A Phase 3 Randomized, Double-blind, Active Comparator-controlled, Lot-to-Lot Consistency Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Adults 18 to 49 Years of Age
Phase: PHASE3
Conditions: Pneumococcal Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05464420 
Document Date: 
21-Oct-2022
A Phase 3 Randomized, Double-blind, Active Comparator-
controlled, Lot-to-Lot Consistency Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of V116 in Adults 18 to 49 
Years of Age

PRODUCT: V116  
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PROTOCOL/AMENDMENT NO.: 004-01
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21-OCT-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Double-blind, Active Comparator-controlled, Lot-
to-Lot Consistency Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 
in Adults 18 to 49 Years of Age
Protocol Number: 004-01
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):
IND
19316
EudraCT
2022-000265-41
Approval Date: 21 October 2022
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PRODUCT: V116  
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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PRODUCT: V116  
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 1
21-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in 
an entity name change and update to the address.
Original Protocol
30-MAR-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
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PRODUCT: V116  
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................20
2.2.1
Pharmaceutical and Therapeutic Background .............................................20
2.2.2
Information on Other Study-related Therapy ..............................................21
2.2.2.1
PPSV23..............................................................................................21
2.2.2.2
Pneumococcal Vaccination Guidelines..............................................22
2.3
Benefit/Risk Assessment......................................................................................22
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................23
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................26
4.2.1
Rationale for Endpoints ...............................................................................26
4.2.1.1
Immunogenicity Endpoints................................................................26
4.2.1.2
Safety Endpoints................................................................................27
4.2.1.3
Future Biomedical Research..............................................................27
4.2.2
Rationale for the Use of Comparator...........................................................28
4.3
Justification for Dose...........................................................................................28
4.4
Beginning and End-of-Study Definition ............................................................28
4.4.1
Clinical Criteria for Early Study Termination .............................................28
5
STUDY POPULATION ................................................................................................29
5.1
Inclusion Criteria.................................................................................................29
5.2
Exclusion Criteria................................................................................................30
5.3
Lifestyle Considerations......................................................................................32
5.4
Screen Failures.....................................................................................................32
5.5
Participant Replacement Strategy......................................................................32
6
STUDY INTERVENTION............................................................................................32
6.1
Study Intervention(s) Administered...................................................................32
6.1.1
Medical Devices...........................................................................................34
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6.2
Preparation/Handling/Storage/Accountability .................................................34
6.2.1
Dose Preparation..........................................................................................34
6.2.2
Handling, Storage, and Accountability........................................................34
6.3
Measures to Minimize Bias: Randomization and Blinding..............................35
6.3.1
Intervention Assignment..............................................................................35
6.3.2
Stratification.................................................................................................35
6.3.3
Blinding........................................................................................................35
6.4
Study Intervention Compliance..........................................................................36
6.5
Concomitant Therapy..........................................................................................36
6.5.1
Rescue Medications and Supportive Care ...................................................36
6.6
Dose Modification ................................................................................................36
6.7
Intervention After the End of the Study............................................................36
6.8
Clinical Supplies Disclosure................................................................................37
6.9
Standard Policies..................................................................................................37
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................37
7.1
Discontinuation of Study Intervention...............................................................37
7.2
Participant Withdrawal From the Study...........................................................37
7.3
Lost to Follow-up .................................................................................................38
8
STUDY ASSESSMENTS AND PROCEDURES........................................................38
8.1
Administrative and General Procedures ...........................................................39
8.1.1
Informed Consent.........................................................................................39
8.1.1.1
General Informed Consent.................................................................39
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................40
8.1.1.3
Consent and Collection of Specimens for Optional Assay 
Development......................................................................................40
8.1.2
Inclusion/Exclusion Criteria ........................................................................40
8.1.3
Participant Identification Card.....................................................................40
8.1.4
Medical History ...........................................................................................41
8.1.5
Prior and Concomitant Medications Review...............................................41
8.1.5.1
Prior Medications...............................................................................41
8.1.5.2
Concomitant Medications..................................................................41
8.1.6
Assignment of Screening Number...............................................................41
8.1.7
Assignment of Treatment/Randomization Number.....................................41
8.1.8
Study Intervention Administration ..............................................................42
8.1.8.1
Timing of Dose Administration.........................................................42
8.1.9
Electronic Vaccination Report Card ............................................................42
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8.1.10
Telephone Contact Questionnaire................................................................43
8.1.11
Discontinuation and Withdrawal .................................................................43
8.1.11.1
Withdrawal From Future Biomedical Research ................................43
8.1.12
Participant Blinding/Unblinding..................................................................44
8.1.13
Calibration of Equipment.............................................................................44
8.2
Immunogenicity Assessments .............................................................................45
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................45
8.2.2
Pneumococcal Electrochemiluminescence (Pn ECL)..................................45
8.3
Safety Assessments...............................................................................................46
8.3.1
Physical Examinations.................................................................................46
8.3.2
Pregnancy Testing........................................................................................46
8.3.3
Body Temperature Measurement.................................................................46
8.3.4
Postvaccination Observation Period ............................................................47
8.3.5
Clinical Safety Laboratory Assessments .....................................................47
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................47
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................48
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......50
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...50
8.4.4
Regulatory Reporting Requirements for SAE .............................................50
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................50
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................51
8.4.7
Events of Clinical Interest............................................................................51
8.4.8
Medical Device and Drug-device Combination Products -
PQCs/Malfunctions......................................................................................51
8.4.9
Adverse Events on the VRC ........................................................................51
8.4.9.1
Solicited Adverse Event.....................................................................51
8.4.9.2
Unsolicited Adverse Events...............................................................52
8.5
Treatment of Overdose........................................................................................52
8.6
Pharmacokinetics.................................................................................................52
8.7
Pharmacodynamics..............................................................................................52
8.8
Biomarkers ...........................................................................................................52
8.9
Future Biomedical Research Sample Collection...............................................52
8.10
Optional Assay Development Blood Sample Collection...................................53
8.11
Medical Resource Utilization and Health Economics.......................................53
8.12
Visit Requirements...............................................................................................53
8.12.1
Screening......................................................................................................53
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8.12.2
Treatment Period/Vaccination Visit ............................................................53
9
STATISTICAL ANALYSIS PLAN .............................................................................53
9.1
Statistical Analysis Plan Summary.....................................................................53
9.2
Responsibility for Analyses/In-house Blinding .................................................55
9.3
Hypotheses/Estimation ........................................................................................55
9.4
Analysis Endpoints...............................................................................................55
