A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by Administration of PNEUMOVAX™23 Eight Weeks Later in Children Infected With Human Immunodeficiency Virus (HIV) (PNEU-WAY PED)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03921424 
Document Date: 
27-MAR-2019
A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator 
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of 
V114 Followed by Administration of PNEUMOVAX™23 Eight Weeks Later 
in Children Infected with Human Immunodeficiency Virus (HIV) (PNEU–
WAY PED)

PRODUCT: V114  
1
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed 
by Administration of PNEUMOVAX™23 Eight Weeks Later in Children Infected with 
Human Immunodeficiency Virus (HIV) (PNEU–WAY PED)
Protocol Number: 030-00
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
EudraCT
14115
2019-000341-12
Approval Date: 27 March 2019
 
 
056H74
06DQ25

PRODUCT: V114  
2
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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
 
 
056H74
06DQ25

PRODUCT: V114  
3
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original Protocol
27-Mar-2019
Not applicable
 
 
056H74
06DQ25

PRODUCT: V114  
4
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
1
PROTOCOL SUMMARY ............................................................................................11
1.1
Synopsis.................................................................................................................11
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities (SoA)................................................................................16
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................23
2.2.1
V114 and Pneumococcal Disease................................................................23
2.2.2
Preclinical and Clinical Studies ...................................................................24
2.2.3
Information on Other Study-related Therapy ..............................................24
2.2.3.1
Prevnar 13™......................................................................................24
2.2.3.2
PNEUMOVAX™23..........................................................................24
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................25
4
STUDY DESIGN............................................................................................................26
4.1
Overall Design......................................................................................................26
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................28
4.2.1.1
Immunogenicity Endpoints................................................................28
4.2.1.2
Safety Endpoints................................................................................29
4.2.1.3
Future Biomedical Research..............................................................29
4.2.2
Rationale for the Use of Comparator...........................................................29
4.3
Justification for Dose...........................................................................................30
4.4
Beginning and End of Study Definition .............................................................30
4.4.1
Clinical Criteria for Early Study Termination .............................................30
5
STUDY POPULATION ................................................................................................30
5.1
Inclusion Criteria.................................................................................................30
5.2
Exclusion Criteria................................................................................................31
5.3
Lifestyle Considerations......................................................................................34
5.4
Screen Failures.....................................................................................................34
5.5
Participant Replacement Strategy......................................................................34
6
STUDY INTERVENTION............................................................................................34
6.1
Study Intervention(s) Administered...................................................................34
6.2
Preparation/Handling/Storage/Accountability .................................................36
 
 
056H74
06DQ25

PRODUCT: V114  
5
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
6.2.1
Dose Preparation..........................................................................................36
6.2.2
Handling, Storage, and Accountability........................................................36
6.3
Measures to Minimize Bias: Randomization and Blinding..............................37
6.3.1
Intervention Assignment..............................................................................37
6.3.2
Stratification.................................................................................................37
6.3.3
Blinding........................................................................................................37
6.4
Study Intervention Compliance..........................................................................38
6.5
Concomitant Therapy..........................................................................................38
6.5.1
Rescue Medications and Supportive Care ...................................................38
6.6
Dose Modification (Escalation/Titration/Other)...............................................38
6.7
Intervention After the End of the Study............................................................39
6.8
Clinical Supplies Disclosure................................................................................39
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................39
7.1
Discontinuation of Study Intervention...............................................................39
7.2
Participant Withdrawal From the Study...........................................................40
7.3
Lost to Follow-up .................................................................................................40
8
STUDY ASSESSMENTS AND PROCEDURES........................................................41
8.1
Administrative and General Procedures ...........................................................42
8.1.1
Informed Consent/Assent.............................................................................42
8.1.1.1
General Informed Consent/Assent.....................................................42
8.1.1.2
Consent/Assent and Collection of Specimens for Future
Biomedical Research .........................................................................43
8.1.2
Inclusion/Exclusion Criteria ........................................................................43
8.1.3
Participant Identification Card.....................................................................43
8.1.4
Medical History ...........................................................................................43
8.1.5
Prior and Concomitant Medications Review...............................................44
8.1.5.1
Prior Medications...............................................................................44
8.1.5.2
Concomitant Medications..................................................................44
8.1.6
Assignment of Screening Number...............................................................44
8.1.7
Assignment of Treatment/Randomization Number.....................................44
8.1.8
Study Intervention Administration ..............................................................45
8.1.8.1
Timing of Dose Administration.........................................................46
8.1.9
Electronic Vaccination Report Card ............................................................46
8.1.10
Day 15 Postdose Telephone Contact Guide.................................................46
8.1.11
Telephone Contact Questionnaire................................................................47
8.1.12
Discontinuation and Withdrawal .................................................................47
8.1.12.1
Withdrawal From Future Biomedical Research ................................47
 
 
056H74
06DQ25

PRODUCT: V114  
6
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.1.13
Participant Blinding/Unblinding..................................................................48
8.1.14
Calibration of Equipment.............................................................................48
8.2
Immunogenicity Assessments .............................................................................48
8.2.1
Pneumococcal Electrochemiluminescence (PnECL)...................................49
8.2.2
Multiplex Opsonophagocytic Assay (MOPA).............................................49
8.3
Safety Assessments...............................................................................................49
8.3.1
Physical Examinations.................................................................................50
8.3.2
Pregnancy Test.............................................................................................50
8.3.3
HIV Serology, CD4+ T-cell count, and Plasma HIV RNA Testing............50
8.3.4
Body Temperature Measurement.................................................................50
8.3.5
Safety Assessments and Use of the eVRC...................................................51
8.3.6
Clinical Laboratory Assessments.................................................................51
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................52
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................52
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......54
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...54
8.4.4
Regulatory Reporting Requirements for SAE .............................................54
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................54
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................55
8.4.7
Events of Clinical Interest (ECIs) ................................................................55
8.5
Treatment of Overdose........................................................................................55
8.6
Pharmacokinetics.................................................................................................55
8.7
Pharmacodynamics..............................................................................................55
8.8
Biomarkers ...........................................................................................................55
8.9
Planned Genetic Analysis Sample Collection....................................................55
8.10
Future Biomedical Research Sample Collection...............................................55
8.11
Health Economics Medical Resource Utilization and Health Economics.......56
8.12
Visit Requirements...............................................................................................56
8.12.1
Screening......................................................................................................56
8.12.2
Treatment Period/Vaccination Visit ............................................................56
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........56
9
STATISTICAL ANALYSIS PLAN .............................................................................56
9.1
Statistical Analysis Plan Summary.....................................................................57
9.2
Responsibility for Analyses/In-house Blinding .................................................58
9.3
Hypotheses/Estimation ........................................................................................58
 
 
056H74
06DQ25

PRODUCT: V114  
7
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
9.4
Analysis Endpoints...............................................................................................58
9.4.1
Immunogenicity Endpoints..........................................................................58
9.4.2
Safety Endpoints..........................................................................................59
9.5
Analysis Populations............................................................................................60
9.5.1
Immunogenicity Analysis Populations ........................................................60
9.5.2
Safety Analysis Populations ........................................................................60
9.6
Statistical Methods...............................................................................................61
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................61
9.6.2
Statistical Methods for Safety Analyses ......................................................62
9.6.3
Demographic and Baseline Characteristics .................................................64
9.7
Interim Analyses ..................................................................................................64
9.8
Multiplicity ...........................................................................................................64
9.9
Sample Size and Power Calculations .................................................................65
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................65
9.9.2
Sample Size and Power for Safety Analyses ...............................................65
9.10
Subgroup Analyses...............................................................................................66
9.11
Compliance (Medication Adherence).................................................................66
9.12
Extent of Exposure...............................................................................................66
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................67
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........67
10.1.1
Code of Conduct for Clinical Trials.............................................................67
10.1.2
Financial Disclosure.....................................................................................69
10.1.3
Data Protection.............................................................................................69
10.1.3.1
Confidentiality of Data ......................................................................70
10.1.3.2
Confidentiality of Participant Records...............................................70
10.1.3.3
Confidentiality of IRB/IEC Information............................................70
10.1.4
Committees Structure...................................................................................70
10.1.4.1
Scientific Advisory Committee..........................................................70
10.1.4.2
Executive Oversight Committee........................................................70
10.1.4.3
External Data Monitoring Committee ...............................................71
10.1.5
Publication Policy........................................................................................71
10.1.6
Compliance with Study Registration and Results Posting Requirements ...71
10.1.7
Compliance with Law, Audit, and Debarment ............................................72
10.1.8
Data Quality Assurance ...............................................................................72
10.1.9
Source Documents .......................................................................................73
10.1.10
Study and Site Closure.................................................................................74
10.2
Appendix 2: Clinical Laboratory Tests..............................................................75
 
 
056H74
06DQ25

PRODUCT: V114  
8
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................76
10.3.1
Definition of AE ..........................................................................................76
10.3.2
Definition of SAE ........................................................................................77
10.3.3
Additional Events Reported.........................................................................78
10.3.4
Recording AE and SAE ...............................................................................78
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................81
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................83
10.5
Appendix 5: Contraceptive Guidance................................................................84
10.5.1
Definitions....................................................................................................84
10.5.2
Contraception Requirements........................................................................85
10.5.3
Pregnancy Testing........................................................................................86
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................87
10.7
Appendix 7: Country-specific Requirements....................................................92
10.8
Appendix 8: Abbreviations .................................................................................93
11
REFERENCES...............................................................................................................95
 
 
056H74
06DQ25

PRODUCT: V114  
9
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
LIST OF TABLES
Table 1
Study Interventions..........................................................................................35
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types...42
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................53
Table 4
Analysis Strategy for Immunogenicity Variables............................................62
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination...........63
Table 6
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying 
Standard Deviations With 160 Evaluable Participants in Each Vaccination 
Group ...............................................................................................................65
Table 7
Protocol-required Safety Laboratory Assessments..........................................75
 
 
056H74
06DQ25

PRODUCT: V114  
10
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
LIST OF FIGURES
Figure 1
V114-030 Study Design.............................................................................15
 
 
056H74
06DQ25

PRODUCT: V114  
11
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed 
by Administration of PNEUMOVAX™23 Eight Weeks Later in Children Infected with 
Human Immunodeficiency Virus (HIV) (PNEU–WAY PED)
Short Title: Safety and Immunogenicity of V114 in Children Infected with HIV
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-030 (PNEU–WAY PED)
Hypotheses, Objectives, and Endpoints:
There is no formal hypothesis testing in this study.
The following objectives and endpoints will be evaluated in children 6 to 17 years of age 
inclusive infected with HIV (CD4+ T-cell count ≥200 cells/µL and plasma HIV RNA 
<50,000 copies/mL tested at Screening [Visit 1]).
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following vaccination with V114:
- Solicited injection-site AEs from Day 1 
through Day 14 postvaccination
- Solicited systemic AEs from Day 1 
through Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
- Objective: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
Geometric Mean Concentrations (GMCs) at 
30 days postvaccination (Day 30) with V114 
or Prevnar 13™ by each vaccination group.
- Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained in 
V114 at Day 30
 
 
056H74
06DQ25

PRODUCT: V114  
12
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the safety and 
tolerability of PNEUMOVAX™23 
administered 8 weeks following V114 with 
respect to the proportion of participants with 
AEs.
Following vaccination with 
PNEUMOVAX™23:
- Solicited injection-site AEs from Day 1 
through Day 14 postvaccination
- Solicited systemic AEs from Day 1 
through Day 14 postvaccination
- Objective: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic activity 
(OPA) Geometric Mean Titers (GMTs) at 30 
days postvaccination (Day 30) with V114 or 
Prevnar 13™ by each vaccination group.
- Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes contained in 
V114 at Day 30
- Objective: To evaluate the anti-PnPs 
serotype-specific OPA GMTs and IgG 
GMCs at 30 days postvaccination with 
PNEUMOVAX™23 (Week 12) by each 
vaccination group.
- Anti-PnPs Serotype-specific OPA and 
IgG responses for the 15 serotypes 
contained in V114 at Week 12
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Children 6 to 17 years of age infected with HIV
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
 
 
056H74
06DQ25

PRODUCT: V114  
13
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Masking
Participant or Subject
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 19 months from the time the first 
participant signs the informed consent/assent until the last 
participant’s last study-related telephone call or visit.
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 400 participants will be randomized, with approximately 200 participants in 
each intervention group.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
V114
V114
Refer to 
IB
Single 
dose
IM
Single Dose 
at Visit 2
(Day 1)
Experi
mental
PNEUMOVAX™23
Refer to 
product 
labeling
Single 
dose
IM
Single Dose 
at Visit 4 
(Week 8)
Experi
mental
Prevnar 
13™
Prevnar 13™
Refer to 
product 
labeling
Single 
dose
IM
Single Dose 
at Visit 2
(Day 1)
Experi
mental
PNEUMOVAX™23
Refer to 
product 
labeling
Single 
dose
IM
Single Dose 
at Visit 4 
(Week 8)
Experi
mental
Abbreviations: Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular
 
 
056H74
06DQ25

PRODUCT: V114  
14
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 6 months
from the time the participant or participant’s legally acceptable 
representative signs the Informed Consent Form (ICF) through the final 
contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
056H74
06DQ25

PRODUCT: V114  
15
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
1.2
Schema
The key components of the study design are depicted in Figure 1.
Figure 1
V114-030 Study Design
 
 
056H74
06DQ25

PRODUCT: V114  
16
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
1.3
Schedule of Activities (SoA)
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
Administrative and General Procedures
Screening Procedures
Informed Consent/Assent
X
Consent/assent must be 
obtained before any 
study procedures.
Informed Consent/Assent for Future 
Biomedical Research
X
Participation in future 
biomedical research is 
optional and 
consent/assent must be 
obtained before the 
collection of saliva DNA 
samples.
Assignment of Screening Number
X
Participant Identification Card
X
X
Inclusion/Exclusion Criteria
X
X
Review of prior 
medications/vaccinations
, a complete physical 
examination, 
temperature 
measurement, and 
pregnancy testing are 
required at Visit 2 (Day 
1) to determine 
eligibility.
Serum for HIV Serology
X
Blood Sample for CD4+ T-cell 
Count
X
 
 
056H74
06DQ25

PRODUCT: V114  
17
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
Blood Sample for Plasma HIV RNA 
Testing
X
Medical History
X
X
The participant’s 
medical history for the 5 
years prior to these visits 
will be reviewed.
Post-Randomization Procedures
Assignment of Randomization 
Number
X
Prior/Concomitant Medication and 
Non-Study Vaccination Review
X
X
X
X
X
X
X
V114 or Prevnar 13™ 
Administration (Blinded)
X
At Visit 2 (Day 1),
participants will receive 
either a single dose of
V114 or a single dose of 
Prevnar 13™.
PNEUMOVAX™23 Administration 
(Open-label)
X
At Visit 4 (Week 8), all 
participants will receive 
a single dose of 
PNEUMOVAX™23.
 
