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 Adults Infected With HIV (PNEU-WAY)
Phase: PHASE3
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03480802 
Document Date: 
01-Jun-2018
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 
Adults Infected with HIV (PNEU–WAY)

PRODUCT: V114 
1
PROTOCOL/AMENDMENT NO.: 018-01
V114-018-01-FINAL PROTOCOL
01-JUN-2018
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 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 Adults Infected with HIV 
(PNEU–WAY)
Protocol Number: 018-01
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
14977
2017-001909-32
Approval Date: 01-JUN-2018
 
 
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PRODUCT: V114 
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PROTOCOL/AMENDMENT NO.: 018-01
V114-018-01-FINAL PROTOCOL
01-JUN-2018
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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PRODUCT: V114 
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PROTOCOL/AMENDMENT NO.: 018-01
V114-018-01-FINAL PROTOCOL
01-JUN-2018
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The primary purpose of this amendment is to remove the collection of medical device incidents from the protocol (removal of Section 
6.1.1, Section 8.4.8, and Appendix 4). The implementation of the FDA guidance for reporting events related to combination products 
has been delayed until January 2020. Therefore, the current protocol is not within the scope of medical device reporting requirements. 
Other clarifications and editorial revisions were also made as shown in the Summary of Changes Table below.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
2.2.1
V114 and Pneumococcal Disease
Licensure dates for Prevnar 13™ were added to 
the third paragraph.
Revisions were made in the fourth paragraph to 
better align with the cited literature.
Revisions made for accuracy.
4.2.1.1 Immunogenicity Endpoints
The following revision has been made to the first 
sentence (revision in bold):
Sera from participants will be used to measure 
vaccine-induced, serotype-specific OPA and IgG 
responses for all 15 serotypes (1, 3, 4, 5, 6A, 6B, 
7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) 
included in V114 using the Multiplexed 
Opsonophagocytic Assay (MOPA) assay and 
pneumococcal electrochemiluminescence 
(PnECL) assay.
Revision made for accuracy.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
6.1.1 Medical Devices
8.4.8
Medical Device Incidents 
(Including Malfunctions)
10.4
Appendix 4: Medical Device 
Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and 
Reporting
Sections removed.
The implementation of the FDA 
guidance for reporting events related 
to combination products has been 
delayed until January 2020. 
Therefore, the current protocol is not 
within the scope of medical device 
reporting requirements.
6.5 Concomitant Therapy
The following addition has been made (in bold) 
to #3:
3. Participants should not receive systemic 
corticosteroids (prednisone equivalent of ≥20 
mg/day for ≥14 consecutive days) starting from 
30 days prior to through 30 days following 
vaccination.
Concomitant corticosteroid rules were updated to 
align with other protocols in the V114 program.
Added for consistency with other 
sections to clarify the specific steroid 
used as a reference. Updates also 
necessary for program consistency.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.1.10 Telephone Contact Questionnaire
1.3 Schedule of Activities (SoA)
The text in Section 8.1.10 was revised as 
follows:
Original: All participants will be contacted by 
telephone at Month 6 to complete the Telephone 
Contact Questionnaire. Data to be reported on 
this questionnaire will include SAEs and/or any 
updates to concomitant medications, nonstudy 
vaccinations, and previously reported safety 
information.
Revised: Site personnel will contact study 
participants 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 concomitant medications, 
nonstudy vaccinations, and previously reported 
safety information.
The revised text was also added to the SoA.
Revisions were made to clarify the 
process for administering the 
telephone contact questionnaire.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.4.1
Time Period and Frequency for 
Collecting AE, SAE, and Other Reportable 
Safety Event Information
The following text was deleted from the second 
paragraph in this section:
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 (42 days for live attenuated 
vaccines) 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.
Live attenuated vaccines are not 
provided as part of the study.
8.5 Treatment of Overdose
The definition of overdose was revised as 
follows:
Original: In this study, an overdose is any dose 
higher than 1 dose of any individual study 
vaccine during the individual’s participation in 
the study.
Revised: In this study, an overdose is the 
administration of more than 1 dose of any 
individual study vaccine in any 24-hour period.
Revisions made for accuracy.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.4.1
Immunogenicity Endpoints
The following sentence was added:
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.
Text added to clarify that immune 
responses will be tested for the 
serotypes contained in V114 and not 
for all of the PNEUMOVAX™23 
serotypes.
9.6.2
Statistical Methods for Safety 
Analyses, Table 5 
Tier 2 safety endpoint was revised as follows 
(changes in bold):
“Any SAE and vaccine-related AE” was changed 
to “Any vaccine-related SAE”
Table was revised to align with 
safety analysis plan and text under 
Tier 2 events.
Throughout
Editorial revisions
Changes are minor and have not 
been summarized individually.
 
 
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PRODUCT: V114 
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PROTOCOL/AMENDMENT NO.: 018-01
V114-018-01-FINAL PROTOCOL
01-JUN-2018
Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA) ................................................................................20
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................25
2.2.1
V114 and Pneumococcal Disease ................................................................25
2.2.2
Preclinical and Clinical Studies ...................................................................26
2.2.3
Information on Other Study-related Therapy ..............................................26
2.2.3.1
Prevnar 13™......................................................................................26
2.2.3.2
PNEUMOVAX™23 ..........................................................................27
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................29
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design ......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................32
4.2.1
Rationale for Endpoints ...............................................................................33
4.2.1.1
Immunogenicity Endpoints................................................................33
4.2.1.2
Safety Endpoints ................................................................................33
4.2.1.3
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.3
Justification for Dose ...........................................................................................34
4.4
Beginning and End of Study Definition .............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................34
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria ................................................................................................36
5.3
Lifestyle Considerations ......................................................................................38
5.4
Screen Failures.....................................................................................................38
5.5
Participant Replacement Strategy......................................................................38
6
STUDY INTERVENTION............................................................................................38
6.1
Study Intervention(s) Administered...................................................................38
6.2
Preparation/Handling/Storage/Accountability .................................................40
 
 
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6.2.1
Dose Preparation..........................................................................................40
6.2.2
Handling, Storage, and Accountability........................................................40
6.3
Measures to Minimize Bias: Randomization and Blinding..............................40
6.3.1
Intervention Assignment..............................................................................40
6.3.2
Stratification.................................................................................................41
6.3.3
Blinding........................................................................................................41
6.4
Study Intervention Compliance..........................................................................41
6.5
Concomitant Therapy..........................................................................................42
6.5.1
Rescue Medications and Supportive Care ...................................................42
6.6
Dose Modification (Escalation/Titration/Other)...............................................42
6.7
Intervention After the End of the Study............................................................42
6.8
Clinical Supplies Disclosure................................................................................43
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................43
7.1
Discontinuation of Study Intervention...............................................................43
7.2
Participant Withdrawal From the Study...........................................................44
7.3
Lost to Follow Up.................................................................................................44
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................45
8.1
Administrative and General Procedures ...........................................................46
8.1.1
Informed Consent.........................................................................................46
8.1.1.1
General Informed Consent.................................................................46
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................47
8.1.2
Inclusion/Exclusion Criteria ........................................................................47
8.1.3
Participant Identification Card.....................................................................47
8.1.4
Medical History ...........................................................................................47
8.1.5
Prior and Concomitant Medications Review ...............................................47
8.1.5.1
Prior Medications...............................................................................47
8.1.5.2
Concomitant Medications ..................................................................48
8.1.6
Assignment of Screening Number...............................................................48
8.1.7
Assignment of Treatment/Randomization Number .....................................48
8.1.8
Study Intervention Administration ..............................................................48
8.1.8.1
Timing of Dose Administration.........................................................49
8.1.9
Electronic Vaccination Report Card ............................................................49
8.1.10
Telephone Contact Questionnaire................................................................50
8.1.11
Discontinuation and Withdrawal .................................................................50
8.1.11.1
Withdrawal From Future Biomedical Research ................................50
8.1.12
Participant Blinding/Unblinding..................................................................50
 
