (V116-001) and a Phase 1 study in Japan (V116-002) have been 
conducted with V116 in pneumococcal vaccine-naïve adults. Results from the Phase 1 part of 
V116-001 were used to select the vaccine formulation for subsequent development. Results 
from both studies showed that V116 is immunogenic and has acceptable safety and 
tolerability in healthy adults. Refer to the IB for detailed background information on V116.
2.2.1
Pharmaceutical and Therapeutic Background
Pneumococcal disease (disease caused by S pneumoniae) is one of the single largest 
vaccine-preventable causes of death in children and older adults (≥65 years of age) 
worldwide. PCV use in children has decreased the incidence of disease caused by vaccine 
serotypes and has led to indirect protection in unvaccinated individuals from other age 
groups. This has resulted in a decrease in hospital admissions for pneumococcal disease in 
adults ≥65 years of age, including estimated decreases of 29% and 34% in admissions due to 
IPD and noninvasive pneumococcal pneumonia, respectively [Simonsen, L., et al 2014]. In 
some countries, including the US, the decrease in pneumococcal disease in children 
vaccinated with PCV has led to the recommendation to vaccinate adults with PCVs. 
However, surveillance data over the last 5 years does not definitively indicate that the use of 
PCVs in adults results in a similar reduction in pneumococcal disease after recent vaccination 
efforts and public health initiatives [Matanock, A. 2018]. There is a residual burden of 
disease in the US that is estimated at 1.8, 16.6, and 24 cases of IPD per 100,000 in adults 18 
to 49, 50 to 64, ≥65 years of age, respectively, and surveillance data estimates that serotypes 
included in PCVs licensed during this time account for approximately 23% to 50% of these 
cases [Centre for Disease Control and Prevention 2016] [Centers for Disease Control and 
Prevention 2019] [Kobayashi, M., et al 2022] [Zhang, D., et al 2018]. This elevated risk in 
adults results in a substantial clinical and economic burden to public health.
This residual burden of disease in adults reflects the difference in serotype distribution in 
adults compared with infants and children. An increasing incidence of disease due to 
serotypes not included in the licensed PCVs has been observed, particularly in adults [Miller, 
Elizabeth, et al 2011] [Moore, M. R., et al 2015] [Pilishvili, T. 2015] [van der Linden, M., et 
al 2015] [Golden, A. R., et al 2016]. Increases in IPD cases due to nonvaccine serotypes (3, 
7F, and 19A after implementation of PCV7; 22F and 33F after widespread usage of PCV13) 
have been observed in both pediatric and older adult (≥65 years of age) populations in the US 
[Hicks, L. A., et al 2007] [Pilishvili, Tamara, et al 2010] [Waight, P. A., et al 2015] [Moore, 
M. R., et al 2015] [Demczuk, W. H. B., et al 2013]. Similarly, in the EU, serotype 
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replacement due to nonvaccine serotypes is being observed in older adults and may decrease 
the potential additional benefit of vaccination with currently available PCVs [European 
Center for Disease Prevention and Control 2018].
Serotypes were selected for inclusion in V116 based, in part, on available global 
epidemiology data with a primary focus on older adults (≥65 years of age) in the US and EU, 
regions with an established pediatric vaccination program. V116 includes serotypes that are 
the largest contributors to adult residual disease, including select serotypes from PPSV23, 
PCV13, PCV15, and PCV20, as well as unique serotypes not included in any licensed 
pneumococcal vaccine. The V116 serotypes are responsible for >80% of adult IPD in the US, 
Germany, France, Canada, and Japan, approximately 90% of IPD in the UK, and 
approximately 70% of IPD in Australia, based on data from 2018 [Public Health Agency of 
Canada 2018] [Demczuk, W. H. B., et al 2018] [Public Health England 2021] [Public Health 
England 2021] [van der Linden, M., et al 2019] [Batah, J. 2018] [National Institute of 
Infectious Diseases 2018] [Nakano, S., et al 2016]. In 2019, the most recent year for which 
serotype-specific data are available in both the EU and US, the serotypes in V116 accounted 
for 82% and 85% of IPD, respectively, in adults ≥65 years [European Centre for Disease 
Prevention and Control 2022] (Centers for Disease Control and Prevention, IPD serotype 
data 2019, as compiled from data provided through Active Bacterial Core surveillance 
[ABCs]).
V116 is designed to target serotypes that account for the majority of IPD in adults, including 
serotypes not currently contained in any licensed pneumococcal vaccine, thereby addressing 
the unmet medical need of preventing residual pneumococcal disease in adults. It is being 
developed to support an indication for active immunization for the prevention of invasive 
disease and pneumonia caused by S pneumoniae serotypes 3, 6A, 6C, 7F, 8, 9N, 10A, 11A, 
12F, 15A, 15B, 15C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, and 35B in adults 
18 years of age and older. Note that serotype 15C represents deOAc15B as the molecular 
structures for deOAc15B and 15C are similar.
2.2.2
Information on Other Study-related Therapy
2.2.2.1
PCV15
Refer to approved labeling for detailed background information on PCV15.
PCV15 is a pneumococcal conjugate vaccine that includes 15 serotypes (1, 3, 4, 5, 6A, 6B,
7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) individually conjugated to the CRM197 and
formulated with aluminum phosphate adjuvant.
2.2.2.2
PPSV23
Refer to approved labeling for detailed background information on PPSV23.
PPSV23 is comprised of the polysaccharides from 23 of the serotypes causing disease in 
adults (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 
22F, 23F, and 33F). The formulation is not adjuvanted and no carrier protein is used.
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2.2.2.3
Pneumococcal Vaccination Guidelines
Many countries have implemented age-based and/or risk-based recommendations for 
pneumococcal vaccination of adults. Age-based recommendations typically start at 65 years 
of age due to the increased risk of pneumococcal disease associated with age.
Two expanded valent PCVs (PCV15 and PCV20) have been recently approved in the US, 
EU, and elsewhere. In the US, the ACIP updated their vaccination guidelines to recommend 
that adults ≥65 years of age should receive either PCV15 followed by PPSV23, or PCV20 
alone [Kobayashi, M., et al 2022]. It is expected that, globally, vaccination guidelines will be 
updated to include these newer PCVs. However, PCV13 and PPSV23 are currently the 2 
most broadly available vaccines in the majority of countries in the EU and other countries 
outside the US. While there is variability in the vaccination guidelines, PPSV23 alone, and 
PCV13 followed by PPSV23 are the 2 most common regimens recommended in European 
countries that have age-based guidelines for adults [European Centre for Disease Prevention 
and Control 2021] [Bonnave, C., et al 2019]. Despite national vaccination guidelines and 
recommendations from institutions such as the European Council and the World Coalition on 
Adult Vaccination, surveys have estimated that only 20% to 30% of adults ≥65 years of age 
in Europe are currently vaccinated [Independent Polling System Of Society 2017].
Recommendations generally address vaccination of individuals who have an increased risk of 
pneumococcal disease, with the level of risk categorized based on the underlying condition. 
Conditions associated with increased risk include, but are not limited to, diabetes mellitus, 
chronic heart disease, chronic liver disease (including cirrhosis), chronic lung disease 
(including COPD and asthma), chronic kidney disease (without kidney failure), alcoholism, 
and cigarette smoking. Conditions associated with the highest risk include, but are not 
limited to, congenital or acquired asplenia, sickle cell disease/other hemoglobinopathies, 
chronic kidney failure, congenital or acquired immunodeficiencies, generalized malignancy, 
hematologic malignancy, HIV infection, nephrotic syndrome, solid organ transplant, and 
hematopoietic stem cell transplant [Kobayashi, M., et al 2022]. Vaccination 
recommendations for these groups with increased risk or high risk vary across countries.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Despite the public health impact of currently available pneumococcal vaccines, 
pneumococcal disease in adults remains a significant unmet medical need. S pneumoniae is a 
major cause of vaccine-preventable disease worldwide, resulting in considerable morbidity 
and mortality [Troeger, C., et al 2018].
Vaccination with PCVs has reduced the incidence of disease caused by vaccine serotypes in 
the population targeted by the vaccination (primarily children <5 years of age in most 
countries) and has had an indirect effect in other age groups. However, in several countries, 
infant vaccination with PCVs has also led to increases in IPD due to serotypes not included 
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in the licensed PCVs, particularly in adults. This has resulted in an unmet medical need in 
this population.
V116 is designed to provide substantially broader pneumococcal disease coverage in adults 
as compared with currently licensed pneumococcal vaccines and is anticipated to have a 
generally comparable safety profile. Clinically important safety findings have not been 
identified to date based on data from early phase clinical studies with V116.
The benefit-risk profile for V116 supports continued evaluation.
In this study, approximately 25% of participants will receive PCV15 followed by PPSV23, a 
vaccine regimen recommended for the prevention of pneumococcal disease in vaccine-naïve 
adults 19 to 64 years of age with certain underlying medical conditions for pneumococcal 
disease [Kobayashi, M., et al 2022]. V116 is expected to provide immune responses 
comparable to PCV15+PPSV23 for the common serotypes in both regimens while providing 
additional coverage for the serotypes unique to V116. It is unknown if the investigational 
V116 will have the same clinical benefit as PCV15+PPSV23.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no hypothesis testing in this study.
Objectives and endpoints described below will be evaluated in pneumococcal vaccine-naïve 
participants 18 to 64 years of age (inclusive) who are at increased risk for pneumococcal 
disease due to an underlying medical condition.