 
056H74
06DQ25

PRODUCT: V114  
18
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
Provide eVRC
X
An eVRC will be 
provided at Visit 2 (Day 
1) to record AEs, body 
temperature, 
concomitant 
medications, and non-
study vaccinations. 
Instructions for using the 
eVRC will be reviewed 
with the participant or 
participant’s legally 
acceptable 
representative.
Review eVRC data with Participant 
or Participant’s Legally Acceptable 
Representative
X
X
X
X
See Section 8.1.9 for 
details.
Collect eVRC from Participant or 
Participant’s Legally Acceptable 
Representative
X
Complete the Telephone Contact 
Questionnaire 
X
See Section 8.1.11 for 
details.
Safety Procedures
Complete Physical Examination 
X
To be performed by the 
investigator or medically 
qualified designee before 
study vaccine is 
administered (see 
Section 8.3.1).
 
 
056H74
06DQ25

PRODUCT: V114  
19
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
Targeted Physical Examination
X
To be performed by the 
investigator or medically 
qualified designee before 
study vaccine is 
administered (see 
Section 8.3.1).
Pregnancy Test – if applicable
X
X
A pregnancy test 
consistent with local 
requirements must be 
performed before 
administration of the 
study vaccine in women 
of child-bearing 
potential. Urine or serum 
tests can be used, and 
results must be negative 
before vaccination can 
occur.
Body Temperature Measurement
X
X
Each participant’s body 
temperature must be 
taken before vaccination 
(see Section 8.3.4 for 
method). Participants 
who have febrile illness 
at or within 72 hours of 
vaccination must be 
rescheduled.
30-Minute Postvaccination 
Observation Period
X
X
To be performed by 
blinded study site 
personnel only.
 
 
056H74
06DQ25

PRODUCT: V114  
20
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
AE Monitoring
X
X
X
X
X
X
X
X
Nonserious AEs are to 
be reported from Days 1 
through 14 following 
each vaccination. SAEs 
and deaths are to be 
reported throughout the 
duration of an 
individual’s study 
participation. AEs 
(serious and nonserious) 
that occur after the 
consent is signed, but 
before 
allocation/randomization
, are also to be reported 
(Section 8.4.1).
Immunogenicity Procedures
Serum for Immunogenicity Assays 
(Including Retention Serum)
X
X
X
Blood samples must be 
collected before study 
vaccination when 
applicable.
 
 
056H74
06DQ25

PRODUCT: V114  
21
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Study Period
Screening
Intervention
Follow-up
Comments
Visit Number:
1
2
Telephone 
Contact
3
4
Telephone 
Contact
5
Telephone 
Contact
Scheduled Time:
Screening
Day 1
Day 15
Day 30
Week 8
Week 10
Week 12
Month 6
Visit Window:
30 days 
or less 
after 
Visit 1
Day 15 to 
Day 19
after
Visit 2a
Day 30 to 
Day 44 
after
Visit 2a
Day 56 to 
Day 70 
after
Visit 2a
Day 15 to 
Day 19 
after
Visit 4b
Day 30 to
Day 44 
after
Visit 4b
Day 166 to 
Day 194 
after
Visit 2a
The results from all 
screening procedures at 
Visit 1 must be 
available before 
enrollment into the 
study at Visit 2 (Day 1).
Future Biomedical Research
Saliva (DNA) for Future Biomedical 
Research
X
Saliva DNA samples for 
analysis should be 
obtained prior to
vaccination at Visit 2, on 
randomized and FBR-
consented participants 
only, or at a later date as 
soon as the informed 
consent is obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic Vaccination Report Card; FBR = future biomedical research; HIV = human immunodeficiency virus; RNA 
= ribonucleic acid; SAE = serious adverse event
a
The Telephone Contact (Day 15), Visit 3 (Day 30), Visit 4 (Week 8), and Month 6, should be scheduled relative to the date of Visit 2 (Day 1).
b
The Telephone Contact (Week 10) and Visit 5 (Week 12) should be scheduled relative to the date of Visit 4.
 
 
056H74
06DQ25

PRODUCT: V114  
22
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent 
pneumococcal conjugate vaccine (PCV) (referred to as V114) for the prevention of 
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 23F) present in the licensed vaccine Prevnar 
13™ (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein], Wyeth 
Pharmaceuticals, a subsidiary of Pfizer, Inc., Philadelphia, PA), plus 2 additional serotypes 
(22F, 33F).
2.1
Study Rationale
Human immunodeficiency virus (HIV) infection leads to defects in the humoral and cell-
mediated immune systems of infected children. These children are then at an increased risk 
for infection with various microbial agents, including Streptococcus pneumoniae [Janoff, E. 
N., et al 1992] [Janoff, E. N., et al 1993] [Bliss, S. J., et al 2008] [Madhi, S. A., et al 2000] 
[Madhi, S. A., et al 2000]. The incidence of invasive pneumococcal disease (IPD) is 
estimated to be 9- to 43-fold higher in HIV infected children as compared with HIV 
uninfected children and this burden is more apparent in resource-poor settings [Madhi, S. A., 
et al 2000] [Madhi, S. A., et al 2001] [Peters, V. B., et al 1994] [Spector, S. A., et al 1994] 
[Dankner, W. M., et al 2001] [Andiman, W. A., et al 1996] [Jones, N., et al 1998] [Nachman, 
S., et al 2005] [Laufer, M. K., et al 2006].
Routine PCV immunization of children is effective in preventing vaccine serotype-specific 
pneumococcal disease, including in HIV infected children, where it has been shown to 
decrease the risk of IPD [Centers for Disease Control and Prevention 2005] [Whitney, C. G., 
et al 2003]. Given the high morbidity and mortality associated with IPD, immunization 
guidelines recommend that children and adolescents infected with HIV who have not been 
vaccinated with the 13-valent Prevnar 13™vaccine, receive a catch-up dose of Prevnar 13™. 
These guidelines also recommend that children infected with HIV receive the 23-valent 
pneumococcal polysaccharide (PnPs) vaccine, PNEUMOVAX™23, at least 8 weeks after 
receiving PCV, followed by another dose of PNEUMOVAX™23 not less than 5 years later
[Bliss, S. J., et al 2008] [Robinson, C. L., et al 2018] [Centers for Disease Control and 
Prevention (CDC) 2013] [National Center for Immunization and Respiratory Diseases 2018].
Despite the commercial availability of pneumococcal vaccines, pneumococcal disease 
remains an important worldwide concern due to lack of universal availability of vaccines and 
due to the emergence of non-vaccine serotypes. V114 contains all the pneumococcal 
serotypes contained in Prevnar 13™plus 2 additional serotypes (22F, 33F), which have 
emerged as important causes of IPD (Section 2.2.1).
This clinical study is designed to evaluate the safety, tolerability, and immunogenicity of
V114 in children (6 to 17 years of age inclusive) infected with HIV (CD4+ T-cell count ≥200 
cells/μL and a plasma HIV ribonucleic acid [RNA] value <50,000 copies/mL tested at 
Screening). In comparison to Prevnar 13™, V114 has the potential to provide comparable 
protection against pneumococcal disease caused by the serotypes in common between the 2 
 
 
056H74
06DQ25

PRODUCT: V114  
23
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
vaccines and offer additional protection against IPD caused by the 2 PnPs serotypes (22F and 
33F) not contained in Prevnar 13™.
2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the Investigator’s Brochure (IB) for V114 for detailed background, including 
information on pneumococcal disease burden.
S. pneumoniae remains a significant cause of disease worldwide, with clinical manifestations 
including meningitis, sepsis, pneumonia, sinusitis and otitis media. Currently, many countries 
worldwide have incorporated licensed PCVs (eg, Prevnar 13™ and/or Synflorix™ 
(pneumococcal polysaccharide conjugate vaccine [adsorbed], GlaxoSmithKline Biologicals 
S.A, Rixensart, Belgium) into their infant immunization programs. Prevnar™ was first 
licensed in 2000 and later replaced by Prevnar 13™ in 2009 (European Union) and 2010 
(United States). Synflorix™ was licensed in the European Union in 2009. Although 
Prevnar 13™ is indicated for children and adults, Synflorix™ is only indicated for children 
up to 5 years of age. Widespread use of PCVs have reduced the burden of pneumococcal 
disease caused by the serotypes contained in the vaccines in children who received the 
vaccines, as well as unvaccinated individuals through herd protection [Centers for Disease 
Control and Prevention 2008] [Ruckinger, S., et al 2009] [Farrell, D. J, et al 2007] [Pilishvili, 
Tamara, et al 2010] [Lexau, C. A., et al 2005] [Metlay, J. P., et al 2006] [Whitney, Cynthia 
G., et al 2003] [Moore, M. R., et al 2015] [Lepoutre, A., et al 2015] [Weiss, S., et al 2015] 
[Martinelli, D., et al 2014] [Guevara, M., et al 2016] [Waight, P. A., et al 2015] [Jokinen, J., 
et al 2015] [Palmu, A. A., et al 2015] [Wagenvoort, G. H., et al 2016]. Despite this, an 
increase in the burden of IPD caused by serotypes not contained in currently available 
vaccines has been observed.
V114 contains all the pneumococcal serotypes contained in Prevnar 13™ plus 2 additional 
serotypes (22F, 33F). The selection of 22F and 33F was primarily based on the emergence of 
these 2 serotypes as important causes of IPD in the era of Prevnar™ and Prevnar 13™. 
Approximately 4 years after inclusion of Prevnar™ in the United States infant immunization 
schedule, serotypes 22F and 33F accounted for approximately 13% of IPD cases in children 
<5 years of age (incidence rate of IPD due to 22F and 33F combined of 3.1 cases per 100,000 
person-years), in contrast to 1.3% of IPD cases in the pre-PCV7 era (incidence rate of 22F 
and 33F IPD of 1.2 cases per 100,000 person-years) [Hicks, L. A., et al 2007]. By 2013, both 
22F and 33F were among the leading serotypes causing IPD beyond those already included 
in Prevnar 13™, accounting for approximately 21% of all IPD in children <5 years of age in 
the United States [Moore, M. R., et al 2015].
The additional serotypes contained in V114 will provide broader coverage against the leading 
serotypes associated with pneumococcal disease worldwide. V114 is designed to meet 
continuing medical and public health needs for PCVs globally, as well as address the 
emergence of pneumococcal disease caused by serotypes not contained in currently licensed 
PCVs.
 
 
056H74
06DQ25

PRODUCT: V114  
24
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
V114.
2.2.3
Information on Other Study-related Therapy
2.2.3.1
Prevnar 13™
Refer to approved labeling for detailed background information on Prevnar 13™.
Prevnar 13™ contains the 7 pneumococcal serotypes included in Prevnar™ (4, 6B, 9V, 14, 
18C, 19F, 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A). In many countries, 
Prevnar 13™ is given as a part of routine immunization schedules for all infants and children 
2 to 59 months of age.
Prevnar 13™ was studied in individuals ≥6 years of age infected with HIV in an open-label, 
single-arm, descriptive study. In the study, 3 doses of Prevnar 13™ were administered 1 
month apart to individuals with CD4+ T-cell counts ≥200 cells/µL who had not previously 
been vaccinated with a pneumococcal vaccine. For all vaccine serotypes, antibody responses 
were numerically higher after the first dose compared to prevaccination and generally 
comparable following the first, second and third dose [Bhorat, A. E., et al 2015].
Prevnar™ and Prevnar 13™ are also known as Prevenar™ and Prevenar 13™ in many 
countries outside of the United States; these vaccines will be referred to as Prevnar™ and 
Prevnar 13™ throughout this document.
2.2.3.2
PNEUMOVAX™23
Refer to approved labeling for detailed background information on PNEUMOVAX™23.
PNEUMOVAX™23 is comprised of the polysaccharides from 23 of the most important 
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.
PNEUMOVAX™23 is recommended by World Health Organization (WHO) and the 
Advisory Committee on Immunization Practices (ACIP) for use in children 2 years or older 
at increased risk for pneumococcal disease (including children with HIV infection) [World 
Health Organization Europe 2007] [Kobayashi, M., et al 2015]. In this population, a dose of 
PNEUMOVAX™23 is recommended ≥8 weeks following a dose of Prevnar 13™ 
[Kobayashi, M., et al 2015]. Many countries follow similar age-based and/or risk-based 
recommendations for the use of PNEUMOVAX™23 [Castiglia P. 2014].
 
 
056H74
06DQ25

PRODUCT: V114  
25
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 efficacy of an investigational medicine.
Approximately 50% of participants will receive Prevnar 13™, the standard of care, as the 
active comparator in this study. V114 is expected to provide comparable immune responses 
and a comparable safety profile to Prevnar 13™ for the shared pneumococcal serotypes while 
providing additional coverage for the 2 serotypes (22F and 33F) unique to V114. It is 
unknown if the investigational V114 will have the same benefit/risk profile as Prevnar 13™. 
All participants will also receive PNEUMOVAX™23 after 8 weeks as recommended to 
enhance immune responses and broaden protection against additional serotypes.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent/assent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no formal hypothesis testing in this study.
Objectives
Endpoints
Primary

Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following vaccination with V114:

Solicited injection-site AEs from Day 1 
through Day 14 postvaccination

Solicited systemic AEs from Day 1 
through Day 14 postvaccination

Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation

Objective: To evaluate the 
anti-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G 
(IgG) Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination (Day 
30) with V114 or Prevnar 13™by each
vaccination group.

Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at Day 30
 
 
056H74
06DQ25

PRODUCT: V114  
26
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Objectives
Endpoints
Secondary

Objective: To evaluate the safety and 
tolerability of PNEUMOVAX™23 
administered 8 weeks following V114 
with respect to the proportion of 
participants with AEs.
Following vaccination with 
PNEUMOVAX™23:

Solicited injection-site AEs from Day 1 
through Day 14 postvaccination

Solicited systemic AEs from Day 1
through Day 14 postvaccination

Objective: To evaluate the anti-PnPs 
serotype-specific opsonophagocytic 
activity (OPA) Geometric Mean Titers 
(GMTs) at 30 days postvaccination (Day 
30) with V114 or Prevnar 13™by each 
vaccination group.

Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes 
contained in V114 at Day 30

Objective: To evaluate the anti-PnPs 
serotype-specific OPA GMTs and IgG 
GMCs at 30 days postvaccination with 
PNEUMOVAX™23 (Week 12) by each 
vaccination group.

Anti-PnPs Serotype-specific OPA and 
IgG responses for the 15 serotypes
contained in V114 at Week 12
Tertiary/Exploratory

Objective: To evaluate the Anti-PnPs
serotype-specific Geometric Mean Fold 
Rises (GMFRs) from prevaccination 
(Day 1) to 30 days postvaccination (Day 
30) with V114 or Prevnar 13™for both 
OPA and IgG responses by each 
vaccination group.

Anti-PnPs serotype-specific OPA and 
IgG responses for the 15 serotypes 
contained in V114 at Day 1 and Day 30
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active comparator-controlled, parallel-group, multi-site, double-blind 
(with in-house blinding), study of V114 in participants 6 to 17 years of age inclusive infected 
with HIV. Approximately 400 participants will be randomly assigned in a 1:1 ratio to receive 
either V114 or Prevnar 13™ on Visit 2 (Day 1).
 
