A Phase I-II, Randomized, Double-Blind, Study to Evaluate the Safety, Tolerability, and Immunogenicity of Different Formulations of V114 in Healthy Adults and Infants
Phase: PHASE1
Conditions: Pneumococcal Infections
Sponsor: Merck Sharp & Dohme LLC

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase I-II, Randomized, Double-Blind, Study to Evaluate the 
Safety, Tolerability, and Immunogenicity of Different Formulations 
of V114 in Healthy Adults and Infants 
 
NCT number: 
NCT02531373
Document Date: 
29-Oct-2015

Product:  V114 
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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., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase I-II, Randomized, Double-Blind, Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of Different Formulations of V114 in Healthy Adults and Infants
IND NUMBER:  14115
EudraCT NUMBER:  [Not Applicable]

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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 14
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Other Objectives (Exploratory Objectives )....................................................... 17
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Pre-clinical and Completed Clinical Trials......................................................... 18
4.1.2
Ongoing Clinical Trials....................................................................................... 19
4.1.3
Information on Other Trial-Related Therapy...................................................... 19
4.1.4
Rationale................................................................................................................ 19
4.2
Rationale for the Trial and Selected Subject Population .................................... 19
4.2.1
Rationale for Dose Selection/Regimen............................................................... 20
4.2.2
4.2.2.1
Rationale for The Use of Comparator.......................................................... 21
Rationale for Endpoints ...................................................................................... 22
4.2.3
4.2.3.1
Immunogenicity Endpoints.......................................................................... 22
4.2.3.2
Safety Endpoints .......................................................................................... 23
4.2.3.3
Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 26
4.3
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 27
5.1.1
Subject Inclusion Criteria.................................................................................... 27
5.1.2
Subject Exclusion Criteria .................................................................................. 29
5.1.3

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Trial Vaccination(s) .............................................................................................. 32
5.2
Dose Selection .................................................................................................... 33
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 33
Timing of Dose Administration .......................................................................... 33
5.2.2
Trial Blinding/Masking....................................................................................... 34
5.2.3
Randomization or Vaccine Allocation ................................................................ 34
5.3
Stratification.......................................................................................................... 34
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 35
5.5
Rescue Medications & Supportive Care............................................................. 36
5.6
Diet/Activity/Other Considerations..................................................................... 37
5.7
Subject Withdrawal/Discontinuation Criteria................................................... 37
5.8
Subject Replacement Strategy............................................................................. 37
5.9
Beginning and End of the Trial ........................................................................... 37
5.10
Clinical Criteria for Early Trial Termination ................................................... 38
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 39
7.0
TRIAL PROCEDURES ........................................................................................... 43
Trial Procedures ................................................................................................... 43
7.1
Administrative Procedures.................................................................................. 43
7.1.1
7.1.1.1
Informed Consent......................................................................................... 43
7.1.1.1.1
General Informed Consent.................................................................... 43
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 44
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 44
7.1.1.3
Subject Identification Card .......................................................................... 44
7.1.1.4
Medical History ........................................................................................... 44
7.1.1.5
Prior and Concomitant Medications Review ............................................... 44
7.1.1.5.1
Prior Medications.................................................................................. 44
7.1.1.5.2
Concomitant Medications..................................................................... 44
7.1.1.6
Assignment of Screening Number............................................................... 45
7.1.1.7
Assignment of Randomization Number....................................................... 45
7.1.1.8
Trial Compliance ......................................................................................... 45
7.1.1.8.1
Study Vaccination................................................................................. 45

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7.1.1.8.2
Concomitant Vaccinations.................................................................... 47
7.1.1.9
Dispense Electronic Vaccination Report Cards........................................... 48
Clinical Procedures/Assessments........................................................................ 48
7.1.2
7.1.2.1
Physical Examinations................................................................................. 48
7.1.2.2
Temperature Methods .................................................................................. 49
7.1.2.3
Assess Adverse Experiences........................................................................ 49
Laboratory Procedures/Assessments .................................................................. 50
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 50
7.1.3.2
Future Biomedical Research........................................................................ 52
Other Procedures................................................................................................. 52
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 52
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 52
7.1.4.2
Blinding/Unblinding .................................................................................... 53
7.1.4.3
Domiciling ................................................................................................... 53
7.1.4.4
Calibration of Critical Equipment................................................................ 54
Visit Requirements.............................................................................................. 54
7.1.5
7.1.5.1
Screening...................................................................................................... 54
7.1.5.2
Treatment Period/Vaccination Visit ............................................................ 54
7.1.5.3
Post-Trial...................................................................................................... 54
Assessing and Recording Adverse Events .......................................................... 54
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 55
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 56
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 56
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 56
7.2.3.2
Events of Clinical Interest............................................................................ 57
Evaluating Adverse Events ................................................................................. 58
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 61
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 61
7.3
Executive Oversight Committee ......................................................................... 61
7.3.1
Data Monitoring Committee ............................................................................... 61
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 62

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Statistical Analysis Plan Summary ..................................................................... 63
8.1
Responsibility for Analyses/In-House Blinding ................................................. 65
8.2
Hypotheses/Estimation ......................................................................................... 65
8.3
Analysis Endpoints ............................................................................................... 65
8.4
Immunogenicity Endpoints................................................................................. 66
8.4.1
Safety Endpoints ................................................................................................. 66
8.4.2
Analysis Populations............................................................................................. 66
8.5
Immunogenicity Analysis Populations ............................................................... 66
8.5.1
Safety Analysis Populations ............................................................................... 67
8.5.2
Statistical Methods................................................................................................ 67
8.6
Statistical Methods for Efficacy Analyses .......................................................... 67
8.6.1
Statistical Methods for Safety Analyses ............................................................. 69
8.6.2
Summaries of Demographic and Baseline Characteristics ................................. 71
8.6.3
Interim Analyses ................................................................................................... 71
8.7
Multiplicity ............................................................................................................ 73
8.8
Sample Size and Power Calculations .................................................................. 73
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 74
8.10
Extent of Exposure................................................................................................ 75
8.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 75
Investigational Product ........................................................................................ 75
9.1
Packaging and Labeling Information ................................................................. 75
9.2
Clinical Supplies Disclosure................................................................................. 75
9.3
Storage and Handling Requirements.................................................................. 76
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 76
9.5
Standard Policies................................................................................................... 76
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 76
Confidentiality....................................................................................................... 76
10.1
Confidentiality of Data ....................................................................................... 76
10.1.1
Confidentiality of Subject Records ..................................................................... 77
10.1.2
Confidentiality of Investigator Information........................................................ 77
10.1.3
Confidentiality of IRB/IEC Information............................................................. 78
10.1.4

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Compliance with Financial Disclosure Requirements....................................... 78
10.2
Compliance with Law, Audit and Debarment ................................................... 78
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 80
10.4
Quality Management System............................................................................... 80
10.5
Data Management................................................................................................. 81
10.6
Publications ........................................................................................................... 81
10.7
11.0
LIST OF REFERENCES......................................................................................... 83
12.0
APPENDICES........................................................................................................... 84
Merck Code of Conduct for Clinical Trials........................................................ 84
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 86
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 92
Approximate Blood Volumes Drawn by Trial Visit and by Sample Types... 103
12.4
List of Abbreviations .......................................................................................... 104
12.5
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
12.6
Enrolled in Preventative Vaccine Clinical Trials............................................. 106
13.0
SIGNATURES......................................................................................................... 107
Sponsor's Representative ................................................................................... 107
13.1
Investigator.......................................................................................................... 107
13.2

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LIST OF TABLES
Table 1
Trial Vaccination – Adult Cohort ......................................................................... 32
Table 2
Trial Vaccination – Infant Cohort......................................................................... 33
Table 3
Evaluating Adverse Events................................................................................... 59
Table 4
Analysis Strategy for Key Immunogenicity Variables......................................... 69
Table 5
Analysis Strategy for Infant Cohort Safety Parameters........................................ 71
Table 6
Summary of Interim Analysis Strategy................................................................. 72
Table 7
Power for Detecting a Lower Response for Varying Standard Deviation 
and True Differences with 45 Evaluable Subjects................................................ 74
Table 8
95% CIs for Varying Standard Deviation and GMC Values with 45 
Evaluable Subjects................................................................................................ 74
Table 9
Product Descriptions............................................................................................. 75

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LIST OF FIGURES
Figure 1
Trial Design of Stage 1 (Adults)......................................................................... 14
Figure 2
Trial Design of Stage 2 Parts I and II (Infants)................................................... 15

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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
6.0 
7.1.2.1
Trial Flow Chart
Physical Examinations
For the Infant Cohort, a full physical examination will 
be performed at Visit 1 and a targeted physical 
examination will be performed at all subsequent 
vaccination
visits (Visits 2, 3, and 5). Physical 
examinations at these time points in the infant cohort are 
no longer optional, per investigator’s discretion.
Revision
2.1
4.3
5.6
Trial Design
Benefit/Risk
Rescue 
Medications 
& 
Supportive Care
Include an additional criterion for rescue dose: 
pneumococcal IgG antibody, as measured by Pn ECL 
assay, below 0.35 μg/mL for serotype 19A. 
New Addition

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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.1.3
Ongoing 
Clinical 
Trials
Added V114-006 as an ongoing clinical trial.
New Addition
5.1.2
Subject 
Inclusion 
Criteria
Infant Cohort, Inclusion Criterion #1: removed “if 
warranted” as physical examination is mandatory at Visit 1.
Clarification
8.6.1
Statistical Methods for 
Efficacy Analyses
Added a sentence clarifying that RCDCs will be included in 
the CSR.
Clarification
9.1
Investigational 
Product
Removed text related to clinical supplies for replacement 
subjects and other supplies.
Clarification
Overall
Overall
Minor editorial edits have been made in various sections 
throughout the protocol.
Revisions

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1.0 TRIAL SUMMARY
Abbreviated Title
Safety/Immunogenicity of Different Formulations of V114
Sponsor Product Identifiers
V114
Trial Phase
I-II
Clinical Indication
Prevention of Pneumococcal Disease
Trial Type
Interventional
Type of control
Active Control
Route of administration
Intramuscular
Trial Blinding
Double-blind
Vaccination Groups
Vaccine groups for V114 recipients are represented as V114 medium or 
V114 high  as they respectively refer to the concentration of 
polysaccharide for each of the vaccine serotypes (1, 3, 4, 5, 6A, 6B, 7F, 
9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) and Merck Aluminum 
Phosphate Adjuvant (MAPA). 
V114 medium contains capsular 
polysaccharides at 2µg/dose for all serotypes except 6B at 4µg/dose 
formulated with MAPA at 125µg/dose. 
In comparison, V114 high 
contains twice the amount of polysaccharide for each serotype (4µg/dose 
for all serotypes except 6B at 8µg/dose) and MAPA (250µg/dose).  
The 
investigational 
15-valent 
pneumococcal 
conjugate 
vaccine
containing all 15 serotypes conjugated to the same carrier protein 
(CRM197) will be simply referred to as V114 while the investigational 
15-valent pneumococcal conjugate vaccine containing at least one 
serotype conjugated to an alternative carrier protein and the remaining 
serotypes conjugated to CRM197 will be referred to as V114 with an 
alternative carrier protein.
Stage 1 - Adult Cohort: 
Four (4) groups randomly assigned to receive a single dose of either 
V114 medium, V114 high, V114 medium with an alternative carrier 
protein, or V114 high with an alternative carrier protein.
Stage 2 - Infant Cohort: 
Five (5) groups randomly assigned to receive either V114 medium, V114 
high, V114 medium with an alternative carrier protein, V114 high with 
an alternative carrier protein, or Prevnar 13™ (control group). (See 
section 5.2 for a detailed description of the V114 formulation).
Number of trial subjects
Approximately 80 adult and 250 infant subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 21 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Stage 1 - Adult Cohort: Each subject will participate in the trial for 
approximately 30 days from the time the subject signs the Informed 
Consent Form (ICF) through the final contact.  Each subject will receive 
a single dose of the study vaccine on Day 1.  After vaccination, each 
subject will be followed for 14 days for adverse experiences (AEs).
Serious AEs (SAEs) will be collected from the time the consent is signed 
through completion of the subject’s participation in the study (i.e., 30 
days postvaccination). 
Blood samples will be collected prior to 
vaccination and 30 days postvaccination. 

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Stage 2 - Infant Cohort: Each subject will participate in the trial for 
approximately 11 to 14 months from the time the parent/legal guardian
signs the ICF through the final contact.  Each subject will receive 4 doses 
of the study vaccine given at 2, 4, 6, and 12 to 15 months of age.  After 
each vaccination, the study subject will be followed for 14 days for AEs. 
SAEs will be collected from the time the consent form is signed through 
30 days postdose 4 (PD4) and/or completion of the subject’s 
participation in the study. Blood samples will be collected 30 days 
following the 3rd dose, immediately prior to the 4th dose, and 30 days 
following the 4th dose.
Randomization Ratio
Stage 1 (adult cohort): 1:1:1:1
Stage 2 (infant cohort): 1:1:1:1:1
A list of abbreviations used in this document can be found in Section 12.5.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multicenter, randomized, double-blind (with in-house blinding procedures) study  to 
evaluate the safety, tolerability, and immunogenicity of 4 different formulations of V114 in 
healthy adults and infants to be conducted in conformance with Good Clinical Practices
(GCPs) at approximately 24 sites in the United States (US).  Prevnar 13™ (pneumococcal 
13-valent conjugate vaccine [diphtheria CRM197 protein], Wyeth Pharmaceuticals, Inc., 
Philadelphia, Pa) will serve as an active control in the infant stage of the study.  This study 
will enroll approximately 80 healthy adults 18 to 49 years of age (Stage 1) and 250 healthy 
infants 6 to 12 weeks (≥42 to ≤90 days) of age (Stage 2). Prior to enrollment of infants, the 
safety and tolerability of a single-dose of the study vaccine must be demonstrated in healthy 
adults.
Similarly, the safety and tolerability of the first dose of study vaccine must be 
demonstrated in a small cohort of infants prior to enrollment of the full infant cohort.
Stage 1 - Adult Cohort:
A total of 80 adult subjects will be randomly assigned to 1 of 4 formulations of V114:
(1) Merck investigational V114 medium (N=20)
(2) Merck investigational V114 high (N=20)
(3) Merck investigational V114 medium with an alternative carrier protein (N=20)
(4) Merck investigational V114 high with an alternative carrier protein (N=20)
The adult stage of this study is designed to evaluate the safety and tolerability of a single 
dose of 4 different formulations of V114 when administered intramuscularly to 80 healthy 
adults (20 per vaccination group).