Primary Objectives
Primary Endpoints
To evaluate the safety and tolerability of 
V116 as assessed by the proportion of 
participants with adverse events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination.
•
Solicited systemic AEs from Day 1 
through Day 5 postvaccination.
•
Vaccine-related Serious Adverse 
Events (SAEs) from Day 1 through the 
duration of participation in the study.
To evaluate the serotype-specific 
opsonophagocytic activity (OPA) geometric 
mean titers (GMTs) postvaccination with 
V116 (30 days postvaccination [Day 30]) 
and PCV15 + PPSV23 (30 days 
postvaccination with the final dose in the 
regimen [Week 12]) within each vaccination 
group separately.
Serotype-specific OPA responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
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Secondary Objectives
Secondary Endpoints
To evaluate the serotype-specific 
Immunoglobulin G (IgG) geometric mean 
concentrations (GMCs) postvaccination with 
V116 (Day 30) and PCV15 + PPSV23 
(Week 12) within each vaccination group 
separately.
Serotype-specific IgG responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
To evaluate the serotype-specific geometric 
mean fold rises (GMFRs) and proportions of 
participants with a ≥4-fold rise from baseline 
(Day 1) to postvaccination with V116 (Day 
30) and from baseline (Day 1) to 
postvaccination with PCV15 + PPSV23 
(Week 12) for both OPA and IgG responses 
within each vaccination group separately.
Serotype-specific OPA and IgG responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the ratios of serotype-specific 
OPA GMTs and IgG GMCs postvaccination 
with V116 (Day 30) compared with PCV15 
+ PPSV23 (Week 12).
Serotype-specific OPA and IgG responses:
•
13 serotypes common between V116 
and PCV15 + PPSV23.
•
8 serotypes unique to V116.
To evaluate the cross-reactive immune 
responses to serotypes within a serogroup 30 
days postvaccination.
Serotype-specific OPA and IgG responses.
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multisite, double-blind 
study of V116 in adults 18 to 64 years of age with increased risk for pneumococcal disease.
Approximately 500 participants who have not previously received any pneumococcal 
vaccines other than routine childhood PCVs (vaccine naïve) will be randomized in a 3:1 ratio 
to receive either V116 on Day 1 followed by placebo at Week 8, or PCV15 on Day 1 
followed by PPSV23 at Week 8. Randomization will be stratified by age at time of 
randomization (18 to 49 years and 50 to 64 years) and the type/number of increased-risk 
conditions for pneumococcal disease (diabetes mellitus only, chronic heart disease only, 
chronic kidney disease only, chronic liver disease only, chronic lung disease only, and 
≥2 increased-risk conditions). At least 20% of participants will be 18 to 49 years of age. For 
participants with a single increased-risk condition, it is expected that at least 5% of 
participants with each individual condition will be enrolled.
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Participants must be on stable treatment for their risk condition for ≥3 months with no
anticipated major change in treatment expected during the study, with a maximum of 
1 hospitalization directly related to the risk condition within 3 months before the first study 
vaccination.
An eVRC will be used by all participants to record solicited injection-site AEs, solicited 
systemic AEs, and daily body temperature from Day 1 through Day 5 following each 
vaccination. Unsolicited AEs will be collected through Day 30 following each vaccination. 
All participants will be provided an electronic device or have their own electronic device 
configured, if compatible, to complete the eVRC.
Blood samples for immunogenicity assays will be drawn on Day 1 (Visit 2), Day 30 (Visit 4), 
and at Week 12 (Visit 7).
Information for SAEs and deaths, regardless of whether the events are considered to be 
vaccine related by the investigator, will be collected through completion of participation in 
the study.
An external DMC will conduct a periodic review of safety and tolerability data for the V116 
Phase 3 program. A description of the structure and function of the DMC, along with the 
timing and content of the safety reviews, will be outlined in the DMC charter. Information 
regarding the composition of the DMC is provided in Appendix 1.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will evaluate the safety, tolerability, and immunogenicity of V116 in 
vaccine-naïve adults 18 to 64 years of age at increased risk for pneumococcal disease. 
Adults with stable chronic medical conditions, including diabetes mellitus, chronic heart 
disease, chronic kidney disease, chronic liver disease, and chronic lung disease will be 
included in this study. These individuals are at 2- to 8-fold increased risk for pneumococcal 
disease relative to healthy adults [Kyaw, M. H., et al 2005] [Weycker, D., et al 2016] 
[Curcio, D., et al 2015] [Morton, J. B., et al 2017] [Torres, A., et al 2015]. As it is expected 
that the number of participants enrolled with each risk condition will vary, this study will be 
stratified by the type and number or risk conditions to ensure balance between the 
intervention group.
The randomization ratio of 3:1 was chosen to increase the number of participants exposed to 
V116 to expand the V116 safety and immunogenicity data in a population at increased risk 
for pneumococcal disease.
Individuals with severe or end-stage heart, liver, lung, or kidney disease, and those with 
uncontrolled diabetes will be excluded from this study to allow them to prioritize their 
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medical care over participation in this study and to avoid confusion of medical treatment 
effects with the safety and immunogenicity of the vaccine.
Individuals 50 to 64 years of age have been included in this study as older adults with 
chronic underlying disease are at even greater risk for pneumococcal disease and its 
associated morbidity and mortality as the incidence of IPD is directly related to age, with 
over half of all cases occurring in adults ≥50 years of age [Drijkoningen, J. J 2014] [Imai, K., 
et al 2018].
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating PCVs.
Sera from participants will be used to assess vaccine-induced, anti-PnPs, serotype-specific 
OPA and IgG responses using the validated MOPA and Pn ECL assay, respectively. 
Immunogenicity endpoints will be evaluated for all serotypes included in V116 and for 
cross-reactive serotypes within a serogroup.
Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. OPA assesses 
levels of functional antibodies capable of opsonizing pneumococcal capsular polysaccharides 
for presentation to phagocytic cells for engulfment and subsequent killing; therefore, it is 
considered an important immunologic surrogate for protection against IPD in adults. It is 
noted that IgG antibody concentration and OPA titer threshold values that correlate with 
protection in adults have not been defined; however, OPA responses are considered an 
accepted endpoint for the evaluation of novel pneumococcal vaccines in adults.
The OPA GMT, IgG GMC, GMFR, and proportion of participants with a 4-fold rise in OPA 
and IgG responses are acceptable assessments used to evaluate novel PCVs.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
4.2.1.2
Safety Endpoints
Safety information will be collected from all participants on an eVRC. The eVRC used to 
record AEs during the postvaccination periods (Section 8.1.9) is structured as recommended 
in the final US FDA Patient-reported Outcome Guidance [U.S. Food and Drug 
Administration 2009].
The safety endpoints (ie, AEs and temperature) evaluated in this study are consistent with 
previous studies of V116 and published data from marketed PCVs. Detailed information for 
the safety endpoints evaluated in this study can be found in Section 9.4.2.
Definitions and reporting requirements for AEs are provided in Appendix 3.
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4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebo-controlled clinical studies for new PCVs are no longer practical given the proven 
clinical efficacy and widespread use of licensed pneumococcal vaccines worldwide.
The sequential regimen of a PCV followed by PPSV23 8 weeks later is recommended in 
many countries for individuals at increased risk for pneumococcal disease [Kobayashi, M., et 
al 2022] [Robert Koch Institut 2017]. Of the approved pneumococcal vaccines, the sequential 
regimen of PCV15 followed by PPSV23 (PCV15+PPSV23) 1 year later for individuals at 
increased risk for pneumococcal disease is consistent with US ACIP recommendations 
[Kobayashi, M., et al 2022] and has the broadest coverage against S pneumoniae serotypes. It 
is expected that many global vaccination guidelines will include this regimen of 
PCV15+PPSV23.
The sequential regimen of PCV15 + PPSV23 has 13 serotypes in common with V116: 
6 serotypes (3, 6A, 7F, 19A, 22F, and 33F) contained in PCV15 and 7 serotypes (8, 9N, 10A, 
11A, 12F, 17F, and 20) contained in PPSV23 but not included in PCV15. V116 contains 
8 unique serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31, and 35B) not included in any 
licensed pneumococcal vaccine. Note that serotype 15C represents deOAc15B as the 
molecular structures for deOAc15B and 15C are similar.
Placebo is used in this study to maintain blinding. The placebo is sterile saline for injection.
4.3
Justification for Dose
The V116 dose of 4 µg/each PnPs was selected based on review of safety and 
immunogenicity data from the Phase 1 and Phase 2 studies. In Phase 1, 2 doses of V116 were 
evaluated: a single dose containing 2 µg/each PnPs and a single dose of 4 µg/each PnPs. 
Based on the data from Phase 1, the V116 dose of 4 µg/each PnPs was selected for further 
evaluation in Phase 2. Results from Phase 2 showed that the V116 dose of 4 µg/each PnPs is 
well tolerated and generates serotype-specific immune responses. These data support the 
selection of the V116 dose of 4 µg/each PnPs for further development in Phase 3.
Refer to the IB for detailed background information on V116.