 
056H74
06DQ25

PRODUCT: V114  
27
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Randomization will be stratified by CD4+ T-cell count as follows:
•
Stratum 1: CD4+ T-cell count ≥200 to <500 cells/µL.
•
Stratum 2: CD4+ T-cell count ≥500 cells/µL.
Approximately 20% or more of the participants will be enrolled into Stratum 1.
All participants will also receive a single dose of PNEUMOVAX™23 at Visit 4 (Week 8).
Participants will be followed for injection-site and systemic AEs through Day 14 following 
each vaccination. Information for SAEs and deaths, regardless of whether the events are 
considered to be vaccine-related by the investigator, will be collected from the time consent 
is signed through completion of participation in the study. An external Data Monitoring 
Committee (DMC) will conduct a periodic review of safety and tolerability data for the V114 
Phase 3 pediatric 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 immediately before V114 or 
Prevnar 13™ vaccination at Visit 2 (Day 1), at 30 days postvaccination at Visit 3 (Day 30), 
and 30 days after PNEUMOVAX™23 vaccination at Visit 5 (Week 12).
After completion of immunogenicity testing to evaluate the study objectives, serum samples 
will be stored to conduct any additional study-related testing as required by regulatory 
agencies or the Sponsor. For randomized study participants who provided consent/assent for 
future biomedical research, 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.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will be conducted in HIV infected children 6 to 17 years of age inclusive, who (1) 
are PCV naïve, previously vaccinated with a <13-valent PCV, partially vaccinated with 
Prevnar 13™, or have a history of previous Prevnar 13™vaccination ≥3 years and (2) are 
PnPs vaccine naïve or have a history of previous PnPs vaccination ≥5 years.
PCV-induced immunity in HIV infected children is generally lower and less durable than in 
HIV-uninfected children. Long-term studies of efficacy and antibody responses to PCV 
vaccination in HIV infected children indicate a more rapid decline in antibody concentrations 
and a decreased proportion of vaccine serotype-specific antibody concentrations ≥0.2 µg/mL
when compared to HIV uninfected children [Madhi, S. A., et al 2009] [Madhi, S. A., et al 
2007]. HIV-infected children who have received the PCV series ≥3 years prior stand to 
 
 
056H74
06DQ25

PRODUCT: V114  
28
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
benefit from the additional PCV vaccination. A vaccination interval of >5 years for the 
second dose of PnPs vaccine is in keeping the ACIP guidelines for persons at higher risk for 
pneumococcal infection [Kobayashi, M., et al 2015].
This study is designed to evaluate safety and immunogenicity of V114 and includes children 
with CD4+ T-cell counts >200 cells/µL and HIV RNA <50,000 copies/mL as this represents 
a population of children who are less likely to be suffering from opportunistic infection and 
are more likely to mount an immune response to vaccination. The primary and secondary 
immunogenicity endpoints (IgG and OPA) measure anti-pneumococcal serotype-specific 
antibody responses, which are known to be associated with protection from IPD. Injection-
site reactions and systemic symptoms following vaccination will be solicited for 14 days. 
Participants will be followed for 6 months following immunization with V114 or 
Prevnar 13™for reports of SAEs or death. The immunogenicity and safety objectives are 
descriptive with no formal hypotheses.
Stratification according to CD4+ T-cell count will occur at randomization. Stratum 1 
includes children with CD4+ T-cell count of >200 to <500 cells/µL, which represents a 
group of HIV infected individuals with moderate immunosuppression. Stratum 2 includes 
children with CD4+ T-cell count >500 cells/µL, which represents HIV infected individuals 
with minimal immunosuppression. Stratification will allow for equal distribution of
vaccination with V114 or Prevnar™ among participants with moderate and minimal 
immunosuppression.
V114 has the potential to offer additional protection against IPD caused by 2 PnPs serotypes 
not contained in Prevnar 13™ in addition to boosting immune responses to serotypes shared 
with Prevnar 13™. Safety and immunogenicity data collected in this study will support 
recommendations for V114 catch-up vaccination in HIV infected children who received a 
PCV containing fewer than 15 serotypes or who are PCV-naïve.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating PCVs.
The pneumococcal electrochemiluminescence (PnECL) assay and the multiplexed 
opsonophagocytic assay (MOPA) will be used to measure vaccine-induced, anti-PnPs 
serotype-specific immune responses for all 15 serotypes included in V114. PnECL assay
measures serotype-specific IgG concentrations (primary endpoint based on GMCs), and 
MOPA measures serotype-specific OPA titers (secondary endpoint based on GMTs). OPA 
GMTs represent functional antibodies capable of inhibiting growth of S. pneumoniae in 
culture. Additional information on the immunogenicity assays can be found in Section 8.2.
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 
 
 
056H74
06DQ25

PRODUCT: V114  
29
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
for presentation to phagocytic cells for engulfment and subsequent killing, and therefore is 
considered an important immunologic surrogate for protection against IPD. It is noted that 
threshold values that correlate with protection in children with HIV have not been defined for 
either assay.
Details on the immunogenicity endpoints evaluated in this study can be found in 
Section 9.4.1.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs, and guidance
from regulatory agencies during product development. The electronic Vaccination Report 
Card (eVRC) used to record AEs during the post vaccination periods, as defined in 
Section 8.1.9, was structured as recommended in the final Food and Drug Administration 
Patient Reported Outcome Guidance [U.S. Food and Drug Administration 2009].
Details on the safety endpoints evaluated in this study can be found in Section 8.3.5 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Placebo-controlled clinical studies for new PCVs are no longer acceptable given the proven 
clinical efficacy, public health impact, and widespread use of licensed PCVs worldwide. 
Prevnar 13™ is currently the most widely recommended vaccine for the prevention of 
pneumococcal disease in infants and children in many countries worldwide, includes the 
largest number of serotypes, and will be used as the active comparator in this study.
 
 
056H74
06DQ25

PRODUCT: V114  
30
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Refer to approved labeling for detailed background information on Prevnar 13™.
4.3
Justification for Dose
The dosing regimen of V114 is similar to that used for at-risk pediatric populations
(excluding infants) in which 1 dose resulted in a robust immune response and had an 
acceptable safety and tolerability profile.
The doses of Prevnar 13™ and PNEUMOVAX™23 selected for use in this study are the
approved doses.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, 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, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male or female participants infected with HIV between the ages of 6 and 17 years (inclusive) 
will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Is infected with HIV and has a CD4+ T-cell count ≥200 cells/µL and plasma HIV RNA 
<50,000 copies/mL tested at Screening (Visit 1).
 
 
056H74
06DQ25

PRODUCT: V114  
31
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
2. Is PCV naïve, previously vaccinated with a <13-valent PCV, partially vaccinated with 
Prevnar 13™, or has a history of previous Prevnar 13™vaccination ≥3 years before 
Visit 2 (Day 1) (additional guidance is provided in the Investigator Trial File Binder for 
this study).
3. Is PnPs vaccine naïve or has a history of one previous PnPs vaccination ≥5 years before 
Visit 2 (Day 1) (additional guidance is provided in the Investigator Trial File Binder for 
this study).
Demographics
4. Is male or female, from 6 years to 17 years of age inclusive, at the time of obtaining the
informed consent/assent.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
5. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a.
Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP must agree to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 6 weeks after the last dose of study intervention.
Informed Consent/Assent
6. Has a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. As appropriate based on local guidelines, 
the participant will also provide written informed assent for the study. The participant or 
the participant’s legally acceptable representative may also provide assent/consent for 
future biomedical research. However, the participant may participate in the main study 
without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a World Health Organization (WHO) HIV classification of clinical Stage 4 disease 
within the past 12 months (conditions defined in the Investigator Trial File Binder for this 
study).
 
 
056H74
06DQ25

PRODUCT: V114  
32
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
2. *Has a history of active hepatitis with elevation in pretreatment aspartate transaminase or 
alanine transaminase values >5 times the upper limit of normal within 6 months before 
the first vaccination at Visit 2 (Day 1).
3. 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 2 (Day 1).
4. Has a known hypersensitivity to any component of PnPs vaccine, PCV, or any diphtheria 
toxoid-containing vaccine.
5. Has a known or suspected congenital immunodeficiency (other than 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).
6. Has a bleeding disorder contraindicating intramuscular vaccinations.
7. *Had a recent febrile illness (defined as oral temperature ≥38.1°C [≥100.5°F]; axillary 
temperature ≥37.8°C [≥100.0°F]) occurring within 72 hours prior to receipt of study 
vaccine.
8. Has a history of malignancy ≤5 years prior to signing informed consent/assent, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
9. Is a WOCBP who has a positive urine or serum pregnancy test before the first 
vaccination at Visit 2 (Day 1).
Prior/Concomitant Therapy
10. Is expected to receive any pneumococcal vaccine during the study outside of the protocol.
11. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for ≥14 
consecutive days and has not completed this course of treatment at least 30 days prior 
to any dose of study vaccine.
b. Has received or is expected to receive systemic corticosteroids exceeding physiologic 
replacement doses (approximately 5 mg/day prednisone equivalent) within 14 days 
prior to any dose of study vaccine.
c.
Is expected to require systemic corticosteroids within 30 days after any study 
vaccination during conduct of the study.
Note: Topical, ophthalmic, intra-articular or soft-tissue [eg, bursa, tendon steroid 
injections], and inhaled/nebulized steroids are permitted
 
 
056H74
06DQ25

PRODUCT: V114  
33
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
12. Is receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, and interventions associated with organ or bone marrow 
transplantation, or autoimmune disease.
Note: Hydroxyurea is permitted.
13. *Has received any licensed, non-live vaccine within the 14 days before receipt of study 
vaccine or is scheduled to receive any licensed, non-live vaccine within 30 days 
following receipt of any study vaccine. Exception: Inactivated influenza vaccine may be 
administered but must be given at least 7 days before receipt of any study vaccine or at 
least 15 days after receipt of any study vaccine.
14. *Has received any licensed live vaccine within 30 days before receipt of study vaccine or 
is scheduled to receive any live vaccine within 30 days following receipt of any study 
vaccine.
15. Has received a blood transfusion or blood products, including immunoglobulins within 
the 6 months before receipt of study vaccine or is scheduled to receive a blood 
transfusion or blood product within 30 days of receipt of study vaccine. Autologous 
blood transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
16. Has participated in another clinical study of an investigational product within 2 months 
before the first vaccination at Visit 2 (Day 1) or is planning to participate in another 
clinical study anytime during the duration of the current clinical study. Participants 
enrolled in observational studies may be included. Any prior participation in a clinical 
study or current participation in an observational study must be reviewed on a case-by-
case basis for approval by the Sponsor.
Other Exclusions
17. Is, at the time of signing informed consent/assent, a user of recreational or illicit drugs or 
has had a recent history (within the last year) of drug or alcohol abuse or dependence as 
assessed by the study investigator.
18. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
circumstance that might expose the participant to risk by participating in the study, 
confound the results of the study, or interfere with the participant’s participation for the 
full duration of the study in the opinion of the investigator.
19. Is or has an immediate family member (eg, parent/legal guardian or sibling) who is 
investigational site or Sponsor staff directly involved with this study. 
For items with an asterisk (*), if the participant meets these exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
 
 
056H74
06DQ25

PRODUCT: V114  
34
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent 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 Consolidated Standards of Reporting Trials (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 (V114, Prevnar13™, and PNEUMOVAX™23) 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.
 
 
056H74
06DQ25

PRODUCT: V114  
35
PROTOCOL/AMENDMENT NO.: 030-00 
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Single Dose 
at Visit 2 
(Day 1)
Experi
mental
IMP
Central
PNEUMOVAX™23
Biological/
Vaccine
Sterile 
Solution
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 4 
(Week 8)
Experi
mental
IMP
Central
Prevnar 
13™
Active 
Comparator
Prevnar 13™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 2 
(Day 1)
Experi
mental
IMP
Central or
Local
PNEUMOVAX™23
Biological/
Vaccine
Sterile 
Solution
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 4 
(Week 8)
Experi
mental
IMP
Central
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal product
Definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
 
 
056H74
06DQ25

PRODUCT: V114  
36
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided inSection 4.3. Information on preparation and administration of 
study vaccines is provided in Section 6.3.3 and Section 8.1.8.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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.
 
 
056H74
06DQ25

PRODUCT: V114  
37
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to receive V114 and PNEUMOVAX™23 or Prevnar 13™ and 
PNEUMOVAX™23.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:

Stratum 1: CD4+ T-cell count ≥200 to <500 cells/µL

Stratum 2: CD4+ T-cell count ≥500 cells/µL
Approximately 20% or more of the participants will be enrolled into Stratum 1.
Stratification will be managed by the IRT system.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevnar 13™will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
Because V114 and Prevnar 13™ have a different appearance, a member of the study site staff 
will be unblinded for the purposes of receiving, maintaining, preparing, and administering 
these study vaccines. PNEUMOVAX™23 will also be prepared and administered by 
unblinded study site staff for consistency even though it is being provided open-label in this 
study. Procedures for handling, preparing, and administering the unblinded vaccines are in 
the Investigator Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
 
 
056H74
06DQ25

PRODUCT: V114  
38
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114 or Prevnar 13™ vaccination at 
Visit 2 (Day 1) and PNEUMOVAX™23 vaccination at Visit 4 (Week 8) require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study (see Section 5.2 for details). If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
If a medical condition requires the use of a prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate electronic Case Report Form (eCRF) per data entry guidelines. It is important to 
record any analgesic or antipyretic use that occurs on the day of vaccination on the eVRC 
and appropriate eCRF.
During influenza season, it is anticipated that participants may be given an influenza vaccine. 
Influenza vaccine should be administered at least 7 days prior to or at least 15 days after the 
administration of the study vaccine. Other non-study pediatric vaccines are permitted and 
should be administered according to the local recommended schedule and according to 
restrictions outlined in Section 5.2.
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
 
 
056H74
06DQ25

PRODUCT: V114  
39
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
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 8.1.13). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/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 8.1.13 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.12 and Section 
8.12.3.
 
 
056H74
06DQ25

PRODUCT: V114  
40
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a confirmed positive urine or serum pregnancy test before vaccination 
with PNEUMOVAX™23 at Visit 4 (Week 8).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.12.3 for those procedures to be completed at each 
specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
 
 
056H74
06DQ25

PRODUCT: V114  
41
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may 
require that additional informed consent, and assent if applicable, be obtained from the 
participant. In these cases, such evaluations/testing will be performed in accordance with 
those regulations.
Table 2 shows the approximate blood volumes drawn by study visit and by sample type. The 
maximum amount of blood collected from each participant at each study visit will not exceed 
12 mL and the total amount of blood for the entire study will not exceed 42 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
056H74
06DQ25

PRODUCT: V114  
42
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types
Study Visit
Visit 1 
(Screening)
Visit 2
(Day 1)
Visit 3
(Day 30)
Visit 4
(Week 8)
Visit 5
(Week 12)
Blood parameter
Approximate Blood Volume (mL)
Serum for HIV serology
4 mL
N/A
N/A
N/A
N/A
Blood sample for CD4+ T-cell 
count 
2 mL
N/A
N/A
N/A
N/A
Blood sample for plasma HIV 
RNA testing
6 mL
N/A
N/A
N/A
N/A
Serum for immunogenicity 
assays (including retention 
serum)
N/A
10 mL
10 mL
N/A
10 mL
Expected total (mL)
12 mL
10 mL
10 mL
N/A
10 mL
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study or 
future biomedical research.If there are changes to the participant’s status during the study 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant must receive the 
IRB/IEC’s approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated 
signature.
 