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Adverse events will be collected for 14 days following vaccination. After completion of a 
review of safety data from the adult cohort by an external Data Monitoring Committee 
(eDMC), Stage 2 of the study will begin.
Stage 2 - Infant Cohort:
Stage 2 will consist of 2 parts (Part I and Part II) during which a 0.5mL intramuscular dose of 
the study vaccine will be administered to healthy infants at 2, 4, 6, and 12 to 15 months of 
age. Each formulation of V114 will be first evaluated in a small number of infants (n=50) 
during Part I before initiating Part II which will enroll the remaining 200 infants.  Prevnar 
13™ will serve as control in both Part I and Part II.
Part I will involve 50 healthy infants (10 infants/group) who will be randomly assigned to 
receive 4 doses of 1 out of 4 different formulations of V114 or Prevnar 13™.  Safety data 
following the first dose [Postdose 1; (PD1)] will be reviewed by the eDMC prior to initiation 
of Part II.  In Part II, an additional 200 healthy infants (40 infants/group) will be enrolled into 
the trial.
In Part I and Part II, infants will be given either:
(1) V114 medium
(2) V114 high
(3) V114 medium with an alternative carrier protein
(4) V114 high with an alternative carrier protein
(5) Prevnar 13™
(See Section 5.2 for a detailed description of the V114 formulations).
The safety and tolerability profiles of the different formulations of V114 and procedures 
within the clinical trial will be carefully monitored throughout the study by the SPONSOR in 
accordance with standard procedures and also by the eDMC. For this Phase I/II study, a 
Merck Research Laboratories (MRL) statistician and a MRL statistical programmer assigned 
to the protocol will be unblinded throughout the duration of the study to allow for timely 
review of the interim safety data by the eDMC. All personnel directly involved with the 
conduct of this trial will remain blinded to the subject’s treatment assignment until 
medical/scientific review of all safety and immunogenicity data has been performed, protocol 
deviations have been identified, and data have been declared final and complete. Any study 
subject from Stage 2 (infant cohort) with serotype-specific anti-pneumococcal IgG (as 
measured by pneumococcal electrochemiluminescence [Pn ECL] assay) below 0.35μg/mL 
for serotype 19A (individually) and/or 4 or more serotypes in common with Prevnar 13™ at 
1 month Postdose 3 (PD3) will be offered an additional dose of licensed pneumococcal 
conjugate vaccine outside of this protocol. See Section 5.6 Rescue Medications & Supportive 
Care for additional details of the rescue plan.

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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1 and Figure 2
Figure 1
Trial Design of Stage 1 (Adults)

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Figure 2
Trial Design of Stage 2 Parts I and II (Infants)
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
No hypothesis testing will be performed.
For Stage 2 (Infants ONLY), the primary and secondary objectives in Section 3.0 will 
address the safety and immunogenicity (as measured by IgG) of 2 different formulations of 
V114 (medium and high as related to their contents in polysaccharide and adjuvant) 
containing the same carrier protein for all 15 serotypes in the vaccine, and Prevnar 13.  The 

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exploratory objectives will address the safety and immunogenicity (as measured by IgG) of 2 
additional formulations of V114 (medium and high as related to their contents in 
polysaccharide and adjuvant) containing an alternative carrier protein for at least one of the 
15 serotypes in the vaccine, as well as the opsonophagocytic activity (OPA) from all 
vaccination groups (4 different formulations of V114 and Prevnar 13), as measured by 
multiplexed OPA [MOPA-4] assay.
Stage 1 - (Adults ONLY)
1. To evaluate the safety profile of a single dose of V114 with or without an alternative 
carrier protein.
Stage 2 - Parts I and II (Infants ONLY)
1. To evaluate the safety and tolerability profiles following receipt of each dose and 
across all doses of V114 medium, V114 high, and Prevnar 13™ when administered 
as a 4-dose regimen to healthy infants at 2, 4, 6, and 12 to 15 months of age.
2. To evaluate the serotype-specific IgG geometric mean concentrations (GMCs) of 
V114 medium, V114 high, and Prevnar 13™, and the IgG GMC ratios between each 
of these V114 formulations and Prevnar 13™ for the 13 common serotypes at 1 
month postdose 3.
Secondary Objective(s) & Hypothesis(es)
3.2
Stage 1 - (Adults ONLY)
1. To evaluate the serotype-specific IgG GMCs and fold-rises from baseline of V114 
medium and V114 high at 1 month postvaccination.
Stage 2 - Parts I and II (Infants ONLY)
1. To evaluate the serotype-specific IgG response rates of V114 medium, V114 high, 
and Prevnar 13™, and the differences in IgG response rates between each of these 
V114 formulations and Prevnar 13™for the 13 common serotypes at 1 month PD3, 
pre-dose 4, and 1 month PD4.

Serotype-specific IgG response rates will be based on the proportion of recipients 
of V114 and Prevnar 13™ achieving the World Health Organization (WHO)-
accepted threshold value of 0.35µg/mL using the Pn ECL assay for each V114 
formulation and Prevnar 13™.
2. To evaluate the serotype-specific IgG GMCs of V114 medium, V114 high, and 
Prevnar 13™, and the IgG GMC ratios between each of these V114 formulations and 
Prevnar 13™for the 13 common serotypes at pre-dose 4 and 1 month PD4.

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Other Objectives (Exploratory Objectives )
3.3
Stage 1 - Adults Only
1. To evaluate the serotype-specific IgG GMCs of V114 medium with an alternative 
carrier protein and V114 high with an alternative carrier protein at 1 month 
postvaccination.
Stage 2 – Infants Only
1. To evaluate the safety and tolerability profiles following receipt of each dose of V114 
medium with an alternative carrier protein and V114 high with an alternative carrier 
protein when administered as a 4-dose regimen to healthy infants at 2, 4, 6, and 12 to 
15 months of age.
2. To evaluate the serotype-specific IgG responses of V114 medium with an alternative 
carrier protein and V114 high with an alternative carrier protein, and the differences 
in IgG response rates/GMC ratios between each of these V114 formulations and 
Prevnar 13™for the 13 common serotypes at 1 month PD3, pre-dose 4, and 1 month 
PD4.

Serotype-specific IgG responses will be based on the GMCs, the proportion of 
recipients of V114 with an alternative carrier protein achieving the WHO-
accepted threshold value of 0.35µg/mL using the Pn ECL assay for each V114 
formulation, and IgG GMC ratios between each V114 formulation with an 
alternative carrier protein and Prevnar 13.
3. To evaluate the effects of different pneumococcal polysaccharide/MAPA 
concentrations and use of an alternative carrier protein on serotype-specific GMCs 
measured at 1 month PD3 across the different formulations of V114.
4. To describe the proportions of subjects with OPA titer ≥8 and OPA geometric mean 
titers (GMTs) in all vaccination groups for the 13 common and 2 non-common 
serotypes between V114 and Prevnar 13™ at 1 month PD3, pre-dose 4, and 1 month 
PD4. 
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on V114.
Pharmaceutical and Therapeutic Background
4.1.1
The investigational Merck pneumococcal conjugate vaccine (hereafter referred to as V114) is 
a 15-valent vaccine that contains all of the pneumococcal polysaccharide conjugates in 
Prevnar 13™ (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 23F), plus 2 additional 

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serotypes (22F, 33F).  The serotypes contained in V114 will provide broad coverage of the 
leading serotypes associated with pneumococcal disease worldwide.  The vaccine is designed 
to meet continuing medical and public health needs for pneumococcal conjugate vaccines 
globally as well as to address the emergence of pneumococcal disease caused by serotypes 
not contained in Prevnar™ (pneumococcal 7-valent conjugate vaccine [diphtheria CRM197
protein], Wyeth Pharmaceuticals, Inc., Philadelphia, Pa) and Prevnar 13™ or other late-stage
investigational pneumococcal conjugate vaccines.  The serotype composition of V114 was
based on the need to maintain coverage of the serotypes included in Prevnar 13™, and to add 
serotypes guided by current epidemiology data and emerging trends.
Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, and 
causes the deaths of 0.7 to 1 million children <5 years of age, mostly in developing countries 
[1].  Starting in 2000, Prevnar™ was introduced into national childhood vaccination 
schedules in the US, European Union (EU), and several other countries.  According to the US 
pediatric vaccination schedule, the vaccine is administered to infants in a 3-dose infant series 
(2, 4, and 6 months of age), followed by a fourth dose at age 12 to 15 months. Widespread 
use of the vaccine has led to a significant reduction in invasive pneumococcal disease (IPD), 
pneumonia and otitis media caused by the 7 serotypes contained in the vaccine [1].  Use of 
the vaccine in children has also been shown to lower the prevalence of IPD caused by the 
vaccine serotypes in the non-vaccinated population via herd protection.  Prevnar 13™ was 
approved in the EU in 2009, the US in 2010, and subsequently in other countries worldwide.  
The vaccine is licensed globally as Prevnar 13™ and Prevenar 13™, and in this protocol the 
vaccine will be referred to by the name Prevnar 13™.  In 2009 a 10-valent pneumococcal 
conjugate vaccine, Synflorix™ (pneumococcal 10-valent conjugate vaccine [Non-Typeable 
Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates], 
GlaxoSmithKline Biologicals s.a., Rixensart, Belgium) was licensed in Europe and other 
countries worldwide.  Synflorix™ contains the serotypes contained in Prevnar™ conjugated 
to 3 different carrier proteins, plus 3 additional capsular polysaccharide conjugates (serotypes 
1, 5, and 7F).  This vaccine is not licensed in the US.
Despite these significant advances, serotype replacement remains a concern as new serotypes 
begin to fill the niche created by the suppression of nasopharyngeal colonization of vaccine 
serotypes.  In particular, serotypes 22F and 33F, the 2 additional serotypes contained in V114 
which are not contained in Prevnar 13™, contributed to approximately 1.3% of overall IPD 
in children under 5 years of age in the US in 1998 [2], but have now been estimated to 
represent 22.7% of IPD cases in this age group in 2011 (
 US CDC, personal 
communication). This phenomenon of serotype replacement substantiates the need for the 
development of more broadly-based pneumococcal conjugate vaccines and the search for 
antigens, such as proteins, that are commonly shared among all pneumococcal serotypes.
Pre-clinical and Completed Clinical Trials
4.1.2
Preclinical immunogenicity studies of V114 formulations have been conducted in 2 animal 
models (refer to the V114 IB).
PPD

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A first-in-man Phase I study (V114-001) evaluated the safety and immunogenicity of a single 
dose of V114 in healthy adults and healthy toddlers who had completed a full 3-dose infant 
series of Prevnar™.  A multicenter, randomized, double-blind Phase II trial (V114-003) was 
conducted to evaluate the safety, tolerability, and immunogenicity of V114 compared to 
Prevnar 13™ in approximately 1110 healthy infants.  Study vaccines in V114-003 were 
administered concomitantly with other licensed pediatric vaccines routinely given at 2, 4, 6, 
and 12 to 15 months of age.  Subjects were randomly assigned to 1 of 3 vaccination groups 
(1) V114, aluminum adjuvanted, (2) V114, non-adjuvanted, or (3) Prevnar 13™.  Both 
formulations of V114 generated an immune response to all 15 serotypes contained within the 
vaccine and displayed an acceptable safety profile (see V114 IB).
Ongoing Clinical Trials
4.1.3
V114-004, a multicenter, randomized, double-blind dose ranging trial is currently being 
conducted to evaluate the safety and immunogenicity of various formulations of V114 
containing different concentrations of polysaccharides and/or MAPA in healthy adults and 
infants. This study is ongoing and the data remain blinded.
V114-006, a randomized, multicenter, double-blind trial is currently being conducted to 
evaluate the safety, tolerability, and immunogenicity of a single dose of 2 different 
formulations of V114 in healthy, pneumococcal vaccine-naïve adults 50 years of age or 
older. The study is ongoing and the data remain blinded.
Information on Other Trial-Related Therapy
4.1.4
In Stage 2 (infants ONLY) of this study, Prevnar 13™ will be administered as one of the 
study vaccines, to serve as the active comparator.  In addition to the administration of study 
vaccine (V114 or Prevnar 13™), other pediatric vaccines will be administered concomitantly 
according to the recommended schedule.  These childhood vaccines will be representative of 
those recommended by the US Advisory Committee on Immunization Practices (ACIP) and 
are routinely administered at specified time points.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
This study is designed to support formulation optimization of the vaccine for those serotypes 
that yielded suboptimal antibody responses in a previous clinical trial and to evaluate the 
clinical performance of a V114 formulation consisting of at least one serotype conjugated to 
an alternative carrier protein.  The vaccine formulations for this study also include a new 
excipient, Polysorbate 20 (PS20) instead of Poloxamer 188 used in V114-004. PS20 is an 
acceptable excipient with a good safety profile and will help ensure necessary product 
stability as well as the manufacturing robustness of the vaccine. Preclinical studies have 
demonstrated that the use of PS20 results in a vaccine product that is more resistant to the 
routinely occurring physical stresses of processing, manufacturing, and shipping and does not 
negatively impact chemical stability or potency of the PCV15 antigen. Also included in this 

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study is a limited evaluation of dose range with respect to polysaccharide conjugates and 
MAPA.
This study will aid in the clinical assessment of the impact of conjugated polysaccharide and 
adjuvant concentration on the safety and immunogenicity of V114.  Because of limitations in 
preclinical models and the uniqueness of the immature immune system of infants, this 
assessment can only be done adequately by conducting clinical studies in the relevant 
population, to further inform on the development of the vaccine.
Healthy adults (18 to 49 years of age) will be included in Stage 1, which will assess the 
safety of a single-dose of 4 different formulations of V114 with or without an alternative 
carrier protein.  Stage 2 will enroll healthy infants at approximately 2 months of age, which is 
consistent with current recommendation of routine vaccination with pneumococcal conjugate 
vaccine in early childhood.
Rationale for Dose Selection/Regimen
4.2.2
Polysaccharide Conjugate Concentration:
This study is designed to evaluate the safety and immunogenicity of formulations containing 
conjugates produced using a modified conjugation process aimed at increasing the number of 
conjugate bonds. The proposed dose levels of polysaccharide conjugate to be evaluated in 
the study will be 2µg/dose for each serotype with the exception of serotype 6B (4µg/dose) or 
4µg/dose for each serotype with the exception of 6B (8µg/dose). These 2 concentrations of 
polysaccharides are also being evaluated in the currently ongoing V114-004 trial.
For 2 formulations of V114, all serotypes will be conjugated to CRM 197; the remaining 2
other formulations of V114 will consist of up to 14 serotypes conjugated to CRM197 and at 
least one serotype conjugated to an alternative carrier protein. This study will compare the 
clinical performance of V114 containing 2 different carrier proteins for at least one serotype. 
Dose of Aluminum Phosphate Adjuvant:
Two (2) different concentrations of MAPA (125µg/dose and 250µg/dose) will be evaluated 
in this trial.  The lowest concentration was already evaluated in V114-003 and study results 
showed that V114 formulated with 125µg of MAPA was associated with a small 
improvement in the magnitude of vaccine-induced antibody responses in comparison to the 
non-adjuvanted formulation of V114.  Importantly, a higher amount of MAPA (250µg/dose) 
appears to be helpful with stability of the V114 formulation containing higher amounts of
polysaccharide.  It is anticipated that the doubling of the amount of MAPA in V114 may 
provide higher levels of serotype-specific antibodies than that induced by V114 containing a 
lower amount of MAPA.
These MAPA concentrations are also being evaluated in the 
currently ongoing V114-004 trial.