9.4.1
Immunogenicity Endpoints..........................................................................55
9.4.2
Safety Endpoints..........................................................................................56
9.5
Analysis Populations............................................................................................57
9.5.1
Immunogenicity Analysis Populations ........................................................57
9.5.2
Safety Analysis Populations ........................................................................57
9.6
Statistical Methods...............................................................................................58
9.6.1
Statistical Methods for Immunogenicity Analyses......................................58
9.6.2
Statistical Methods for Safety Analyses ......................................................60
9.6.2.1
Overall Safety Assessment ................................................................61
9.6.3
Demographic and Baseline Characteristics .................................................62
9.7
Interim Analyses ..................................................................................................62
9.8
Multiplicity ...........................................................................................................63
9.9
Sample Size and Power Calculations .................................................................63
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................63
9.9.2
Sample Size and Power for Safety Analyses ...............................................64
9.10
Subgroup Analyses...............................................................................................65
9.11
Compliance (Medication Adherence).................................................................65
9.12
Extent of Exposure...............................................................................................65
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................66
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........66
10.1.1
Code of Conduct for Clinical Trials.............................................................66
10.1.2
Financial Disclosure.....................................................................................68
10.1.3
Data Protection.............................................................................................69
10.1.3.1
Confidentiality of Data ......................................................................69
10.1.3.2
Confidentiality of Participant Records...............................................69
10.1.3.3
Confidentiality of IRB/IEC Information............................................69
10.1.4
Committees Structure...................................................................................70
10.1.4.1
Executive Oversight Committee........................................................70
10.1.4.2
External Data Monitoring Committee ...............................................70
10.1.4.3
Scientific Advisory Committee (SAC)..............................................70
10.1.5
Publication Policy........................................................................................70
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PRODUCT: V116  
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10.1.6
Compliance with Study Registration and Results Posting Requirements ...71
10.1.7
Compliance with Law, Audit, and Debarment ............................................71
10.1.8
Data Quality Assurance ...............................................................................72
10.1.9
Source Documents .......................................................................................72
10.1.10
Study and Site Closure.................................................................................73
10.2
Appendix 2: Clinical Laboratory Tests..............................................................74
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................75
10.3.1
Definition of AE ..........................................................................................75
10.3.2
Definition of SAE ........................................................................................76
10.3.3
Additional Events Reported.........................................................................77
10.3.4
Recording AE and SAE ...............................................................................78
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................83
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................85
10.4.1
Definitions....................................................................................................85
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....86
10.5
Appendix 5: Contraceptive Guidance................................................................88
10.5.1
Definitions....................................................................................................88
10.5.2
Contraception Requirements........................................................................89
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................90
10.7
Appendix 7: Country-specific Requirements....................................................95
10.8
Appendix 8: Abbreviations .................................................................................96
11
REFERENCES...............................................................................................................98
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PRODUCT: V116  
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................33
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type ....39
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................49
Table 4
Solicited Adverse Events .................................................................................52
Table 5
Analysis Strategy for Immunogenicity Variables............................................60
Table 6
Analysis Strategy for Safety Parameters..........................................................62
Table 7
Differences in the Incidence of Adverse Event Rates Between the 
2 Intervention Groups That Can be Detected With an Approximately 80% 
Probability........................................................................................................64
Table 8
Protocol-required Safety Laboratory Assessments..........................................74
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PRODUCT: V116  
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LIST OF FIGURES
Figure 1
V116-004 Study Design...................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double-blind, Active Comparator-controlled, Lot-
to-Lot Consistency Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 
in Adults 18 to 49 Years of Age
Short Title: Lot-to-Lot consistency of V116 in vaccine-naïve adults
Acronym: STRIDE-4
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 18 to 
49 years of age who are administered a single dose of V116 or PNEUMOVAX™23 (also 
known as PPSV23).
Objectives
Endpoints
Primary
• Objective: To evaluate the safety and 
tolerability profile 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
• Objective: To compare the serotype-specific 
opsonophagocytic activity (OPA) Geometric 
Mean Titers (GMTs) at 30 days 
postvaccination across 3 different lots of 
V116 for all serotypes included in V116.
Hypothesis: All 3 lots of V116 are equivalent 
as assessed by the serotype-specific OPA 
GMTs at 30 days postvaccination for all 
serotypes included in V116.
(The statistical criterion for equivalence 
requires the bounds of the 95% confidence 
interval [CI] of the OPA GMT ratio for each 
pairwise V116 lot-to-lot comparison to be 
within 0.5 to 2.0)
•
Serotype-specific OPA responses
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PRODUCT: V116  
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Objectives
Endpoints
Secondary
•
Objective: To evaluate the serotype-specific 
OPA GMTs at 30 days postvaccination in 
combined lots of V116 compared with 
PPSV23 for all serotypes included in V116.
•
Serotype-specific OPA responses
•
Objective: To evaluate the serotype-specific 
Immunoglobulin G (IgG) Geometric Mean 
Concentrations (GMCs) at 30 days 
postvaccination compared across the 
3 different lots of V116 and evaluate 
combined lots of V116 compared with 
PPSV23 for all serotypes included in V116.
•
Serotype-specific IgG responses
•
Objective: To evaluate the serotype-specific 
geometric mean fold rises (GMFRs) and 
proportions of participants with a ≥4-fold 
rise from baseline to 30 days postvaccination 
for both OPA and IgG responses separately 
for 3 different lots of V116 for all serotypes 
included in V116.
•
Serotype-specific OPA and IgG 
responses
•
Objective: To evaluate the serotype-specific 
OPA GMTs at 30 days postvaccination 
separately for 3 different lots of V116 for 
cross-reactive immune responses to 
serotypes within a serogroup
•
Serotype-specific OPA responses
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PRODUCT: V116  
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Adults 18 to 49 years of age
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 9
months from the time the first participant (or their legally 
acceptable representative) provides documented informed consent 
until the last participant’s last study-related contact.
For purposes of analysis and reporting, the overall study ends 
when the Sponsor receives the last laboratory result or at the time 
of final contact with the last participant, whichever comes last.
Number of Participants:
Approximately 2040 participants will be randomized, with 510 participants in each of the 3 
V116 intervention groups and 510 participants in the PPSV23 intervention group.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Vaccination 
Regimen
Use
V116 Lot 1
V116
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, 
35B)
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Test Product
V116 Lot 2
V116
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, 
35B)
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Test Product
V116 Lot 3
V116
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, 
35B)
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Test Product
PPSV23
PPSV23
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)
Single 
Dose
IM
Single Dose 
at Visit 1 
(Day 1)
Comparator
Abbreviations: Admin=administration; IM=intramuscular; PnPs=pneumococcal capsular 
polysaccharide; PPSV23= pneumococcal vaccine, polyvalent (23-valent) (Pneumovax 23™); 
V116=pneumococcal 21-valent conjugate vaccine.
Other current or former names(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
4
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 Volunteers: Yes
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
V116-004 Study Design
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1.3
Schedule of Activities
Study Period:
Intervention
Notes
Visit Number:
1
2
3
4
5
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 7
Day 30
Day 90
Day 180
Visit Window:
-
Day 7 to 
Day 10
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
Administrative Procedures
Screening Procedures
Informed Consent
X
Must be obtained before any study procedures are 
conducted.
Informed Consent for Optional Assay Development 
Blood Samples
X
Must be obtained before any sample collection.
Informed Consent for FBR
X
Must be obtained before sample collection.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Medical History
X
Postrandomization Procedures
Assignment of Randomization Number
X
Participant Identification Card
X
Prior/Concomitant Medication and Nonstudy 
Vaccination Review
X
X
X
V116/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
Collect Electronic Device From Participant
X
Complete Telephone Contact Questionnaire
X
X
Safety Procedures
Complete Physical Examination
X
Performed by the investigator or medically qualified 
designee at screening and before vaccination.
