Clinical trial NCT04016714
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-08-28; Completion date: 2021-10-29
Enrollment: 1191 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical study is to evaluate the safety and immunogenicity of a 3-dose schedule (2-dose primary series followed by a toddler dose) of pneumococcal conjugate vaccine (PCV) as one of the currently recommended schedules by the World Health Organization (WHO) Strategic Advisory Group of Experts (SAGE) on Immunizations and practiced in many countries.

The primary hypotheses are that V114 is non-inferior to Prevenar 13™ for the 13 shared serotypes based on response rates and on anti-pneumococcal polysaccharide (PnPs) serotype-specific Immunoglobulin G (IgG) geometric mean concentrations (GMCs) at 30 days following Dose 3; that V114 is superior to Prevenar 13™ for the 2 serotypes unique to V114 based on the response rates and on anti-PnPs serotype-specific IgG GMCs at 30 days following Dose 3; and that Vaxelis™ administered concomitantly with V114 is non-inferior to Vaxelis™ administered concomitantly with Prevenar 13™ at 30 days following Dose 3 for each antigen included in Vaxelis™.

Detailed description:

Arms: arm 1: Participants will receive a single 0.5 mL intramuscular (IM) injection of V114 at Visit 1, 2, and 4 (approximately 3, 5, and 12 months of age). As part of the study design, participants will also receive other pediatric vaccines, including Vaxelis™ (0.5 mL single dose at Visits 1, 2, and 4); M-M-R™II (0.5 mL single dose at Visit 4); and VARIVAX™ (0.5 mL single dose at Visit 4, except participants in Norway and Denmark, who will receive a second dose of VARIVAX™ at Visit 5, according to local vaccination requirements). arm 2: Participants will receive a single 0.5 mL IM injection of Prevenar 13™ at Visit 1, 2, and 4 (approximately 3, 5, and 12 months of age). As part of the study design, participants will also receive other pediatric vaccines, including Vaxelis™ (0.5 mL single dose at Visits 1, 2, and 4); M-M-R™II (0.5 mL single dose at Visit 4); and VARIVAX™ (0.5 mL single dose at Visit 4, except participants in Norway and Denmark, who will receive a second dose of VARIVAX™ at Visit 5, according to local vaccination requirements).
Interventions: intervention 1: V114 intervention 2: Prevenar 13™ intervention 3: Vaxelis™ intervention 4: M-M-R®II intervention 5: VARIVAX™
Intervention descriptions: intervention 1: 15-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F, serotype 6B and aluminum phosphate adjuvant in each 0.5 mL dose. intervention 2: 13-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F, serotype 6B in each 0.5. mL dose. intervention 3: Intramuscular 0.5 mL single dose intervention 4: Subcutaneous 0.5 mL single dose intervention 5: Subcutaneous 0.5 mL single dose

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04016714 
Document Date: 
14-Sep-2021
A Phase 3, Multicenter, Randomized, Double-blind, 
Active-comparator controlled Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of a 3-dose Regimen of V114 
in Healthy Infants (PNEU-PED-EU-2)