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Dosing Regimen:
The dosing regimen is consistent with current recommendations for the administration of 
licensed pneumococcal conjugate vaccines in infants in many countries worldwide, including 
the US.  A 0.5-mL dose of study vaccine will be administered intramuscularly to healthy 
adults (single dose) or as a 4-dose series to healthy infants at 2, 4, 6, and 12 to 15 months of 
age.  Pneumococcal vaccine is not currently recommended for routine immunization of 
healthy adults 18 to 49 years of age.
Rationale for the use of Polysorbate 20:
Polysorbates are non-ionic surfactants and are acceptable excipients used in cosmetics and in 
parenteral administration of biologics and vaccines.  A surfactant is needed in order to reduce 
potential risk of agitation-induced aggregation associated with physical stresses of 
processing, manufacturing, and shipping of the vaccine.  Both Polysorbate 80 (PS80) and 
Polysorbate 20 (PS20) have been used in many pediatric and adult vaccines including 
Prevnar 13™, Infanrix™, Pentacel™, Havrix™, Twinrix™, Fluarix™, and Flubok™. 
Polysorbate 20 was selected in the formulation of V114 as it was shown to provide 
satisfactory results and did not negatively impact the chemical stability of the vaccine 
antigen.  A concentration up to 0.2% (w/v) per dose will be used to accommodate the 
different concentrations of polysaccharide and adjuvant to be evaluated in the study. 
Among PS20-containing products administered in infants, an intravenously infused 
multivitamin (M.V.I. Pediatric®, Hospira, Lake Forest, IL) containing 0.8 mg of PS20 per 5 
mL/dose is indicated as daily multivitamin maintenance dosage for infants and children 
receiving parenteral nutrition weighing as low as less than 1kg.  Infants weighing 3kg or 
more are to receive the full dose of 5 mL which is equivalent to a total dose of up to 0.3 
mg/kg of PS20.  The administration of such amount of PS20 has been shown to be safe and 
well-tolerated.  This dose is higher than the highest dose of PS20 projected to be used in 
V114 as 0.2% is equal to an administered dose of 0.2 mg/kg for an infant weighing 5 kg, the 
mean weight of a 6-8 weeks old infant.
Rationale for the use of an alternative protein carrier:
Previous studies have indicated that levels of serotype-specific antibodies required for 
protection against IPD vary between serotypes.  The induction of a satisfactory response for 
serotypes requiring high antibody concentrations has been a challenge for many pediatric 
pneumococcal conjugate vaccines.  The use of a different carrier protein with higher content 
in T helper epitopes than carrier proteins used in licensed PCVs could provide better 
antibody responses to those measured with currently licensed vaccines (See V114 IB).
4.2.2.1
Rationale for The Use of Comparator
Prevnar 13™ will be used as the comparator for this trial. Prevnar 13™ is currently the
recommended vaccine for the prevention of invasive pneumococcal disease in infants.

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Rationale for Endpoints
4.2.3
4.2.3.1
Immunogenicity Endpoints
Adult Cohort (Stage 1)
For the adult cohort, serum will be collected at 2 pre-specified time points during the trial:
1) Prevaccination
2) Approximately 30 days postvaccination
Sera will be used for the following measurements in adults:
1. The measurement of serotype-specific IgG using Pn ECL assay.
2. Immunogenicity measurements for the development and validation of future 
pneumococcal assays.
3. If there are remaining sera after IgG testing, and development of future pneumococcal 
assays, the leftover sera may be used for Future Biomedical Research (FBR), (Section 
4.2.3.3) providing the FBR Informed Consent Form (ICF) has been signed.
In this study, immunogenicity objectives for the adult cohort are not tested as primary 
objectives; they are evaluated as secondary and exploratory objectives.
Infant Cohort (Stage 2 - Parts I and II)
For the infant cohorts, serum will be collected at 3 pre-specified time points during the trial:
1) Approximately 30 days PD3
2) Pre-dose 4
3) Approximately 30 days PD4
Sera will be used for the following measurements:
1. IgG responses measured using the Pn ECL assay for the study objectives.
2. Functional antibody activity, OPA, will be measured using the MOPA-4 assay in the 
first 50% of infant subjects who have sufficient serum volume at PD3 to perform both 
the PnECL and MOPA-4 assays.
3. Immunogenicity measurements for the development and validation of future 
pneumococcal assays.

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4. If there are remaining sera after IgG testing, OPA testing, and development of future 
pneumococcal assays, the leftover sera may be used for Future Biomedical Research 
(FBR), (Section 4.2.3.3) providing the FBR Informed Consent Form (ICF) has been 
signed.
A primary immunogenicity objective is to summarize the antibody response induced by 
V114 medium, V114 high, and Prevnar 13™, based on the serotype-specific IgG GMCs 
measured by Pn ECL assay at 1 month following receipt of the third dose of the study 
vaccine.
A secondary immunogenicity objective of the study is to summarize the proportion of 
subjects meeting the serotype-specific threshold value of ≥0.35 μg/mL by Pn ECL assay at 1 
month following receipt of the third dose of the study vaccine.
The threshold value of ≥0.35 μg/mL measured in the Pn ECL assay corresponds to the IgG 
level of ≥0.35 μg/mL in the WHO reference ELISA for the 7 serotypes in Prevnar™ (4, 6B, 
9V, 14, 18C, 19F, and 23F), based on the results of an analytical bridging study comparing 
the 2 assays.  The use of the ≥0.35 μg/mL threshold value as measured by the WHO 
reference ELISA has been recommended by a WHO expert panel as an acceptable threshold 
value for evaluating the clinical performance of pneumococcal conjugate vaccines[3],[4].
Another secondary immunogenicity objective is to summarize the serotype-specific 
responses for V114 medium, V114 high, and Prevnar 13™, based on IgG GMCs and the 
proportion of subjects meeting the serotype-specific threshold value of ≥0.35μg/mL by Pn
ECL assay immediately prior (pre-dose 4) and 1 month following receipt of the fourth dose 
of the study vaccine.
Functional antibody activity, OPA, will also be evaluated in approximately 50% of infants
with sufficient serum available at PD3 to perform both the Pn ECL assay and the OPA 
testing on all 15 serotypes in V114.  Pre-dose 4 and PD4 OPA measurements will be 
conducted for all of the subjects who had PD3 OPAs performed and for which there is 
sufficient serum.  The proportion of subjects meeting OPA titer ≥8 and the OPA GMTs at 
PD3 and separately at pre-dose 4 and PD4 will be summarized for each serotype.
4.2.3.2
Safety Endpoints
Adult Cohort (Stage 1)
Adverse experiences (AEs) will be documented on a validated vaccination report card 
(VRC).  The VRC was developed to be administered electronically via a hand-held device.  
All AEs will be graded for severity.
1. Subjects will be observed for 30 minutes postvaccination for any immediate AEs.
2. Solicited injection-site AEs (redness, swelling, and pain/tenderness) will be collected 
Day 1 to Day 5 after vaccination.

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3. Solicited systemic AEs (muscle pain, joint pain, headache, and tiredness) will be 
collected Day 1 to Day 14 after vaccination.
4. Any other unsolicited systemic or injection-site AEs will be collected Day 1 to Day 
14 after vaccination.
5. Serious AEs will be collected from the time the consent form is signed through 
completion of the subject’s participation in the study (approximately 30 days 
postvaccination).
6. Body temperature will be measured during Day 1 to Day 5 after vaccination.
7. Severity of AEs will be assessed according to a toxicity grading scale as mild (Grade 
1), moderate (Grade 2), severe (Grade 3), and potentially life-threatening and death 
(Grade 4) for both serious and non-serious adverse experiences, in this study.  During 
the safety follow-up period, clinical adverse experiences will be recorded on the VRC 
by the subject at the time of occurrence.  The investigator will use the information 
provided by the subject both on the VRC, and verbally at the time of VRC review, to 
apply the appropriate toxicity grade (1 through 4).  The grade assigned by the 
investigator will be recorded in the electronic database on the corresponding eCRF.  
Death is not mentioned in the Toxicity Grade Guidance for Industry.  For this 
protocol, a death will be assessed as toxicity Grade 4.  This study uses an alpha scale 
for injection-site toxicity grading (A through E).  For this protocol, use the Injection-
Site AE Toxicity Grading Scale that follows the Industry Guidance in Appendix 12.6.  
All other toxicity evaluations must be performed per the applicable industry guidance.  
Refer to the Investigator File Trial Binder for guidance. The scale provided in the 
appendices is to be used for the measurement of the injection site AEs of redness, 
swelling, and pain/tenderness.
This adverse experience toxicity grading is in addition to the grading of adverse experiences 
by maximum intensity (mild, moderate, or severe).
The 14-day safety follow-up period for AEs occurring following receipt of each dose of the 
study vaccine is consistent with our Phase II study in healthy adults (V114-002), the ongoing 
clinical trial in healthy adults (V114-006), and other clinical trials evaluating the safety of 
licensed pneumococcal conjugate vaccines in healthy adults.
Infant Cohort (Stage 2 - Parts I and II)
Adverse experiences (AEs) will be documented on a validated vaccination report card 
(VRC).  The VRC was developed to be administered electronically via a hand-held device.  
All AEs will be graded for severity.
1. Study subjects will be observed for 30 minutes postvaccination for any immediate 
AEs.

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2. Solicited injection-site AEs (redness, swelling, hard lump, and pain/tenderness) and 
solicited systemic AEs (irritability, drowsiness, hives/welts, and appetite lost) will be 
collected Day 1 to Day 14 after each vaccination.
3. Any other unsolicited systemic or injection-site AEs will be collected Day 1 to Day 
14 after each vaccination.
4. Serious AEs will be collected from the time the consent form is signed through 30 
days PD4 and/or completion of the subject’s participation in the study.
5. Body temperature will be measured during Day 1 to Day 7 after each vaccination.  If 
fever is suspected, temperature will also be measured during Day 8 to Day 14 
postvaccination.
The 14-day safety follow-up period for AEs occurring following receipt of each dose of the 
study vaccine is consistent with our Phase II study in healthy infants (V114-003), the 
ongoing clinical trial (V114-004), and other clinical trials evaluating the safety of licensed 
pneumococcal conjugate vaccines in healthy infants.
Safety Monitoring
Safety and tolerability profiles will be carefully monitored throughout the study by the 
SPONSOR in accordance with standard procedures and also by an external Data Monitoring 
Committee (eDMC).  The eDMC consists of experienced physicians and scientists in the 
field of infectious diseases and/or vaccines who are not employees of the SPONSOR.  An 
eDMC charter of operations will be written and approved by the eDMC before the eDMC 
reviews any clinical data.  The eDMC will have the responsibility of study surveillance to 
monitor safety outcome events and identify safety issues in order to make recommendations 
(including the potential to terminate the study due to a safety concern) to the Merck clinical 
director.  The Merck clinical director will then forward the recommendations to the 
Executive Oversight Committee (EOC) who will decide the path forward for the trial based 
on the recommendations made by the eDMC.  The eDMC will meet at pre-specified time 
points, defined in the eDMC charter, to review safety data, and a set of safety criteria 
proposed as stopping rules will be used by the eDMC in their evaluation of the safety data 
during the conduct of the study (see section 7.3.2 Data Monitoring Committee).  The eDMC 
will review the safety data from the adult cohort (Stage 1) prior to the initiation of the small 
infant cohort (Stage 2 – Part I).  
In order to evaluate the safety profile of V114 in infants, VRC-prompted injection-site 
adverse experiences (redness, swelling, hard lump [rated by size] and pain/tenderness) and 
VRC-prompted systemic adverse experiences (irritability, drowsiness, appetite lost, hives/
welts) will be recorded for 14 days.  If a hard lump at the injection site is present for 72 
hours, the subject's parent/legal guardian should immediately contact the site to schedule an 
appointment with the study site for an evaluation within 48 hours, where the study doctor 
will diagnose the injection-site reaction (e.g., induration or nodule).  If hives/welts (urticaria) 
occur, the subject's parent/legal guardian should immediately contact the site to schedule an 

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appointment with the study site for an evaluation within 48 hours, where the study doctor 
will determine whether the hives/welts represent an urticarial-like eruption.  Unsolicited 
systemic or injection-site adverse experiences or serious adverse experiences will be 
collected from Day 1 through Day 14 after each vaccination. All serious adverse experiences 
(regardless of the investigator's assessment of causality) from the time the consent form is 
signed through completion of the subject's participation in the study at 30 days after the last 
dose of study vaccine will be collected.  Any immediate adverse experiences occurring in the 
30 minutes postvaccination observation period will be recorded.  Information about any 
medications, including any analgesic/antipyretic use on the day of vaccination that the 
subject receives, should be documented throughout the study on the VRC for the 14-day 
safety follow-up period following each vaccination.
4.2.3.3
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
A subset of subjects will receive Prevnar 13™ which is the standard of care and is serving as 
the active comparator in this study. 
V114 is aimed at providing comparable immune 
responses to Prevnar 13™ for the shared 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 as Prevnar 13™. As a possible rescue medication in this study, 
subjects who fail to achieve adequate immune responses to serotype 19A (individually) 
and/or to 4 or more serotypes in common between Prevnar 13™ and V114 following the 

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third dose of study vaccine will be offered an additional dose of licensed pneumococcal 
conjugate vaccine between 9 and 12 months of age. (See section 5.6 Rescue Medications & 
Supportive Care for additional details).
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Healthy male and female subjects between the ages of 18 and 49 years of age for the adult 
cohort AND between 42 and 90 days (approximately 2 months of age) for the infant cohort
(inclusive) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
Adult Cohort (Stage 1):
1. Be an adult, age 18 to 49 years and in good health.  Any underlying chronic illness 
must be documented to be in stable condition.
2. Is able to read, understand, and complete the study questionnaires (i.e., the VRC).
3. Be able to attend all scheduled visits and to comply with the study procedures.
4. Meet one of the following categories:
a) The subject is a male.
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) is postmenopausal (defined as at least 12 months with no menses in 
women ≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy, 
bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to 
screening; OR (3) has a congenital or acquired condition that prevents childbearing.
c) The subject is a female who is of reproductive potential and agrees to avoid 
becoming pregnant while receiving study vaccine and for 6 weeks after the last dose 
of study vaccine by complying with one of the following:  (1) practice abstinence†
from heterosexual activity OR (2) use (or have her partner use) acceptable 
contraception during heterosexual activity.  Acceptable methods of contraception 
are‡:

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Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together) 
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
5. Understand the study procedures, alternate treatments available and risks involved 
with the study, and voluntarily agree to participate by giving written informed 
consent.  The subject may also provide consent for FBR.  However, the subject may 
participate in the main trial without participating in the FBR.
Infant Cohort (Stage 2 - Parts I and II):
1. Be  healthy (based on medical history and physical examination) male or female 
infant approximately 2 months of age (42 days to 90 days), inclusive.
2. Have a parent/legal guardian who understands the study procedures, alternate 
treatments available, and risks involved with the study.