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Study Period:
Intervention
Notes
Visit Number:
1
2
3
4
5
Visit Type
Site 
Visit
Telephone 
Contact
Site
Visit
Telephone 
Contact
Telephone 
Contact
Scheduled Time:
Day 1
Day 7
Day 30
Day 90
Day 180
Visit Window:
-
Day 7 to 
Day 10
Day 30 to 
Day 44
Day 76 to 
Day 104
Day 166 to 
Day 194
Pregnancy Test (if applicable)
X
Females of reproductive potential must have a 
negative urine or serum test (consistent with local 
requirements and sensitive to ≤25 IU hCG) result 
before vaccination
Body Temperature Measurement
X
Measure before vaccination. Participants with febrile 
illness within 72 hours before vaccination must be
rescheduled.
Postvaccination Observation Period
X
Observed by blinded study-site personnel for at least 
30 minutes postvaccination.
AE Monitoring
X
X
X
X
X
Nonserious AEs collected through Day 30 
postvaccination; SAEs and deaths collected through 
duration of study participation.
Immunogenicity Procedures
Serum for Immunogenicity Assays
X
X
Visit 1 samples should be collected before 
vaccination.
Future Biomedical Research
Blood (DNA) for FBR
X
Sample should be obtained before vaccination at 
Visit 1 for participants who provided FBR consent,
or at a later date as long as FBR consent is obtained
prior to collection.
Assay Development Samples
Serum for Optional Assay Development
X
X
For participants who provided consent for optional 
assay development, Visit 1 sample should be 
collected before vaccination.
AE=adverse event; DNA=deoxyribonucleic acid; eVRC=electronic vaccination report card; FBR=future biomedical research; hCG=human chorionic gonadotropin; 
ID=identification; IU=international units; PPSV23=Pneumovax 23™; SAE=serious adverse event
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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]. PCV vaccination has 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 has had an indirect effect in other 
age groups.
However, an unmet medical need exists as increases in IPD due to serotypes not included in 
licensed PCVs have been observed in serval countries, especially in adults.
V116 is an investigational PCV designed to address this unmet need and includes 
S pneumoniae serotypes not included in licensed PCVs, which account for the majority of 
IPD observed in adults.
This Phase 3 clinical study is conducted in pneumococcal vaccine-naïve adults 18 to 49 years 
of age to demonstrate the consistency of 3 different lots of V116 with respect to the safety, 
tolerability, and immunogenicity of V116. Participants are categorized as vaccine-naïve if 
they have not received any pneumococcal vaccination (exception: participants with 
childhood pneumococcal vaccination prior to the age of 5 will be permitted).
2.2
Background
To date, a Phase 1/2 study (V116-001) and a Phase 1 study conducted in Japan (V116-002)
have been conducted with V116. Results from the Phase 1 part of V116-001 were used to
select the optimal 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 (ie, 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 decreased 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. 
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However, current surveillance does not definitively indicate that the use of PCVs in adults 
results in a similar reduction in pneumococcal disease [Matanock, A. 2018]. The residual 
burden of disease in the US is estimated as 24 cases of IPD per 100,000 in adults ≥65 years 
of age, and surveillance data estimates serotypes included in currently licensed PCVs 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. 2021].
The 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 following 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, due to the limited 
serotype coverage of the currently licensed vaccines in the EU, serotype 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 on available global epidemiology data 
with a primary focus on data from older adults (≥65 years of age) in the US and EU, regions 
with an established pediatric vaccination program. Based on 2018 surveillance data in US 
adults ≥65 years of age, the serotypes selected for inclusion in V116 account for 
approximately 83% of all cases of IPD, 25% to 30% of which are accounted for by the 
serotypes unique to V116 (US CDC ABCs unpublished data 2014 to 2018) [Centre for 
Disease Control and Prevention 2018].
V116 includes serotypes not currently contained in any licensed pneumococcal vaccine.
V116 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
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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PPSV23 was first approved in the US in 1983 and is now licensed in more than 50 countries 
worldwide. PPSV23 is indicated for the prevention of pneumococcal disease in adults 
≥50 years of age and in individuals ≥2 years of age at increased risk for pneumococcal 
disease.
2.2.2.2
Pneumococcal Vaccination Guidelines
Many countries have implemented age-based and/or risk-based recommendations for 
pneumococcal vaccination. Age-based recommendations typically start at 65 years of age due 
to the increased risk of pneumococcal disease associated with age.
Prior to 2014, the US ACIP recommended that all adults ≥65 years of age receive a single 
dose of PPSV23. In 2014, ACIP recommended the sequential vaccination regimen of PCV13 
followed by PPSV23 for all adults ≥65 years of age, with the intent to reevaluate this 
recommendation. The guideline was updated in 2019 to remove the recommendation for 
routine use of PCV13 among adults ≥65 years and continued to recommend a routine single 
dose of PPSV23 for adults aged ≥65 years [Matanock, A., et al 2019]. The ACIP updated the 
guidelines in 2021 to recommend that adults ≥65 years of age should receive either PCV15 
followed by PPSV23, or PCV20 alone [Kobayashi, M., et al 2022].
Risk-based recommendations generally include individuals with an increased risk of 
pneumococcal disease who are categorized as immunocompetent at-risk or as high-risk. 
Conditions associated with immunocompetent at-risk include, but are not limited to, chronic 
heart disease, chronic lung disease (including chronic obstructive pulmonary disease, 
emphysema, and asthma), diabetes mellitus, alcoholism, chronic liver disease (including 
cirrhosis), and cigarette smoking. Conditions associated with high-risk include, but are not 
limited to, congenital or acquired asplenia, sickle cell disease/other hemoglobinopathies, 
chronic renal 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]. In the US, recommendations 
for immunocompetent at-risk individuals 19 to 64 years of age previously included a single 
dose of PPSV23, with the exception of individuals with cochlear implants or CSF leaks, who 
should receive PCV13 followed by PPSV23. High-risk individuals were recommended to
receive 1 dose of PCV13 followed by 1 dose of PPSV23 ≥8 weeks later, and an additional 
dose of PPSV23 ≥5 years later [Matanock, A., et al 2019]. Similar to the age-based 
recommendations, the ACIP guidelines were updated in 2021, and now recommend that 
immunocompetent at-risk individuals and high-risk individuals 19 to 64 years of age receive 
PCV15 followed by PPSV23, or PCV20 alone [Kobayashi, M., et al 2022].
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 
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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 
in the licensed PCVs, particularly in adults. This has resulted in an unmet medical need in 
this population.
V116 is designed to provide significantly broader pneumococcal disease coverage in adults 
as compared to currently licensed pneumococcal vaccines and is anticipated to have a 
generally comparable safety profile. No clinically important safety findings have been 
identified to date based on data from early phase clinical studies with V116.
The benefit-risk profile for V116 supports continued evaluation.
Approximately 25% of participants will receive PPSV23, a vaccine indicated for the 
prevention of pneumococcal disease that is licensed in more than 50 countries worldwide. 
