A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of the Concomitant Administration of Either 23-Valent Pneumococcal Polysaccharide Vaccine or 15-Valent Pneumococcal Conjugate Vaccine With a Booster Dose of SARS-CoV-2 mRNA Vaccine in Healthy Adults 50 Years of Age or Older.
Phase: PHASE3
Conditions: Pneumococcal Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05158140 
Document Date: 
12-Dec-2022
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to
 Evaluate the Safety, Tolerability, and Immunogenicity of the 
Concomitant Administration of Either 23-Valent Pneumococcal Polysaccharide 
Vaccine or 15-Valent Pneumococcal Conjugate Vaccine with a Booster Dose 
of SARS-CoV-2 mRNA Vaccine in Healthy Adults 50 Years of Age or Older.

PRODUCT: V110
1
PROTOCOL/AMENDMENT NO.: 911-03
V110-911-03 FINAL PROTOCOL
12-DEC-2022
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, and Immunogenicity of the Concomitant Administration of Either 
23-Valent Pneumococcal Polysaccharide Vaccine or 15-Valent Pneumococcal Conjugate 
Vaccine with a Booster Dose of SARS-CoV-2 mRNA Vaccine in Healthy Adults 50 Years of 
Age or Older.
Protocol Number: 911-03
Compound Number: V110
Sponsor Name: Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05158140
EU CT
Not applicable
EudraCT
2021-003414-39
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
00618
IND
14977
Approval Date: 12 December 2022
08DX3L

PRODUCT: V110
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PROTOCOL/AMENDMENT NO.: 911-03
V110-911-03 FINAL PROTOCOL
12-DEC-2022
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
08DX3L

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PRODUCT: V110
4
PROTOCOL/AMENDMENT NO.: 911-03
V110-911-03 FINAL PROTOCOL
12-DEC-2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment:
The primary purpose of this amendment is to change from a hypothesis-driven study to a descriptive study design due to early closure 
of enrollment brought on by the rescinding of the monovalent booster EUA.
Section # and Name
Description of Change 
Brief Rationale 
Section 1.1 Synopsis
Section 1.2 Schema
Section 2 Introduction
Section 3 Hypotheses, Objective, and 
Endpoints
Section 4.1 Overall Design
Section 9 Statistical Analysis Plan
Section 9.1 Statistical Analysis Plan 
Summary
Section 9.3 Hypotheses/Estimation
Section 9.6.1 Statistical Methods for 
Immunogenicity Analyses
Section 9.6.2 Statistical Methods for 
Safety Analyses
Section 9.8 Multiplicity
Section 9.9 Sample Size and Power 
Calculations

Changed the study design from comparative, 
hypothesis-driven to descriptive.

Changed the planned enrollment from approximately 
1300 to the approximately 850 participants currently 
enrolled and dosed (with or without a single booster of 
the mRNA-1273 SARS-CoV-2) in the study.

Changed study duration from approximately 18 months
to approximately 14 months.
The EUA for the monovalent 
booster (mRNA-1273) was 
rescinded on 31-AUG-2022
and is no longer available for 
use as a booster dose.
08DX3L

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PRODUCT: V110
6
PROTOCOL/AMENDMENT NO.: 911-03
V110-911-03 FINAL PROTOCOL
12-DEC-2022
TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
2
INTRODUCTION..........................................................................................................22
2.1
Study Rationale....................................................................................................22
2.2
Background ..........................................................................................................23
2.2.1
Pharmaceutical and Therapeutic Background .............................................23
2.2.2
Preclinical and Clinical Studies ...................................................................24
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................25
4
STUDY DESIGN............................................................................................................28
4.1
Overall Design......................................................................................................28
4.2
Scientific Rationale for Study Design.................................................................29
4.2.1
Rationale for Endpoints ...............................................................................29
4.2.1.1
Immunogenicity Endpoints................................................................29
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints..............................29
4.2.1.1.2
SARS-CoV-2 Immunogenicity Endpoints...............................30
4.2.1.2
Safety Endpoints................................................................................30
4.2.1.3
Future Biomedical Research..............................................................30
4.2.2
Rationale for the Use of Comparator/Placebo .............................................31
4.3
Justification for Dose...........................................................................................31
4.4
Beginning and End-of-Study Definition ............................................................31
4.4.1
Clinical Criteria for Early Study Termination .............................................31
5
STUDY POPULATION ................................................................................................32
5.1
Inclusion Criteria.................................................................................................32
5.2
Exclusion Criteria................................................................................................33
5.3
Lifestyle Considerations......................................................................................35
5.4
Screen Failures.....................................................................................................35
5.5
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................37
6.1
Study Intervention(s) Administered...................................................................37
6.1.1
Medical Devices...........................................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................40
6.2.1
Dose Preparation..........................................................................................40
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6.2.2
Handling, Storage, and Accountability........................................................40
6.3
Measures to Minimize Bias: Randomization and Blinding..............................41
6.3.1
Intervention Assignment..............................................................................41
6.3.2
Stratification.................................................................................................41
6.3.3
Blinding........................................................................................................41
6.4
Study Intervention Compliance..........................................................................42
6.5
Concomitant Therapy..........................................................................................42
6.5.1
Rescue Medications and Supportive Care ...................................................43
6.6
Dose Modification ................................................................................................43
6.7
Intervention After the End of the Study............................................................43
6.8
Clinical Supplies Disclosure................................................................................43
6.9
Standard Policies..................................................................................................44
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................45
7.1
Discontinuation of Study Intervention...............................................................45
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................46
8
STUDY ASSESSMENTS AND PROCEDURES........................................................47
8.1
Administrative and General Procedures ...........................................................48
8.1.1
Informed Consent.........................................................................................48
8.1.1.1
General Informed Consent.................................................................48
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................48
8.1.2
Inclusion/Exclusion Criteria ........................................................................48
8.1.3
Participant Identification Card.....................................................................49
8.1.4
Medical History ...........................................................................................49
8.1.5
Prior and Concomitant Medications Review...............................................49
8.1.5.1
Prior Medications...............................................................................49
8.1.5.2
Concomitant Medications..................................................................49
8.1.6
Assignment of Screening Number...............................................................50
8.1.7
Assignment of Treatment/Randomization Number.....................................50
8.1.8
Study Intervention Administration ..............................................................50
8.1.8.1
Timing of Dose Administration.........................................................51
8.1.9
Electronic Vaccination Report Card ............................................................51
8.1.10
Telephone Contact on Day 10 Postvaccination ...........................................51
8.1.11
Telephone Contact Questionnaire................................................................51
8.1.12
Discontinuation and Withdrawal .................................................................51
8.1.12.1
Withdrawal From Future Biomedical Research ................................52
8.1.13
Participant Blinding/Unblinding..................................................................52
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8.1.14
Calibration of Equipment.............................................................................53
8.2
Immunogenicity Assessments .............................................................................53
8.2.1
Multiplex Opsonophagocytic Assay............................................................53
8.2.2
SARS-CoV-2 Electrochemiluminescence Assay ........................................54
8.2.3
SARS-CoV-2 Neutralizing Antibody Assay ...............................................54
8.3
Safety Assessments...............................................................................................54
8.3.1
Physical Examinations.................................................................................55
8.3.2
Pregnancy Testing........................................................................................55
8.3.3
Body Temperature Measurement.................................................................55
8.3.4
Postvaccination Observation Period ............................................................55
8.3.5
Clinical Safety Laboratory Assessments .....................................................56
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................56
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................56
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......59
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...59
8.4.4
Regulatory Reporting Requirements for SAE .............................................59
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................59
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................60
8.4.7
Events of Clinical Interest............................................................................60
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions......................................................................................60
8.4.9
Adverse Events on the VRC ........................................................................60
8.4.9.1
Solicited Adverse Event.....................................................................60
8.4.9.2
Unsolicited Adverse Events...............................................................61
8.5
Treatment of Overdose........................................................................................61
8.6
Pharmacokinetics.................................................................................................61
8.7
Pharmacodynamics..............................................................................................61
8.8
Biomarkers ...........................................................................................................61
8.9
Future Biomedical Research Sample Collection...............................................62
8.10
Health Economics Medical Resource Utilization and Health Economics.......62
8.11
Visit Requirements...............................................................................................62
8.11.1
Screening......................................................................................................62
8.11.2
Treatment Period/Vaccination Visit ............................................................62
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................62
9
STATISTICAL ANALYSIS PLAN .............................................................................63
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9.1
Statistical Analysis Plan Summary.....................................................................63
9.2
Responsibility for Analyses/In-house Blinding .................................................64
9.3
Hypotheses/Estimation ........................................................................................64
9.4
Analysis Endpoints...............................................................................................64
9.4.1
Immunogenicity Endpoints..........................................................................64
9.4.2
Safety Endpoints..........................................................................................65
9.5
Analysis Populations............................................................................................66
9.5.1
Immunogenicity Analysis Populations ........................................................66
9.5.2
Safety Analysis Populations ........................................................................67
9.6
Statistical Methods...............................................................................................67
9.6.1
Statistical Methods for Immunogenicity Analyses......................................67
9.6.2
Statistical Methods for Safety Analyses ......................................................68
9.6.3
Demographic and Baseline Characteristics .................................................71
9.7
Interim Analyses ..................................................................................................71
9.8
Multiplicity ...........................................................................................................71
9.9
Sample Size and Power Calculations .................................................................71
9.9.1
Immunogenicity Analyses ...........................................................................71
9.9.2
Safety Analyses............................................................................................72
9.10
Subgroup Analyses...............................................................................................72
9.11
Compliance (Medication Adherence).................................................................72
9.12
Extent of Exposure...............................................................................................72
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................73
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........73
10.1.1
Code of Conduct for Clinical Trials.............................................................73
10.1.2
Financial Disclosure.....................................................................................76
10.1.3
Data Protection.............................................................................................77
10.1.3.1
Confidentiality of Data ......................................................................77
10.1.3.2
Confidentiality of Participant Records...............................................77
10.1.3.3
Confidentiality of IRB/IEC Information............................................77
10.1.4
Publication Policy........................................................................................78
10.1.5
Compliance with Study Registration and Results Posting Requirements ...78
10.1.6
Compliance with Law, Audit, and Debarment ............................................78
10.1.7
Data Quality Assurance ...............................................................................79
10.1.8
Source Documents .......................................................................................80
10.1.9
Study and Site Closure.................................................................................80
10.2
Appendix 2: Clinical Laboratory Tests..............................................................81
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................82
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10.3.1
Definition of AE ..........................................................................................82
10.3.2
Definition of SAE ........................................................................................87
10.3.3
Additional Events Reported.........................................................................88
10.3.4
Recording AE and SAE ...............................................................................88
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................93
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................95
10.4.1
Definitions....................................................................................................95
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....96
10.5
Appendix 5: Contraceptive Guidance................................................................97
10.5.1
Definitions....................................................................................................97
10.5.2
Contraceptive Requirements........................................................................98
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................99
10.7
Appendix 7: Country-specific Requirements..................................................103
10.8
Appendix 8: Abbreviations ...............................................................................104
11
REFERENCES.............................................................................................................107
08DX3L