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3. Have a parent/legal guardian who is able to read, understand, and complete the VRC 
and voluntarily agree to participate by giving written informed consent.
4. Be able to attend all scheduled visits and to comply with the study procedures.
5. Have a parent/legal guardian that has access to a telephone.
6. The subjects' parent/legal guardian may also provide written informed consent for 
FBR.  However, the subject may participate in the main trial without participating in 
FBR.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 
Visit may be rescheduled for a time when these criteria are not met.
Adult Cohort (Stage 1):
1. Has had prior administration of any pneumococcal vaccine.
2. Has a history of invasive pneumococcal disease (positive blood culture, positive 
cerebrospinal fluid culture, or other sterile site) or known history of other culture-
positive pneumococcal disease.
3. Has known hypersensitivity to any component of the pneumococcal conjugate 
vaccine, or any diphtheria toxoid-containing vaccine.
4. Has known or suspected impairment of immunological function, history of congenital 
or acquired immunodeficiency (e.g. splenomegaly), documented HIV infection, 
functional or anatomic asplenia, history of autoimmune disease including multiple 
sclerosis (MS), MS-like disease, systemic lupus erythematosus, polymyositis, 
inclusion body myositis, dermatomyositis, Hashimoto’s thyroiditis, Sjogren’s 
syndrome, rheumatoid arthritis, or other autoimmune disorders.
5. Has a coagulation disorder contraindicating intramuscular vaccinations.
6. *Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing > 10 kg) for ≥14 consecutive days and 
has not completed treatment at least 30 days prior to study entry.  Has received 
systemic corticosteroids exceeding physiologic replacement doses (~5 mg/d 
prednisone equivalent) within 14 days prior to the first vaccination.
7. *Has received other licensed non-live vaccines within the 14 days before receipt of 
study vaccine.  (Exception:  Inactivated influenza vaccine may be administered 

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during the study but must be given at least 2 weeks prior to receipt of the study 
vaccine or at least 4 weeks after receipt of the study vaccine).
8. *Has received a licensed live virus vaccine within 30 days prior of receipt of study 
vaccine.
9. *Had a recent febrile illness (≥100.4°F [38.0°C] oral or equivalent) or received 
antibiotic therapy for any acute illness occurring within 72 hours before receipt of 
study vaccine.
10. Has received a blood transfusion or blood products, including immunoglobulins 
within the 6 months before receipt of study vaccine or is scheduled to receive a blood 
transfusion or blood product within 30 days of receipt of study vaccine.  Autologous 
blood transfusions are not considered an exclusion criterion.
11. Has participated in another clinical study of an investigational product within 2 
months before the beginning of or any time during the duration of the current clinical 
study.  Subjects enrolled in observational studies may be included; these will be 
reviewed on a case-by-case basis for approval by the SPONSOR.
12. Is breast-feeding.
13. Cannot be adequately followed for safety according to the protocol.
14. Is unlikely to adhere to study procedures, keep appointments, or is planning to 
relocate during the study.
15. Has any other reason that, in the opinion of the investigator, may interfere with the 
evaluation required by the study.
16. Is or has an immediate family member (e.g. spouse, parent/legal guardian, sibling, or
child) who is investigational site or sponsor staff directly involved with this trial.
For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 
Visit may be rescheduled for a time when these criteria are not met.
Infant Cohort (Stage 2 - Parts I and II):
1. Had prior administration of any pneumococcal vaccine.
2. Has a known hypersensitivity to any component of the pneumococcal conjugate 
vaccine, or any diphtheria toxoid-containing vaccine.
3. *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 of receipt of study 
vaccine.

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4. Has a known or suspected impairment of immunological function.
5. Has a history of congenital or acquired immunodeficiency (e.g. splenomegaly).
6. Has or his/her mother has a documented Human immunodeficiency virus (HIV) 
infection.
7. Has or his/her mother has a documented hepatitis B surface antigen - positive. 
8. Has functional or anatomic asplenia.
9. Has a history of failure to thrive.
10. Has a coagulation disorder contraindicating intramuscular vaccination.
11. Has a history of autoimmune disease including systemic lupus erythematosus, anti-
phospholipid syndrome, Behcet's disease, autoimmune thyroid disease, polymyositis 
and dermatomyositis, scleroderma, type I diabetes mellitus, and other autoimmune 
disorders.
12. Has 
a 
known 
neurologic 
or 
cognitive 
behavioral 
disorder, 
including 
encephalitis/myelitis, acute disseminating encephalomyelitis, pervasive development 
disorder, and related disorders.
13. Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing > 10 kg) for ≥14 consecutive days and 
has not completed treatment at least 30 days prior to study entry.  Has received 
systemic corticosteroids within 14 days prior to the first vaccination or is expected to 
require systemic corticosteroids within 30 days after each vaccination during conduct 
of the study.
14. Has received other licensed non-live vaccines within the 14 days before receipt of 
study vaccine.
15. Has received a licensed live virus vaccine within the 30 days prior of receipt of study 
vaccine.
16. Had prior receipt of a blood transfusion or blood products, including 
immunoglobulins.
17. Has participated in another clinical study of an investigational product before the 
beginning or anytime during the duration of the current clinical study. Subjects 
enrolled in observational studies may be included; these will be reviewed on a case-
by-case basis for approval by the SPONSOR.

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18. Has a history of invasive pneumococcal disease (positive blood culture, positive 
cerebrospinal fluid culture, or other sterile site) or known history of other culture 
positive pneumococcal disease.
19. Cannot be adequately followed for safety according to the protocol plan.
20. Has a parent/legal guardian who is unlikely to adhere to study procedures, keep 
appointments, or is planning to relocate during the study.
21. Has any other reason that in the opinion of the investigator may interfere with the 
evaluation required by the study.
22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Vaccination(s)
5.2
The vaccines to be used in this trial are outlined below in Table 1 and Table 2.
Table 1
Trial Vaccination – Adult Cohort
Vaccination at Visit 1 (18 to 49 years of age) with 0.5mL given IM
Vaccine
Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14
18C, 19F, 19A, 22F, 23F  and 33F
MAPA
Use in Study
V114
medium
2 µg; 
except 6B (4 µg)
125 µg
Investigational
V114
high
4 µg; 
except 6B (8 µg)
250 µg
Investigational
V114 medium 
with an alternative 
carrier protein
2 µg; 
except 6B (4 µg)
125 µg
Investigational
V114
high with an 
alternative carrier 
protein
4 µg; 
except 6B (8 µg)
250 µg
Investigational

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Table 2
Trial Vaccination – Infant Cohort
Vaccination at Visit 1 (~2 months of age), Visit 2 (~4 months of age), Visit 3 (~6 months of age) and 
Visit 5 (~12 to 15 months of age) with 0.5-mL given IM
Vaccine
Serotypes 1, 3, 4, 5, 6A, 6B, 7F,  9V, 
14 18C, 19F, 19A, 22F, 23F  and 33F
MAPA
Use in Study
V114
medium
2 µg; 
except 6B (4 µg)
125 µg
Investigational
V114
high
4 µg; 
except 6B (8 µg)
250 µg
Investigational
V114
medium with an 
alternative carrier 
protein
2 µg; 
except 6B (4 µg)
125 µg
Investigational
V114
high with an 
alternative carrier 
protein
4 µg; 
except 6B (8 µg)
250 µg
Investigational
Prevnar 13™
Prevnar 13™
Active comparator
Trial vaccination is given on the day of randomization or as close as possible to the date on 
which the subject is allocated/assigned.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Timing of Dose Administration
5.2.2
For adult cohort (Stage 1), V114 will be administered as a 0.5-mL intramuscular injection at 
Visit 1.
For the infant cohorts (Stage 2, Parts I and II), V114 or Prevnar 13™ will be administered as 
a 0.5-mL intramuscular injection at Visit 1 (approximately 2 months of age [≥42 or ≤90 days 
of age]), Visit 2 (4 months of age to 1 day prior to 5 months of age), Visit 3 (6 months of age 
to 1 day prior to 7 months of age) and Visit 5 (12 months of age to 1 day prior to 16 months 
of age).  Other pediatric vaccines will be administered concomitantly on the same day as 
study vaccine according to the recommended schedule.  Concomitant oral vaccines may be 

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administered prior to the study vaccine and other injectable concomitant vaccines.  
Precautions must be taken to prevent choking during the administration of oral vaccines. 
Concomitant injectable vaccines should be administered on the same day as study vaccine 
and after the study vaccine has been administered.  To avoid any confounding results, non-
study injectable vaccines should not be administered in the same limb as study vaccine.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used. V114 will be dispensed in a blinded fashion 
by an unblinded pharmacist or qualified trial site personnel. The subject, the investigator and 
Sponsor personnel or delegate(s) who are involved in the vaccine administration or clinical 
evaluation of the subjects are unaware of the group assignments.
In-house blinding procedures will be used.  Note: Because the study vaccine and Prevnar 
13™ have a different appearance, a member of the study site staff will be unblinded for the 
purpose of receiving, maintaining, and preparing/administering the study vaccine. In order to 
avoid bias, the unblinded study personnel will have no further contact with study subjects for 
any study-related procedures/assessments after administration of study vaccines, which 
includes all safety follow up procedures. Contact between subjects and unblinded study 
personnel after vaccination administration is strictly prohibited.
For this Phase I-II study, MRL statisticians and an MRL statistical programmer assigned to 
the protocol will be unblinded throughout the duration of the study to facilitate reviews of the 
safety data by the eDMC, and the performing of the 2 planned interim analyses of the 
immunogenicity and safety data.
All other MRL employees directly involved with the 
conduct of this trial will remain blinded to the subject level treatment assignment, and will 
receive only group level summaries of immunogenicity and safety data from the analyses.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Vaccine Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 4 V114 adult vaccination arms.  Subjects will 
be assigned randomly in a 1:1:1:1 ratio to each of the 4 V114 vaccination groups in Stage 1, 
for the adult cohort. The infant cohort (Stage 2) will have 5 vaccination arms during which 
subjects will be randomly assigned in a 1:1:1:1:1 ratio to each of the 4 V114 vaccination 
groups or control (Prevnar 13™), respectively.
Each formulation of V114 will be first 
evaluated in a small number of infants (10/arm) during Part I before initiating Part II, which 
will enroll the remainder of the infant cohort.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.

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Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 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 subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Any concurrent medication or medical treatment must be recorded on the appropriate 
electronic case report form (eCRF).  During the influenza season, it is anticipated that study 
subjects 6 months of age and older may be given an influenza vaccine.  Influenza vaccine 
should be administered either 2 weeks prior to or 4 weeks after the administration of the 
study vaccine.
If a medical condition requires the use of 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 immediately and any such use must be documented on the 
appropriate eCRF.
Adults:
Subjects should not receive systemic corticosteroids during the study, unless medically 
required and with a goal of down-titrating/discontinuing as soon as medically feasible.  
Short-term (< 14 days) or alternate day administration at low to moderate doses (equivalent
of < 2 mg/kg total daily dose of prednisone or < 20 mg/d for persons weighing > 10 kg) are 
approaches to mitigate potential risks associated with  immunosuppression.
Subject should not receive systemic corticosteroids (equivalent of > 2 mg/kg total daily dose 
of prednisone or > 20 mg/d for persons weighing > 10 kg  for > 14 consecutive days) 
following vaccine administration through the VRC specified follow-up period.
Intra-articular or soft-tissue (e.g., bursa, tendon) injections of steroids are permitted. Topical, 
ophthalmic and inhaled steroids are also permitted.
For the adult cohort (Stage 1), V114 will be administered at Visit 1.  No other investigational 
compound or device or prohibited concomitant vaccines (see Section 5.1.3 Subject Exclusion 
Criteria) may be administered at any time during this study without prior approval by the 
SPONSOR.
Infants:
For the infant cohort (Stage 2, Parts I and II) the study vaccines (V114 and Prevnar 13™) 
will be administered at 2, 4, 6, and 12 to 15 months of age.  On the day of vaccination, it is 

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important to record the use of any analgesic or antipyretic use on the VRC and appropriate 
eCRF.
Subjects should not receive systemic corticosteroids (equivalent of 2 mg/kg total daily dose 
of prednisone or 20 mg/d for persons weighing >10 kg for 14 consecutive days) starting 
from 30 days prior to vaccination through 30 days after 
each vaccination.  Topical, 
ophthalmic and inhaled steroids are permitted.
Other pediatric vaccines will be administered concomitantly according to the recommended 
schedule.  These concomitant non-study vaccinations will be recorded on the appropriate 
eCRF.  
Concomitant vaccines (oral or injectable) should be administered on the same day as study 
vaccine. Concomitant oral vaccines may be administered prior to the study vaccine and other 
injectable concomitant vaccines.  Precautions must be taken to prevent choking during the 
administration of oral vaccines.
Other pediatric injectable vaccines administered 
concomitantly should be given after the study vaccine.  To avoid any confounding results, 
non-study injectable vaccines should not be administered in the same limb as study vaccine.  
Documentation of which limb was used for the administration of study vaccine should be 
recorded on the appropriate eCRF.  As the study is reporting injection-site AEs from the 
study vaccine (and not from the concomitant vaccines), this information should also be 
recorded on the VRC to inform the parent/legal guardian of the appropriate limb to monitor 
for AEs ONLY related to the study vaccine. 
No other investigational compound or device may be administered at any time during this 
study without prior approval by the SPONSOR.
Rescue Medications & Supportive Care
5.6
Infant subjects who fail to achieve adequate serologic responses following the third dose of 
study vaccine will be offered an additional dose of licensed pneumococcal conjugate vaccine 
outside of this protocol.  Any study subject with serotype-specific pneumococcal IgG (as 
measured by Pn ECL assay) below 0.35 μg/mL for serotype 19A (individually) and/or 4 or
more serotypes in common between V114 and Prevnar 13™ at 1 month PD3, will be given 
one dose of licensed pneumococcal conjugate vaccine as soon as possible after serological 
results are available.  All subjects who meet the rescue criterion must be discontinued from 
the study prior to administering the additional dose of licensed pneumococcal conjugate
vaccine. The discontinuation date should be the date the parent/legal guardian was notified of 
the child’s meeting the rescue criterion. Adverse events or changes to medical history 
occurring after the 14 days of safety follow up for Dose 3 and the discontinuation should be 
reported in the database; no additional immunogenicity blood sample should be drawn. If an 
SAE occurs between the 14 days of safety follow up for Dose 3 and the discontinuation, that 
event must be reported. The serologic threshold value of 0.35 μg/mL was recommended by a 
WHO expert panel as an acceptable threshold value for evaluating the clinical performance 
of pneumococcal conjugate vaccines in infants [3],[4].  Adequate treatment provisions, 

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including epinephrine, should be available for immediate use should an anaphylactic or 
anaphylactoid reaction occur.
Diet/Activity/Other Considerations
5.7
No special dietary restrictions apply to this study.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from vaccination but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  
Discontinuation from vaccination is permanent.  Once a subject has discontinued 
vaccination, even though he/she continues to be monitored in the trial, he/she shall not be
allowed to begin vaccination again.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or SPONSOR, places the subject at unnecessary risk through 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.