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The doses of PCV15 and PPSV23 selected for use in this study are the approved doses that 
are consistent with the approved US and EU dosing and product labeling of 
VAXNEUVANCE™ and PNEUMOVAX™23, respectively.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 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 as described in Appendix 1.10.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), 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 and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Documented result(s) of ≥1 of the following risk conditions for pneumococcal disease
(Participants who are living with ≥2 increased-risk conditions listed below must meet the 
respective diagnostic criteria for each condition to be eligible for enrollment):
•
Diabetes mellitus, receiving treatment with ≥1 approved antidiabetic medication, with 
all HbA1c measurements ≤9% within 6 months before first study vaccination
(Day 1).
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•
Compensated chronic liver disease. Participants must meet ≥1 of the following:
-
Laboratory-confirmed FIB-4 score of ≥1.45 within 6 months before first study 
vaccination (Formula: age [years] x AST [IU/L]/platelet count [109/L] x ALT1/2
[IU/L]) [World Health Organization 2018].
-
Laboratory-confirmed APRI of >0.5 within 6 months before first study 
vaccination (APRI formula: AST ÷ laboratory ULN for AST x 100 ÷ [platelet 
count ÷ 100]).
-
Prior FibroTest® (FibroSure®) with Fibrosis Score >0.25 performed within 
5 years before first study vaccination (Day 1). 
-
Prior imaging (including FibroScan® with interpretable score >7 kPa) showing 
cirrhosis and/or fibrosis within 5 years before first study vaccination (Day 1).
-
Prior biopsy showing cirrhosis and/or fibrosis within 5 years before first study 
vaccination (Day 1).
•
Diagnosis of COPD managed per local guidelines, and confirmed based on ≥1 of the 
following:
-
Spirometric data in the 5 years before first study vaccination (Day 1) showing 
postbronchodilator FEV1/FVC ratio <0.7 and FEV1 ≥30% predicted, 
corresponding to spirometric Global Initiative for Chronic Obstructive Lung 
Disease Stage 1 to 3 by severity assessment [Global Initiative for Chronic 
Obstructive Lung Disease 2019].
-
A postbronchodilator improvement in PEFR by <20% performed in the 5 years 
before first study vaccination (Day 1) based on WHO PEN Disease Interventions 
for Primary Health Care (2020) [World Health Organization 2020].
•
Diagnosis of mild or moderate persistent asthma managed per local guidelines, and 
confirmed based on ≥1 of the following:
-
Documented reversible airflow obstruction on spirometry consistent with 
guidelines for the diagnosis of asthma performed within 5 years before first study 
vaccination (Day 1). 
-
A postbronchodilator improvement in PEFR by ≥20% in the 5 years before first 
study vaccination (Day 1), based on WHO PEN Disease Interventions for Primary 
Health Care (2020) [World Health Organization 2020].
•
Confirmed diagnosis of chronic heart disease managed per local guidelines,
including: 
-
Cardiomyopathies documented within 5 years before first study vaccination 
(Day 1)
-
Congestive heart failure documented within 5 years before first study vaccination 
(Day 1)
-
Noncyanotic congenital heart disease.
•
Confirmed diagnosis of chronic kidney disease (>3 months duration) in 1 of the 
eligible KDIGO-recommended stages of GFR AND albuminuria categories [Kidney 
Disease: Improving Global Outcomes 2013] specified in Table 1 within 6 months 
before first study vaccination (Day 1)
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Table 1
Eligibility Based on KDIGO-recommended Stages of GFR and Albuminuria
Albuminuria
A1
A2
A3
GFR
(mL/min/1.73 m2)
<3 mg/mmol or 
<30 mg/g
3 to 30 mg/mmol or
30 to 300 mg/g
>30 mg/mmol or 
>300 mg/g
G1
≥90
Not eligible
Eligible
Not eligible
G2
60 to 89
Eligible
G3a
45 to 59
G3b
30 to 44
Not eligible
Not eligible
G4
15 to 29
G5
<15
GFR=glomerular filtration rate.
Note: Diagnostic assessments specified above may be conducted if not available in 
medical records.
2. Receiving stable medical management for the risk conditions listed in Inclusion 
Criterion 1 for ≥3 months with no anticipated major change in treatment expected for the 
duration of the study and with ≤1 hospitalization directly related to the risk condition 
within 3 months before first study vaccination (Day 1).
Note: The participant may have other comorbidities if they are assessed to be stable as 
per the investigator’s judgment.
Demographics
3. Is an individual of any sex/gender, from 18 years to 64 years of age inclusive, at the time 
of providing informed consent.
Female Participants
4. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
-
Is not a POCBP
OR
-
Is a POCBP and:
◦
Uses an acceptable contraceptive method or is abstinent from penile-vaginal
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and 
for at least 6 weeks after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention. 
Contraceptive use by POCBPs should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
If the contraception requirements in the local label for any of the study 
interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
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◦
Has a negative highly sensitive pregnancy test (urine or serum as required by 
local regulations) within 24 hours 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. Additional requirements for 
pregnancy testing during and after study intervention are in Section 8.3.2.
◦
Medical history, menstrual history, and recent sexual activity has been reviewed 
by the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
6. The participant has the ability to complete eVRC data collection without assistance based 
on judgment of the investigator.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a history of active hepatitis with elevation in pretreatment AST or ALT values 
>5 times ULN within 3 months before first study vaccination (Day 1) 
2. Has a history of diabetic ketoacidosis or 2 or more episodes of severe, symptomatic 
hypoglycemia within 3 months before first study vaccination (Day 1).
3. Has a history of myocardial infarction, acute coronary syndrome, transient ischemic 
attack, or ischemic or hemorrhagic stroke within 3 months before first study vaccination 
(Day 1).
4. Has a history of severe pulmonary hypertension with WHO functional class ≥3 or history 
of Eisenmenger syndrome.
5. Has a history of autoimmune related chronic kidney disease, chronic kidney failure, a 
reversible cause of kidney disease, nephrotic syndrome, or any ineligible 
KDIGO-recommended stage of GFR AND Albuminuria specified in Table 1.
6. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or 
positive culture at another sterile site) or known history of other culture-positive 
pneumococcal disease within 3 years before first study vaccination (Day 1).
7. Has a known hypersensitivity to any component of V116, PCV15, or PPSV23, including 
diphtheria toxoid.
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8. Has a known or suspected impairment of immunological function including, but not 
limited to, congenital or acquired immunodeficiency, documented HIV infection, 
functional or anatomic asplenia, or autoimmune disease (including, but not limited to, the 
autoimmune conditions outlined in the Investigator Trial File Binder for this study).
9. Has a coagulation disorder contraindicating IM vaccination.
10. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4 °F 
[≥38.0 °C] or axillary or temporal temperature ≥99.4 °F [≥37.4 °C]) or received antibiotic 
therapy for any acute illness occurring within 72 hours before receipt of any study 
vaccine.
11. Has a known malignancy that is progressing or has required active treatment <3 years 
before randomization. Note: Participants with basal cell and/or squamous cell carcinoma 
of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
12. Planned organ transplantation (heart, liver, lung, kidney, or pancreas) or other planned 
major surgical procedure during the duration of this study.
13. Expected survival for <1 year according to the investigator’s judgment.
Prior/Concomitant Therapy
14. Received any prior pneumococcal vaccine or is expected to receive any pneumococcal 
vaccine during the study outside the protocol. Exception: participants with childhood 
pneumococcal vaccination before the age of 5 will be permitted.
15. *Received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed intervention ≥14 days before receipt of 
study vaccine at Visit 2 (Day 1). Note: Physiologic replacement doses (prednisone 
equivalent of approximately 5 mg/day), topical, ophthalmic, intraarticular or soft-tissue 
(eg, bursa, tendon steroid injections), and inhaled/nebulized steroids are permitted.
16. Is currently receiving systemic immunosuppressive therapy, including chemotherapeutic 
agents or other immunotherapies/immunomodulators used to treat cancer or other 
conditions, and interventions associated with organ or bone marrow transplantation, or 
autoimmune disease.
17. *Received any nonlive vaccine ≤14 days before receipt of any study vaccine or is 
scheduled to receive any nonlive vaccine ≤30 days after receipt of any study vaccine. 
Exception: Inactivated influenza vaccine and SARS-CoV-2 mRNA or SARS-CoV-2
protein subunit vaccine may be administered but must be given ≥7 days before or 
≥15 days after receipt of any study vaccine.
18. *Received any live virus vaccine (including SARS-CoV-2 live virus vaccines) ≤30 days 
before receipt of any study vaccine or is scheduled to receive any live virus vaccine 
≤30 days after receipt of any study vaccine.
19. Received a blood transfusion or blood products, including immunoglobulin ≤6 months 
before receipt of any study vaccine or is scheduled to receive a blood transfusion or blood 
product ≤30 days after receipt of any study vaccine. Autologous blood transfusions are 
not considered an exclusion criterion.
20. Receiving chronic home oxygen therapy.
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Prior/Concurrent Clinical Study Experience
21. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Diagnostic Assessments
Not applicable.
Other Exclusions
22. In the opinion of the investigator, has a history of clinically relevant drug or alcohol use 
that interfere with participation in protocol-specified activities.
23. Has history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
24. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For Exclusion Criteria with an asterisk (*), if the participant meets these exclusion 
criteria, Visit 2 may be rescheduled for a time when these criteria are not met.