V116 is expected to provide comparable immune responses to PPSV23 for the serotypes in 
common while providing additional coverage for the serotypes unique to V116. It is 
unknown if the investigational V116 will have the same clinical benefit as 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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 18 to 
49 years of age who are administered a single dose of V116 or PNEUMOVAX™23 (also 
known as PPSV23).
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability profile 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
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Objectives
Endpoints
•
Objective: To compare the 
serotype-specific opsonophagocytic 
activity (OPA) Geometric Mean Titers 
(GMTs) at 30 days postvaccination 
across 3 different lots of V116 for all 
serotypes included in V116.
Hypothesis: All 3 lots of V116 are 
equivalent as assessed by the 
serotype-specific OPA GMTs at 30 
days postvaccination for all serotypes 
included in V116.
(The statistical criterion for equivalence 
requires the bounds of the 95% 
confidence interval [CI] of the OPA 
GMT ratio for each pairwise V116 lot-
to-lot comparison to be within 0.5 to 
2.0)
•
Serotype-specific OPA responses
Secondary
•
Objective: To evaluate the 
serotype-specific OPA GMTs at 30 
days postvaccination in combined lots 
of V116 compared with PPSV23 for all
serotypes included in V116.
•
Serotype-specific OPA responses
•
Objective: To evaluate the serotype-
specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination 
compared across the 3 different lots of 
V116 and evaluate combined lots of 
V116 compared with PPSV23 for all 
serotypes included in V116.
•
Serotype-specific IgG responses
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Objectives
Endpoints
•
Objective: To evaluate the 
serotype-specific geometric mean fold 
rises (GMFRs) and proportions of 
participants with a ≥4-fold rise from 
baseline to 30 days postvaccination for 
both OPA and IgG responses separately 
for 3 different lots of V116 for all 
serotypes included in V116.
•
Serotype-specific OPA and IgG 
responses
•
Objective: To evaluate the 
serotype-specific OPA GMTs at 30 
days postvaccination separately for 3 
different lots of V116 for cross-reactive 
immune responses to serotypes within a 
serogroup
•
Serotype-specific OPA responses
Tertiary/Exploratory
•
Objective: To evaluate the cross-
reactive immune responses to serotypes 
within a serogroup at 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 pneumococcal vaccine-naïve adults 18 to 49 years of age.
Approximately 2040 participants who have not previously received any pneumococcal 
vaccine (vaccine-naïve) will be randomized in a 1:1:1:1 ratio to receive a single dose of 
either V116 Lot 1, V116 Lot 2, V116 Lot 3, or PPSV23 on Day 1.
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 postvaccination. 
Unsolicited AEs will be collected through Day 30 postvaccination. All participants will be 
provided an electronic device or have their own electronic device configured, if compatible, 
to complete the eVRC. 
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. 
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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.
Blood samples for immunogenicity assays will be drawn on Day 1 and at 30 days 
postvaccination (Visit 3).
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 serve as a clinical lot consistency study for licensure of V116. This study is 
conducted to demonstrate the consistency of the antibody response to 3 different 
manufactured lots of V116 in vaccine-naïve adults 18 to 49 years of age. PPSV23 is included 
as the active comparator in this study to better characterize the safety profile of V116.
Demonstration of lot-to-lot consistency is often required by some national regulatory 
agencies prior to licensure of investigational vaccines. The objective of a clinical lot-to-lot 
consistency study is to show consistency of manufacturing and clinical performance of the 
final product by demonstrating that 3 consecutively manufactured and final formulated 
clinical lots of the vaccine show comparable safety profiles and elicit equivalent immune 
responses. The sample size of this study will allow for a high statistical probability to 
demonstrate consistency of the immune response across 3 lots of V116, while also bolstering 
the size of the overall safety database of the clinical development program.
Adults 18 to 49 years of age are included in this study to allow evaluation of V116 in a 
population that has an overall lower incidence of disease to reduce the likelihood of 
pre-existing pneumococcal antibodies due to prior infection. Inclusion of this population also 
reduces the likelihood of pre-existing antibodies due to prior vaccination, thus allowing a 
more stringent evaluation of lot-to-lot consistency.
Adults with stable chronic medical conditions will be included in this study. These 
individuals are generally categorized as being immunocompetent at-risk, reflecting the 
understanding that while they are at an increased risk of pneumococcal disease, their immune 
responses are not impacted by the chronic medical condition [Curcio, D., et al 2015] 
[Weycker, D., et al 2010] [van Hoek, A. J., et al 2012].
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints and the associated statistical criteria are consistent with 
previous studies evaluating PCVs.
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Sera from participants will be used to measure vaccine-induced, anti-PnPs serotype-specific 
OPA and IgG responses using the validated MOPA and Pn ECL assay, respectively. 
Immunogenicity endpoints will be assessed 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, and therefore 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, the 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 4-fold rise from 
baseline to 30 days postvaccination for 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.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol 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, 
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more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
4.2.2
Rationale for the Use of Comparator
Placebo-controlled clinical studies for new PCVs are no longer practical given the proven 
clinical efficacy and widespread use of licensed pneumococcal vaccines worldwide.
Of the currently licensed pneumococcal vaccines, PPSV23 has the most serotypes in 
common with V116. Globally, PPSV23 is the pneumococcal vaccine most commonly 
recommended for the prevention of pneumococcal disease in adults.
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.
The dose of PPSV23 selected for use in this study is consistent with the approved global, US,
and EU dosing and product labeling of Pneumovax™ 23.
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 (ie, the 
participant is unable to be contacted by the investigator).
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.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. The participant may have underlying chronic conditions if they are assessed to be stable 
as per the investigator’s judgment.
Demographics
2. Is male or female, from 18 years to 49 years of age inclusive, at the time of informed 
consent.
Female Participants
3.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses an acceptable contraceptive method, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 6 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 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies
-
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.
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-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
4. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide documented informed consent for 
FBR and/or assay development sample collection. However, the participant may be 
enrolled in the study without providing consent for FBR or assay development sample 
collection.
Additional Categories
5. 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 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 of Visit 1 (Day 1).
2. Has a known hypersensitivity to any component of V116 or PPSV23, including 
diphtheria toxoid.
3. Has a known or suspected impairment of immunological function including, but not 
limited to, a history of congenital or acquired immunodeficiency, documented HIV 
infection, functional or anatomic asplenia, or history of autoimmune disease (including 
but not limited to the autoimmune conditions outlined in the Investigator Trial File 
Binder for this study).
4. Has a coagulation disorder contraindicating intramuscular vaccination.
5. *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 <72 hours before receipt of study vaccine.
6. Has a known malignancy that is progressing or has required active treatment <3 years 
before enrollment. 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.
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Prior/Concomitant Therapy
7. Received prior administration of any pneumococcal vaccine or is expected to receive any 
pneumococcal vaccine during the study, outside of the protocol. Exception: participants 
with childhood pneumococcal vaccination prior to the age of 5 will be permitted.
8. *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. Note: physiologic replacement doses (prednisone equivalent of 
approximately 5 mg/day), topical, ophthalmic, intra-articular, or soft-tissue (eg, bursa, 
tendon steroid injections), and inhaled/nebulized steroids are permitted.