In stage 2 (Parts I and II), any infant subject that fails to achieve adequate serologic 
responses, as described in Section 5.6, will be discontinued from the study.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).

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Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
The eDMC will be provided with the following stopping rules as guidance for 
temporarily halting or terminating the study:
If any of the following events occurs, administration of study vaccine will be temporarily 
discontinued until a thorough review of accumulated safety data is undertaken by the 
eDMC, the investigator, and /or the SPONSOR’s representative.

Death in any subject, unless the cause of death is due to obvious alternative etiology;

Unexpected life-threatening event in any subject, unless due to obvious alternative 
etiology. Event should not have been previously observed with similar pneumococcal 
vaccines, or vaccines administered concomitantly in this study;

Any serious adverse event, unless due to obvious etiology, with the exception of 
those already reported for pneumococcal conjugate vaccines or for other 
concomitantly administered vaccines and deemed related to those vaccines;

Event which in the opinion of the investigator and/or safety monitoring committee 
contraindicates further dosing of additional subjects.
Conclusions about the overall safety of the investigational product will otherwise be 
determined from any SAE and solicited systemic AEs with a severe intensity rating, 
regardless of relationship to vaccination. The relationship to study vaccine is determined by 
the study investigator. 
The study site and SPONSOR's personnel involved in the conduct of the study (excluding the 
MRL statistician and statistical programmer) will remain blinded as to the treatment 
allocation of the study subject.

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6.0 TRIAL FLOW CHART
Adult Cohort
Visit Number:
1 
2
Visit Timing:
Day 1
DOSE 1
30 days after Visit 1
Visit Window:
+ 14 days
Administrative Procedures
Informed Consenta
X
Informed Consent for Future Biomedical Research (FBR)b
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Urine Pregnancy Testc
X
Medical History
X
Concomitant Medication Review
X
X
Vaccination Allocation/Randomization
X
Study Vaccine Administrationd
X
Provide Electronic Vaccination Report Card (VRC)
X
Review VRC data
X
Clinical Procedures/Assessments
Targeted Physical Examination (optional, per investigator’s discretion; perform if needed to 
assess inclusion/exclusion criteria)
X
Obtain Oral Temperature
X
30 Minutes Postvaccination Observation Period
X
Adverse Experience Monitoringe
X
X
Assess for Serious Adverse Experiencese
X
X
Laboratory Procedures/Assessments
Collect blood samples for immunogenicity assays (40 mL)f,g
X
X
Collect Buccal Swabs for Future Biomedical Research b
X

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Adult Cohort
Visit Number:
1 
2
Visit Timing:
Day 1
DOSE 1
30 days after Visit 1
Visit Window:
+ 14 days
a.
Consent must be obtained prior to any study procedures.
b.
Informed consent for future biomedical research samples must be obtained before the collection of the buccal swab DNA samples.  Buccal swab DNA 
samples for analysis should be obtained prior to the vaccination, on Day 1, on randomized subjects only, or at a later date as soon as the informed consent is 
obtained.
c.
Urine pregnancy test (sensitive to 25 IU β-hCG) must be done prior to vaccination in women of reproductive potential
d.
In order to avoid bias, the unblinded study personnel will have no further contact with study subjects for any study-related 
procedures/assessments following administration of the study vaccines.  This includes all safety follow-up procedures. Contact 
between subjects and unblinded study personnel after vaccination administration is strictly prohibited.
e.
Adverse experiences (serious and non-serious) are to be reported from Day 1 to 14 days following the vaccination. Serious Adverse 
Experiences are to be reported throughout the subject’s study participation.
f.
Leftover serum samples collected from the main study will be stored for future use if the FBR consent is signed.
g.
Collect blood prior to vaccination.

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Infant Cohort
Visit Number:
1a
2a
3
4
5
6
Visit Timing:
Age:~2 months 
DOSE 1
Age:~ 4 months 
DOSE 2
Age:~6 months 
DOSE 3
30 days after 
Visit 3
Age:~12 to 15 
months DOSE 4
30 days after 
Visit 5
Visit Window:
≥42 days of 
age to ≤90
days of age
4 months of age 
to 1 day prior to 
5 months of age
6 months of age 
to 1 day prior to 
7 months of age
28 to 42 days 
PD3
12 months of age 
to 1 day prior to 16 
months of age
28 to 42 days 
PD4
Administrative Procedures
Informed Consentb
X
Informed Consent for Future Biomedical Research
(FBR)c
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
Update Medical History (New condition not 
already recorded as medical history or adverse 
experiences)
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
X
X
Vaccination Allocation/Randomization
X
Study Vaccine Administrationd
X
X
X
X
Childhood Vaccinese
X
X
X
X
Provide Electronic Vaccination
Report Card 
(VRC)
X
Review VRC dataf
X
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
Targeted Physical Examination
X
X
X
Obtain Rectal Temperatureg
X
X
X
X
30 Minutes Postvaccination Observation Period
X
X
X
X
Adverse Experience Monitoringf
X
X
X
X
X
X
Assess for Serious Adverse Experiencesf
X
X
X
X
X
X
Laboratory Procedures/Assessments
Collect blood samples for immunogenicity assays 
(4-5 mL) h, i
X
X
X
Collect Buccal Swabs for Future Biomedical 
Research c
X

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Infant Cohort
Visit Number:
1a
2a
3
4
5
6
Visit Timing:
Age:~2 months 
DOSE 1
Age:~ 4 months 
DOSE 2
Age:~6 months 
DOSE 3
30 days after 
Visit 3
Age:~12 to 15 
months DOSE 4
30 days after 
Visit 5
Visit Window:
≥42 days of 
age to ≤90
days of age
4 months of age 
to 1 day prior to 
5 months of age
6 months of age 
to 1 day prior to 
7 months of age
28 to 42 days 
PD3
12 months of age 
to 1 day prior to 16 
months of age
28 to 42 days 
PD4
a.
For Visits 1 and 2, study coordinator should review the electronic Vaccination Report Card (VRC) in the vendors database at 14 days postvaccination (0 to 
plus 5 day window) and call the parent/legal guardian if there is a need to address questions (document phone call in study chart).  The site will review 
VRC with parent/legal guardian at next visit.
b. Consent must be obtained prior to any study procedures.
c.
Informed consent for future biomedical research samples must be obtained before the collection of the buccal swab DNA samples.  Buccal swab DNA 
samples for analysis should be obtained prior to the vaccination, on Day 1, on randomized subjects only, or at a later date as soon as the informed consent 
is obtained.
d. In order to avoid bias, the unblinded study personnel will have no further contact with study subjects for any study-related procedures/assessments 
following administration of the study vaccines.  This includes all safety follow-up procedures. Contact between subjects and unblinded study personnel 
after vaccination administration is strictly prohibited.
e.
Concomitant (or routine pediatric) vaccines are to be given according to recommended schedule. Any injectable concomitant vaccines provided at the visit 
must be given after the study vaccine and in a separate limb, may be given during the 30-minute observation period, and do not require additional 
observation time
f.
Adverse experiences (serious and non-serious) are to be reported from Day 1 to 14 days following each vaccination. Serious Adverse Experiences are to 
be reported throughout the subject’s study participation.
g. Pre-vaccination temperatures taken by study staff at Visits 1, 2, 3 and 5. Parent/legal guardian to measure and record rectal temperature per VRC 
instructions.
h. Leftover serum samples collected from the main study will be stored for future use if the FBR consent is signed.
i.
Collect blood prior to vaccination.

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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  

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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. A urine 
pregnancy test will be obtained for all female subjects of child bearing potential.  Medical 
history for the adult subjects should be reported for the previous 5 years.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
before starting the trial.  Prior medications should only be reported for a 30 day period prior 
to the first study vaccination.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.

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Any concurrent medication or medical treatment must be recorded on the appropriate 
electronic case report form (eCRF).  On the day of vaccination, it is important to record the 
use of any analgesic or antipyretic use on the VRC and appropriate eCRF.
If a medical condition required the use of immunoglobulins, 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 immediately and any such use must be documented on the 
appropriate eCRF.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements are provided in Section 7.1.5.1.  
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
After the consent form has been signed and dated, the subject’s medical history has been 
reviewed and all eligibility criteria have been met, and after a screening number is assigned, 
the subject will be assigned an allocation/randomization number using IVRS. It is the 
responsibility of the unblinded person(s) to allocate subjects using the IVRS.
7.1.1.8
Trial Compliance
7.1.1.8.1 Study Vaccination
All subjects will be given a card, at the time of screening, identifying them as participants in 
a research study. The card will contain contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer the study vaccine. Unblinded study personnel should not have contact with 
subjects for any study-related procedures/assessments after administration of study vaccines, 
which includes all safety follow up procedures. 

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Prior to administration of Prevnar 13™ or V114, shake vigorously to obtain a homogenous 
white suspension. Do not use the vaccine if it cannot be resuspended.  Visual inspection of 
study vaccine for particulate matter and discoloration prior to administration should be 
completed.  The study vaccine should not be used if particulate matter or discoloration is 
found.  If appearance is otherwise, do not administer.  Partial or empty vaccine syringes
should be properly discarded as biohazardous waste. US sites should follow instructions for 
the Clinical Supplies Return Form and contact your SPONSOR representative for review of 
shipment and form before shipping.
All safety and immunogenicity assessments will be conducted by blinded personnel, and the 
subject or subjects’ parents/guardians will be blinded to the study vaccine received by the 
study subject.  Vaccination information, such as Component Identification Number and time 
of vaccination, must be recorded on the appropriate eCRF as per the Data Entry Guideline 
(DEG) instructions.
Stage 1: Adult Cohort
Subjects will be randomly assigned to 1 of 4 vaccination arms: 
(1) V114 medium
(2) V114 high
(3) V114 medium with an alternative carrier protein
(4) V114 high with an alternative carrier protein
Stage 1 of the study will enroll approximately 80 adult subjects (20 subjects per arm).  A 0.5-
mL intramuscular dose of study vaccine will be administered to healthy adults on Day 1.  
The vaccines should be administered at a 90° angle in the deltoid muscle using the provided 
syringe with a 22- to 25-gauge needle of the following length specifications:

Men and women weighing < 130 lbs (60 kg), use a 5/8- to 1-inch needle

Women weighing 130 to 200 lbs (60 to 90 kg) or men weighing 130 to 260 lbs (60 to 
118 kg), use a 1- to 11/2-inch needle

Women weighing > 200 lbs (90 kg) or men weighing > 260 lbs (118 kg), use a 11/2-
inch needle

Refer to the CDC Pink Book, Appendix D for additional details
Stage 2: Infant Cohort
Subjects will be randomly assigned to 1 of 5 vaccination arms: 
(1) V114 medium

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(2) V114 high
(3) V114 medium with an alternative carrier protein
(4) V114 high with an alternative carrier protein
(5) Prevnar 13™  
Stage 2 of the study will enroll approximately 250 subjects (50 subjects per arm).  A 0.5-mL 
intramuscular dose of study vaccine will be administered to healthy infants at 2, 4, 6, and 12 
to 15 months of age. 
The vaccines should be administered at a 90° angle in the anterolateral thigh muscle using 
the provided syringes with the following needle length and gauge specifications1 : 1 inch 
needle, 22 to 25 gauge for infants (2-6 months) and 1 to 1¼ inch needle, 22 to 25 gauge for 
toddlers (12 to 15 months). (See CDC Pink Book, Appendix D for additional details).
To ensure that parents do not become confused regarding the location of the study vaccine 
injection-site, Doses 1, 2, and 3 of the study vaccine are to be administered in the same limb 
(e.g. if the study vaccine is provided in the right thigh for dose 1, subsequent doses should 
also be provided in the right thigh). Dose 4 may be administered in the deltoid region instead 
of the thigh, at the discretion of the investigator2. If an abnormality (i.e., 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.  (See attachment, CDC Pink Book, Appendix D for additional details). 
7.1.1.8.2 Concomitant Vaccinations
No other investigational compound or device may be administered at any time during this 
study without prior approval by the SPONSOR.
Stage 2: Infant Cohort
The study vaccines will be administered at 2, 4, 6, and 12 to 15 months of age.  Other 
pediatric vaccines will be administered concomitantly according to the mandated schedule at 
sites in the United States.  These concomitant non-study vaccinations will be recorded on the 
appropriate eCRF.  Combination MMRV vaccines should not be given in this study; 
however, MMR and Varicella vaccines are permitted if administered concomitantly in 2 
separate limbs.
                                                
1 Needles provided in Prevnar 13™ blister packages may also be used.
2 Per investigator discretion, dose 4 can be administered in the deltoid muscle instead of the anterolateral thigh 
muscle; if given in the deltoid muscle, the needle length should be 5/8 to 1 inch (a 5/8 inch needle may be 
used only if the skin is stretched tight, subcutaneous tissue is not bunched, and injection is made at a 90-
degree angle).

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Concomitant vaccines (oral or injectable) should be administered on the same day as study 
vaccine. Concomitant oral vaccines may be administered prior to the study vaccine and other 
injectable concomitant vaccines.  Precautions must be taken to prevent choking during the 
administration of oral vaccines.  Concomitant injectable vaccines should be administered 
after the study vaccine.  To avoid any confounding results, non-study injectable vaccines 
should not be administered in the same limb as study vaccine.  Documentation of which limb 
was used for the administration of study vaccine should be recorded on the appropriate 
eCRF.  As we are requesting the reporting of injection-site adverse experiences from the 
study vaccine (and not from the concomitant vaccines), this information should also be 
recorded on the VRC to inform the parent/legal guardian of the appropriate limb to monitor 
for adverse experiences ONLY related to the study vaccine.  
7.1.1.9
Dispense Electronic Vaccination Report Cards
The vaccination report card was developed to be administered electronically via a hand-held 
device.  This item was structured as recommended in the final FDA Patient Reported 
Outcome (PRO) Guidance.  The investigator or delegate will train the subject or parent/legal 
guardian in the use of the electronic vaccination report card prior to dispensing it at Visit 1.  
Body temperatures, injection-site AEs, VRC-prompted systemic
complaints, other 
complaints or illnesses, and medications will be recorded on the VRC throughout the study.  
The investigator or delegate will review the data captured on the VRC with the adult subject 
at Visit 2 and with the parent/legal guardian for the infant stage at Visit 2 through Visit 6.
Interruptions from the protocol specified vaccination require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Physical Examinations
For adult subjects, a targeted physical examination may be performed to assess 
inclusion/exclusion criteria. 
For infant subjects a full physical examination will be performed at Visit 1. Any clinically 
significant abnormality will be recorded as part of the medical history on the appropriate 
eCRF. A targeted physical examination will be performed at subsequent vaccination visits 
(Visits 2, 3, and 5). Any clinically significant abnormality will be recorded as part of the 
updated medical history on the appropriate eCRF.
The full and targeted physical examination procedures both include obtaining vital signs 
(heart rate, respiratory rate, and oral temperature), auscultation of the heart and lung, and 
examination of the abdomen. In addition, a full physical examination will include an 
assessment of the head, eyes, ears, nose and throat (HEENT), skin, lymph nodes, 
neurological system, and musculoskeletal system.