Country-specific criteria are included in Appendix 7.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
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.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (V116, PCV15, PPSV23, and placebo) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
V116
Experimental
Pneumococcal 
21-valent 
conjugate 
vaccine
Biological/
Vaccine
Injection, 
Solution
4 µg of each PnPs 
antigen (3, 6A, 
7F, 8, 9N, 10A, 
11A, 12F, 15A, 
15C, 16F, 17F, 
19A, 20, 22F, 
23A, 23B, 24F, 
31, 33F, and 35B)
0.5 mL
IM
Single dose 
at Visit 2
(Day 1)
Test 
Product
IMP
Central
V116
Experimental
Placebo 
(sterile saline)
Biological/
Vaccine
Injection, 
Solution
N/A
0.5 mL
IM
Single dose 
at Visit 5
(Week 8)
Placebo
IMP
Central or 
local
PCV15 
+ 
PPSV23
Active 
Comparator
Pneumococcal 
15-valent 
conjugate 
vaccine
Biological/
Vaccine
Injection, 
Suspension
2 µg of each PnPs 
antigen (1, 3, 4, 5, 
6A, 7F, 9V, 14, 
18C, 19A, 19F, 
22F, 23F, and 
33F) and 4 µg of 
PnPs antigen 6B
0.5 mL
IM
Single dose 
at Visit 2
(Day 1)
Comparator IMP
Central or 
local
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Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
PCV15 
+ 
PPSV23
Active 
Comparator
Pneumococcal 
vaccine, 
polyvalent (23-
valent)
Biological/
Vaccine
Injection, 
Solution
25 µg of each 
PnPs antigen (1, 
2, 3, 4, 5, 6B, 7F, 
8, 9N, 9V, 10A, 
11A, 12F, 14, 
15B, 17F, 18C, 
19A, 19F, 20, 
22F, 23F, and 
33F)
0.5 mL
IM
Single Dose 
at Visit 5
(Week 8)
Comparator IMP
Central or 
local
Admin=administration; EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal 
product; N/A=not applicable; PCV15=pneumococcal 15-valent conjugate vaccine; PnPs=pneumococcal polysaccharide; PPSV23=pneumococcal vaccine, polyvalent (23-valent); 
V116=pneumococcal 21-valent conjugate vaccine.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Drug-device combination/combination medicinal product(s) provided as prefilled syringes
for use in this study are V116, VAXNEUVANCE™, and PNEUMOVAX™23. Refer to 
Section 8.4.8 and Appendix 4 for reporting events associated with these devices.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
Specific procedures that are required for dose preparation are outlined in the Investigator 
Trial File Binder.
As detailed in Section 6.3.3, study vaccines will be prepared by an unblinded pharmacist or 
qualified study-site personnel.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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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 2 study 
intervention arms. Participants will be assigned randomly in a 3:1 ratio to receive either 
V116 + placebo or PCV15 + PPSV23, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Participant age at time of randomization:
-
18 to 49 years of age
-
50 to 64 years of age
At least 20% of participants will be 18 to 49 years of age.
2. Number and type of increased-risk conditions a participant has at the time of 
randomization:
-
Diabetes mellitus only
-
Chronic heart disease only
-
Chronic kidney disease only
-
Chronic liver disease only
-
Chronic lung disease only
-
≥2 increased-risk conditions (diabetes mellitus, chronic heart disease, chronic kidney 
disease, chronic liver disease, and/or chronic lung disease).
For participants with a single increased-risk condition, it is expected that at least 5% of 
participants with each individual condition will be enrolled.
Disease conditions at increased risk for pneumococcal disease include any chronic condition 
listed under Inclusion Criterion 1 (Section 5.1).
6.3.3
Blinding
A double-blinding technique will be used. V116, PCV15, PPSV23, and placebo will be 
prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified 
study-site personnel. The participant, the investigator, and Sponsor personnel or delegate(s) 
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who are involved in the study intervention administration or clinical evaluation of the 
participants are unaware of the intervention assignments.
Because V116, PCV15, PPSV23, and placebo have a different appearance, the unblinded 
pharmacist (or qualified study-site personnel) will be responsible for receiving, maintaining, 
preparing and/or dispensing, and administering these study vaccines (Section 8.1.8).
To avoid bias, contact between the unblinded study-site personnel and study participants is 
strictly prohibited for any study-related procedures/assessments other than administration of 
study vaccines. Blinded site personnel will be responsible for all other study 
procedures/assessments specified in Section 1.3.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) directly involved with the conduct of this 
study will remain blinded to the participant-level intervention assignment.
See Section 8.1.12 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (Section 5.2). If there is a clinical indication for any medications or 
vaccinations specifically prohibited, discontinuation from study intervention may be 
required. The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant’s primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
It is important to record the use of any analgesic or antipyretic medication that occurs on the 
day of vaccination on the eVRC and appropriate eCRF.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
Administration of a nonstudy pneumococcal vaccine is prohibited during the study.
•
Nonstudy vaccines may only be administered before or after the receipt of study vaccines
according to the time frames specified in the Exclusion Criteria (Section 5.2).
•
Receipt of systemic corticosteroids (prednisone equivalent ≥20 mg/day) for 
≥14 consecutive days is prohibited from 14 days before each vaccination through 30 days 
after each vaccination. Note: physiologic replacement doses (prednisone equivalent of 
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approximately 5 mg/day), topical, ophthalmic, intraarticular or soft-tissue (eg, bursa, 
tendon steroid injections), and inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
Use of prior and concomitant medications/vaccinations should be recorded as described in 
Section 8.1.5.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
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.
6.9
Standard Policies
Not Applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified vaccination 
regimen will continue to participate in the study as specified in Section 1.3 and 
Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.11 and 
Section 8.11.3.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive urine or serum pregnancy test before vaccination 
at Visit 5 (Week 8).
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
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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.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet 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.
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•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the volume mentioned in Appendix 2.
•
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) prior to 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.
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 
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to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The participant’s 
relevant medical history for the 5 years before the first study vaccination (Day 1) will be 
obtained to ensure that the participant satisfies the inclusion and exclusion criteria of the 
study. History of tobacco use will be collected for all participants.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medication taken by the participant within 30 days before the first study vaccination.
The following must be documented before the first study vaccination and recorded on the 
appropriate eCRF:
•
Any analgesic or antipyretic medication taken on the day of vaccination before 
vaccination.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record vaccinations and medications, if any, taken 
by the participant through Day 30 after each vaccination. Outside this period, report only 
concomitant medications related to an SAE.
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Any analgesic or antipyretic medication taken must be recorded on the eVRC and 
appropriate eCRF.
The participant will use their eVRC (Section 8.1.9) to record new and/or concomitant 
medications taken and nonstudy vaccines received from the day of each vaccination through 
30 days postvaccination.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any individual 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 in Section 8.11.1. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel will prepare and administer all study vaccines (Section 6.3.3). 
The unblinded study personnel who administer study vaccines should not have contact with 
the participants for any other study-related procedures/assessments.
Blinded site personnel will not be present in the examination room when study vaccines are 
administered.
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Procedures for handling, preparing, and administering study vaccines are provided in the 
Investigator Trial File Binder.
Study vaccine will be administered as a single IM injection, preferably in the deltoid region 
of the participant’s arm, according to the schedule specified in Section 1.3. Adequate 
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treatment provision, including epinephrine and equipment for maintaining an airway, should 
be available for immediate use should an anaphylactic or anaphylactoid reaction occur
[Centers for Disease Control and Prevention 2015]. 
8.1.8.1
Timing of Dose Administration
Study vaccines will be administered as indicated in Section 1.3. The day of the first study 
vaccination is considered Day 1 of the study. Vaccinations may be administered at any time 
of day and without regard to timing of meals.
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions (Section 8.3.4). This observation must be performed by blinded site personnel 
(Section 6.3.3).
Participants must not have a fever reported within 72 hours before each vaccination 
(Section 1.3 and Section 8.3.3).
Administration of pregnancy tests (if applicable) must be performed before each vaccine 
administration.
The collection of blood samples should be performed before vaccine administration.
8.1.9
Electronic Vaccination Report Card
The eVRC is structured as recommended in the final US FDA Patient-reported Outcome 
Guidance [U.S. Food and Drug Administration 2009]. The investigator or delegate will train 
the participant in the use of the VRC.
The participant will use the eVRC to record body temperature (Section 8.3.3), solicited 
injection-site AEs, and solicited systemic AEs (Section 8.4.9.1). Unsolicited AEs 
(Section 8.4.9.2), concomitant medications (including use of any analgesic or antipyretic 
medication), and nonstudy vaccinations (Section 8.1.5.2) will also be reported. Participants 
will be provided an electronic device or have their own electronic device configured, if 
compatible, to complete the eVRC.
The investigator or delegate will review the data captured on the eVRC with the participant 
as indicated in Section 1.3. Any differences between data reported by the participant on the 
eVRC and data entered into the clinical database must be clearly explained in the 
participant’s source documents.
8.1.10
Telephone Contact Questionnaire
Site personnel will contact the participant (or the participant’s legally acceptable 
representative, as applicable) as indicated in Section 1.3 to collect additional information 
based on a Telephone Contact Questionnaire provided by the Sponsor. Data to be reported 
from this discussion will include SAEs and/or any updates to previously reported safety 
information.
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8.1.11
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.11.3.
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 FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the 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 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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 record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
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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. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG responses. 
These endpoints will be tested for all immunogenicity blood draws specified in Section 1.3.
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual. 
After completion of immunogenicity testing to evaluate the study objectives and hypotheses, 
serum samples will be stored to conduct any additional study-related testing as requested by 
regulatory agencies or the Sponsor. Leftover sera from the study may be used after 
completion of all study-related immunogenicity testing.