9. Is currently receiving 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.
10. *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of 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 study vaccine.
11. *Received any live vaccine ≤30 days before receipt of study vaccine or is scheduled to 
receive any live vaccine ≤30 days after receipt of study vaccine.
12. Received a blood transfusion or blood products, including immunoglobulin ≤6 months 
before receipt of study vaccine or is scheduled to receive a blood transfusion or blood 
product until the Day 30 postvaccination blood draw is complete. Autologous blood 
transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
13. 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
14. In the opinion of the investigator, has a history of clinically relevant drug or alcohol use 
that would interfere with participation in protocol-specified activities.
15. 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, 
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confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study.
16. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
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.
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 and PPSV23) 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 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation Unit Dose Strength(s)
Dosage 
Level(s)
Route 
of 
Admin
Vaccination 
Regimen
Use
IMP
or
NIMP/
AxMP Sourcing
V116 
Lot 1
Experimental
Pneumococcal 
21-valent 
Conjugate 
Vaccine
Biological/
Vaccine
Sterile 
Solution 
(Prefilled 
Syringe)
4 g 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 1 
(Day 1)
Test 
Product
IMP
Central
V116 
Lot 2
Experimental
Pneumococcal 
21-valent 
Conjugate 
Vaccine
Biological/
Vaccine
Sterile 
Solution 
(Prefilled 
Syringe)
4 g 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 1 
(Day 1)
Test 
Product
IMP
Central
V116 
Lot 3
Experimental
Pneumococcal 
21-valent 
Conjugate 
Vaccine
Biological/
Vaccine
Sterile 
Solution 
(Prefilled 
Syringe)
4 g 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 1 
(Day 1)
Test 
Product
IMP
Central
PPSV23
Active 
Comparator
Pneumococcal 
Vaccine, 
Polyvalent 
(23-valent)
Biological/
Vaccine
Sterile 
Solution 
(Prefilled 
Syringe)
25 g 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 1 
(Day 1)
Comparator
IMP
Central
or local
Admin = administration; IM = intramuscular; IMP = investigational medicinal product; NIMP/AxMP =noninvestigational/auxiliary medicinal product; PnPs=pneumococcal 
polysaccharide; PPSV23=pneumococcal vaccine, polyvalent (23-valent) (Pneumovax™ 23); 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 European Economic Area (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 1 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 product(s), which is legally marketed MSD product and medical 
device provided for use in this study are: PNEUMOVAX™23 prefilled syringes. 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 member of the 
study-site staff.
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 
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investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 1:1:1:1 ratio to receive either 
V116 Lot 1, V116 Lot 2, V116 Lot 3, or PPSV23.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. V116 and PPSV23 will be 
prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified study 
site personnel. The participant, the investigator, and Sponsor personnel or delegate(s) who 
are involved in the clinical evaluation of the participants are unaware of the intervention 
assignments.
Because V116 and PPSV23 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 a description of the method of unblinding a participant during the 
study should such action be warranted.
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6.4
Study Intervention Compliance
Given that a single dose of V116 or PPSV23 will be administered in this study, intervention 
compliance will not be assessed.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2). 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.
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 vaccine 
according to the time frames specified in the Exclusion Criteria (Section 5.2).
•
Receipt of systemic corticosteroids (exceeding prednisone equivalent ≥20 mg/day) for 
≥14 consecutive days is prohibited from 14 days before vaccination through 30 days 
following vaccination. Note: physiologic replacement doses (prednisone equivalent of 
approximately 5 mg/day), topical, ophthalmic, intra-articular, 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.
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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.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
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 
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.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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The maximum amount of blood collected from each participant at each visit will not exceed 
80 mL, and the total amount of blood collected over the duration of the study will not exceed 
150 mL (Table 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type
Visit 1
Visit 3
Total
Parameter
Approximate Blood Volume
Immunogenicity 
assessment
30 mL
30 mL
60 mL
DNA for Future 
Biomedical Researcha
8.5 mL
N/A
8.5 mL
Assay developmenta
40 mL
40 mL
80 mL
Expected total
78.5 mL
70 mL
148.5 mL
DNA=deoxyribonucleic acid; N/A= not applicable.
a  Samples for future biomedical research and assay development will only be obtained from participants who provide 
separate consent for collection of these optional 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 
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continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.1.3
Consent and Collection of Specimens for Optional Assay Development
The investigator or medically qualified designee will explain the consent for the optional 
assay development blood samples to the participant, or the participant’s legally acceptable 
representative, answer all of their questions, and obtain documented informed consent before 
performing any procedure related to the optional assay development blood sample collection. 
A copy of the informed consent will be given to the participant.
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.
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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 Visit 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 prior vaccinations and medication taken by 
the participant within 30 days before study vaccination at Visit 1. 
The following must be documented before vaccination at Visit 1 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 medication, if any, taken 
by the participant during the study.
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.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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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 
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 the unblinded 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 
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. 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 vaccination (Section 1.3 
and Section 8.3.3).
Administration of pregnancy tests (if applicable) must be performed before 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 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 vaccines (Section 8.1.5.2) will also be reported. Participants will 
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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 eVRC data and AEs entered into the 
clinical database must be clearly explained in the participant’s source documentation.
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.
8.1.11
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
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.
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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.
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 must be discontinued from study 
intervention, but 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.
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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.
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.
Serotype-specific IgG will be measured using the Pn ECL assay to assess the concentration 
of binding antibodies to capsular polysaccharide of S pneumoniae.
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. For participants who provide optional consent for FBR, 
leftover sera from the study may be used for other purposes, such as the development and/or 
validation of pneumococcal assays after completion of all study-related immunogenicity 
testing.
8.2.1
Multiplex Opsonophagocytic Assay (MOPA)
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 (Pn ECL)
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 
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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.
 
 
ssay validation studies showed excellent 
performance operating characteristics for precision (intra- and inter-assay), 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. 
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard before vaccination at 
Visit 1 (Day 1).
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 vaccination at Visit 1 in WOCBP as described in Section 1.3.
Urine or serum tests can be used, and results must be negative before vaccination can occur. 
A detailed definition of WOCBP 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 subject's participation in the study.
8.3.3
Body Temperature Measurement
Each participant’s body temperature must be taken by study-site staff before 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 
CCI
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tympanic temperature ≥100.4°F [≥38.0°C]; axillary or temporal temperature ≥99.4°F 
[≥37.4°C]) <72 hours before 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 after each vaccination.
8.3.4
Postvaccination Observation Period
All participants will be observed 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.
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).
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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 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.
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 intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, 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 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.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified 
Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(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 towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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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 including those that involve a participant or any user/associated person 
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 Time Period
Injection-site
Injection-site pain/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 of the solicited time 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
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
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8.10
Optional Assay Development Blood Sample Collection
If the participant provides documented informed consent for the optional assay development 
blood samples, these additional blood samples will be used to support future development 
work on improving bioanalytical measurements, which requires high-volume single-donor 
samples to monitor performance of the assay over time.
Sample collection, storage, and shipment instructions for the optional assay development 
blood samples will be provided in the operations/laboratory manual.