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Findings related to the physical examinations should be documented in the subject 
chart/source documentation.
7.1.2.2
Temperature Methods
Stage 1: Adult Cohort
Subjects will be instructed to record their oral temperature on the VRC from Day 1 through 
Day 5 postvaccination.  Measurements of body temperature should be taken at approximately 
the same time each day.  In addition, subjects will be instructed to record any concomitant 
medications and/or vaccinations on the VRC.
Stage 2: Infant Cohort
The subject’s parent/legal guardian will be asked to record a rectal temperature reading on 
the VRC from Day 1 through Day 7 following each vaccination.  Temperature measurement 
must be recorded in the VRC if fever is suspected during Day 8 through Day 14.  Although 
underarm (axillary) temperature measurement is acceptable, rectal temperature is the 
preferred method for fever evaluation.  If an axillary temperature is performed and is 
reported to be ≥37.8°C (≥100.0°F), it must be confirmed with a rectal temperature.  In this 
case, both axillary and rectal temperatures must be recorded on the VRC.  Temperature 
readings should be taken at approximately the same time each day.
7.1.2.3
  Assess Adverse Experiences
Stage 1: Adult Cohort
Study subjects will be observed for 30 minutes postvaccination for any immediate AEs.  The 
time at which the event occurred within the 30 minute timeframe, as well as the event itself 
and resolution of the event must be recorded on the appropriate eCRF.  Instructions on 
completing the VRC will be reviewed with each study subject.  Solicited injection-site AEs 
(swelling, redness, and pain/tenderness) occurring Day 1 through Day 5 postvaccination and 
systemic AEs (muscle pain, joint pain, headache, and tiredness) occurring Day 1 through Day 
14 following vaccination will be recorded by the subject on the electronic VRC.  See Section 
7.2 for detailed information concerning the assessment and recording of AEs.
Stage 2: Infant Cohort
Study subjects will be observed for 30 minutes postvaccination for any immediate AEs.  The 
time at which the event occurred within the 30 minute timeframe, as well as the event itself 
and resolution of the event must be recorded on the appropriate eCRF.  Instructions on 
completing the VRC will be reviewed with each study subject's parent/legal guardian.  
Injection-site and systemic AEs occurring Day 1 through Day 14 following each vaccination 
will be recorded by the subject's parent/legal guardian on the electronic VRC; this includes 
VRC-prompted injection-site AEs (redness, swelling, hard lump, and pain/tenderness) and 
VRC-prompted systemic AEs (irritability, drowsiness, appetite lost, hives or welts).  See
Section 7.2 for detailed information concerning the assessment and recording of AEs.

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Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial (from 
pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per subject can be found in Section 12.4.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
There are no laboratory safety evaluations required by the protocol.
Pneumococcal Electrochemiluminescence (Pn ECL) Assay
The purpose of the Pn ECL assay is to detect serum IgG antibody to the pneumococcal 
polysaccharides (PnPs) serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F, 23F, 
and 33F before and after vaccination with PnPs containing vaccine(s).  The serotypes are 
assayed in a group of 7 (types 1, 5, 6A, 7F, 19A, 22F, 33F) and a group of 8 (types 3, 4, 6B, 
9V, 14, 18C, 19F, 23F). Antibodies to these serotypes are measured in mass units (μg/mL) 
read from a standard curve prepared from a pool of adult serum, collected postvaccination 
with a PPV23 and referred to as 007sp.
The assay is based on the MSD™ technology which employs multi-spot microtiter plates 
fitted with a series of electrodes associated with the bottom of the well.  Serotype-specific 
PnPs are spotted to the MSD™ plates and used as the solid phase antigen.  Experimental, 
control, and standard curve sera are pre-adsorbed with pneumococcal cell wall 
polysaccharide (CPs) and non-vaccine heterologous serotype PnPs (types 25 and 72) to 
reduce the nonspecific antibody response in the assay, and subsequently incubated in the 
PnPs antigen-coated wells.  Anti-PnPs, which bind to the solid phase PnPs, are subsequently 
detected with a ruthenium-labeled anti-human IgG conjugate.  Plates are read by measure of 
the chemiluminescent signal emitted from the ruthenium tag upon electrochemical 
stimulation initiated at the electrode surfaces of the microplates.  The intensity of the 
luminescence is directly proportional to the amount of anti-PnPs in the sample.
Standard curves are prepared from the human Pneumococcal Standard Reference Serum, 
007sp (Center for Biologics Evaluation and Research, U.S. FDA).  The following standard 
and controls are run in each assay: (a) a 12-point standard curve which includes a serum 
diluent blank and an 11-point, 2.5-fold dilution series of 007sp that begins with an initial 
dilution of 1:400; (b) two different dilutions (1:1000 and 1:10,000) of Giebink serum 16 
(G16) and one dilution (1:1000) of Giebink serum 5 (G5), both individual human immune 
sera obtained after vaccination with PPV23 by 
 
(c) a serum sample from a previous Merck clinical trial tested at 1:10,000 dilution.  
Clinical testing on the Pn ECL assay will be performed at Merck Research Laboratories 
(MRL) or its designated partners that are qualified to perform the assay.
PPD

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Multiplex Opsonophagocytic Assay (MOPA-4)
The 4-Fold Multiplexed Opsonophagocytic Killing Assay for antibodies against 
Streptococcus pneumoniae (MOPA-4) is used to measure sera of patients vaccinated with 
multivalent pneumococcal vaccines for antibody titers (opsonic activity/killing) against the 
capsular polysaccharides for specific S. pneumoniae serotypes. The method is multiplexed 
permitting testing of 4 serotypes per run, eliminating excessive use of infant sera. The assay 
utilizes complement (baby rabbit source), a critical component, which requires qualification 
prior to use in the MOPA-4. The opsonophagocytic killing assay (OPA) also utilizes HL-60 
human Promyelocytic Leukemia cells which are transformed into phagocytes for this assay.
Complement is added in addition to bacterial strains (pneumococcal serotypes 1, 3, 4, 5, 6A, 
6B, 7F, 9V, 14, 19A, 18C, 19F, 22F, 23F, and 33F; strains tested in groups of 4) and patient 
sera. The ability of antibodies in patient sera, at a series of dilutions, to initiate the killing of 
the pneumococcal bacteria is the basis for assignment of antibody titer of the sample. The 
opsonization titers (OT) are defined as the serum dilution that kills 50% of bacteria and are 
determined using a linear interpolation algorithm. The results are reported as the reciprocal 
of the dilution.  The MOPA-4 was developed and published by Professor Moon Nahm 
(Director of the US WHO and NIH pneumococcal serology reference laboratory) [5].
Merck has been involved in the development and implementation of the MOPA-4 in 
collaboration with 
(University of Alabama [UAB], Birmingham) and 
with 
 (Institute of Child Health [ICH], London England).  Both 
labs are qualified to generate clinical results and one of them will support MOPA-4 testing 
for this study.
Both the UAB and ICH MOPA-4 produced results comparable to other OPAs, including 
those used by industry, in a WHO-sponsored inter-laboratory comparison study [6]. The 
assay has been subject to a number of iterative development and optimization cycles, 
especially at the ICH.  
Stage 1: Adult Cohort
Serum samples (approximately 40 mL) collected on Day 1 prior to vaccination and on Day 
30 postvaccination will be used to measure vaccine-induced immune responses (IgG) to the 
15 serotypes contained in V114. These serum samples will be assayed using the Meso-Scale 
Discovery MSD Pn ECL assay, which was developed by Merck & Co., Inc. for the 
measurement of pneumococcal capsular polysaccharide IgG antibodies. After completion of 
protocol-specified immunogenicity assays, leftover sera may be used for the development of
future pneumococcal assays. 
Any remaining sample will then be retained for future 
biomedical research providing the future biomedical research (FBR) consent has been signed.
Stage 2: Infant Cohort
Subjects will have blood drawn (approximately 4-5 mL) at 3 time points: (1) Day 30 
following the third study vaccination (PD3), (2) immediately prior to administration of the 
fourth study vaccination, and (3) Day 30 following the fourth study vaccination (PD4). Sera 
PPD
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will be used to measure vaccine-induced immune responses (IgG and opsonophagocytic 
killing activity [OPA]) to all 15 vaccine serotypes included in V114. These serum samples 
will be assayed using the Meso-Scale Discovery MSD Pn ECL assay, which was developed 
by Merck & Co., Inc. for the measurement of pneumococcal capsular polysaccharide IgG 
antibodies. Serum samples will also be assayed using a 4-Fold Multiplex Opsonophagocytic 
Assay which Merck has developed and implemented in collaboration with 
 
 from the University of Alabama. If a serum sample does not have enough volume for 
both the IgG and OPA testing, the IgG testing will take priority.  OPA will be evaluated in 
approximately 50% of subjects with sufficient PD3 sera available to perform both the PnECL 
and the OPA testing on all 15 serotypes in V114.  PD4 OPAs will be conducted for all of the 
subjects who had PD3 OPAs performed and for which there is sufficient serum.  Leftover 
sera may also be used for the development of future pneumococcal assays. Any remaining 
sera will be retained for future biomedical research providing the future biomedical research 
(FBR) consent has been signed.
7.1.3.2
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Buccal swabs for genomics use

Leftover serum samples collected in the main study, which would routinely be 
discarded after the main study is over
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from vaccination prior to completion of the vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
 and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
PPD
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responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity/toxicity grade
of the adverse experiences observed,   their relation to study drug, the reason thereof, etc., in 
the medical chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
7.1.4.3
Domiciling
Adult subjects will report to the clinical research unit (CRU) on the day of trial vaccination 
administration (Day 1) and remain in the CRU for 30 minutes following vaccination.  
Subjects will return 30 days later for Visit 2.  
Infant subjects will report to the CRU on the day of the administration of study vaccine (Visit 
1, 2, 3, and 5) and remain in the unit for 30 minutes postvaccination.  At the discretion of the 
investigator, subjects may be requested to remain in the CRU longer. Infants will return to 
the CRU at Visits 4 and 6 for blood draws.

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7.1.4.4
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Refrigerators

-20° freezers

Centrifuges
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Screening procedures will be performed at Visit 1.  A separate screening visit is not required.
7.1.5.2
Treatment Period/Vaccination Visit
Adult subjects will be required to come to the clinic for 2 visits.  Infant subjects will be 
required to come to the clinic for 6 visits.  See Section 6.0 for details.
7.1.5.3
Post-Trial
This protocol does not require post trial visits.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.

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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, 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. From the time of allocation/randomization through 14 days (42 days for live 
attenuated vaccines) following the first vaccination(s) and from the time of any subsequent 
vaccination(s) through 14 days (42 days for live attenuated vaccines) thereafter, all adverse 
events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets. The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
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).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is the administration of more than 1 dose of any individual study 
vaccine in any 24-hour period.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 

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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).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, 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.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours 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).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.

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Refer to Table 3 for additional details regarding each of the above criteria.  
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following the last study vaccination, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause, whether or not related to the Sponsor's 
product, must be reported within 24 hours 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).
Additionally, any serious adverse event brought to the attention of an investigator who is a 
qualified physician at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor if the event is either:
1. A death that occurs prior to the subject completing the trial, but outside the time period 
specified in the previous paragraph.
or
2. A serious adverse event that is considered by an investigator who is a qualified physician 
to be vaccine related.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours 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).

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Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
No additional events of clinical interest have been identified for this program.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 3. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 3 for instructions in evaluating adverse events.

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Table 3
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities) 
Injection site redness or swelling or hard lump (infants only) from the day of vaccination through Day 5 post-vaccination for 
adults and Day 14 post-vaccination for infants will be evaluated by maximum size.
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements; or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection 
purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the test vaccine to be discontinued?
Relationship 
to test vaccine 
Did the test vaccine cause the adverse event?   The determination of the likelihood that the test vaccine caused the adverse event will be provided by an investigator 
who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test vaccine and the adverse event based upon the 
available 
information.  
The following components are to be used to assess the relationship between the test vaccine and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the test vaccine caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the test vaccine such as:  reliable history, acceptable compliance assessment 
(e.g., diary), seroconversion or identification of vaccine virus in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the test vaccine? 
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

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Relationship
The following components are to be used to assess the relationship between the test vaccine and the AE:  (continued)
to test vaccine 
Dechallenge
(not applicable for vaccines)
(continued) 
Rechallenge
Was the subject reexposed to the test vaccine in this trial?
      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 trial is a single-dose 
vaccine trial.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE 
BEEN CAUSED BY THE TEST VACCINE, OR IF REEXPOSURE TO THE TEST VACCINE POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with Trial 
Vaccine Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test vaccine or vaccine class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.  
Record one of the following:
Use the following criteria as guidance (not all criteria must be present to be indicative of a vaccine relationship).
Yes, there is a reasonable possibility of 
vaccine relationship.
There is evidence of exposure to the test vaccine.  The temporal sequence of the AE onset relative to the administration of the test vaccine 
is reasonable.  The AE is more likely explained by the test vaccine than by another cause.
No, there is not a reasonable possibility of 
vaccine relationship
Subject did not receive the test vaccine OR temporal sequence of the AE onset relative to administration of the test vaccine is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose 
without an associated AE.)

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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Executive Oversight Committee
7.3.1
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
eDMC regarding the trial.
Data Monitoring Committee
7.3.2
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial 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 trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
Safety Monitoring
The eDMC will include clinicians experienced in vaccinology, infectious diseases 
and/or pediatrics as well as a statistician; this is in addition to the unblinded MRL 
statistician who will be a non-voting member of the committee.  
The eDMC will be provided with the following stopping rules as guidance for 
temporarily halting or terminating the study:

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If any of the following events occurs, administration of study vaccine will be 
temporarily discontinued until a thorough review of accumulated safety data is
undertaken by the eDMC, the investigators, and/or the SPONSOR’s representative.