8.2.1
Multiplex Opsonophagocytic Assay
The MOPA will be used for measuring OPA responses. Opsonization of pneumococci for 
phagocytosis is an important mechanism by which antibodies to polysaccharides protect 
against disease in vivo. The OPA assay is a useful tool for assessing the protective function 
of serotype-specific antibodies and, therefore, the immunogenicity of pneumococcal vaccine 
formulations.
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The MOPA is an antibody-mediated killing assay that measures the ability of human serum 
to kill S pneumoniae serotypes with the help of complement and phagocytic effector cells 
[Burton, Robert L. and Nahm, Moon H. 2006]. The ability of the assay to simultaneously test 
4 serotypes at a time reduces the amount of serum needed for testing. The assay readout is 
the opsonization index, which is the reciprocal of the highest dilution that gives ≥50% 
bacterial killing, as determined by comparison to assay background controls. The Sponsor 
has developed and optimized the MOPA in a high throughput microcolony platform, which 
not only covers all 21 serotypes in V116, but also includes serotypes 6C and 15B so that 
antibodies induced by vaccine serotypes 6A and 15C but cross-reactive to serotypes 6C and 
15B, respectively, can be measured. The assay has been validated for various performance 
parameters of the assay including precision, ruggedness, relative accuracy/dilutional 
linearity, and the limit of detection of the assay.
8.2.2
Pneumococcal Electrochemiluminescence Assay
Serotype-specific IgG will be measured using the Pn ECL assay to assess the concentration 
of binding antibodies to capsular polysaccharide of S pneumoniae.
The Sponsor has developed, optimized, and validated a multiplex, ECL-based detection 
method for the quantitation of IgG serotype-specific antibodies. This multiplexed ECL assay
not only detects all 21 serotypes contained in V116 but also detects serotypes 6C and 15B so 
that antibodies induced by vaccine serotypes 6A and 15C but cross-reactive to serotypes 6C 
and 15B, respectively, can be measured. The ECL assay is based on the Meso-Scale 
Discovery technology, which employs disposable multispot microtiter plates. Briefly, PnPs 
are bound to the surface of 96-well 10 plex carbon microplates, and serum containing 
purported anti-PnPs antibodies is added. The anti-PnPs antibodies bind to the coated plates 
and form an antibody-antigen complex. The bound antibody-antigen complex can be detected 
using a ruthenium labeled anti-human IgG. Plates are read by measure of the 
chemiluminescent signal emitted from the ruthenium tag upon electrochemical stimulation 
initiated at the electrode surfaces of the microplates. To improve the specificity to the 
pneumococcal serotypes in the vaccine, capsular polysaccharide, PnPs 25, and PnPs 72 are 
used for preadsorption of samples, standard, and controls. Assay validation studies showed 
excellent performance operating characteristics for precision (intraassay and interassay), 
dilutability, ruggedness (to different plate lots and analysts), relative accuracy, and 
specificity.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination and a brief directed physical examination will be 
conducted by an investigator or medically qualified designee (consistent with local 
requirements) per institutional standard as indicated in Section 1.3. The directed physical 
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examination should focus on examining systems related to any ongoing conditions and/or 
follow-up on previously reported AEs.
Findings related to the physical examinations should be documented in the source 
documents. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.3.2
Pregnancy Testing
A pregnancy test consistent with local requirements (sensitive to at least 25 IU hCG) must be 
performed before study vaccination at Visit 2 (Day 1) and Visit 5 in POCBP as described in 
Section 1.3.
Urine or serum tests can be used, and results must be negative before each vaccination can 
occur. A detailed definition of POCBP is provided in Appendix 5.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.3
Body Temperature Measurements
Each participant’s body temperature must be taken by study-site staff before each vaccination 
as described in Section 1.3. The prevaccination temperature should be documented in the 
participant’s source documents. Participants who have febrile illness (defined as oral or 
tympanic temperature ≥100.4 °F [≥38.0 °C]; axillary or temporal temperature ≥99.4 °F 
[≥37.4 °C]) within 72 hours before any vaccination must be rescheduled. 
Participants will also record oral body temperature measurements using the eVRC 
(Section 8.1.9) from Day 1 to Day 5 postvaccination.
8.3.4
Postvaccination Observation Period
All participants will be observed by blinded study site personnel for at least 30 minutes after 
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, and resolution of the event must be 
recorded on the appropriate eCRF.
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8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 30 to 44 days after the last dose of study intervention, 
every attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events, Serious Adverse Events, 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. 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.
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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.
All nonserious AEs and other reportable safety events (excluding pregnancy and lactation 
exposure) must be reported by the investigator from the day of randomization through 30 
days after the first vaccination and from the time of each subsequent vaccination through 30 
days postvaccination.
All pregnancies and lactation exposure during breastfeeding must be reported by the 
investigator from the day of randomization through 6 weeks postvaccination.
All SAEs must be reported by the investigator throughout the duration of the individual’s 
participation in the study, regardless of whether related to the study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
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 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 3
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
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)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, 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 toward 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 SAEs) 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 that the fetus will be 
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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 
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 ECIs for this study.
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions
The method of documenting and reporting of such events (complaints associated with 
medical devices including PQCs/malfunctions) will occur as below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per 
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions must be reported to the Sponsor. Sponsor shall review reported events by 
the investigator to fulfill the legal responsibility of notifying appropriate regulatory 
authorities and other entities about certain safety information relating to medical devices and 
drug-device combination products being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.4.9
Adverse Events on the VRC
Participants will use an eVRC to report solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.9.1
Solicited Adverse Event
Solicited AEs for this study are summarized in Table 4.
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Table 4
Solicited Adverse Events
Type of Solicited 
Adverse Event
Predefined Solicited Adverse Events (Preferred Term)
Solicited Period
Injection site

Injection-site pain or tenderness (injection-site pain)

Injection-site redness (injection-site erythema)

Injection-site swelling (injection-site swelling)
Day 1 to Day 5
postvaccination
Systemic

Headache (headache)

Muscle aches all over body (myalgia)

Tiredness (fatigue)
Day 1 to Day 5
postvaccination
8.4.9.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 4 or 
2) predefined in Table 4 but reported at any time outside the solicited period.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 1 dose of study vaccine in any 24-hour 
period.
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.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3. Potential 
participants will be evaluated to determine whether they fulfill the entry requirements in 
Section 5.
If a participant fulfills all entry requirements at Visit 1, then Visit 2 should occur the same 
day as Visit 1.
If diagnostic assessments are required to confirm eligibility (Section 5.1) or if Visit 2 needs 
to be rescheduled (Section 5.2), then Visit 2 should occur ≤30 days after screening (Visit 1).
8.11.2
Treatment Period/Vaccination Visits
Requirements during the treatment period are outlined in Section 1.3.
If Visit 2 does not occur on the same day as Visit 1, a review of inclusion/exclusion criteria, 
prior medications/vaccinations, and medical history must be repeated before vaccination.
Visit 2 should occur ≤30 days after Visit 1.
If Visit 2 is rescheduled (see Section 5.2 and Section 8.3.3), a pregnancy test (if applicable); 
a body temperature measurement; and a review of inclusion/exclusion criteria, prior 
medications/vaccinations, and medical history must be repeated before vaccination.
If Visit 5 is rescheduled (see Section 8.3.3), a pregnancy test (if applicable); a body 
temperature measurement, prior medications/vaccinations, and medical history must be 
repeated before vaccination
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
A participant who discontinues from study intervention will continue to participate in 
protocol-specified activities as outlined in Sections 1.3, including blood draws for 
immunogenicity testing and AE-monitoring activities, as long as the participant does not 
withdraw consent.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in an sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design 
Overview
A Phase 3, Randomized, Double-blind, Active Comparator-controlled 
Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity 
of V116 in Pneumococcal Vaccine-naïve Adults 18 to 64 years of Age 
With Increased Risk for Pneumococcal Disease.
Treatment 
Assignment
Participants will be randomly assigned in a 3:1 ratio to receive V116 + 
placebo or PCV15 + PPSV23. Randomization will be stratified based on 
the participant’s age (18 to 49 years, and 50 to 64 years), and by the 
type/number of increased-risk conditions for pneumococcal disease at the 
time of randomization as defined in Section 6.3.2.
Analysis Populations
Immunogenicity: PP population
Safety: APaT population
Primary Endpoint(s)
Immunogenicity:
•
Serotype-specific OPA GMTs postvaccination with V116 (30 days 
postvaccination [Day 30]) or PCV15 + PPSV23 (30 days 
postvaccination with the final dose in the regimen [Week 12])
Safety:
•
Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, and tenderness/pain) from Day 1 
through Day 5 postvaccination
•
Proportion of participants with solicited systemic AEs (muscle aches 
all over body/myalgia, headache, and tiredness/fatigue) from Day 1 
through Day 5 postvaccination
•
Proportion of participants with vaccine-related SAEs from Day 1 
through the duration of participation in the study
Key Secondary 
Endpoints
Serotype-specific IgG GMCs postvaccination with V116 (Day 30) or 
PCV15 + PPSV23 (Week 12)
Statistical Methods 
for Key 
Immunogenicity 
Analyses
Immunogenicity analyses will be conducted separately for each serotype 
in V116 within each vaccination group.