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures will be conducted at Visit 1 (Day 1) as outlined in Section 1.3.
Potential participants will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 5.
If Visit 1 is rescheduled (see Section 5.2), a pregnancy test (if applicable), a body 
temperature measurement, a review of inclusion/exclusion criteria, prior 
medications/vaccinations, and medical history must be repeated before vaccination.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section describes the statistical analysis strategy and procedures for the study. The study 
will be amended if, after the study has begun, but prior to any unblinding/final database lock, 
changes are made to primary hypothesis, or the statistical methods related to that hypothesis 
(consistent with ICH Guideline E-9). Changes to exploratory or other nonconfirmatory 
analyses made after the protocol has been finalized, but prior to any unblinding/final database 
lock, 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 SAP are summarized below; the comprehensive plan is provided in 
Section 9.2 through 9.12.
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Study Design Overview
A Phase 3 Randomized, Double-blind, Active Comparator-controlled, 
Lot-to-Lot Consistency Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V116 in Adults 18 to 49 Years of Age
Treatment Assignment
Approximately 2040 participants will be randomly assigned in a 1:1:1:1
ratio into 1 of 4 vaccination groups: V116 Lot 1, V116 Lot 2, V116 Lot 
3, or PPSV23. 
Analysis Populations
Immunogenicity: PP population
Safety: APaT population
Primary Endpoint(s)
Immunogenicity:

Serotype-specific OPA GMTs at 30 days postvaccination for all 
serotypes included in V116
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 OPA GMTs and IgG GMCs at 30 days 
postvaccination for all serotypes included in V116
Statistical Methods for Key 
Immunogenicity Analyses
To compare the serotype-specific OPA GMTs at 30 days postvaccination 
across the 3 different lots of V116, analyses will be conducted for each 
of the 21 serotypes in V116 for the primary immunogenicity objective.
Each possible pairwise comparison of lots will be made (Lot 1 to Lot 2, 
Lot 1 to Lot 3, and Lot 2 to Lot 3) for each serotype. Each pairwise 
comparison of lots will consist of two 1-sided tests at the type 1 error =
0.025 level. Rejecting the null hypothesis of nonequivalence for any test 
is equivalent to requiring the bounds of the 95% CI on the pairwise lot-
to-lot comparison of the GMT ratios to be between 0.5 and 2.0.
Estimation of the serotype-specific OPA GMT ratios and 95% CIs will 
be conducted using the cLDA method [Liang, K-Y and Zeger, S. L. 
2000]. 
Statistical Methods for Key 
Safety Analyses
For the overall safety evaluation, safety parameters will be summarized 
via descriptive statistics. For select safety parameters, between-group 
95% CIs will be provided for the percentage of participants using the 
M&N method [Miettinen, O. and Nurminen, M. 1985].
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 upon request to enable a benefit-risk assessment.
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Multiplicity
The study will be considered to have met the primary objective if success 
is achieved for all 3 pairwise comparisons for V116 lots for all serotypes 
contained in V116. Since comparisons are made individually for each 
serotype and for each pairwise comparison, this approach controls the 
overall type 1 error rate at 0.05 (2-sided), and no multiplicity adjustment 
is required.
Sample Size and Power
This study will randomize approximately 510 participants into each of 3 
manufactured lots of V116 (Lot 1, Lot 2, and Lot 3) and 510 participants 
into the PPSV23 group.
For the primary hypothesis on all serotypes contained in V116, this study 
has > 90% power to demonstrate equivalent immunogenicity across the 3 
V116 lots as assessed by the OPA GMTs at 30 days postvaccination at an 
overall type 1 error = 0.05 (2-sided) level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. 
This study will be conducted as a double-blind study under in-house blinding procedures. 
The 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 intervention assignment. Randomization will be implemented in an IRT. 
Blinding issues related to the planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be evaluated for within- and/or 
between-group differences are listed below.
9.4.1
Immunogenicity Endpoints
Immune responses will be measured for all 21 serotypes contained in V116 (3, 6A, 7F, 8, 9N, 
10A, 11A, 12F, 15A, 15C, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, and 35B), and 2 
cross-reactive serotypes (6C and 15B).
The primary immunogenicity endpoint is the serotype-specific OPA GMTs at 30 days 
postvaccination for all serotypes included in V116.
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The secondary immunogenicity endpoints for all serotypes contained in V116 include the 
following:
•
Serotype-specific OPA GMTs at 30 days postvaccination in combined lots of V116 
compared with PPSV23
•
Serotype-specific IgG GMCs at 30 days postvaccination compared across the 3 different 
lots of V116 and combined lots of V116 compared with PPSV23
•
Serotype-specific GMFRs and proportions of participants with a ≥4-fold rise from 
baseline to 30 days postvaccination for both OPA and IgG responses separately for 3 
different lots of V116
The secondary immunogenicity endpoints for cross-reactive immune responses to serotypes 
within a serogroup include the following:
•
Serotype-specific OPA GMTs at 30 days postvaccination separately for 3 different lots of 
V116
The exploratory immunogenicity endpoints include the summaries of the cross-reactive 
immune responses to serotypes within a serogroup using serotype-specific OPA and IgG 
responses at 30 days postvaccination.
9.4.2
Safety Endpoints
The safety endpoints for overall safety assessment that address the primary objectives 
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
•
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 broad AE categories consisting of any AE, any unsolicited 
AE, and any vaccine-related AE from Day 1 through Day 30 postvaccination.
•
Proportion of participants with broad AE categories consisting of any SAE, any vaccine-
related SAE, and death from Day 1 through the duration of participation in the study. As 
this is a single-dose study, the broad AE category of discontinuation of study intervention 
due to an AE is not applicable.
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•
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 
endpoint(s). Potential deviations that may result in the exclusion of a participant from the PP 
population for all immunogenicity analyses include:
•
Failure to receive any study vaccine at Visit 1 (Day 1)
•
Failure to receive correct clinical material as per randomization schedule at Visit 1 
(Day 1)
•
Receipt of prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant’s 
measurement from a specific time point assessment in the PP population for immunogenicity 
analyses include:
•
Receipt of prohibited medication or prohibited vaccine prior to a blood sample collection
•
Collection of blood sample outside of 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. 
A supportive analysis using the FAS population will also be performed for the primary 
immunogenicity endpoints. The FAS population consists of all randomized participants who 
received 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 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 
intervention group corresponding to the study vaccine actually received.
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At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analyses of temperature.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Methods related to exploratory objectives will be described in 
the sSAP.
Immunogenicity analyses will be conducted for each serotype separately.
Primary Endpoint/Hypothesis (H1)
The primary objective to compare the serotype-specific OPA GMTs at 30 days 
postvaccination across the 3 different lots of V116 for all serotypes included in V116 will be 
assessed via the primary hypothesis.
Each possible pairwise comparison of lots will be made (Lot 1 to Lot 2, Lot 1 to Lot 3, and 
Lot 2 to Lot 3). Each possible pairwise comparison of lots will consist of two 1-sided tests at 
the type 1 error = 0.025 level. Rejecting the null hypothesis of nonequivalence for any test is 
equivalent to requiring the bounds of the 95% CI on the pairwise lot-to-lot comparison of the 
V116 GMT ratios to be between 0.5 and 2.0.