PRODUCT: V114  
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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 a 3-dose 
Regimen of V114 in Healthy Infants (PNEU-PED-EU-2)
Protocol Number: 026-03
Compound Number: V114
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
EudraCT
14115
2018-003788-70
Approval Date: 14 September 2021
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
14-SEP-2021
Amendment to expand the visit windows for Visit 2 (Dose 2 vaccination), Visit 3 
(postdose 2 blood draw), Visit 4 (Dose 3 vaccination), and Visit 5 (postdose 3 blood 
draw) to allow inclusion of more participants in the immunogenicity analysis based on the 
per-protocol population. This change is being made in response to the COVID-19 global 
pandemic which impacted the ability of many participants to attend study visits within the 
prescribed visit windows due to local conditions and travel restrictions. 
Amendment 2
12-SEP-2019
This country-specific amendment incorporates feedback received from the Norwegian 
Health Authority and study investigators in Denmark.
Amendment 1
25-JUL-2019
This country-specific amendment incorporates feedback received from the Swedish 
Health Agency. 
Original Protocol
22-FEB-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
The COVID-19 global pandemic impacted the ability of many participants to attend study visits within the prescribed visit windows 
due to local conditions and travel restrictions. The primary purpose of this amendment is to expand the visit windows for Visit 2 (Dose 
2 vaccination), Visit 3 (postdose 2 blood draw), Visit 4 (Dose 3 vaccination), and Visit 5 (postdose 3 blood draw) to allow inclusion of
more participants in the immunogenicity analysis based on the per-protocol population.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities
Section 10.7.2.2
Schedule 
of Activities (For Sites in 
Norway and Denmark Only)
The visit window for Visit 2 (Dose 2
vaccination) and Visit 4 (Dose 3 
vaccination) was expanded by 14 days. 
The visit windows for Visit 3 (postdose 2 
blood draw) and Visit 5 (postdose 3 blood 
draw) were expanded by 18 days.
The expansion of the visit windows will allow 
inclusion of more participants in the immunogenicity 
analysis based on the per-protocol population. This 
change is being made in response to the COVID-19 
global pandemic which impacted the ability of many 
participants to attend study visits within the prescribed 
visit windows due to local conditions and travel 
restrictions.
Section 9.5.1
Immunogenicity Analysis 
Populations
Text describing potential deviations that 
may result in the exclusion from the 
PP population immunogenicity analyses at 
a particular time point was revised to align 
with the changes to the visits windows for 
Visit 2 and Visit 4 (vaccination visits).
Revision to align with changes to the visit windows for 
vaccination visits.
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Section # and Name
Description of Change 
Brief Rationale 
Section 10.8
Appendix 8: 
Abbreviations
Added COVID-19 to the List of 
Abbreviations.
Revision made for completeness.
Throughout
Editorial revisions
Changes are minor and have not been summarized 
individually.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................27
2.2.1
V114 and Pneumococcal Disease................................................................27
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.2.3
Information on Other Study-related Therapy ..............................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................32
4.1
Overall Design......................................................................................................32
4.2
Scientific Rationale for Study Design.................................................................33
4.2.1
Rationale for Endpoints ...............................................................................33
4.2.1.1
Immunogenicity Endpoints................................................................33
4.2.1.2
Safety Endpoints................................................................................35
4.2.1.3
Future Biomedical Research..............................................................35
4.2.2
Rationale for the Use of Comparator/Placebo .............................................35
4.3
Justification for Dose...........................................................................................36
4.4
Beginning and End of Study Definition .............................................................36
4.4.1
Clinical Criteria for Early Study Termination .............................................36
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
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6.2.2
Handling, Storage, and Accountability........................................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................45
6.5.1
Rescue Medications and Supportive Care ...................................................46
6.6
Dose Modification (Escalation/Titration/Other)...............................................47
6.7
Intervention After the End of the Study............................................................47
6.8
Clinical Supplies Disclosure................................................................................47
6.9
Standard Policies..................................................................................................47
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................47
7.1
Discontinuation of Study Intervention...............................................................47
7.2
Participant Withdrawal From the Study...........................................................48
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................49
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................50
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................51
8.1.5
Prior and Concomitant Medications Review...............................................51
8.1.5.1
Prior Medications...............................................................................51
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Assignment of Screening Number...............................................................52
8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................53
8.1.8.1
Timing of Dose Administration.........................................................54
8.1.9
Electronic Vaccination Report Card ............................................................54
8.1.10
Day 15 Postdose Telephone Contact Guide.................................................54
8.1.11
Telephone Contact Questionnaire................................................................55
8.1.12
Discontinuation and Withdrawal .................................................................55
8.1.12.1
Withdrawal From Future Biomedical Research ................................55
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8.1.13
Participant Blinding/Unblinding..................................................................56
8.1.14
Calibration of Equipment.............................................................................56
8.2
Immunogenicity Assessments .............................................................................56
8.2.1
Pneumococcal Electrochemiluminescence ..................................................57
8.2.2
Multiplex Opsonophagocytic Assay............................................................57
8.2.3
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen 
Serology Assay ............................................................................................58
8.2.4
Haemophilis Influenzae Type B ELISA ......................................................58
8.2.5
Hepatitis B Enhanced Chemiluminescence (ECi) Assay.............................59
8.2.6
Micrometabolic Inhibition Test (MIT)-based Virus Neutralization 
Assay (polio MIT)........................................................................................59
8.3
Safety Assessments...............................................................................................60
8.3.1
Physical Examinations.................................................................................60
8.3.2
Body Temperature Measurements ...............................................................60
8.3.3
Safety Assessment and use of the eVRC .....................................................60
8.3.4
Clinical Safety Laboratory Assessments .....................................................61
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................61
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................62
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...63
8.4.4
Regulatory Reporting Requirements for SAE .............................................64
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................64
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.4.7
Events of Clinical Interest (ECIs)................................................................64
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................65
8.7
Pharmacodynamics..............................................................................................65
8.8
Biomarkers ...........................................................................................................65
8.9
Planned Genetic Analysis Sample Collection....................................................65
8.10
Future Biomedical Research Sample Collection...............................................65
8.11
Medical Resource Utilization and Health Economics.......................................65
8.12
Visit Requirements...............................................................................................65
8.12.1
Screening......................................................................................................65
8.12.2
Treatment Period/Vaccination Visit ............................................................66
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........66
9
STATISTICAL ANALYSIS PLAN .............................................................................66
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9.1
Statistical Analysis Plan Summary.....................................................................67
9.2
Responsibility for Analyses/In-house Blinding .................................................68
9.3
Hypotheses/Estimation ........................................................................................69
9.4
Analysis Endpoints...............................................................................................69
9.4.1
Immunogenicity Endpoints..........................................................................69
9.4.2
Safety Endpoints..........................................................................................70
9.5
Analysis Populations............................................................................................71
9.5.1
Immunogenicity Analysis Populations ........................................................71
9.5.2
Safety Analysis Populations ........................................................................72
9.6
Statistical Methods...............................................................................................72
9.6.1
Statistical Methods for Immunogenicity......................................................72
9.6.2
Statistical Methods for Safety Analyses ......................................................75
9.6.3
Summaries of Baseline Characteristics........................................................77
9.7
Interim Analyses ..................................................................................................77
9.8
Multiplicity ...........................................................................................................78
9.9
Sample Size and Power Calculations .................................................................78
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................78
9.9.2
Sample Size and Power for Safety Analyses ...............................................80
9.10
Subgroup Analyses...............................................................................................81
9.11
Compliance (Medication Adherence).................................................................81
9.12
Extent of Exposure...............................................................................................81
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................82
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........82
10.1.1
Code of Conduct for Clinical Trials.............................................................82
10.1.2
Financial Disclosure.....................................................................................84
10.1.3
Data Protection.............................................................................................84
10.1.3.1
Confidentiality of Data ......................................................................85
10.1.3.2
Confidentiality of Participant Records...............................................85
10.1.3.3
Confidentiality of IRB/IEC Information............................................85
10.1.4
Committees Structure...................................................................................85
10.1.4.1
Scientific Advisory Committee..........................................................85
10.1.4.2
Executive Oversight Committee........................................................85
10.1.4.3
External Data Monitoring Committee ...............................................86
10.1.5
Publication Policy........................................................................................86
10.1.6
Compliance with Study Registration and Results Posting Requirements ...86
10.1.7
Compliance with Law, Audit, and Debarment ............................................87
10.1.8
Data Quality Assurance ...............................................................................87
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10.1.9
Source Documents .......................................................................................88
10.1.10
Study and Site Closure.................................................................................89
10.2
Appendix 2: Clinical Laboratory Tests..............................................................90
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................91
10.3.1
Definition of AE ..........................................................................................91
10.3.2
Definition of SAE ........................................................................................92
10.3.3
Additional Events Reported.........................................................................93
10.3.4
Recording AE and SAE ...............................................................................93
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................96
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................98
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................99
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................100
10.7
Appendix 7: Country-specific Requirements..................................................105
10.7.1
Country-specific request from Swedish Health Authority.........................105
10.7.1.1
Benefit/Risk Assessment .................................................................105
10.7.1.2
Ethics Committee Review [Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)] ..................................107
10.7.1.3
Informed Consent.............................................................................107
10.7.2
Country-specific information for Norway and Denmark...........................108
10.7.2.1
Study Design....................................................................................108
10.7.2.2
Schedule of Activities (For Sites in Norway and Denmark Only) ..109
10.8
Appendix 8: Abbreviations ...............................................................................116
11
REFERENCES.............................................................................................................118
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LIST OF TABLES
Table 1
Study Interventions....................................................................................41
Table 2
Concomitant Vaccine Schedule.................................................................46
Table 3
Recommended Injection-site Location for Study Interventions................46
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................63
Table 5
Summary of Endpoints for Concomitant Vaccine Antigens......................70
Table 6
Analysis Strategy for Immunogenicity Variables......................................74
Table 7
Analysis Strategy for Safety Parameters....................................................76
Table 8
Summary of Endpoints and Power for Concomitant Vaccine Antigens....80
Table 9
Differences in Incidence of Adverse Event Rates Between the 2 
Vaccination Groups That Can be Detected With an ~80% Probability 
(Assuming 2-sided 5% Alpha Level With 590 Participants in Each 
Group)........................................................................................................81
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LIST OF FIGURES
Figure 1
V114-026 Study Design.............................................................................18
Figure 2
V114-026-02 Study Design (For Sites in Norway and Denmark Only)..108
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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 a 3-dose 
Regimen of V114 in Healthy Infants (PNEU-PED-EU-2)
Short Title: Safety, tolerability, and immunogenicity of V114 in healthy infants
Acronym: PNEUmococcal Conjugate Vaccine Trials: V114-026 (PNEU-PED-EU-2)
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 3 months of age (from 70 to 111 days [inclusive]) administered V114 or 
Prevenar 13™. The statistical criteria for the primary hypotheses are provided in the table 
below and for the secondary hypotheses can be found in Section 9.9.1.
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following any vaccination with V114:
- Solicited injection-site AEs from Day 1 
through Day 14 postvaccination
- Solicited systemic AEs from Day 1 
through Day 14 postvaccination
- Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
- Objective: To compare the anti-
-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G (IgG) 
response rates (proportion of participants 
meeting serotype--specific IgG threshold 
value of ≥0.35 μg/mL) at 30 days following 
Dose 3 for participants administered V114 
versus participants administered 
Prevenar 13™.
Hypothesis (H1): V114 is noninferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based on 
response rates at 30 days following Dose 3.
- Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained in 
V114 at 30 days Postdose 3 (PD3)
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(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 
95% CI for the difference in responses rates 
[V114 minus Prevenar 13™] to be greater 
than -0.1).
Hypothesis (H2): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique to 
V114 based on the response rates at 30 days 
following Dose 3.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for the difference in response rates 
[V114 minus Prevenar 13™] to be greater 
than 0.1).
- Objective: To compare anti-PnPs serotype-
specific IgG geometric mean concentrations 
(GMCs) at 30 days following Dose 3 for 
participants administered V114 versus 
participants administered Prevenar 13™.
Hypothesis (H3): V114 is noninferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based on 
anti-PnPs serotype-specific IgG GMCs at 
30 days following Dose 3.
(The statistical criterion for non-inferiority 
requires the lower bound of the 2-sided 
95% CI for anti-PnPs serotype-specific IgG 
GMC ratio [V114/ Prevenar 13™] to be 
greater than 0.5).
Hypothesis (H4): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique to 
V114 based on anti-PnPs serotype-specific 
IgG GMCs at 30 days following Dose 3.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for anti-PnPs serotype-specific IgG 
GMC ratio [V114/ Prevenar 13™] to be 
greater than 2.0).
- Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes contained in 
V114 at 30 days PD3
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Secondary Objectives
Secondary Endpoints
- Objective: To compare the antigen-specific 
response rate to each antigen included in 
Vaxelis™ at 30 days following Dose 3 for 
participants administered V114 
concomitantly with Vaxelis™ versus 
participants administered Prevenar 13™ 
concomitantly with Vaxelis™.
Hypothesis (H5): Vaxelis™ administered 
concomitantly with V114 is non-inferior to 
Vaxelis™ administered concomitantly with 
Prevenar 13™ at 30 days following Dose 3 
for each antigen included in Vaxelis™.
Antibody responses to: 
- diphtheria toxoid 
- tetanus toxoid 
- pertussis toxin (PT) 
- pertussis filamentous hemagglutinin 
(FHA) 
- pertussis fimbriae 2/3 (FIM 2/3) 
- pertussis pertactin (PRN) 
- Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-PRP) 
- hepatitis B surface antigen (HBsAg)
- poliovirus serotypes 1, 2, and 3 
at 30 days PD3 of V114 or Prevenar 13™
- Objective: To evaluate the anti-PnPs 
serotype-specific- IgG response rates and 
GMCs at 30 days following Dose 2 by each 
vaccination group.
- Anti-PnP serotype-specific IgG responses 
for the 15 serotypes contained in V114 at 
30 days PD2
- Objective (OPA Subset): To evaluate the 
anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) GMTs and 
response rate at 30 days following Dose 3 by 
each vaccination group.
- Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes contained in 
V114 at 30 days PD3
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal disease
Population
Healthy infants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
Study Blinding
Double-blind, with in-house blinding
Masking
Participant or Subject
Care Provider
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 20 months from the time that written 
informed consent is provided for the first participant until 
the last participant’s last study-related telephone call or 
visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
Number of Participants:
Approximately 1180 participants will be randomized, with approximately 590 in each 
intervention group.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
V114
V114
Refer to 
IB
3 doses
IM
Single dose 
at Visits 1, 
2, and 4 
(~3, 5 and 
12 months 
of age, 
respectively)
Experimental
Prevenar 13™Prevenar 13™
Refer to 
product 
labeling
3 doses
IM
Single dose 
at Visits 1, 
2, and 4 
(~3, 5, and 
12 months 
of age, 
respectively)
Experimental
Admin = administration; IB = Investigator’s Brochure; IM = intramuscular.
Note: All participants will also receive other pediatric vaccines, including Vaxelis™, M-M-R™II, 
and VARIVAX™, as part of the study design (Table 1 and Table 2). Tradenames for licensed 
vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 15 months, 
from the time the participant’s legally acceptable representative signs the 
Informed Consent Form (ICF) through the final contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1. The study design for participants enrolled at sites in Norway and Denmark is provided in 
Figure 2 (Appendix 7, Section 10.7.2.1).
Figure 1
V114-026 Study Design
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1.3
Schedule of Activities (SoA)
The schedule of activities for participants enrolled at sites in Norway and Denmark is provided in Appendix 7 (Section 10.7.2.2).
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Administrative and General Procedures
Screening Procedures
Informed Consent/Assent
X
Consent must be obtained 
before any study 
procedures.
Informed Consent/Assent for 
Future Biomedical Research
X
Participation in future 
biomedical research is 
optional and consent must 
be obtained before 
collection of buccal swab 
DNA samples.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Review of prior 
medications/vaccinations, a 
complete physical 
examination, and 
temperature measurement 
are required at Visit 1 to 
determine eligibility.
Medical History 
X
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Post-Randomization Procedures
Assignment of Randomization 
Number
X
Prior/Concomitant Medication 
and Nonstudy Vaccination 
Review
X
X
X
X
X
X
X
X
V114 or Prevenar 13™b
Administration (Blinded)
X
X
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given (see Section 8.1.8). 
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Concomitant Vaccine 
Administration (Open-label)b
Vaxelis™ 
X
X
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given. (see Section 8.1.8). 
See Section 6.5 for details 
on concomitant vaccines.
Vaxelis™ should be given 
after V114 or Prevenar 
13™.
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Concomitant Vaccine 
Administration (Open-label)b
M-M-R™II
VARIVAX™
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given (see Section 8.1.8).
M-M-R™II and 
VARIVAX™should be 
given after V114 or 
Prevenar 13™(see 
Section 6.5).
Provide eVRC
X
An eVRC will be provided 
at Visit 1 to record AEs, 
body temperature, 
concomitant medications, 
and nonstudy vaccinations. 
Instructions for using the 
eVRC will be reviewed 
with the participant’s 
legally acceptable 
representative.
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Review eVRC data with 
participant’s legally acceptable 
representative
X
X
X
X
X
X
X
See Section 8.1.9 for 
details.
Collect eVRC from participant’s 
legally acceptable representative
X
Complete the Telephone Contact 
Questionnaire 
X
See Section 8.1.11 for 
details.
Safety Procedures
Complete Physical Examination
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered
(see Section 8.3.1).
Targeted Physical Examination
X
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered
(see Section 8.3.1).
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Body Temperature Measurement
X
X
X
Each participant’s body 
temperature must be taken 
before vaccination (see 
Section 8.3.2 for method). 
Participants who have 
febrile illness at or within 
72 hours of vaccination
must be rescheduled.
30-minute Postvaccination 
Observation Period
X
X
X
To be performed by 
blinded study site 
personnel only.
AE Monitoring
X
X
X
X
X
X
X
X
X
Nonserious AEs are to be 
reported from Days 1 
through 14 following each 
vaccination with V114 or 
Prevenar 13™. SAEs and 
deaths are to be reported 
throughout the duration of 
an individual’s study 
participation.
Immunogenicity Procedures
Serum for Immunogenicity 
Assays (Including Retention 
Serum)
X
X
X
Blood samples must be 
collected before 
vaccination where 
applicable.
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Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
~1 month 
after Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5 
months 
of age 
to 1 day 
prior to 
6 
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Future Biomedical Research
Collect Buccal Swabs for Future 
Biomedical Research
X
Buccal swab DNA samples 
for analysis should be 
obtained prior to 
vaccination at Visit 1, on 
randomized and FBR 
consented participants 
only, or at a later date as 
soon as the informed 
consent is obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = Future Biomedical Research; SAE = serious adverse event; 
TC = telephone contact.
a
For calculating the visit windows, the day of vaccination is considered Day 1. To calculate visit windows for subsequent vaccinations, confirm participant date of birth and 
ensure the age of the participant will fall within the appropriate age range for each study visit.
b
Tradenames for licensed vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
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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 the prevention of 
pneumococcal disease caused by the serotypes in the vaccine. V114 contains the 13 serotypes 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) present in the licensed vaccine 
Prevenar 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
Routine PCV immunization of children is effective in preventing vaccine serotype--specific 
pneumococcal disease. Despite the availability of PCVs, pneumococcal disease remains a 
concern as non-vaccine serotypes have emerged in increasing frequency in invasive 
pneumococcal disease (IPD) isolates. Given the high morbidity and mortality of IPD 
worldwide, the evolving serotype distribution, and the value of multiple suppliers to 
strengthen global supply, there is a continued need to develop new PCVs with expanded 
serotype coverage. V114 includes an additional 2 key serotypes compared with 
Prevenar 13™ and will address an unmet medical and public health need for a PCV with 
expanded coverage. This clinical study, to be conducted in healthy infants approximately 
3 months of age (70 to 111 days of age), is part of a Phase 3 pediatric clinical program to 
support an initial registration of V114 for use in healthy infants and children for the 
prevention of pneumococcal disease caused by the 13 pneumococcal serotypes contained in 
Prevenar 13™ and the 2 additional serotypes (22F and 33F) in V114.
The purpose of this clinical study is to evaluate the safety and immunogenicity of a 3-dose 
schedule (2-dose primary series followed by a toddler dose) of PCV as one of the currently 
recommended by the World Health Organization (WHO) Strategic Advisory Group of 
Experts (SAGE) on Immunizations and practiced in many countries. Country--specific 
routine immunization regimens vary by schedule and number of doses. In this study, infants 
will be given 3 doses of the study vaccine at approximately 3, 5, and 12 months of age.
In most countries, it is recommended that PCVs are to be given at the same time as other 
recommended pediatric vaccines. The concomitant administration of V114 with 
recommended pediatric vaccines will be evaluated as part of the Phase 3 pediatric clinical 
program. This study will evaluate the concomitant administration of V114 and the pediatric 
vaccine, Vaxelis™. Other routine vaccines (M--M--R™II, and VARIVAX™) will also be 
provided in the study (Section 6.5). In addition to concomitant vaccines being provided in the 
study, other nonstudy pediatric vaccines may be permitted according to local, regional, 
and/or country guidelines.
Countries participating in this study must follow the vaccination schedule being evaluated in 
the study with respect to PCV and the concomitant vaccines.
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2.2
Background
2.2.1
V114 and Pneumococcal Disease
Refer to the IB for detailed background information on V114 including information on 
pneumococcal disease burden.
Streptococcus pneumoniae remains a significant cause of disease worldwide, with clinical 
manifestations including meningitis, sepsis, pneumonia, sinusitis, and otitis media. Currently, 
many countries worldwide have incorporated licensed PCVs (eg, Prevenar 13™ and/or 
Synflorix™ [pneumococcal polysaccharide conjugate vaccine (adsorbed), GlaxoSmithKline 
Biologicals S.A, Rixensart, Belgium]) into their infant immunization programs. Prevnar™ 
was first licensed in 2000 and later replaced by Prevenar 13™ in 2009 (European Union, EU) 
and Prevnar 13™ 2010 (United States, US). Synflorix™ was licensed in the EU in 2009. 
Although Prevenar 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 serotypes contained in the vaccines in children who 
received the vaccines, as well as unvaccinated individuals through herd protection [Centers 
for Disease Control and Prevention 2008] [Ruckinger, S., et al 2009] [Farrell, D. J, et al 
2007] [Pilishvili, Tamara, et al 2010] [Lexau, C. A., et al 2005] [Metlay, J. P., et al 2006] 
[Whitney, Cynthia G., et al 2003] [Moore, M. R., et al 2015] [Lepoutre, A., et al 2015] 
[Weiss, S., et al 2015] [Martinelli, D., et al 2014] [Guevara, M., et al 2016] [Waight, P. A., et 
al 2015] [Jokinen, J., et al 2015] [Palmu, A. A., et al 2015] [Wagenvoort, G. H., et al 2016]. 
Despite this, an increase in the burden of IPD caused by serotypes not contained in currently 
available vaccines has been observed.
V114 contains all the pneumococcal serotypes contained in Prevenar 13™ plus 2 additional 
serotypes (22F and 33F). The selection of 22F and 33F was primarily based on the 
emergence of these 2 serotypes as important causes of IPD in the era of Prevenar™ and 
Prevenar 13™. Approximately 4 years after inclusion of Prevenar™ in the US infant 
immunization schedule, serotypes 22F and 33F accounted for approximately 13% of IPD 
cases in children <5 years of age (incidence rate of IPD due to 22F and 33F combined of 
3.1 cases per 100,000 person-years), in contrast to 1.3% of IPD cases in the pre-PCV7 era 
(incidence rate of 22F and 33F IPD of 1.2 cases per 100,000 person-years) [Hicks, L. A., et 
al 2007]. By 2013, both 22F and 33F were among the leading serotypes causing IPD beyond 
those already included in Prevenar 13™, accounting for approximately 21% of all IPD in 
children <5 years of age in the US [Moore, M. R., 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]. In a systematic 
review and meta-analysis of serotype distribution of S pneumoniae causing invasive disease 
in children conducted across geographical regions, including Europe, serotypes 22F and 33F 
were identified among the overall predominant non-Prevenar 13™ serotype [Balsells, E., et 
al 2017].
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The additional serotypes contained in V114 will provide broader coverage against the leading 
serotypes associated with pneumococcal disease worldwide. V114 is designed to meet 
continuing medical and public health needs for PCVs globally, as well as address the 
emergence of pneumococcal disease caused by serotypes not contained in currently licensed 
PCVs.
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
Refer to approved labeling for detailed background information on Prevenar 13™ and other 
licensed pediatric vaccines administered concomitantly.
Prevenar 13™ contains the 7 pneumococcal serotypes included in Prevenar™ (4, 6B, 9V, 14, 
18C, 19F, and 23F) plus 6 additional serotypes (1, 3, 5, 6A, 7F, and 19A).
Prevenar™ and Prevenar 13™ are also known as Prevnar™ and Prevnar 13™ in the US; 
these vaccines will be referred to as Prevenar™ and Prevenar 13™ throughout this 
document.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Approximately 50% of participants will receive 3 doses of Prevenar 13™, the standard of 
care, as the active comparator in this study. V114 is expected to provide comparable immune 
responses and a comparable safety profile to Prevenar 13™ for the shared pneumococcal 
serotypes while providing additional coverage for the 2 serotypes (22F and 33F) unique to 
V114. It is unknown if the investigational V114 will have the same benefit/risk profile as 
Prevenar 13™.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents. See 
Appendix 7 for Country-specific requirements for Sweden.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives and endpoints will be evaluated in healthy infants enrolled at 
approximately 3 months of age (from 70 to 111 days [inclusive]) administered V114 or 
Prevenar 13™. The statistical criteria for the primary hypotheses are provided in the table 
below and for the secondary hypotheses can be found in Section 9.9.1.
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Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability of V114 with respect to the 
proportion of participants with adverse 
events (AEs).
Following any vaccination with V114:
•
Solicited injection-site AEs from 
Day 1 through Day 14 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 14 postvaccination
•
Vaccine-related serious adverse events 
(SAEs) through completion of study 
participation
•
Objective: To compare the anti-
-pneumococcal polysaccharide (PnPs) 
serotype-specific Immunoglobulin G 
(IgG) response rates (proportion of 
participants meeting serotype--specific 
IgG threshold value of ≥0.35 μg/mL) at 
30 days following Dose 3 for participants 
administered V114 versus participants 
administered Prevenar 13™.
Hypothesis (H1): V114 is noninferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based 
on response rates at 30 days following 
Dose 3.
(The statistical criterion for 
non-inferiority requires the lower bound 
of the 2-sided 95% CI for the difference 
in responses rates [V114 minus 
Prevenar 13™] to be greater than -0.1).
Hypothesis (H2): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique 
to V114 based on the response rates at 
30 days following Dose 3.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for the difference in response 
rates [V114 minus Prevenar 13™] to be 
greater than 0.1).
Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days 
Postdose 3 (PD3)
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Objectives
Endpoints
•
Objective: To compare anti-PnPs 
serotype-specific IgG geometric mean 
concentrations (GMCs) at 30 days 
following Dose 3 for participants 
administered V114 versus participants 
administered Prevenar 13™.
Hypothesis (H3): V114 is noninferior to 
Prevenar 13™ for the 13 shared serotypes 
between V114 and Prevenar 13™ based 
on anti-PnPs serotype-specific IgG GMCs 
at 30 days following Dose 3.
(The statistical criterion for 
non-inferiority requires the lower bound 
of the 2-sided 95% CI for anti-PnPs 
serotype-specific IgG GMC ratio [V114/ 
Prevenar 13™] to be greater than 0.5).
Hypothesis (H4): V114 is superior to 
Prevenar 13™ for the 2 serotypes unique 
to V114 based on anti-PnPs serotype-
specific IgG GMCs at 30 days following 
Dose 3.
(The statistical criterion for superiority 
requires the lower bound of the 2-sided 
95% CI for anti-PnPs serotype-specific 
IgG GMC ratio [V114/ Prevenar 13™] to 
be greater than 2.0).
•
Anti-PnPs serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days PD3
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Objectives
Endpoints
Secondary
•
Objective: To compare the antigen-
specific response rate to each antigen 
included in Vaxelis™ at 30 days 
following Dose 3 for participants 
administered V114 concomitantly with 
Vaxelis™versus participants 
administered Prevenar 13™
concomitantly with Vaxelis™.
Hypothesis (H5): Vaxelis™
administered concomitantly with V114 is 
non-inferior to Vaxelis™ administered 
concomitantly with Prevenar 13™ at 
30 days following Dose 3 for each 
antigen included in Vaxelis™.
Antibody responses to:
•
diphtheria toxoid 
•
tetanus toxoid 
•
pertussis toxin (PT) 
•
pertussis filamentous 
hemagglutinin (FHA) 
•
pertussis fimbriae 2/3 (FIM 2/3) 
•
pertussis pertactin (PRN) 
•
Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-
PRP) 
•
hepatitis B surface antigen 
(HBsAg)
•
poliovirus serotypes 1, 2, and 3 
at 30 days PD3 of V114 or Prevenar 13™
•
Objective: To evaluate the anti-PnPs 
serotype-specific- IgG response rates and 
GMCs at 30 days following Dose 2 by 
each vaccination group.
•
Anti-PnP serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 at 30 days PD2
•
Objective (OPA Subset): To evaluate 
the anti-PnPs serotype-specific 
opsonophagocytic activity (OPA) GMTs 
and response rate at 30 days following 
Dose 3 by each vaccination group.
•
Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes 
contained in V114 at 30 days PD3
Tertiary/Exploratory
•
Objective: To evaluate the anti-PnPs 
serotype-specific IgG GMCs immediately 
prior to Dose 3 by each vaccination 
group.
•
Anti-PnP serotype-specific IgG 
responses for the 15 serotypes 
contained in V114 immediately prior 
to Dose 3 (Predose 3)
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Objectives
Endpoints
•
Objective: To evaluate the 
antigen-specific response rate to each 
antigen included in Vaxelis™ at 30 days 
following Dose 2 for participants 
administered V114 concomitantly with 
Vaxelis™versus participants 
administered Prevenar 13™
concomitantly with Vaxelis™.
Antibody responses to: 
•
diphtheria toxoid 
•
tetanus toxoid 
•
pertussis toxin (PT) 
•
pertussis filamentous 
hemagglutinin (FHA) 
•
pertussis fimbriae 2/3 (FIM 2/3) 
•
pertussis pertactin (PRN) 
•
Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-
PRP) 
•
hepatitis B surface antigen 
(HBsAg)
•
poliovirus serotypes 1, 2, and 3 
at 30 days PD2 of V114 or Prevenar 13™
•
Objective (OPA Subset): To evaluate 
the anti-PnPs serotype-specific OPA 
GMTs and response rate at 30 days 
following Dose 2 and immediately prior 
to Dose 3 by each vaccination group.
•
Anti-PnPs serotype-specific OPA 
responses for the 15 serotypes 
contained in V114 at 30 days PD2 and
Predose 3
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, parallel-group, multi-site, double--blind
(with in-house blinding) study of V114 in healthy infants enrolled at approximately 3 months 
of age (from 70 to 111 days [inclusive]). Approximately 1180 healthy infant participants will 
be randomly assigned, in a 1:1 ratio, to receive either V114 (590 participants) or 
Prevenar 13™ (590 participants). 
A 0.5-mL intramuscular dose of V114 or Prevenar 13™will be administered (blinded) to 
healthy infants at approximately 3, 5, and 12 months of age. All participants will also be 
administered concomitant pediatric vaccines (ie, Vaxelis™, M-M-R™II, and VARIVAX™) 
during the study (Section 1.3). These vaccines will be administered open label.
Participants will be followed for injection-site and systemic AEs through Day 14 following 
each vaccination with V114 or Prevenar 13™. Information for SAEs and deaths, regardless 
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of whether the events are considered vaccine related by the investigator, will be collected 
from the time consent is signed through completion of participation in the study. An external 
Data Monitoring Committee (DMC) will conduct a periodic review of safety and tolerability 
data for the V114 Phase 3 pediatric program. A description of the structure and function of
the DMC, along with the timing and content of the safety reviews will be outlined in the 
DMC charter. Information regarding the composition of the DMC is provided in Appendix 1.
Blood samples (approximately 5 mL) for immunogenicity assays will be drawn at 3 time 
points: (1) 30 days after the 2-dose primary series of V114 or Prevenar 13™ (PD2), 
(2) immediately before receipt of Dose 3 of V114 or Prevenar 13™ administered at Visit 4 
(Predose 3), and (3) 30 days following the toddler dose of V114 or Prevenar 13™(PD3).
After completion of immunogenicity testing to evaluate the study objectives and hypotheses, 
serum samples will be stored to conduct any additional study-related testing as required by 
regulatory agencies or the Sponsor. For randomized study participants who provided consent 
for Future Biomedical Research, leftover sera from the study may be used for other purposes 
such as the development and/or validation of pneumococcal assays after completion of all 
study-related immunogenicity testing.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will be conducted in healthy infants approximately 3 months of age (70 to 
111 days of age) at enrollment. These infants are at increased risk for pneumococcal disease 
and its associated morbidity and mortality [Drijkoningen, J. J 2014]. The study will assess 
safety, tolerability, and immunogenicity of the 2+1 PCV vaccination schedule and 
concomitant use with other pediatric vaccines recommended in many countries worldwide. 
The immune response to Vaxelis™ when administered concomitantly with V114 will also be 
evaluated in this study.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints are consistent with previous studies evaluating PCVs and the 
concomitantly administered pediatric vaccines in this study.
The pneumococcal electrochemiluminescence (PnECL) assay and the multiplexed 
opsonophagocytic assay (MOPA) will be used to measure vaccine-induced, anti-PnPs 
serotype-specific immune responses for all 15 serotypes included in V114. PnECL measures 
serotype-specific IgG concentrations (primary endpoint based on GMCs), and MOPA 
measures serotype-specific OPA titers (secondary endpoint based on GMTs). OPA GMTs 
represent functional antibodies capable of inhibiting growth of S pneumoniae in culture. 
Additional information on the immunogenicity assays can be found in Section 8.2.
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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]. Since MOPA 
requires more serum than the PnECL assay, the PnECL will be used to test the primary 
immunogenicity hypotheses in this study.
The use of the serotype-specific IgG antibody level of ≥0.35 µg/mL has been recommended 
by a WHO expert panel as an acceptable threshold value for evaluating the clinical 
performance of PCVs following a routine childhood vaccination regimen [World Health 
Organization 2008] [World Health Organization 2005]. The response rate (ie, the proportion 
of participants meeting the serotype-specific IgG threshold value of ≥0.35 μg/mL) is a
primary endpoint in this study.
Anti-PnPs serotype-specific IgG and OPA responses will be measured at 3 time points:
•
Approximately 30 days following Dose 2 to evaluate the immune response to the primary 
vaccination series (IgG GMCs, IgG response rates, OPA GMTs, and OPA response rates) 
•
Immediately prior to Dose 3 to evaluate the persistence of protective immunity (IgG 
GMCs, OPA GMTs, and OPA response rates) 
•
Approximately 30 days following Dose 3 to evaluate anamnestic antibody responses (IgG 
GMCs, IgG response rates, OPA GMTs, and OPA response rates)
Measurement at 30 days following Dose 3 was selected for the primary endpoint, as this time
point is considered the completion of the PCV series, where immune memory is boosted. 
Due to the larger serum requirements of the MOPA assay, functional antibody activity (as by 
OPA GMTs) will be assessed in the first 20% of all participants with sufficient serum 
volume at PD2 to evaluate OPA responses (OPA Subset). Additionally, evaluation of OPA
responses will be conducted at Predose 3 and PD3 for all participants who had OPA 
performed at PD2 for whom there is sufficient volume.
In addition, sera from study participants will be used to measure the immune responses to the 
following antigens contained in the pediatric vaccines administered concomitantly with either 
V114 or Prevenar 13™:
•
Diphtheria toxoid, tetanus toxoid, pertussis (PT, FHA, FIM 2/3, and PRN), Hib-PRP, 
HBsAg and poliovirus (serotypes 1, 2, and 3) at PD2 and PD3
The endpoints used to evaluate the immune responses to the concomitantly administered 
pediatric vaccines are consistent with established protective and acceptable antibody levels 
[Plotkin, S. A. 2010]. For pertussis, there are no benchmark antibody concentrations that are 
widely accepted as correlates of protection; therefore, the pertussis antigen endpoints are 
based on previously published standards that are also above assay lower limit of quantitation
[Edwards, K. M. 2014].
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Results from clinical studies with Prevenar 13™indicate that Prevenar 13™can be 
administered concomitantly with the pediatric vaccines being administered in this study
[Bryant, K. A., et al 2013]. Interference between V114 and these vaccines is not anticipated.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies, published data from marketed PCVs, and guidance
from regulatory agencies during product development. Data from this study will also 
contribute to the overall safety database of V114 to support initial licensure in infants. 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 (FDA) Guidance for Industry: Patient-Reported Outcome Measures 
[U.S. Food and Drug Administration 2009].
Details on the safety endpoints evaluated in this study can be found in Section 8.3.3 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Placebo-controlled clinical studies for new PCVs are no longer acceptable given the proven 
clinical efficacy, public health impact, and widespread use of licensed PCVs worldwide. 
Prevenar 13™ is currently the most widely recommended vaccine for the prevention of 
pneumococcal disease in infants in many countries worldwide, includes the largest number of 
serotypes, and will be used as the active comparator in this study.
Refer to approved labeling for detailed background information on Prevenar 13™.
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4.3
Justification for Dose
The dose and dosing schedule of V114 is similar to that used in previous pediatric V114 
clinical studies, which demonstrated safety and comparable immune responses to those of 
Prevenar 13™. Refer to the V114 IB for details on dosing schedule.
This study will support initial licensure of V114 in countries that use the approved 2+1 
Prevenar 13™ dosing schedule for full-term infants (2 doses in infant primary series 
followed by 1 toddler dose). This schedule has also been recommended by WHO SAGE on 
Immunizations and implemented in many countries including those in the EU.
4.4
Beginning and End of Study Definition
The overall study begins when written informed consent is provided for the first participant. 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study, or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy male and female infants approximately 3 months of age, from 70 to 111 days 
(inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Is healthy (based on review of medical history and physical examination) based on the 
clinical judgment of the investigator.
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Demographics
2. Is male or female, approximately 3 months of age, from 70 days to 111 days inclusive, at 
the time of signing the informed consent.
Informed Consent
3. Has a legally acceptable representative who understands the study procedures, alternate 
treatments available, and risks involved with the study and voluntarily agrees to 
participate by giving written informed consent. The legally acceptable representative may 
also provide consent for future biomedical research. However, the participant may 
participate in the main study without participating in future biomedical research. See 
Appendix 7 for Sweden-specific information regarding the informed consent process.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
1. Was born prior to 37 weeks of gestation.
Medical Conditions
2. Has a history of IPD (positive blood culture, positive cerebrospinal fluid culture, or other 
sterile site) or known history of other culture positive pneumococcal disease.
3. Has a known hypersensitivity to any component of the PCV, any component of the 
licensed pediatric vaccines to be administered concomitantly in the study, or any 
diphtheria toxoid containing vaccine.
4. Has any contraindication to the concomitant study vaccines being administered in the 
study (concomitant vaccine contraindication details provided in the Investigator Trial File 
Binder).
5. *Had a recent febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) occurring within 72 hours prior to receipt of study 
vaccine.
6. Has a known or suspected impairment of immunological function.
7. Has a history of congenital or acquired immunodeficiency.
8. Has, or his/her mother has, a documented human immunodeficiency virus (HIV) 
infection.
9. Has, or his/her mother has, a documented hepatitis B surface antigen – positive test.
10. Has known or history of functional or anatomic asplenia.
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11. Has failure to thrive based on the clinical judgment of the investigator.
12. Has a bleeding disorder contraindicating intramuscular vaccination.
13. Has a history of autoimmune disease (including but not limited to systemic lupus 
erythematosus, antiphospholipid syndrome, Behcet’s disease, autoimmune thyroid 
disease, polymyositis and dermatomyositis, scleroderma, type 1 diabetes mellitus, or 
other autoimmune disorders).
14. Has a known neurologic or cognitive behavioral disorder, including encephalitis/myelitis, 
acute disseminating encephalomyelitis, pervasive development disorder, and related 
disorders.
Prior/Concomitant Therapy
15. Has received a dose of any pneumococcal vaccine prior to study entry.
16. Has received >1 dose of monovalent hepatitis B vaccine or hepatitis B-based combination 
vaccine prior to study entry.
17. Has received a dose of any acellular pertussis- or whole cell pertussis-based combination 
vaccines, Haemophilus influenzae type b conjugate vaccine, poliovirus vaccine, or any 
other combination thereof, prior to study entry.
18. *Meets one or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/day for persons weighing >10 kg) for ≥14 consecutive 
days and has not completed this course of treatment at least 30 days prior to the 
first dose of study vaccine at randomization.
b.
Has received or is expected to receive systemic corticosteroids within 14 days 
prior to any dose of study vaccine.
c.
Is expected to require systemic corticosteroids within 30 days after any study 
vaccination during conduct of the study.
Note: Topical, ophthalmic, and inhaled steroids are permitted.
19. *Has received other licensed non-live vaccines within 14 days before receipt of the first 
dose of study vaccines.
20. *Has received a licensed live vaccine within 30 days before receipt of the first dose of 
study vaccines. Exception: Rotavirus vaccine may be administered according to local 
guidelines.
21. Has received a blood transfusion or blood products, including immunoglobulins.
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Prior/Concurrent Clinical Study Experience
22. Has participated in another clinical study of an investigational product before the 
beginning or anytime during the duration of the current clinical study. Participants 
enrolled in observational studies may be included; these will be reviewed on a 
case-by-case basis for approval by the Sponsor.
Other Exclusions
23. Has any other reason that, in the opinion of the investigator, may interfere with the 
evaluation required by the study. Reasons may include, but are not limited to, being 
unable to keep appointments or planning to relocate during the study.
24. Is or has an immediate family member (eg, parent/legal guardian or sibling) who is 
investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 
may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides
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, Prevenar 13™, and concomitant vaccines listed in Table 2) will be 
packaged to support enrollment. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
V114
Experimental
V114
Biological/
Vaccine
Sterile 
Suspension
Refer to IB
0.5 mL
IM
Single dose 
at Visits 1, 
2, and 4
Experi-
mental
IMP
Central
V114
Experimental
Vaxelis™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visits 1, 
2, and 4
Experi-
mental
IMP
Central
V114
Experimental
M-M-R™II
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
SC
Single dose 
at Visit 4
Experi-
mental
NIMP
Central
V114
Experimental
VARIVAX™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
SC
Single dose 
at Visit 4a
Experi-
mental
NIMP
Central
Prevenar 
13™
Active 
Comparator
Prevenar 
13™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visits 1, 
2, and 4
Experi-
mental
IMP
Central
Prevenar 
13™
Active 
Comparator
Vaxelis™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visits 1, 
2, and 4
Experi-
mental
IMP
Central
Prevenar 
13™
Active 
Comparator
M-M-R™II
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
SC
Single dose 
at Visits 4
Experi-
mental
NIMP
Central
Prevenar 
13™
Active 
Comparator
VARIVAX™
Biological/
Vaccine
Sterile 
Suspension
Refer to 
product 
labeling
0.5 mL
SC
Single dose 
at Visit 4a
Experi-
mental
NIMP
Central
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route 
of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Admin. = administration; IB = Investigator’s Brochure; IM = intramuscular; IMP =Investigational medicinal product; NIMP = non-investigational medicinal product; SC = 
subcutaneous.
Definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or country differences of the definition of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
a Participants enrolled at sites in Norway and Denmark will receive a second dose of VARIVAX™ at Visit 5 according to local vaccination requirements. The second dose of 
VARIVAX™ may be locally sourced by sites in Norway and Denmark. See Appendix 7 (Section 10.7.2) for country-specific information.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. Information on preparation and administration of 
study vaccines is provided in Section 6.3.3 and Section 8.1.8.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to V114 study intervention or Prevenar 13™.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. V114 and Prevenar 13™ will be prepared and/or 
dispensed by an unblinded pharmacist or unblinded qualified study site personnel. The 
participant and the investigator who are involved in the clinical evaluation of the participants 
will remain blinded to the group assignments.
Because V114 and Prevenar 13™ have a different appearance, a member of the study site 
staff will be unblinded for the purposes of receiving, maintaining, preparing, and 
administering these study vaccines. The pediatric vaccines being provided in the study (ie,
Vaxelis™, M-M-R™II, and VARIVAX™) will also be prepared and administered by 
unblinded study site staff for consistency even though these vaccines are being provided 
open label in this study. Procedures for handling, preparing, and administering the unblinded 
vaccines are in the Investigator Trial File Binder.
To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Additionally, blinded site 
personnel will not be present in the examination room when study vaccines are administered. 
Contact between participants and unblinded study personnel after vaccination administration 
is strictly prohibited. Blinded site personnel will be responsible for all safety and 
immunogenicity follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and Merck Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified plan for V114, Prevenar 13™, and all concomitant
vaccinations, as indicated in Section 1.3, require consultation between the investigator and 
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the Sponsor and written documentation of the collaborative decision on participant 
management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the study (see Section 5.2 for details). Although there are restrictions on licensed 
vaccines in the exclusion criteria before administration of the first dose of study vaccines, 
other nonstudy pediatric vaccines (such as rotavirus and influenza vaccines) are permitted 
during the study according to local, regional, and/or country guidelines. If there is a clinical 
indication for any medications or vaccinations specifically prohibited, discontinuation from 
study intervention may be required. The investigator should discuss any questions regarding 
this with the Sponsor Clinical Director. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participant’s primary physician. However, 
the decision to continue the participant on study intervention requires the mutual agreement 
of the investigator, the Sponsor, and the participant’s legally acceptable representative.
If a medical condition requires the use of a prohibited steroid regimen, immunoglobulin, 
blood, or blood products during a subject's participation in this study, one of the individuals 
listed on the Sponsor Contact Information page must be notified as soon as possible. Any 
concurrent medication or medical treatment must be recorded on the appropriate eCRF. It is 
important to record the use of any analgesic or antipyretic medication that occurs on the day 
of vaccination on the eVRC and appropriate eCRF.
All participants will receive licensed pediatric vaccines according to the recommended 
schedule (Table 2). Countries participating in this study must follow the vaccination schedule 
being evaluated in the study with respect to PCV and the concomitant vaccines.
Administration of meningococcal vaccine is permitted; however, administration of a 
meningococcal vaccine with a CRM197 or other diphtheria toxoid carrier protein (details 
provided in the Investigator Trial File Binder) should be given after the final blood draw of 
the study (Visit 5). Meningococcal B vaccine must not be given within 14 days before or 
after receipt of V114 or Prevenar 13™, or within 30 days before any scheduled blood draw. 
During influenza season, it is possible that participants 6 months of age and older could 
receive an inactivated influenza vaccine. Influenza vaccine should be administered at least
7 days prior to or at least 15 days after the administration of V114 or Prevenar 13™.
If the participant is scheduled to receive any other nonstudy pediatric vaccine (except for 
rotavirus, meningococcal, and influenza vaccines), the investigator should discuss this with 
the Sponsor Clinical Director as soon as possible. All nonstudy vaccinations should be 
recorded on the appropriate eCRF.
Concomitant vaccines should be administered on the same day as V114 or Prevenar 13™.
Other nonstudy pediatric vaccines should be administered according to the local 
recommended schedule. Participants enrolled at sites in Norway and Denmark will receive a 
second dose of VARIVAX™ at Visit 5 according to local vaccination requirements. See 
Appendix 7 (Section 10.7.2) for country-specific information. If given at a study visit, oral 
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vaccines should be administered prior to the study vaccine and other injectable vaccines. 
Precautions must be taken to prevent choking during the administration of oral vaccines. 
Other injectable vaccines should be given after V114 or Prevenar 13™. To avoid any
confounding results, concomitant injectable vaccines and other nonstudy pediatric vaccines 
should not be administered in the same limb as V114 or Prevenar 13™. Recommended 
injection-site locations for V114 or Prevenar 13™ and concomitant injectable vaccines being 
provided in the study are listed in Table 3. Injection -site AEs for the licensed, concomitantly 
administered vaccines will not be collected.
No other investigational compound or device may be administered at any time during this 
study without prior approval by the Sponsor.
Table 2
Concomitant Vaccine Schedule
Vaccine Tradename a, b
(Generic Name)
Indication
Visit 1
(~3
months 
of age)
Visit 2
(~5
months 
of age)
Visit 4
(~12 
months 
of age)
Vaxelis™(Diphtheria, tetanus, pertussis 
(acellular, component), hepatitis B (rDNA), 
poliomyelitis (inactivated), and Haemophilus 
type b conjugate vaccine (adsorbed))
Prevention of diphtheria, 
tetanus, pertussis, hepatitis B, 
poliomyelitis, and invasive 
disease due to Haemophilus 
influenzae type b
X
X
X
M-M-R™II (Measles, Mumps, and Rubella
Virus Vaccine Live)
Prevention of measles, 
mumps, and rubella
X
VARIVAX™(Varicella Vaccine Live)
Prevention of varicella
X c
rDNA = ribosomal deoxyribonucleic acid.
a
Tradenames for licensed vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
b
Injectable vaccines administered in the study should be given after V114 or Prevenar 13™.
c
Participants enrolled at sites in Norway and Denmark will receive a second dose of VARIVAX™ at Visit 5 
according to local vaccination requirements. See Appendix 7 (Section 10.7.2) for country-specific information.
Table 3
Recommended Injection-site Location for Study Interventions
Vaccine
Recommended Injection Site
V114 or Prevenar 13™
Right thigh
Vaxelis™
Left thigh
M-M-R™II
Deltoid right arm
VARIVAX™
Deltoid left arm
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
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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.
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 the 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 8.1.13). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3, unless the 
consent is withdrawn for the participant (Section 7.2). A participant may discontinue from 
study intervention (including receipt of V114, Prevenar 13™, and concomitant vaccines 
provided in the study) but continue to participate in protocol-specified, AE-monitoring 
activities (see Section 8.12.3 for details).
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.12 and 
Section 8.12.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant’s legally acceptable representative requests to discontinue study 
intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
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’s legally acceptable 
representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.12. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
contacted, the participant’s legally acceptable representative 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’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the participant’s legally acceptable representative last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant’s legally 
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acceptable representative. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
Approximately 5 ml of blood will be drawn at each of Visits 3, 4, and 5 for immunogenicity 
assays. The maximum amount of blood collected from each participant over the duration of 
the study will not exceed approximately15 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant’s legally acceptable 
representative prior to participating in a clinical study or future biomedical research.If there 
are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented on the consent form by the dated signature of the participant’s 
legally acceptable representative 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’s legally 
acceptable representative before the individual’s participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant’s legally acceptable representative must receive the Institutional Review 
Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable opinion in advance 
of use. The participant’s legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the willingness for the 
participant 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 dated signature of the participant’s legally acceptable representative.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
See Appendix 7 for Sweden-specific information regarding the informed consent process.
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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’s legally acceptable representative, 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’s legally acceptable representative.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. The investigator should 
consult with the Sponsor’s Clinical Director for any questions about participation eligibility.
If the participant meets any of the exclusion criteria with and asterisk (*), Visit 1 may be 
rescheduled for a time when these criteria are not met.
8.1.3
Participant Identification Card
The legally acceptable representative for each participant will be given a Participant 
Identification Card identifying the individual as a participant in a research study. The card 
will contain study site contact information (including direct telephone numbers) to be utilized
in the event of an emergency. The investigator or qualified designee will provide the legally 
acceptable representative for each participant with a Participant Identification Card
immediately after written informed consent is provided. At the time of treatment
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee before 
vaccination at Visit 1. Note: birth weight (kg) and gestational age will be documented in the 
participant’s medical history.
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 1. The receipt of hepatitis B vaccine at birth must be reviewed and documented in the 
participant’s chart and recorded in the study database.
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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.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin, 
blood, or blood products during a participant's participation in this study, one of the 
individuals listed on the Sponsor Contact Information page must be notified as soon as 
possible. Any concurrent medication or medical treatment must be recorded on the 
appropriate eCRF. 
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination 
on the eVRC and appropriate eCRF. Concomitant medications taken after Visit 1 and 
nonstudy vaccines received since Visit 1 will be recorded with the eVRC as specified in 
Section 8.3.3.
The administration of pediatric vaccines listed in Table 2 will be recorded on the appropriate 
eCRF. To avoid any confounding results, concomitant injectable vaccines should not be 
administered in the same limb as V114 or Prevenar 13™. Documentation of which limb was 
used for the administration of V114 or Prevenar 13™ must be recorded on the eVRC 
(Section 8.3.3) and appropriate eCRF. Documentation of injection-site location for the 
concomitant injectable vaccines must be recorded on the appropriate eCRF.
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.
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8.1.8
Study Intervention Administration
Before each vaccine administration, the investigator (or designee) must review medical 
history to ensure that the participant has no new contraindication to the vaccine(s) scheduled 
to be given. This information should be documented in the participant’s chart. 
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. Study vaccines should be prepared and administered by 
appropriately qualified members of the study personnel (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacist or medical assistant) as allowed by local/state, 
country and institutional guidance. Procedures for handling, preparing, and administering the 
unblinded vaccines are provided in the Investigator Trial File Binder. Unblinded study 
personnel should follow the preparation and administration instructions for Prevenar 13™ as 
specified in the product label.
Study vaccines should be removed from the refrigerator no more than 1 hour before 
vaccination. The time of removal and time of vaccination should be documented in the 
participant’s chart. 
If the V114 is provided as a syringe: Prior to administration of study vaccine, the unblinded 
pharmacist should shake vigorously to obtain a homogenous white suspension. If 
white-colored insoluble particle appears, the unblinded pharmacist should use rapid, 
horizontal hand-shaking for 5 to 10 seconds while holding the syringe in between the thumb 
and index finger until complete resuspension. This action should be repeated, as necessary. If 
appearance is otherwise, the vaccine should not be administered.
If V114 is provided as a vial: Prior to administration of study vaccine, the unblinded 
pharmacist should use rapid, horizontal hand-shaking for up to 5 seconds while holding the 
vial in between the thumb and index finger to obtain a homogenous white suspension. This 
action should be repeated, as necessary. If appearance is otherwise, the vaccine should not be 
administered.
The vaccine should not be used if the vaccine cannot be resuspended.
Prevenar 13™ will be supplied as a pre-filled syringe.
A 0.5-mL intramuscular dose of study vaccine will be administered to healthy infants at 
approximately 3, 5, and 12 months of age. The study vaccines are to be administered at the 
locations recommended in Table 3 (Section 6.5). Documentation of which limb was used for 
the administration of V114 or Prevenar 13™ should be recorded on the appropriate eCRF. 
This information should also be recorded on the eVRC to inform the participant’s legally 
acceptable representative of the appropriate limb to monitor for AEs related to the V114 or 
Prevenar 13™. 
If an abnormality (ie, rash) is observed at the site where the previous dose of the study 
vaccine was administered, it is permissible to use the anterolateral muscle of the other limb to 
administer the following dose of the study vaccine. Adequate treatment provision, including 
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epinephrine and equipment for maintaining an airway, should be available for immediate use 
should an anaphylactic or anaphylactoid reaction occur [Centers for Disease Control and 
Prevention 2015].
Unblinded study personnel should not have contact with participants for any study -related 
procedures/assessments after administration of study vaccines, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant or participant’s parent/guardian will be blinded to the 
study vaccine received by the participant. Vaccination information, such as Component 
Identification Number and time of vaccination, must be recorded on the appropriate eCRF as 
per the data entry guidelines.
8.1.8.1
Timing of Dose Administration
V114 or Prevenar 13™ will be administered as indicated in Section 1.3. All participants will 
be observed for at least 30 minutes following each vaccination for any immediate reactions. 
This observation must be performed by blinded site personnel for V114 and Prevenar 13 ™ 
(Section 1.3 and Section 6.3.3).
Participants must be afebrile for at least 72 hours prior to vaccination (Section 1.3 and 
Section 8.3.2).
Blood samples must be collected before study vaccination.
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 FDA Guidance for Industry: Patient-Reported 
Outcome Measures [U.S. Food and Drug Administration 2009]. The investigator or delegate 
will train the participant’s legally acceptable representative in the use of the eVRC as 
indicated in Section 1.3.
Body temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or nonstudy vaccinations will be recorded on the 
eVRC as described in Section 1.3 and Section 8.3.3. The investigator or delegate will review 
the data captured on the eVRC with the participant’s legally acceptable representative as 
indicated in Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant’s legally acceptable representative both on the eVRC, and verbally at the time of 
eVRC review, to apply the appropriate assessment of intensity as described in Appendix 3.
8.1.10
Day 15 Postdose Telephone Contact Guide
Site personnel will contact the participant’s legally acceptable representative on Day 15 after 
each vaccination dose of V114 or Prevenar 13™ to review eVRC data. The Day 15 Postdose 
Telephone Contact Guide will be provided by the Sponsor. This guide is designed to assist 
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site personnel to collect any updates or edits to data previously entered on the eVRC from the 
participant’s legally acceptable representative. Any differences between eVRC data and the 
clinical database must be clearly explained in the participant’s source documentation with an 
indication of where the information was obtained (eg, from the Day 15 Postdose Telephone 
Contact with the participant’s legally acceptable representative).
8.1.11
Telephone Contact Questionnaire
Site personnel will contact the participant’s legally acceptable representative approximately 
6 months after the last dose of study vaccine to collect additional information based on a 
Telephone Contact Questionnaire provided by the Sponsor. Data to be reported from this 
discussion will include SAEs and/or any updates to previously reported safety information.
8.1.12
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the protocol-specified 
vaccination regimen should be encouraged to continue to be followed for all remaining study 
visits as outlined in Section 1.3 and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 5) should be performed (at the time of withdrawal). 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4.
8.1.12.1
Withdrawal From Future Biomedical Research
Consent for future biomedical research may be withdrawn by the participant’s legally 
acceptable representative. Consent may be withdrawn by the legally acceptable 
representative 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’s legally acceptable representative
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. 
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8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Two immunogenicity assays (PnECL and MOPA) will be used to measure vaccine-induced, 
anti-PnPs serotype-specific immune responses for all 15 serotypes included in V114.
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Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
8.2.1
Pneumococcal Electrochemiluminescence
The Sponsor has developed and optimized a multiplex, ECL-based detection method for the 
quantitation of IgG serotype-specific antibodies to the 15 PnPs serotypes contained in V114. 
The PnECL v2.0 assay is based on the Meso Scale Discovery technology, which employs 
disposable multi-spot microtiter plates. The benefits of the ECL multiplex technology over 
the prior enzyme-linked immunosorbent assay (ELISA) methodology include speed, 
equivalent or better sensitivity, increased dynamic range, the ability to multiplex, and 
reduction in required serum sample and reagent volumes. The measurement of immune 
responses to the 15 serotypes included in V114 is performed using an assay format consisting 
of 2 groups of 7 and 8 serotypes each. The PnECL v2.0 assay for all 15 serotypes has 
undergone validation. The validation study evaluated various performance parameters of the 
assay, including precision, ruggedness, relative accuracy, dilutional linearity, selectivity, and 
specificity. The validation results were evaluated against prespecified acceptance criteria for 
each of the parameters.
The WHO Expert Committee on Biological Standardization has recommended that in house 
assays used in immunogenicity studies designed to evaluate protection against IPD be 
bridged to the WHO reference assay to maintain the link between immune responses to 
vaccination and the clinical demonstration of protective efficacy against IPD conferred by the 
7 conjugated polysaccharides in Prevenar™. In 2012 and 2014, the Sponsor formally bridged 
the original PnECL assay to the WHO IgG ELISA in order to determine the PnECL 
threshold values that correspond to 0.35 µg/mL in the WHO ELISA for each of the 
7 Prevenar™ serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and for each of the additional 
6 serotypes (1, 3, 5, 6A, 7F, and 19A) in Prevenar 13™.
A confirmatory study was performed to formally bridge the optimized PnECL assay (v2.0) to 
the WHO reference ELISA, and to assess the PnECL threshold values that correspond to 
0.35 µg/mL measured using the WHO ELISA for each of the serotypes in V114, including 
the Prevenar 13™ serotypes and serotypes 22F and 33F, which were not previously assessed. 
The bridging of the optimized PnECL to the WHO ELISA is complete, and the data showed 
good concordance between the PnECL and WHO ELISA around the 0.35 μg/mL threshold 
value for all 15 serotypes. It is recommended that a single PnECL threshold value of 
0.35 µg/mL be applied to each of the 15 serotypes.
8.2.2
Multiplex Opsonophagocytic Assay
The MOPA, developed and published by Professor Moon Nahm (Director of the US WHO
Pneumococcal Serology Reference Laboratory and National Institutes of Health 
Pneumococcal Reference Laboratory), 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 
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reduces the amount of serum needed for testing. The assay readout is the opsonization index, 
which is the reciprocal of the highest dilution that gives ≥50% bacterial killing, as 
determined by comparison to assay background controls. The Sponsor has developed and 
optimized the MOPA in a high throughput micro-colony platform. The MOPA assay for all 
15 V114 serotypes has undergone validation. The validation study evaluated various 
performance parameters of the assay, including precision, relative accuracy/dilutional 
linearity, and specificity. The validation results were evaluated against prespecified
acceptance criteria for each of the parameters.
8.2.3
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen Serology 
Assay
The diphtheria, tetanus, and pertussis 6-valent IgG (DTP-6 IgG) assay measures total IgG 
antibodies specific to the following antigens: pertussis toxin (PT), filamentous hemagglutinin 
(FHA), pertactin (PRN), fimbriae types 2/3 (FIM 2/3), diphtheria toxoid, and tetanus toxoid.
Antigen-specific immunoglobulin serum antibodies bind directly to the epitopes on antigens 
covalently conjugated to 6 distinct Luminex microspheres. The measured fluorescent signal 
of the phycoerythrin-labeled detection antibody is directly proportional to the amount of 
antigen-specific IgG antibodies present in a serum sample. Samples are read on a Luminex 
200 instrument, which identifies the specific Luminex microspheres by their distinct red and 
infrared fluorescent dye spectral properties. Quantitation of the human IgG antibodies to 
DTP-6 antigens, or titer, is determined by comparison of the resulting test fluorescence 
measurement to the reference standard serum which was calibrated to 06/140 for PT, FHA, 
and PRN, FDA Lot 3 for FIM2/3, to TE-3 for tetanus toxoid and to 00/496 for diphtheria 
toxoid.
8.2.4
Haemophilis Influenzae Type B ELISA
The Haemophilis influenzae type b (Hib) IgG ELISA for the in-vitro measurement of specific 
IgG antibodies against Hib capsular polysaccharide in human serum uses the Vacczyme™ 
Human Anti-Haemophilus influenzae type b Enzyme Immunoassay Kit purchased from The 
Binding Site (catalog # MK016), which was further validated for use in clinical trials. The kit 
contains microtiter wells pre-coated with Hib polysaccharide antigen conjugated to human 
serum albumin. Diluted serum is added to the microtiter wells and allowed to incubate. After 
incubation and washing to remove non-bound serum proteins, horseradish peroxidase 
(HRP)-conjugated rabbit anti-human IgG is added, which binds to any captured Hib-specific 
IgG molecules. After another wash step, tetramethylbenzidine substrate is added; the ensuing 
color development reaction is then stopped at a defined time point by the addition of a dilute 
acid solution. The OD is measured at 450 nm and is directly proportional to the amount of 
anti-Hib IgG present in the serum specimen. Levels of anti-Hib IgG are quantified by 
interpolation from a standard curve that has been calibrated to the FDA Lot 1983 reference 
serum.
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8.2.5
Hepatitis B Enhanced Chemiluminescence (ECi) Assay
The purpose of the hepatitis B ECi assay is to detect total antibody to human plasma-derived 
HBsAg subtypes ad and ay after vaccination with HBsAg-containing vaccine(s). This is the 
primary assay used to evaluate the serological response to the vaccine(s). The assay is a solid 
phase sandwich enzyme-labeled immunoassay. Results for the assay are reported in mIU/mL.
This assay involves the reaction of anti-HBs in a test sample with HBsAg (ad and ay 
subtypes) coated onto the wells. An HRP-labeled HBsAg conjugate (ad and ay subtypes) 
then forms a complex with the bound anti-HBs, forming an “antigen sandwich”. Unbound 
materials are removed by washing. A reagent that contains luminogenic substrates (a luminol 
derivative and a peracid salt) and an electron transfer agent will be added to the wells. The 
HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing 
light. The electron transfer agent will increase the level and duration of the light produced. 
The amount of HRP conjugate bound and subsequent light produced is indicative of the 
concentration of anti-HBs present in the sample.
Three internally prepared control serum pools, consisting of a high-positive, low-positive, 
and negative control, will be used to monitor the performance of the assay. These pools will 
each be prepared from 4 individual human immune sera obtained from an external vendor. 
Additionally, there will be anti-HBs positive and negative manufacturer-supplied controls, 
which will be prepared from freeze-dried recalcified human plasma. The hepatitis B WHO 
International reference standard at 10 mIU/mL will also run as a control in every assay. The 
lower limit of quantification of the assay is 5 mIU/mL.
8.2.6
Micrometabolic Inhibition Test (MIT)-based Virus Neutralization Assay 
(polio MIT)
The Polio method quantifies neutralizing (functional) antibodies to poliovirus serotypes 1, 2,
and 3 in serial dilutions of serum using a MIT-based virus neutralization assay (polio MIT). 
The polio MIT assay quantifies the level of neutralizing antibodies to poliovirus type 1, type 
2, and type 3 in human sera. The process that was validated is an assay method involving 
challenging serial diluted sera with Poliovirus type 1, type 2, or type 3. Tissue culture cells 
are then added to the serum-virus mixture, incubated for 6 to 8 days, and the ability of the 
sera to neutralize the cytotoxic effects of a particular type of poliovirus is determined. 
Poliovirus exerts a profound shut down of normal cell function. Metabolism and CO2
production are stopped in mammalian cells infected with virus; consequently, the pH remains 
at 7.4 or higher as indicated by the red color of the phenol red indicator in the cell culture 
medium. Control cells that are incubated with antibody that neutralizes the virus, metabolize 
and produce CO2 in normal amounts, lowering the pH of the cell culture medium to <7.0 and 
changing the color of the pH indicator to yellow. Therefore, poliovirus neutralizing antibody 
titers correlate with the ability of the serum to neutralize viral infectivity, which prevents the 
metabolic effects of infection on mammalian cells. Results are determined by the inverse 
serum dilution where the change in pH occurs, ranging from a titer of 4.0 to 65,536.0.
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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/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in 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) at Visit 1 for all participants. A targeted 
physical examination will be performed at subsequent vaccination visits as indicated in 
Section 1.3. Any clinically significant abnormality will be recorded on the appropriate eCRF.
Complete and targeted physical examination procedures include obtaining vital signs (heart 
rate, respiratory rate, and rectal temperature), auscultation of the heart and lung, and 
examination of the abdomen. In addition, a complete physical examination will include an 
assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, neurological system, 
and musculoskeletal system. 
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurements
Pre-vaccination rectal temperatures will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) within 72 hours of vaccination must be rescheduled. 
The participant’s legally acceptable representative will be asked to record the participant’s 
temperature reading on the eVRC from Day 1 through Day 7 following each vaccination. 
Temperature measurement must be recorded in the eVRC if fever is suspected during Day 8 
through Day 14.
Rectal is the preferred method of obtaining participant’s temperature. Axillary (underarm) is 
an acceptable method but temperature needs to be confirmed by rectal measurement if fever 
is detected. If an axillary temperature is reported to be ≥37.8°C (≥100.0°F), a rectal 
temperature must be taken. In this case, both axillary and rectal temperatures must be 
recorded on the eVRC. Temperature readings should be taken at approximately the same 
time each day. Use of temporal or tympanic thermometers to collect temperature for this 
study is prohibited.
8.3.3
Safety Assessment and use of the eVRC
All participants will be observed for at least 30 minutes after each vaccination for any 
immediate reactions. If any immediate AEs are observed during this period, the time at which 
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the event occurred within this timeframe, as well as the event itself, any concomitant 
medications that were administered, and resolution of the event, must be recorded on the 
appropriate eCRF.
The limb that was used for the administration of V114 or Prevenar 13™ will be recorded in 
the eVRC (Note: the study will report injection-site AEs from V114 or Prevenar 13™only; 
the location of V114 or Prevenar 13™ administration can be used by the participant or 
participant’s legally acceptable representative to monitor the appropriate limb for injection-
site AEs related to V114 or Prevenar 13™).
Participant’s legally acceptable representative will use the eVRC (Section 8.1.9) to document 
the following information:
•
Rectal temperatures measured Day 1 (day of vaccination) through Day 7 following each 
vaccination; Day 8 through Day 14 following each vaccination if fever is suspected.
•
Solicited injection-site AEs (swelling, redness, pain or tenderness, and hard lump) Day 1 
through Day 14 postvaccination.
•
Solicited systemic AEs (irritability, drowsiness, appetite lost, and hives or welts) Day 1 
through Day 14 postvaccination.
•
Any other unsolicited injection-site or systemic AEs Day 1 through Day 14 
postvaccination.
•
Use of any analgesic or antipyretic on the day of vaccination.
•
Concomitant medications and nonstudy vaccinations Day 1 to Day 14 postvaccination.
8.3.4
Clinical Safety Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.
All AEs, SAEs, and other reportable safety events must be reported by the investigator from 
the day of allocation/randomization to the first vaccination and from the day of each 
vaccination through 14 days postvaccination. SAEs must also be reported throughout the 
duration of the individual's participation in the study, regardless of whether or not related to 
the Sponsor's product.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:

A death that occurs prior to the participant completing the study.
OR

An SAE that is considered by an investigator who is a qualified physician to be vaccine-
related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
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 4.
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion 
of study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Not applicable since participants are infants.
Event of Clinical 
Interest
There are no ECIs 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
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
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including cancer, and overdose will be followed until resolution, stabilization, until the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
There are no events of clinical interest for this study.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of any individual study 
vaccine in a 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.
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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 EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Future Biomedical Research Sample Collection
If the participant’s legally acceptable representative signs the future biomedical research 
consent, the following specimens will be obtained as part of future biomedical research:
•
Buccal swab DNA for future research
•
Leftover study serum at the central laboratory stored for future research after aliquoting 
samples for completion of immunogenicity testing
8.11
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3.
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8.12.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
If the participant develops a new clinical condition during the study that makes him/her 
ineligible for the study, the investigator should discuss with the Sponsor Clinical Director as 
soon as possible. The decision to continue the participant on study intervention requires the 
mutual agreement of the investigator, the Sponsor, and the participant’s legally acceptable 
representative.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
A participant may discontinue from study intervention (including receipt of V114, Prevenar 
13™, and concomitant vaccines provided in the study) but continue to participate in 
protocol-specified, AE-monitoring activities as outlined in Section 1.3, as long as the 
participant’s legally acceptable representative does not withdraw consent. Blood draws for 
immunogenicity testing could occur if agreed to by the participant’s legally acceptable 
representative at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with International Council for Harmonisation [ICH]
Guideline E-9). Changes to exploratory or other non-confirmatory 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 Section 9.2 through Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Active-comparator-
controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 
3-dose Regimen of V114 in Healthy Infants (PNEU-PED-EU-2)
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to V114 or 
Prevenar 13™, respectively.
Analysis Populations
Immunogenicity: Per-Protocol (PP)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Immunogenicity:

Anti-PnPs serotype-specific IgG response rates (proportion of participants 
meeting serotype-specific IgG threshold value of ≥0.35 μg/mL) at 30 days 
PD3

Anti-PnPs serotype-specific IgG GMCs at 30 days PD3
Safety:

Proportion of participants with solicited injection--site AEs (swelling, 
redness/erythema, tenderness/pain, and hard lump/induration) from Day 1 
through Day 14 following any vaccination with V114 or Prevenar 13™

Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, appetite lost/decreased appetite, and hives or 
welts/urticaria) from Day 1 through Day 14 following any vaccination 
with V114 or Prevenar 13™

Proportion of participants with vaccine-related SAEs from Day 1 through 
completion of study participation
Key Secondary 
Endpoints

Antigen-specific responses for all antigens included in Vaxelis™ at 30 
days PD3 of V114 or Prevenar 13™ for participants administered V114 
concomitantly with Vaxelis™ versus participants administered 
Prevenar 13™concomitantly with Vaxelis™ 

Anti-PnPs serotype-specific IgG response rates (proportion of participants 
meeting serotype-specific IgG threshold value of ≥0.35 μg/mL) and 
GMCs for the 15 serotypes contained in V114 at 30 days PD2
Statistical Methods for 
Key Immunogenicity
To address the primary immunogenicity non-inferiority/superiority objectives 
(H1 and H2), the comparison between groups will be made based on the 
proportion of anti-PnPs serotype-specific IgG ≥0.35 μg/mL for the 15 
serotypes contained in V114 at 30 days PD3. The between-treatment 
difference (V114 minus Prevenar 13™) and its 95% CI will be calculated 
using the Miettinen and Nurminen (M&N) method [Miettinen, O. and 
Nurminen, M. 1985].
To address the primary immunogenicity non-inferiority/superiority objectives 
(H3 and H4), the comparison between groups will be made based on serotype-
specific IgG GMCs for the 15 serotypes contained in V114 at 30 days PD3. The 
estimation of the IgG GMC ratios and computation of the corresponding 95% 
CIs will be calculated using the t-distribution with the variance estimate from a 
linear model utilizing the log-transformed antibody concentration as the 
response and a single term for vaccination group.
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To address the secondary objectives regarding the non-inferiority evaluation of 
concomitant antigens contained in Vaxelis™at 30 days PD3, the comparison 
between groups will be made based on the proportion of participants achieving 
the antigen-specific antibody threshold value described in Section 9.9.1. The 
between-treatment difference (V114 minus Prevenar 13™) and the 
corresponding 95% CIs will be calculated using the M&N method [Miettinen, 
O. and Nurminen, M. 1985].
All hypothesis testing, including both non-inferiority and superiority, will be 
based on the lower bound of the 2-sided 95% CI to be greater than the 
prespecified margins listed in Section 9.9.1.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. p--values (Tier 1 
endpoints) and 95% CIs (Tier 1 and Tier 2 endpoints) will be provided for 
between-vaccination group differences in the percentage of participants with 
events; these analyses will be performed using the M&N method [Miettinen, 
O. and Nurminen, M. 1985].
Interim Analyses
To support the periodic review of safety and tolerability data across the V114 
Phase 3 pediatric 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
The study will be considered to have met its primary immunogenicity objective 
if non-inferiority is demonstrated with respect to IgG GMCs and response rates 
for the 13 shared serotypes and superiority is demonstrated respect to IgG 
GMCs and response rates for the 2 unique serotypes at 30 days PD3. All 
hypotheses will be tested individually for each serotype at a 1-sided 
0.025- alpha level. This approach controls the 1-sided type---I error rate at 
0.025, thus no multiplicity adjustment is required. The study will be considered 
to have met its secondary objective for a specific concomitant vaccine if non-
inferiority is demonstrated for all the antigens included in that concomitant 
vaccine.
No multiplicity adjustments will be made for the safety objective.
Sample Size and Power 
The study will randomize participants in a 1:1 ratio to V114 or Prevenar 13™, 
respectively. The overall sample size will be approximately 1180 with 
590 participants into each vaccination group. For primary objectives/hypotheses, 
the study has >95% power. The overall power for the secondary hypotheses 
regarding concomitant vaccine evaluation of Vaxelis™is ~90%. Details are 
provided in Section 9.9.1.
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.
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment 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 and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below.
9.4.1
Immunogenicity Endpoints
The primary immunogenicity analysis endpoints include:
•
The proportion of participants with anti-PnPs serotype-specific IgG ≥0.35 µg/mL at 30 
days PD3
•
Anti-PnPs IgG GMCs at 30 days PD3
The secondary immunogenicity analysis endpoints include:
•
Antigen-specific response rates at 30 days PD3 for all antigens included in Vaxelis™
when administered concomitantly with V114 or Prevenar 13™(Table 5)
•
Anti-PnPs serotype-specific IgG response rates (proportion of participants with IgG 
≥0.35 µg/mL) and IgG GMCs at 30 days PD2
•
Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PD3
The exploratory immunogenicity analysis endpoints include:
•
Anti-PnPs serotype-specific IgG GMCs for the 15 serotypes contained in V114 Predose 3
•
Antigen-specific response rates for all antigens included in Vaxelis™ at 30 days PD2 of 
V114 or Prevenar 13™
•
Anti-PnPs serotype-specific OPA GMTs and response rates at 30 days PD2 and 
Predose 3
Detailed immunogenicity endpoints for concomitant vaccines are listed in Table 5.
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Table 5
Summary of Endpoints for Concomitant Vaccine Antigens
Vaccine
Antigen
Endpoint
Time Point†
Vaxelis™
Diphtheria toxoid
%  ≥0.1 IU/mL
PD3
Tetanus toxoid
% ≥0.1 IU/mL
PD3
Pertussis – PT
% ≥5 EU/mL
PD3
Pertussis – FHA
% ≥5 EU/mL
PD3
Pertussis – FIM 2/3
% ≥20 EU/mL
PD3
Pertussis – PRN
% ≥5 EU/mL
PD3
Hib-PRP
% ≥0.15 µg/mL
PD3
HBsAg
% ≥10 mIU/mL
PD3
Poliovirus 1 
% with Nab ≥1:8 dilution
PD3
Poliovirus 2
% with Nab ≥1:8 dilution
PD3
Poliovirus 3
% with Nab ≥1:8 dilution
PD3
EU = endotoxin unit; FHA = filamentous hemagglutinin; FIM 2/3 = fimbriae types 2 and 3; HBsAg = hepatitis B surface 
antigen; IU = international unit; Nab = neutralizing antibodies; PD = postdose; PRN = pertactin; PRP = polyribosylribitol 
phosphate; PT = pertussis toxin.
† Same endpoints will be evaluated at PD2 as exploratory analyses. 
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements following any vaccination with V114 or 
Prevenar 13™.
The safety analysis endpoints include:
•
Proportion of participants with solicited injection-site AEs (swelling, redness/erythema, 
tenderness/pain, and hard lump/induration) from Day 1 through Day 14 following any 
vaccination with V114 or Prevenar 13™
•
Proportion of participants with solicited systemic AEs (irritability, 
drowsiness/somnolence, hives or welts/urticaria, and appetite loss/decreased appetite) 
from Day 1 through Day 14 following any vaccination with V114 or Prevenar 13™
•
Proportions of participants with the broad AE categories consisting of any AE and a 
vaccine-related AE from Day 1 through Day 14 following any vaccination with V114 or 
Prevenar 13™
•
Proportions of participants with an SAE, a vaccine-related SAE, and discontinuation due 
to an AE, and death from Day 1 through 6 months following the vaccination 3 with V114 
or Prevenar 13™
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•
Participants body temperature measured Day 1 (day of vaccination) through Day 7 
following any vaccination with V114 or Prevenar 13™
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoint(s). Potential deviations that may result in the exclusion of a participant from the 
PP population for all immunogenicity analyses include:
•
Failure to receive infant series vaccination (V114 or Prevenar 13™Doses 1 and 2) as per 
randomization schedule
•
Receipt of prohibited medication or prohibited vaccine prior to the first study vaccination
Additional potential deviations that may result in the exclusion from the PP population 
immunogenicity analyses at a particular time point include:
•
Failure to receive Dose 3 of V114 or Prevenar 13™according to the vaccination 
schedule required at the time point for the analysis 
•
Failure to receive Vaxelis™ according to the vaccination schedule required at the time
point for the analysis
•
Failure to receive the scheduled doses of V114 or Prevenar 13™ (at least 28 days 
between Doses 1 and 2 [5 months of age to 1 day prior to 6 months of age (+14 days)]
[for PD2 and Predose 3 analysis], 12 months to 1 day prior to 13 months of age [+14 
days] for Dose 3 [for PD3 analyses])
•
Receipt of prohibited medication or prohibited vaccine prior to a blood sample collection
•
Collection of blood sample at the time point for the analysis outside of the pre-specified 
window (as described in Section 1.3)
The final determination on protocol deviations, and thereby the composition of the 
PP population, will be made 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 FAS population will also be performed for the primary 
immunogenicity endpoints and the secondary endpoints for the evaluation of concomitant 
vaccines. The FAS population consists of all randomized participants who received all study 
vaccinations required at the time point for the analysis and have 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.
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9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study vaccination. Participants will be included 
in the group corresponding to the study vaccination they actually received for the analysis of 
safety data using the APaT population. This will be the group to which they are randomized 
except for participants who take incorrect study vaccination; such participants will be 
included in the vaccination group corresponding to the study vaccination actually received.
Safety parameters for cross-treated participants (ie, those who received vaccinations of both
V114 and Prevenar 13™) will be summarized separately.
At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analysis 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. Unless otherwise stated, all statistical tests will 
be conducted at the α=0.05 (2-sided) level. Section 9.6.3 describes how demographic and 
baseline characteristics will be summarized.
9.6.1
Statistical Methods for Immunogenicity
This section describes the statistical methods that address the primary, secondary, and 
exploratory immunogenicity objectives.
Primary Endpoint
Primary Endpoints/Hypotheses (H1 and H2)
The primary endpoint, anti-PnPs serotype-specific IgG responses at or above the threshold 
value of 0.35 μg/mL for 13 shared serotypes contained in V114 and Prevenar 13™ at 30 days 
PD3 will be assessed via the following non-inferiority hypotheses:
H0: p1-p2 ≤-0.1 versus
H1: p1-p2 >-0.1,
and for the 2 unique serotypes contained in V114, the primary endpoint, anti--PnPs IgG 
responses will be assessed via the following superiority hypotheses:
H0: p1-p2 ≤0.1 versus
H1: p1-p2 >0.1,
where p1 is the response rate for the V114 group and p2 is the response rate for the 
Prevenar 13™ group. V114 is non-inferior to Prevenar 13TM if the lower bound of the 
2-sided 95% CI for the between-treatment differences (V114 minus Prevenar 13™) is greater 
than -0.1 for the 13 shared serotypes, and superior to Prevenar 13TM if the lower bound of the 
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2-sided 95% CI for the between-treatment differences (V114 minus Prevenar 13™) is greater 
than 0.1 for the 2 unique serotypes contained in V114. The Miettinen and Nurminen (M&N) 
method (1985), an unconditional, asymptotic method, will be used for this analysis 
[Miettinen, O. and Nurminen, M. 1985].
Primary Endpoints/Hypotheses (H3 and H4)
The primary endpoint, anti-PnPs serotype-specific IgG GMCs for 13 shared serotypes 
contained in V114 and Prevenar 13™ at 30 days PD3 will be assessed via the following 
non-inferiority hypotheses:
H0: GMC1/GMC2 ≤0.5 versus
H1: GMC1/GMC2 >0.5,
and for the 2 unique serotypes contained in V114, the primary endpoint, anti--PnPs IgG 
GMCs will be assessed via the following superiority hypotheses:
H0: GMC1/GMC2 ≤2.0 versus
H1: GMC1/GMC2 >2.0
where GMC1 is the anti-PnPs serotype-specific IgG GMCs for V114 group and GMC2 is the 
anti-PnPs serotype-specific IgG GMCs for the Prevenar 13™. For the 13 shared serotypes, 
V114 is non-inferior to Prevenar 13™ if the lower bound of the 2-sided 95% CI for the GMC 
ratios (V114/Prevenar 13™) is greater than 0.5; for the 2 unique serotypes, V114 is superior 
to Prevenar 13™ if the lower bound of the 2-sided 95% CI for the GMC ratios 
(V114/Prevenar 13™) is greater than 2.0. Estimation of the IgG GMC ratios and computation 
of the corresponding 95% CIs will be calculated using t--distribution with the variance 
estimate from a linear model utilizing the log-transformed antibody concentrations as the 
response and a single term for vaccination group.
Secondary Endpoints
Secondary Endpoint/Hypothesis (H5)
For this hypothesis (H5), the antigen-specific response rates for participants administered 
V114 concomitantly with Vaxelis™ will be compared with participants administered 
Prevenar 13™concomitantly with Vaxelis™ at 30 days PD3 via the following 
non-inferiority hypotheses:
H0: p1-p2 ≤δ versus
H1: p1-p2 >δ
where p1 is the response rate for the V114 group, p2 is the response rate for the 
Prevenar 13™group, and δ is the prespecified non-inferiority margin and the values of δ are 
listed in Table 8. Vaxelis™ administered concomitantly with V114 is non-inferior to 
Vaxelis™ administered concomitantly with Prevenar 13TM if the lower bound of the 2-sided 
95% CI for the between-treatment difference between V114 vs Prevenar 13™greater than δ. 
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The M&N method (1985) will be used for this analysis.
Other Secondary Endpoints/Exploratory Endpoints
Other secondary/exploratory objectives include the evaluation of anti--PnPs serotype-
-specific IgG GMCs at 30 days PD2 and Predose 3, anti-PnPs serotype-specific IgG response 
rates at 30 days PD2, and anti--PnPs serotype-specific OPA GMTs and response rates at 
30 days PD2, Predose 3, and 30 days PD3. The evaluations of these objectives will be 
performed within each vaccination group separately. Descriptive statistics with point 
estimates and within--group 95% CIs will be provided. For the continuous endpoints, the 
point estimates will be calculated by exponentiating the estimates of the mean of the natural 
log values and the within--group CIs will be derived by exponentiating the bounds of CIs of 
the mean of the natural log values based on the 1-sample t-distribution. For the dichotomous 
endpoints, the within--group CIs will be calculated based on the exact method proposed by 
Clopper and Pearson [CLOPPER, C. J. and PEARSON, E. S. 1934].
Reverse Cumulative Distribution Curves for IgG concentrations at 30 days PD3 will be 
graphically displayed by serotype.
A detailed analysis strategy for immunogenicity endpoints is listed in Table 6.
Table 6
Analysis Strategy for Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Primary Endpoint (H1 – H2)
Anti-PnPs serotype-specific IgG 
response rates at 30 days PD3
P
Miettinen and 
Nurminen
(estimate, 95% CI, p-
-value)
PP
Missing data 
will not be 
imputed
S
FAS
Primary Endpoint (H3 – H4)
Anti-PnPs serotype-specific IgG 
GMCs at 30 days PD3
P
t-distribution with the 
variance estimate from 
a linear model‡
(estimate, 95% CI, p-
-value)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoint (H5)
Antigen-specific response rates for all 
antigens included in Vaxelis™at 
30 days PD3 of V114 or 
Prevenar 13™
P
Miettinen and 
Nurminen
(estimate, 95% CI, p-
-value)
PP
Missing data 
will not be 
imputed
S
FAS
S
FAS
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Other Secondary Endpoints
Anti-PnPs serotype-specific IgG
response rates and GMCs for the 15 
serotypes contained in V114 at 30 
days PD2
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
Anti-PnPs serotype-specific OPA 
GMTs and response rates at 30 days 
PD3 
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
CI = confidence interval; FAS = Full Analysis Set; GMC = geometric mean concentration; GMT = geometric mean titer; 
H = hypothesis; IgG = Immunoglobulin G; OPA = opsonophagocytic activity; PD = postdose; PnPs = pneumococcal 
polysaccharide; PP = Per-Protocol.
†
P = Primary approach; S = Supportive approach.
‡
Estimation of the IgG GMC ratios and computation of the corresponding 95% CIs will be calculated using 
t-distribution with the variance estimate from a linear model utilizing the log-transformed antibody titers as the 
response and a single term for vaccination group. 
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. Additional summaries on key safety 
parameters will also be provided following each vaccination.
The analysis of safety results will follow a tiered approach (Table 7). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either pre-specified as “Tier 1” endpoints, or will be classified 
as belonging to “Tier 2” or “Tier 3” based on the number of events observed. 
Tier 1 Events
Safety parameters or AEs of special interest that are identified constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance with p-values 
and 95% CIs to be provided for between-treatment differences in the proportion of 
participants with events; these analyses will be performed using the Miettinen and Nurminen 
(M&N) method (1985), an unconditional, asymptotic method. However, these p-values and 
CIs should be regarded as helpful descriptive measures to be used in review, not formal 
methods for assessing the statistical significance of the between-treatment differences in 
AEs. For this protocol, solicited injection-site AEs (redness/erythema, swelling, hard 
lump/induration, and tenderness/pain) from Day 1 through Day 14 postvaccination and 
solicited systemic AEs (irritability, drowsiness, hives or welts, and appetite loss) from Day 1 
through Day 14 postvaccination are considered Tier 1 events.
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the M&N method [1985]) [Miettinen, 
O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 4 participants in any treatment group show the 
event. The threshold of at least 4 events was chosen because the 95% confidence interval for 
the between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% CIs for Tier 2 events 
may be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in AEs.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a vaccine-
related AE, an SAE, a vaccine-related SAE, discontinuation due to an AE, and death will be 
considered Tier 2 endpoints. The proportion of participants with maximum temperature 
measurements meeting the Brighton Collaboration cut points (Days 1 to 7) will also be 
considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Between-
Group 
Comparison
Descriptive
Statistics
Tier 1
Injection-site redness/erythema (Days 1 to 14)
X
X
X
Injection-site swelling (Days 1 to 14)
X
X
X
Injection-site tenderness/pain (Days 1 to 14)
X
X
X
Injection-site hard lump/induration (Days 1 to 14)
X
X
X
Irritability (Days 1 to 14)
X
X
X
Drowsiness/somnolence (Days 1 to 14)
X
X
X
Hives or welts/urticaria (Days 1 to 14)
X
X
X
Appetite loss/decreased appetite (Days 1 to 14)
X
X
X
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Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Between-
Group 
Comparison
Descriptive
Statistics
Tier 2
Any AE†
X
X
Any Vaccine-Related AE†
X
X
Any SAE†
X
X
Any Vaccine-Related SAE†
X
X
Discontinuation due to AE†
X
X
Death†
X
X
Maximum temperature measurements meeting the 
Brighton Collaboration cut points (Days 1 to 7) 
X
X
Specific AEs by SOC and PT‡ (incidence ≥4
participants in one of the vaccination groups)
X
X
Tier 3
Specific AEs by SOC and PT‡ (incidence <4
participants in all of the vaccination groups)
X
AE = adverse event; CI = confidence interval; PT = preferred term; SAE = serious adverse event; SOC = system organ 
class; X = results will be provided
†
These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least one AE.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
9.6.3
Summaries of Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed using summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (eg, age, race, gender, birth weight, and gestational age), 
baseline characteristics, and prior and concomitant vaccinations and therapies will be 
summarized by vaccination group either by descriptive statistics or categorical tables. 
9.7
Interim Analyses
A periodic review of safety and tolerability data across the V114 Phase 3 pediatric program 
will be conducted by an independent, unblinded, external DMC. A description of the 
structure and function of the DMC, along with the timing and content of the safety review 
will be outlined in the DMC charter. Information regarding the composition of the DMC is 
provided in Appendix 1. There are no plans to conduct an interim analysis of unblinded 
immunogenicity data in this study. However, unblinded immunogenicity data will be made 
available to the DMC upon request to enable a benefit-risk assessment.
The DMC will serve as the primary reviewer of the results of ongoing safety reviews and will 
make recommendations for discontinuation of the study or protocol modifications to an 
executive committee of the Sponsor (see Appendix 1 for details on the Committees Structure 
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for this study). If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, this Executive Oversight Committee (EOC) of the Sponsor (and 
potentially other limited Sponsor personnel) may be unblinded to results at the intervention 
level to act on these recommendations. The extent to which individuals are unblinded with 
respect to ongoing safety reviews will be documented by the external unblinded statistician. 
Additional logistical details will be provided in the DMC charter.
Study enrollment is likely to be ongoing at the time of external DMC review. Blinding to 
intervention assignment will be maintained at all investigational sites. Participant--level 
unblinding will be restricted to an external unblinded statistician performing ongoing safety 
reviews. Intervention-level ongoing safety reviews will be provided by the external 
unblinded statistician to the DMC. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
safety reviews.
9.8
Multiplicity
The study will be considered to have met its primary immunogenicity objective if 
non-inferiority is demonstrated with respect to IgG GMCs and response rates for the 
13 shared serotypes and superiority is demonstrated respect to IgG GMCs and response rates
for the 2 unique serotypes at 30 days PD3. All hypotheses will be tested individually for each 
serotype at a 1-sided 0.025 alpha level. This approach controls the 1-sided type--I error rate 
at 0.025, thus no multiplicity adjustment is required. The study will be considered to have 
met its secondary objective for a specific concomitant vaccine if non-inferiority is 
demonstrated for all the antigens included in that concomitant vaccine.
No multiplicity adjustments will be made for the safety comparisons. 
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
The study will randomize participants in a 1:1 ratio to the 2 vaccination groups. The overall 
sample size will be approximately 1180 with 590 participants into each vaccination group. 
The sample size was chosen to ensure sufficient power for the multiple endpoints across both 
primary and secondary hypotheses. It is assumed that approximately 472 participants per 
vaccination group will be evaluable for PP immunogenicity analyses at 30 days PD2 (based 
on an 80% evaluability rate), and approximately 443 participants per vaccination group will 
be evaluable for PP immunogenicity analyses at 30 days PD3 (based on a 75% evaluability 
rate).
With this study sample size and the assumptions listed below, the overall power for the 
primary hypotheses is >95% for demonstrating non-inferiority of V114 to Prevenar 13™ for 
the 13 shared serotypes and superiority for the 2 unique serotypes for V114 formulations. 
The overall power for the secondary hypotheses for concomitant antigens evaluation is 
~90%. The power for individual hypothesis components is provided below.
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For the primary immunogenicity endpoint/hypothesis (H1), the study has >95% power at 
a 1--sided 2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days 
PD3 for anti-PnPs serotype-specific IgG responses at or above the threshold value of 
0.35 μg/mL for the 13 shared serotypes between V114 and Prevenar 13™ based on the 
following assumptions: (1) an approximately 75% evaluability rate at PD3 as observed in 
previous Phase 2 V114 pediatric studies; (2) a non-inferiority margin of --0.1 for the 
difference (V114-Prevenar 13™); and (3) underlying serotype-specific IgG response rates 
(proportion of participants meeting serotype-specific IgG threshold value of ≥0.35 μg/mL at 
30 days PD3 of V114 or Prevenar 13™) are 95% at 30 days PD3.
For the primary immunogenicity endpoint/hypothesis (H2), the study has >95% power at 
a 1--sided 2.5% alpha level to demonstrate V114 is superior to Prevenar 13™at 30 days PD3
for anti-PnPs serotype-specific IgG responses at or above the threshold value of 0.35 μg/mL 
for the 2 unique serotypes contained in V114 based on the following assumptions: (1) an 
approximately 75% evaluability rate at 30 days PD3 as observed in previous V114 pediatric 
Phase 2 studies; (2) a superiority margin of 0.1 for the difference (V114-Prevenar 13™); and
(3) underlying serotype-specific IgG response rates (proportion of participants meeting 
serotype-specific IgG threshold value of ≥0.35 μg/mL at 30 days PD3 of V114 or 
Prevenar 13™) are 95% in V114 group and 2% in Prevenar 13™ group at 30 days PD3.
For the primary immunogenicity endpoint/hypothesis (H3), the study has >95% power at 
a 1--sided 2.5% alpha level to demonstrate V114 is non-inferior to Prevenar 13™at 30 days 
PD3 for anti-PnPs serotype-specific IgG GMCs at 30 days PD3 based on the following 
assumptions: (1) an approximately 75% evaluability rate at 30 days PD3 as observed in 
previous V114 pediatric Phase 2 studies; (2) a non-inferiority margin of 
0.5 (V114/Prevenar 13™); (3) SD of anti-PnPs serotype-specific IgG GMCs in log scale is 
1.1 as those observed in previous MSD studies, and (4) the true GMC ratio 
(V114/Prevenar 13™) for anti--PnPs serotype-specific IgG GMCs is 1.0.
For the primary immunogenicity endpoint/hypothesis (H4), the study has >95% power at 
a 1-sided 2.5% alpha level to demonstrate V114 is superiority to Prevenar 13™at 30 days 
PD3 for anti-PnPs serotype-specific IgG GMCs for the 2 unique serotypes contained in V114 
based on the following assumptions: (1) an approximately 75% evaluability rate at PD3 as 
observed in previous Phase 2 V114 pediatric studies; (2) a superiority margin of 
2.0 (V114/Prevenar 13™); and (3) SD of anti-PnPs serotype-specific IgG GMCs in log scale 
is 1.1 as those observed in previous MSD studies, and (4) the true GMC ratio 
(V114/Prevenar 13™) for anti-PnPs serotype-specific IgG GMCs is 10.0.
The study is considered to have met its primary objective if V114 is non-inferior to 
Prevenar 13™ for the 13 shared serotypes and superior to Prevenar 13™ for the 2 unique 
serotypes contained in V114.
For the secondary immunogenicity endpoint/hypothesis (H5), the power is ~90.9% the 
non-inferiority hypotheses when Vaxelis™administered concomitantly with V114 or 
Prevenar 13™, respectively. This is based on the assumptions of approximately 75% 
evaluability rate at PD3 for Vaxelis™. The assumed response rates, GMT, and 
non-inferiority margins are listed in Table 8.
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Table 8
Summary of Endpoints and Power for Concomitant Vaccine Antigens
Antigen
Endpoint
Time 
point
Assumed 
Response 
Rate or 
Standard 
Deviation
NI 
Margin
Power
Vaxelis™
Diphtheria 
toxoid
% ≥0.1 IU/mL
PD3
95%
-10%
90.9%
Tetanus toxoid
% ≥0.1 IU/mL
PD3
97%
-5%
Pertussis – PT
% ≥5 EU/mL
PD3
90%
-10%
Pertussis – FHA
% ≥5 EU/mL
PD3
90%
-10%
Pertussis – FIM
2/3
% ≥20 EU/mL
PD3
90%
-10%
Pertussis – PRN
% ≥5 EU/mL
PD3
90%
-10%
Hib-PRP
% ≥0.15 µg/mL
PD3
90%
-10%
HBsAg
% ≥10 mIU/mL
PD3
95%
-10%
Poliovirus 1 
% with Nab ≥1:8 
dilution
PD3
97%
-5%
Poliovirus 2
% with Nab ≥1:8 
dilution
PD3
97%
-5%
Poliovirus 3
% with Nab ≥1:8 
dilution
PD3
97%
-5%
EU = endotoxin unit; FHA = filamentous hemagglutinin; FIM 2/3 = fimbriae types 2 and 3; HBsAg = hepatitis B surface 
antigen; Hib= Haemophilus influenzae type b; IU = international unit; Nab = neutralizing antibodies; 
NI = non-inferiority; PD = postdose; PRN = pertactin; PRP = polyribosylribitol phosphate; PT = pertussis toxin; 
SD = standard deviation (in log scale).
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with an SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least one SAE among 
590 participants in each of the V114 group and Prevenar 13™group if the underlying 
incidence of an SAE is 0.27% (1 of every 368 participants receiving the vaccine). There is a 
50% chance of observing at least one SAE among 590 participants in each of the V114 group 
and Prevenar 13™group if the underlying incidence of an SAE is 0.12% (1 of every 
861 participants receiving the vaccine). If no SAEs are observed among 590 participants in 
each of the V114 group and Prevenar 13™group, this study will provide 97.5% confidence 
that the underlying percentage of participants with an SAE is <0.62% (1 in every 
160 participants).
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Table 9 summarizes the percentage point differences between the 2 vaccination groups that 
could be detected with 80% probability for a variety of hypothetical underlying incidences of 
an adverse event. These calculations assume 590 participants in each group and are based on 
a 2-sided 5% alpha level. The calculations are based on an asymptotic method proposed by 
Farrington and Manning (1990) [Farrington, C. P. 1990]; no multiplicity adjustments were 
made.
Table 9
Differences in Incidence of Adverse Event Rates Between the 2 Vaccination 
Groups That Can be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level 
With 590 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
V114 (%)
N=590
Prevenar 13™ (%)
N=590
Percentage Points
1.6
0.1
1.5
5.0
2
3.0
9.2
5
4.2
15.4
10
5.4
21.3
15
6.3
26.9
20
6.9
37.7
30
7.7
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, C. P. 1990].
9.10
Subgroup Analyses
Subgroup analyses based on sex (female vs male) and race will be performed for primary 
immunogenicity endpoint and selected safety endpoints (summary of AEs). Details of 
subgroup analyses will be documented in the supplemental Statistical Analysis Plan. 
9.11
Compliance (Medication Adherence)
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 Prevenar 13™, and Vaxelis™at each vaccination 
schedule.
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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 (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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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 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 GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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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
Not applicable.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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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 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

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.

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.

Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.

Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies, extremely distressed or unable to do usual activities).
•
Injection site redness, swelling, or hard lump from the day of vaccination through Day 14 
postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
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-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
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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 AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
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•
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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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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 
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 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific request from Swedish Health Authority
10.7.1.1
Benefit/Risk Assessment
Prior to the evaluation of V114 in humans, preclinical animal studies were conducted in rats, 
mice, rabbits, and non-human primates, and study results showed that the vaccine was 
immunogenic and displayed an acceptable safety profile. V114 contains similar components 
as the licensed vaccines Prevenar™ and Prevenar 13™ which comprise a subset of 
respectively 7 and 13 of the 15 PnPs conjugated to the CRM197 carrier protein found in V114, 
as well as Aluminum Phosphate Adjuvant (APA). The safety profiles for Prevenar™ and 
Prevenar 13™ can be found in the respective product labeling. Two different formulations of 
V114 were studied in 8 Phase 1 and Phase 2 clinical studies involving 4140 subjects 
comprising of 2960 children (90 toddlers, 12 to 18 months of age and 2870 infants, 6 to 
12 weeks of age) who received a 4-dose regimen of study vaccine given at 2, 4, 6, and 12 to 
15 months of age and 1810 adults (180 young adults 18 to 49 years of age and 1630 adults 
≥50 years of age) who received a single dose of the study vaccine. A total of 2685 subjects 
(1950 children and 735 adults) received at least 1 dose of V114. 
Both nonadjuvanted V114 and APA-adjuvanted V114 were evaluated in early Phase 1 
(single dose in toddlers and young adults 18-49 years of age) and Phase 2 (4-dose regimen in 
infants) clinical studies. The 2 vaccines displayed acceptable safety profiles comparable to 
Prevenar™ and Prevenar 13™. In 1 adult Phase 2 clinical study comparing the safety and 
immunogenicity of V114 to Prevenar 13™ and PNEUMOVAX™23, the safety profile of 
V114 was also shown to be comparable to PNEUMOVAX™23. Following vaccination with 
V114, the most frequently reported AEs were those solicited in the clinical study and 
included injection-site pain/tenderness (72% in infants and 60% in adults), redness (59% in 
infants and 14% in adults), and swelling (49% in infants and 20% in adults). Most frequently 
reported systemic AEs were those solicited in the studies; muscle pain (29%), fatigue (25%), 
headache (17%), and joint pain (17%) were commonly reported among adults while 
irritability (86%), drowsiness (72%), decreased appetite (57%) were commonly reported in 
infants following any vaccination. Vaccine-induced immune responses were directed to all 
15 serotypes included in V114 and recipients of the adjuvanted V114 vaccine generally
tended to exhibit higher serotype-specific IgG GMCs and OPA GMTs for the majority of the 
serotypes included in V114, justifying the inclusion of APA in the vaccine formulation to
provide optimal antibody responses. Although the antibody responses measured in adults 
vaccinated with V114 were comparable to those measured in recipients of Prevenar 13™for 
most shared serotypes, antibody responses measured in infants vaccinated with V114 were 
generally lower than those vaccinated with Prevenar 13™ for some shared serotypes at 1 
month PD3. The results from study V114-003 indicated a need for formulation optimization 
of the candidate vaccine, particularly the need for determining the optimal amount of 
polysaccharide for each serotype and optimal concentration of aluminum adjuvant needed in 
V114 to elicit optimal serotype-specific IgG and OPA responses in infants.
The Sponsor conducted additional clinical studies to optimize the vaccine formulation and 
assess its tolerability, safety, and immunogenicity profiles. As part of the formulation 
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optimization, 2 formulations of V114 (Formulation A and Formulation B) were tested 
clinically in several Phase 1/2 clinical studies involving a small number (20 to 50 subjects per
arm) of young adults (18 to 49 years of age) and infants (V114-004 and V114-005), as well 
as larger number (125 to 230 subjects per arm) of pneumococcal vaccine-naïve adults 
50 years of age and older (V114-006) and adults 65 years of age or older with prior history 
(at least 1 year prior to study entry) of vaccination with PNEUMOVAX™23 (V114-007). 
Both V114 formulations displayed an acceptable safety profile and induced comparable 
levels of antibodies to Prevenar 13™ for the shared serotypes. V114 also induced higher 
antibodies to serotypes 22F and 33F, which are not included in Prevenar 13™ and have 
emerged recently as important causes of pneumococcal disease in both children and adults.
Results from these studies identified a formulation (Formulation B) with improved clinical 
performance in both infants and older adults. A pediatric Phase 2 study (V114-008) involving 
1050 infants (350 per arm) is ongoing to confirm the performance of Formulation B observed 
in V114-005. Following vaccination with V114 Formulation B, the most frequently reported 
AEs were those solicited in the clinical study and included injection-site pain/tenderness 
(64% in infants and 60% in adults), redness (38% in infants and 11% in adults), and swelling 
(20% in infants and 16% in adults). Most frequently reported systemic AEs were those 
solicited in the studies; muscle pain (18%), fatigue (17%), headache (12%), and joint pain 
(7%) were commonly reported among adults, while irritability (82%), drowsiness (60%), 
decreased appetite (32%) were commonly reported in infants following any vaccination.
Previous studies comparing the safety and immunogenicity of the investigational V114 to 
Prevenar 13™and/or PNEUMOVAX™23 did not show a difference in the frequency and 
severity of AEs reported following vaccination [Ermlich, S. J., et al 2018]. The comparable 
safety and immunogenicity profiles of V114 to Prevenar 13™ and PNEUMOVAX™23 in 
previous clinical studies involving healthy children and adults indicate that V114 will likely 
display comparable safety and immunogenicity profiles to these licensed in the current study. 
Although V114 induces antibody responses to 2 more serotypes (22F and 33F) than 
Prevenar 13™, it cannot be guaranteed that participants in V114 clinical studies will directly 
benefit from intervention during participation, as clinical studies are designed to provide 
information about the safety and effectiveness of an investigational vaccine.
In conclusion, the investigational V114 vaccine has comparable safety and immunogenicity 
profiles to Prevenar 13™ and PNEUMOVAX™23, 2 licensed pneumococcal vaccines that 
were clinically evaluated in a number of clinical studies and currently recommended for the 
prevention against pneumococcal disease. The satisfactory clinical performance and general 
tolerability of V114 in healthy children and adults to date supports the clinical evaluation of 
the investigational vaccine in the current study. Given the accepted benefit of vaccinating 
with Prevenar 13™ and PNEUMOVAX™23 by professional societies and national 
immunization institutions/agencies, the benefit/risk for vaccinating with V114 in the current 
study is favorable. The safety profile of the investigational V114 vaccine is closely 
monitored on a continuing basis by an external DMC.
06G9V5
07X5BR


PRODUCT:  V114  
107
PROTOCOL/AMENDMENT NO.:  026-03  
V114-026-03 FINAL PROTOCOL
14-SEP-2021
10.7.1.2
Ethics Committee Review [Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)]
The following statement will replace the Participant Protection Section III, Part A of 
Appendix 1, Code of Conduct for Clinical Trials:
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents must be submitted to and approved by the applicable Competent Authority and 
IRB/IEC before the study is initiated in accordance with EU Directive 2001/20/EC, Article 
10 (a) and/or local requirements.
Any amendments to the protocol will require IRB/IEC and Competent Authority approval 
before implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants [2001/20/EC, Article 10 (b)].
10.7.1.3
Informed Consent
According to Swedish law, Medical Products law (2015:315) 7 chapter 3 §, informed consent 
for minors should be obtained from both legally acceptable representatives or guardians 
(when there are 2 guardians).
06G9V5
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PRODUCT: V114  
108
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
10.7.2
Country-specific information for Norway and Denmark
10.7.2.1
Study Design
The study design for study sites in Norway and Denmark is shown in Figure 2.
Figure 2
V114-026-02 Study Design (For Sites in Norway and Denmark Only)
06G9V5
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PRODUCT: V114  
109
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
10.7.2.2
Schedule of Activities (For Sites in Norway and Denmark Only)
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Administrative and General Procedures
Screening Procedures
Informed Consent/Assent
X
Consent must be obtained 
before any study 
procedures.
Informed Consent/Assent for 
Future Biomedical Research
X
Participation in future 
biomedical research is 
optional and consent must 
be obtained before 
collection of buccal swab 
DNA samples.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Review of prior 
medications/vaccinations, a 
complete physical 
examination, and 
temperature measurement 
are required at Visit 1 to 
determine eligibility.
Medical History 
X
06G9V5
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PRODUCT: V114  
110
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Post-Randomization Procedures
Assignment of Randomization 
Number
X
Prior/Concomitant Medication 
and Nonstudy Vaccination 
Review
X
X
X
X
X
X
X
X
V114 or Prevenar 13™b
Administration (Blinded)
X
X
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given (see Section 8.1.8). 
06G9V5
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PRODUCT: V114  
111
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Concomitant Vaccine 
Administration (Open-label)b
Vaxelis™ 
X
X
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given. (see Section 8.1.8). 
See Section 6.5 for details 
on concomitant vaccines.
Vaxelis™ should be given 
after V114 or Prevenar 
13™.
06G9V5
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PRODUCT: V114  
112
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Concomitant Vaccine 
Administration (Open-label)b
M-M-R™II
X
Before vaccine 
administration, the 
investigator (or designee) 
must review medical 
history to ensure the 
participant has no new 
contraindication to the 
vaccine(s) scheduled to be 
given (see Section 8.1.8). 
M-M-R™II and 
VARIVAX™ should be 
given after V114 or 
Prevenar 13™ (see 
Section 6.5). The second 
dose of VARIVAX™ at 
Visit 5 should be given 
after the blood draw.
Concomitant Vaccine 
Administration (Open-label)b
VARIVAX™
X
X
06G9V5
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PRODUCT: V114  
113
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Provide eVRC
X
An eVRC will be provided 
at Visit 1 to record AEs, 
body temperature, 
concomitant medications, 
and nonstudy vaccinations. 
Instructions for using the 
eVRC will be reviewed 
with the participant’s 
legally acceptable 
representative.
Review eVRC data with 
participant’s legally acceptable 
representative
X
X
X
X
X
X
X
See Section 8.1.9 for 
details.
Collect eVRC from participant’s 
legally acceptable representative
X
Complete the Telephone Contact 
Questionnaire 
X
See Section 8.1.11 for 
details.
Safety Procedures
Complete Physical Examination
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered
(see Section 8.3.1).
06G9V5
07X5BR


PRODUCT: V114  
114
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Targeted Physical Examination
X
X
X
To be performed by the 
investigator or medically 
qualified designee before 
vaccine is administered
(see Section 8.3.1).
Body Temperature Measurement
X
X
X
X
Each participant’s body 
temperature must be taken 
before vaccination (see 
Section 8.3.2 for method). 
Participants who have 
febrile illness at or within 
72 hours of vaccination
must be rescheduled.
30-minute Postvaccination 
Observation Period
X
X
X
To be performed by 
blinded study site 
personnel only.
AE Monitoring
X
X
X
X
X
X
X
X
X
Nonserious AEs are to be 
reported from Days 1 
through 14 following each 
vaccination with V114 or 
Prevenar 13™. SAEs and 
deaths are to be reported 
throughout the duration of 
an individual’s study 
participation.
06G9V5
07X5BR


PRODUCT: V114  
115
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Study Period
Intervention
Follow-
up
Visit Number
1 
TC
2
TC
3
4
TC
5
TC
Comments
Scheduled Time
Age: ~3
months 
(Dose 
1)
Day 15 
after 
Dose 1
Age: ~5
months
(Dose 2)
Day 15 
after 
Dose 2
~1 
month 
after 
Dose 2
Age: 
~12
months
(Dose 3)
Day 15 after 
Dose 3
At least 1
month after 
Dose 3
~6 
months 
after 
Dose 3
Months of age is calculated 
according to the 
participant’s birth date.
Visit Windowa
≥70
days of 
age to 
≤111
days of 
age
Day 15 to 
Day 19 
Postdose 1
5
months 
of age 
to 1 day 
prior to 
6
months 
of age
(+14 
days)
Day 15 
to Day 
19 
Postdose 
2
Day 28 
to Day 
60 
Postdose 
2
12 
months 
of age 
to 1 day 
prior to 
13
months 
of age
(+14 
days)
Day 15 to 
Day 19 
Postdose 3
Day 28 to 
Day 60 
Postdose 3
Day 166 
to 
Day 194 
Postdose 
3
Immunogenicity Procedures
Serum for Immunogenicity 
Assays (Including Retention 
Serum)
X
X
X
Blood samples must be 
collected before 
vaccination where 
applicable.
Future Biomedical Research
Collect Buccal Swabs for Future 
Biomedical Research
X
Buccal swab DNA samples 
for analysis should be 
obtained prior to 
vaccination at Visit 1, on 
randomized and FBR 
consented participants 
only, or at a later date as 
soon as the informed 
consent is obtained.
AE = adverse event; DNA = deoxyribonucleic acid; eVRC = electronic vaccination report card; FBR = Future Biomedical Research; SAE = serious adverse event; 
TC = telephone contact.
a
For calculating the visit windows, the day of vaccination is considered Day 1. To calculate visit windows for subsequent vaccinations, confirm participant date of birth and 
ensure the age of the participant will fall within the appropriate age range for each study visit.
b
Tradenames for licensed vaccines may vary depending on where clinical supplies are sourced by the Sponsor.
06G9V5
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PRODUCT: V114  
116
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
All Participants as Treated
CI
confidence interval
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CRF
case report form
CSR
clinical study report
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECi
enhanced chemiluminescence
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic case report form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EU
European Union
eVRC
electronic vaccination report card
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FHA
filamentous hemagglutinin
FIM 2/3
fimbriae types 2/3
GCP
Good Clinical Practice 
GMC
geometric mean concentration
GMT
geometric mean titer
H
hypothesis
HBsAg
hepatitis B surface antigen
Hib
Haemophilus influenzae type b
HIV
human immunodeficiency virus
HRP
horseradish peroxidase
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IPD
invasive pneumococcal disease
IRB
Institutional Review Board 
IRT
interactive response technology
M&N
Miettinen and Nurminen
MIT
micrometabolic inhibition test
MOPA
multiplexed opsonophagocytic activity
MSD
Merck Sharp & Dohme
OD
optical density
OPA
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PD
postdose
PnECL
pneumococcal electrochemiluminescence
PnPs
pneumococcal polysaccharide
06G9V5
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PRODUCT: V114  
117
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
Abbreviation
Expanded Term
PP
Per-Protocol
PRN
pertactin
PRP
polyribosylribitol phosphate
PT
pertussis toxin
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAGE
Strategic Advisory Group of Experts
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
US
United States
WHO
World Health Organization
06G9V5
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PRODUCT: V114  
118
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
11
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V114-026-03 FINAL PROTOCOL
14-SEP-2021
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14-SEP-2021
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PROTOCOL/AMENDMENT NO.: 026-03 
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[04MG9J]
06G9V5
07X5BR


PRODUCT: V114  
122
PROTOCOL/AMENDMENT NO.: 026-03 
V114-026-03 FINAL PROTOCOL
14-SEP-2021
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07X5BR