To address the primary immunogenicity objective, evaluation of the OPA 
GMTs postvaccination with V116 (Day 30) or PCV15 + PPSV23 (Week 
12) will include descriptive summaries and within-group 95% CIs for 
each vaccination group.
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Statistical Methods 
for Key Safety 
Analyses
For the overall safety evaluation, safety parameters will be summarized 
via descriptive statistics. For select safety parameters, point estimates and
within-group 95% CIs will be provided.
Interim Analyses
To support the periodic review of safety and tolerability data across the 
adult V116 Phase 3 program, an external unblinded statistician will
provide unblinded interim safety summaries to an independent external 
DMC for their review. Unblinded immunogenicity data will be made 
available to the DMC on request to enable a benefit-risk assessment.
Multiplicity
No multiplicity adjustment is planned as there is no hypothesis testing.
Sample Size and 
Power
This study will randomize approximately 375 participants into the V116 
group and 125 participants into the PCV15 + PPSV23 group. It is 
assumed that approximately 338 participants in the V116 group and 113 
in the PCV15 + PPSV23 group will be evaluable for PP immunogenicity 
analyses (90% evaluability rate). There are no hypotheses to be 
evaluated. Section 9.9.1 provides information about the expected 
variability of the OPA GMTs given the sample size.
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 official, final database will not be unblinded until medical/scientific review has been
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented in an IRT system.
Blinding issues related to the planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study and no hypothesis 
testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be summarized are listed below.
9.4.1
Immunogenicity Endpoints
Immune responses will be measured for each of the serotypes contained in V116: the 6 
serotypes in common with PCV15 (3, 6A, 7F, 19A, 22F, and 33F); 7 additional serotypes in 
common with PPSV23 but not included in PCV15 (8, 9N, 10A, 11A, 12F, 17F, and 20); 
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8 unique serotypes in V116 (15A, 15C, 16F, 23A, 23B, 24F, 31, and 35B); and 2 cross-
reactive serotypes (6C and 15B).
The primary immunogenicity endpoint includes:
•
Serotype-specific OPA GMTs postvaccination with V116 (30 days postvaccination 
[Day 30]) or PCV15 + PPSV23 (30 days postvaccination with the final dose in the 
regimen [Week 12])
-
13 serotypes common between V116 and PCV15 + PPSV23
-
8 serotypes unique to V116 relative to PCV15 + PPSV23
The secondary immunogenicity endpoints include:
•
Serotype-specific IgG GMCs postvaccination with V116 (Day 30) or PCV15 + PPSV23 
(Week 12)
-
13 serotypes common between V116 and PCV15 + PPSV23
-
8 serotypes unique to V116 relative to PCV15 + PPSV23
•
Serotype-specific GMFR and proportion of participants with a ≥4-fold rise from baseline 
(Day 1) to postvaccination with V116 (Day 30) or PCV15 + PPSV23 (Week 12) for both 
OPA and IgG responses
-
13 serotypes common between V116 and PCV15 + PPSV23
-
8 serotypes unique to V116 relative to PCV15 + PPSV23
The exploratory immunogenicity endpoints include:
•
Serotype-specific OPA GMTs and IgG GMCs postvaccination with V116 (Day 30) or 
PCV15 + PPSV23 (Week 12)
-
13 serotypes common between V116 and PCV15 + PPSV23
-
8 serotypes unique to V116 relative to PCV15 + PPSV23
•
Summaries of the cross-reactive immune responses to serotypes within a serogroup using 
serotype-specific OPA and IgG responses
9.4.2
Safety Endpoints
The safety endpoints for overall safety assessment that address the primary safety objective 
include:
•
Proportion of participants with solicited injection-site AEs (redness/erythema, swelling, 
and tenderness/pain) from Day 1 through Day 5 postvaccination
•
Proportion of participants with solicited systemic AEs (muscle aches all over 
body/myalgia, headache, and tiredness/fatigue) from Day 1 through Day 5 
postvaccination
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•
Proportion of participants with vaccine-related SAEs from Day 1 through the duration of 
participation in the study
Additional safety endpoints for overall safety assessment include:
•
Proportion of participants with the broad AE categories consisting of any AE, any 
unsolicited AEs, and any vaccine-related AE from Day 1 through Day 30 postvaccination
•
Proportion of participants with the broad AE categories consisting of any SAE, any 
vaccine-related SAE, discontinuation due to an AE, and death from Day 1 through the 
duration of participation in the study
•
Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 5 postvaccination
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoints. Potential deviations that may result in the exclusion of a participant from the PP 
population for all immunogenicity analyses include:
•
Failure to receive study vaccine at Visit 2 (Day 1)
•
Failure to receive correct clinical material as per randomization schedule
•
Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP 
population for specific immunogenicity analyses (depending on the time point) include:
•
Failure to receive study vaccine at Visit 5 (Week 8)
•
Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection
•
Collection of a blood sample outside the prespecified window
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database and will be documented 
in a separate memo. Participants will be included in the vaccination group to which they are 
randomized for the analysis of immunogenicity data using the PP population.
A supportive analysis using the FAS population will also be performed for the primary 
immunogenicity endpoint. The FAS population consists of all randomized participants who 
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received at least 1 study vaccination and have at least 1 serology result. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study vaccination. Participants will be included in 
the group corresponding to the study vaccination they actually received for the analysis of 
safety data using the APaT population. This will be the group to which they are randomized 
except for participants who receive incorrect study vaccination; such participants will be 
included in the group corresponding to the study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analysis of temperature.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary, secondary, and 
exploratory immunogenicity objectives. More details for methods related to the exploratory 
immunogenicity objectives will be further described in the sSAP.
Immunogenicity analyses will be conducted for each of the 21 pneumococcal serotypes in 
V116 separately. To address the primary immunogenicity objective, evaluation of the OPA 
GMTs postvaccination with V116 (Day 30) or PCV15 + PPSV23 (Week 12) will include 
descriptive summaries and within-group 95% CIs for each vaccination group.
For the secondary immunogenicity objectives, to evaluate IgG GMCs postvaccination with 
V116 (Day 30) or PCV15 + PPSV23 (Week 12), a similar statistical approach described in 
the primary objective will be used. Also, GMFR and proportions of participants with a 
≥4-fold rise for both OPA and IgG responses will be calculated for V116 (from Day 1 to 
Day 30) or PCV15 + PPSV23 (from Day 1 to Week 12). Descriptive statistics with point 
estimates and within-group 95% CIs will be provided for these endpoints.
For the continuous endpoints, the point estimates will be calculated by exponentiating the 
estimates of the mean of the natural log values and the within-group CIs will be derived by 
exponentiating the bounds of the CIs of the mean of the natural log values based on the t-
distribution. For the dichotomous endpoints, the within-group CIs will be calculated based on 
the exact method proposed by Clopper and Pearson [CLOPPER, C. J. and PEARSON, E. S. 
1934].
To address the exploratory immunogenicity objective to evaluate the immune responses for 
V116 (Day 30) compared with PCV15 + PPSV23 (Week 12), the serotype-specific OPA 
GMTs will be compared between intervention groups through the estimation of 
serotype-specific OPA GMT ratios. Estimation of the OPA GMT ratios and computation of 
the corresponding 95% CIs will be calculated using a cLDA method proposed by Liang and 
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Zeger [Liang, K-Y and Zeger, S. L. 2000]. Details regarding the cLDA models will be 
included in the sSAP. A similar statistical approach will be used to analyze the IgG GMCs 
between the 2 intervention groups.
Reverse Cumulative Distribution Curves for OPA titers and IgG concentrations will be 
graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 5.
Table 5
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
OPA GMTs postvaccination 
with V116 (Day 30) or 
PCV15 + PPSV23 
(Week 12)
P
Descriptive 
Statistics 
(estimate, 95% CI)
PP
Missing data will 
not be imputed
S
FAS
Secondary Endpoints
IgG GMCs postvaccination 
with V116 (Day 30) or 
PCV15 + PPSV23 
(Week 12)
P
Descriptive 
Statistics 
(estimate, 95% CI)
PP
Missing data will 
not be imputed
GMFR and proportion of 
participants who achieved a 
≥4-fold rise from baseline 
(Day 1) to postvaccination 
with V116 (Day 30) or 
PCV15 + PPSV23 
(Week 12) for both OPA 
and IgG responses
P
Descriptive 
Statistics 
(estimate, 95% CI)
PP
Missing data will 
not be imputed
CI=confidence interval; FAS=full analysis set; GMC=geometric mean concentration; GMFR=geometric mean fold rise; 
GMT=geometric mean titer; IgG=immunoglobulin G; OPA=opsonophagocytic activity; PP=per-protocol.
a
P=primary approach; S=supportive approach.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination temperature measurements. The safety profile will be 
assessed via point estimates and 95% CIs (for select safety endpoints) across vaccination 
groups. Summaries on safety parameters will be provided after any vaccination and after
each vaccination.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary (ie, number and percentage) of 
participants with any AEs, any unsolicited AEs, any vaccine-related AEs, any SAEs, any 
vaccine-related SAEs, discontinuation due to an AE, and an AE resulting in death. Point 
estimates and within-group 95% CIs for the percentages of participants will be provided for 
these events.
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The number and percentage of participants with specific AEs will also be provided. Point 
estimates and within-group 95% CIs for the percentages of participants with specific AEs 
will be provided for solicited AEs and AEs that occur in ≥5% of participants in any 
vaccination group.