For each serotype in V116 and for each pairwise comparison, OPA GMTs between 
participants administered different lots of V116 at 30 days postvaccination will be compared 
via the following equivalence hypotheses:
H0: GMTx/GMTy ≤0.5 or GMTx/GMTy ≥2.0 versus
H1: 0.5 < GMTX/GMTy <2.0
where GMTx is serotype-specific OPA GMT for one of the V116 lots and GMTy is 
serotype-specific OPA GMT for another V116 lot. A ratio between 0.5 and 2.0 corresponds 
to ensuring that there’s no more than a 2.0-fold difference between OPA GMTs across any of 
the V116 lots (Lot 1 vs Lot 2, Lot 1 vs Lot 3, and Lot 2 vs Lot 3). Rejecting the null 
hypothesis (H0) at the two 1-sided type 1 error = 0.025 level corresponds to the bounds of the 
95% CI on the GMT ratio between each V116 lot (Lot 1/Lot 2, Lot 1/Lot 3, and Lot 2/Lot 3) 
being between 0.5 and 2.0 and would lead to the conclusion that the OPA responses across 
the V116 lots are equivalent.
Estimation of the GMT ratios, 95% CIs, and the hypothesis test (ie, 1-sided p-value) will be 
conducted using a cLDA method proposed by Liang and Zeger [Liang, K-Y and Zeger, S. L. 
2000] utilizing data from the participants randomized to the 3 V116 lots. In this model, the 
response vector consists of the log-transformed antibody titers at baseline and 30 days 
postvaccination. The repeated-measures model will include terms for vaccination group 
(V116 Lot 1, V116 Lot 2, and V116 Lot 3), time, and the interaction of time-by-vaccination 
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group (with a restriction of the same baseline mean across groups). This model will restrict 
the baseline mean to be the same for all V116 vaccination groups. The term for time will be 
treated as a categorical variable. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. The Kenward-Roger adjustment will be used with 
REML to make proper statistical inference. This model allows the inclusion of participants 
who are missing either the baseline or postbaseline measurements, thereby increasing 
efficiency.
Secondary Endpoints
A similar statistical model as used for the primary objective will be used to address the 
secondary objective that evaluates the serotype-specific IgG GMCs at 30 days 
postvaccination across 3 different lots of V116, and the secondary objective that evaluates
the combined lots of V116 with PPSV23 for both OPA GMTs and IgG GMCs. 
Given the disparity in sample size across the intervention groups for the combined lots of 
V116 versus PPSV23 comparison, convergence issues for the model are possible due to 
sensitivity of the model to differences in covariance structure between time points across 
intervention groups. Details of the methods to be used for this analysis if any of the models 
fail to converge will be provided in the sSAP.
Descriptive statistics with point estimates and within-group 95% CIs will be provided for all 
other immunogenicity 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].
Reverse Cumulative Distribution Curves for both OPA titers and IgG concentrations at 
30 days postvaccination with each lot of V116 will be graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 5.
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Table 5
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical 
Method
Analysis 
Population
Missing Data Approach
Primary Endpoint
OPA GMTs at 30 days 
postvaccination for all 
serotypes included in V116
P
cLDAb
(estimate, 95% 
CI, p-values)
PP
Model-based
S
FAS
Secondary Endpoint
OPA GMTsc and IgG GMCsc
at 30 days postvaccination for 
all serotypes included in V116
P
cLDAb
(estimate, 95% 
CI)
PP
Model-based
GMFRs and proportions of 
participants with a ≥4-fold rise 
from baseline to 30 days 
postvaccination for both OPA 
and IgG responses for all 
serotypes included in V116
P
Descriptive 
Statistics
(estimate, 95% 
CI)
PP
Missing data will not be 
imputed
OPA GMTs at 30 days 
postvaccination for the cross-
reactive serotypes
P
Descriptive 
Statistics
(estimate, 95% 
CI)
PP
Missing data will not be 
imputed
CI = confidence interval; cLDA = constrained longitudinal data analysis; FAS = Full Analysis Set; 
GMC = Geometric Mean Concentration; GMFR = geometric mean fold rise; GMT = Geometric Mean Titer; 
IgG = Immunoglobulin G; OPA= opsonophagocytic killing activity; PP = Per-Protocol.
a P = Primary approach; S = Supportive approach.
b cLDA model with terms for vaccination group, time, and the interaction of time-by-vaccination.
c Include the following endpoints: serotype-specific OPA GMTs at 30 days postvaccination in combined lots 
of V116 compared with PPSV23; serotype-specific IgG GMCs at 30 days postvaccination compared across 
the 3 different lots of V116 and combined lots of V116 compared with PPSV23.
Baseline is the day of vaccination (Day 1); 30 days postvaccination is the day of the Visit 3 blood draw 
(Day 30).
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.
Consistency of the safety profile across lots will be assessed via point estimates and 95% CIs 
(for select safety endpoints) for each lot of the V116 separately. Details will be provided in 
the sSAP. The evaluation of safety will be performed for V116 overall (combining the Lot 1, 
Lot 2, and Lot 3) versus the PPSV23 group as detailed below (Table 6). 
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9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary (ie, number and percentage) by 
intervention group (V116 overall and PPSV23 group) of participants with any AEs, any 
unsolicited AEs, any vaccine-related AEs, any SAEs, any vaccine-related SAEs, and any
AEs resulting in death after vaccination. Point estimates and 95% CIs for the between-
treatment differences (combined lots of V116 compared with PPSV23) in the percentages of 
participants with the event will be provided for these events. 
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 95% CIs for the differences between intervention groups in the percentages of 
participants with specific AEs will be provided for solicited AEs and AEs that occur in ≥1% 
of participants in the combined lots of V116 group or PPSV23 group. Events reported less 
frequently than in 1% of participants would obscure the assessment of the overall safety 
profile and add little to the interpretation of potentially meaningful differences.
The number and percentage of participants with maximum temperature measurements 
meeting the Brighton Collaboration cut points [Marcy, S. M., et al 2004] will be provided 
along with point estimates and 95% CIs of between-group differences to evaluate elevated 
temperatures.
CIs for between-group differences will be provided using the M&N method [Miettinen, O. 
and Nurminen, M. 1985]. CIs that are not adjusted for multiplicity 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 of between-group differences. Rainfall plots with point 
estimates and 95% CIs will be displayed for AEs that occur in ≥5% of participants in the 
combined lots of V116 group or PPSV23 group.
The analysis strategy for safety endpoints is summarized in Table 6.
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Table 6
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% Between-
group CI
Graphical 
Display
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
Deathb
X
X
Specific AEs by SOC and PTc
X
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, 95% Between-group CI, and Graphical Display will be provided for specific AEs with 
incidence >0%, ≥1%, and ≥5% of participants, respectively, in the combined V116 group or the PPSV23group.