 
056H74
06DQ25

PRODUCT: V114  
43
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
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. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participant eligibility.
If the participant meets any of the Exclusion Criteria with an asterisk (*), Visit 1 (Screening)
may be rescheduled for a time when these criteria are not met.
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 written informed consent/assent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at Visit 1 
(Screening visit) and will be confirmed before vaccination at Visit 2 (Day 1).
The participant’s medical history for up to 5 years prior to Visit 2 (Day 1) will be obtained to 
ensure that the participant satisfies the inclusion and exclusion criteria of the study.
 
 
056H74
06DQ25

PRODUCT: V114  
44
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medications and vaccinations taken 
by the participant before Visit 1 (Screening) to ensure the participant satisfies the inclusion 
and exclusion criteria. At Visit 2 (Day 1), prior medications and vaccinations taken by the 
participant within 30 days before the first dose of study vaccine will be reviewed and
documented in the participant’s chart and recorded in the study database.
The receipt of any pneumococcal vaccine and/or current antiretroviral therapy (ART) needs 
to be reviewed and documented in the participant’s chart and recorded in the study database
regardless of timing prior to Visit 2 (Day 1).
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication on the appropriate eCRF, if 
any, taken by the participant during the study per data entry guidelines.
If a medical condition requires the use of a prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible.
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination 
on the eVRC and appropriate eCRF. Concomitant medications taken after Visit 2 and non-
study vaccines received since Visit 2 will be recorded with the eVRC as specified in 
Section 8.3.5.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.12.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
 
 
056H74
06DQ25

PRODUCT: V114  
45
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. 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. Unblinded study 
personnel should follow the preparation and administration instructions for Prevnar 13™ and 
PNEUMOVAX™23 as specified in the product labels. PNEUMOVAX™23 will be 
administered open-label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart.
If V114 is provided as a syringe: Prior to administration of study vaccine, the unblinded 
pharmacist should shake vigorously to obtain a homogenous white suspension. If 
white-colored insoluble particle appears, the unblinded pharmacist should use rapid, 
horizontal hand-shaking for 5 to 10 seconds while holding the syringe in between the thumb 
and index finger until complete resuspension. This action should be repeated, as necessary. If 
appearance is otherwise, the vaccine should not be administered.
If V114 is provided as a vial: Prior to administration of study vaccine, the unblinded 
pharmacist should use rapid, horizontal hand-shaking for up to 5 seconds while holding the 
vial in between the thumb and index finger to obtain a homogenous white suspension. This 
action should be repeated, as necessary. If appearance is otherwise, the vaccine should not be 
administered.
The vaccine should not be used if the vaccine cannot be resuspended.
Prevnar 13™ and PNEUMOVAX™23 will be supplied as pre-filled syringes.
Study vaccine will be administered as a single 0.5-mL intramuscular injection in the deltoid 
region or the participant’s arm. Documentation of which limb was used for the administration 
of study vaccine should be recorded on the appropriate eCRF. This information should also 
be recorded on the eVRC to inform the participant or participant’s legally acceptable 
representative of the appropriate limb to monitor for AEs related to the V114 or Prevnar 13™
and PNEUMOVAX™23.
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].
 
 
056H74
06DQ25

PRODUCT: V114  
46
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant or participant’s legally acceptable representative will 
be blinded to the study vaccine (ie, V114 or Prevnar 13™) received by the participant. 
Vaccination information, such as Component Identification Number and time of vaccination, 
must be recorded on the appropriate eCRF as per the Data Entry Guidelines.
8.1.8.1
Timing of Dose Administration
Study vaccine will be administered as indicated in Section 1.3. All participants will be 
observed for at least 30 minutes following each vaccination for any immediate reactions. 
This observation must be performed by blinded site personnel for all study vaccines
(Section 1.3 and Section 6.3.3).
Participants must be afebrile for at least 72 hours prior to vaccination (Section 1.3 and 
Section 8.3.4).
Blood samples must be collected before study vaccination at Visit 2 (Day 1) and pregnancy 
tests (in WOCBP) must be administered before study vaccination at Visit 2 (Day 1) and 
Visit 4 (Week 8).
8.1.9
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final Food and Drug Administration Patient Reported 
Outcome Guidance [U.S. Food and Drug Administration 2009]. The investigator or delegate 
will train the participant or participant’s legally acceptable representative in the use of the 
eVRC as indicated in Section 1.3.
Body temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or non-study vaccinations will be recorded on the 
eVRC as described in Section 1.3 and Section 8.3.5. The investigator or delegate will review 
the data captured on the eVRC with the participant or participant’s legally acceptable 
representative as indicated in Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant or participant’s legally acceptable representative both on the eVRC, and verbally 
at the time of eVRC review, to apply the appropriate assessment of intensity as described in 
Appendix 3.
8.1.10
Day 15 Postdose Telephone Contact Guide
Site personnel will contact the participant or the participant’s legally acceptable 
representative on Day 15 after each study vaccination to review eVRC data. The Day 15 
Postdose Telephone Contact Guide will be provided by the Sponsor. This guide is designed 
to assist site personnel to collect any updates or edits to data previously entered on the eVRC 
 
 
056H74
06DQ25

PRODUCT: V114  
47
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
from the participant or the participant’s legally acceptable representative. Any differences 
between eVRC data and the clinical database must be clearly explained in the participant’s 
source documentation with an indication of where the information was obtained (eg, from the 
Day 15 Postdose Telephone Contact with the participant’s legally acceptable representative).
8.1.11
Telephone Contact Questionnaire
Site personnel will contact the participant or the participant’s legally acceptable 
representative approximately 6 months after Visit 2 (Day 1) 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.
8.1.12
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the protocol-specified 
vaccinations should be encouraged to continue to be followed for all remaining study visits
as outlined in Section 1.3 and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (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.
8.1.12.1
Withdrawal From Future Biomedical Research
A Participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate) and their specimens and 
all derivatives destroyed. A participant’s consent may be withdrawn at any time by 
contacting the principal investigator for the main study. If medical records for the main study 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com). Subsequently, the participant's consent for 
Future Biomedical Research will be withdrawn. A letter will be sent from the Sponsor to the 
investigator confirming the withdrawal. It is the responsibility of the investigator to inform 
the participant of completion of withdrawal. Any analyses in progress at the time of request 
for withdrawal or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research study data and results. No new analyses 
would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
 
 
056H74
06DQ25

PRODUCT: V114  
48
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
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. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Two immunogenicity assays (PnECL and MOPA) will be used to measure vaccine-induced, 
anti-PnPs serotype-specific immune responses for all 15 serotypes included in V114.
 
 
056H74
06DQ25

PRODUCT: V114  
49
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
8.2.1
Pneumococcal Electrochemiluminescence (PnECL)
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs serotypes contained in V114. 
The PnECL v2.0 assay is based on the Meso-Scale Discovery technology, which employs 
disposable multi-spot microtiter plates. The benefits of the ECL multiplex technology over 
the prior enzyme-linked immunosorbent assay (ELISA) methodology include speed,
equivalent or better sensitivity, increased dynamic range, the ability to multiplex, and 
reduction in required serum sample and reagent volumes. The measurement of immune 
responses to the 15 serotypes included in V114 is performed using an assay format consisting 
of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 assay for all 15 serotypes has 
undergone validation. The validation study evaluated various performance parameters of the 
assay including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, and 
specificity. The validation results were evaluated against pre-specified acceptance criteria for 
each of the parameters.
8.2.2
Multiplex Opsonophagocytic Assay (MOPA)
The MOPA, developed and published by Professor Moon Nahm (Director of the United 
States World Health Organization Pneumococcal Serology Reference Laboratory and 
National Institutes of Health pneumococcal reference laboratories), is a multiplexed OPA 
assay capable of measuring 4 serotypes at a time, against a total of 16 serotypes of 
pneumococci [Burton, Robert L. and Nahm, Moon H. 2006]. The OPA 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. The ability of the assay 
to simultaneously test 4 serotypes/run 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 micro-colony 
platform. The MOPA assay for all 15 V114 serotypes has undergone validation. The 
validation study evaluated various performance parameters of the assay including precision, 
relative accuracy/dilutional linearity, and specificity. The validation results were evaluated 
against pre-specified acceptance criteria for each of the parameters.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in this section. The total amount of blood/tissue to be drawn/collected over the 
course of the study (from prestudy to poststudy visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant, can be found in
Table 2.
Planned time points for all safety assessments are provided in the SoA.
 
 
056H74
06DQ25

PRODUCT: V114  
50
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 2 (Day 1). A 
targeted physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 4 (Week 8). Any 
clinically significant abnormality will be recorded per data entry guidelines.
The complete and targeted physical examination procedures both include obtaining vital 
signs (heart rate, respiratory rate, and body temperature), auscultation of the heart and lung, 
and examination of the abdomen. In addition, a complete physical examination will include 
an assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, neurological 
system, and musculoskeletal system.
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Pregnancy Test
A pregnancy test consistent with local requirements (sensitive to at least 25 IU beta human 
chorionic gonadotropin [β-hCG]) must be performed before vaccination in WOCBP as 
described in Section 1.3. Urine or serum tests can be used, and results must be negative 
before vaccination can occur.
8.3.3
HIV Serology, CD4+ T-cell count, and Plasma HIV RNA Testing
Serum for assessment of HIV serology and a blood sample for CD4+ T-cell count and 
plasma HIV RNA testing will be collected at Visit 1 (Screening) to confirm inclusion criteria
related to HIV infection. 
8.3.4
Body Temperature Measurement
Pre-vaccination body temperature will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (defined as oral temperature ≥38.1°C [≥100.5°F] or 
axillary ≥37.8°C [≥100.0°F]) within 72 hours of vaccination must be rescheduled.
The participant or the participant’s legally acceptable representative will be asked to record a 
body temperature reading on the eVRC from Day 1 through Day 7 postvaccination. 
Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14 postvaccination.
Oral is the preferred method of obtaining participant’s temperature. Axillary (underarm) is an 
acceptable method but temperature needs to be confirmed by oral measurement if fever is 
detected. If an axillary temperature is reported to be ≥37.8°C (≥100.0°F), an oral temperature 
must be taken. In this case, both axillary and oral temperatures must be recorded on the 
eVRC. Temperature readings should be taken at approximately the same time each day. Use 
of temporal or tympanic thermometers to collect temperature for this study is prohibited.
 
 
056H74
06DQ25

PRODUCT: V114  
51
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.3.5
Safety Assessments and Use of the eVRC
All participants will be observed for at least 30 minutes after each 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.
The participant or the participant’s legally acceptable representative will use the eVRC 
(Section 8.1.9) to document the following information:

Body temperatures measured Day 1 (day of vaccination) through Day 7 postvaccination; 
Day 8 through Day 14 postvaccination if fever is suspected

Solicited injection-site AEs (redness, swelling, tenderness, and hard lump) Day 1 through 
Day 14 postvaccination

Solicited systemic AEs (muscle pain, joint pain, headache, tiredness, and hives or welts) 
Day 1 through Day 14 postvaccination

Any other injection-site or systemic AEs Day 1 through Day 14 postvaccination

Use of any analgesic or antipyretic on the day of vaccination

Concomitant medications and non-study vaccinations Day 1 to Day 14 postvaccination
8.3.6
Clinical 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.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and Section 1.3.
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, 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.
 
 
056H74
06DQ25

PRODUCT: V114  
52
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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 consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. SAEs must also be reported throughout the 
duration of the individual’s participation in the study, regardless of whether or not related to 
the Sponsor’s product.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
A death that occurs prior to the participant completing the study.
OR
An SAE that is considered by an investigator, who is a qualified physician, to be vaccine 
related.
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 
 
 
056H74
06DQ25

PRODUCT: V114  
53
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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:
Nonserious Adverse 
Event (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
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion 
of study
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest
There are no events of clinical interest for this study.
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 calendar 
days of learning 
of event
 
 
056H74
06DQ25

PRODUCT: V114  
54
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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, 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 wth 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 suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
056H74
06DQ25

PRODUCT: V114  
55
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
There are no events of clinical interest for this study.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the electronic data collection (EDC) data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Saliva DNA for future research
 
 
056H74
06DQ25

PRODUCT: V114  
56
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019

Leftover study serum at the central laboratory stored for future research after 
aliquoting samples for completion of immunogenicity testing
8.11
Health Economics 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 as outlined in Section 1.3.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
If the participant develops a new clinical condition during the study that makes him/her 
ineligible for the study, the investigator should discuss with the Sponsor Clinical Director as 
soon as possible. The decision to continue the participant on study intervention requires the 
mutual agreement of the investigator, the Sponsor, and the participant or the participant’s 
legally acceptable representative.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
A participant may discontinue from study intervention but continue to participate in protocol-
specified, AE-monitoring activities as outlined in Section 1.3, as long as the participant or 
participant’s legally acceptable representative does not withdraw consent. Blood draws for 
immunogenicity testing could occur if agreed to by the participant or the participant’s legally 
acceptable representative at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental Statistical Analysis Plan and referenced in the Clinical Study 
Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR.
 
 
056H74
06DQ25

PRODUCT: V114  
57
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of V114 Followed by Administration of 
PNEUMOVAX™23 Eight Weeks Later in Children Infected with 
Human Immunodeficiency Virus (HIV) (PNEU–WAY PED)
Intervention Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or 
Prevnar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes 
contained in V114 at 30 days postvaccination with V114 or
Prevnar 13™
Safety:

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, tenderness/pain, and hard 
lump/induration) from Day 1 through Day 14 following V114 or
Prevnar 13™

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, tiredness/fatigue, and 
hives or welts/urticaria) from Day 1 through Day 14 following V114
or Prevnar 13™

Proportion of participants with vaccine-related SAEs through 
completion of study participation
Key Secondary Endpoints
Immunogenicity:

Anti-PnPs serotype-specific OPA GMTs for the 15 serotypes 
contained in V114 at 30 days postvaccination with V114 or
Prevnar 13™

Anti-PnPs Serotype-specific OPA GMTs and IgG GMCs at 30 
days postvaccination with PNEUMOVAX™23 (Week 12)
Statistical Methods for Key 
Immunogenicity Analyses 
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes contained in V114 separately. To address the 
primary immunogenicity objective, evaluation of the IgG GMCs at
30 days postvaccination with V114 or Prevnar 13™ will include 
descriptive summaries. The point estimates will be calculated by 
exponentiating the estimates of the mean of the natural log values and the 
within-group confidence intervals (CIs) will be derived by 
exponentiating the CIs of the mean of the natural log values based on the 
t-distribution.
Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters following vaccination is 
described in Section 9.6.2. Safety parameters will be summarized via 
descriptive statistics. In addition, for select safety parameters, 95% 
within-group CIs will be provided.
 
 
056H74
06DQ25

PRODUCT: V114  
58
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Interim Analyses

To support the periodic review of safety and tolerability data across 
the V114 Phase 3 pediatric program, an external unblinded 
statistician will provide unblinded interim safety summaries to an 
independent DMC for their review. There are no plans to conduct an 
interim analysis of unblinded immunogenicity data in this study. 
However, unblinded immunogenicity data will be made available to 
the DMC upon request to enable a benefit-risk assessment.
Multiplicity
No multiplicity adjustment is planned 
Sample Size and Power 
Immunogenicity:
The planned sample size is 400 participants. Participants are to be 
randomly assigned in 1:1 ratio to V114 or Prevnar 13™, respectively.
There are no hypotheses to be evaluated for primary objectives.
Section 9.9.1 provides information about the expected variability of 
IgG GMCs given the sample size.
Safety:
Section 9.9.2 provides information about the ability of this study to 
estimate the incidence of AEs within and between the V114 group.
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 using an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
Immune responses will be measured for each of the following serotypes contained in V114: 
1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F.
 