The number and percentage of participants with maximum temperature measurements 
categorized by Brighton Collaboration cut points [Marcy, S. M., et al 2004] will be provided 
along with point estimates and within-group 95% CIs to evaluate elevated temperatures.
Within-group CIs will be calculated using the Clopper Pearson method [CLOPPER, C. J. and 
PEARSON, E. S. 1934]. CIs should only be regarded as helpful descriptive measures for the 
review of the safety profile and not as a formal method for assessing statistical significance.
The analysis strategy for safety endpoints is provided in Table 6.
Table 6
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
Within-group 
95% CI
Overall Safety 
Assessment
Solicited injection-site AE
(Day 1 through Day 5 postvaccination)a
X
X
Solicited systemic AE
(Day 1 through Day 5 postvaccination)a
X
X
Any AEb
X
X
Any unsolicited AEb
X
X
Any vaccine-related AEb
X
X
Any SAEb
X
X
Any vaccine-related SAEb
X
X
Discontinuation due to AEb
X
X
Deathb
X
X
Specific AEs by SOC and PTc
X
X
Maximum temperatures
(Day 1 through Day 5 postvaccination)d
X
X
AE=adverse event; CI=confidence interval; PT=preferred term; SAE=serious adverse event; SOC=system organ class
a
Solicited injection-site AEs include redness/erythema, swelling, and tenderness/pain; solicited systemic AEs include 
muscle aches all over body/myalgia, headache, and tiredness/fatigue.
b
These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” 
will provide the number and percentage of participants with at least 1 AE.
c
Descriptive statistics will be provided for specific AEs with incidence >0% of participants in any vaccination group; 
additionally within-group 95% CIs will be provided for specific AEs with an incidence ≥5% of participants in any 
vaccination group.
d
Maximum temperature measurements are categorized by Brighton Collaboration cut points.
9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants randomized 
and discontinued from the study and discontinuation reasons will be displayed. Demographic 
variables (eg, age, race, ethnicity, sex, and gender), baseline characteristics, and prior and 
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concomitant vaccinations and medications will be summarized by vaccination group either 
by descriptive statistics or categorical tables.
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V116 Phase 3 adult program will 
be conducted by an independent, unblinded, external DMC. A description of the structure 
and function of the DMC, along with the timing and content of the safety review, will be 
outlined in the DMC charter. Information regarding the composition of the DMC is provided 
in Appendix 1. In addition, unblinded immunogenicity data will be made available to the 
DMC on request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of the ongoing safety reviews and 
will make recommendations for continuation of the study (with or without protocol 
modifications) or discontinuation of the study to an executive oversight committee of the 
Sponsor (see Appendix 1 for details on the Committees Structure for this study). If the DMC 
recommends modifications to the design of the protocol or discontinuation of the study, the 
oversight committee (and potentially other limited Sponsor personnel) may be unblinded to 
results at the intervention level to act on these recommendations. The extent to which 
individuals are unblinded with respect to ongoing safety reviews will be documented. 
Additional logistical details will be provided in the DMC charter.
Study enrollment may be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant-level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
No multiplicity adjustment is planned as there is no hypothesis testing.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. This study will randomize approximately 375 participants into the 
V116 group and 125 participants into the PCV15 + PPSV23 group. It is assumed that 
approximately 338 participants in the V116 group and 113 in the PCV15 + PPSV23 group
will be evaluable for PP immunogenicity analyses (based on a 90% evaluability rate).
The width of the within-group 95% CIs for the serotype-specific OPA GMTs depend on the 
sample size, variability of the natural log titers, and the magnitude of the OPA GMTs. The 
95% CIs for various hypothetical OPA GMTs and various hypothetical standard deviation 
estimates for the natural log titers are displayed in Table 7.
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Table 7
Within-group 95% CIs for Varying Hypothetical OPA GMTs and Varying 
Standard Deviations
Standard 
Deviation of 
Natural Log 
Titersa
Serotype-specific OPA GMTa
500
1000
5000
V116
PCV15 + 
PPSV23
V116
PCV15 + 
PPSV23
V116
PCV15 + 
PPSV23
1.0
(449, 556)
(415, 602)
(899, 1113)
(830, 1205)
(4493, 5565)
(4150, 6024)
1.5
(426, 587)
(378, 661)
(852, 1174)
(756, 1323)
(4259, 5870)
(3780, 6613)
2.0
(404, 619)
(344, 726)
(807, 1239)
(689, 1452)
(4037, 6193)
(3444, 7259)
2.5
(383, 653)
(314, 797)
(765, 1307)
(628, 1594)
(3827, 6533)
(3138, 7968)
CI=confidence interval; GMT=geometric mean titer; OPA=opsonophagocytic activity; PCV15=pneumococcal 15-valent 
conjugate vaccine; PPSV23=pneumococcal vaccine, polyvalent (23-valent); V116=pneumococcal 21-valent conjugate 
vaccine.
a
The estimates of the standard deviation and OPA GMTs are representative of those observed in V116-001.
Based on 338 evaluable participants in the V116 group and 113 evaluable participants in the PCV15 + PPSV23 
group.
9.9.2
Sample Size and Power for Safety Analyses
The sample size was selected to achieve a reasonably sized safety database in this population 
exposed to V116. The selected sample size allows for the detection of a minimum level of 
SAEs with a high degree of confidence for the overall study as described below. The 
probability of observing at least 1 SAE in this study depends on the number of participants 
vaccinated and the underlying incidence of participants with a SAE in the study population. 
Calculations below assume that 100% of the randomized participants will be evaluable for 
safety analyses. There is an 80% chance of observing at least 1 SAE among 375 participants 
in the V116 group if the underlying incidence of an SAE is 0.43% (1 of 234 participants 
receiving the vaccine). There is a 50% chance of observing at least 1 SAE among 
375 participants in the V116 group if the underlying incidence of an SAE is 0.18% (1 of 
542 participants receiving the vaccine). If no SAEs are observed among the 375 participants 
in the V116 group, this study will provide 97.5% confidence that the underlying percentage 
of participants with an SAE is <0.98% (1 of 102 participants) in the V116 group.
9.10
Subgroup Analyses
Serotype-specific OPA GMTs and their corresponding within-group 95% CIs for V116 
(Day 30) or PCV15 + PPSV23 (Week 12) will be calculated within each vaccination group 
for each subgroup of the following classification variables:
•
Age category (18 to 49, 50 to 64 years of age)
•
Sex
•
Race
•
Ethnicity
•
Number of concurrent increased-risk conditions (1 or ≥2)
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•
Type of increased risk-condition (diabetes mellitus only, chronic heart disease only, 
chronic kidney disease only, chronic liver disease only, chronic lung disease only)
In addition, a summary of AEs and a summary of solicited AEs will be provided for each of 
the subgroups listed above (point estimates only).
Further details of subgroup analyses will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Given that participants will receive a single dose of V116 or PCV15 followed by a single 
dose of placebo or PPSV23, compliance will not be calculated. However, the number and 
proportion of randomized participants receiving each vaccination will be summarized 
(Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V116, placebo, PCV15, or PPSV23.
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and 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 (eg, 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 (ie, 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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors using a risk-based approach. 
Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
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 prespecified 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.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 (eg, 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.
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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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 
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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.
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 on 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 (Section 9.7) 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.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
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various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials 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, ICH 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.
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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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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.
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The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
hCG=human chorionic gonadotropin; POCBP=participant/participants of childbearing potential.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Blood volumes collected from each participant over the duration of the study are detailed in 
Table 9.
Table 9
Blood Volumes Collected by Visit
Visit 2
Visit 4
Visit 7
Total
Parameter
Approximate Blood Volume
Immunogenicity assessment
30 mL
30 mL
30 mL
90 mL
DNA for FBRa
8.5 mL
N/A
N/A
8.5 mL
Expected total
38.5 mL
30 mL
30 mL
98.5 mL
DNA=deoxyribonucleic acid; FBR=future biomedical research; N/A=not applicable.
a Samples for FBR will only be obtained from participants who provide separate consent for collection of this optional 
sample.
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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 potential to 
lead to harm to the patient.
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 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 preexisting 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.”
•
Any new cancer or progression of existing cancer.
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
Definition of Unsolicited and Solicited AE
•
An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant/participant’s legally authorized representative who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs.
•
Solicited AEs are predefined local (at the injection/administration site) and systemic 
events for which the participant/participant’s legally authorized representative is 
specifically questioned, and which are noted by the participant/participant’s legally 
authorized representative in their VRC.
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
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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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
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.
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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.
•
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 assess the overall intensity of 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 are adapted from the “FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, September 2007” [Food and Drug Administration 2007].
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Table 10
Injection-site AE Overall Intensity Grading Scale
Injection-site 
Reaction to Study 
Vaccine/Placebo
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 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Erythema/Redness
Size measured as
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or 
exfoliative 
dermatitis or 
results in ED visit 
or hospitalization
Swelling
Size measured as 
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or ED 
visit or 
hospitalization
Other
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED 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 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
AE=adverse event; ED=emergency department.
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 Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
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Table 11
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 
nonnarcotic pain 
reliever >24 hours 
or some interference 
with activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ED visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
ED=emergency department.
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 Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
Table 12
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
ED visit or 
hospitalization
AE=adverse event; ED=emergency department; eVRC=electronic Vaccine Report Card; SAE=serious adverse event.