PRODUCT: V110
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PROTOCOL/AMENDMENT NO.: 911-03
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12-DEC-2022
LIST OF TABLES
Table 1
Study Interventions..........................................................................................38
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Type ....47
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................58
Table 4
Solicited Adverse Events .................................................................................61
Table 5
Analysis Strategy for Key Immunogenicity Variables....................................68
Table 6
Analysis Strategy for Safety Parameters..........................................................69
Table 7
Within-group 95% CIs for Varying OPA/bAb GMTs and Standard 
Deviations ........................................................................................................71
Table 8
Protocol-required Safety Laboratory Assessments..........................................81
08DX3L

PRODUCT: V110
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LIST OF FIGURES
Figure 1
Study Design................................................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, and Immunogenicity of the Concomitant Administration of Either 
23-Valent Pneumococcal Polysaccharide Vaccine or 15-Valent Pneumococcal Conjugate 
Vaccine with a Booster Dose of SARS-CoV-2 mRNA Vaccine in Healthy Adults 50 Years of 
Age or Older.
Short Title: Coadministration of V110 or V114 With mRNA-1273 in Healthy Adults
Acronym: None
Hypotheses, Objectives, and Endpoints:
Objectives and endpoints described below will be evaluated in adults 50 years of age and 
older who previously completed a 2-dose primary series of the mRNA-1273 SARS-CoV-2 
vaccine with or without a single booster dose of the mRNA-1273 SARS-CoV-2 vaccine:
Primary Objectives
Primary Endpoints
•
To evaluate the safety and tolerability of 
V110 and mRNA-1273 when 
administered concomitantly or 
nonconcomitantly with respect to the 
proportion of participants with adverse 
events (AEs) within each vaccination 
group, separately
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related serious adverse events 
(SAEs)
•
To evaluate the safety and tolerability of 
V114 and mRNA-1273 when 
administered concomitantly or
nonconcomitantly with respect to the 
proportion of participants with AEs
within each vaccination group,
separately
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related SAEs
•
To evaluate the serotype-specific 
opsonophagocytic activity (OPA) 
geometric mean titers (GMTs) at 30 
days postvaccination with V110 when 
administered concomitantly or
nonconcomitantly with mRNA-1273 
within each vaccination group,
separately
•
Serotype-specific OPA responses
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PRODUCT: V110
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PROTOCOL/AMENDMENT NO.: 911-03
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•
To evaluate the serotype-specific OPA 
GMTs at 30 days postvaccination with 
V114 when administered concomitantly 
or nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately
•
Serotype-specific OPA responses
•
To evaluate the SARS-CoV-2-specific 
binding antibody (bAb) GMTs at 30 
days postvaccination when administered 
concomitantly or nonconcomitantly with 
V110 within each vaccination group, 
separately
•
SARS-CoV-2-specific bAb responses
•
To evaluate the SARS-CoV-2-specific 
bAb GMTs at 30 days postvaccination 
when administered concomitantly or 
nonconcomitantly with V114 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
Secondary Objectives
Secondary Endpoints
•
To evaluate the serotype-specific 
geometric mean fold rises (GMFRs) and 
proportions of participants with a 
≥4-fold rise from baseline 
(prevaccination with V110) to 30 days 
postvaccination with V110 for OPA 
responses for participants administered 
V110 concomitantly or 
nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately 
•
Serotype-specific OPA responses
•
To evaluate the serotype-specific 
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline 
(prevaccination with V114) to 30 days 
postvaccination with V114 for OPA 
responses for participants administered 
V114 concomitantly or 
nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately
•
Serotypes-specific OPA responses
08DX3L

PRODUCT: V110
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PROTOCOL/AMENDMENT NO.: 911-03
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•
To evaluate the GMFRs and proportions 
of participants with a ≥4-fold rise from 
baseline (prevaccination with 
mRNA-1273) to 30 days 
postvaccination with mRNA-1273 for 
SARS-CoV-2-specific bAb responses 
for participants administered 
mRNA-1273 concomitantly or 
nonconcomitantly with V110 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
•
To evaluate the GMFRs and proportions 
of participants with a ≥4-fold rise from 
baseline (prevaccination with 
mRNA-1273) to 30 days 
postvaccination with mRNA-1273 for 
SARS-CoV-2-specific bAb responses 
for participants administered 
mRNA-1273 concomitantly or 
nonconcomitantly with V114 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Pneumococcal infection
Population
Adults 50 years of age and older who 
previously completed a 2-dose primary 
series of the mRNA-1273 SARS-CoV-2 
vaccine with or without a single booster 
dose of the mRNA-1273 SARS-CoV-2 
vaccine
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
08DX3L

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CCI
';/

PRODUCT: V110
17
PROTOCOL/AMENDMENT NO.: 911-03
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
V110
Concomitant Group
V110
Refer to 
product 
labeling
0.5 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V110 Concomitant 
Group
mRNA-1273
50 µg
0.25 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V110 Concomitant 
Group
Placebo 
(Sterile 
Saline)
N/A
0.5 mL
IM
Single Dose at Visit 3
(Day 30)
Placebo
V110 
Nonconcomitant 
Group
Placebo 
(Sterile 
Saline)
N/A
0.5 mL
IM
Single Dose at Visit 1 
(Day 1)
Placebo
V110 
Nonconcomitant 
Group
mRNA-1273
50 µg
0.25 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V110 
Nonconcomitant 
Group
V110
Refer to 
product 
labeling
0.5 mL
IM
Single Dose at Visit 3
(Day 30)
Test 
Product
V114 Concomitant 
Group
V114
Refer to 
product 
labeling
0.5 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V114 Concomitant 
Group
mRNA-1273
50 µg
0.25 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V114 Concomitant 
Group
Placebo 
(Sterile saline)
N/A
0.5 mL
IM
Single Dose at Visit 3 
(Day 30)
Test 
Product
V114 
Nonconcomitant 
Group
Placebo 
(Sterile saline)
N/A
0.5 mL
IM
Single Dose at Visit 1 
(Day 1)
Placebo
V114 
Nonconcomitant 
Group
mRNA-1273
50 µg
0.25 mL
IM
Single Dose at Visit 1 
(Day 1)
Test 
Product
V114 
Nonconcomitant 
Group
V114
Refer to 
product 
labeling
0.5 mL
IM
Single Dose at Visit 3 
(Day 30)
Test 
Product
Total Number of 
Intervention Groups/Arms
4
Duration of Participation
Each participant will participate in the study for 
approximately 6 months from the time the participant 
provides documented informed consent through the final 
contact.
08DX3L

PRODUCT: V110
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study.
Study Accepts Healthy Participants: Yes
A list of abbreviations is in Appendix 8.
08DX3L

PRODUCT: V110
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
08DX3L

PRODUCT: V110
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1.3
Schedule of Activities
Study Period
Intervention
Follow-up
Notes
Visit Type:
Visit
(Vaccination 1)
TC
Visit 
(Vaccination 2)
TC
Visit
TC
Visit Number:
1
2
3
4
5
6
Scheduled Time: 
Day 1
Day 10
Day 30
Day 40
Day 60
Month 6
Visit Window:
Day 10 to 
Day 14
after Visit 1
Day 30 to
Day 44
after Visit 1
Day 10 to 
Day 14
after Visit 3
Day 30 to 
Day 44
after Visit 3
Day 166 to 
Day 194
after Visit 1
For calculating the visit windows, the day of 
vaccination is considered Day 1.
Administrative and General Procedures
Screening Procedures
Informed Consent
X
Documented consent must be obtained before any 
study procedures.
Informed Consent for FBR
X
Participation in FBR is optional and documented 
consent must be obtained before the blood sample 
(DNA sample) is collected.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Medical History
X
Postrandomization Procedures
Assignment of Randomization 
Number
X
Participant Identification Card
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
X
X
X
Pneumococcal Vaccine (V110 or 
V114) or Placebo Administration 
(Blinded)-Left Arm
X
X
SARS-CoV-2 Vaccine 
(mRNA-1273) Administration 
(Open label)-Right Arm
X
Provide or Configure Electronic 
Device for eVRC Data Collection
X
Review eVRC Data With 
Participant 
X
X
X
X
Collect Electronic Device From
Participant
X
For participants who received an electronic device.
Complete Telephone Contact 
Questionnaire
X
08DX3L

PRODUCT: V110
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Study Period
Intervention
Follow-up
Notes
Visit Type:
Visit
(Vaccination 1)
TC
Visit 
(Vaccination 2)
TC
Visit
TC
Visit Number:
1
2
3
4
5
6
Scheduled Time: 
Day 1
Day 10
Day 30
Day 40
Day 60
Month 6
Visit Window:
Day 10 to 
Day 14
after Visit 1
Day 30 to
Day 44
after Visit 1
Day 10 to 
Day 14
after Visit 3
Day 30 to 
Day 44
after Visit 3
Day 166 to 
Day 194
after Visit 1
For calculating the visit windows, the day of 
vaccination is considered Day 1.
Safety Procedures
Complete Physical Examination 
X
Performed by the investigator or medically qualified 
designee at screening and before vaccination.
Targeted Physical Examination
X
Performed by the investigator or medically qualified 
designee before vaccination.
Pregnancy Test (If Applicable)
X
X
Urine or serum pregnancy test consistent with local 
requirements (sensitive to ≤25 IU hCG) must be 
performed and negative results available before 
vaccination of females of reproductive potential.
Body Temperature Measurement 
Before Vaccination
X
X
Measured before vaccination. Participants with 
febrile illness within 72 hours before vaccination 
must be rescheduled.
Postvaccination Observation 
Period
X
X
Observed by blinded study-site personnel for 
≥30 minutes postvaccination.
AE Monitoring
X
X
X
X
X
X
Nonserious AEs reported Day 1 through Day 28 after 
each vaccination. AESIs, SAEs, and deaths reported 
Day 1 through the duration of study participation.
Immunogenicity Procedures
Serum for Pneumococcal 
Immunogenicity Assay (Including 
Retention Serum)
X
X
X
Samples at Visit 1 and Visit 3 collected before
vaccination.
Serum for SARS-CoV-2 
Immunogenicity Assays (Including 
Retention Serum)
X
X
Samples collected before vaccination.
Future Biomedical Research
Blood (DNA) for FBR
X
Samples obtained before vaccination at Visit 1 for 
participants who provided FBR consent, or at a later 
date as soon as the FBR consent is obtained.
AE=adverse event; AESI=adverse event of special interest; DNA=deoxyribonucleic acid; eVRC=electronic Vaccination Report Card; FBR=future biomedical research; 
FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.
08DX3L

PRODUCT: V110
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PROTOCOL/AMENDMENT NO.: 911-03
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12-DEC-2022
2
INTRODUCTION
PNEUMOVAX™23 (V110) is a 23-valent pneumococcal polysaccharide vaccine indicated 
for the prevention of pneumococcal disease caused by the 23 serotypes contained in the 
vaccine (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 
22F, 23F, and 33F) in persons 50 years of age and older and in persons 2 years of age and 
older who are at risk for pneumococcal disease.
VAXNEUVANCE™ (V114) is a 15-valent PCV indicated for the prevention of invasive 
pneumococcal disease caused by the 15 serotypes contained in the vaccine (1, 3, 4, 5, 6A, 
6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F) in persons 18 years of age and older.
mRNA-1273 (Moderna Inc., Cambridge, MA) is a nucleoside-modified mRNA vaccine 
indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in persons 
18 years of age and older. mRNA-1273 was authorized for use in the US under an EUA as a 
first booster dose in individuals 18 years of age and older who have completed primary
COVID-19 vaccination and as a second booster dose in individuals 50 years of age and older 
and adults 18 years of age and older with certain immunocompromising conditions. As of 31-
AUG-2022, mRNA-1273 is no longer authorized for use as a booster.
The purpose of this study is to evaluate the concomitant and nonconcomitant use of mRNA-
1273 with V110 and V114.
2.1
Study Rationale
The initial EUA (December 2020) of a 2-dose regimen of mRNA-1273 for persons 18 years 
of age and older was based on a clinical study (mRNA-1273-P301; NCT04470427) that 
showed an acceptable safety profile and clinical efficacy of the vaccine in preventing 
symptomatic, laboratory-confirmed SARS-CoV-2 infection [Baden, L. R., et al 2021]. The 
majority of adults 50 years of age and older in the US have been vaccinated with a COVID-
19 vaccine; however, given the emergence of new variants and waning immunity, booster 
vaccination is also recommended. Various studies have demonstrated the effectiveness of the 
mRNA-1273 booster doses [Andrews, N., et al 2022] [Regev-Yochay, G., et al 2022].
Pneumococcal pneumonia is a serious complication of COVID-19 that can result in death. 
Although most individuals experience fever, mild or moderate coughing, and shortness of 
breath, some individuals develop severe pneumonia. Pneumococcal vaccines are 
immunogenic and effective with a favorable safety profile [Dinleyici, EC and Yargic, ZA 
2008] [Bonten, M. J., et al 2015] [Tomczyk, S., et al 2014] and can be used to decrease 
respiratory disease burden and health care utilization.
Previous studies have shown the additive benefit of concomitant administration of 
pneumococcal vaccines and influenza vaccine in elderly populations. The concomitant 
administration of PCVs with influenza vaccine is supported by the results of clinical studies 
with both V114 (NCT03615482) and other PCVs [Frenck, R. W. Jr., et al 2012] [Schwarz, T. 
F., et al 2011] [Schwarz, T. F. 2013] [Song, J. Y., et al 2017], while the concomitant use of 
V110 and influenza vaccine is effective in preventing pneumonia, death, and hospitalization 
08DX3L

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CCI
CCI
';/

PRODUCT: V110
24
PROTOCOL/AMENDMENT NO.: 911-03
V110-911-03 FINAL PROTOCOL
12-DEC-2022
the completion of a primary series. In addition, adults 50 years of age and older, as well as 
people aged 18 and older with immunocompromising conditions, were eligible for a second 
booster dose 4 months after receipt of the first booster dose. As of 31-AUG-2022, the 
mRNA-1273 is no longer authorized for use as a booster.
2.2.2
Preclinical and Clinical Studies
Refer to the approved labeling for information on clinical study experience with V110.
Refer to the V114 IB for information on completed preclinical studies and completed and 
ongoing clinical studies conducted with V114.
Refer to the approved labeling for clinical study experience with mRNA-1273. Preliminary 
data are available from an ongoing clinical study assessing the safety and immunogenicity of 
a single 50-µg booster dose of mRNA-1273 in 20 participants vaccinated at least 6 months 
prior with 2 doses of mRNA-1273 [Wu, K., et al 2021]. In this study, a single 50-µg booster 
dose of mRNA-1273 had an acceptable safety profile and was immunogenic. The most 
common solicited injection-site AE was injection-site pain (90%); the most common 
solicited systemic AEs were fatigue (70%), headache (55%), arthralgia (50%), and myalgia 
(45%); and fever was reported by 15% of participants. The majority of solicited injection-site 
and systemic AEs were mild or moderate in intensity, and there were no SAEs reported. Two 
weeks after the booster vaccination, antibody neutralization titers against the wild-type 
original SARS-CoV-2 strain, in addition to the B.1.351 and P.1 variants, increased to levels 
similar to or higher than peak titers measured after the primary series vaccination.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational vaccine.
Both V110 and V114 are approved for use in the population enrolled in this study.
A first booster dose of mRNA-1273 was recommended in adults 18 years of age and older 
who have completed primary COVID-19 vaccination. A second booster dose of mRNA-1273
was recommended in individuals 50 years of age and older and adults 18 years of age and 
older with certain immunocompromising conditions.
All participants in this study will receive a booster dose of mRNA-1273 at Visit 1, with 
approximately 50% of participants receiving mRNA-1273 concomitantly with V110 or 
concomitantly with V114. Participants who do not receive V110 or V114 concomitantly with 
mRNA-1273 will receive V110 or V114 30 days later.
Additional details regarding specific benefits and risks for participants of this clinical study 
may be found in the accompanying IB and informed consent documents.
08DX3L

PRODUCT: V110
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12-DEC-2022
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Objectives and endpoints described below will be evaluated in adults 50 years of age and 
older who previously completed a 2-dose primary series of the mRNA-1273 SARS-CoV-2 
vaccine with or without a single booster dose of the mRNA-1273 SARS-CoV-2 vaccine:
Primary Objectives
Primary Endpoints
•
To evaluate the safety and tolerability of 
V110 and mRNA-1273 when 
administered concomitantly or 
nonconcomitantly with respect to the 
proportion of participants with adverse 
events (AEs) within each vaccination 
group, separately
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related serious adverse events 
(SAEs)
•
To evaluate the safety and tolerability of 
V114 and mRNA-1273 when 
administered concomitantly or 
nonconcomitantly with respect to the 
proportion of participants with AEs 
within each vaccination group, 
separately
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
Vaccine-related SAEs
•
To evaluate the serotype-specific 
opsonophagocytic activity (OPA) 
geometric mean titers (GMTs) at 30 
days postvaccination with V110 when 
administered concomitantly or 
nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately
•
Serotype-specific OPA responses
•
To evaluate the serotype-specific OPA 
GMTs at 30 days postvaccination with 
V114 when administered concomitantly 
or nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately
•
Serotype-specific OPA responses
•
To evaluate the SARS-CoV-2-specific 
binding antibody (bAb) GMTs at 30 
days postvaccination when administered 
concomitantly or nonconcomitantly with 
V110 within each vaccination group,
separately
•
SARS-CoV-2-specific bAb responses
08DX3L

PRODUCT: V110
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•
To evaluate the SARS-CoV-2-specific 
bAb GMTs at 30 days postvaccination 
when administered concomitantly or 
nonconcomitantly with V114 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
Secondary Objectives
Secondary Endpoints
•
To evaluate the serotype-specific 
geometric mean fold rises (GMFRs) and 
proportions of participants with a 
≥4-fold rise from baseline 
(prevaccination with V110) to 30 days 
postvaccination with V110 for OPA 
responses for participants administered 
V110 concomitantly or 
nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately 
•
Serotype-specific OPA responses
•
To evaluate the serotype-specific 
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline 
(prevaccination with V114) to 30 days 
postvaccination with V114 for OPA 
responses for participants administered 
V114 concomitantly or 
nonconcomitantly with mRNA-1273 
within each vaccination group, 
separately
•
Serotypes-specific OPA responses
•
To evaluate the GMFRs and proportions 
of participants with a ≥4-fold rise from 
baseline (prevaccination with 
mRNA-1273) to 30 days 
postvaccination with mRNA-1273 for 
SARS-CoV-2-specific bAb responses 
for participants administered 
mRNA-1273 concomitantly or 
nonconcomitantly with V110 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
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•
To evaluate the GMFRs and proportions 
of participants with a ≥4-fold rise from 
baseline (prevaccination with 
mRNA-1273) to 30 days 
postvaccination with mRNA-1273 for 
SARS-CoV-2-specific bAb responses 
for participants administered 
mRNA-1273 concomitantly or 
nonconcomitantly with V114 within 
each vaccination group, separately
•
SARS-CoV-2-specific bAb responses
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
•
To evaluate SARS-CoV-2 specific 
neutralizing antibody (nAb) GMTs at 
30 days postvaccination with 
mRNA-1273 for participants 
administered mRNA-1273
concomitantly or nonconcomitantly with 
V110 within each vaccination group, 
separately
•
SARS-CoV-2-specific nAb responses
•
To evaluate SARS-CoV-2 specific nAb 
GMTs at 30 days postvaccination with 
mRNA-1273 for participants 
administered mRNA-1273
concomitantly or nonconcomitantly with 
V114 within each vaccination group, 
separately
•
SARS-CoV-2-specific nAb responses
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multisite, double-blind study of a 
pneumococcal vaccine (V110 or V114) administered concomitantly or nonconcomitantly 
with a booster dose of SARS-CoV-2 vaccine (mRNA-1273) in adults 50 years of age and 
older who previously completed a 2-dose primary series of the mRNA-1273 SARS-CoV-2
vaccine ≥5 months (150 days) before receipt of study vaccine at Visit 1. Participants may 
also have received a first booster dose of mRNA-1273 if given ≥4 months (120 days) before 
receipt of study vaccine at Visit 1.
Approximately 850 participants will be randomly assigned in a 1:1:1:1 ratio to receive either 
V110 or V114 with concomitant or nonconcomitant mRNA-1273 (Figure 1). Randomization 
will be stratified by age (50 to 64, 65 to 74, and ≥75 years of age), history of prior 
pneumococcal vaccination (Yes or No), receipt of prior mRNA-1273 booster dose (Yes or 
No), and history of prior SARS-CoV-2 infection (Yes or No).
Participants enrolled in the concomitant groups will receive either V110 or V114 (blinded) in 
the left arm and mRNA-1273 (open label) in the right arm on Day 1, and then will receive 
placebo (blinded) in the left arm 30 days later at Visit 3 (Day 30).
Participants enrolled in the nonconcomitant groups will receive placebo (blinded) in the left 
arm and mRNA-1273 (open label) in the right arm on Day 1, and then will receive V110 or 
V114 (blinded) in the left arm 30 days later at Visit 3 (Day 30).
An eVRC will be used by all participants to record solicited injection-site AEs, solicited 
systemic AEs, and daily body temperatures from Day 1 through Day 7 after each vaccination. 
Unsolicited AEs will also be recorded from Day 1 through Day 28 after each vaccination. All 
participants will be provided an electronic device or have their own electronic device 
configured, if compatible, to complete the eVRC.
Information for SAEs and deaths, regardless of whether the events are considered to be 
vaccine-related by the investigator, will be collected from the time consent is obtained 
through completion of participation in the study.
Blood samples for immunogenicity assays will be drawn immediately before the first 
vaccination at Visit 1 (Day 1), before vaccination at Visit 3 (Day 30), and at Visit 5 (Day 60). 
After completion of immunogenicity testing to evaluate the study objectives, serum samples 
will be stored to conduct any additional study-related testing as required by regulatory 
agencies or the Sponsor. For participants who provide optional consent for FBR, leftover sera 
from the study may be used for other purposes, such as the development and/or validation of 
pneumococcal assays after completion of all study-related immunogenicity testing.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
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4.2
Scientific Rationale for Study Design
This clinical study will evaluate the safety, tolerability, and immunogenicity of a booster 
dose of mRNA-1273 administered concomitantly and nonconcomitantly with V110 or V114 
in healthy adults 50 years of age and older. This population is at elevated risk for 
pneumococcal disease and COVID-19 and associated morbidity and mortality from both 
diseases [Drijkoningen, J. J 2014] [Centers for Disease Control and Prevention 2021]. 
Because the majority of adults 50 years of age and older in the US have been vaccinated with 
a COVID-19 vaccine and a first and second booster dose are now recommended in this 
population, this study will include participants who have completed a 2-dose primary series 
of mRNA-1273 ≥5 months before receipt of study vaccine at Visit 1. This study will also 
include participants who have not yet received a booster dose or who have previously 
received a first booster dose of mRNA-1273 ≥4 months prior to receipt of study vaccine at 
Visit 1.
To show that concomitant administration of pneumococcal vaccines with a booster dose of 
mRNA-1273 does not adversely affect the antibody response to or safety profile of either 
vaccine, this study is blinded using a saline placebo to the pneumococcal vaccine 
administered on Day 1 and Day 30. All 4 intervention groups will receive a booster dose of 
mRNA-1273 and a dose of pneumococcal vaccine (either V110 or V114) in the study.
In the setting of the ongoing COVID-19 pandemic, all participants will receive mRNA-1273
at Visit 1.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity endpoints and associated comparative statistical criteria are consistent 
with previous studies evaluating V110, V114, and mRNA-1273.
4.2.1.1.1
Pneumococcal Immunogenicity Endpoints
Sera from participants will be used to measure vaccine-induced, antipneumococcal 
polysaccharide serotype-specific OPA GMTs using the validated MOPA.
Several studies have shown a positive correlation between serotype-specific IgG antibody 
concentrations and OPA titers in children and adults [Centers for Disease Control and 
Prevention 2010] [Anttila, M., et al 1999] [Romero-Steiner, S., et al 1997]. OPA assesses 
levels of functional antibodies capable of opsonizing pneumococcal capsular polysaccharides 
for presentation to phagocytic cells for engulfment and subsequent killing, and, therefore, is 
considered an important immunologic surrogate for protection against IPD in adults. It is 
noted that IgG antibody and OPA titer threshold values that correlate with protection in 
adults have not been defined; however, the OPA functional assay is considered an accepted 
endpoint in adults.
Immune responses will be measured for serotypes included in the validated MOPA (Section 
8.2.1). This includes 14 of 23 serotypes contained in V110 (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 
08DX3L

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CCI
CCI
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4.2.2
Rationale for the Use of Comparator/Placebo
Placebo (sterile saline for injection) is used in this study to maintain blinding to the 
concomitant and nonconcomitant group assignments.
4.3
Justification for Dose
The dose of V110 and V114 selected for use in this study are consistent with the approved 
US dosing and product labeling of PNEUMOVAX™23 and VAXNEUVANCE™, 
respectively.
The dose of mRNA-1273 selected for use in this study is consistent with the EUA 
Prescribing Information authorized by the FDA for the mRNA-1273 booster dose.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory test result or at 
the time of final contact with the last participant, whichever comes last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant is eligible for inclusion in the study if the participant meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Is in good health. Any underlying chronic illness must be documented to be in stable 
condition.
2. *Has received a 2-dose primary series of the Moderna mRNA SARS-CoV-2 vaccine 
≥5 months (150 days) before receipt of study vaccine at Visit 1.
In addition to the 2-dose primary series, a participant may have received either:
•
A first booster dose of the Moderna mRNA SARS-CoV-2 vaccine ≥4 months (120 
days) before receipt of study vaccine at Visit 1, or
•
No booster dose of the Moderna mRNA SARS-CoV-2 vaccine.
Demographics
3. Is male or female, ≥50 years of age, at the time of signing the informed consent.
Female Participants
4. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 3 months after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) before the first dose of study intervention.
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-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention 
are in Section 8.3.2.
-
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR; However, the 
participant may participate in the study without participating in FBR.
Additional Requirement(s)
6. The participant has the ability to complete eVRC data collection without assistance.
For items with an asterisk (*), if the participant does not meet these inclusion criteria, 
the Day 1 visit may be rescheduled for a time when these criteria are met.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has a current SARS-CoV-2 infection or a known history of SARS-CoV-2 infection 
<3 months (90 days) before receipt of study vaccine at Visit 1.
2. Has a history of myocarditis and/or pericarditis.
3. Has a known hypersensitivity to any component of pneumococcal polysaccharide 
vaccine, PCV, any diphtheria toxoid-containing vaccine, or following a previous dose of 
pneumococcal polysaccharide vaccine or PCV.
4. Has a known hypersensitivity to any component of the mRNA-1273 vaccine or following 
a previous dose of any COVID-19 vaccine.
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5. Has a known or suspected impairment of immunological function including, but not 
limited to, a history of congenital or acquired immunodeficiency, documented HIV 
infection, functional or anatomic asplenia, or history of autoimmune disease.
6. Has a coagulation disorder contraindicating intramuscular vaccinations.
7. *Had a recent febrile illness (defined as oral or tympanic temperature ≥100.4°F 
[≥38.0°C]; axillary or temporal temperature ≥99.4°F [≥37.4°C]) or received antibiotic 
therapy for an acute illness occurring <72 hours before receipt of study vaccine at Visit 1.
8. Has a known malignancy that is progressing or has required active treatment <3 years 
before receipt of study vaccine at Visit 1. Note: participants with basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
Prior/Concomitant Therapy
9. Received prior administration of a pneumococcal polysaccharide vaccine <5 years before 
receipt of study vaccine at Visit 1 or is expected to receive a pneumococcal 
polysaccharide vaccine during the study outside the protocol.
10. Received prior administration of a PCV <1 year before receipt of study vaccine at Visit 1 
or is expected to receive a PCV during the study outside the protocol.
11. Received prior administration of any SARS-CoV-2 vaccine other than the 2-dose primary 
series of the Moderna mRNA vaccine with or without a first booster dose of the Moderna 
mRNA vaccine, or is expected to receive any SARS-CoV-2 vaccine during the study 
outside the protocol.
12. Received prior monoclonal antibody treatment for SARS-CoV-2 infection.
13. Received antiviral treatment for SARS-CoV-2 infection <3 months (90 days) before 
receipt of study vaccine at Visit 1.
14. Received systemic corticosteroids (≥20 mg/day prednisone equivalent) for ≥14 
consecutive days and has not completed intervention ≥30 days before receipt of study 
vaccine at Visit 1.
15. Received systemic corticosteroids exceeding physiologic replacement doses 
(approximately 5 mg/day prednisone equivalent) ≤14 days before receipt of study 
vaccine. Note: Topical, ophthalmic, intraarticular or soft-tissue (eg, bursa, tendon steroid 
injections), and inhaled/nebulized steroids are permitted.
16. Is currently receiving immunosuppressive therapy, including chemotherapeutic agents 
used to treat cancer or other conditions, and interventions associated with organ or bone 
marrow transplantation, or autoimmune disease.
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17. *Received any nonlive vaccine ≤14 days before receipt of study vaccine or is scheduled 
to receive any nonlive vaccine ≤30 days after receipt of study vaccine. Exception:
Inactivated influenza vaccine allowed if given ≥7 days before or ≥15 days after receipt of 
study vaccine.
18. *Received any live virus vaccine ≤30 days before receipt of study vaccine or is scheduled 
to receive any live virus vaccine ≤30 days after receipt of study vaccine.
19. Received a blood transfusion or blood products (including globulin) ≤6 months before 
receipt of study vaccine or is scheduled to receive a blood transfusion or blood product 
≤30 days after receipt of study vaccine. Autologous blood transfusions are not considered 
an exclusion criterion.
Prior/Concurrent Clinical Study Experience
20. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 2 months of participating in this current study.
Diagnostic Assessments
Not applicable.
Other Exclusions
21. In the opinion of the investigator, has a history of clinically relevant drug or alcohol use 
that would interfere with participation in protocol-specified activities.
22. Has a history or current evidence of any condition, therapy laboratory abnormality, or 
other circumstance that might predispose the participant to risk by participating in the 
study, confound the results of the study, or interfere with the participant’s participation 
for the full duration of the study in the opinion of the investigator.
23. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, the Day 
1 visit may be rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
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information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP Sourcing
V110
Concomitant 
Group
Experimental V110
Biological/Vaccine Solution
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central
V110 
Concomitant 
Group
Experimental mRNA-1273 Biological/Vaccine Suspension
50 µg
0.25 mL IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central 
and 
Local
V110 
Concomitant 
Group
Experimental Placebo 
(Sterile 
Saline)
Biological/Vaccine Solution
N/A
0.5 mL
IM
Single Dose 
at Visit 3
(Day 30)
Placebo IMP
Central
V110 
Nonconcomitant 
Group
Experimental Placebo 
(Sterile 
Saline)
Biological/Vaccine Solution
N/A
0.5 mL
IM
Single Dose 
at Visit 1 
(Day 1)
Placebo IMP
Central
V110 
Nonconcomitant 
Group
Experimental mRNA-1273 Biological/Vaccine Suspension
50 µg
0.25 mL IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central 
and 
Local
V110 
Nonconcomitant 
Group
Experimental V110
Biological/Vaccine Solution
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 3
(Day 30)
Test 
Product
IMP
Central
V114 
Concomitant 
Group
Experimental V114
Biological/Vaccine Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central
V114 
Concomitant 
Group
Experimental mRNA-1273 Biological/Vaccine Suspension
50 µg
0.25 mL IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central 
and 
Local
V114 
Concomitant 
Group
Experimental Placebo 
(Sterile 
saline)
Biological/Vaccine Solution
N/A
0.5 mL
IM
Single Dose 
at Visit 3 
(Day 30)
Test 
Product
IMP
Central
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Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP Sourcing
V114 
Nonconcomitant 
Group
Experimental Placebo 
(Sterile 
saline)
Biological/Vaccine Solution
N/A
0.5 mL
IM
Single Dose 
at Visit 1 
(Day 1)
Placebo IMP
Central
V114 
Nonconcomitant 
Group
Experimental mRNA-1273 Biological/Vaccine Suspension
50 µg
0.25 mL IM
Single Dose 
at Visit 1 
(Day 1)
Test 
Product
IMP
Central 
and 
Local
V114 
Nonconcomitant 
Group
Experimental V114
Biological/Vaccine Suspension
Refer to 
product 
labeling
0.5 mL
IM
Single Dose 
at Visit 3 
(Day 30)
Test 
Product
IMP
Central
Admin=administration; EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; mRNA-1273=Moderna SARS-CoV-2 vaccine; N/A=not 
applicable; NIMP/AxMP=noninvestigational/auxiliary medicinal product; V110=PNEUMOVAX™23; V114=VAXNEUVANCE™.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Drug-device combination product(s), which is legally marketed, provided for use in this 
study are: PNEUMOVAX™23 prefilled syringes and VAXNEUVANCE™ prefilled 
syringes. Refer to Section 8.4.8 and Appendix 4 for reporting events associated with these 
devices.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
Specific procedures that are required for dose preparation are outlined in the Investigator 
Trial File Binder.
As detailed in Section 6.3.3, study vaccines will be prepared by an unblinded member of the 
study-site staff.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 1:1:1:1 ratio to receive either 
V110 concomitantly with mRNA-1273, V114 concomitantly with mRNA-1273, V110 
nonconcomitantly with mRNA-1273, or V114 nonconcomitantly with mRNA-1273.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
•
Participant age at time of randomization (50 to 64, 65 to 74, ≥75 years of age). The 
categories for age stratification are consistent with prior clinical studies of pneumococcal 
vaccines in adults.
•
History of prior pneumococcal vaccination (Yes, No), where “Yes” includes any prior 
vaccination with a pneumococcal polysaccharide vaccine and/or PCV, and “No” 
indicates no prior vaccination with a pneumococcal polysaccharide vaccine or PCV (ie, 
vaccine-naïve).
•
Receipt of prior mRNA-1273 booster dose (Yes, No).
•
History of prior SARS-CoV-2 infection (Yes, No).
6.3.3
Blinding
A double-blinding technique will be used. V110, V114, and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
Because V110, V114, and placebo have different appearances, a member of the study-site 
staff will be unblinded for the purposes of receiving, maintaining, preparing and/or 
dispensing, and administering these study vaccines (Section 8.1.8). Although mRNA-1273 is 
provided open label in this study, it will also be prepared and/or dispensed and administered 
by unblinded study-site staff for consistency. Procedures for handling, preparing, and 
administering the unblinded vaccines are in the Investigator Trial File Binder.
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To avoid bias, the unblinded study personnel will have no further contact with study 
participants for any study-related procedures/assessments after administration of study 
vaccines, which includes all safety follow-up procedures. Blinded site personnel will not be 
present in the examination room when study vaccines are administered. Contact between 
participants and unblinded study personnel after vaccination administration is strictly 
prohibited. Blinded site personnel will be responsible for all safety and immunogenicity 
follow-up procedures after vaccine administration.
An unblinded Clinical Research Associate will monitor vaccine accountability at the study 
site. All other Sponsor personnel or delegate(s) and MSD Research Laboratories employees 
directly involved with the conduct of this study will remain blinded to the participant-level 
intervention assignment.
See Section 8.1.13 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan (see Section 1.2) require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medications or vaccinations 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
It is important to record the use of any analgesic or antipyretic medication that occurs on the 
day of vaccination on the eVRC and appropriate eCRF.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
Any administration of a nonstudy pneumococcal vaccine or SARS-CoV-2 vaccine is 
prohibited during the study.
•
Administration of monoclonal antibody treatment for SARS-CoV-2 infection is 
prohibited during the study.
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•
Nonstudy vaccines may only be administered before or after the receipt of study vaccines 
according to the time frames specified in the Exclusion Criteria (Section 5.2). If the 
participant is scheduled to receive any nonstudy vaccine, the investigator should discuss 
this with the Sponsor Clinical Director as soon as possible. Exception: Inactivated 
influenza vaccine may be administered but must be given at least 7 days before receipt of 
study vaccine or at least 15 days after receipt of study vaccine.
•
Participants should not receive systemic corticosteroids (≥20 mg/day prednisone 
equivalent) for ≥14 consecutive days starting from 30 days before each vaccination 
through 30 days after each vaccination.
•
Participants should not receive systemic corticosteroids exceeding physiologic 
replacement doses (approximately 5 mg/day prednisone equivalent) starting from 14 days 
before any vaccination. Note: Topical, ophthalmic, intraarticular or soft-tissue (eg, bursa, 
tendon steroid injections), and inhaled/nebulized steroids are permitted.
Any deviation from the above requires consultation between the investigator and the Sponsor 
and written documentation of the collaborative decision on participant management.
Use of prior and concomitant medications/vaccinations should be recorded as described in 
Section 8.1.5.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study-site personnel will be used to blind supplies. Study intervention 
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.13). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention allocation/randomization system (IRT) should be used to unblind 
participants and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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See Section 8.1.13 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified vaccination 
regimen will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.12 and Section 
8.11.3.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study, for any of the following reasons:
•
The participant requests to discontinue study intervention.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.12. The procedures to be performed should a participant repeatedly fail to return 
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for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The participant’s 
relevant medical history for the 5 years before Visit 1, including any known history of 
SARS-CoV-2 infection, will be obtained to ensure that the participant satisfies the inclusion 
and exclusion criteria of the study. History of tobacco use will be collected for all 
participants.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior vaccinations and 
medication taken by the participant within 30 days before the study vaccination at Visit 1.
The following must be documented before vaccination at Visit 1 and recorded on the 
appropriate eCRF:
•
Any analgesic or antipyretic medication taken on the day of vaccination before 
vaccination
•
SARS-CoV-2 vaccination history
•
Any history of vaccination with a pneumococcal polysaccharide vaccine or PCV
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record vaccinations and medications, if any, taken 
by the participant during the study.
Any analgesic or antipyretic medication taken must be recorded on the eVRC and 
appropriate eCRF.
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The participant will use their eVRC (Section 8.1.9) to record new and/or concomitant 
medications taken and nonstudy vaccines received from the day of each vaccination through 
28 days postvaccination.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Unblinded study personnel not otherwise involved in the conduct of the study will prepare 
and administer all study vaccines (Section 6.3.3). Study vaccines should be prepared and 
administered by appropriately qualified members of the study personnel (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacist, or medical assistant) as allowed 
by local/state, country, and institutional guidance. Unblinded study personnel should follow 
the procedures for handling, preparing, and administering V110 and V114 as specified in the 
product label and mRNA-1273 as specified in the EUA Prescribing Information; these 
documents are provided in the Investigator Trial File Binder.
The time of vaccination should be documented in the participant’s medical record.
Study vaccine will be administered according to the schedule specified in Section 1.3. V110, 
V114, or placebo should be administered as a single IM injection in the deltoid region of the 
participant’s left arm, while mRNA-1273 should be administered as a single IM injection in 
the deltoid region of the participant’s right arm. mRNA-1273 will be administered open 
label. Adequate treatment provision, including epinephrine and equipment for maintaining an 
airway, should be available for immediate use should an anaphylactic or anaphylactoid 
reaction occur [Centers for Disease Control and Prevention 2015].
Unblinded study personnel should not have contact with participants for any study-related 
procedures/assessments after administration of study vaccine, which includes all safety 
follow-up procedures. All safety and immunogenicity assessments will be conducted by 
blinded personnel, and the participant will be blinded to the study vaccine received. 
Vaccination information, such as time of vaccination, must be recorded on the appropriate 
eCRF as per the data entry guidelines.
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8.1.8.1
Timing of Dose Administration
Study vaccines will be administered as indicated in Section 1.3. Vaccinations may be 
administered at any time of day and without regard to timing of meals.
All participants will be observed for at least 30 minutes after vaccination for any immediate 
reactions (Section 8.3.4). This observation must be performed by blinded site personnel for 
all study vaccines (Section 6.3.3).
Participants must be afebrile for at least 72 hours before vaccination (Section 1.3 and Section 
8.3.3).
The collection of blood samples and administration of pregnancy tests (if applicable) must be 
performed before vaccine administration.
8.1.9
Electronic Vaccination Report Card
The eVRC is structured as recommended in the final Food and Drug Administration Patient-
reported Outcome Guidance [U.S. Food and Drug Administration 2009].
The participant will use the eVRC to record body temperature (Section 8.3.3), solicited 
injection-site AEs, and solicited systemic AEs (Section 8.4.9.1). Unsolicited AEs (Section 
8.4.9.2), concomitant medications (including use of any analgesic or antipyretic medication), 
and nonstudy vaccinations (Section 8.1.5.2) will also be reported. Participants will be 
provided an electronic device or have their own electronic device configured, if compatible, 
to complete the eVRC.
The investigator or delegate will review the data captured on the eVRC with the participant 
as indicated in Section 1.3.
8.1.10
Telephone Contact on Day 10 Postvaccination
Site personnel will contact the participant on Day 10 after each vaccination to review eVRC 
data. Any differences between eVRC data and AEs entered into the clinical database must be 
clearly explained in the participant’s source documentation.
8.1.11
Telephone Contact Questionnaire
Site personnel will contact the participant approximately 6 months after Visit 1 to collect 
additional information based on a Telephone Contact Questionnaire provided by the Sponsor. 
Data to be reported from this discussion will include AESIs, SAEs, and/or any updates to 
previously reported safety information.
8.1.12
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.11.3.
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Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.12.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.13
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
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Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.14
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure pneumococcal vaccine-induced OPA 
responses and mRNA-1273-induced bAb and nAb responses. These endpoints will be tested 
for all immunogenicity blood draws specified in Section 1.3. The total amount of blood to be 
drawn over the course of the study, including approximate blood volumes drawn by visit and 
by sample type per participant, can be found in Section 8. Blood collection, storage, and 
shipment instructions for serum samples will be provided in the operations/laboratory 
manual.
The MOPA will be used for measuring OPA responses. Opsonization of pneumococci for 
phagocytosis is an important mechanism by which antibodies to polysaccharides protect 
against disease in vivo. The OPA assay is a useful tool for assessing the protective function 
of serotype-specific antibodies and, therefore, the immunogenicity of pneumococcal vaccine 
formulations.
The SARS-CoV-2 ECL assay will be used to measure the concentration of bAbs to the 
SARS-CoV-2 Spike protein, nucleocapsid, and receptor binding domain.
The SARS-CoV-2 nAb assay will be used to measure nAb activity directed against the 
SARS-CoV-2 Spike envelope protein.
8.2.1
Multiplex Opsonophagocytic Assay
The MOPA is an antibody-mediated killing assay that measures the ability of human serum 
to kill S. pneumoniae serotypes with the help of complement and phagocytic effector cells 
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard before vaccination 
at Visit 1. A targeted physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard before 
vaccination at Visit 3. A targeted physical examination includes obtaining vital signs (heart 
rate, respiratory rate, blood pressure, body temperature) and a physical examination focused 
on complaints based on medical history. The targeted physical examination should focus on 
examining systems related to any ongoing conditions and/or follow up on previously reported 
AEs.
Findings related to the physical examinations should be documented in the source 
documents. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.3.2
Pregnancy Testing
A pregnancy test consistent with local requirements (sensitive to at least 25 IU hCG) must be 
performed before vaccination at Visit 1 and Visit 3 in WOCBP as described in Section 1.3. 
Urine or serum tests can be used and results must be negative before vaccination can occur. 
A detailed definition of WOCBP is provided in Appendix 5.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
8.3.3
Body Temperature Measurement
Each participant’s body temperature must be taken by study-site staff before each vaccination 
as described in Section 1.3. Participants who have febrile illness (defined as oral or tympanic 
temperature ≥100.4°F [≥38.0°C]; axillary or temporal temperature ≥99.4°F [≥37.4°C]) 
<72 hours before vaccination must be rescheduled.
Participants will also record oral body temperature measurements using the eVRC 
(Section 8.1.9) from Day 1 to Day 7 after each vaccination.
8.3.4
Postvaccination Observation Period
All participants will be observed for at least 30 minutes after each vaccination for any 
immediate reactions. If any immediate AEs are observed during this period, the time at which 
the event occurred within this timeframe, as well as the event itself, any concomitant 
medications that were administered, and resolution of the event must be recorded on the 
appropriate eCRF.
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8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 to 44 days after the last dose of study intervention, 
every attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before randomization, must be reported by the 
investigator if they cause the participant to be excluded from the study, or are the result of a 
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protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, placebo, or a procedure.
All nonserious AEs and other reportable safety events (excluding pregnancy and lactation 
exposure) must be reported by the investigator from the day of randomization through 28 
days after the first vaccination and from the time of each subsequent vaccination through 28 
days postvaccination.
All SAEs and AESIs must be reported by the investigator throughout the duration of the 
individual’s participation in the study, regardless of whether related to the study intervention.
•
In this study, myocarditis and pericarditis are always considered to be SAEs. The 
investigator should ensure that all applicable serious criteria outlined in Appendix 3 are 
recorded in the study database. Definitions of myocarditis and pericarditis are provided in 
Appendix 3.
•
The list of AESIs for this study is provided in Appendix 3.
All pregnancies and lactation exposure during breastfeeding must be reported by the 
investigator from the day of randomization through 3 months postvaccination.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 3
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of 
Event
Reporting Period:
Consent to Randomization/
Allocation
Reporting Period:
Randomization/
Allocation Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-specified 
intervention
– causes exclusion
– participant is receiving 
placebo run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-specified 
intervention
– causes exclusion
– participant is receiving 
placebo run-in or other run-in 
treatment
Report all
Report if:
– drug/vaccine 
related.
– any death 
until 
participant 
completion 
of study
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
– participant has been exposed 
to any protocol-specified 
intervention (eg, procedure, 
washout or run-in treatment 
including placebo run-in)
Exception: A positive 
pregnancy test at the time of 
initial screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
There are no ECIs for this study.
ECI (do not 
require 
regulatory 
reporting)
There are no ECIs for this study.
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo run-in or 
other run-in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable for this study.
8.4.7
Events of Clinical Interest
There are no ECIs for this study.
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions
The method of documenting and reporting of such events (Complaints associated with 
medical devices including PQCs/malfunctions) will occur as below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per 
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions including those that involve a participant or any user/associated person 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.4.9
Adverse Events on the VRC
Participants will use a VRC to report solicited and unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.9.1
Solicited Adverse Event
Solicited AEs for this study are summarized in Table 4.
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Table 4
Solicited Adverse Events
Type of Solicited 
Adverse Event
Predefined Solicited Adverse Events
(Preferred Term)
Solicited Time Period
Injection site
•
Injection-site redness (erythema)
•
Injection-site swelling
•
Injection-site pain/tenderness
•
Underarm gland swelling or tenderness 
(lymphadenopathy)
Day 1 to Day 7 postvaccination
Systemic
•
Headache
•
Tiredness (fatigue)
•
Muscle aches all over body (myalgia)
•
Joint pain (arthralgia)
•
Nausea
•
Vomiting
•
Chills
Day 1 to Day 7 postvaccination
8.4.9.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 4 or 
2) predefined in Table 4 but reported at any time outside the solicited time period.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 1 dose of any individual study vaccine in 
any 24-hour period.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
•
Leftover serum from immunogenicity testing stored for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Not applicable.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures will be conducted at Visit 1 as outlined in Section 1.3. Potential 
participants will be evaluated to determine that they fulfill the entry requirements as set forth 
in Section 5.
If Visit 1 is rescheduled (see Section 5.1 and Section 5.2), a review of prior 
medications/vaccinations and medical history, a complete physical examination, and a body 
temperature measurement must be repeated before vaccination.
8.11.2
Treatment Period/Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
A participant who discontinues from study intervention will continue to participate in 
protocol-specified activities as outlined in Section 1.3, including blood draws for 
immunogenicity testing and AE monitoring activities, as long as the participant does not 
withdraw consent.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary analyses, or the 
statistical methods related to those analyses, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but before unblinding/final database lock, will be 
documented in an sSAP and referenced in the CSR for the study.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design 
Overview
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability, and Immunogenicity of the Concomitant Administration of 
Either 23-Valent Pneumococcal Polysaccharide Vaccine or 15-Valent 
Pneumococcal Conjugate Vaccine with a Booster Dose of SARS-CoV-2 mRNA-
1273 Vaccine in Healthy Adults 50 Years of Age or Older.
Treatment 
Assignment
Approximately 850 participants will be randomly assigned in a 1:1:1:1 ratio to 
receive either V110 or V114 with concomitant or nonconcomitant mRNA-1273. 
Randomization will be stratified by age (50 to 64, 65 to 74, and ≥75 years of age), 
history of prior pneumococcal vaccination (Yes or No), receipt of prior mRNA-
1273 booster dose (Yes, No), and history of prior SARS-CoV-2 infection (Yes, 
No).
Analysis Populations
Safety: APaT population
Immunogenicity: PP population
Primary Endpoint(s)
Safety
•
Proportion of participants with solicited injection-site AEs from Day 1 
through Day 7 after any vaccination
•
Proportion of participants with solicited systemic AEs from Day 1 through 
Day 7 after any vaccination
•
Proportion of participants with vaccine-related SAEs from Day 1 through 
Month 6
Immunogenicity
•
Serotype-specific OPA GMTs at 30 days postvaccination with V110
•
Serotype-specific OPA GMTs at 30 days postvaccination with V114
•
SARS-CoV-2-specific bAb GMTs at 30 days postvaccination with mRNA-
1273
Statistical Methods 
for Key 
Immunogenicity 
Analyses
Immunogenicity analyses will be conducted separately for 14 of 23 pneumococcal 
serotypes in V110, each of the 15 serotypes in V114 and SARS-CoV-2 of 
mRNA-1273.
To address the primary immunogenicity objective, evaluation of the OPA GMTs 
or bAb GMTs at 30 days postvaccination receiving V110 or V114 when 
administered concomitantly or nonconcomitantly with mRNA-1273 will include 
descriptive summaries and within-group 95% CIs for each vaccination group.
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Statistical Methods 
for Key Safety 
Analyses
The analysis of safety will follow a tiered approach. Point estimates with the 
corresponding within-group 95% CIs based on the exact binomial method 
proposed by Clopper and Pearson [Clopper, C. J. 1934] will be provided for the 
proportion of participants with events.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No multiplicity adjustment will be required, as there is no formal hypothesis 
testing.
Sample Size and 
Power
Immunogenicity:
The planned sample size is approximately 850 participants. Participants are to be
randomly assigned in a 1:1:1:1 ratio to receive either V110 or V114 with 
concomitant or nonconcomitant mRNA-1273. It is assumed that 190 participants 
in each group will be evaluable for PP immunogenicity analyses (90% 
evaluability rate). There are no hypotheses to be evaluated, but Section 9.9.1 
provides information about the expected variability of the OPA GMTs of 
V110/V114 and bAb GMTs of mRNA-1273.
Safety:
Section 9.9.2 provides information about the ability of this study to estimate the 
incidence of AEs within the concomitant and nonconcomitant groups for V114 
and V110.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. This study will be conducted as a 
double-blind study under in-house blinding procedures.
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using an IRT.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
A description of the immunogenicity assays is provided in Section 8.2.
For endpoints related to V110 and V114, immune responses will be measured for serotypes 
included in the validated MOPA. This includes 14 of 23 serotypes contained in V110 (1, 3, 4, 
5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) and all 15 serotypes included in V114 
(1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F).
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The primary immunogenicity endpoints include:
•
Serotype-specific OPA GMTs at 30 days postvaccination with V110
•
Serotype-specific OPA GMTs at 30 days postvaccination with V114
•
SARS-CoV-2-specific bAb GMTs at 30 days postvaccination with mRNA-1273
The secondary immunogenicity analysis endpoints include:
•
Serotype-specific GMFRs and proportions of participants with a 4-fold rise from baseline 
(prevaccination with V110) to 30 days postvaccination with V110 for OPA responses
•
Serotype-specific GMFRs and proportions of participants with a 4-fold rise from baseline 
(prevaccination with V114) to 30 days postvaccination with V114 for OPA responses
•
GMFRs and proportions of participants with a ≥4-fold rise from baseline (prevaccination 
with mRNA-1273) to 30 days postvaccination with mRNA-1273 for 
SARS-CoV-2-specific bAb responses
The exploratory immunogenicity analysis endpoints include:
•
SARS-CoV-2-specific nAb GMTs at 30 days postvaccination with mRNA-1273
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, including 
AEs and postvaccination body temperature measurements after each vaccination.
The safety endpoints that address the primary objectives include:
•
Proportion of participants with solicited injection-site AEs (redness/erythema, swelling, 
pain/tenderness, underarm gland swelling or tenderness/lymphadenopathy) from Day 1 
through Day 7 after any vaccination
•
Proportion of participants with solicited systemic AEs (headache, tiredness/fatigue, 
muscle aches all over body/myalgia, joint pain/arthralgia, nausea, vomiting, chills) from 
Day 1 through Day 7 after any vaccination
•
Proportion of participants with vaccine-related SAEs from Day 1 through Month 6
Additional safety endpoints include:
•
Proportion of participants with the broad AE categories of any AE and any 
vaccine-related AE from Day 1 through Day 28 after any vaccination
•
Proportions of participants with the broad AE categories consisting of any AESI, any 
SAE, discontinuation of study intervention due to an AE, and death from Day 1 through 
duration of participation in the study
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•
Proportion of participants with maximum temperature measurements meeting the 
Brighton Collaboration cut points from Day 1 through Day 7 after any vaccination
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the primary population for the analysis of immunogenicity 
data in this study. The PP population consists of all randomized participants without 
deviations from the protocol that may substantially affect the results of the immunogenicity 
endpoints. Potential deviations that may result in the exclusion of a participant from the PP 
population for immunogenicity analyses include, but are not limited to:
•
Failure to receive any study vaccine at Visit 1 (Day 1)
•
Failure to receive correct clinical material as per randomization schedule at Visit 1 
(Day 1)
•
Receipt of a prohibited medication or prohibited vaccine before study vaccination
Additional potential deviations that may result in the exclusion of a participant from the PP 
population for specific immunogenicity analyses (depending on the time point or specific 
immunogenicity endpoint) include, but are not limited to:
•
Failure to receive any study vaccine at Visit 3 (Day 30)
•
Failure to receive correct clinical material as per randomization schedule at Visit 3 (Day 
30)
•
Receipt of a prohibited medication or prohibited vaccine before a blood sample collection
•
Collection of a blood sample outside the prespecified window (as described in 
Section 1.3)
•
Participants who develop COVID-19 during the study
The final determination on protocol deviations that impact the immunogenicity analysis, and 
thereby the composition of the PP population, will be made before the final unblinding of the 
database. Participants will be included in the vaccination group to which they are randomized 
for the analysis of immunogenicity data using the PP population.
A supportive analysis using the FAS population will also be performed for the primary 
immunogenicity endpoints. The FAS population consists of all randomized participants who 
received at least 1 study vaccination and have at least 1 serology result. Participants will be 
included in the vaccination group to which they are randomized for the analysis of 
immunogenicity data using the FAS population.
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9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study vaccination. Participants will be included in 
the group corresponding to the study vaccination they actually received. Data for participants 
who receive the same vaccine at both Visit 1 and Visit 3 (ie, they inadvertently receive 2 
doses of V110, 2 doses of V114, 2 dose of mRNA-1273, or 2 doses of placebo) will be 
excluded from the APaT and will be summarized separately.
At least 1 temperature measurement obtained after administration of study intervention is 
required for inclusion in the analysis of temperature.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
Primary Endpoints
Immunogenicity analyses will be conducted for each of the 14 of 23 pneumococcal serotypes 
in V110 and for each of the 15 serotypes in V114 separately. To address the primary 
immunogenicity objective, evaluation of the OPA GMTs at 30 days postvaccination with 
V114 or V110 will include descriptive summaries and within-group 95% CIs for each 
vaccination group. The point estimates will be calculated by exponentiating the estimates of 
the mean of the natural log values, and the within-group CIs will be derived by
exponentiating the CIs of the mean of the natural log values based on the t-distribution.
Similarly, evaluation of the SARS-CoV-2-specific bAb GMT at 30 days postvaccination with 
mRNA-1273 will include descriptive summaries and within-group 95% CIs for each 
vaccination group. The V110 nonconcomitant group and V114 nonconcomitant group will be 
combined, as they share the same administration for the first visit (mRNA-1273 and 
placebo).
Secondary/Exploratory Endpoints
Descriptive statistics with point estimates and within-group 95% CIs will be provided for all 
other immunogenicity endpoints. For the continuous endpoints, a similar statistical approach 
described in the primary objective will be used. For the dichotomous endpoints, the 
within-group CIs will be calculated based on the exact method proposed by Clopper and 
Pearson [Clopper, C. J. 1934].
Reverse Cumulative Distribution Curves for OPA titers at 30 days postvaccination with 
V110 and V114 will be graphically displayed by serotype. Reverse Cumulative Distribution 
Curves for SARS-CoV-2-specific bAb titers at 30 days postvaccination with mRNA-1273 
will be graphically displayed.
A detailed analysis strategy for key immunogenicity endpoints is listed in Table 5.
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Table 5
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methoda
Analysis 
Population
Missing Data 
Approach
Primary Endpoints
OPA GMTs at 30 days postvaccination 
with V110
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
OPA GMTs at 30 days postvaccination 
with V114
P
Descriptive Statistics
(estimate, 95% CI)
PP 
Missing data 
will not be 
imputed
S
FAS
bAb GMTs at 30 days postvaccination 
with mRNA-1273
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
S
FAS
Secondary Endpoints
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline to 
30 days postvaccination with V110 for 
OPA responses
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline to 
30 days postvaccination with V114 for 
OPA responses
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
GMFRs and proportions of participants 
with a ≥4-fold rise from baseline to 
30 days postvaccination with 
mRNA-1273 for SARS-CoV-2-specific 
bAb responses
P
Descriptive Statistics
(estimate, 95% CI)
PP
Missing data 
will not be 
imputed
bAb=binding antibody; CI=confidence interval; FAS=full analysis set; GMFR=geometric mean fold rise; 
GMT=geometric mean titer; OPA=opsonophagocytic activity; P=primary; PP=per-protocol; S=supportive.
a
The statistical methods for immunogenicity are described in Section 9.6.1.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements. The primary safety analysis will consist 
of safety summaries for all safety endpoints after any vaccination. Separate summaries will 
be provided for the V110 concomitant and V110 nonconcomitant groups and for the V114 
concomitant and V114 nonconcomitant groups.
The V110 nonconcomitant group and the V114 nonconcomitant group will be combined to 
summarize the safety results following vaccination 1 as they share the same vaccinations 
(mRNA-1273 and placebo) at Day 1. The V110 concomitant group and the V114 
concomitant group will be combined to summarize the safety results following vaccination 2 
as they share the same vaccinations (placebo alone) at Day 30.
The analysis of AEs and temperature measurements will follow a tiered approach (Table 6). 
The tiers differ with respect to the analyses that will be performed. AEs (specific terms as 
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well as SOC terms) are either prespecified as Tier 1 events or will be classified as belonging 
to Tier 2 or Tier 3 based on the number of events observed.
Tier 1 Events
Safety events or AESI that are identified a priori constitute Tier 1 events that will be subject 
to inferential testing for statistical significance. No Tier 1 events are defined for this study.
Tier 2 Events
Tier 2 events will be assessed via point estimates with the corresponding within-group 95% 
CIs based on the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 
1934].
For this study, solicited injection-site AEs, solicited systemic AEs, and body temperature 
measurements collected from Day 1 though Day 7 postvaccination are considered Tier 2 
events. In addition, the broad AE categories consisting of the proportion of participants with 
any AE, any vaccine-related AE, any AESI, any SAE, any vaccine-related SAE, 
discontinuation of study intervention due to an AE, and death will be considered Tier 2 
events. Nonserious AEs will be followed for 28 days after each vaccination and AESIs and 
SAEs will be followed through the duration of participation in the study.
Tier 3 Events
Events not defined above are considered Tier 3 events. Only point estimates by treatment 
group will be provided for Tier 3 events.
Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoints
Within Groupa
95% CI
Descriptive Statistics
Tier 2
Solicited injection-site AE (redness/erythema, 
swelling, pain/tenderness, underarm gland swelling 
or tenderness/lymphadenopathy from Days 1 
through Day 7 after any vaccination)
X
X
Solicited systemic AE (headache, tiredness/fatigue, 
muscle aches all over body/myalgia, joint 
pain/arthralgia, nausea, vomiting, chills from Days 1 
through Day 7 after any vaccination)
X
X
Any vaccine-related SAEb,c
X
X
Any AEb
X
X
Any vaccine-related AEb,c
X
X
Any AESId
X
X
Any SAEb
X
X
Discontinuation of study intervention due to an AEb
X
X
Deathb
X
X
Maximum temperature measurements (Days 1 to 
Day 7)
X
X
Tier 3
AEs by SOC and PTe
-
X
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Safety Tier
Safety Endpoints
Within Groupa
95% CI
Descriptive Statistics
AE=adverse event; AESI=adverse event of special interest; CI=confidence interval; PT=preferred term; SAE=serious 
adverse event; SOC=system organ class; X=results will be provided.
a
Within-group 95% CIs are based on the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 
1934].
b
These endpoints are broad AE categories. For example, descriptive statistics for the safety endpoint of “Any AE” will 
provide the number and percentage of participants with at least 1 AE.
c
Determined by the investigator to be vaccine-related.
d
A list of AESIs pertaining to the safety evaluation of mRNA-1273 is provided in Appendix 3. This list is consistent 
with the safety evaluation of mRNA-1273 in Phase 3 studies per regulatory guidance.
e
Includes only those endpoints not prespecified as Tier 2 endpoints.
In addition to the primary safety analysis following any vaccination, a supportive analysis of 
select safety endpoints will be provided after each vaccination. Point estimates by 
vaccination group will be provided for injection-site AEs following V110, V114, mRNA-
1273, and placebo separately. That is, the proportion of participants with injection-site AEs 
after administration of V110 or V114 will include AEs reported from Day 1 through Day 7 
after V110 or V114 administration in the limb corresponding to the location of V110 or 
V114 administration. Similarly, the proportion of participants with injection-site AEs after 
administration of mRNA-1273 will include AEs reported from Day 1 through Day 7 after 
mRNA-1273 administration in the limb corresponding to the location of mRNA-1273 
administration. The proportion of participants with injection-site AEs after administration of 
placebo will include both the V110 and V114 nonconcomitant groups for AEs reported from 
Day 1 through Day 7 after Visit 1 and both the V110 and V114 concomitant groups for AEs 
reported from Day 1 to Day 7 after Visit 3.
Additionally, descriptive summaries of systemic AEs reported from Day 1 through Day 7 
will be summarized following administration of:
•
V110 and mRNA-1273 in the concomitant group at Visit 1 (Day 1)
•
V114 and mRNA-1273 in the concomitant group at Visit 1 (Day 1)
•
mRNA-1273 with placebo in both the V110 nonconcomitant group and V114 
nonconcomitant group at Visit 1 (Day 1)
•
V110 alone in the nonconcomitant group at Visit 3 (Day 30)
•
V114 alone in the nonconcomitant group at Visit 3 (Day 30)
•
Placebo alone in both the V110 concomitant group and V114 concomitant group at 
Visit 3 (Day 30)
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
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9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant demographic and baseline 
characteristic will be assessed by the use of summary tables. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, and gender), baseline characteristics, 
and prior and concomitant vaccinations and therapies will be summarized by vaccination 
group either by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No multiplicity adjustment will be required, as there is no formal hypothesis testing.
9.9
Sample Size and Power Calculations
9.9.1
Immunogenicity Analyses
This is a descriptive study. This study will randomize 212 participants into each V110 and 
V114 concomitant group and 212 participants into each V110 and V114 nonconcomitant 
group. It is assumed that approximately 190 in each group will be evaluable for PP 
immunogenicity analyses (based on a 90% evaluability rate).
The width of the within-group 95% CIs for the serotype-specific OPA GMTs and 
SARS-CoV-2-specific bAb GMTs depend on the sample size, variability of the natural log 
concentrations, and the magnitude of the OPA or bAb GMTs. In Table 7, 95% CIs for 
various hypothetical OPA and bAb GMTs and various hypothetical standard deviation 
estimates for the natural log titers are displayed.
Table 7
Within-group 95% CIs for Varying OPA/bAb GMTs and Standard Deviations
SD of 
Natural 
log Titers
Serotype-specific OPA GMT or SARS-CoV-2-specific bAb GMT
500
1000
5000
V110/V114
mRNA-1273
V110/V114
mRNA-1273
V110/V114
mRNA-1273
1.0
(433, 577)
-
(867, 1154)
-
(4333, 5768)
-
1.5
(403, 620)
(403, 620)
(807, 1239)
(807, 1239)
(4034, 6197)
(4034, 6197)
2.0
(376, 666)
-
(751, 1331)
-
(3756, 6657)
-
bAb=binding antibody; CI=confidence interval; GMT=geometric mean tier; OPA=opsonophagocytic 
activity; SD=standard deviation.
Based on 190 evaluable participants in each of the group.
The estimates of the standard deviation and OPA GMTs are representative of those observed in V114-019 
and V110-029, which is between 1 to 2. The estimates of the standard deviation of SARS-CoV-2 specific 
bAb is representative of those observed in mRNA-1273 studies, which is around 1.5. 
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9.9.2
Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants vaccinated and the underlying incidence of participants with a SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. There is an 80% chance of observing at least 1 SAE among 
212 participants in each of the concomitant/nonconcomitant groups if the underlying 
incidence of a SAE is 0.76% (1 of every 132 participants receiving the vaccine). There is a 
50% chance of observing at least 1 SAE among 212 participants in each of the 
concomitant/nonconcomitant groups if the underlying incidence of a SAE is 0.33% (1 of 
every 303 participants receiving the vaccine). If no SAEs are observed among 212
participants in each of the concomitant/nonconcomitant groups, this study will provide 
97.5% confidence that the underlying percentage of participants with a SAE is <1.73% (1 in 
every 58 participants).
9.10
Subgroup Analyses
Subgroup analyses will be performed for the primary immunogenicity endpoints and selected 
safety endpoints (summary of AEs and summary of solicited AEs). Subgroup classification 
variables include age (50 to 64 years, 65 to 74 years, and ≥75 years), sex, race, ethnicity, 
prior pneumococcal vaccination (Yes or No), receipt of prior mRNA-1273 booster dose (Yes 
or No) and history of prior SARS-CoV-2 infection (Yes or No). The 95% CI will only be 
calculated if there are more than 10 participants in each vaccination group for each subgroup.
9.11
Compliance (Medication Adherence)
Compliance will not be calculated as participants will receive a single dose of V110 or V114 
and a single dose of mRNA-1273. The number and proportion of randomized participants 
receiving each vaccination will be summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V110, the number and proportion of randomized participants 
administered V114, and the number and proportion of randomized participants administered 
mRNA-1273.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 
in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. All trial protocols are and will be assessed for the need and capability to 
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enroll underrepresented groups. Participants must meet protocol entry criteria to 
be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
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All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
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completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy Testing

Highly sensitive serum or urine hCG pregnancy test (as needed for 
WOCBP)
Other Screening Tests

FSH (as needed in WONCBP only)
FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; WOCBP=women of childbearing potential; 
WONCBP=women of nonchildbearing potential.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol-specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Definition of Unsolicited and Solicited AE
•
An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant/participant’s legally authorized representative who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs.
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•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will assess the overall intensity of each AE and SAE (and other 
reportable event) reported during the study. An overall intensity grade will be assigned to 
injection-site AEs, specific systemic AEs, other systemic AEs, and vital sign 
(temperature) AEs as shown in the following tables. The overall intensity grading scales 
used in this study are adapted from the “FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, September 2007” [Food and Drug Administration 2007].
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Injection-site AE Overall Intensity Grading Scale
Injection-site 
Reaction to Study 
Vaccine/Placeboa
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially 
Life-threatening
(Grade 4)
Injection-site AEs occurring Days 1 through 7 following receipt of study vaccine/placebo
Pain/Tenderness
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Erythema/Redness
Size measured as
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or 
exfoliative 
dermatitis or 
results in ED visit 
or hospitalization
Swelling
Size measured as 
≤5 cm
Size measured as
5.1 to 10 cm
Size measured as
>10 cm
Necrosis or ED 
visit or 
hospitalization
Lymphadenopathy
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Other
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Any injection-site reaction that begins ≥8 days after receipt of study vaccine/placebo
Pain/Tenderness
Erythema/Redness
Swelling
Lymphadenopathy
Other
Does not interfere 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
or interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ED visit or 
hospitalization
AE=adverse event; ED=emergency department; eVRC=electronic Vaccine Report Card.
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Based on information provided by the participant on the eVRC and verbally during VRC review. Erythema/Redness
and Swelling are specific injection-site AEs with size designations of letters A (<2.5 cm), B (2.5 to 5 cm), C (5.1 to 
7.4 cm), D (7.5 to 10 cm), or E (>10 cm), based on a graphic in the eVRC. If the participant has an ED visit or is 
hospitalized for any injection-site AE, that AE is to be assigned an overall intensity of Grade 4, regardless of the 
size measured.
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Specific Systemic AE Overall Intensity Grading Scale
Systemic (General)
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-threatening
(Grade 4)
Headache
No interference 
with activity
Repeated use of 
nonnarcotic pain 
reliever >24 hours or 
some interference 
with activity
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity
ED visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Arthralgia
No interference 
with activity
Some interference 
with activity
Significant; 
prevents daily 
activity
ED visit or 
hospitalization
Nausea
No interference 
with activity or 1 to 
2 episodes/24 hours
Some interference 
with activity or 
>2 episodes/24 hours
Prevents daily 
activity, requires 
outpatient IV 
hydration
ED visit or 
hospitalization 
for hypotensive 
shock
Vomiting
No interference 
with activity or 1 to 
2 episodes/24 hours
Some interference 
with activity or 
>2 episodes/24 hours
Prevents daily 
activity, requires 
outpatient IV 
hydration
ED visit or 
hospitalization 
for hypotensive 
shock
Chills
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
requires medical 
intervention
ED visit or 
hospitalization
AE=adverse event; ED=emergency department; IV=intravenous.
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
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Other Systemic AE Overall Intensity Grading Scale
Systemic Illnessa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-threatening
(Grade 4)b
Illness or clinical 
AE (as defined 
according to 
applicable 
regulations)
No interference 
with activity
Some interference 
with activity not 
requiring medical 
intervention
Prevents daily 
activity and 
required medical 
intervention
ED visit or 
hospitalization
AE=adverse event; ED=emergency department; eVRC=electronic Vaccine Report Card; SAE=serious adverse event.
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Based on information provided by the participant on the eVRC and verbally during the eVRC review during the 
primary safety follow-up period. For SAEs reported beyond the primary safety follow-up period, grading will be 
based on the initial report and/or follow-up of the event.
b
AEs resulting in death will be assessed as Grade 4.
Vital Sign (Temperature) Overall Intensity Grading Scale
Vital Signsa
Mild 
(Grade 1)
Moderate 
(Grade 2)
Severe 
(Grade 3)
Potentially 
Life-threatening
(Grade 4)
Fever
(°C)b
(°F)b
38.0 to 38.4
100.4 to 101.1
38.5 to 38.9
101.2 to 102.0
39.0 to 40.0
102.1 to 104.0
>40.0
>104.0
The overall intensity grading scales used in this study are adapted from the “FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September 
2007” [Food and Drug Administration 2007].
a
Participant should be at rest for all vital sign requirements.
b
Oral temperature; no recent hot or cold beverages or smoking.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This 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 product and the AE based on the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (diary, etc.), 
seroconversion or identification of vaccine virus in bodily specimen?
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant reexposed to the study intervention in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose vaccine study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
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•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product comprised of 2 or more regulated components (ie, a drug 
and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Customer Feedback – A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark that may suggest an improvement in the 
functionality or quality of a medical device, or device like features of a drug delivery 
system).
Malfunction – The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device – Any instrument, apparatus, appliance, material, or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment, or alleviation of disease,
•
diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or 
handicap,
•
investigation, replacement, or modification of the anatomy or of a physiological process,
•
control of conception,
and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological, or metabolic means, but which may be assisted in its 
function by such means.
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PQC – Any communication that describes a potential defect related to the identity, strength, 
quality, purity, or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury – An injury or illness that:
1. Is life-threatening,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1
via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
Progestogen- only contraceptive implantc
IUSd
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionc
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action
Male or female condom with or without spermicide
Cervical cap, diaphragm, or sponge with spermicide
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to those 
which inhibit ovulation.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACE2
Angiotensin-converting enzyme 2
ACIP
Advisory Committee on Immunization Practices
AE
adverse event 
AESI
adverse event of special interest
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ARDS
adult respiratory distress syndrome
AST
aspartate aminotransferase
bAb
binding antibody
CDC
Centers for Disease Control
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained longitudinal data analysis
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CRF
Case Report Form
CSR
Clinical Study Report
CTFG
Clinical Trials Facilitation Group
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
events of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection
EEA
European Economic Area
EMA
European Medicines Agency
EU
European Union
EUA
Emergency Use Authorization
eVRC
electronic Vaccination Report Card
FAS
Full Analysis Set
FBR
future biomedical research
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Abbreviation
Expanded Term
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GMFR
geometric mean fold rise
GMT
geometric mean titer
hCG
human chorionic gonadotropin
HEK293
Human embryonic kidney 293
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IM
intramuscular
IPD
invasive pneumococcal disease
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhea method
MOPA
multiplexed opsonophagocytic assay
mRNA
messenger ribonucleic acid
nAb
neutralizing antibody
OPA 
opsonophagocytic activity
PCV
pneumococcal conjugate vaccine
PK
pharmacokinetic
PP
Per-protocol
PQC
product quality complaint
RNA
ribonucleic acid
SAE
serious adverse event
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Abbreviation
Expanded Term
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SLAB
supplemental laboratory test
SoA
Schedule of Activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TMPRSS2
Transmembrane serine protease 2
US
United States
V110
PNEUMOVAX™23 (Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 
12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F)
V114
VAXNEUVANCE™ (Serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F, 22F, 23F, and 33F)
VRC
vaccination report card
WOCBP
woman (or women) of childbearing potential
WONCBP
woman (or women) of nonchildbearing potential
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11
REFERENCES
[Andrews, N., et al 2022]
Andrews N, Stowe J, Kirsebom F, Toffa S, 
Sachdeva R, Gower C, et al. Effectiveness 
of COVID-19 booster vaccines against 
COVID-19-related symptoms, 
hospitalization and death in England. Nat 
Med. 2022 Apr;28:831-7. Additional 
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V110-911-03 FINAL PROTOCOL
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PRODUCT: V110
110
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V110-911-03 FINAL PROTOCOL
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08DX3L

PRODUCT: V110
111
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PRODUCT: V110
112
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12-DEC-2022
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