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 (age, race, ethnicity, sex, and gender), baseline characteristics, and prior and 
concomitant vaccinations and medications will be summarized by intervention 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 
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in Appendix 1. In addition, unblinded immunogenicity data will be made available to the 
DMC upon 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 the 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, this 
oversight committee of the Sponsor (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 
by the external unblinded statistician. 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
The study will be considered to have met the primary objective if success is achieved for all 
3 pairwise comparisons for V116 lots for all serotypes contained in V116. Since comparisons 
are made individually for each serotype and for each pairwise comparison, this approach 
controls the overall type 1 error rate at 0.05 (2-sided), and no multiplicity adjustment is 
required.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This study will randomize approximately 510 participants to receive each of 3 manufactured 
lots of V116 (Lot 1, Lot 2, and Lot 3) and 510 participants to receive PPSV23.
Primary Immunogenicity Endpoint/Hypothesis (H1)
For the primary hypothesis, this study has >90% power to demonstrate equivalent 
immunogenicity across the 3 V116 lots as assessed by the OPA GMTs at 30 days 
postvaccination for all serotypes contained in V116 at an overall type 1 error = 0.05 (2-
sided). The power and sample size are based on the following assumptions:
•
90% evaluability rate (approximately 459 evaluable participants in each of 
3 manufactured lots of V116)
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•
The underlying serotype-specific OPA GMT ratios are 1.0 for all serotypes
•
The variabilities for OPA titers in the V116 vaccination groups are the same as those 
observed in V116-001 Phase 2 for all serotypes. That is, the standard deviations of the 
natural log titers range from 1.06 to 1.95
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an 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 
1530 participants in V116 group (Lot 1, Lot 2, Lot 3 combined) if the underlying incidence 
of an SAE is 0.11% (1 of every 951 participants receiving the vaccine). There is a 50% 
chance of observing at least 1 SAE among 1530 participants in the V116 group if the 
underlying incidence of an SAE is 0.046% (1 of every 2208 participants receiving the 
vaccine). If no SAEs are observed among 1530 participants, this study will provide 97.5% 
confidence that the underlying percentage of participants with an SAE is <0.24% (1 in every 
415 participants) in the V116 group (Lot 1, Lot 2, Lot 3 combined).
The percentage point differences between the 2 intervention groups that could be detected 
with 80% probability are summarized in Table 7 for a variety of hypothetical underlying 
incidences of an AE.
Table 7
Differences in the Incidence of Adverse Event Rates Between the 2 Intervention
Groups That Can be Detected With an Approximately 80% Probability 
Incidence of Adverse Event
Risk Difference
V116 (%)
N=1530
PPSV23 (%)
N=510
Percentage Points
1.1
0.1
1.0
4.4
2.0
2.4
8.5
5.0
3.5
14.6
10.0
4.6
20.4
15.0
5.4
26.0
20.0
6.0
36.7
30.0
6.7
The incidences presented here are hypothetical and do not represent actual adverse experiences in either 
group. The incidences assume a 2-sided 5% alpha level, with sample sizes of 1530 participants in the V116 
group (Lot 1, Lot 2, Lot 3 combined) and 510 participants in the PPSV23 group. No multiplicity adjustments 
were made.
The calculations are based on an asymptotic method proposed by Farrington and Manning (1990)[Farrington, 
C. P. 1990].
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9.10
Subgroup Analyses
Subgroup analyses will be performed for select safety endpoints as well as primary 
immunogenicity endpoints. The following subgroups are planned for evaluation:
•
Chronic medical condition
•
Sex
•
Race
•
Ethnicity
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 PPSV23, compliance will not be 
calculated. However, the number and proportion of randomized participants receiving V116 
or PPSV23 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 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 Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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.
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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 pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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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 
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 
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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 a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to 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.
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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.
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 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
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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 
WOCBP)
hCG=human chorionic gonadotropin; WOCBP=women of childbearing potential
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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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.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.4
Recording AE 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 make an assessment of overall intensity grade for each AE and SAE 
(and other reportable event) reported during the study. An overall intensity grade will be 
assigned to injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The overall intensity grading scales 
used in this study 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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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 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/Redness
Size measured as
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or 
exfoliative 
dermatitis or 
results in ER visit 
or hospitalization
Swelling
Size measured as 
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or ER 
visit or 
hospitalization
Other 
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins ≥6 days after receipt of study vaccine/placebo
Pain/Tenderness
Erythema/Redness
Swelling
Other
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ER visit or 
hospitalization
AE=adverse event; ER=emergency room; eVRC=electronic Vaccine Report Card
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 2007” [Food 
and Drug Administration 2007].
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Specific Systemic AE Overall Intensity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-
threatening
(Grade 4)
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ER visit or 
hospitalization
ER=emergency room
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].
Other Systemic AE Overall Intensity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-
threatening
(Grade 4)b
Illness or clinical 
AE (as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and required 
medical intervention
ER visit or 
hospitalization
AE=adverse event; ER=emergency room; 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 upon information provided by the patient on the eVRC and verbally during the eVRC review during the primary 
safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be based upon the 
initial report and/or follow-up of the event.
b AEs resulting in death will be assessed as Grade 4.
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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.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
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(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
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.
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•
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.
10.3.5
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).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: 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 two 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 which 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: 

Is life-threatening, 

Results in permanent impairment of a body function or permanent damage to a body 
structure, or 

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 judgement 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.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc
•
IUSd
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods).
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.   Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.   Scope of Future Biomedical 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.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical 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 are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.   Biorepository Specimen 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, 
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 utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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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.
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.
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13. References
1.   National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.   Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
AE
adverse event 
APaT
All-Participants-as-Treated
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained Longitudinal Data Analysis
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
deOAc
de-O-acylated
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
EMA
European Medicines Agency
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
GCP
Good Clinical Practice 
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMT
geometric mean titer
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IA(s)
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
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 diseases
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
M&N
Miettinen and Nurminen
MOPA
Multiplexed Opsonophagocytic Assay
mRNA
messenger RNA
NIMP
noninvestigational medicinal product
NSAE
nonserious adverse event
OPA
opsonophagocytic killing activity
PCV
pneumococcal conjugate vaccine
PCV13
Prevnar 13™
PCV15
VAXNEUVANCE™ (Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 
19A, 19F, 22F, 23F, and 33F)
Pn ECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide
PP
per-protocol
PPSV23
PNEUMOVAX™23 (Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 
11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F)
PQC
product quality complaint
PT
preferred term
REML
restricted maximum likelihood
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
SLAB
Supplemental laboratory test(s)
SUSAR
suspected unexpected serious adverse reaction
US
United States
VRC
Vaccination Report Card
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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[03RKY7]
08JDW9

PRODUCT:  V116  
102
PROTOCOL/AMENDMENT NO.:  004-01  
V116-004-01 FINAL PROTOCOL
21-OCT-2022
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[04KVRV]
08JDW9

PRODUCT:  V116  
103
PROTOCOL/AMENDMENT NO.:  004-01  
V116-004-01 FINAL PROTOCOL
21-OCT-2022
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[04KTF2]
08JDW9

PRODUCT:  V116  
104
PROTOCOL/AMENDMENT NO.:  004-01  
V116-004-01 FINAL PROTOCOL
21-OCT-2022
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08JDW9