Death in any subject, unless the cause of death is due to obvious alternative 
etiology;

Unexpected life-threatening event in any subject, unless due to obvious 
alternative etiology.  Event should not have been previously observed with 
similar pneumococcal vaccines, or vaccines administered concomitantly in 
this study;

Any serious adverse event, unless due to obvious alternative etiology, with the 
exception of those already reported for pneumococcal conjugate vaccines or 
for other concomitantly administered vaccines and deemed related to those 
vaccines;

Event in which in the opinion of the investigator and/or safety monitoring 
committee contraindicates further dosing of additional subjects.
Conclusions about the overall safety of the investigational product will otherwise be 
determined from any SAE and solicited systemic AEs with a severe intensity rating, 
regardless of relationship to vaccination.  The relationship to study vaccine is determined by 
the study investigator.
The study site and SPONSOR’s personnel involved in the conduct of the study (excluding 
the study statistician and statistical programmer) will remain blinded as to the treatment 
allocation of the study subject.  The eDMC, unblinded statistician, and statistical programmer 
will be unblinded throughout the study. The EOC will be blinded, however it may be 
unblinded to evaluate the eDMC recommendations.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) 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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Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.11.  
Study Design Overview
A Phase I-II, Randomized, Double-Blind, Study to Evaluate the 
Safety, Tolerability, and Immunogenicity of Different Formulations of 
V114 in Healthy Adults and Infants
Treatment Assignment
This is a double-blind study consisting of two cohorts.
Stage 1 - Adult Cohort: 
Four (4) groups randomly assigned (1:1:1:1 ratio) to receive a single 
dose of either V114 medium, V114 high, V114 medium with an 
alternative carrier protein, or V114 high with an alternative carrier 
protein. 
Stage 2 - Infant Cohort: 
Five (5) groups randomly assigned (1:1:1:1:1 ratio) to receive either 
V114 medium, V114 high, V114 medium with an alternative carrier 
protein, V114 high with an alternative carrier protein, or Prevnar 13™ 
(control group).
Analysis Populations
Efficacy: Per-protocol (PP)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Stage 1 – Adult Cohort:
   There are no primary immunogenicity endpoints.
Stage 2 – Infant Cohort:
1.
The GMCs for the 15 serotypes in V114 and 13 serotypes in 
Prevnar 13™ based on the serotype-specific IgG responses as 
measured in the Pn ECL assay at 1 month PD3.
Key Secondary Endpoints
Stage 1 – Adult Cohort:
1.
The GMCs and fold-rises from baseline for the 15 serotypes 
in V114 based on the serotype-specific IgG responses as 
measured in the Pn ECL assay at 1 month PD1.
Stage 2 – Infant Cohort:
1.
The proportion of subjects achieving IgG concentrations 
≥0.35µg/mL as measured in the Pn ECL assay for the 15 
serotypes in V114 and 13 serotypes in Prevnar 13™ at PD3, 
pre-dose 4, and PD4.
2.
The GMCs for the 15 serotypes in V114 and 13 serotypes in 
Prevnar 13™based on the serotype-specific IgG responses as 
measured in the Pn ECL assay at pre-dose 4 and PD4.
Statistical Methods for Key 
Immunogenicity Analyses
For the infant cohort, GMCs at PD3 along with two-sided 95% CIs 
will be computed for the 15 serotypes in V114 and 13 serotypes in 
Prevnar 13™.  Additionally, GMC ratios (V114/Prevnar 13™) along 
with two-sided 95% CIs will be computed for the 13 serotypes in 
common between V114 and Prevnar 13™ for each V114 vaccination 
arm with Prevnar 13™.  The CI for the ratio will be calculated using a 
2-sample t-test approach based on the natural logarithm of the ratio.

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Statistical Methods for Key 
Safety Analyses
For the adult cohort, within group summaries of safety (incidence 
rates and 95% CIs) will be provided for each V114 arm following a 
single dose. For the infant cohort, comparisons will be made between 
the V114 arms and Prevnar 13™ following each dose and across all 
doses.  The analysis of safety results for the infant cohort will follow a 
tiered approach (Tier 1 through Tier 3).  The Tier 1 safety endpoints in 
this study consist of the solicited injection-site (redness, swelling, and 
pain/tenderness) and solicited systemic (irritability, drowsiness, 
hives/welts, and appetite lost) AEs from the infant cohort and will be 
subject to inferential testing for statistical significance with p-values 
and 
95% 
confidence 
intervals 
provided 
for 
between-group 
comparisons (V114 versus Prevnar 13™). Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided 
for between-group (V114 versus Prevnar 13™) comparisons; only 
point estimates by treatment group are provided for Tier 3 safety 
parameters.  These analyses will be performed using the Miettinen and 
Nurminen method, an unconditional, asymptotic method.
Interim Analyses
Two interim analyses will be conducted during this study: 
(1) A first interim analysis will be performed when ~100% of the 
vaccinated subjects in the adult cohort and small infant cohort have 
completed postvaccination safety follow-up (single dose for adult 
cohort and postdose 3 for the small infant cohort) and ~100% of the 
immunogenicity results of IgG responses adult (postvaccination) and 
small cohort infant (postdose3) immunogenicity results of IgG 
responses are available; 
(2) A second interim analysis will be performed in this study when 
~100% of PD3 immunogenicity results for all infants in Stage 2 (small 
and large cohorts) are available. 
An internal statistician and statistical programmer assigned to the 
protocol will be unblinded throughout the duration of the study to 
facilitate the performing of the interim analysis as well as creation of 
the eDMC safety reports for ongoing safety review.
Results of the interim analysis will be provided and reviewed by the 
eDMC, and group summaries will be reviewed by the Sponsor’s study 
team. The Sponsor’s study team (except for the MRL statistician and 
programmer) will be blinded to the V114 formulation at the subject 
level. The Sponsor’s study team will use the results to make scientific 
decisions regarding future studies. It may also inform certain scientific 
consultations. 
Multiplicity
No multiplicity adjustment is planned since there are no formal 
hypothesis tests in this study.
Sample Size and Power 
For the infant stage of the study, approximately 250 subjects will be 
enrolled, with approximately 50 subjects in each of the five 
vaccination arms.  Assuming 90% evaluability at PD3 (~45 subjects 
per group), a standard deviation of the natural log antibody 
concentrations at PD3 of 1.0, and a one-sided alpha of 0.05, there is 
>90% power to detect a lower response (as measured by the GMC) in 
V114 for a given serotype if the true fold difference is 2-fold lower
between any two vaccination groups.

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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
This study that will be conducted in 2 stages which will enroll an adult cohort (Stage 1) and 
an infant cohort (Stage 2).  Additionally, the infant cohort will be enrolled in 2 parts (I and II) 
in order to evaluate safety in a smaller group of infants prior to full enrollment of Stage 2.  
Prior to proceeding between Stage 1 and 2, as well as between Stage 2 part I and Stage 2 part 
II, the safety and tolerability of V114 will be carefully evaluated by the eDMC.  For this 
Phase I-II study, an internal statistician and statistical programmer assigned to the protocol 
will be unblinded throughout the duration of the study to facilitate the interim reviews of the 
safety data by the eDMC.  All other MRL employees directly involved with the conduct of 
this trial will remain blinded to the subject’s treatment assignment until medical/scientific 
review of all safety and immunogenicity data has been performed, protocol deviations have 
been identified, and data have been declared final and complete.
The 2 planned interim analyses are described in Section 8.7.  The results of each interim 
analysis will not be shared with the investigators prior to the completion of the study.  
Subject-level unblinding will be restricted to an internal unblinded statistician and an 
unblinded statistical programmer performing the interim analysis.
Results of the interim analyses will be provided by the unblinded statistician to the eDMC.  
Group summaries will be reviewed by the Sponsor’s study team in order to make scientific 
decisions for future studies.
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.  This is an estimation study and no formal 
hypothesis testing will be performed.
Analysis Endpoints
8.4
Immunogenicity and safety endpoints that will be evaluated for within- and between-
treatment differences are listed below.

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Immunogenicity Endpoints
8.4.1
Adult Stage
For the adult stage of the study, there are no primary immunogenicity endpoints.  The 
secondary immunogenicity endpoints are the serotype-specific IgG GMCs and fold-rises 
from baseline as measured in the Pn ECL assay at 1 month postvaccination for the 15 
serotypes in V114.
Infant Stage
For the infant stage of the study, the primary immunogenicity endpoints are the serotype -
specific IgG GMCs as measured in the Pn ECL assay at 1 month PD3 for the 15 serotypes in 
V114 and 13 serotypes in Prevnar 13™.
The secondary immunogenicity endpoints include (1) the proportion of subjects achieving 
IgG concentrations ≥0.35µg/mL at 1 month PD3, pre-dose 4, and 1 month PD4, and (2) the 
GMCs at pre-dose 4 and 1 month PD4 for the 15 serotypes in V114 and 13 serotypes in 
Prevnar 13™.
The exploratory immunogenicity endpoints include the proportion of subjects with OPA titer 
≥8 and OPA GMTs at 1 month PD3, pre-dose 4, and 1 month PD4 for the 15 serotypes in 
V114 and 13 serotypes in Prevnar 13™.
Safety Endpoints
8.4.2
Refer to Section 4.2.3.2 for the description of the safety measures in this study.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, within both the adult and infant cohorts.  Tier 1 events for this study will consist of the 
solicited injection-site and solicited systemic AEs in the infant cohort.
Analysis Populations
8.5
Immunogenicity Analysis Populations
8.5.1
The primary immunogenicity analysis population will be the PP population.  The PP 
population consists of those subjects who are not considered protocol violators.  For the adult 
cohort, the violations include, but are not limited to: failure to receive the scheduled dose of 
correct clinical material, and lack of valid serology results available from 30 to 44 days
following dose 1.  For the infant cohort, the violations include, but are not limited to: failure 
to receive the scheduled doses (at least 28 days between doses 1 and 2 and between doses 2 
and 3, and dose 4 at 12 months to 15 months of age) of correct clinical material, and lack of 
valid serology results available from 28 to 42 days following dose 3 or dose 4.  The final 
determination on protocol violators will be made prior to unblinding of the database and will 
be documented in a separate memo.

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The Full Analysis Set (FAS) population will also be used for supplementary analysis of the 
primary analyses.  The FAS population consists of all randomized subjects who received at 
least one vaccination and have at least one serology result.  Subjects will be included in the 
treatment group to which they are randomized for the analysis of immunogenicity data.  
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received.  
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
Analysis of the immunogenicity data from the infant stage of the study will be based on the 
combined data from Stage 2 Part I and Stage 2 Part II.
To address the primary infant immunogenicity objective #2, GMCs at 1 month PD3 along 
with two-sided 95% CIs will be computed for the 15 serotypes in V114 for V114 medium, 
V114 high, and 13 serotypes in Prevnar 13™.  Point estimates of GMCs are the 
exponentiated estimates of the mean loge concentrations.  The confidence intervals for GMCs 
are the exponentiated confidence intervals for the mean loge concentrations, based on 1-
sample t-distributions.  Additionally, GMC ratios (V114/Prevnar 13™) along with two-sided 
95% CIs will be computed for each of V114 medium and V114 high relative to Prevnar 13™
for the 13 common serotypes.  The CI for the ratio will be calculated using a 2-sample t-test 
approach based on the natural logarithm of the ratio.
To address the secondary infant immunogenicity objective #1, the proportion of subjects 
achieving the serotype-specific threshold value of ≥ 0.35µg/mL for the 15 serotypes at 1 
month PD3 along with the 95% CI will be calculated for V114 medium, V114 high, and the 
13 serotypes in Prevnar 13™.  The one-sample two-sided CIs will be computed using the 
exact CI method for a single binomial proportion given in Collett [7].  Additionally, the 

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difference (V114 minus Prevnar 13™) in the proportion of subjects achieving an IgG 
concentration ≥0.35µg/mL along with two-sided 95% CIs will be computed for each of V114 
medium and V114 high relative to Prevnar 13™for the 13 serotypes in common.  The CI for 
the difference will be computed using the method of Miettinen and Nurminen [8].
The additional secondary infant immunogenicity objective (#2) as well as the secondary adult 
immunogenicity objective #1 will utilize similar statistical methods as those outlined above.
Reverse cumulative distribution functions for both IgG and OPA levels at PD3 and PD4 will 
be graphically displayed by serotype in the CSR.
Table 4 summarizes the key immunogenicity analyses.

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Table 4
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Objectives
PD3 GMCs, for the 15 serotypes in 
V114 and the 13 serotypes in 
Prevnar 13™  
[V114 medium, V114 high, 
Prevnar 13™] 
(Infant Primary Objective #2)
Within-group 
GMCs 
and 95% CI
GMC 
ratio 
(V114 
arm/Prevnar 13™) and 
95% CI (2-sample t-
test)
for 
common 
serotypes
Infant Per-Protocol
Missing data will be 
dropped
PD3 GMCs, for the 15 serotypes in 
V114 and the 13 serotypes in 
Prevnar 13™
[V114 medium, V114 high, 
Prevnar 13™] 
(Infant Primary Objective #2)
Within-group 
GMCs 
and 95% CI
GMC 
ratio 
(V114 
arm/Prevnar 
13™) 
and 95% CI (2-sample 
t-test)
for common 
serotypes
Infant FAS
[Supportive]
Missing data will be 
dropped
Secondary Objectives
PD3, pre-dose 4, PD4 %0.35, for 
the 15 serotypes in V114 and the 
13 serotypes in Prevnar 13™
[V114 medium, V114 high, 
Prevnar 13™]
(Infant Secondary Objective #1)
Within-group %0.35 
and 95% CI
Difference in %0.35 
(V114 
arm-Prevnar 
13™) and 95% CI 
(M&N) for common 
serotypes
Infant Per-Protocol
Missing data will be 
dropped
Pre-dose 4 and PD4 GMCs, for the 
15 serotypes in V114 and the 13 
serotypes in Prevnar 13™
[V114 medium, V114 high, 
Prevnar 13™]
(Infant Secondary Objective #2)
Within-group 
GMCs 
and 95% CI
GMC 
ratio 
(V114 
arm/Prevnar 13™) and 
95% CI (2-sample t-
test)
for 
common 
serotypes
Infant Per-Protocol
Missing data will be 
dropped
PD1 GMCs and fold-rises from 
baseline, for 15 serotypes in 
V114 and the 13 serotypes in 
Prevnar 13™
[V114 medium, V114 high]
(Adult Secondary Objective #1)
Within-group 
GMCs 
and 95% CI
Within-group 
fold-
rises from baseline and 
95% CI
Adult Per-Protocol
Missing data will be 
dropped
The strategy to address multiplicity issues is described in Section 8.7, Interim Analyses and 
in Section 8.8, Multiplicity.
Statistical Methods for Safety Analyses
8.6.2
Analysis of the safety data from the infant stage of the study will be based on the combined 
data from Stage 2 Part I and Stage 2 Part II.

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There are no safety hypotheses for this study.  Safety and tolerability will be assessed by 
clinical review of all relevant parameters including AEs, within both the adult and infant
cohorts.  For the adult cohort, within group summaries of safety (incidence rates and 95% 
CIs) will be provided for each V114 arm following a single dose.  For the infant cohort, 
comparisons will be made between the V114 arms and Prevnar 13™ following each dose, 
and across all doses as outlined below.  
The analysis of safety results for the infant cohort will follow a tiered approach (Table 5).  
The tiers differ with respect to the analyses that will be performed.  The Tier 1 safety 
endpoints in this study consist of the solicited injection-site (redness, swelling, and 
pain/tenderness) and solicited systemic (irritability, drowsiness, hives/welts, and appetite 
lost) AEs from the infant cohort and will be subject to inferential testing for statistical 
significance with p-values and 95% confidence intervals provided for between-group 
comparisons (V114 versus Prevnar 13™).  Other safety parameters will be considered Tier 2 
or Tier 3.  Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group (V114 versus Prevnar 13™) comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. 
Adverse experiences that are not pre-specified as Tier-1 endpoints will be classified as 
belonging to "Tier 2" or "Tier 3", based on the number of events observed.  Membership in 
Tier 2 requires that at least 4 subjects in any treatment group exhibit the event; all other 
adverse experiences will belong to Tier 3.
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% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals 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 adverse experiences.
For this protocol, the broad clinical and laboratory AE categories consisting of the percentage 
of subjects with any AE, a vaccine related AE, a serious AE, an AE which is both vaccine-
related and serious, and who discontinued due to an AE will be considered Tier 2 endpoints. 
For Tier 2, 95% confidence intervals will be provided for between-treatment differences in 
the percentage of subjects with events; these analyses will be performed using the Miettinen 
and Nurminen method (1985) [8], an unconditional, asymptotic method.