 
056H74
06DQ25

PRODUCT: V114  
59
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
The primary immunogenicity analysis endpoint is:

Anti-PnPs serotype-specific IgG GMCs at 30 days postvaccination (Day 30) with 
V114 or Prevnar 13™.
The secondary immunogenicity analysis endpoints include:

Anti-PnPs serotype-specific OPA GMTs at 30 days postvaccination (Day 30) with 
V114 or Prevnar 13™.

Anti-PnPs serotype-specific OPA GMTs and IgG GMCs at 30 days postvaccination 
with PNEUMOVAX™23 (Week 12).
The exploratory immunogenicity analysis endpoint includes:

Anti-PnPs serotype-specific GMFRs from Prevaccination (Day 1) to 30 days 
postvaccination (Day 30) with V114 or Prevnar 13™for both OPA and IgG 
responses.
9.4.2
Safety Endpoints
A description of safety measures is presented in Sections 8.3 and 8.4. The method of safety 
analysis is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events and postvaccination temperature measurements following V114 or Prevnar 
13™ and PNEUMOVAX™23 (separately).
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration) from Day 1 through Day 14
postvaccination

Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue, and hives or welts/urticaria) from
Day 1 through Day 14 postvaccination

Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 14 postvaccination

Proportion of participants with an SAE, a vaccine-related SAE, discontinuation due to 
an AE, and a death from Day 1 through Month 6 (ie, 6 months postvaccination with 
V114 or Prevnar 13™)

Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 7 postvaccination 
 
 
056H74
06DQ25

PRODUCT: V114  
60
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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. Potential deviations that may result in the exclusion of a participant from the 
PP population for all immunogenicity analyses include:

Failure to receive study vaccine at Visit 2 (Day 1)

Failure to receive correct clinical material as per randomization schedule (ie, 
participants who were cross-treated)

Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion from the PP population for 
specific immunogenicity analyses (depending on the time point) include:

Failure to receive PNEUMOVAX™23 at Visit 4 (Week 8)

Receipt of a prohibited medication or prohibited vaccine prior to a blood sample 
collection 

Collection of a blood sample outside of the pre-specified window (as described in 
Section 1.3)
The final determination on protocol deviations, and thereby the composition of the 
PP population, will be made prior to the final unblinding of the database. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the PP population.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed 
for the primary immunogenicity endpoint. The FAS population consists of all randomized 
participants who received the study vaccination and have at least 1 serology result. 
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data using the FAS population.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study vaccination. Participants will be included in 
the group corresponding to the study vaccination they actually received for the analysis of 
safety data using the APaT population. This will be the group to which they are randomized 
except for participants who take incorrect study vaccination; such participants will be 
included in the treatment group corresponding to the study vaccination actually received.
 
 
056H74
06DQ25

PRODUCT: V114  
61
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analyses of temperature.
9.6
Statistical Methods
Statistical methods for immunogenicity and safety analyses are described in Section 9.6.1 
and Section 9.6.2, respectively. Section 9.6.3 describes how demographic and baseline 
characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Methods related to exploratory objectives will be further 
described in the supplemental statistical analysis plan.
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes 
contained in V114 separately. To address the primary immunogenicity objective, evaluation 
of the serotype-specific IgG GMCs at 30 days post-vaccination with V114 or Prevnar 13™
(Day 30) will include descriptive summaries and within-group 95% CIs to be calculated for 
each vaccination group. Point estimates for the IgG GMCs will be calculated by 
exponentiating the estimates of the mean of the natural log values. The within-group CIs will 
be derived by exponentiating the CIs of the mean of the natural log values based on the t-
distribution.
A similar statistical approach will be used to evaluate serotype-specific OPA responses at 
Day 30, and IgG and OPA responses at 30 days postvaccination with PNEUMOVAX™23 
(Week 12) for each vaccination group. Point estimates of serotype-specific GMFR and its 
associated 95% CI will be calculated based on the t-distribution of natural log-transformed 
fold rise.
Reverse Cumulative Distribution Curves for OPA titers and IgG concentrations will be 
graphically displayed by serotype at each of the following timepoints: Day 30 and Week 12.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 4.
 
 
056H74
06DQ25

PRODUCT: V114  
62
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Anti-PnPs IgG GMCs at Day 30
P
Descriptive 
Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
Anti-PnPs OPA GMTs at Day 30
P
Descriptive 
Statistics (estimate, 
95% CI)
PP
Missing data 
will not be 
imputed
Anti-PnPs IgG GMCs/OPA GMTs at
Week 12
P
Descriptive 
Statistics (estimate, 
95% CI)
PP
Missing data 
will not be 
imputed
†
P = primary approach; S = supportive approach.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration; 
GMFR = Geometric Mean Fold Rise; GMT = Geometric Mean Titer; IgG = immunoglobulin G; 
OPA = opsonophagocytic activity; PnPs = pneumococcal polysaccharide; PP = Per-Protocol
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements.
The analysis strategy for safety parameters following each vaccination is summarized in 
Table 5. The proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain, and hard lump/induration Day 1 to Day 14 postvaccination) and 
solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, 
tiredness/fatigue, and hives or welts/urticaria from Day 1 to Day 14 postvaccination) will be 
provided along with the corresponding within-group 95% CIs (based on the exact binomial 
method proposed by Clopper and Pearson [Collett, D. 1999]. In addition, the broad AE 
categories consisting of the proportion of participants with any AE, a vaccine-related AE, a 
SAE, an AE which is both vaccine-related and serious, discontinuation due to an AE, and 
death will be summarized in the same manner. The proportion of participants with maximum 
temperature measurements meeting the Brighton Collaboration cut points (from Day 1 
through Day 7) will also will be provided along with the corresponding within-group 95% 
CIs. Point estimates by vaccination group will be provided for all other safety parameters 
(specific AE terms and system organ class terms).
The analysis of safety parameters will be evaluated at 2 separate time points: (1) following 
administration of V114 or Prevnar 13™ and (2) following administration of 
PNEUMOVAX™23. Descriptive summaries of AEs following administration of V114 or 
Prevnar 13™ will include nonserious AEs within 14 days of vaccination and SAEs occurring 
 
 
056H74
06DQ25

PRODUCT: V114  
63
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Day 1 through completion of study participation. Descriptive summaries of AEs following 
administration of PNEUMOVAX™23 will include nonserious AEs within 14 days of 
vaccination and SAEs through completion of study participation.
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination
Safety Endpoint
Within-Group 95% CI 
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 14)†
X
X
Injection-site swelling (Days 1 to 14)†
X
X
Injection-site tenderness/pain (Days 1 to 14)†
X
X
Injection-site hard lump/induration (Days 1 to 14)
X
X
Muscle pain/myalgia (Days 1 to 14)†
X
X
Joint pain/arthralgia (Days 1 to 14)†
X
X
Headache (Days 1 to 14)†
X
X
Tiredness/fatigue (Days 1 to 14)†
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
Any AE‡
X
X
Any vaccine-related AE‡
X
X
Any SAE‡
X
X
Any vaccine-related SAE‡
X
X
Discontinuation due to AE‡
X
X
Death‡
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7)
X
X
Specific AEs by SOCs and PT
X
† Includes solicited events only.
‡ These endpoints are broad adverse event 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.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = 
System Organ Class; X = results will be provided.
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
 
 
056H74
06DQ25

PRODUCT: V114  
64
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, race, and gender), baseline characteristics, prior 
and concomitant vaccinations and therapies will be summarized by vaccination group either 
by descriptive statistics or categorical tables.
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric 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 reviews 
will be outlined in the DMC charter. Information regarding the composition of the DMC is 
provided in Appendix 1. There are no plans to conduct an interim analysis of unblinded 
immunogenicity data in this study. However, 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 discontinuation of the study or protocol modifications to an 
executive 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 Executive Oversight Committee (EOC) 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 results of ongoing safety reviews will be documented by the external unblinded 
statistician. Additional logistical details will be provided in the DMC Charter.
Study enrollment is likely to 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 review.
9.8
Multiplicity
No adjustment will be made for multiplicity.
 
 
056H74
06DQ25

PRODUCT: V114  
65
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. The planned sample size is 400 participants. Participants are to be 
randomly assigned in 1:1 ratio to V114 or Prevnar 13™. It is assumed that approximately
160 participants per vaccination group will be evaluable for PP immunogenicity analyses at 
Day 30 (based on an 80% evaluability rate).
The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends on the 
sample size, variability of the natural log concentrations, and the magnitude of the IgG GMC. 
In Table 6, 95% CIs for various hypothetical IgG GMCs at 30 days postvaccination with 
V114 or Prevnar 13™and various hypothetical standard deviation estimates for the natural 
log titers are displayed.
Table 6
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying 
Standard Deviations With 160 Evaluable Participants in Each Vaccination Group
Standard Deviation of 
Natural Log Titers†
Observed Serotype-specific IgG GMC†
1
5
10
1.0
(0.86, 1.17)
(4.28, 5.84)
(8.55, 11.69)
1.5
(0.79, 1.26)
(3.96, 6.32)
(7.91, 12.64)
2.0
(0.73, 1.37)
(3.66, 6.83)
(7.32, 13.67)
† The estimates of the standard deviation and IgG GMC ratio are representative of those observed in a 
previous MSD study
CI = confidence interval; GMC = Geometric Mean Concentration
9.9.2
Sample Size and Power for Safety Analyses
The sample size was selected to achieve a reasonably sized safety database in this population 
exposed to V114. The probability of observing at least 1 SAE in this study depends on the 
number of participants vaccinated and the underlying percentage of participants with a SAE 
in the study population. Calculations below assume that 100% of the randomized participants 
will be evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE 
among 200 participants in the V114 group if the underlying incidence of a SAE is 0.8% (1 of 
every 125 participants receiving the vaccine). There is a 50% chance of observing at least 
1 SAE among 200 participants in the V114 group if the underlying incidence of a SAE is 
0.35% (1 of every 289 participants receiving the vaccine). If no SAEs are observed among 
the 200 participants in the V114 group, this study will provide 97.5% confidence that the 
underlying percentage of participants with a SAE is <1.82 % (1 in every 55 participants) in 
the V114 group.
 
 
056H74
06DQ25

PRODUCT: V114  
66
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
9.10
Subgroup Analyses
Serotype-specific IgG GMCs and their corresponding within-group 95% CIs at Day 30 will 
be calculated for each subgroup (ie, CD4+ T-cell count, sex, age, race, prior vaccination of 
PCV) within each vaccination group. The 95% CI will only be calculated if there are more 
than 10 participants in each vaccination group for each subgroup. In addition, a summary of 
AEs and a summary of solicited AEs will be provided for each subgroup (point estimates 
only). Further details of subgroup analyses will be documented in the supplemental 
Statistical Analysis Plan.
9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of V114/Prevnar 13™ and a single dose 
of PNEUMOVAX™23, compliance will not be calculated. However, the number and 
proportion of randomized participants receiving each vaccination will be summarized 
(Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V114 or Prevnar 13™ and the number and proportion of 
randomized participants administered PNEUMOVAX™23.
 
 
056H74
06DQ25

PRODUCT: V114  
67
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
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 fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
056H74
06DQ25

PRODUCT: V114  
68
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
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. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), 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 to identify potentially eligible participants.
 
 
056H74
06DQ25

PRODUCT: V114  
69
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
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.
 
 
056H74
06DQ25

PRODUCT: V114  
70
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (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.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
external DMC regarding the study.
 
 
056H74
06DQ25

PRODUCT: V114  
71
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.1.4.3
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 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
 
 
056H74
06DQ25

PRODUCT: V114  
72
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
 
 
056H74
06DQ25

PRODUCT: V114  
73
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
 
 
056H74
06DQ25

PRODUCT: V114  
74
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 will 
promptly notify that study site’s IRB/IEC.
 
 
056H74
06DQ25

PRODUCT: V114  
75
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 7 will be performed according to local requirements.
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 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serum or urine β-hCG pregnancy test (as needed for WOCBP)

Serum for HIV Serology

Blood sample for CD4+ T-cell count and plasma HIV RNA testing
β-hCG = β human chorionic gonadotropin; HIV = human immunodeficiency virus; RNA = ribonucleic acid; 
WOCBP = woman/women of childbearing potential
 
 
056H74
06DQ25

PRODUCT: V114  
76
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer or progression of existing cancer.
 
 
056H74
06DQ25

PRODUCT: V114  
77
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
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, 
 
 
056H74
06DQ25

PRODUCT: V114  
78
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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
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 
 
 
056H74
06DQ25

PRODUCT: V114  
79
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).

Injection site redness, swelling, or hard lump from the day of vaccination through Day 14 
postvaccination will be evaluated by maximum size.
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:
 
 
056H74
06DQ25

PRODUCT: V114  
80
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
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:
 
 
056H74
06DQ25

PRODUCT: V114  
81
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
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 electronic data collection 
(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.
 
 
056H74
06DQ25

PRODUCT: V114  
82
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Study File Binder (or equivalent).
 
 
056H74
06DQ25

PRODUCT: V114  
83
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
 
 
056H74
06DQ25

PRODUCT: V114  
84
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
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 follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
056H74
06DQ25

PRODUCT: V114  
85
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.5.2
Contraception Requirements
Female Participants
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,

Intrauterine hormone-releasing system (IUS)c. IUS is a progestin releasing IUD.

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraception
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraception
-
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.
Acceptable Contraceptive Methods
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)d
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).
a.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
implants are limited to those which inhibit ovulation
b.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, 
but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
 
 
056H74
06DQ25

PRODUCT: V114  
86
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
056H74
06DQ25

PRODUCT: V114  
87
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.   Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.   Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
056H74
06DQ25

PRODUCT: V114  
88
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, 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.
 
 
056H74
06DQ25

PRODUCT: V114  
89
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
5.   Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6.   Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.   Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
056H74
06DQ25

PRODUCT: V114  
90
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.   Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.   Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.  Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.  Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12.  Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
056H74
06DQ25

PRODUCT: V114  
91
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
13.  References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [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/
 
 
056H74
06DQ25

PRODUCT: V114  
92
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
056H74
06DQ25

PRODUCT: V114  
93
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
AE
adverse event 
APaT
All Participants as Treated
ART
antiretroviral therapy
β-hCG
β human chorionic gonadotropin
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
eVRC
electronic Vaccination Report Card
FAS
Full Analysis Set
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GMC
Geometric Mean Concentration
GMFR
Geometric Mean Fold Rise
GMT
Geometric Mean Titer
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
intramuscular
IMP
investigational medicinal product
IND
Investigational New Drug 
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MOPA
multiplex opsonophagocytic assay
MSD
Merck Sharp & Dohme Corp.
NDA
New Drug Application 
NIMP
non-investigational medicinal product
NSAE
nonserious adverse event
OPA
opsonophagocytic activity
 
 
056H74
06DQ25

PRODUCT: V114  
94
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
Abbreviation
Expanded Term
PCV
pneumococcal conjugate vaccine
PD
postdose
PK
pharmacokinetic
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide
PP
per-protocol
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
 
 
056H74
06DQ25

PRODUCT: V114  
95
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
11
REFERENCES
[Andiman, W. A., et al 1996]
Andiman WA, Simpson BJ, Holtkamp C, 
Pearson HA. Invasive pneumococcal 
infections in children infected with HIV are 
not associated with splenic dysfunction. AIDS 
Patient Care STDS. 1996;10(6):336-41.
054LBP
[Anttila, M., et al 1999]
Anttila M, Voutilainen M, Jäntti V, Eskola J, 
Käyhty H. Contribution of serotype-specific 
IgG concentration, IgG subclasses and relative 
antibody avidity to opsonophagocytic activity 
against Streptococcus pneumoniae. Clin Exp 
Immunol 1999;118(3):402-7.
03QY70
[Bhorat, A. E., et al 2015]
Bhorat AE, Madhi SA, Laudat F, Sundaraiyer 
V, Gurtman A, Jansen KU, et al. 
Immunogenicity and safety of the 13-valent 
pneumococcal conjugate vaccine in HIV-
infected individuals naive to pneumococcal 
vaccination. AIDS. 2015 Jul 17;29(11):1345-
54.
04NRV9
[Bliss, S. J., et al 2008]
Bliss SJ, O'Brien KL, Janoff EN, Cotton MF, 
Musoke P, Coovadia H, et al. The evidence 
for using conjugate vaccines to protect HIV-
infected children against pneumococcal 
disease. Lancet Infect Dis. 2008 Jan;8:67-80.
053PRS
[Burton, Robert L. and Nahm, 
Moon H. 2006]
Burton RL, Nahm MH. Development and 
validation of a fourfold multiplexed 
opsonization assay (MOPA4) for 
pneumococcal antibodies. Clin Vaccine 
Immunol 2006;13(9):1004-9.
03QT2R
[Castiglia P. 2014]
Castiglia P. Recommendations for 
pneumococcal immunization outside routine 
childhood immunization programs in Western 
Europe. Adv Ther. 2014Oct;31(10):1011-44.
04P7LW
 
 
056H74
06DQ25

PRODUCT: V114  
96
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Centers for Disease Control 
and Prevention (CDC) 2013]
Centers for Disease Control and Prevention 
(CDC). Use of 13-valent pneumococcal 
conjugate vaccine and 23-valent 
pneumococcal polysaccharide vaccine among 
children aged 6-18 years with 
immunocompromising conditions: 
recommendations of the Advisory Committee 
on Immunization Practices (ACIP). MMWR 
Morb Mortal Wkly Rep. 2013 Jun 
28;62(25):521-4.
043QRD
[Centers for Disease Control 
and Prevention 2005]
Centers for Disease Control and Prevention. 
Direct and indirect effects of routine 
vaccination of children with 7-valent 
pneumococcal conjugate vaccine on incidence 
of invasive pneumococcal disease - United 
States, 1998-2003. MMWR 2005;54(36):893-
7.
03Q7ZJ
[Centers for Disease Control 
and Prevention 2008]
Centers for Disease Control and Prevention 
(CDC). Invasive pneumococcal disease in 
children 5 years after conjugate vaccine 
introduction-eight states,1998-2005. MMWR 
Morb Mortal Wkly Rep. 2008 Feb 
15;57(6):144-8.
04KW8S
[Centers for Disease Control 
and Prevention 2010]
Centers for Disease Control and Prevention. 
Prevention of Pneumococcal Disease Among 
Infants and Children - Use of 13-Valent 
Pneumococcal Conjugate Vaccine and 23-
Valent Pneumococcal Polysaccharide 
Vaccine; Recommendations of the Advisory 
Committee on Immunization Practices 
(ACIP). MMWR 2010;59(RR-11):1-19.
03RSB6
[Centers for Disease Control 
and Prevention 2015]
Centers for Disease Control and Prevention. 
Epidemiology and prevention of vaccine-
preventable diseases. 13th ed. Hamborsky J, 
Kroger A, Wolfe S, editors. Washington 
(DC): Department of Health and Human 
Services (HHS); c2015. Chapter 6, Vaccine 
administration; p. 79-106.
0508PV
 
 
056H74
06DQ25

PRODUCT: V114  
97
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Collett, D. 1999]
Collett D. Statistical inference for binary data. 
In: Collett D, ed. Modelling Binary Data. New 
York: Chapman & Hall, 1999:17-42.
03NVVC
[Dankner, W. M., et al 2001]
Dankner WM, Lindsey JC, Levin MJ. 
Correlates of opportunistic infections in 
children infected with the human 
immunodeficiency virus managed before 
highly active antiretroviral therapy. Pediatr
Infect Dis J. 2001 Jan;20(1):40-8.
0432W6
[Farrell, D. J, et al 2007]
Farrell DJ, Klugman KP, Pichichero M. 
Increased antimicrobial resistance among 
nonvaccine serotypes of Streptococcus 
pneumoniae in the pediatric population after 
the introduction of 7-valent pneumococcal 
vaccine in the United States. Pediatr Infect Dis 
J. 2007 Feb;26(2):123-8.
04KWD9
[Guevara, M., et al 2016]
Guevara M, Barricarte A, Torroba L, Herranz 
M, Gil-Setas A, Gil F, et al. Direct, indirect 
and total effects of 13-valent pneumococcal 
conjugate vaccination on invasive 
pneumococcal disease in children in Navarra, 
Spain, 2001 to 2014: cohort and case-control 
study. Euro Surveill. 2016;21(14).
04KSQ3
[Hicks, L. A., et al 2007]
Hicks LA, Harrison LH, Flannery B, Hadler 
JL, Schaffner W, Craig AS, et al. Incidence of 
Pneumococcal Disease Due to Non-
Pneumococcal Conjugate Vaccine (PCV7) 
Serotypes in the United States during the Era 
of Widespread PCV7 Vaccination, 1998-2004. 
J Infect Dis 2007;196:1346-54.
03QT0G
[Janoff, E. N., et al 1992]
Janoff EN, Breiman RF, Daley CL, Hopewell 
PC. Pneumococcal disease during HIV 
infection: epidemiologic, clinical, and 
immunologic perspectives. Ann Intern Med. 
1992 Aug 15;117(4):314-24.
053PSS
 
 
056H74
06DQ25

PRODUCT: V114  
98
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Janoff, E. N., et al 1993]
Janoff EN, O'Brien J, Thompson P, Ehret J, 
Meiklejohn G, Duvall G, et al. Streptococcus 
pneumoniae colonization, bacteremia, and 
immune response among persons with human 
immunodeficiency virus infection. J Infect 
Dis. 1993 Jan;167:49-56.
053PV9
[Jokinen, J., et al 2015]
Jokinen J, Rinta-Kokko H, Siira L, Palmu AA, 
Virtanen MJ, Nohynek H, et al. Impact of ten-
valent pneumococcal conjugate vaccination on 
invasive pneumococcal disease in Finnish 
children a population-based study. PLoS One. 
2015 Mar 17;10(3):e0120290.
04KW7F
[Jones, N., et al 1998]
Jones N, Huebner R, Khoosal M, Crewe-
Brown H, Klugman K. The impact of HIV on 
Streptococcus pneumoniae bacteraemia in a 
South African population. AIDS. 
1998;12(16):2177-84.
054LBR
[Kobayashi, M., et al 2015]
Kobayashi M, Bennett NM, Gierke R, 
Almendares O, Moore MR, Whitney CG, et 
al. Intervals Between PCV13 and PPSV23 
Vaccines: Recommendations of the Advisory 
Committee on Immunization Practices 
(ACIP). MMWR Morb Mortal Wkly Rep. 
2015 Sep 4;64(34):944-7.
04P7LH
[Laufer, M. K., et al 2006]
Laufer MK, van Oosterhout JJG, Perez MA, 
Kanyanganlika J, Taylor TE, Plowe CV, et al. 
Observational cohort study of HIV-infected 
African children. Pediatr Infect Dis J. 2006 
Jul;25(7):623-7.
054LBV
[Lepoutre, A., et al 2015]
Lepoutre A, Varon E, Georges S, Dorleans F, 
Janoir C, Gutmann L, et al. Impact of the 
pneumococcal conjugate vaccines on invasive 
pneumococcal disease in France, 2001-2012. 
Vaccine. 2015 Jan 3;33(2):359-66.
04KW88
[Lexau, C. A., et al 2005]
Lexau CA, Lynfield R, Danila R, Pilishvili T, 
Facklam R, Farley MM, et al. Changing 
epidemiology of invasive pneumococcal 
disease among older adults in the era of 
pediatric pneumococcal conjugate vaccine. 
JAMA 2005;294(16):2043-51.
03RBPW
 
 
056H74
06DQ25

PRODUCT: V114  
99
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Madhi, S. A., et al 2000]
Madhi SA, Petersen K, Madhi A, Khoosal M, 
Klugman KP. Increased disease burden and 
antibiotic resistance of bacteria causing severe 
community-acquired lower respiratory tract 
infections in human immunodeficiency virus 
type 1-infected children. Clin Infect Dis. 2000 
Jul;31:170-6.
053R2B
[Madhi, S. A., et al 2000]
Madhi SA, Petersen K, Madhi A, Wasas A, 
Klugman KP. Impact of human 
immunodeficiency virus type 1 on the disease 
spectrum of Streptococcus pneumoniae in 
South African children. Pediatr Infect Dis J. 
2000 Dec;19(12):1141-7.
053R0G
[Madhi, S. A., et al 2001]
Madhi SA, Madhi A, Petersen K, Khoosal M, 
Klugman KP. Impact of human 
immunodeficiency virus type 1 infection on 
the epidemiology and outcome of bacterial 
meningitis in South African children. Int J 
Infect Dis. 2001;5(3):119-25.
054LBX
[Madhi, S. A., et al 2007]
Madhi SA, Adrian P, Kuwanda L, Jassat W, 
Jones S, Little T, et al. Long-term 
immunogenicity and efficacy of a 9-valent 
conjugate pneumococcal vaccine in human 
immunodeficient virus infected and non-
infected children in the absence of a booster 
dose of vaccine. Vaccine. 2007;25:2451-7.
054LBY
[Madhi, S. A., et al 2009]
Madhi SA, Klugman KP, Kuwanda L, 
Cutland C, Kayhty H, Adrian P. Quantitative 
and qualitative anamnestic immune responses 
to pneumococcal conjugate vaccine in HIV-
infected and HIV-uninfected children 5 years 
after vaccination. J Infect Dis. 2009 Apr 
15;199:1168-76.
054LBZ
[Martinelli, D., et al 2014]
Martinelli D, Pedalino B, Cappelli MG, 
Caputi G, Sallustio A, Fortunato F, et al 
Towards the 13-valent pneumococcal 
conjugate universal vaccination: effectiveness 
in the transition era between PCV7 and 
PCV13 in Italy, 2010-2013. Hum Vaccin 
Immunother. 2014;10(1):33-9.
04KW8B
 
 
056H74
06DQ25

PRODUCT: V114  
100
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Metlay, J. P., et al 2006]
Metlay JP, Fishman NO, Joffe M, Edelstein 
PH. Impact of pediatric vaccination with 
pneumococcal conjugate vaccine on the risk 
of bacteremic pneumococcal pneumonia in 
adults. Vaccine 2006;24:468-75.
03RC46
[Moore, M. R., et al 2015]
Moore MR, Link-Gelles R, Schaffner W, 
Lynfield R, Lexau C, Bennett NM, et al. 
Effect of use of 13-valent pneumococcal 
conjugate vaccine in children on invasive 
pneumococcal disease in children and adults 
in the USA: analysis of multisite, population-
based surveillance. Lancet Infect Dis. 2015 
Feb 3. [Epub ahead of print].
043MRP
[Nachman, S., et al 2005]
Nachman S, Gona P, Dankner W, Weinberg 
A, Yogev R, Gershon A, et al. The rate of 
serious bacterial infections among HIV-
infected children with immune reconstitution 
who have discontinued opportunistic infection 
prophylaxis. Pediatrics. 2005 
Apr;115(4):e488-94.
054LC2
[National Center for 
Immunization and 
Respiratory Diseases 2018]
National Center for Immunization and 
Respiratory Diseases (NCIRD). Immunization 
schedules [Internet]. Atlanta (GA): Centre for 
Disease Prevention and Control. 2018 Jan 1. 
Recommended immunization schedule for 
children and adolescents aged 18 years or 
younger, United States, 2018; [cited 2018 Jul 
23]; 8 p. Available from: 
https://www.cdc.gov/vaccines/schedules/down
loads/child/0-18yrs-child-combined-
schedule.pdf.
04ZJ72
[Palmu, A. A., et al 2015]
Palmu AA, Kilpi TM, Rinta-Kokko H, 
Nohynek H, Toropainen M, Nuorti JP, et al. 
Pneumococcal conjugate vaccine and 
clinically suspected invasive pneumococcal 
disease. Pediatrics. 2015 Jul;136(1):e22-7.
04KVRL
 
 
056H74
06DQ25

PRODUCT: V114  
101
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Peters, V. B., et al 1994]
Peters VB, Hyatt AC, Schechter C, Diamant 
EP, Hodes DS. Evaluation of prophylaxis 
against invasive pneumococcal infections in 
human immunodeficiency virus-infected 
children. Pediatr Infect Dis J. 1994 
Jul;13(7):667-9.
054LC6
[Pilishvili, Tamara, et al 
2010]
Pilishvili T, Lexau C, Farley MM, Hadler J, 
Harrison LH, Bennett NM, et al. Sustained 
reductions in invasive pneumococcal disease 
in the era of conjugate vaccine. J Infect Dis 
2010;201(1):32-41.
03R5S4
[Robinson, C. L., et al 2018]
Robinson CL, Romero JR, Kempe A, 
Pellegrini C, Szilagyi P. Advisory Committee 
on Immunization Practices recommended 
immunization schedule for children and 
adolescents aged 18 years or younger - United 
States, 2018. MMWR Morb Mortal Wkly 
Rep. 2018 Feb 9;67(5):156-7.
053R2H
[Romero-Steiner, S., et al 
1997]
Romero-Steiner S, Libutti D, Pais LB, Dykes 
J, Anderson P, Whitin JC, et al. 
Standardization of an opsonophagocytic assay 
for the measurement of functional antibody 
activity against streptococcus pneumoniae
using differentiated HL-60 cells. Clin Diagn 
Lab Immunol 1997;4(4):415-22.
03NWQ5
[Ruckinger, S., et al 2009]
Ruckinger S, van der Linden M, Reinert RR, 
von Kries R, Burckhardt F, Siedler A. 
Reduction in the incidence of invasive 
pneumococcal disease after general 
vaccination with 7-valent pneumococcal 
conjugate vaccine in Germany. Vaccine 
2009;27:4136-41.
03QYQQ
[Spector, S. A., et al 1994]
Spector SA, Gelber RD, McGrath N, Wara D, 
Barzilai A, Abrams E, et al. A controlled trial 
of intravenous immune globulin for the 
prevention of serious bacterial infections in 
children receiving zidovudine for advanced 
human immunodeficiency virus infection. N 
Engl J Med. 1994 Nov 3;331(18):1181-7.
054LC8
 