 
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8.1.13
Calibration of Equipment.............................................................................51
8.2
Immunogenicity Assessments .............................................................................51
8.2.1
Multiplex Opsonophagocytic Assay (MOPA).............................................52
8.2.2
Electrochemiluminescence (ECL) ...............................................................52
8.3
Safety Assessments...............................................................................................53
8.3.1
Physical Examinations.................................................................................53
8.3.2
Pregnancy Test.............................................................................................53
8.3.3
HIV Serology, CD4+ T-cell count, and Plasma HIV RNA Testing............53
8.3.4
Body Temperature Measurement.................................................................53
8.3.5
Safety Assessments and Use of the eVRC...................................................54
8.3.6
Clinical Laboratory Assessments.................................................................54
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................55
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information.............................................................................55
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......57
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...57
8.4.4
Regulatory Reporting Requirements for SAE .............................................57
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................57
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ................................................................................................58
8.4.7
Events of Clinical Interest............................................................................58
8.5
Treatment of Overdose........................................................................................58
8.6
Pharmacokinetics.................................................................................................58
8.7
Pharmacodynamics..............................................................................................58
8.8
Future Biomedical Research Sample Collection...............................................58
8.9
Planned Genetic Analysis Sample Collection ....................................................58
8.10
Biomarkers ...........................................................................................................59
8.11
Medical Resource Utilization and Health Economics.......................................59
8.12
Visit Requirements...............................................................................................59
8.12.1
Screening......................................................................................................59
8.12.2
Treatment Period/Vaccination Visit ............................................................59
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........59
9
STATISTICAL ANALYSIS PLAN .............................................................................59
9.1
Statistical Analysis Plan Summary.....................................................................60
9.2
Responsibility for Analyses/In-house Blinding .................................................61
9.3
Hypotheses/Estimation ........................................................................................61
9.4
Analysis Endpoints...............................................................................................61
 
 
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9.4.1
Immunogenicity Endpoints..........................................................................62
9.4.2
Safety Endpoints ..........................................................................................62
9.5
Analysis Populations............................................................................................63
9.5.1
Immunogenicity Analysis Populations ........................................................63
9.5.2
Safety Analysis Populations ........................................................................63
9.6
Statistical Methods...............................................................................................64
9.6.1
Statistical Methods for Immunogenicity Analyses ......................................64
9.6.2
Statistical Methods for Safety Analyses ......................................................65
9.6.3
Demographic and Baseline Characteristics .................................................66
9.7
Interim Analyses ..................................................................................................66
9.8
Multiplicity ...........................................................................................................67
9.9
Sample Size and Power Calculations .................................................................67
9.9.1
Sample Size and Power for Immunogenicity Analyses ...............................67
9.9.2
Sample Size and Power for Safety Analyses ...............................................68
9.10
Subgroup Analyses...............................................................................................68
9.11
Compliance (Medication Adherence).................................................................69
9.12
Extent of Exposure...............................................................................................69
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................70
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........70
10.1.1
Code of Conduct for Clinical Trials.............................................................70
10.1.2
Financial Disclosure.....................................................................................72
10.1.3
Data Protection.............................................................................................72
10.1.3.1
Confidentiality of Data ......................................................................73
10.1.3.2
Confidentiality of Participant Records...............................................73
10.1.3.3
Confidentiality of IRB/IEC Information............................................73
10.1.4
Committees Structure...................................................................................73
10.1.4.1
Scientific Advisory Committee..........................................................73
10.1.4.2
Executive Oversight Committee........................................................73
10.1.4.3
External Data Monitoring Committee ...............................................74
10.1.5
Publication Policy........................................................................................74
10.1.6
Compliance with Study Registration and Results Posting Requirements ...74
10.1.7
Compliance with Law, Audit, and Debarment ............................................75
10.1.8
Data Quality Assurance ...............................................................................75
10.1.9
Source Documents .......................................................................................76
10.1.10
Study and Site Closure.................................................................................76
10.2
Appendix 2: Clinical Laboratory Tests..............................................................77
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................78
10.3.1
Definition of AE ..........................................................................................78
10.3.2
Definition of SAE ........................................................................................79
10.3.3
Additional Events Reported.........................................................................80
10.3.4
Recording AE and SAE ...............................................................................80
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor85
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................87
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................88
10.5.1
Definitions....................................................................................................88
10.5.2
Contraception Requirements........................................................................89
10.5.3
Pregnancy Testing........................................................................................90
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................91
10.7
Appendix 7: Country-specific Requirements ....................................................96
10.8
Appendix 8: Abbreviations .................................................................................97
11
REFERENCES...............................................................................................................99
 
 
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01-JUN-2018
LIST OF TABLES
Table 1
Study Interventions ..........................................................................................39
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types ...46
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................56
Table 4
Analysis Strategy for Immunogenicity Variables............................................65
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination ...........66
Table 6
Within-Group 95% CIs for Varying Hypothetical OPA GMTs and IgG GMCs 
and Varying Standard Deviations with 135 Evaluable Participants in Each 
Vaccination Group...........................................................................................68
Table 7
Protocol-required Safety Laboratory Assessments..........................................77
Table 8
Contraceptive Methods ....................................................................................89
 
 
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LIST OF FIGURES
Figure 1
V114-018 Study Design.............................................................................19
 
 
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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 Adults Infected with HIV (PNEU–
WAY)
Short Title: Safety and Immunogenicity of V114 in Adults Infected with HIV
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-018 (PNEU–WAY)
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in pneumococcal vaccine-naïve adults 
≥18 years of age infected with HIV (with CD4+ T-cell count ≥50 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 and Prevnar 13™ with 
respect to the proportion of participants with 
adverse events (AEs) within each vaccination 
group separately.
Following vaccination with V114 or 
Prevnar 13™:
- Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) from Day 1 to Week 8
- Objective: To evaluate the serotype-specific 
opsonophagocytic activity (OPA) Geometric 
Mean Titers (GMTs) and Immunoglobulin G 
(IgG) Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination (Day 30) 
with V114 and Prevnar 13™ within each 
vaccination group separately. 
- Serotype-specific OPA and IgG responses for 
the 15 serotypes in V114 at Day 30
 
 
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Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the safety and 
tolerability of PNEUMOVAX™23 
administered 8 weeks following V114 and of 
PNEUMOVAX™23 administered 8 weeks 
following Prevnar 13™ with respect to the 
proportion of participants with AEs within 
each vaccination group separately. 
Following vaccination with 
PNEUMOVAX™23:
- Solicited injection-site AEs from Day 1 
through Day 5 postvaccination 
- Solicited systemic AEs from Day 1 through 
Day 14 postvaccination 
- Vaccine-related SAEs from Week 8 to 
Month 6
- Objective: To evaluate the serotype-specific 
OPA GMTs and IgG GMCs at 30 days 
postvaccination with PNEUMOVAX™23 
(Week 12) for participants administered V114 
and separately for participants administered 
Prevnar 13™ 8 weeks before receipt of 
PNEUMOVAX™23. 
- Serotype-specific OPA and IgG responses for 
the 15 serotypes in V114 at Week 12
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Adults 18 years of age or older 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
Masking
Participant
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 21 months from the time the first participant 
signs the informed consent 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 serology assay 
result.
 
 
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Number of Participants:
Approximately 300 participants will be randomized, with approximately 150 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)
Experimental
PNEUMOVAX™23
Refer to 
product
labeling
Single 
dose
IM
Single Dose 
at Visit 4 
(Week 8)
Experimental
Prevnar 
13™
Prevnar 13™
Refer to 
product 
labeling
Single 
dose
IM 
Single Dose 
at Visit 2
(Day  1)
Experimental
PNEUMOVAX™23
Refer to 
product 
labeling
Single 
dose
IM
Single Dose 
at Visit 4 
(Week 8)
Experimental
IB = Investigator’s Brochure; IM = intramuscular.
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 6 months from 
the time the participant 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.
 
 
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Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The key components of the study design are depicted in Figure 1.
Figure 1
V114-018 Study Design
 
 
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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
Informed Consent
X
Consent must be obtained 
before any study procedures.
Informed Consent for Future Biomedical 
Research
X
Informed consent for future 
biomedical research samples 
must be obtained before the 
blood sample (DNA sample) is 
collected.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
X
Serum for HIV Serology
X
Blood sample for CD4+ T-cell count
X
X
X
Blood sample for plasma HIV RNA 
testing
X
X
X
Medical History
X
X
The participant’s medical 
history for the 5 years prior to 
these visits will be reviewed.
History of tobacco use will also 
be collected for all participants.
Assignment of Randomization Number
X
Participant Identification Card
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™. 
 
 
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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).
PNEUMOVAX™23 Administration 
(Open-label) 
X
At Visit 4 (Week 8), all 
participants will receive a 
single dose of 
PNEUMOVAX™23. Study 
vaccine 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.
Provide electronic Vaccination Report 
Card (eVRC) 
X
All participants will be 
provided an eVRC at Visit 2 
(Day 1) to record AEs and body 
temperature measurements. 
Instructions for using the eVRC 
will be reviewed with the 
participant.
Review eVRC data with participant
X
X
X
X
Collect eVRC from participant 
X
Complete the Telephone Contact 
Questionnaire 
X
Site personnel will contact 
study participants 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 concomitant 
medications, nonstudy 
vaccinations, and previously 
reported safety information.
 
 
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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).
Safety Procedures
Complete Physical Examination 
X
To be performed by the 
investigator or medically 
qualified designee before study 
vaccine is administered.
Directed Physical Examination
X
To be performed by the 
investigator or medically 
qualified designee before study 
vaccine is administered.
Pregnancy Test – if applicable
X
X
A pregnancy test consistent 
with local requirements 
(sensitive to at least 25 IU beta 
human chorionic gonadotropin, 
β-hCG) must be performed 
before administration of the 
study vaccine in females who 
are of reproductive potential. 
Urine or serum tests can be 
used, and results must be 
negative before vaccination can 
occur.
Body Temperature Measurement Before 
Vaccination
X
X
Each participant's body 
temperature must be taken 
before vaccination. Participants 
who present with fever (oral or 
tympanic temperature ≥100.4°F 
[≥38.0°C]; axillary or temporal 
temperature ≥99.4°F [≥37.4°C]; 
or rectal temperature ≥101.4°F 
[≥38.6°C]) will have the 
vaccination delayed until fever 
is resolved for 72 hours.
30-Minute Postvaccination Observation 
Period
X
X
To be performed by blinded 
trial site personnel only.
 
 
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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
AEs (serious and nonserious) 
are to be reported from Days 1 
through 14 following each 
vaccination. SAEs and deaths 
are to be reported throughout 
the duration of the participant’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).
 
 
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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).
Immunogenicity Procedures
Serum for immunogenicity assays 
(including retention serum)
X
X
X
Blood samples must be 
collected before study 
vaccination when applicable.
After completion of 
opsonophagocytic (OPA) and 
electrochemiluminescence 
(ECL) testing, serum samples 
will be stored to conduct any 
additional study-related testing 
as required by regulatory 
agencies or the Sponsor. 
Leftover sera from the study 
may be used for the 
development and/or validation 
of pneumococcal assays after 
completion of all study-related 
immunogenicity testing; this 
applies only to sera received 
from randomized study 
participants who provided 
consent for future biomedical 
research.
Future Biomedical Research
Blood (DNA) for Future Biomedical 
Research
X
Collected from randomized 
participants who provided 
consent for future biomedical 
research (See Section 8.8)
a
When scheduling the Telephone Contact (Day 15), Visit 3 (Day 30), and Visit 4 (Week 8), and the Telephone Contact (Month 6), “Day 1” is the date of Visit 2.
b
When scheduling the Telephone Contact (Week 10) and Visit 5 (Week 12), “Day 1” is the date of Visit 4.
 
 
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2
INTRODUCTION
Merck Sharp & Dohme Corp. (MSD) is developing an investigational 15-valent 
pneumococcal conjugate vaccine (PCV) (referred to as V114) for prevention of 
pneumococcal disease caused by the serotypes contained 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
Individuals infected with the human immunodeficiency virus (HIV) are at an increased risk 
of invasive pneumococcal disease (IPD) compared to uninfected individuals. Currently, 
treatment guidelines in many countries recommend the use of a PCV as part of a proposed 
immunization regimen for individuals infected with HIV [Centers for Disease Control and 
Prevention (CDC) 2012] [Castiglia P. 2014].  
This clinical study is designed to evaluate the safety, tolerability, and immunogenicity of 
V114 and Prevnar 13™ in adults (≥18 years of age) infected with HIV (CD4+ T-cell count 
≥50 cells/µL and a plasma HIV ribonucleic acid (RNA) value <50,000 copies/mL prior to 
study entry) who have not received a pneumococcal vaccine (vaccine-naïve). This study will 
also describe the safety and tolerability of PNEUMOVAX™23 (pneumococcal vaccine, 
polyvalent [23-valent], MSD) when administered 8 weeks after receipt of either V114 or 
Prevnar 13™ and the immune responses to the 15 serotypes contained in V114 following 
PNEUMOVAX™23 administration. The data from this study will contribute to the overall 
safety database and immunogenicity profile of V114 to support initial licensure in adults.
2.2
Background
2.2.1
V114 and Pneumococcal Disease  
Refer to the Investigator’s Brochure (IB) for V114 for more detailed background, including 
information on pneumococcal disease burden.
Streptococcus pneumoniae is a significant cause of disease worldwide, with clinical 
manifestations including pneumonia, meningitis, otitis media, sinusitis, and sepsis. Adults 
with comorbid conditions, in particular immunocompromised individuals, have a higher 
incidence of IPD morbidity and mortality in all age groups compared to adults without the 
comorbid conditions [Lexau, C. A., et al 2005]. 
Currently licensed pneumococcal conjugate vaccines (eg, Prevnar™, Synflorix™, and 
Prevnar 13™) were first implemented in infant immunization programs in many countries 
worldwide. Prevnar™ was first licensed in 2000 and later replaced by Prevnar 13™ in 2009 
for the European Union and in 2010 for the United States. 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 has reduced the burden of pneumococcal disease caused by the 
 
 
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serotypes contained in the vaccines in children who were targeted by the vaccination 
programs and unvaccinated individuals from other age groups (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]. 
Prevnar 13™ was also shown to be efficacious against vaccine-type nonbacteremic 
pneumococcal pneumonia and IPD in adults ≥65 years of age [Bonten, M. J., et al 2015]. 
These study results were the basis of the recommendation from the ACIP for the sequential 
administration of Prevnar 13™ followed at least 12 months later by PNEUMOVAX™23 in 
adults ≥65 years of age [Tomczyk, S., et al 2014] [Kobayashi, M., et al 2015].
Although cases of IPD have decreased following implementation of PCVs, an increase in 
IPD caused by serotypes not covered by currently available vaccines has been observed. 
V114 contains 2 additional serotypes (22F, 33F) compared with Prevnar 13™. The selection 
of 22F and 33F was primarily based on epidemiological importance of these 2 additional 
serotypes. Recent data from the United States suggest that 22F is the most common serotype 
not included in Prevnar 13™ in adults ≥18 years of age, causing 13% of IPD cases. 
Serotype 33F is associated with an additional 5% of IPD cases [Moore, M. R., et al 2015]. 
Data from the United Kingdom also showed that, in 2013/2014, 22F and 33F are frequent 
serotypes in adults ≥65 years of age, accounting for approximately 10% and 4% of IPD cases 
in that age group, respectively [Waight, P. A., et al 2015]. Data from 2014 reported in the 
2016 annual epidemiological report on IPD by the European Centre for Disease Prevention 
and Control showed that both serotypes 22F and 33F are among the most common serotypes 
causing IPD [European Centre for Disease Prevention and Control 2016].
The serotypes included in V114 will provide broad coverage of 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 to address the emergence of 
pneumococcal disease caused by serotypes not contained in currently licensed PCVs. V114 is 
designed to offer broader serotype coverage than Prevnar 13™ against pneumococcal disease 
in both pediatric and adult populations.
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™.
 
 
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Prevnar 13™ contains all of the pneumococcal serotypes included in Prevnar™ (4, 6B, 9V, 
14, 18C, 19F, 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
The adult indication was approved based on immune responses elicited by Prevnar 13™ in 
comparison with PNEUMOVAX™23. A placebo-controlled clinical efficacy trial 
(Community Acquired Pneumonia Immunization Trial in Adults [CAPiTA]) evaluated the 
efficacy of Prevnar 13™ against pneumococcal pneumonia and IPD in immunocompetent 
adults ≥65 years of age. Results from CAPiTA showed that Prevnar 13™ was 45.6% (95%
confidence interval [CI]: 21.8% to 62.5%) efficacious against vaccine-type nonbacteremic 
pneumococcal pneumonia and 75.0% (95% CI: 41.4% to 90.8%) efficacious against vaccine-
type IPD in adults ≥65 years of age [Bonten, M. J., et al 2015].
Prevnar 13™ was studied in individuals infected with HIV in 2 open-label, single-arm, 
descriptive studies. In one study, 3 doses of Prevnar 13™ were administered 6 months apart 
to adults ≥18 years of age infected with HIV (CD4+ T-cell count of ≥200 cells/µL and HIV 
viral load of <50,000 copies/mL). All participants had previously received 
PNEUMOVAX™23 at least 6 months prior to enrollment. Antibody responses were 
numerically higher for all vaccine serotypes after the first dose compared to pre-vaccination 
and generally comparable following the first, second and third dose [Penaranda, M., et al 
2010]. In the second study, 3 doses of Prevnar 13™ were administered 1 month apart to 
individuals ≥6 years of age infected with HIV with CD4+ T-cell counts ≥200 cells/µL, and 
HIV viral load <50,000 copies/mL 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 are 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. 
In the United States, PNEUMOVAX™23 is recommended by the ACIP for routine use in 
immunocompetent adults ≥65 years of age as sequential administration at least 1 year after 
Prevnar 13™ [Kobayashi, M., et al 2015]. It is also recommended for use in adults aged 19 
through 64 years of age with underlying medical conditions that increase the risk for serious 
pneumococcal infection. These conditions include, but are not limited to, chronic heart 
disease, chronic lung disease (including chronic obstructive pulmonary disease, emphysema, 
and asthma), diabetes mellitus, alcoholism, chronic liver disease (including cirrhosis), and 
cigarette smoking [Centers for Disease Control and Prevention 2010].
 
 
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PNEUMOVAX™23 is also recommended in immunocompromised adults ≥19 years of age; 
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].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational vaccine.
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 
to Prevnar 13™ for the shared serotypes while providing additional coverage for the 
2 serotypes (22F, 33F) unique to V114. It is unknown if the investigational V114 will have 
the same benefit 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 Form (ICF).
 
 
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in pneumococcal vaccine-naïve 
adults ≥18 years of age infected with HIV (with CD4+ T-cell count ≥50 cells/µL and plasma 
HIV RNA <50,000 copies/mL tested at Screening [Visit 1]).
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability of V114 and Prevnar 13™ 
with respect to the proportion of 
participants with adverse events
(AEs) within each vaccination group 
separately.
Following vaccination with V114 or 
Prevnar 13™:
•
Solicited injection-site AEs from 
Day 1 through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination
•
Vaccine-related serious adverse 
events (SAEs) from Day 1 to Week 8
•
Objective: To evaluate the serotype-
specific opsonophagocytic activity 
(OPA) Geometric Mean Titers 
(GMTs) and Immunoglobulin G (IgG)
Geometric Mean Concentrations 
(GMCs) at 30 days postvaccination 
(Day 30) with V114 and Prevnar 13™
within each vaccination group 
separately.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Day 30
Secondary
•
Objective: To evaluate the safety and 
tolerability of PNEUMOVAX™23 
administered 8 weeks following V114 
and of PNEUMOVAX™23 
administered 8 weeks following 
Prevnar 13™ with respect to the 
proportion of participants with AEs
within each vaccination group 
separately.
Following vaccination with 
PNEUMOVAX™23:
•
Solicited injection-site AEs from Day 
1 through Day 5 postvaccination 
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination 
•
Vaccine-related SAEs from Week 8 
to Month 6
 
 
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Objectives
Endpoints
•
Objective: To evaluate the serotype-
specific OPA GMTs and IgG GMCs 
at 30 days postvaccination with 
PNEUMOVAX™23 (Week 12) for 
participants administered V114 and 
separately for participants 
administered Prevnar 13™ 8 weeks 
before receipt of 
PNEUMOVAX™23.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Week 12
Tertiary/Exploratory
•
Objective: To evaluate the serotype-
specific OPA GMTs and IgG GMCs 
at 30 days postvaccination (Day 30)
with V114 compared with Prevnar 
13TM.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Day 30
•
Objective: To evaluate the serotype-
specific OPA GMTs and IgG GMCs 
at 30 days postvaccination with 
PNEUMOVAX™23 (Week 12) for 
participants administered V114 
compared with participants 
administered Prevnar 13™ 8 weeks 
before receipt of 
PNEUMOVAX™23.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Week 12
•
Objective: To evaluate the serotype-
specific Geometric Mean Fold Rises
(GMFRs) and proportions of 
participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days 
postvaccination (Day 30) for both 
OPA and IgG responses for 
participants administered V114 and 
separately for participants 
administered Prevnar 13™.  
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Day 1 and Day 30
 
 
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Objectives
Endpoints
•
Objective: To evaluate the serotype-
specific GMFRs and proportions of 
participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days 
postvaccination with 
PNEUMOVAX™23 (Week 12) for 
both OPA and IgG responses for 
participants administered V114 and 
separately for participants 
administered Prevnar 13™ 8 weeks 
before receipt of 
PNEUMOVAX™23.
•
Serotype-specific OPA and IgG 
responses for the 15 serotypes in 
V114 at Day 1 and Week 12
4
STUDY DESIGN
4.1
Overall Design
Approximately 300 individuals will be randomly assigned in a 1:1 ratio to receive either 
V114 (150 participants) or Prevnar 13™ (150 participants) on Visit 2 (Day 1).  
Randomization will be stratified by CD4+ T-cell count as follows:
•
Stratum 1: CD4+ T-cell count ≥50 to <200 cells/µL
•
Stratum 2: CD4+ T-cell count ≥200 to <500 cells/µL
•
Stratum 3: CD4+ T-cell count ≥500 cells/µL.
At least 50% of participants will be enrolled into Stratum 2.  
All participants will also receive a single dose of PNEUMOVAX™23 at Visit 4 (Week 8).
Participants will be followed for local 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 adult 
V114 Phase 3 program. A description of the structure, function, and guidelines for decision-
making by 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.
 
 
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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 OPA and electrochemiluminescence (ECL) testing, serum samples will 
be stored to conduct any additional study-related testing as required by regulatory agencies or 
the Sponsor. Leftover sera from the study may be used for the development and/or validation 
of pneumococcal assays after completion of all study-related immunogenicity testing; this 
applies only to sera received from randomized study participants who provided consent for 
future biomedical research. 
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
The enrollment of adults 18 years of age or older who are infected with HIV, pneumococcal 
vaccine naïve, and have a documented CD4+ T-cell count ≥50 cells/µL as well as plasma 
HIV RNA <50,000 copies/mL prior to study entry is intended to assess safety, tolerability, 
and immunogenicity in a population that is representative of individuals infected with HIV 
for whom vaccination with a pneumococcal conjugate vaccine is recommended. Excluding 
individuals with CD4+ T-cell count <50 cells/µL or plasma HIV RNA ≥50,000 copies/mL is 
based on the priority of optimizing combination ART therapy to increase the CD4+ T-cell 
count and decrease plasma HIV RNA rather than participating in a clinical trial.
Stratum 1 represents individuals infected with HIV with the most significant immune 
suppression such as those who have been recently diagnosed with HIV or are not well-
controlled with CD4+ T-cell count values <200 cells/μL. CD4+ T-cell counts are an 
important measure of immune suppression and values <200 cells/μL indicate significant 
immune suppression associated with decreased life expectancy [World Health Organization 
2013]. With the availability of combination ART, individuals infected with HIV live longer, 
maintain CD4+ T-cell count values above 200 cells/μL, and maintain low levels of blood 
plasma HIV RNA [World Health Organization 2013]. Recent studies have shown that only 
approximately 15% of individuals with HIV infection have CD4+ T-cell count values <200 
cells/μL [Young, J., et al 2012] such that the enrollment into this stratum will not have a 
minimum sample size.
Stratum 2 represents individuals infected with HIV with moderate immune suppression 
(CD4+ T-cell count values ≥200 cells/µL to <500 cells/µL). Data in this population have 
been previously obtained with Prevnar 13™. A CD4+ T-cell count of ≥200 cells/µL to <500
cells/µL is being used in order to ensure that a sufficiently large sample size of participants 
with moderate immune suppression is studied (excluding the possibility that the majority of 
individuals with CD4+ T-cell count of ≥500 cells/µL will be enrolled). This stratum will 
represent at least 50% of the sample size.
 
 
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Stratum 3 represents individuals infected with HIV with the least immune suppression with 
CD4+ T-cell count values ≥500 cells/µL. This stratum will not have a minimum sample size.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, serotype-specific OPA and 
IgG responses for all 15 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 
and 33F) included in V114 using the Multiplexed Opsonophagocytic Assay (MOPA) assay 
and pneumococcal electrochemiluminescence (PnECL) assay. 
Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. OPA assesses 
levels of functional antibodies capable of opsonizing pneumococcal capsular polysaccharides 
for presentation to phagocytic cells for engulfment and subsequent killing, and therefore, is 
considered an important immunologic surrogate for protection against IPD in adults. Note 
that no antibody concentration or titer for either assay has been defined as the threshold value 
that correlates with protection in adults.
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 feedback 
received from regulatory agencies during product development. The electronic Vaccination 
Report Card (eVRC) used to record AEs during the postvaccination 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.
 
 
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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
This study utilizes Prevnar 13™ as the active comparator as this is the only PCV licensed in 
many developed countries for use in adults and is the standard of care in individuals with 
HIV.  Including the active comparator that is the current standard of care is expected to 
provide meaningful safety and immunogenicity data against which the clinical performance 
of V114 may be compared in HIV-infected participants.
Prevnar 13™ is approved for adults 18 years of age and older for the prevention of 
pneumococcal pneumonia and invasive disease caused by 13 S. pneumoniae serotypes (1, 3, 
4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F).
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 in previous adult V114 clinical studies in 
which 1 dose has resulted in a robust immune response.
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 ICF. 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 serology assay result.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
 
 
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5
STUDY POPULATION
Male/Female participants infected with HIV of at least 18 years of age 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
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Infected with HIV and CD4+ T-cell count ≥50 cells/µL and plasma HIV RNA 
<50,000 copies/mL tested at Screening (Visit 1).
2. Receiving combination ART for at least 6 weeks prior to study entry with no intended 
changes to combination ART therapy for 3 months after randomization.
Demographics
3. Participant is Male or Female ≥18 years of age.
Female Participants
4. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP who agrees to use 1 of the contraceptive methods as defined in 
Appendix 5 during the treatment period and for at least 6 weeks after the last dose of 
study intervention.
Informed Consent
5. The participant provides written informed consent for the study. The participant may also 
provide consent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
 
 
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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of opportunistic infections within 12 months before the first vaccination at Visit 2 
(Day 1).
2. History of non-infectious acquired immune deficiency syndrome-related illness such as 
Kaposi's sarcoma, wasting syndrome, or HIV-associated nephropathy.
3. *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).
4. 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).
5. Known hypersensitivity to any component of pneumococcal polysaccharide vaccine, 
pneumococcal conjugate vaccine, or any diphtheria toxoid-containing vaccine.
6. Known or suspected congenital immunodeficiency, 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).
7. Coagulation disorder contraindicating intramuscular vaccinations.
8. *Recent febrile illness (defined as oral or tympanic temperature ≥100.4°F [≥38.0°C]; 
axillary or temporal temperature ≥99.4°F [≥37.4°C]; or rectal temperature ≥101.4°F 
[≥38.6°C]) or received antibiotic therapy for any acute illness occurring within 72 hours 
before receipt of study vaccine.
9. History of malignancy ≤5 years prior to signing informed consent, except for adequately 
treated basal cell or squamous cell skin cancer or in situ cervical cancer.
10. A WOCBP who has a positive urine or serum pregnancy test before the first vaccination 
at Visit 2 (Day 1).
Prior/Concomitant Therapy
11. Prior administration of any pneumococcal vaccine or expected to receive any 
pneumococcal vaccine during the study outside of the protocol.
12. Received systemic corticosteroids (prednisone equivalent of ≥20 mg/day) for 
≥14 consecutive days and has not completed treatment at least 30 days before study 
entry.  
 
 
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13. Received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) within 14 days before vaccination.  
(Note: Topical, ophthalmic, intra-articular or soft-tissue [eg, bursa, tendon steroid 
injections], and inhaled/nebulized steroids are permitted).
14. Receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, and treatments associated with organ or bone marrow 
transplantation, or autoimmune disease.  
15. *Received any licensed, non-live vaccine within the 14 days before receipt of any 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.
16. *Received any live vaccine within 30 days before receipt of any study vaccine or is 
scheduled to receive any live vaccine within 30 days following receipt of any study 
vaccine. 
17. 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
18. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Other Exclusions 
19. Is breastfeeding
20. Is, at the time of signing informed consent, 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.
21. Has 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.
22. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
 
 
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5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
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™, 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
 
 
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The study intervention(s) to be used in this study are outlined in Table 1.
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 
(prefilled 
syringe)
Refer to IB
0.5 mL
IM
Single Dose 
at Visit 2 
(Day 1)
Experimental
IMP
Central
PNEUMOVAX™23
Biological/Vaccine
Sterile solution 
(prefilled 
syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 4 
(Week 8)
Experimental
IMP
Central
Prevnar 
13™
Active 
Comparator
Prevnar 13™
Biological/Vaccine
Sterile 
suspension 
(prefilled 
syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 2 
(Day 1)
Experimental
IMP
Central
PNEUMOVAX™23
Biological/Vaccine
Sterile solution 
(prefilled 
syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 4 
(Week 8)
Experimental
IMP
Central
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product
The definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or country differences ofthe definition of IMP/NIMP 
may exist. In these circumstances, local legislation is followed.
All supplies indicated in Table 1 will be provided per the “Sourcing” column depending upon local country operational requirements. 
Every attempt should be made to source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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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 in Section 4.3. 
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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment 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 V114 and Prevnar 13™, respectively.
 
 
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6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Stratum 1: CD4+ T-cell count ≥50 to <200
2. Stratum 2: CD4+ T-cell count ≥200 to <500
3. Stratum 3: CD4+ T-cell count ≥500
At least 50% of participants will be enrolled into Stratum 2.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevnar 13™will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who is involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because the 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/or 
dispensing, and administering these study vaccines. PNEUMOVAX™23 will also be 
prepared and/or dispensed and administered by unblinded study site staff for consistency 
even though it will be provided open-label in this study. In order 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 exam 
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.
See Section 8.1.12 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
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.
 
 
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Listed below (items 1 to 4) are specific restrictions for concomitant therapy or vaccination
during the course of the study:
1. Any administration of a non-study pneumococcal vaccine is prohibited during the study.
2. Live and non-live vaccines may only be administered prior to or following the receipt of 
study vaccine according to the time frames specified in Exclusion Criteria (Section 5.2). 
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.
3. Participants should not receive systemic corticosteroids (prednisone equivalent of 
≥20 mg/day for ≥14 consecutive days) starting from 30 days prior to through 30 days 
following vaccination. Note: Topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, 
tendon steroid injections), and inhaled/nebulized steroids are permitted.
4. Participants should not receive systemic corticosteroids exceeding physiologic 
replacement doses (prednisone equivalent dose >5 mg/day) within 14 days before any 
vaccination. Note: Topical, ophthalmic, intra-articular or soft-tissue (eg, bursa, tendon 
steroid injections), and inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
 
 
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6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or unblinded qualified study site personnel will be used to maintain the blinding 
of study staff who are directly involved in the clinical evaluation of participants in the study. 
Study intervention identity (name, strength, or potency) is included in the label text; random 
code/disclosure envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.12). 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 8.1.12 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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 vaccinations
will still continue to participate in the study as specified in Section 1.3 and Section 8.12.3,
unless the participant withdraws consent (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.11.
 
 
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A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant requests to discontinue study intervention.
•
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 withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study treatment 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 8.1.11. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
 
 
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•
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 or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Study 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.
•
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained from 
the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
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 
50 mL and the total amount of blood for the entire study will not exceed 160 mL. For those 
participants that consent to future biomedical research, an additional blood sample of 
approximately 8.5 mL will be taken.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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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
2 mL
N/A
2 mL
Blood sample for plasma HIV 
RNA testing
6 mL
N/A
6 mL
N/A
6 mL
Serum for immunogenicity assays 
(including retention serum)
N/A
40 mL
40 mL
N/A
40 mL
Blood (DNA) for Future 
Biomedical Research
N/A
8.5 mL
N/A
N/A
N/A
Expected total (mL)
12 mL
48.5 mL
48 mL
N/A
48 mL
DNA = deoxyribonucleic acid; HIV = human immunodeficiency virus; N/A = not applicable; RNA = 
ribonucleic acid.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant 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 is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent form or addendum to 
the original consent form that captures the participant’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
 
 
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The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, 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.
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. At the time of intervention
allocation/randomization, site personnel will add the intervention/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 before 
vaccination at Visit 2 (Day 1). The participant’s medical history for the 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. History of tobacco use will also be collected for all 
participants.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medications taken by the participant within 30 days before the first dose of study vaccine at 
Visit 2 (Day 1).
 
 
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
New and/or concomitant medications taken after the first dose of study vaccination at Visit 2 
(Day 1) 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.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
V114 or Prevnar 13™ will be administered at Visit 2 (Day 1). PNEUMOVAX™23 will be 
administered at Visit 4 (Week 8).
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.
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer V114, Prevnar 13™, or PNEUMOVAX™23 at the study site. 
PNEUMOVAX™23 will be administered open-label.
Prior to administration of V114, the unblinded pharmacist should shake the product 
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 
 
 
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resuspension. 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.
Study personnel should follow the preparation and administration instructions for 
Prevnar 13™ and PNEUMOVAX™23 as specified in the product labels.
Study vaccine will be administered as a single 0.5-mL intramuscular injection in the deltoid 
region of the participant’s arm. Vaccination information, such as Component Identification 
Number and time of vaccination, must be recorded on the appropriate electronic case report 
form (eCRF) per the Data Entry Guidelines.
All safety and immunogenicity assessments will be conducted by blinded personnel, and the 
participant will be blinded to the intervention (ie, V114 or Prevnar 13™) received.
8.1.8.1
Timing of Dose Administration
Vaccinations may be administered at any time of day, and without regard to timing of meals. 
Each participant's body temperature must be taken before each vaccine administration.  
Individuals who present with fever (oral or tympanic temperature ≥100.4°F [≥38.0°C]; 
axillary or temporal temperature ≥99.4°F [≥37.4°C]; or rectal temperature ≥101.4°F 
[≥38.6°C]) will have the vaccination delayed until fever is resolved for at least 72 hours.
The collection of blood samples and administration of pregnancy tests (if applicable) must be 
done before each vaccine administration. 
All participants will be observed for 30 minutes after 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).
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 in the use of the eVRC at Visit 2 (Day 1). 
Temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or vaccinations will be recorded on the eVRC as 
described in the Section 1.3 and Section 8.3.5. The investigator or delegate will review the 
data captured on the eVRC with the participant at the Telephone Contact (Day 15), Visit 3 
(Day 30), Telephone Contact (Week 10), and Visit 5 (Week 12).
For the AEs outlined above, the investigator will use the information provided by the 
participant both on the eVRC, and verbally at the time of eVRC review, to apply the 
appropriate assessment of intensity and toxicity as described in Appendix 3.
 
 
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8.1.10
Telephone Contact Questionnaire
Site personnel will contact study participants 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 concomitant medications, nonstudy 
vaccinations, and previously reported safety information.
8.1.11
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.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 5 [Week 12]) should be performed if the participant 
can attend during the Day 30 window or the Week 12 window. If the participant withdraws at 
any other time, the Month 6 Telephone contact activities 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.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the 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. 
8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
 
 
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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 treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the 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.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study. Participants may receive PNEUMOVAX™23 at Visit 4 (Week 8) after a benefit/risk 
assessment and consultation between the investigator/delegate and Sponsor.
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.     
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure vaccine-induced OPA and IgG for serotypes 
included in V114 and Prevnar 13™. These endpoints will be tested for all blood draws. 
Blood collection, storage and shipment instructions for serum samples will be provided in the 
operations/laboratory manual. 
The MOPA will be used for measuring OPA GMTs. Opsonization of pneumococci for 
phagocytosis is an important mechanism by which antibodies to polysaccharides protect 
against disease in vivo. The OPA assay is a useful tool for assessing the protective function 
 
 
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of serotype-specific antibodies and therefore, the immunogenicity of pneumococcal vaccine 
formulations.
Measurement of serotype-specific IgG will be measured using the PnECL v2.0 assay to 
assess the concentration of binding antibodies to capsular polysaccharide of S. pneumoniae
for the serotypes included in the study vaccines.
8.2.1
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. MSD 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.
8.2.2
Electrochemiluminescence (ECL)
MSD has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 pneumococcal polysaccharide 
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 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.
 
 
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 2 (Day 1).  A 
directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) before vaccination at Visit 4 (Week 8).
Investigators should pay special attention to clinical signs related to previous illnesses.
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 at Visit 2 (Day 1) 
and Visit 4 (Week 8) 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. Additionally a blood sample for CD4+ T-cell count and plasma HIV 
RNA testing will be collected at Visit 3 (Day 30) and Visit 5 (Week 12).
8.3.4
Body Temperature Measurement 
Each participant's body temperature must be taken before vaccination as described in 
Section 1.3.
Oral body temperatures will also be documented by participants using their eVRC during the 
eVRC-specified postvaccination follow-up period (Section 8.3.5).
For this study, any oral or tympanic temperature ≥100.4°F (≥38.0°C), axillary or temporal
temperature ≥99.4°F (≥37.4°C), or rectal temperature ≥101.4°F (≥38.6°C) will be considered 
an AE of fever. All fevers must be reported Day 1 through Day 14, unless the fever is a 
symptom of another reported AE.
 
 
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8.3.5
Safety Assessments and Use of the eVRC
All participants will be observed for 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.
Participants will use the eVRC (Section 8.1.9) to document the following information:

Oral body temperatures measured Day 1 (day of vaccination) through Day 5 
postvaccination;

Solicited injection-site AEs (redness/erythema, swelling, and tenderness/pain) Day 1 
through Day 5 postvaccination;

Solicited systemic AEs (muscle pain/myalgia, joint pain/arthralgia, headache, and 
tiredness/fatigue) Day 1 through Day 14 postvaccination;

Any other injection-site or systemic AEs Day 1 through Day 14 postvaccination; and

Concomitant medications and nonstudy 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 the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 to 44 days after the last dose of study 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
 
 
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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 or surrogate).
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 AE, 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:
1. A death that occurs prior to the participant completing the study.
OR
2. An SAE that is considered by an investigator who is a qualified physician to be vaccine 
related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
 
 
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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
Timeframe to 
Report Event 
and Follow-
up 
Information 
to 
SPONSOR:
Non-Serious 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
Events of Clinical 
Interest
There are no Events of Clinical Interest for this study 
Not 
applicable
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
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE 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 AE, SAE, 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. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
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.
 
 
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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
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
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
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:
•
DNA for future research
•
Leftover study serum after completion of immunogenicity testing stored for future 
research
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
 
 
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8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Approximately 30 days prior to treatment allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5.1. Screening procedures may be repeated after consultation with the Sponsor.
8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
In this trial, a participant may discontinue from study treatment (ie, vaccination) but continue 
to participate in subsequent protocol visits as outlined in Section 1.3, as long as the 
participant does not withdraw consent.  Protocol-specified activities including AE monitoring 
should occur at these visits.
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.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in 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 Adults Infected with HIV
(PNEU – WAY)
Intervention Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or 
Prevnar 13™, respectively. Randomization will be stratified into 3 
groups based on the participant’s CD4+ T-cell count at screening (≥50 to 
<200, ≥200 to <500, and ≥500) as described in Section 6.3.2.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Serotype-specific OPA GMTs and IgG GMCs at 30 days 
postvaccination with V114 or Prevnar 13™ (Day 30)
Safety: 

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, tenderness/pain) from Day 1 through 
Day 5 following V114 or Prevnar 13™ 

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue)
from Day 1 through Day 14 following V114 or Prevnar 13™

Proportion of participants with vaccine-related SAEs in the 8 weeks 
following V114 or Prevnar 13™(from Day 1 through Week 8)
Key Secondary Endpoints
Immunogenicity:

Serotype-specific OPA GMTs and IgG GMCs at 30 days 
postvaccination with PNEUMOVAX™23 (Week 12)
Safety: 

Proportion of participants with solicited injection-site AEs 
(redness/erythema, swelling, tenderness/pain) from Day 1 through 
Day 5 following PNEUMOVAX™23

Proportion of participants with solicited systemic AEs (muscle 
pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue)
from Day 1 through Day 14 following PNEUMOVAX™23

Proportion of participants with vaccine-related SAEs in the 4 
months following PNEUMOVAX™23 (from Week 8 through 
Month 6)
Statistical Methods for Key 
Immunogenicity Analyses
Immunogenicity analyses will be conducted for each of the 15 
pneumococcal serotypes in V114 separately. To address the primary 
immunogenicity objective, evaluation of the OPA GMTs and 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. A similar statistical approach will be used to 
evaluate the OPA and IgG responses at Week 12.
 
 
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Statistical Methods for Key 
Safety Analyses
The analysis strategy for safety parameters following each 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. 
Interim Analyses
To support the periodic review of safety and tolerability data across the 
adult V114 Phase 3 program, an external unblinded statistician will 
provide unblinded interim safety summaries to an independent external 
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 adjustment will be made for multiplicity.
Sample Size and Power 
Immunogenicity:
This study will randomize approximately 150 participants into the V114 
group and 150 participants into the Prevnar 13™ group.  It is assumed 
that approximately 135 participants per group will be evaluable for the 
PP immunogenicity analyses at Day 30 (90% evaluability rate). There 
are no hypotheses to be evaluated, but Section 9.9.1 provides information 
about the expected variability of the OPA GMTs and 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 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 in 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
Immunogenicity and safety analysis endpoints that will be summarized are listed below.
 
 
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9.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is contained in Section 8.2.
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 endpoints are the serotype-specific OPA GMTs and 
IgG GMCs at 30 days postvaccination with V114 or Prevnar 13™ (Day 30).
The secondary immunogenicity analysis endpoints are the serotype-specific OPA GMTs and 
IgG GMCs at 30 days postvaccination with PNEUMOVAX™23 (Week 12).
The exploratory immunogenicity analysis endpoints include:

Serotype-specific GMFRs and proportions of participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days postvaccination with V114 or Prevnar 13™(Day 
30) for both OPA and IgG responses

Serotype-specific GMFRs and proportions of participants with a ≥4-fold rise from 
prevaccination (Day 1) to 30 days postvaccination with PNEUMOVAX™23 
(Week 12) for both OPA and IgG responses
9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 8.4. The analysis of safety 
results 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 following PNEUMOVAX™23 (separately). 
The safety analysis endpoints include:

Proportion of participants with solicited injection-site AEs (redness/erythema, 
swelling, tenderness/pain) from Day 1 through Day 5 postvaccination

Proportion of participants with solicited systemic AEs (muscle pain/myalgia, joint 
pain/arthralgia, headache, and tiredness/fatigue) from Day 1 through Day 14 
postvaccination 

Proportions of participants with the broad AE categories consisting of any AE, a 
vaccine-related AE, a SAE, an AE which is both vaccine-related and serious, and 
discontinuation due to an AE and the proportion of participants who died

Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 5 postvaccination
 
 
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9.5
Analysis Populations
9.5.1
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(s). Potential deviations that may result in the exclusion of a 
participant from the PP population for all immunogenicity analyses include:

Failure to receive any study vaccine at Visit 2 (Day 1)

Failure to receive correct clinical material as per randomization schedule (ie, 
participants who were cross-treated) 

Receipt of prohibited medication or prohibited vaccine prior to study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP 
population for specific immunogenicity analyses (depending on the time point) include:

Failure to receive PNEUMOVAX™23

Receipt of prohibited medication or prohibited vaccine prior to a blood sample 
collection 

Collection of 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 endpoints. The FAS population consists of all randomized 
participants who received at least 1 vaccination and have at least 1 serology result. 
Participants will be included in the vaccination group to which they are randomized for the 
analysis of immunogenicity data using the FAS population. 
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 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 
 
 
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vaccination; such participants will be included in the treatment group corresponding to the 
study vaccination actually received.
At least 1 temperature measurement obtained subsequent to study intervention is required for 
inclusion in the analyses of temperature.  
9.6
Statistical Methods
Statistical testing and inference 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 in 
V114 separately. To address the primary immunogenicity objective, evaluation of the OPA 
GMTs and IgG GMCs at 30 days postvaccination 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 OPA GMTs and 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 the OPA and IgG responses at 30 days 
postvaccination with PNEUMOVAX™23 (Week 12). 
To address the exploratory immunogenicity objectives aiming to evaluate the OPA GMTs
and the IgG GMCs 30 days postvaccination with V114 or Prevnar 13™ (Day 30) and at 30 
days postvaccination with PNEUMOVAX™23 (Week 12) for participants administered 
V114 compared to participants administered Prevnar 13™, the serotype-specific OPA GMTs 
and IgG GMTs will be compared between vaccination groups through the estimation of 
serotype-specific OPA GMT ratios and IgG GMC ratios for each of the 15 serotypes in V114
at each of these timepoints. Estimation of the OPA GMT ratios and IgG GMC ratios and 
computation of the corresponding 95% CIs will be calculated using a constrained 
longitudinal data analysis (cLDA) method proposed by Liang and Zeger [Liang, K-Y and 
Zeger, S. L. 2000]. Details regarding the cLDA models will be included in the supplemental 
Statistical Analysis Plan.
Reverse Cumulative Distribution Curves for OPA titers and IgG concentrations will be 
graphically displayed by serotype at each of the following time points: Day 30 and Week 12.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 4.
 
 
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Table 4
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
OPA GMTs and IgG GMCs at Day 30
P
Descriptive 
Statistics
(estimate, 95%
CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
OPA GMTs and IgG GMCs 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; GMT = 
Geometric Mean Titer; IgG = Immunoglobulin G; OPA = opsonophagocytic activity; 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 from Day 1 to Day 5 postvaccination) and solicited systemic AEs 
(muscle pain/myalgia, joint pain/arthralgia, headache, and tiredness/fatigue 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. 
and Pearson, E. S. 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 the proportion of participants who died 
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 5) 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 non-serious adverse events (NSAEs) within 14 days of vaccination 
and SAEs occurring Day 1 through Week 8 (before vaccination with PNEUMOVAX™23). 
Descriptive summaries of AEs following administration of PNEUMOVAX™23 will include 
 
 
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NSAEs within 14 days of vaccination and SAEs occurring Week 8 (Day 1 relative to 
vaccination with PNEUMOVAX™23) through Month 6 (end of the study). 
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
Table 5
Analysis Strategy for Safety Parameters Following Each Vaccination
Safety Endpoint
95% CI for Within-Group 
Comparison
Descriptive Statistics
Injection-site redness/erythema (Days 1 to 5)†
X
X
Injection-site swelling (Days 1 to 5)†
X
X
Injection-site tenderness/pain (Days 1 to 5)†
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
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 5)
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.
9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by the use of 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 adult V114 Phase 3 program will 
be conducted by an independent, unblinded, external DMC. A description of the structure, 
function, and guidelines for decision-making by the DMC, along with the timing and content 
of the safety reviews will be outlined in the DMC charter. Information regarding the 
 
 
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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.
Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
intervention assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician performing 
the interim analysis.
The DMC will serve as the primary reviewer of the results of the safety interim analyses 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 committee (and potentially other limited Sponsor
personnel) may be unblinded to results at the intervention level in order to act on these 
recommendations. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented by the unblinded statistician. Additional logistical 
details will be provided in the DMC Charter. 
Intervention-level results from the safety interim analysis will be provided by the unblinded 
statistician to the DMC. Prior to final study unblinding, the 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 interim analyses.
9.8
Multiplicity
No adjustment will be made for multiplicity.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is a descriptive study. This study will randomize approximately 150 participants into 
the V114 group and 150 participants into the Prevnar 13™group. It is assumed that 
approximately 135 participants per vaccination group will be evaluable for PP
immunogenicity analyses at Day 30 (based on a 90% evaluability rate).
The width of the within-group 95% CIs for the serotype-specific OPA GMTs and IgG GMCs 
depend on the sample size, variability of the natural log concentrations, and the magnitude of 
the OPA GMT and IgG GMC. In Table 6, 95% CIs for various hypothetical Day 30 OPA 
GMTs and Day 30 IgG GMCs and various hypothetical standard deviation estimates for the 
natural log titers are displayed.
 
 
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Table 6
Within-Group 95% CIs for Varying Hypothetical OPA GMTs and IgG GMCs and 
Varying Standard Deviations with 135 Evaluable Participants in Each Vaccination Group
Standard Deviation of 
Natural Log Titers †
Serotype-specific OPA GMT†
500
1000
5000
1.5
(388, 644)
(776, 1288)
(3882, 6439)
2
(357, 700)
(713, 1401)
(3568, 7006)
2.5
(328, 762)
(656, 1525)
(3280, 7623)
Serotype-specific IgG GMC†
1
5
10
1.0
(0.84, 1.18)
(4.22, 5.92)
(8.45, 11.84)
1.5
(0.78, 1.29)
(3.88, 6.44)
(7.76, 12.88)
2.0
(0.71, 1.40)
(3.57, 7.01)
(7.14, 14.01)
†The estimates of the standard deviation and OPA GMTs and IgG GMCs are representative of those observed 
in V114-006.
CI = Confidence Interval; GMC = Geometric Mean Concentration; GMT = Geometric Mean Titer; IgG = 
Immunoglobulin G; OPA = Opsonophagocytic Activity.
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 150 participants in the V114 group if the underlying incidence of a SAE is 1.1% (1 of 
every 93 participants receiving the vaccine). There is a 50% chance of observing at least 1
SAE among 150 participants in the V114 group if the underlying incidence of a SAE is 0.5% 
(1 of every 213 participants receiving the vaccine). If no SAEs are observed among the 150 
participants in the V114 group, this study will provide 97.5% confidence that the underlying 
percentage of participants with a SAE is <2.4% (1 in every 41 participants) in the V114 
group.  
9.10
Subgroup Analyses
Serotype-specific OPA GMTs and serotype-specific IgG GMCs and their corresponding 
within-group 95% CIs at Day 30 will be calculated for each CD4+ T-cell count subgroup (ie, 
≥50 to <200, ≥200 to <500, and ≥500) 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 of CD4+ T-cell count (point estimates only).
 
 
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9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of V114 or 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.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp 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 
 
 
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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 (Institutiona 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.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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.
 
 
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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 report form 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.
 
 
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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) 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.
 
 
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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 good clinical practice); 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.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
 
 
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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. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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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.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as 
Sponsor’s product) includes any pharmaceutical product, biological product, vaccine, 
device, diagnostic agent, or protocol specified procedure whether investigational 
(including placebo or active comparator product) or marketed, 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, or are 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.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of 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 8.4.7 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.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity/Toxicity
•
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/erythema or swelling from the day of vaccination through Day 
5 postvaccination will be evaluated by maximum size.
•
The investigator will make an assessment of toxicity for each AE and SAE (and other 
reportable event) reported during the study.  A toxicity grade will be assigned to 
injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The toxicity grading scales used 
in this study are adapted from the “FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, September 2007.”
 
 
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Injection-site AE Toxicity Grading Scale
Injection-site Reaction 
to Study 
Vaccine/Placeboa
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring Days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative dermatitis 
or results in ER visit 
or hospitalization
Induration/Swelling
Size measured as 
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER visit 
or hospitalization
Other 
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins ≥ 6 days after receipt of study vaccine/placebo
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Abbreviations:  AE = adverse event; ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious 
adverse event.
a Based upon information provided by the patient on the eVRC and verbally during VRC review.  Erythema/Redness and 
Induration/Swelling are specific injection-site AEs with size designations of letters A through E→, based upon a graphic in 
the eVRC.  Size A is not assigned a toxicity grade; however, injection-site AEs that measure size A should be reported as 
adverse experiences.  If the participant has an ER visit or is hospitalized for any injection-site AE, that AE is to be assigned 
a toxicity grade of 4, regardless of the size measured.
Specific Systemic AE Toxicity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Headache
No interference with 
activity
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity
Significant; any use of 
narcotic pain reliever 
or prevents daily 
activity
ER visit or 
hospitalization
Fatigue
No interference with 
activity
Some interference with 
activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Myalgia
No interference with 
activity
Some interference with 
activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Abbreviations: AE = adverse event; ER = emergency room.
 
 
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Other Systemic AE Toxicity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)b
Illness or clinical AE 
(as defined according 
to applicable 
regulations)
No interference with 
activity
Some interference with 
activity not requiring 
medical intervention
Prevents daily activity 
and required medical 
intervention
ER visit or 
hospitalization
Abbreviations: ER = emergency room; eVRC = electronic Vaccine Report Card; SAE = serious adverse event.
a Based upon information provided by the patient on the eVRC and verbally during the eVRC review during the primary 
safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be based upon the 
initial report and/or follow-up of the event.
b AEs resulting in death will be assessed as Grade 4
Vital Sign (Temperature) Toxicity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening
(Grade 4)
Fever 
(°C) b
(°F) b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
a Participant should be at rest for all vital sign requirements
b Oral temperature; no recent hot or cold beverages or smoking
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
 
 
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-
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:
 
 
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-
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 AE, SAE, 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).
 
 
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•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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
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 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
1 of the contraception methods described in Table 8 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
Table 8
Contraceptive Methods
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
●Male or female condom with or without spermicide
●Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen-only contraceptive implantb,c 
●Intrauterine hormone-releasing system (IUS)b
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner 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.
●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.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
b
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation.
 
 
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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.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions

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. 

Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2

Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2

DNA: Deoxyribonucleic acid.

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.
 
 
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3. Summary of Procedures for Future Biomedical Research.
1. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
2. 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.
3. 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.
4. 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 treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
 
 
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At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in 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 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 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 
 
 
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answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
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.
 
 
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12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACIP
Advisory Committee on Immunization Practices
AE
adverse event
APaT
All Participants as Treated
ART
antiretroviral therapy
β-hCG
beta-human chorionic gonadotropin
CAPiTA
Community-Acquired Pneumonia Immunization Trial in Adults
CI
confidence interval
cLDA
constrained Longitudinal Data Analysis
CRM197
cross-reacting material 197
CSR
Clinical Study Report
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data collection
EMA
European Medicines Agency
EOC
Executive Oversight Committee
eVRC
Electronic Vaccination Report Card
FAS
Full Analysis Set
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
hormonal replacement therapy 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation Good Clinical Practice
IgG
Immunoglobulin G
IMP
investigational medicinal product
IRB
Institutional Review Board
IPD
Invasive Pneumococcal Disease
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MOPA
Multiplexed Opsonophagocytic Assay
MSD
Merck Sharp & Dohme Corp.
NIMP
non-investigational medicinal product
NSAE
nonserious adverse event
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PCV13
Prevnar 13™
PnECL
pneumococcal electrochemiluminescence
PP
Per-Protocol
PT
preferred term
PPV23
PNEUMOVAX™23
 
 
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Abbreviation
Expanded Term
RNA
ribonucleic acid
SAE
serious adverse event
SLAB
supplemental laboratory test
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental statistical analysis plan
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
 
 
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11
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03NWQ5
 
 
04Y2KD
 
 
05KG4L

PRODUCT: V114 
102
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05KG4L

PRODUCT: V114 
103
PROTOCOL/AMENDMENT NO.: 018-01 
V114-018-01-FINAL PROTOCOL
01-JUN-2018
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04NKF6
 
 
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05KG4L