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 Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Based on information provided by the participant 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 
on the initial report and/or follow-up of the event.
b
AEs resulting in death will be assessed as Grade 4.
Table 13
Vital Sign (Temperature) 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
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 Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
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 study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 initialed 
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 on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 reexposed to the study intervention 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; (2) the study is a single-dose vaccine study; or (3) study 
intervention(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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention 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 their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide and assessment of causality for each AE/SAE 
and document this in the medical records.
•
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 their 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 
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.
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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 email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product comprised of 2 or more regulated components (ie, a drug 
and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Customer Feedback – A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark that may suggest an improvement in the 
functionality or quality of a medical device, or device like features of a drug delivery 
system).
Malfunction – The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device – Any instrument, apparatus, appliance, material, or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment, or alleviation of disease,
•
diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or 
handicap,
•
investigation, replacement, or modification of the anatomy or of a physiological process,
•
control of conception,
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and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological, or metabolic means, but which may be assisted in its 
function by such means.
PQC – Any communication that describes a potential defect related to the identity, strength, 
quality, purity, or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury – An injury or illness that:
1. Is life-threatening,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1
via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
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Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
Country-specific definitions and documenting/reporting requirements can be found in 
Appendix 7.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participant of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile and capable of becoming 
pregnant 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.
Participants assigned sex at birth who are in the following categories are not capable of 
becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal 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, Müllerian 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
-
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 participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are 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
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.

Progestogen- only contraceptive implantb,c

IUSb,d

Nonhormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.

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 penile-
vaginal intercourse with partner(s) capable of producing sperm during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action

Penile/external or vaginal/internale condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of penile/external condom with either cervical cap, diaphragm, or sponge with 
spermicide (double barrier methods)
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b
Penile/external condoms must be used in addition to POCBPs participant hormonal contraception.
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.
e
Vaginal/internal condom used for contraceptive purposes.
Note: The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.

Penile/external and vaginal/internal condom should not be used together (due to risk of failure with 
friction).e
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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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be used 
in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
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.
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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 Research3, 4
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 is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that 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 Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the 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 study use only. If specimens were 
collected from study participants specifically for FBR, 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, 
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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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used 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 Security3, 4
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 Participants3, 4
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 Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
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11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@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
10.7.1
Country-specific Requirements for South Korea
For study sites in South Korea, the following criterion replaces Exclusion Criterion 21 in 
Section 5.2:
21. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 6 months of participating in this current study.
10.7.2
Country-specific Requirements for Japan
Section 5.2 Exclusion Criteria
For study sites in Japan, to comply with current Japan national guidance, the following 
criterion replaces Exclusion Criterion 17 in Section 5.2:
17 *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of any study vaccine. Exception: 
inactivated influenza vaccine may be administered but must be given ≥7 days before or 
≥15 days after receipt of study vaccine. SARS-CoV-2 mRNA or protein subunit vaccines 
may be administered but must be given ≥14 days before or ≥15 days after receipt of study 
vaccine. SARS-CoV-2 vaccines other than mRNA and protein subunit vaccines are not 
eligible for this exception and are subject to requirements of exclusion criteria 17 and 18.
Section 6.1.1 Medical Devices
Combination Medicinal Product(s) (MSD marketed/MSD investigation medicinal product 
and medical device or non-MSD marketed/non-MSD investigational product and medical 
device) provided for use in this study are V116 prefilled syringes, VAXNEUVANCE™ 
prefilled syringes, and PNEUMOVAX™23 prefilled syringes. Refer to below for instruction 
on reporting events associated with these devices.
Appendix 4 Medical Device and Drug-device Combination Products: Product Quality 
Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices/combination medicinal products as described below. For purposes of this section, 
medical devices/combination medicinal products in scope for device information collection 
include devices/combination medicinal products intended to be used by a study participant 
according to the study protocol, which are manufactured by the Sponsor or for the Sponsor 
by a third party, licensed by the Sponsor for human use and/or drug-device combination 
products, as listed above. Product quality complaints/malfunctions must be reported to the
Sponsor.
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10.4.1 Definitions
Medical Device – Devices, etc, (other than regenerative medicine products) intended for use 
in the diagnosis, treatment, or prevention of disease in humans or animals, or intended to 
affect the structure or functions of the body of humans or animals.
Combination Medicinal Product – A product comprised of 2 or more regulated 
components, ie, a drug and a device; a device and a cellular and tissue-based products; a 
cellular and tissue-based products and a drug; or a drug, a device, and a cellular and tissue-
based products according to Japan regulations.
Malfunction – Failure of quality, safety, and performance, etc, of investigational device in a 
broad sense such as damage or operational failure.
Serious Adverse Event due to Malfunction – Any SAE due to malfunction in the 
characteristics and/or performance of a device (this study is a prefilled syringe) as well as 
any inadequacy in the labeling or the instructions for use that might lead to or might have led 
to the death of a participant and/or the associated person or to a serious deterioration in their 
state of health.
Malfunction That may Lead to Serious Adverse Events – Any malfunction of a medical 
device that might have led to the death of a participant and/or the associated person or to a 
serious deterioration in their state of health. “That might have led to” means that there is the 
possibility that death or a serious deterioration might have occurred in a participant and/or 
the associated person, although these cases have not actually occurred.
10.4.2 Medical Device/Combination Medicinal Products – Documenting and Reporting
In order to fulfill Japan regulatory reporting obligations, medical device/combination 
medicinal product information will be collected. SAEs due to malfunction will be reported to 
the Sponsor in the same time frame as SAEs as per Section 8.4.1 via CRF (paper or 
electronic) and as per data entry guidelines. All SAEs due to malfunction will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant or 
associated person is lost to follow-up. Malfunction that may lead to SAEs will be reported to 
the Sponsor within 5 calendar days of learning of the information via a paper reporting form.
Sponsor shall review reported events by the investigator to fulfill the legal responsibility of 
notifying appropriate regulatory authorities and other entities as needed about certain safety 
information relating to medical devices/combination medicinal products being used in 
clinical studies.
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10.4.3 Recording, Assessing Causality, and Follow-up of Adverse Events due to 
Malfunctions (Serious and Nonserious)
Recording
•
When AEs due to malfunctions (serious or nonserious) occur, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, laboratory 
reports, and diagnostic reports) related to the event.
•
Any AEs due to malfunctions (serious or nonserious) occurring during the study will be 
recorded in the participant’s medical records, in accordance with the investigator’s 
normal clinical practice, and on the appropriate CRF (paper or electronic) as per 
instructions in the EDC data entry guidelines (or equivalent).
•
It is important that the investigator provides an assessment of causality (relationship to 
the medical device) at the time of the initial report.
Assessing Causality
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes should also be considered and investigated, such as underlying 
disease(s), concomitant therapy, and other risk factors as well as the temporal relationship 
of the event to study intervention administration.
Follow-up
•
The investigator will 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 event as fully as possible.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ABCs
Active Bacterial Core Surveillance
ACIP
Advisory Committee on Immunization Practices
ACR
Albumin to creatinine ratio
AE
Adverse event
AER
Albumin excretion rate
ALT
Alanine aminotransferase
APaT
All-Participants-as-Treated
APRI
Aspartate aminotransferase : platelet ratio index
AST
Aspartate aminotransferase
BNP
Brain natriuretic peptide
CI
Confidence interval
cLDA
Constrained longitudinal data analysis
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CFR
Code of Federal Regulations
CRF
Case report form
CSR
Clinical study report
CTFG
Clinical Trial Facilitation Group
deOAc
De-O-acetylated
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
ECL
Electrochemiluminescence
eCRF
electronic case report form
EF
Ejection fraction
EDC
Electronic data collection
EEA
European Economic Area
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOC
Executive Oversight Committee
EU
European Union
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
FEV1
Forced expiratory volume in 1 second
FIB-4
Fibrosis-4
FSH
Follicle-stimulating hormone
FSR
First site ready
FVC
Forced vital capacity
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GMC
Geometric mean concentration
GMFR
Geometric mean fold rise
GMT
Geometric mean titer
HbA1c
Hemoglobin A1c
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HRT
Hormone-replacement therapy
IA
Interim analysis(ses)
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID
identification
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
Intramuscular(ly)
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Abbreviation
Expanded Term
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IPD
Invasive pneumococcal disease
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
KDIGO
Kidney Disease: Improving Global Outcomes
LAM
Lactational amenorrhea method
M&N
Miettinen and Nurminen
MOPA
Multiplexed Opsonophagocytic Assay
mRNA
Messenger RNA
NYHA
New York Heart Association
OPA
Opsonophagocytic activity
PCV
Pneumococcal conjugate vaccine
PEFR
Peak expiratory flow rate
PEN
Package of Essential Noncommunicable
PK
pharmacokinetic
Pn ECL
Pneumococcal electrochemiluminescence
PnPs
Pneumococcal polysaccharide
POCBP
Participant/participants of childbearing potential
PP
Per-protocol
PQC
Product quality complaint
RNA
Ribonucleic acid
SAC
Scientific Advisory Committee
SAE
Serious Adverse Event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SLAB
Supplemental laboratory test(s)
SoA
Schedule of activities
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Abbreviation
Expanded Term
SOC
System organ class
sSAP
Supplemental statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
TEE
Transesophageal echocardiography
TTE
Transthoracic echocardiography
ULN
Upper limit of normal
US
United States
VRC
Vaccination report card
WHO
World Health Organization
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