 
056H74
06DQ25

PRODUCT: V114  
102
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[U.S. Food and Drug 
Administration 2009]
U.S. Food and Drug Administration (CDER, 
CBER, CDRH). Guidance for industry 
patient-reported outcome measures: use in 
medical product development to support 
labeling claims [Internet]. Washington: U.S. 
Department of Health and Human Services; 
2009. Available from: 
https://www.fda.gov/downloads/drugs/guidan
ces/ucm193282.pdf
04MG9J
[Wagenvoort, G. H., et al 
2016]
Wagenvoort GH, Knol MJ, de Melker HE, 
Vlaminckx BJ, van der Ende A, Rozenbaum  
MH, et al.  Risk and outcomes of invasive 
pneumococcal disease in adults with 
underlying conditions in the post-PCV7 era, 
The Netherlands. Vaccine. 2016 Jan 
12;34(3):334-40.
04KTDB
[Waight, P. A., et al 2015]
Waight PA, Andrews NJ, Ladhani SN, 
Sheppard CL, Slack MP, Miller E. Effect of 
the 13-valent pneumococcal conjugate vaccine 
on invasive pneumococcal disease in England 
and Wales 4 years after its introduction: an 
observational cohort study. Lancet Infect Dis. 
2015 May;15(5):535-43.
04KTF2
[Weiss, S., et al 2015]
Weiss S, Falkenhorst G, van der Linden M, 
Imohl M, von Kries R. Impact of 10-  and 13-
valent pneumococcal conjugate vaccines on 
incidence of invasive pneumococcal disease in 
children aged under 16 years in Germany, 
2009 to 2012. Euro Surveill. 2015 Mar 
12;20(10):21057.
04KTFC
[Whitney, C. G., et al 2003]
Whitney CG, Farley MM, Hadler J, Harrison 
LH, Bennett NM, Lynfield R, et al. Decline in 
invasive pneumococcal disease after the 
introduction of protein―polysaccharide 
conjugate vaccine. N Engl J Med 
2003;348(18):1737-46.
03PP7G
 
 
056H74
06DQ25

PRODUCT: V114  
103
PROTOCOL/AMENDMENT NO.:  030-00  
V114-030-00 FINAL PROTOCOL
27-MAR-2019
[Whitney, Cynthia G., et al 
2003]
Whitney CG, Farley MM, Hadler J, Harrison 
LH, Bennett NM, Lynfield R, et al. Decline in 
invasive pneumococcal disease after the 
introduction of protein-polysaccharide 
conjugate vaccine. N Engl J Med 
2003;348(18):1737-46.
03QT0D
[World Health Organization 
Europe 2007]
World Health Organization Europe.  
HIV/AIDS treatment and care: clinical 
protocols for the WHO European Region.
03QK75
 
 
056H74
06DQ25

V114
PAGE 1
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Supplemental Statistical Analysis Plan (sSAP)
TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................1
LIST OF TABLES.............................................................................................................2
1 
INTRODUCTION............................................................................................................3
2 
SUMMARY OF CHANGES...........................................................................................3
2.1 
Summary of Changes from Protocol SAP...........................................................3
2.2 
Summary of Changes from Previous Versions of the sSAP...............................5
3 
ANALYTICAL AND METHODOLOGICAL DETAILS...........................................5
3.1 
Statistical Analysis Plan Summary.......................................................................5
3.2 
Responsibility for Analyses/In-house Blinding ...................................................6
3.3 
Hypotheses/Estimation..........................................................................................7
3.4 
Analysis Endpoints.................................................................................................7
3.4.1 
Immunogenicity Endpoints............................................................................7
3.4.2 
Safety Endpoints............................................................................................7
3.5 
Analysis Populations..............................................................................................8
3.5.1 
Immunogenicity Analysis Populations..........................................................8
3.5.2 
Safety Analysis Populations..........................................................................9
3.6 
Statistical Methods.................................................................................................9
3.6.1 
Statistical Methods for Immunogenicity Analyses......................................10
10
3.6.2 
Statistical Methods for Safety Analyses......................................................12
12
3.6.3 
Demographic and Baseline Characteristics .................................................14
14
3.7 
Interim Analyses ..................................................................................................14
14
3.8 
Multiplicity ...........................................................................................................15
15
3.9 
Sample Size and Power Calculations .................................................................15
15
3.9.1 
Sample Size and Power for Immunogenicity Analyses...............................15
15
3.9.2 
Sample Size and Power for Safety Analyses...............................................15
15
3.10 Subgroup Analyses...............................................................................................16
16
3.11 Compliance (Medication Adherence).................................................................16
16
3.12 Extent of Exposure...............................................................................................16
16
4 
REFERENCES...............................................................................................................17
17
06CT36
06DQ2B

V114
PAGE 2
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
LIST OF TABLES
Table 1 
Analysis Strategy for Immunogenicity Variables......................................11
11
Table 2 
Limits of Quantitation for OPA and IgG Serotype-specific Responses....12
12
Table 3 
Analysis Strategy for Safety Parameters Following Each Vaccination.....13
13
Table 4 
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and
Varying Standard Deviations With 160 Evaluable Participants in Each
Vaccination Group.......................................................................................................15
15
06CT36
06DQ2B

V114
PAGE 3 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
1 
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the
information presented in the protocol SAP which provides the principal features of
confirmatory analyses for this trial, this sSAP provides additional statistical analysis
details/data derivations and documents modifications or additions to the analysis plan that are
not “principal” in nature and result from information that was not available at the time of
protocol finalization.
2 
SUMMARY OF CHANGES
2.1 
Summary of Changes from Protocol SAP
A summary of changes is provided in the table below:
Section
Description of Change 
Rationale
Section 3.4.2 Safety
Endpoints
Added a paragraph to specify the timeframe 
associated with the reporting of AEs.
Revisions made for clarity.
Section 3.5.1
Immunogenicity Analysis
Populations
Changed the example of exclusion of a 
participant from the PP population for all
immunogenicity analyses in the 2nd bullet
from “participants who were cross-treated”
to “a participant who was randomized to
V114 but received Prevnar 13TM, or vice
versa” to explain the incorrect treatment
scenarios more precisely.
Revisions made for clarity.
Section 3.5.1
Immunogenicity Analysis
Populations
Deleted the sentence “Participants will be
included in the vaccination group to which
they are randomized for the analysis of
immunogenicity data using the PP
population.”
Participants who receive
incorrect study vaccination at
Day 1 are excluded from all PP
immunogenicity analyses.
Therefore, the deleted text is
not needed.
Section 3.5.1
Immunogenicity Analysis
Populations
Updated one sentence in this section from
“The FAS population consists of all
randomized participants who received the
study vaccination and have at least 1
serology result.” to “The FAS population
consists of all randomized participants who
received the relevant study vaccination(s)
and have at least 1 serology result relevant
to the timepoint of interest (ie, a participant
who was randomized and missed the
vaccination at Visit 2 [Day 1] is removed
from the FAS population at all visits; a
participant who was randomized and missed
vaccination at Visit 4 [Week 8] is removed
from the FAS population at Visit 5 [Week
12]).”
Revisions made to clarify the
criteria for inclusion in the FAS
population.
06CT36
06DQ2B

V114
PAGE 4
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Section
Description of Change
Rationale
Section 3.5.2 Safety
Analysis Populations
Updated one sentence in this section from
“Safety analyses will be conducted in the
APaT population, which consists of all
randomized participants who received at
least 1 dose of study vaccination.” to
“Safety analyses will be conducted in the
APaT population, which consists of all
randomized participants who received the
relevant study vaccination for the timepoint
of interest (ie, a participant must receive a
single dose of V114 or Prevnar 13TM at Visit
2 [Day 1] to be included in the analyses
following PCV; a participant must receive a
single dose of PNEUMOVAXTM23 at Visit
4 [Week 8] to be included in the analyses
following PPV23).”
Revisions made to clarify the
criteria for inclusion in the
APaT population.
Section 3.6 Statistical
Methods
Added a sentence to clarify that the correct
stratum will be used for analyses when mis-
stratification occurs.
Added to provide additional
statistical analysis details/data
derivations.
Section 3.6.1 Statistical
Methods for
Immunogenicity Analyses
Added text to describe the statistical
methods used for the exploratory
immunogenicity objective.
Added to provide additional
statistical analysis details/data
derivations.
Section 3.6.1 Statistical
Methods for
Immunogenicity Analyses
Added a paragraph and a table (Table 2) to
explain how values below the LLOQ or
above the ULOQ should be treated in
various analyses.
Added to provide additional
statistical analysis details/data
derivations.
Section 3.6.2 Statistical
Methods for Safety
Analyses
Replaced the reference to Collett, D. 1999
with Clopper, C. J. and Pearson,
E. S. 1934 for the exact confidence interval
for a single binomial proportion.
The method for producing the
confidence interval in the two
references is identical.
Confidence intervals produced
via this method will be
attributed to Clopper, C. J. and
Pearson, E. S. 1934 as it is the
earlier-published reference.
Section 3.6.2 Statistical
Methods for Safety
Analyses
Added a paragraph to explain the rationale
for not including laboratory AEs in the
summary tables.
Added to provide additional
statistical analysis details/data
derivations.
Section 3.6.2 Statistical
Methods for Safety
Analyses
Added a paragraph to describe an additional
supportive analysis of the proportion of
participants with solicited complaints using
the data collected directly from participants
via the VRC.
Added to provide additional
statistical analysis details/data
derivations.
Section 3.10 Subgroup
Analyses
Added details of subgroup analyses.
Added to provide additional
statistical analysis details/data
derivations.
Throughout
Corrected minor typographical and
grammatical errors.
Revisions made for accuracy.
06CT36
06DQ2B

V114
PAGE 5 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
2.2 
Summary of Changes from Previous Versions of the sSAP
Previous 
Version
Current Version 
Section
Description of Change 
Rationale
None 
30 APR 2021 
Not Applicable 
Not Applicable 
This is the first version of the
sSAP.
3 
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1 
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan
is provided in Sections 3.2 through 3.12.
Study Design Overview  
A Phase 3, Multicenter, Randomized, Double-blind, Active Comparator-
controlled Study to Evaluate the Safety, Tolerability, and
Immunogenicity of V114 Followed by Administration of
PNEUMOVAX™23 Eight Weeks Later in Children Infected with
Human Immunodeficiency Virus (HIV) (PNEU–WAY PED)
Intervention Assignment 
Participants will be randomly assigned in a 1:1 ratio to V114 or
Prevnar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:
 
Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes
contained in V114 at 30 days postvaccination with V114 or
Prevnar 13™
Safety:
 
Proportion of participants with solicited injection-site AEs
(redness/erythema, swelling, tenderness/pain, and hard
lump/induration) from Day 1 through Day 14 following V114 or
Prevnar 13™
 
Proportion of participants with solicited systemic AEs (muscle
pain/myalgia, joint pain/arthralgia, headache, tiredness/fatigue, and
hives or welts/urticaria) from Day 1 through Day 14 following V114
or Prevnar 13™
 
Proportion of participants with vaccine-related SAEs through
completion of study participation
Key Secondary Endpoints 
Immunogenicity:
 
Anti-PnPs serotype-specific OPA GMTs for the 15 serotypes
contained in V114 at 30 days postvaccination with V114 or
Prevnar 13™
 
Anti-PnPs serotype-specific OPA GMTs and IgG GMCs at 30
days postvaccination with PNEUMOVAX™23 (Week 12)
06CT36
06DQ2B

V114
PAGE 6 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Statistical Methods for Key
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15
pneumococcal serotypes contained in V114 separately. To address the
primary immunogenicity objective, evaluation of the anti-PnPs serotype-
specific IgG GMCs at 30 days postvaccination with V114 or
Prevnar 13™ will include descriptive summaries. The point estimates
will be calculated by exponentiating the estimates of the mean of the
natural log values and the within-group confidence intervals (CIs) will be
derived by exponentiating the CIs of the mean of the natural log values
based on the t-distribution.
Statistical Methods for Key
Safety Analyses
The analysis strategy for safety parameters following vaccination is
described in Section 3.6.2. Safety parameters will be summarized via
descriptive statistics. In addition, for select safety parameters, 95%
within-group CIs will be provided.
Interim Analyses
 
To support the periodic review of safety and tolerability data across
the V114 Phase 3 pediatric program, an external unblinded
statistician will provide unblinded interim safety summaries to an
independent DMC for their review. There are no plans to conduct an
interim analysis of unblinded immunogenicity data in this study.
However, unblinded immunogenicity data will be made available to
the DMC upon request to enable a benefit-risk assessment.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Immunogenicity:
The planned sample size is 400 participants. Participants are to be
randomly assigned in 1:1 ratio to V114 or Prevnar 13™, respectively.
There are no hypotheses to be evaluated for primary objectives.
Section 3.9.1 provides information about the expected variability of
IgG GMCs given the sample size.
Safety:
Section 3.9.2 provides information about the ability of this study to
estimate the incidence of AEs within each vaccination group.
3.2 
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 using an IRT.
Blinding issues related to the planned interim analyses are described in Section 3.7.
06CT36
06DQ2B

V114
PAGE 7 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
3.3 
Hypotheses/Estimation
Objectives of the study are stated in Section 3 of the protocol. This is an estimation study,
and no formal hypothesis testing will be performed.
3.4 
Analysis Endpoints
3.4.1 
Immunogenicity Endpoints
Immune responses will be measured for each of the following serotypes contained in V114:
1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F.
The primary immunogenicity analysis endpoint is:
 Anti-PnPs serotype-specific IgG GMCs at 30 days postvaccination (Day 30) with
V114 or Prevnar 13™.
The secondary immunogenicity analysis endpoints include:
 Anti-PnPs serotype-specific OPA GMTs at 30 days postvaccination (Day 30) with
V114 or Prevnar 13™.
 Anti-PnPs serotype-specific OPA GMTs and IgG GMCs at 30 days postvaccination
with PNEUMOVAX™23 (Week 12).
The exploratory immunogenicity analysis endpoint includes:
 Anti-PnPs serotype-specific GMFRs from prevaccination (Day 1) to 30 days
postvaccination (Day 30) with V114 or Prevnar 13™for both OPA and IgG
responses.
3.4.2 
Safety Endpoints
A description of safety measures is presented in Sections 8.3 and 8.4of the protocol. The
method of safety analysis is described in Section 3.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including
adverse events and postvaccination temperature measurements following V114 or Prevnar
13™ and PNEUMOVAX™23 (separately).
06CT36
06DQ2B

V114
PAGE 8 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
The safety analysis endpoints include:
 Proportion of participants with solicited injection-site AEs (redness/erythema,
swelling, tenderness/pain, and hard lump/induration) from Day 1 through Day 14
postvaccination
 Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint
pain/arthralgia, headache, tiredness/fatigue, and hives or welts/urticaria) from Day 1
through Day 14 postvaccination
 Proportion of participants with the broad AE categories consisting of any AE and a
vaccine-related AE from Day 1 through Day 14 postvaccination
 Proportion of participants with an SAE, a vaccine-related SAE, a discontinuation due
to an AE, and a death from Day 1 through Month 6 (ie, 6 months postvaccination
with V114 or Prevnar 13™)
 Proportion of participants with maximum temperature measurements meeting the
Brighton Collaboration cut points from Day 1 through Day 7 postvaccination
The timeframe associated with the reporting of AEs is consistent with the collection.
Nonserious adverse events (NSAEs) are reported from Day 1 through Day 14 following each
vaccination. SAEs are reported from Day 1 (following vaccination with PCV [V114 or
Prevnar 13TM]) through Week 8 (prior to vaccination with PPV23 [PNEUMOVAXTM23])
and from Week 8 (following vaccination with PPV23) through Month 6 (completion of study
participation).
3.5 
Analysis Populations
3.5.1 
Immunogenicity Analysis Populations
The Per-Protocol (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. Potential deviations that may result in the exclusion of a
participant from the PP population for all immunogenicity analyses include:
 Failure to receive study vaccine at Visit 2 (Day 1)
 Failure to receive correct clinical material as per randomization schedule (ie, a
participant who was randomized to V114 but received Prevnar 13TM, or vice versa)
 Receipt of a prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion from the PP population for
specific immunogenicity analyses (depending on the time point) include:
06CT36
06DQ2B

V114
PAGE 9 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
 Failure to receive PNEUMOVAX™23 at Visit 4(Week 8)
 Receipt of a prohibited medication or prohibited vaccine prior to a blood sample
collection
 Collection of a blood sample outside of the pre-specified window (as described in
Section 1.3 of the protocol)
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.
A supportive analysis using the Full Analysis Set (FAS) population will also be performed
for the primary immunogenicity endpoint. The FAS population consists of all randomized
participants who received the relevant study vaccination(s) and have at least 1 serology result
relevant to the timepoint of interest (ie, a participant who was randomized and missed the
vaccination at Visit 2 [Day 1] is removed from the FAS population at all visits; a participant
who was randomized and missed vaccination at Visit 4 [Week 8] is removed from the FAS
population at Visit 5 [Week 12]). Participants will be included in the vaccination group to
which they are randomized for the analysis of immunogenicity data using the FAS
population.
3.5.2 
Safety Analysis Populations
Safety analyses will be conducted on the APaT population, which consists of all randomized
participants who received the relevant study vaccination for the timepoint of interest (ie, a
participant must receive a single dose of V114 or Prevnar 13TM at Visit 2 [Day 1] to be
included in the analyses following PCV; a participant must receive a single dose of
PNEUMOVAXTM23 at Visit 4 [Week 8] to be included in the analyses following PPV23).
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 take incorrect study
vaccination; such participants will be included in the treatment group corresponding to the
study vaccination actually received.
At least 1 temperature measurement obtained after study intervention is required for
inclusion in the analyses of temperature.
3.6 
Statistical Methods
Statistical methods for immunogenicity and safety analyses are described in Section 3.6.1
and Section 3.6.2, respectively. Section 3.6.3 describes how demographic and baseline
characteristics will be summarized.
The correct stratum will be used for analysis regardless of the assigned stratum at
randomization (ie, stratification errors will be corrected for the purposes of analysis).
06CT36
06DQ2B

V114
PAGE 10 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
3.6.1 
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary, secondary, and
exploratory immunogenicity objectives.
Immunogenicity analyses will be conducted for each of the 15 pneumococcal serotypes
contained in V114 separately. To address the primary immunogenicity objective, evaluation
of the serotype-specific IgG GMCs at 30 days post-vaccination with V114 or Prevnar 13™
(Day 30) will include descriptive summaries and within-group 95% CIs to be calculated for
each vaccination group. Point estimates for the IgG GMCs will be calculated by
exponentiating the estimates of the mean of the natural log values. The within-group CIs will
be derived by exponentiating the CIs of the mean of the natural log values based on the t-
distribution.
A similar statistical approach will be used to evaluate serotype-specific OPA responses at
Day 30, and IgG and OPA responses at 30 days postvaccination with PNEUMOVAX™23
(Week 12) for each vaccination group. To address the exploratory immunogenicity objective,
point estimates and within-group 95% CIs will be provided for serotype-specific GMFRs
from Day 1 to Day 30 for both IgG and OPA responses. 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.
Reverse Cumulative Distribution Curves for OPA titers and IgG concentrations will be
graphically displayed by serotype at each of the following timepoints: Day 30 and Week 12.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 1.
06CT36
06DQ2B

V114
PAGE 11 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Table 1 
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs.
Supportive 
Approach†
Statistical Method
Analysis
Population
Missing
Data
Approach
Primary Endpoint
Anti-PnPs IgG GMCs at Day 30
P
Descriptive
Statistics
(estimate, 95% CI) 
PP  
Missing data
will not be
imputed
S
FAS
Secondary Endpoints
Anti-PnPs OPA GMTs at Day 30
P
Descriptive
Statistics
(estimate, 95% CI)
PP  
Missing data
will not be
imputed
Anti-PnPs IgG GMCs/OPA GMTs at
Week 12
P
Descriptive
Statistics
(estimate, 95% CI)
PP  
Missing data
will not be
imputed
† 
P = primary approach; S = supportive approach.
CI = confidence interval; FAS = Full Analysis Set; GMC = Geometric Mean Concentration;
GMFR = Geometric Mean Fold Rise; GMT = Geometric Mean Titer; IgG = immunoglobulin G;
OPA = opsonophagocytic activity; PnPs = pneumococcal polysaccharide; PP = Per-Protocol.
The detectable ranges for OPA and IgG responses differ across serotypes. The limits of
quantitation define the range of responses over which the assays provide precise and accurate
measurements. Table 2gives the limits of quantitation defined for each serotype for OPA and
IgG responses. For responses smaller than the lower limit of quantitation (LLOQ), half of the
LLOQ is used for analysis when calculating the OPA GMTs and IgG GMCs, and in the
graphical displays of the Reverse Cumulative Distribution Curves for OPA titers and IgG
concentrations. The value of the LLOQ is used for analysis when calculating the GMFR for
OPA and IgG responses. For OPA and IgG responses that are larger than the upper limit of
quantitation (ULOQ), a value equal to the ULOQ + 1 is used for analysis.
06CT36
06DQ2B

V114
PAGE 12 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Table 2 
Limits of Quantitation for OPA and IgG Serotype-specific Responses
OPA  
IgG
Serotype
LLOQ (1/dil) 
ULOQ (1/dil) 
LLOQ (µg/mL) 
ULOQ (µg/mL)
1
9
30,213
0.05
850
3
19
30,564
0.05
145
4
34
137,160
0.05
173
5
27
119,016
0.10
368
6A
232
210,600
0.05
393
6B
40
105,840
0.05
341
7F
61
251,235
0.05
830
9V
151
224,316
0.05
644
14
62
281,637
0.05
1,520
18C
115
445,230
0.05
730
19A
31
128,304
0.05
1,387
19F
113
158,841
0.05
1,461
22F
15
229,338
0.05
1,054
23F
55
251,829
0.05
595
33F
20
399,600
0.05
833
IgG = immunoglobulin G; LLOQ = lower limit of quantitation; OPA= opsonophagocytic activity; ULOQ =
upper limit of quantitation.
3.6.2 
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs and postvaccination temperature measurements.
The analysis strategy for safety parameters following each vaccination is summarized in
Table 3. The proportion of participants with solicited injection-site AEs (redness/erythema,
swelling, tenderness/pain, and hard lump/induration from Day 1 to Day 14 postvaccination)
and solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache,
tiredness/fatigue, and hives or welts/urticaria from Day 1 to Day 14 postvaccination) will be
provided along with the corresponding within-group 95% CIs (based on the exact binomial
method proposed by Clopper and Pearson [Clopper, C. J. 1934]). In addition, the broad AE
categories consisting of the proportion of participants with any AE, a vaccine-related AE, a
SAE, an AE which is both vaccine-related and serious, discontinuation due to an AE, and
death will be summarized in the same manner. The proportion of participants with maximum
temperature measurements meeting the Brighton Collaboration cut points (from Day 1
through Day 7) will also be provided along with the corresponding within-group 95% CIs.
Point estimates by vaccination group will be provided for all other safety parameters
(specific AE terms and system organ class terms).
06CT36
06DQ2B

V114
PAGE 13 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
The analysis of safety parameters will be evaluated at 2 separate time points: (1) following
administration of V114 or Prevnar 13™ and (2) following administration of
PNEUMOVAX™23. Descriptive summaries of AEs following administration of V114 or
Prevnar 13™ will include nonserious AEs within 14 days of vaccination and SAEs occurring
Day 1 through Week 8 (prior to vaccination with PPV23). Descriptive summaries of AEs
following administration of PNEUMOVAX™23 will include nonserious AEs within 14 days
of vaccination and SAEs occurring Week 8 (following vaccination with PPV23) through
Month 6 (completion of study participation).
Table 3 
Analysis Strategy for Safety Parameters Following Each Vaccination
Safety Endpoint
Within-Group 95% CI 
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 14)†
X
X
Injection-site swelling (Days 1 to 14)†
X
X
Injection-site tenderness/pain (Days 1 to 14)†
X
X
Injection-site hard lump/induration (Days 1 to
14)†
X
X
Muscle pain/myalgia (Days 1 to 14)†
X
X
Joint pain/arthralgia (Days 1 to 14)†
X
X
Headache (Days 1 to 14)†
X
X
Tiredness/fatigue (Days 1 to 14)†
X
X
Hives or welts/urticaria (Days 1 to 14)†
X
X
Any AE‡
X
X
Any vaccine-related AE‡
X
X
Any SAE‡
X
X
Any vaccine-related SAE‡
X
X
Discontinuation due to AE‡
X
X
Death‡
X
X
Maximum temperature measurements meeting
the Brighton Collaboration cut points (Days 1 to
7)
X
X
Specific AEs by SOCs and PT
X
† Includes solicited events only.
‡ These endpoints are broad adverse event 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.
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC =
system organ class; X = results will be provided.
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
06CT36
06DQ2B

V114
PAGE 14 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
Laboratory AEs will not be reported in summary tables as laboratory safety testing is not
performed as part of the study and, therefore, any such AEs would only be reported
spontaneously. A listing of laboratory AEs will be provided.
A supportive analysis summarizing the proportion of participants reporting each of the
solicited complaints on the VRC will be conducted in support of the primary safety analyses
that are based on solicited AEs. This supportive analysis will use the methodology specified
in Table 3for solicited AEs. The analysis will be conducted on the subset of the APaT
population who entered solicited complaints data on the VRC.
3.6.3 
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 screened and
randomized and the primary reasons for screening failure and discontinuation will be
displayed. Demographic variables (eg, age, race, and gender), baseline characteristics, and
prior and concomitant vaccinations and therapies will be summarized by vaccination group
either by descriptive statistics or categorical tables.
3.7 
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric 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 reviews
will be outlined in the DMC Charter. Information regarding the composition of the DMC is
provided in Appendix 1 of the protocol. There are no plans to conduct an interim analysis of
unblinded immunogenicity data in this study. However, 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 discontinuation of the study or protocol modifications to an
executive committee of the Sponsor (see Appendix 1 of the protocol 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 Executive Oversight Committee (EOC) 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 results of ongoing safety reviews will be documented by the
external unblinded statistician. Additional logistical details will be provided in the DMC
Charter.
Study enrollment is likely to 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
06CT36
06DQ2B

V114
PAGE 15 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
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 review.
3.8 
Multiplicity
No adjustment will be made for multiplicity.
3.9 
Sample Size and Power Calculations
3.9.1 
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. The planned sample size is 400 participants. Participants are to be
randomly assigned in 1:1 ratio to V114 or Prevnar 13™. It is assumed that approximately
160 participants per vaccination group will be evaluable for PP immunogenicity analyses at
Day 30 (based on an 80% evaluability rate).
The width of the within-group 95% CIs for the serotype-specific IgG GMCs depends on the
sample size, variability of the natural log concentrations, and the magnitude ofthe IgG GMC.
In Table 4, 95% CIs for various hypothetical IgG GMCs at 30 days postvaccination with
V114 or Prevnar 13™and various hypothetical standard deviation estimates for the natural
log concentrations are displayed.
Table 4 
Within-Group 95% CIs for Varying Hypothetical IgG GMCs and Varying
Standard Deviations With 160 Evaluable Participants in Each Vaccination Group
Standard Deviation of
Natural Log
Concentrations†
Observed Serotype-specific IgG GMC†
1
5 
10
1.0
(0.86, 1.17)
(4.28, 5.84)
(8.55, 11.69)
1.5
(0.79, 1.26)
(3.96, 6.32)
(7.91, 12.64)
2.0
(0.73, 1.37)
(3.66, 6.83)
(7.32, 13.67)
† The estimates of the standard deviation and IgG GMC ratio are representative of those observed in a
previous MSD study.
CI = confidence interval; GMC = geometric mean concentration.
3.9.2 
Sample Size and Power for Safety Analyses
The sample size was selected to achieve a reasonably sized safety database in this population
exposed to V114. The probability of observing at least 1 SAE in this study depends on the
number of participants vaccinated and the underlying percentage of participants with a SAE
in the study population. Calculations below assume that 100% of the randomized participants
will be evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE
among 200 participants in the V114 group if the underlying incidence of a SAE is 0.8% (1 of
every 125 participants receiving the vaccine). There is a 50% chance of observing at least
1 SAE among 200 participants in the V114 group if the underlying incidence of a SAE is
06CT36
06DQ2B

V114
PAGE 16 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
0.35% (1 of every 289participants receiving the vaccine). If no SAEs are observed among
the 200 participants in the V114 group, this study will provide 97.5% confidence that the
underlying percentage of participants with a SAE is <1.82% (1 in every 55 participants) in
the V114 group.
3.10 Subgroup Analyses
Serotype-specific IgG GMCs and their corresponding within-group 95% CIs at Day 30 will
be calculated for each subgroup (eg, CD4+ T-cell count, sex, age, race, prior vaccination of
PCV) within each vaccination group. Analyses will only be performed for each subgroup
with ≥5% of the total number of randomized participants in each vaccination group. In
addition, a summary of AEs and a summary of solicited AEs following PCV will be provided
for each subgroup (point estimates only) with ≥5% of the total number of randomized
participants in each vaccination group.
The following subgroups are planned for evaluation:
 Age category (6 to 9years, 10 to 14years, 15 to 17years)
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
 Race (American Indian or Alaska Native, Asian, Black or African American, Multiple,
Native Hawaiian or Other Pacific Islander, White)
 Sex (Female, Male)
 CD4+ T-cell count category (≥200 to <500 cells/μL, ≥500 cells/μL)
 Prior PCV status (PCV Naïve, Receipt of Prior PCV)
 Prior PPV23 status (PPV23 Naïve, Receipt of Prior PPV23)
3.11 Compliance (Medication Adherence)
Given that participants will receive just a single dose of V114/Prevnar 13™ and a single dose
of PNEUMOVAX™23, compliance will not be calculated. However, the number and
proportion of randomized participants receiving each vaccination will be summarized
(Section 3.12).
3.12 Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized
participants administered V114 or Prevnar 13™ and the number and proportion of
randomized participants administered PNEUMOVAX™23.
06CT36
06DQ2B

V114
PAGE 17 
PROTOCOL NO. 030-00
Supplemental SAP
30 APR 2021
4 
REFERENCES
[Clopper, C. J. 1934] 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits
illustrated in the case of the binomial. Biometrika 1934;26(4):404-13.
06CT36
06DQ2B