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Table 5
Analysis Strategy for Infant Cohort Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Solicited Injection-Site and Solicited Systemic 
AEs
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Vaccine-Related AE
X
X
Any Serious and Vaccine-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs (incidence ≥4 of subjects 
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects 
in all of the treatment groups)
X
†Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; X = results will be provided.
Summaries of Demographic and Baseline Characteristics
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
Interim Analyses
8.7
Two interim analyses will be conducted during this study: (1) A first interim analysis will be 
performed when ~100% of the vaccinated subjects in the adult cohort and small infant cohort 
have completed postvaccination safety follow-up (single dose for adult cohort and postdose 3 
for the small infant cohort) and ~100% of the immunogenicity results of IgG responses for 
adults (postvaccination) and small infant cohort (postdose 3) are available; (2) A second 
interim analysis will be performed in this study when ~100% of PD3 immunogenicity results 
for all infants in Stage 2 (small and large cohorts) are available.  An internal statistician and 
statistical programmer assigned to the protocol will be unblinded throughout the duration of 
the study to facilitate the performing of the interim analysis as well as creation of the eDMC 
safety reports for ongoing safety review.  Results of the interim analysis will be provided to 
the eDMC, and group summaries will be reviewed by the Sponsor’s study team.  The 
Sponsor’s study team (except for the MRL statistician and programmer) will be blinded to 
the V114 formulation at the subject level. The Sponsor’s study team will use the results to 

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make scientific decisions regarding future studies. It may also inform certain scientific 
consultations.  No multiplicity adjustments will be made in either interim analysis as the 
conduct of the study will not be altered.
The endpoints, timing, and purpose of the interim analyses are summarized in Table 6.
Table 6
Summary of Interim Analysis Strategy
Interim 
Analysis
Key Endpoints of Interim Analysis
Timing of Interim Analysis
Purpose of 
Interim 
Analysis
Adult and 
small 
infant 
cohort

Adult GMC ratios for each of 
the 15 serotypes contained in 
V114.

Adult GMCs at baseline 
and1 month postvaccination,
GMFR and % of subjects who 
achieved at least 4-fold rise at 
1 month postvaccination for 
each of the 15 serotypes 
contained in V114.

Adult percentage of subjects 
with any AE, a vaccine related 
AE, a serious AE, an AE 
which is both vaccine-related 
and serious, and who 
discontinued due to an AE.

Small infant cohort PD3 
GMCs and GMC ratios, for 
the 15 serotypes contained in 
V114.

Small infant cohort PD3 
proportion of subjects of 
subjects achieving 
concentrations ≥0.35 µg/mL 
and differences, for each of 
the 15 serotypes in V114.

Percentage of infants in the 
small cohort with any AE, a 
vaccine related AE, a serious 
AE, an AE which is both 
vaccine-related and serious, 
and who discontinued due to 
an AE after each vaccination.
~100% of the adult cohort and small cohort 
of infants have completed safety follow-up 
(postvaccination for adult cohort and 
postdose 3 for small infant cohort) and 
~100% of the immunogenicity results (IgG 
responses) for adult (postvaccination) and 
small infant (postdose 3) cohorts are 
available.
Inform 
scientific 
decisions 
for future 
studies

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Interim 
Analysis
Key Endpoints of Interim Analysis
Timing of Interim Analysis
Purpose of 
Interim 
Analysis
All Infant
Cohorts

Infant PD3 GMCs and ratios, 
for the 15 serotypes contained 
in V114.

Infant PD3 proportion of 
subjects achieving IgG 
concentrations ≥0.35 µg/mL 
and differences, for each of 
the 15 serotypes in V114.

Infant PD3 percentage of 
subjects with any AE, a 
vaccine related AE, a serious 
AE, an AE which is both 
vaccine-related and serious, 
and who discontinued due to 
an AE.
~100% of PD3 immunogenicity results (IgG 
responses) for all infants (small and large 
cohorts) are available.
Inform 
scientific 
decisions 
for future 
studies
Multiplicity
8.8
Since there are no formal hypothesis tests in this study, no adjustment will be made for 
multiplicity.  
Sample Size and Power Calculations
8.9
For the adult stage of the study, a total of 80 subjects will be randomized to one of four 
vaccination groups in order to evaluate the safety of a single vaccination of V114.  
For the infant stage of the study, approximately 250 subjects will be enrolled, with 
approximately 50 subjects in each of the five vaccination arms.  The probability of detecting 
a lower response (as measured by the GMC) for a given serotype between 2 vaccination 
groups depends on the variability of the natural log antibody concentrations and the true 
difference between the groups.  In Table 7, the powers for detecting a lower response for 
various standard deviation estimates and true fold difference are displayed assuming 45 
evaluable subjects per group (90% evaluability) and a one-sided alpha of 0.05. Given the 
standard deviation of the natural log antibody concentrations at PD3 is 1.0 and the true fold 
difference is 2-fold lower between any two vaccination groups, there is >90% (94.7%) power 
to detect a lower response (as measured by the GMC) in V114 for a given serotype.

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Table 7
Power for Detecting a Lower Response for Varying Standard Deviation and 
True Differences with 45 Evaluable Subjects
SD of natural log 
concentrations†
True Fold-Difference Between Groups for a Given Serotype
1.5
2.0
2.5
0.8
77.1%
99.3%
>99%
1.0
60.4%
94.7%
99.6%
1.2
47.8%
85.9%
97.4%
1.4
38.9%
75.3%
92.4%
†The standard deviation (SD) estimates are representative of those observed in V114-003.
The widths of the 95% CIs for the serotype-specific GMCs depend on the sample size, 
variability of the natural log concentrations, and the magnitude of the GMC.  It is assumed 
that 90% (45 subjects) of the subjects in each group will have evaluable immunogenicity 
results at 1 month PD3.  In Table 8, the 95% CIs for various hypothetical GMCs and 
standard deviation estimates for the natural log concentrations are displayed.  
Table 8
95% CIs for Varying Standard Deviation and GMC Values with 45 Evaluable 
Subjects
SD of natural log 
concentrations†
Serotype-specific GMC†
1.0
2.0
3.0
0.8
(0.79, 1.27)
(1.57, 2.54)
(2.36, 3.81)
1.0
(0.74, 1.35)
(1.48, 2.70)
(2.22, 4.05)
1.2
(0.70, 1.43)
(1.39, 2.87)
(2.09, 4.30)
1.4
(0.66, 1.52)
(1.31, 3.05)
(1.97, 4.57)
†The standard deviation (SD) and GMC estimates are representative of those observed in V114-003.
Subgroup Analyses and Effect of Baseline Factors
8.10
No analyses for these factors will be performed.

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Extent of Exposure
8.11
The number of subjects vaccinated at each vaccination visit will be summarized by 
vaccination group.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 9.
Clinical supplies will be packaged to support enrollment as required.
Table 9
Product Descriptions
Product Name & Potency
Dosage Form
V114 medium 
0.5 mL dose sterile suspension for I.M. injection
V114 high 
0.5 mL dose sterile suspension for I.M. injection
V114 medium with an alternative carrier protein 
0.5 mL dose sterile suspension for I.M. injection
V114 high with an alternative carrier protein
0.5 mL dose sterile suspension for I.M. injection
Prevnar 13™
0.5 mL dose sterile suspension for I.M. injection
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Sites will receive open label, single dose syringe kits. Each kit will contain 1 syringe.
Clinical Supplies Disclosure
9.3
This trial is blinded but provided open label; therefore, an unblinded pharmacist or qualified 
trial site personnel will be used to blind supplies. Vaccine identity (name, strength or 
potency) is included in the label text; random code/disclosure envelopes or lists are provided.
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask vaccine identity. In the event that the emergency unblinding 
call center is not available for a given site in this trial, the central electronic randomization 
system (IVRS/IWRS) should be used in order to unblind subjects and to unmask 

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treatment/vaccine identity. The Sponsor will not provide random code/disclosure envelopes 
or lists with the clinical supplies.
Vaccine identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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.
Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign vaccine to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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 

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be divulged to the institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.

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Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  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.
Compliance with Financial Disclosure Requirements
10.2
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 or through a secure password-protected electronic portal 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.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.

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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 

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conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.

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Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 

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paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.

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11.0 LIST OF REFERENCES
[1]
Cherian T. WHO expert consultation on serotype composition of pneumococcal 
conjugate vaccines for use in resource-poor developing countries, 26-27 October 
2006, Geneva. Vaccine 2007;25:6557-64.
[2]
Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, et al. 
Sustained reductions in invasive pneumococcal disease in the era of conjugate 
vaccine. J Infect Dis 2010;201(1):32-41.
[3]
World Health Organization.  WHO Expert Committee on Biological Standardization: 
fifty-fourth report. WHO technical report series, 927; Geneva 2005.
[4]
World Health Organization. WHO/Health Canada Consultation on Serological 
Criteria for Evaluation and Licensing of New Pneumococcal Vaccines.  2008 Jul 7-8. 
Ottawa, Canada, 2008:1-39.
[5]
Burton RL, Nahm MH. Development and validation of a fourfold multiplexed 
opsonization assay (MOPA4) for pneumococcal antibodies. Clin Vaccine Immunol 
2006;13(9):1004-9.
[6]
Rose CE, Romero-Steiner S, Burton RL, Carlone GM, Goldblatt D, Nahm MH, et al. 
Multilaboratory comparison of Streptococcus pneumoniae opsonophagocytic killing 
assays and their level of agreement for the determination of functional antibody 
activity in human reference sera. Clin Vaccine Immunol 2011;18(1):135-42.
[7]
Collett D. Statistical inference for binary data. In: Collett D, ed. Modelling Binary 
Data. New York: Chapman & Hall, 1991:17-42.
[8]
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. Stat Med 
1985;4:213-26.

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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 

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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."

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Collection and Management of Specimens for Future Biomedical Research
12.2
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 collected in this trial as outlined in Section 7.1.3.2 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 

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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in the 
electronic Case Report Forms (eCRFs). Any specimens for which such an informed 
consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Buccal swab specimens for DNA isolation will be obtained at a time when the subject 
is having other trial procedures conducted. Specimens like tissue and bone marrow 
will usually be obtained at a time when the subject is having such a procedure for 
clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject 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 subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 

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privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(
 and a form will be provided by Merck to 
PPD

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obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not 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 acquisition.  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 trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 

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maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
Buccal swab specimens will be collected inside the cheek with no associated 
venipuncture to obtain the specimen. Therefore, there will not be an additional risk for 
the subject.
Merck has developed strict security, policies and procedures to address subject 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.

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13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
PPD

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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff

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Approximate Blood Volumes Drawn by Trial Visit and by Sample Types
12.4
Adult Cohort 
Trial Visit:
Visits 1
Visit 2
Blood Parameter
Approximate Blood 
Volume (mL)
ECL/OPA Assay
40 mL
40 mL
Expected Total (mL)
40 mL
40 mL
Infant Cohort 
Trial Visit:
Visit 4
Visit 5
Visit 6
Blood Parameter
Approximate Blood Volume (mL)
ECL/OPA Assay
5 mL
5 mL
5 mL
Expected Total (mL)
5 mL
5 mL
5 mL

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List of Abbreviations
12.5
ACIP 
U.S. Advisory Committee on Immunization Practices
AEs 
Adverse Events/Experiences
ASaT 
All subjects as treated
CIs 
Confidence Intervals
CSR 
Clinical Study Report
DEG
Data Entry Guideline 
eCRF 
Electronic Case Report Form
eDMC 
external Data Monitoring Committee 
EOC
Executive Oversight Committee
ePRO
Electronic Patient Reported Outcome
ERC 
Ethics Review Committee
EU 
European Union
FBR
Future Biomedical Research
FDAAA 
Food and Drug Administration Amendments Act
FDAMA 
Food and Drug Administration Modernization Act
GCPs 
Good Clinical Practices
GMCs 
Geometric Mean Concentrations
GMTs
Geometric Mean Titers
HEENT
Head, Eyes, Ears, Nose and Throat
IB
Investigator’s Brochure
ICF
Informed Consent Form
IPD 
Invasive Pneumococcal Disease
IRB 
Institutional Review Board
IUD
Intrauterine Device
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
MAPA 
Merck Aluminum Phosphate Adjuvant
MOPA-4
Multiplexed OPA Assay
MRL
Merck Research Laboratories
MSD
Meso-Scale Discovery
OPA 
Opsonophagocytic Killing Activity

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PCV
Pneumococcal Conjugate Vaccine
PD1
Postdose 1
PD3
Postdose 3
PD4
Postdose 4
Pn ECL 
Pneumococcal Electrochemiluminescence
PnPs
Pneumococcal Polysaccharides
PP 
Per-protocol
PRO
Patient Reported Outcome]
PS20
Polysorbate 20
PS80
Polysorbate 80
RCDC
Reverse Cumulative Distribution Curve
SAE
Serious Adverse Event/Experience
SAP 
Statistical Analysis Plan
SOPs 
Standard Operating Procedures
US 
United States
VRC 
Vaccination Report Card
WHO 
World Health Organization

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Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
12.6
Preventative Vaccine Clinical Trials
Protocol Specific Injection-Site AE Toxicity Guidance
Injection-Site AE Toxicity Grading Scale
Injection Site 
Reaction to Study 
Vaccine/Placebo*
Grade 1
Grade 2
Grade 3
Grade 4
Injection-site AEs occurring days 1 through 5 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
Emergency room 
(ER) visit or 
hospitalization
Erythema/Redness
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or 
exfoliative 
dermatitis or results 
in ER visit or 
hospitalization
Induration/Swelling
Size measured as
B
Size measured as
C or D
Size measured as
E→
Necrosis or ER visit 
or hospitalization
Other 
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Any injection-site reaction that begins  ≥ 6 days after receipt of study vaccine
Pain/tenderness
Erythema/Redness
Induration/Swelling
Other
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalization
*Based upon information provided by the patient on the Vaccine Report Card (VRC) and verbally during VRC 
review.  Erythema/Redness/Induration and Swelling are specific injection-site AEs with size designations of letters 
A through E→, based upon a graphic in the VRC. Size A is not assigned a toxicity grade; however, injection-site 
AEs that measure size A should be reported as adverse experiences.  If the patient has an ER visit or is hospitalized 
for any injection-site AE, that AE is to be assigned a toxicity grade of 4, regardless of the size measured.

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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED