A Phase 3, Multicenter, Open-Label Study to Evaluate the Safety and Immunogenicity of 2-dose Regimens of 9vHPV and mRNA-1273 SARS-CoV-2 Vaccines Where the First Dose of Each Vaccine Are Given Concomitantly in Boys and Girls 9 to 11 Years of Age
Phase: PHASE3
Conditions: Papillomavirus Infections, Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05119855 
Document Date: 
15-Feb-2023
A Phase 3, Multicenter, Open-Label Study to Evaluate the Safety 
and Immunogenicity of 2-dose Regimens of 9vHPV and 
mRNA-1273 SARS-CoV-2 Vaccines Where the First Dose of 
Each Vaccine Are Given Concomitantly in Boys and Girls 9 to
11 Years of Age

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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, Multicenter, Open-Label Study to Evaluate the Safety and 
Immunogenicity of 2-dose Regimens of 9vHPV and mRNA-1273 SARS-CoV-2 Vaccines 
Where the First Dose of Each Vaccine Are Given Concomitantly in Boys and Girls 9 to 
11 Years of Age
Protocol Number: 076-03
Compound Number: V503
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
NCT05119855
EU CT
Not applicable
EudraCT
2021-003591-13
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
13447
Approval Date: 15 February 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
15-FEB-2023
The primary purpose of this amendment is to 
change from a hypothesis testing study to an
estimation study design due to early closure of 
enrollment.
Amendment 2
12-JUL-2022
The primary reason for this amendment is to allow 
enrollment of participants with SARS-CoV-2 
infection >90 days prior to enrollment.
Amendment 1
15-DEC-2021
The primary reasons for this amendment are to 
change the age range for study participants to 9 to 
11 years of age and to change the dose (volume) of 
the mRNA-1273 vaccine to 50 µg (0.25 mL) to 
reflect emerging clinical data for the mRNA-1273 
vaccine.
Original Protocol
09-AUG-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendment: The primary purpose of this amendment is to change from a hypothesis testing study to an 
estimation study design due to early closure of enrollment.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1 Synopsis
Section 1.2 Schema
Section 3 Hypotheses, Objective, and Endpoints
Section 4.1 Overall Design
Section 4.2 Scientific Rationale for Study 
Design
Section 9.1 Statistical Analysis Plan Summary
Section 9.3 Hypotheses/Estimation
Section 9.6.1 Statistical Methods for 
Immunogenicity Analyses
Section 9.8 Multiplicity
Section 9.9 Sample Size and Power 
Calculations
Section 9.10 Subgroup Analyses

Changed the study design from 
comparative, hypothesis testing to 
estimation.

Changed the expected enrollment from 
approximately 400 to approximately
160 participants.

Changed study duration from approximately 
12 months to approximately 21 months.
In the setting of the evolving 
COVID-19 pandemic setting, 
enrollment has been slower 
than anticipated. Additionally, 
the mRNA-1273 vaccine 
clinical supply will not be 
available after 1Q2023 to 
support further enrollment. 
Therefore, enrollment will 
conclude with an expected 
enrollment of approximately 
160 participants and the 
planned analyses will be 
converted to descriptive data 
summaries.
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Section Number and Name
Description of Change
Brief Rationale
Other Changes in Amendment
Title Page
Added NCT number.
Include additional study 
identifier.
Section 1.1 Synopsis
Updated indication from “Prevention of 
persistent infection and disease caused by HPV 
Types 6, 11, 16, 18, 31, 33, 45, 52, and 58” to 
“Papilloma viral infection”.
Align with MedDRA preferred 
terminology.
Section 1.1 Synopsis
Section 6.1 Study Intervention(s) Administered

Additional intervention information from 
Table 1 included in Synopsis.

Dose Formation: “Sterile Suspension” 
changed to “Suspension”.

Use: “Experimental” changed to “Test 
Product”.
Clarification and to align with 
global regulatory requirements.
Section 4.4 Beginning and End-of-Study 
Definition
Replaced example for lost to follow-up and 
added reference to the respective section.
Clarification.
Added text to define the European Economic 
Area (EEA).
To align with global regulatory 
requirements.
Section 8.1.10.1 Withdrawal From Future 
Biomedical Research
Appendix 6: Collection and Management of 
Specimens for Future Biomedical Research
Updated Sponsor contact email address for 
future biomedical research.
New email address.
Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-
up, and Reporting
Changed “Sponsor’s product” to “study 
intervention” and emergency room to 
emergency department.
To harmonize terminology.
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Section Number and Name
Description of Change
Brief Rationale
Throughout Document
Minor administrative, formatting, editorial, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of 
the protocol.
The structure of the protocol has been updated.
To comply with current 
industry regulations and 
guidelines. This restructuring 
does not affect the clinical or 
regulatory integrity of the 
protocol. All other relevant 
changes and their primary 
reasons are included for 
completeness.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................20
1.3.1
Scheduled Visits for Concomitant Group....................................................20
1.3.2
Scheduled Visits for Nonconcomitant Group..............................................23
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................26
2.2
Background ..........................................................................................................27
2.2.1
Pharmaceutical and Therapeutic Background .............................................27
2.2.2
Preclinical and Clinical Studies ...................................................................27
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................33
4.2.1.1
Immunogenicity Endpoints................................................................33
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Pharmacodynamic Endpoints.............................................................33
4.2.1.5
Planned Exploratory Biomarker Research.........................................33
4.2.1.6
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator...........................................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End-of-Study Definition ............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................34
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.2
Exclusion Criteria................................................................................................37
5.3
Lifestyle Considerations......................................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
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6.1.1
Medical Devices...........................................................................................42
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................43
6.5.1
Rescue Medications and Supportive Care ...................................................44
6.6
Dose Modification ................................................................................................44
6.7
Intervention After the End of the Study............................................................44
6.8
Clinical Supplies Disclosure................................................................................44
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...........................................................46
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/Assent.............................................................................48
8.1.1.1
General Informed Consent/Assent.....................................................48
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................49
8.1.2
Inclusion/Exclusion Criteria ........................................................................49
8.1.3
Participant Identification Card.....................................................................49
8.1.4
Medical History ...........................................................................................50
8.1.5
Demographics ..............................................................................................50
8.1.6
Prior and Concomitant Medications Review...............................................50
8.1.6.1
Prior Medications...............................................................................50
8.1.6.2
Concomitant Medications..................................................................50
8.1.7
Assignment of Screening Number...............................................................51
8.1.8
Assignment of Treatment/Randomization Number.....................................51
8.1.9
Study Intervention Administration ..............................................................51
8.1.9.1
Timing of Dose Administration.........................................................53
8.1.10
Discontinuation and Withdrawal .................................................................53
8.1.10.1
Withdrawal From Future Biomedical Research ................................53
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8.1.11
Participant Blinding/Unblinding..................................................................54
8.1.12
Calibration of Equipment.............................................................................54
8.2
Immunogenicity Assessments .............................................................................54
8.2.1
SARS-CoV-2 Spike Protein-specific Binding Antibody Measured by 
ECL Assay ...................................................................................................54
8.2.2
Antibody to 9vHPV Vaccine Types Measured by Competitive Luminex 
Immunoassay ...............................................................................................54
8.3
Safety Assessments...............................................................................................55
8.3.1
Physical Examinations.................................................................................55
8.3.2
Oral Temperature Measurement ..................................................................55
8.3.3
Electronic Vaccination Report Card ............................................................55
8.3.4
Postvaccination Observation Period (30 Minutes) ......................................56
8.3.5
Clinical Safety Laboratory Assessments .....................................................57
8.3.6
Pregnancy Testing........................................................................................57
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................58
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................58
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......60
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...61
8.4.4
Regulatory Reporting Requirements for SAE .............................................61
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................61
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................62
8.4.7
Events of Clinical Interest............................................................................62
8.4.8
Medical Device and Drug–Device Combination Products –
PQCs/Malfunctions......................................................................................62
8.4.9
Adverse Events on the VRC ........................................................................62
8.4.9.1
Solicited Adverse Event.....................................................................62
8.4.9.2
Unsolicited Adverse Events...............................................................63
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................64
8.7
Pharmacodynamics..............................................................................................64
8.8
Biomarkers ...........................................................................................................64
8.9
Future Biomedical Research Sample Collection...............................................64
8.10
Medical Resource Utilization and Health Economics.......................................64
8.11
Visit Requirements...............................................................................................65
8.11.1
Screening......................................................................................................65
8.11.2
Intervention and Follow-up Periods.............................................................65
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8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................65
9
STATISTICAL ANALYSIS PLAN .............................................................................66
9.1
Statistical Analysis Plan Summary.....................................................................66
9.2
Responsibility for Analyses/In-house Blinding .................................................68
9.3
Hypotheses/Estimation ........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.4.1
Immunogenicity Endpoints..........................................................................68
9.4.2
Safety Endpoints..........................................................................................69
9.5
Analysis Populations............................................................................................69
9.5.1
Immunogenicity Analysis Population..........................................................69
9.5.2
Safety Analysis Population..........................................................................70
9.6
Statistical Methods...............................................................................................70
9.6.1
Immunogenicity Analysis Methods.............................................................70
9.6.1.1
Estimation of Immune Response Relating to HPV............................70
9.6.1.2
Estimation of Immune Response Relating to SARS-CoV-2 .............71
9.6.1.3
Estimation of Percent Seroconversion and Percent Seroresponse.....71
9.6.2
Safety Analysis Methods .............................................................................72
9.7
Interim Analyses ..................................................................................................74
9.8
Multiplicity ...........................................................................................................74
9.9
Sample Size and Power Calculations .................................................................74
9.9.1
Immunogenicity ...........................................................................................74
9.9.2
Sample Size for Safety Analysis..................................................................74
9.10
Subgroup Analyses...............................................................................................75
9.11
Compliance (Medication Adherence).................................................................75
9.12
Extent of Exposure...............................................................................................75
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................76
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................80
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................80
10.1.4
Committees Structure...................................................................................81
10.1.5
Publication Policy........................................................................................81
10.1.6
Compliance with Study Registration and Results Posting Requirements ...81
10.1.7
Compliance with Law, Audit, and Debarment ............................................81
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10.1.8
Data Quality Assurance ...............................................................................82
10.1.9
Source Documents .......................................................................................83
10.1.10
Study and Site Closure.................................................................................83
10.2
Appendix 2: Clinical Laboratory Tests..............................................................84
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................85
10.3.1
Definition of AE ..........................................................................................85
10.3.2
Definition of SAE ........................................................................................90
10.3.3
Additional Events Reported.........................................................................91
10.3.4
Recording AE and SAE ...............................................................................92
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................97
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................99
10.4.1
Definitions....................................................................................................99
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ..100
10.5
Appendix 5: Contraceptive Guidance..............................................................102
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................103
10.7
Appendix 7: Country-specific Requirements..................................................108
10.8
Appendix 8: Abbreviations ...............................................................................109
11
REFERENCES.............................................................................................................112
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LIST OF TABLES
Table 1
Study Interventions......................................................................................41
Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Types – Concomitant Group........................................................................................48
Table 3
Approximate Blood Volumes Drawn by Study Visit and by Sample 
Types – Nonconcomitant Group..................................................................................48
Table 4
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations for 9vHPV Vaccine................................................................................58
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................59
Table 6
Solicited Adverse Events .............................................................................63
Table 7
Acceptable Day Ranges for Vaccination Visits...........................................70
Table 8
Acceptable Day Ranges for Collection of Serum Samples .........................70
Table 9
Strategy for Analysis of Immunogenicity Endpoints...................................71
Table 10
Strategy for Analysis of Safety Endpoints...................................................73
Table 11
Half-widths of 2-sided 95% CIs for Geometric Mean Ratios by 
Serotype 74
Table 12
Probability of Observing At Least 1 Vaccine-related Serious Adverse 
Event in a Group With 80 Participants ........................................................................75
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LIST OF FIGURES
Figure 1
Study Design for Concomitant Group .........................................................18
Figure 2
Study Design for Nonconcomitant Group ...................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Open-Label Study to Evaluate the Safety and 
Immunogenicity of 2-dose Regimens of 9vHPV and mRNA-1273 SARS-CoV-2 Vaccines 
Where the First Dose of Each Vaccine Are Given Concomitantly in Boys and Girls 9 to 
11 Years of Age
Short Title: Safety and Immunogenicity of 9vHPV Vaccine Coadministered With 
mRNA-1273 SARS-CoV-2 Vaccine
Acronym: None
Hypotheses, Objectives, and Endpoints:
The following objectives and endpoints will be evaluated in boys and girls 9 to 11 years of 
age.
Primary Objectives
Primary Endpoints
•
Objective 1: To evaluate the GMTs of 
antibodies to each of the 9vHPV vaccine 
types at 4 weeks Postdose 2 of a 2-dose 
regimen of 9vHPV vaccine, when the 
first dose of a 2-dose regimen of 9vHPV 
vaccine is administered concomitantly 
or nonconcomitantly with a first dose of 
a 2-dose regimen of mRNA-1273 
vaccine.
•
Serum antibody titers at 4 weeks 
Postdose 2 of 9vHPV vaccine measured 
by cLIA to each of the 9vHPV vaccine 
types (HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58)
•
Objective 2: To evaluate the GMCs of 
SARS-CoV-2 spike protein-specific 
binding antibody at 4 weeks Postdose 2 
of a 2-dose regimen of mRNA-1273 
vaccine, when the first dose of a 2-dose 
regimen of mRNA-1273 vaccine is 
administered concomitantly or 
nonconcomitantly with a first dose of a 
2-dose regimen of 9vHPV vaccine.
•
Serum antibody concentrations at 4 
weeks Postdose 2 of mRNA-1273 
vaccine measured by ECL assay specific 
to the SARS-CoV-2 spike protein
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•
Objective 3: To evaluate the safety and 
tolerability of 2-dose regimens of 
9vHPV and mRNA-1273 vaccines 
where the first dose of each vaccine is 
administered concomitantly.
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
SAEs
•
Vaccine-related SAEs
Secondary Objectives
Secondary Endpoints
•
Objective: For each of the Concomitant 
and Nonconcomitant Groups, to estimate 
percent seroconversion to each of the 
9vHPV vaccine types at 4 weeks 
Postdose 2 induced by a 2-dose regimen 
of 9vHPV vaccine.
•
Serum antibody titers at 4 weeks 
Postdose 2 of 9vHPV vaccine measured 
by cLIA to each of the 9vHPV vaccine 
types (HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58)
•
Objective: For each of the Concomitant 
and Nonconcomitant Groups, to estimate 
percent seroresponse at 4 weeks 
Postdose 2 induced by a 2-dose regimen 
of mRNA-1273 vaccine.
•
Serum antibody concentrations at 4 
weeks Postdose 2 of mRNA-1273 
vaccine measured by ECL assay specific 
to the SARS-CoV-2 spike protein
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Papilloma viral infection
Population
Boys and girls 9 to 11 years of age
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study
Concomitant administrations
Type of Control
Active Control Without Placebo
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
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Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 21 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent/assent until 
the last participant’s last study-related 
contact.
For purposes of analysis and reporting, the 
overall study ends when the Sponsor 
receives the last laboratory result or at the 
time of final contact with the last 
participant, whichever comes last.
Number of Participants:
Approximately 160 participants will be enrolled into the study.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Concomitant 
Group
mRNA-1273 
vaccine
mRNA* 50 µg per dose
0.25 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 1
Test 
Product
Concomitant 
Group
9vHPV 
vaccine
HPV6/11/16/18/31/33/
45/52/58 L1 VLP: 
30/40/60/40/20/20/20/
20/20 mcg per dose
0.5 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 6
Test 
Product
Nonconcomitant 
Group
mRNA-1273 
vaccine
mRNA* 50 µg per dose
0.25 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 1
Test 
Product
Nonconcomitant 
Group
9vHPV 
vaccine
HPV6/11/16/18/31/33/
45/52/58 L1 VLP: 
30/40/60/40/20/20/20/
20/20 mcg per dose
0.5 mL 
per dose
IM
Single dose 
at Month 2 
and Month 8
Test 
Product
HPV=human papillomavirus; IM=intramuscular; IMP=Investigational Medicinal Product; mL=milliliter; 
mRNA=messenger ribonucleic acid; NIMP/AxMP=noninvestigational/auxiliary medicinal product; SARS-CoV-2=severe 
acute respiratory syndrome coronavirus 2
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 European Economic Area (EEA). Country differences with respect to the definition/classification 
of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
*
mRNA encoding the prefusion stabilized spike glycoprotein of SARS-CoV-2 virus (Moderna Inc., Cambridge, MA)
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Other current or former name(s) or alias(es) for study intervention(s) are as follows: Moderna 
COVID-19 vaccine and mRNA-1273 SARS-CoV-2 vaccine for mRNA-1273 vaccine; 
GARDASIL®9 and V503 for 9vHPV vaccine.
Total Number of Intervention Groups/Arms
2 intervention groups
Duration of Participation
Each participant will participate in the study 
for approximately 7 or 9 months from the 
time the participant provides documented 
informed consent/assent through the final 
contact. 
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.
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1.2
Schema
The main features of the study design are depicted in Figure 1 for Concomitant Group and 
Figure 2 for Nonconcomitant Group.
Figure 1
Study Design for Concomitant Group
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Figure 2
Study Design for Nonconcomitant Group
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1.3
Schedule of Activities
1.3.1
Scheduled Visits for Concomitant Group
Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
4a
5a
Scheduled Time
Day 1
Month 1
Month 2
Month 6
Month 7
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
6 months 
after 
Day 1 
±4 weeks
28 to 49 
days 
after 
Visit 4a
To calculate visit windows, assume 1 month = 30 
days and 1 week = 7 days.
Administrative and General Procedures
Obtain Informed Consent/Assent
X
The interval between the date of consent and the date 
of the Day 1 visit should be no more than 14 days. If 
the interval is ≥15 days, then the participant must be 
reconsented.
Obtain Informed Consent/Assent for 
Future Biomedical Research
X
Participation in future biomedical research is optional 
and consent/assent must be obtained before collection 
of blood (DNA) samples.
Review Inclusion/Exclusion Criteria
X
Assign Participant Identification Card
X
Collect Medical History
X
See Section 8.1.4 for details.
Collect Demographics
X
Review Prior/Concomitant Medication 
and Nonstudy Vaccination
X
X
X
X
X
See Section 8.1.6 for details.
Clinical Procedures and Assessments
Measure Oral Temperature
X
X
X
Oral temperature should be measured prior to 
vaccination. If the participant has a fever within the 24-
hour period prior to a vaccination visit, the visit should 
be rescheduled until after the fever has resolved 
(Section 5.2).
Record Height and Weight
X
Height and weight will be recorded on Day 1 before 
vaccination.
Perform Physical Examination
X
Performed at Day 1 to assess inclusion/exclusion 
criteria. After Day 1, a physical examination is 
optional.
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Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
4a
5a
Scheduled Time
Day 1
Month 1
Month 2
Month 6
Month 7
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
6 months 
after 
Day 1 
±4 weeks
28 to 49 
days 
after 
Visit 4a
To calculate visit windows, assume 1 month = 30 
days and 1 week = 7 days.
Laboratory Procedures and Assessments
Perform Pregnancy Testing, Serum or 
Urine (required for all females)
X
X
X
The serum pregnancy test or urine pregnancy test must 
be sensitive to at least 25 mIU/mL β-hCG and 
performed prior to vaccination. Results must be 
negative prior to vaccination (Section 8.3.6).
Collect Blood Sample (Serum for anti-
HPV Antibodies)
X
X
Serum must be collected before vaccination. Serum 
(including retention serum) must be shipped as 
specified by the Sponsor or central laboratory.
Collect Blood Sample (Serum for 
SARS-CoV-2 Spike Protein-specific 
Binding Antibody)
X
X
Collect Blood (DNA) for Future 
Biomedical Research
X
Sample will be collected from randomized participants 
who provided consent for future biomedical research. 
Sample should be obtained before vaccine is 
administered on Day 1 or at a later date as soon as 
informed consent is obtained. Participation in future 
biomedical research is optional.
Randomization, Vaccine Administration, and Safety Procedures/Assessments
Vaccine Allocation/Randomization
X
Provide or Configure Electronic Device 
for eVRC Data Collection
X
Study personnel will train the participant on the use of 
the device for eVRC data collection.
Administer mRNA-1273 SARS-CoV-2 
Vaccine (Right Arm)
X
X
Administer 9vHPV Vaccine (Left Arm)
X
X
30-minute Postvaccination Observation 
Period
X
X
X
Review eVRC Data With Participant
X
X
X
Collect Electronic Device From 
Participant
X
For participants who were provided an electronic 
device.
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Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
4a
5a
Scheduled Time
Day 1
Month 1
Month 2
Month 6
Month 7
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
6 months 
after 
Day 1 
±4 weeks
28 to 49 
days 
after 
Visit 4a
To calculate visit windows, assume 1 month = 30 
days and 1 week = 7 days.
Monitor AEs
X
X
X
X
X
See Section 8.4.1 for details on the timing and 
frequency of AE monitoring.
AE=adverse event; β-hCG=β-human chorionic gonadotropin; DNA=deoxyribonucleic acid; eVRC=electronic Vaccination Report Card; HPV=human papillomavirus; 
mIU=milli international units; mL=milliliter; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
a
Regarding protocol study visit windows, the following situations require consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision: a participant needs to be scheduled earlier than the start of a visit window or the study site is considering skipping a visit.
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1.3.2
Scheduled Visits for Nonconcomitant Group
Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
3b (TC)
4b
5b
Scheduled Time
Day 
1
Month 1
Month 2
Month 3
Month 8
Month 9
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
29 to 35 
days 
after 
Visit 3
6 months 
after Visit 
3 ±4 weeks
28 to 49 
days 
after 
Visit 4b
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days.
Administrative and General Procedures
Obtain Informed Consent/Assent
X
The interval between the date of consent and the 
date of the Day 1 visit should be no more than 14 
days. If the interval is ≥15 days, then the 
participant must be reconsented.
Obtain Informed Consent/Assent 
for Future Biomedical Research
X
Participation in future biomedical research is 
optional and consent/assent must be obtained 
before collection of blood (DNA) samples.
Review Inclusion/Exclusion 
Criteria
X
Assign Participant Identification 
Card
X
Collect Medical History
X
See Section 8.1.4 for details.
Collect Demographics
X
Review Prior/Concomitant 
Medication and Nonstudy 
Vaccination
X
X
X
X
X
X
See Section 8.1.6 for details.
Clinical Procedures and Assessments
Measure Oral Temperature
X
X
X
X
Oral temperature should be measured prior to 
vaccination. If the participant has a fever within 
the 24-hour period prior to a vaccination visit, the 
visit should be rescheduled until after the fever 
has resolved (Section 5.2).
Record Height and Weight
X
Height and weight will be recorded on Day 1 
before vaccination.
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Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
3b (TC)
4b
5b
Scheduled Time
Day 
1
Month 1
Month 2
Month 3
Month 8
Month 9
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
29 to 35 
days 
after 
Visit 3
6 months 
after Visit 
3 ±4 weeks
28 to 49 
days 
after 
Visit 4b
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days.
Perform Physical Examination
X
Performed at Day 1 to assess inclusion/exclusion 
criteria. After Day 1, a physical examination is 
optional.
Laboratory Procedures and Assessments
Perform Pregnancy Testing, 
Serum or Urine (required for all 
females)
X
X
X
X
The serum pregnancy test or urine pregnancy test 
must be sensitive to at least 25 mIU/mL β-hCG 
and performed prior to vaccination. Results must 
be negative prior to vaccination (Section 8.3.6).
Collect Blood Sample (Serum 
for anti-HPV Antibodies)
X
X
Serum must be collected before vaccination. 
Serum (including retention serum) must be 
shipped as specified by the Sponsor or central 
laboratory.
Collect Blood Sample (Serum 
for SARS-CoV-2 Spike Protein-
specific Binding Antibody)
X
X
Collect Blood (DNA) for Future 
Biomedical Research
X
Sample will be collected from randomized 
participants who provided consent for future 
biomedical research. Sample should be obtained 
before vaccine is administered on Day 1 or at a 
later date as soon as informed consent is obtained. 
Participation in future biomedical research is 
optional.
Randomization, Vaccine Administration, and Safety Procedures/Assessments
Vaccine 
Allocation/Randomization
X
Provide or Configure Electronic 
Device for eVRC Data 
Collection
X
Study personnel will train the participant on the 
use of the device for eVRC data collection.
Administer mRNA-1273 
SARS-CoV-2 Vaccine (Right 
Arm)
X
X
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Study Period
Intervention and Follow-up
Notes
Visit Number
1
2
3
3b (TC)
4b
5b
Scheduled Time
Day 
1
Month 1
Month 2
Month 3
Month 8
Month 9
Visit Windowa
28 to 42 
days 
after 
Visit 1
28 to 42 
days 
after 
Visit 2
29 to 35 
days 
after 
Visit 3
6 months 
after Visit 
3 ±4 weeks
28 to 49 
days 
after 
Visit 4b
To calculate visit windows, assume 
1 month=30 days and 1 week=7 days.
Administer 9vHPV Vaccine 
(Left Arm)
X
X
30-minute Postvaccination 
Observation Period
X
X
X
X
Review eVRC Data With 
Participant
X
X
X
X
Collect Electronic Device From 
Participant
X
For participants who were provided an electronic 
device.
Monitor AEs
X
X
X
X
X
X
See Section 8.4.1 for details on the timing and 
frequency of AE monitoring.
AE=adverse event; β-hCG= β-human chorionic gonadotropin; DNA=deoxyribonucleic acid; eVRC=electronic Vaccination Report Card; HPV=human papillomavirus; 
mIU=milli international units; mL=milliliter; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; TC=telephone contact
a
Regarding protocol study visit windows, the following situations require consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision: a participant needs to be scheduled earlier than the start of a visit window or the study site is considering skipping a visit.
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2
INTRODUCTION
The 9-valent HPV vaccine was initially licensed as a 3-dose vaccination series and was 
subsequently approved for 2-dose regimens in individuals 9 to 14 years of age (the main 
target population for vaccination) in many countries. The WHO and the US ACIP changed 
their recommendations in 2014 and 2016, respectively, to include 2-dose regimens for 
individuals 9 to 14 years of age [World Health Organization 2014] [Meites, E., et al 2016].
The mRNA-1273 SARS-CoV-2 vaccine (Moderna Inc., Cambridge, MA) has been studied in 
children 6 to 11 years of age (mRNA-1273-P204; NCT04796896). The interim analysis from 
the study showed a robust neutralizing antibody response after 2 doses of mRNA-1273 
vaccine at the 50-µg dose level with a favorable safety profile [Moderna, Inc. 2021], which 
was the basis for an expanded EUA for primary vaccination series in individuals 6 to 11 
years of age [O'Shaughnessy, J. A. 2022].
2.1
Study Rationale
Licensure and recommendation of 2-dose regimens of the 9vHPV vaccine were based on a 
clinical study (Protocol V503-010; NCT01984697), which demonstrated that 2 doses of the 
9vHPV vaccine administered either 6 or 12 months apart in boys and girls 9 to 14 years of 
age elicited noninferior GMTs to the 9 vaccine-targeted HPV types at 4 weeks after the last 
dose compared with a standard 3-dose regimen (administered at Day 1, Month 2, and 
Month 6) in young women 16 to 26 years of age [Iversen, O. E. 2016].
The initial EUA in December 2020 of a 2-dose regimen of the mRNA-1273 vaccine at the 
100-µg dose level for persons >18 years of age was based on a clinical study (mRNA-1273-
P301; NCT04470427), which demonstrated clinical efficacy in preventing symptomatic, 
laboratory-confirmed COVID-19 infection with an acceptable safety profile [Baden, L. R., et 
al 2021]. A further clinical study (mRNA-1273-P204; NCT04796896) demonstrated strong 
immune response in children 6 to 11 years of age [Moderna, Inc. 2021]. The SARS-CoV-2-
neutralizing antibody geometric mean ratio comparing the response in children 6 to 11 years 
of age to the response in young adults from the mRNA-1273-P301 clinical study was 1.5 
(95% Cl: 1.3, 1.8), with a seroresponse rate of 99.3%. The mRNA-1273 vaccine was 
generally well tolerated in children 6 to 11 years of age with a safety and tolerability profile 
generally consistent with the mRNA-1273-P301 clinical study. The mRNA-1273 vaccine is 
authorized for use for active immunization as a primary series (50 µg dose) to prevent 
COVID-19 illness in individuals 6 to 11 years of age under an EUA [O'Shaughnessy, J. A. 
2022].
Previous studies have demonstrated that the concomitant use of the 9vHPV vaccine with 
other vaccines (ie, meningococcal, poliomyelitis, diphtheria, tetanus, and pertussis) routinely 
administered in this age group was well tolerated and did not interfere with antibody 
responses to any of the vaccines concomitantly administered [Kosalaraksa, P., et al 2015] 
[Schilling, A., et al 2015]. Concomitant administration of vaccines in this age group may 
help minimize the number of vaccination visits required and improve implementation of 
vaccination programs; however, there are no data available for mRNA COVID-19 vaccines 
coadministered with other vaccines. A study designed to rigorously assess the safety and 
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immunogenicity of coadministration of the first doses of a 2-dose 9vHPV vaccine and a 2-
dose mRNA-1273 vaccine is needed.
There are currently limited data available for SARS-CoV-2 vaccines coadministered with 
other vaccines in adult populations [Lazarus, R., et al 2021], but to date, no coadministration 
data for an mRNA COVID-19 vaccine has been generated in pediatric populations. The 
ACIP has not recommended against coadministration of mRNA COVID-19 vaccines with 
other routine vaccinations but noted the lack of current data and called for studies to generate 
safety and immunogenicity data on coadministration [Wallace, M., et al 2021].
The current study will evaluate the safety and immunogenicity of 2-dose regimens of 9vHPV 
and mRNA-1273 vaccines where the first dose of each vaccine are administered 
concomitantly in boys and girls 9 to 11 years of age, compared with nonconcomitant 
administration of the 2 vaccines.
2.2
Background
Refer to the IB/approved labeling for detailed background information on 9vHPV vaccine.
Refer to the approved labeling and EUA prescribing information for detailed background 
information on mRNA-1273 vaccine.
2.2.1
Pharmaceutical and Therapeutic Background
The 9vHPV vaccine is an aluminum-adjuvanted recombinant protein vaccine prepared from 
the highly purified VLPs of the recombinant major capsid (L1) protein of HPV Types 6, 11, 
16, 18, 31, 33, 45, 52, and 58. The 9vHPV vaccine is currently indicated for the prevention of 
disease caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
The mRNA-1273 vaccine is based on a platform of nucleoside-modified mRNA encoding the 
pre-fusion stabilized spike glycoprotein of SARS-CoV-2 virus. The mRNA-1273 vaccine is 
indicated for active immunization as a primary series to prevent COVID-19 illness caused by 
SARS-CoV-2 in individuals 18 years of age and older. The mRNA-1273 vaccine was also 
authorized for use 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. The mRNA-1273 vaccine (50 µg dose) is authorized for 
use for active immunization as a primary series to prevent COVID-19 illness in individuals 6 
to 11 years of age under an EUA [O'Shaughnessy, J. A. 2022].
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on completed preclinical and clinical studies conducted with 
the 9vHPV vaccine.
Refer to the approved labeling, the EUA, and the clinical study (mRNA-1273-P204; 
NCT04796896) in boys and girls 6 to 11 years of age for clinical study experience with the 
mRNA-1273 vaccine [Moderna, Inc. 2021] [O'Shaughnessy, J. A. 2022].
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
A 2-dose schedule with a 6- to 12-month interval between doses is approved for HPV 
vaccines and recommended in many countries for individuals 9 to 14 years of age [World 
Health Organization 2017] [Meites, E., et al 2016]. This study is designed to enroll 
individuals before they age out of the recommended target population for 2-dose schedules 
and to enable completion of a 2-dose vaccine series before increased risk of exposure to 
HPV. In this study, all participants will receive 2 doses of the 9vHPV vaccine 6 months 
apart.
The 9vHPV vaccine has been shown to be efficacious in preventing persistent anogenital 
HPV infection and disease associated with HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. 
The frequency, severity, and magnitude of AEs identified in previous studies and post 
marketing surveillance support a favorable benefit to risk analysis for the 9vHPV vaccine in 
the study population.
All participants will also receive a 2-dose regimen of mRNA-1273 vaccine. The frequency, 
severity, and magnitude of AEs identified in a previous clinical study support a favorable 
benefit to risk analysis for the mRNA-1273 vaccine in all studied populations. The 
mRNA-1273 vaccine has been shown to be efficacious in preventing COVID-19 illness in 
adolescents and adults. In the setting of an ongoing pandemic with increasing numbers of 
adults completing COVID-19 vaccination, preadolescents and young adolescents specifically 
represent a growing proportion of new COVID-19 cases reported to the US CDC and have 
been shown to contribute to household transmission [Lessler, J., et al 2021]. Individuals <18 
years of age are estimated to account for approximately 20% of COVID-19 cases in all 
regions of the US, with growing recognition that primary vaccination series in this population 
will increasingly include preadolescents and young adolescents who were previously infected 
[Cull, B. 2022]. In the setting of continued SARS-CoV-2 pandemic transmission, a 
population seronegative for SARS-CoV-2 may be challenging to recruit and enroll.
Though there are currently no published data on evidence of immunogenicity and safety of
SARS-CoV-2 vaccination in pediatric individuals with prior SARS-CoV-2 infection, current 
CDC guidance recommends vaccination after recovery from acute illness in individuals >6 
months old and continues to recommend coadministration with other vaccines without 
respect to prior SARS-CoV-2 infection status [Centers for Disease Control and Prevention 
2022].
Approximately 50% of participants will receive the first dose of mRNA-1273 vaccine 
concomitantly with 9vHPV vaccine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The following objectives and endpoints will be evaluated in boys and girls 9 to 11 years of 
age.
Primary Objective
Primary Endpoint
•
Objective 1: To evaluate the GMTs of 
antibodies to each of the 9vHPV vaccine 
types at 4 weeks Postdose 2 of a 2-dose 
regimen of 9vHPV vaccine, when the 
first dose of a 2-dose regimen of 9vHPV 
vaccine is administered concomitantly 
or nonconcomitantly with a first dose of 
a 2-dose regimen of mRNA-1273 
vaccine.
•
Serum antibody titers at 4 weeks 
Postdose 2 of 9vHPV vaccine measured 
by cLIA to each of the 9vHPV vaccine 
types (HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58)
•
Objective 2: To evaluate the GMCs of 
SARS-CoV-2 spike protein-specific 
binding antibody at 4 weeks Postdose 2 
of a 2-dose regimen of mRNA-1273 
vaccine, when the first dose of a 2-dose 
regimen of mRNA-1273 vaccine is 
administered concomitantly or 
nonconcomitantly with a first dose of a 
2-dose regimen of 9vHPV vaccine.
•
Serum antibody concentrations at 4 
weeks Postdose 2 of mRNA-1273 
vaccine measured by ECL assay specific 
to the SARS-CoV-2 spike protein
•
Objective 3: To evaluate the safety and 
tolerability of 2-dose regimens of 
9vHPV and mRNA-1273 vaccines 
where the first dose of each vaccine is 
administered concomitantly.
•
Solicited injection-site AEs
•
Solicited systemic AEs
•
SAEs
•
Vaccine-related SAEs
Secondary Objectives
Secondary Endpoints
•
Objective: For each of the Concomitant 
and Nonconcomitant Groups, to estimate 
percent seroconversion to each of the 
9vHPV vaccine types at 4 weeks 
Postdose 2 induced by a 2-dose regimen 
of 9vHPV vaccine.
•
Serum antibody titers at 4 weeks 
Postdose 2 of 9vHPV vaccine measured 
by cLIA to each of the 9vHPV vaccine 
types (HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58)
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•
Objective: For each of the Concomitant 
and Nonconcomitant Groups, to estimate 
percent seroresponse at 4 weeks 
Postdose 2 induced by a 2-dose regimen 
of mRNA-1273 vaccine.
•
Serum antibody concentrations at 4 
weeks Postdose 2 of mRNA-1273 
vaccine measured by ECL assay specific 
to the SARS-CoV-2 spike protein
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, open-label, multicenter study to evaluate the safety and 
immunogenicity of a 2-dose regimen of 9vHPV vaccine, where the first dose is administered 
concomitantly with a first dose of a 2-dose regimen of mRNA-1273 vaccine versus 
nonconcomitant administration of 9vHPV and mRNA-1273 vaccines in boys and girls 9 to 
11 years of age. Approximately 160 participants will be randomly assigned in a 1:1 ratio to
1 of the following groups:
Concomitant Group: Participants will receive their first dose of 9vHPV vaccine and first 
dose of mRNA-1273 vaccine on Day 1; they will then receive their second dose of 
mRNA-1273 vaccine at Month 1 and their second dose of 9vHPV vaccine at Month 6.
Nonconcomitant Group: Participants will receive their first and second doses of 
mRNA-1273 vaccine on Day 1 and at Month 1, respectively; they will then receive their first 
and second doses of 9vHPV vaccine at Months 2 and 8, respectively.
Blood samples for immunogenicity assays will be collected prior to the first dose of each 
vaccine and 4 weeks Postdose 2 of each vaccine.
After completion of immunogenicity testing to evaluate the study objectives, all leftover 
serum samples will be stored to conduct any additional study-related testing as required by 
regulatory agencies or the Sponsor. For study participants who provided consent for future 
biomedical research, leftover sera from the study will be deidentified and may be used for 
other purposes such as the development and/or validation of HPV assays or biomarker 
development after completion of all study-related immunogenicity testing (Section 8.9).
Participants will be followed for local and systemic AEs from Day 1 through Day 28 
following each vaccination (see Section 8.4.1). Information for all AEs resulting in 
discontinuation from study, MAAEs (see Section 10.3.1), and SAEs, regardless of whether 
the events are considered to be vaccine-related by the investigator, will be collected from the 
time consent is signed through completion of participation in the study (see Section 8.4.1).
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.
4.2
Scientific Rationale for Study Design
This study was originally designed to have a target enrollment of 400 boys and girls for 
sufficient power to test hypotheses to demonstrate noninferior immunogenicity of 9vHPV 
vaccine and mRNA-1273 in the Concomitant Group versus the Nonconcomitant Group. In 
the setting of the evolving COVID-19 pandemic setting, enrollment has been slower than 
anticipated. Additionally, the mRNA-1273 vaccine clinical supply will not be available after 
1Q2023 to support further enrollment. Therefore, enrollment will conclude in 1Q2023, with
expected enrollment of approximately 160 boys and girls 9 to 11 years of age. Participants
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will be randomized in an open-label manner to receive 2 preventative vaccinations: 9vHPV 
and mRNA-1273 vaccines. The study design will allow evaluation of safety and 
immunogenicity when the first dose of these 2 vaccines are administered concomitantly 
compared with nonconcomitant administration of the 2 vaccines. The 2-dose series for 
9vHPV vaccine is licensed in this age group to be administered 6 to 12 months apart. The 2-
dose series for the mRNA-1273 vaccine is administered 28 days apart. As the timing of the 
2-dose series differs between the 2 vaccines, this study will generate data to inform 
coadministration of the first dose of each vaccine. Overall, this design is similar to that used 
in previous coadministration studies (NCT00988884, NCT01073293) of the 9vHPV vaccine,
including coadministration with meningococcal, poliomyelitis, diphtheria, tetanus, and 
pertussis vaccines [Kosalaraksa, P., et al 2015] [Schilling, A., et al 2015].
Efficacy of the 9vHPV vaccine was demonstrated in a clinical study in young women 16 to 
26 years of age who received 3 doses of vaccine [Joura, E. A., et al 2015] [Huh, W . K., et al 
2017] [Giuliano, A. R., et al 2019]. Clinical efficacy of HPV vaccines cannot be directly 
assessed in young adolescents because of limited exposure to HPV. Therefore, efficacy 
results in young women were extrapolated to pre- and young adolescents receiving a 3-dose 
regimen based on immunogenicity bridging [Van Damme, P., et al 2015]. The licensure and 
recommendation of 2-dose regimens of 9vHPV vaccine was based on the demonstration of 
noninferior immunogenicity at 1 month after the last dose in girls and boys 9 to 14 years of 
age who received 2 doses compared with young women 16 to 26 years of age who received 3 
doses [Iversen, O. E. 2016]. Because the incidence of HPV infection has been demonstrated
to peak soon after onset of sexual activity, and HPV prevalence has been highly correlated 
with the number of recent and lifetime genital sex partners, young adolescents are an 
appropriate group in which to implement HPV vaccination [Kjaer, S. K., et al 2001] 
[Malagon, T., et al 2019].
Efficacy of the mRNA-1273 vaccine was demonstrated in a clinical study in participants ≥18 
years of age who received 2 doses administered 28 days apart [Baden, L. R., et al 2021]. A 
subsequent study in boys and girls 6 to 11 years of age demonstrated strong immune 
response compared with the young adult vaccine recipients[Moderna, Inc. 2021]. In the 
setting of a global pandemic, preadolescents and young adolescents are an appropriate group 
in which to implement COVID-19 vaccination as widespread vaccination is a critical tool 
during pandemic conditions. Continued COVID-19 vaccination programs, including these
age groups, will likely continue to be important after transition from pandemic to endemic 
conditions for SARS-CoV-2.
Given that the 9vHPV vaccine is currently recommended in individuals 9 to 14 years of age 
[Meites, E., et al 2016], and that an mRNA COVID-19 vaccine currently has EUA for 
individuals 6 to 11 years of age, concomitant administration of these vaccines in the study 
population may help facilitate implementation of vaccine recommendations. The 
development of a combined immunization strategy may lead to better compliance for each of 
these vaccines, which is critical in the setting of an ongoing pandemic, and specifically to the 
goal of maintenance of routine vaccination for preventable diseases in a prolonged COVID-
19 pandemic setting. In the context of the ongoing COVID-19 pandemic, participants in the 
Nonconcomitant Group will receive the mRNA-1273 vaccine first before initiation of the 
9vHPV vaccine.
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4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Humoral immune responses to 9vHPV vaccination will be evaluated based on the previously 
established cLIA [Roberts, C., et al 2014]. Serum may also be tested using the HPV9 IgG 
LIA [Opalka, D., et al 2010]. These assays are consistent with those in the previous studies 
that supported the licensure of the 9vHPV vaccine.
Immune responses to mRNA-1273 vaccine will be measured by ECL assay specific to the 
SARS-CoV-2 spike protein, consistent with those in the Phase 3 studies evaluating the 
mRNA-1273 vaccine.
Details on the immunogenicity assessments and endpoints evaluated in this study can be 
found in Section 8.2 and Section 9.4.1, respectively.
4.2.1.2
Safety Endpoints
Detailed safety information will be collected for all participants on an eVRC, with time 
points optimized based on the expected timing of local and systemic reactions to vaccination 
(see Section 8.4.9). The eVRC used to record AEs during the postvaccination periods, as 
defined in Section 8.3.3, is structured as recommended in the final US FDA Patient-Reported 
Outcome Guidance [U.S. Food and Drug Administration 2009].
Details on the safety endpoints evaluated in this study can be found in Section 8.3 and 
Section 9.4.2.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
4.2.1.3
Pharmacokinetic Endpoints
No pharmacokinetic endpoints will be evaluated in this study.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints will be evaluated in this study.
4.2.1.5
Planned Exploratory Biomarker Research
Exploratory biomarker research is not planned for this study.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent/assent was provided during 
this study. This research may include genetic analyses (DNA), gene expression profiling 
(RNA), proteomics, metabolomics (serum, plasma), and/or the measurement of other 
analytes, depending on which specimens are consented for FBR.
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately 
consented/assented participants. The objective of collecting/retaining specimens for FBR is 
to explore and identify biomarkers that inform the scientific understanding of diseases and/or 
their therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
4.2.2
Rationale for the Use of Comparator
This is an open-label study, and all participants will receive a 2-dose regimen of 9vHPV 
vaccine and a 2-dose regimen of mRNA-1273 vaccine. As the main objective of the study is 
to compare the safety and immunogenicity in participants who receive the first dose of the 
2 vaccines concomitantly versus participants who receive the 2 vaccines nonconcomitantly, 
no comparator vaccine or placebo is required as part of the study design.
4.3
Justification for Dose
The 9vHPV vaccine administered as a 2-dose regimen in the study population is consistent 
with the approved dosing and product labeling of GARDASIL®9 (US, EU, and other 
countries).
The mRNA-1273 vaccine administered as a 2-dose regimen in the study population is 
consistent with the dosing regimen in the mRNA-1273-P204 (NCT04796896) study 
conducted in participants 6 to 11 years of age.
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/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent/assent, or is lost to 
follow-up (Section 7.3). 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.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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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In the event that ≥2 participants experience myocarditis and/or pericarditis per the CDC case 
definition (Section 10.3.1), all further doses of mRNA-1273 vaccine for participants enrolled 
in the study must be discontinued, and the Sponsor will stop study enrollment. For 
participants already enrolled, dosing with 9vHPV vaccine as well as all laboratory and safety 
procedures and assessments may continue.
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5
STUDY POPULATION
Healthy male and female participants between the ages of 9 and 11 years (inclusive) will be
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is a healthy individual who meets all inclusion criteria and none of the exclusion criteria 
defined in this section.
Demographics
2. Is male or female, from 9 years to 11 years of age inclusive, at the time of signing the 
informed consent/assent.
3. Has not yet had coitarche and does not plan on becoming sexually active during the 
vaccination period.
Informed Consent/Assent
4. Participant or participant’s legally acceptable representative understands the study 
procedures, alternate treatments available, and risks involved with the study and 
voluntarily agrees to participate by providing documented informed consent. As 
appropriate based on local guidelines, the participant will also provide documented 
informed assent for the study. The participant or the participant’s legally acceptable 
representative may also provide assent/consent for future biomedical research. However, 
the participant may participate in the main study without participating in future 
biomedical research.
Additional Categories
5. Agrees to provide study personnel with a primary telephone number as well as an 
alternate form of contact, if available, for follow-up purposes.
6. Participant or participant’s legally acceptable representative can read, understand, and 
complete the eVRC.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. *Has a fever (defined as oral temperature ≥100.0° F or ≥37.8° C) within the 24-hour 
period prior to the Day 1 visit.
2. Has a history of severe allergic reaction (eg, swelling of the mouth and throat, difficulty 
breathing, hypotension, or shock) that required medical intervention.
3. Is allergic to any component of the 9vHPV or mRNA-1273 vaccine, including aluminum, 
yeast, or BENZONASE™ (nuclease, Nycomed [used to remove residual nucleic acids 
from 9vHPV vaccine and other vaccines]). For this exclusion criterion, an allergy to 
vaccine components is defined as an allergic reaction that met the criteria for severe AEs 
or SAEs defined in Appendix 3.
4. Has a condition that is a contraindication to vaccination as indicated in the package insert 
of 9vHPV vaccine or EUA prescribing information of mRNA-1273 vaccine.
5. Has known thrombocytopenia or any coagulation disorder that would contraindicate 
intramuscular injections.
6. Is currently immunocompromised or has been diagnosed as having congenital or acquired 
immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus erythematosus, 
rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, or other 
autoimmune condition.
7. Has a history of splenectomy.
8. Has a history of myocarditis and/or pericarditis.
9. Is, at the time of signing informed consent/assent, a user of recreational or illicit drugs or 
has had a recent history (within the last year) of drug or alcohol abuse or dependence at 
the discretion of the investigator. Alcohol abusers are defined as those who drink despite 
recurrent social, interpersonal, and/or legal problems because of alcohol use.
10. Has a history of a positive test for HPV.
11. Has a history of a clinical or microbiological diagnosis of COVID-19, ≤90 days prior to 
Day 1 visit or history of MIS-C at any time prior to Day 1 visit.
12. (Female participants only) Is pregnant as determined by a serum pregnancy test or urine 
pregnancy test that is sensitive to at least 25 mIU/mL β-hCG.
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13. Has a history or current evidence of any condition, therapy, laboratory abnormality or 
other circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate by judgment of investigator.
The history of medical conditions will be based on the self-report or medical record provided 
by the participant or the participant’s legally acceptable representative.
Prior/Concomitant Therapy
14. Has received within 12 months prior to enrollment, is receiving, or plans to receive 
during the study, the following immunosuppressive therapies: radiation therapy, 
cyclophosphamide, azathioprine, methotrexate, any chemotherapy, cyclosporin, 
leflunomide (Arava™), TNF-α antagonists, monoclonal antibody therapies (including 
rituximab [Rituxan™]), IVIG, antilymphocyte sera, or other therapy known to interfere 
with the immune response. Regarding systemic corticosteroids, a participant will be 
excluded if he/she is currently receiving steroid therapy, has recently (defined as within 2 
weeks of Day 1 vaccination) received such therapy, or has received 2 or more courses of 
corticosteroids lasting at least 1 week in duration in the year prior to Day 1 vaccination. 
Participants using inhaled, nasal, or topical steroids are considered eligible for the study.
15. Has received within the 3 months prior to the Day 1 vaccination, is receiving, or plans to 
receive during the study, any immune globulin product (including RhoGAM™ 
[Ortho-Clinical Diagnostics]) or blood-derived product.
16. *Has received inactivated or recombinant vaccines within 14 days prior to Day 1 
vaccination or receipt of live vaccines within 21 days prior to Day 1 vaccination (Note: If 
there is local requirement for the longer period between receipt of live vaccines and study 
vaccine, then it should follow local regulatory requirement.)
Prior/Concurrent Clinical Study Experience
17. Is concurrently enrolled in other clinical studies of investigational agents.
18. Has previously received a marketed or investigational HPV vaccine.
19. Has previously received a marketed or investigational COVID-19 vaccine.
20. Has participated in a clinical study for any HPV vaccine or any COVID-19 vaccine 
(receiving either active agent or placebo).
Diagnostic Assessments
None.
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Other Exclusions
21. Is unlikely to adhere to the study procedures, keep appointments, or is planning to 
permanently relocate from the area prior to the completion of the study or to leave for an 
extended period when study visits would need to be scheduled.
22. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
* For items denoted with an asterisk, if the exclusion criterion is met, then the Day 1 visit 
may be rescheduled for a time when the criterion is not met.
5.3
Lifestyle Considerations
There are no lifestyle restrictions for participants in this study.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently enrolled 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 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 discontinues from study vaccination or 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 (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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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 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Concomitant 
Group
Experi-
mental
mRNA-1273 
vaccine
Biological/
Vaccine
Suspension
mRNA* 50 µg per 
dose
0.25 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 1
Test 
Product
IMP
Central 
or local
Concomitant 
Group
Experi-
mental
9vHPV 
vaccine
Biological/
Vaccine
Suspension
HPV6/11/16/18/
31/33/45/52/58 L1 
VLP: 
30/40/60/40/20/20/
20/20/20 mcg per 
dose
0.5 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 6
Test 
Product
IMP
Central
Nonconcomitant 
Group
Experi-
mental
mRNA-1273 
vaccine
Biological/
Vaccine
Suspension
mRNA* 50 µg per 
dose
0.25 mL 
per dose
IM
Single dose 
at Day 1 and 
Month 1
Test 
Product
IMP
Central 
or local
Nonconcomitant 
Group
Experi-
mental
9vHPV 
vaccine
Biological/
Vaccine
Suspension
HPV6/11/16/18/
31/33/45/52/58 L1 
VLP: 
30/40/60/40/20/20/
20/20/20 mcg per 
dose
0.5 mL 
per dose
IM
Single dose 
at Month 2 
and Month 8
Test 
Product
IMP
Central
HPV=human papillomavirus; IM=intramuscular; IMP=Investigational Medicinal Product; mL=milliliter; mRNA=messenger ribonucleic acid; 
NIMP/AxMP=noninvestigational/auxiliary medicinal product; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
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 European Economic Area (EEA). 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
*
mRNA encoding the prefusion stabilized spike glycoprotein of SARS-CoV-2 virus (Moderna Inc., Cambridge, MA)
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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 where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Drug-device combination product(s), which is/are legally marketed and provided for use in 
this study are: GARDASIL®9 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.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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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 allocation/randomization will occur centrally using an IRT system. There are 2
study intervention arms. Participants will be assigned randomly in a 1:1 ratio to the 
Concomitant Group and Nonconcomitant Group, respectively.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination plan specified in Section 1.3 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.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
See the exclusion criteria for specific restrictions for prior and concomitant medications 
at Day 1 (Section 5.2).
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•
If possible, participants should not receive “special medications” (eg, corticosteroids, 
immunosuppressives, immune globulins, and blood products) from Day 1 through 1 
month after the completion of vaccination regimen, nonstudy inactivated or recombinant 
vaccines from 14 days prior to each study vaccination through 14 days after each study 
vaccination, or nonstudy live vaccines from 21 days prior to each study vaccination 
through 14 days after each study vaccination.
•
Participants may receive allergen desensitization therapy and tuberculin skin testing 
while participating in the study.
Use of prior and concomitant medications/vaccination should be recorded as described in 
Section 8.1.6.
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 open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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 8.1.10 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 or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
For mRNA-1273 vaccine only: The participant experiences 1 or more of the following 
AEs assessed as clearly related to the mRNA-1273 vaccine after receiving the first dose: 
multisystem inflammatory syndrome in children, myocarditis, pericarditis, anaphylaxis, 
or generalized urticaria. In this case, the second dose of the mRNA-1273 vaccine must be 
discontinued.
•
Note: In addition to the stopping rule above, in the event that ≥2 participants 
experience myocarditis and/or pericarditis per the CDC case definition (Section 
10.3.1), then all further doses of mRNA-1273 vaccine for participants enrolled in the 
study must be discontinued (Section 4.4.1).
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, see Section 1.3 and Section 8.11.3 for those procedures to be completed at each
specified visit.
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Discontinuation from mRNA-1273 vaccine or 9vHPV vaccine is “permanent.” Once a 
participant is discontinued from a study intervention, they shall not be allowed to restart the 
same study intervention; however, the participant may be administered the other study 
intervention as scheduled.
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/assent 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 8.1.10. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent/assent be obtained from the participant. In 
these cases, such evaluations/testing will be performed in accordance with those 
regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed 30.5 mL (Table 2 for Concomitant Group and Table 3 for 
Nonconcomitant Group).
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
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Table 2
Approximate Blood Volumes Drawn by Study Visit and by Sample Types –
Concomitant Group
Study Visit
Visit 1 
(Day 1)
Visit 2
(Month 
1)
Visit 3
(Month 
2)
Visit 4a 
(Month 
6)
Visit 5a 
(Month 7)
Parameter
Approximate Blood Volume (mL)
Anti-HPV Immunogenicity Testing
6 mL
NA
NA
NA
6 mL
SARS-CoV-2 Spike Protein-specific 
Binding Antibody
5 mL
NA
5 mL
NA
NA
Blood (DNA) for FBRa
8.5 mL
NA
NA
NA
NA
DNA=deoxyribonucleic acid; FBR=Future Biomedical Research; HPV=human papillomavirus; mL=milliliter; NA=not 
applicable; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
a
Sample should be obtained before vaccine is administered on Day 1 or at a later date as soon as informed consent 
for future biomedical research is obtained.
Table 3
Approximate Blood Volumes Drawn by Study Visit and by Sample Types –
Nonconcomitant Group
Study Visit
Visit 1 
(Day 1)
Visit 2
(Month 
1)
Visit 3
(Month 
2)
Visit 4b
(Month 
8)
Visit 5b 
(Month 
9)
Parameter
Approximate Blood Volume (mL)
Anti-HPV Immunogenicity Testing
NA
NA
6 mL
NA
6 mL
SARS-CoV-2 Spike Protein-specific Binding 
Antibody
5 mL
NA
5 mL
NA
NA
Blood (DNA) for FBRa
8.5 mL
NA
NA
NA
NA
DNA=deoxyribonucleic acid; FBR=Future Biomedical Research; HPV=human papillomavirus; mL=milliliter; NA=not 
applicable; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
a
Sample should be obtained before vaccine is administered on Day 1 or at a later date as soon as informed consent 
for future biomedical research is obtained.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent/assent 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/assent is in place.
8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent 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/assent discussion.
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A copy of the signed and dated informed consent/assent 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/assent form or addendum to the original consent/assent 
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/assent form.
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the FBR consent/assent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent/assent before performing any procedure 
related to FBR. A copy of the informed consent/assent 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.
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/assent. 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.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
At the Day 1 visit, the participant’s medical history for the year prior to Day 1 and any other 
medically relevant history in the opinion of the investigator, including history of HPV-related 
and COVID-related diagnoses, will be obtained by the investigator or qualified designee.
8.1.5
Demographics
Demographics will be collected in the data collection system, as discussed in the eCRF entry 
guidelines.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medications or vaccinations on 
Day 1. A participant receiving any of the prior medications or vaccinations prohibited in the 
exclusion criteria (Section 5.2) should not be enrolled into the study. Prior and concomitant 
medicines or vaccinations should be documented in the eCRF per the following timeframe:
•
Any analgesic or antipyretic medication taken on the day of vaccination prior to 
vaccination.
•
“Special medications” (corticosteroids, immunosuppressive therapies as defined in the 
exclusion criteria, immune globulins, and blood-derived products) from 3 days prior to 
Day 1 through 1 month after completion of the vaccination regimen.
•
“Other medications” from 3 days prior to each study vaccination through 14 days after 
each study vaccination.
•
“Nonstudy inactivated or recombinant vaccines” from 14 days prior to each study 
vaccination through 14 days after each study vaccination.
•
“Nonstudy live vaccines” from 21 days prior to each study vaccination through 14 days 
after each study vaccination.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medications or vaccinations, if any, taken 
by the participant during the study time frames specified in Section 8.1.6.1.
For a specific case where a participant mistakenly receives any nonstudy HPV or COVID-19 
vaccine, the nonstudy HPV or COVID-19 vaccine must be reported in the eCRF, regardless 
of when the nonstudy HPV or COVID-19 vaccine was received.
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Any analgesic or antipyretic medication will be recorded on the eVRC (see Section 8.3.3) 
and appropriate eVRC.
Participants may receive allergen desensitization therapy and tuberculin skin testing while 
participating in the study.
8.1.7
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.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
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.
Adequate treatment provisions should be available for immediate use should an anaphylactic 
or anaphylactoid reaction occur [Centers for Disease Control and Prevention 2015].
Preparation of Study Vaccine by Study Personnel
9vHPV Vaccine
The 9vHPV vaccine must be stored at 2.0°C to 8.0°C (35.6°F to 46.4°F). Do NOT freeze the 
study vaccine. Protect the study vaccine from light. The study vaccine must be used as 
supplied (no dilution before administration). The study vaccine will be supplied as a prefilled 
syringe.
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The syringe should be shaken before use. Attach the appropriate needle (as recommended by 
the product label) by twisting in a clockwise direction until the needle fits securely on the 
syringe. Administer the entire dose as an intramuscular injection.
mRNA-1273 Vaccine
The mRNA-1273 multiple-dose vials contain a frozen suspension that does not contain a 
preservative and are stored at -50°C to -15°C (-58°F to 5°F). It must be thawed prior to 
administration. Remove the required number of vial(s) from storage and thaw each vial 
before use following the instructions below.
If provided as a 5.5 mL vial: Thaw in refrigerated conditions between 2° to 8°C for 2 hours 
and 30 minutes. Let each vial stand at room temperature for 15 minutes before administering. 
Alternatively, thaw at room temperature between 15° to 25°C for 1 hour.
If provided as a 7.5 mL vial: Thaw in refrigerated conditions between 2° to 8°C for 3 hours. 
Let each vial stand at room temperature for 15 minutes before administering. Alternatively, 
thaw at room temperature between 15° to 25°C for 1 hour and 30 minutes.
After thawing, do not refreeze. Swirl vial gently after thawing and between each withdrawal. 
Do not shake. Do not dilute the vaccine. The mRNA-1273 is a white to off-white suspension. 
It may contain white or translucent product-related particulates. Visually inspect the vial for 
other particulate matter and/or discoloration prior to administration. If either of these 
conditions exists, the vaccine should not be administered.
After the first dose has been withdrawn, the vial should be held between 2° to 25°C (36° to 
77°F). Record the date and time of first use on the vial label. The maximum number of doses 
that may be extracted from either vial presentation should not exceed 20 doses. Do not 
puncture the vial stopper more than 20 times. If the vial stopper has been punctured 20 times, 
discard the vial and contents. Discard vial after 12 hours. Do not refreeze.
Study Vaccine Administration
Study vaccine will be administered as specified in Section 1.3. At each vaccination visit, 
participants will receive a single dose of 9vHPV vaccine (0.5 mL) and/or mRNA-1273 
vaccine (0.25 mL) as an intramuscular injection. For all participants (Concomitant and 
Nonconcomitant Groups), the 9vHPV vaccine should be administered in the deltoid muscle 
of the left arm and the mRNA-1273 vaccine should be administered in the deltoid muscle of 
the right arm. The deltoid muscle of the assigned arm is the preferred site of vaccination. 
Injections should not be given within 2 cm of a tattoo, scar, or skin deformation. If the 
assigned deltoid does not meet criteria for injection, then the vaccination intended for that 
deltoid should be administered in the ipsilateral thigh. Study vaccinations should not be 
administered in the buttocks area.
Injections should be administered at a 90° angle into the muscle tissue using a needle long 
enough to ensure intramuscular deposition of study vaccine. The study vaccine should be 
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administered in the deltoid muscle using prefilled syringe for 9vHPV vaccine or a 1.0 mL 
syringe for mRNA-1273 vaccine with the following needle length and gauge specifications:
•
1-inch needle, 22 to 23 gauge for participants weighing <200 pounds (<90.9 kg)
•
1½-inch needle, 22 to 23 gauge for participants weighing ≥200 pounds (≥90.9 kg)
Observing Participants After Vaccination
All participants will be observed by study personnel for at least 30 minutes after each study 
vaccination for any untoward effects, including allergic reactions. This observation period 
will be documented in the participant’s study chart.
Vaccination information, such as Component Identification Number, time of vaccination, and 
the arms the vaccines are administered, must be recorded on the appropriate eCRF as per the 
data entry guidelines.
8.1.9.1
Timing of Dose Administration
The first dose of study vaccine will be administered at Day 1, which should be the day of 
enrollment. Subsequent doses will be administered as specified in Section 1.3.
If possible, all Day 1 visit procedures should be performed on the day of consent. If date of 
Day 1 visit (and all procedures) is later than the consent date, the interval between the date of 
consent and the date of the Day 1 visit should be no more than 14 days. If the interval is 
15 days or longer, then the participant must be reconsented and rescreened.
8.1.10
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.
Participants who discontinue either study vaccine may receive the other study vaccine.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the review of safety data 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.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent/assent for FBR. Participants may withdraw 
consent/assent 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/assent 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 
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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.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.12
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
8.2.1
SARS-CoV-2 Spike Protein-specific Binding Antibody Measured by ECL 
Assay
PPD VSD in Richmond, VA, has developed and validated an ECL Method for the Detection 
of SARS-CoV-2 Spike, Nucleocapsid, and Receptor Binding Domain antibodies in human 
serum. The assay is based on the Meso-Scale Discovery technology, which employs 
disposable multispot microtiter plates. The validation study established the assay operating 
characteristics, evaluated the precision and ruggedness, and assessed the dilutional linearity, 
selectivity, and relative accuracy of the SARS-CoV-2 antigens. The SARS-CoV-2 ECL assay 
met the prespecified acceptance criteria and is considered validated with regard to precision, 
ruggedness, relative accuracy, dilutional linearity, specificity, and selectivity.
8.2.2
Antibody to 9vHPV Vaccine Types Measured by Competitive Luminex 
Immunoassay
The 9-valent HPV cLIA will be used as a primary method to evaluate antibodies specific for 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 in serum [Roberts, C., et al 2014]. The purpose of 
the assay is to detect these HPV antibodies before and after vaccination with the 9vHPV 
vaccine. The testing will be performed by Q Squared Solutions (California, USA).
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For the 9-valent HPV cLIA, HPV type-specific, yeast-derived VLPs are coupled to 9 distinct 
Luminex magnetic microspheres. Each VLP-coupled microsphere has its own distinct 
fluorescent dye that can be recognized by excitation with an infrared laser, allowing for the 
measurement of antibodies against multiple HPV types from a single test of an individual’s 
serum. HPV type-specific monoclonal antibodies labeled with R-Phycoerythrin compete with 
an individual’s serum antibodies for binding to the neutralizing epitopes of the VLPs. The 
fluorescent signal from the R-Phycoerythrin-labeled, type-specific monoclonal antibodies is 
inversely proportional to the anti-HPV antibody concentration of a sample. Antibody 
concentrations are derived from a standard curve, which is generated using a reference 
standard made from a pool of serum from individuals immunized against the 9 HPV vaccine 
types. A standard curve for each HPV vaccine type is calculated using a weighted 4 
parameter logistic curve fit. Results are expressed as mMU/mL.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A physical examination will be conducted by an investigator or medically qualified designee 
(consistent with local requirements) per institutional standard on Day 1 to determine whether 
the participant meets eligibility criteria for enrollment.
Height and weight will be recorded on Day 1 before administration of study vaccine.
Physical examination details will be recorded in the participant’s study chart. Any medical 
condition identified during physical examination will be documented in the data collection 
system. Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Oral Temperature Measurement
Oral temperature will be assessed at each vaccination visit prior to the administration of 
study vaccine. If the participant has a fever (defined as an oral temperature of ≥100.0° F or 
≥37.8° C) within the 24-hour period prior to receiving a study vaccination, the participant 
should not receive the study vaccine, and the vaccination visit should be rescheduled until 
after the fever has resolved.
Postvaccination, if an oral temperature indicates a fever (defined as an oral temperature of 
≥37.8° C or ≥100.0° F), then an AE of “fever” must be documented in the eCRF.
8.3.3
Electronic Vaccination Report Card
The eVRC was developed to be administered electronically via a hand-held device. This item 
was structured as recommended in the final Food and Drug Administration Patient-Reported 
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Outcome Guidance [U.S. Food and Drug Administration 2009]. 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 train the participant in the use of the 
eVRC at Visit 1 (Day 1). The investigator or delegate will review the data captured on the 
eVRC with the participant at specific visits as described in Section 1.3.
Temperatures, injection-site reactions, solicited complaints, other complaints or illnesses, and 
concomitant medications or vaccinations will be recorded on the eVRC by the participant. 
All participants will be expected to bring the eVRC to the study site at specific visits as 
described in Section 1.3. Participants should be informed to contact the investigator 
immediately in the event of a hospitalization or visit to another physician.
The participant/participant’s legally acceptable representative will use the eVRC to document 
the following information:
•
Oral body temperatures measured Day 1 (day of vaccination) through Day 7 
postvaccination
•
Left arm (postvaccination with 9vHPV vaccine): Solicited injection-site AEs (Section 
8.4.9.1) Day 1 through Day 7 postvaccination
•
Right arm (postvaccination with mRNA-1273 vaccine): Solicited injection-site AEs 
(Section 8.4.9.1) Day 1 through Day 7 postvaccination
•
Solicited systemic AEs (Section 8.4.9.1) Day 1 through Day 7 postvaccination
•
Any other injection-site or systemic AEs (Section 8.4.9.2) Day 1 through Day 28 
postvaccination
•
Concomitant medications (including analgesic or antipyretic medication) and nonstudy 
vaccinations Day 1 through Day 28 postvaccination
For the AEs outlined above, the investigator will use the information provided by the 
participant both on the eVRC, and verbally at the time of eVRC review, to apply the 
appropriate assessment of causality as described in Appendix 3.
8.3.4
Postvaccination Observation Period (30 Minutes)
All participants will be observed for at least 30 minutes after each vaccination for any 
immediate reactions. If any immediate AEs (including allergic reactions) 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.
•
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, 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.
8.3.6
Pregnancy Testing
All female participants will have a serum or urine pregnancy test (sensitive to at least 
25 mIU/mL β-hCG) performed at each vaccination visit as outlined in Section 1.3 per the 
manufacturer’s instructions and based on local requirements. All materials used for serum 
and/or urine pregnancy testing will be provided by the study sites.
The pregnancy test results must be obtained prior to each study vaccination (on the day the 
participant is vaccinated). Any participant found to be pregnant at Day 1 will not be enrolled 
in the study. For randomized participants who become pregnant after receiving study 
vaccinations, study visits and vaccinations will be paused until resolution of the pregnancy 
(eg, term, elective termination, spontaneous abortion). For participants found to be pregnant 
before the second dose of mRNA-1273 vaccine, no further dosing with mRNA-1273 vaccine 
should be administered and participants should be asked to remain in the study for safety 
follow-up. Study visits and study vaccination with 9vHPV vaccine in pregnant participants 
will be handled as described in Table 4.
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Table 4
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations for 9vHPV Vaccine
Time When Pregnancy is 
Detected
Action
Day 1 (before first 
vaccination)
Do not enroll.
Between First and Second 
Doses of 9vHPV Vaccine

No scheduled visits until resolution of the pregnancy (eg, term, 
elective termination, spontaneous abortion).

The second dose of 9vHPV vaccine should be administered at least 
4 weeks after resolution of pregnancy and after normalization of 
β-hCG levels.

A blood sample should be collected 4 weeks Postdose 2 of 9vHPV 
vaccine. Scheduling of subsequent blood draws will be managed on a 
case-by-case basis.
After Vaccination Visits

Continue with scheduled study visits during the pregnancy.

Safety follow-up will be conducted after resolution of the pregnancy 
(eg, term, elective termination, spontaneous abortion).
β-hCG=β-human chorionic gonadotropin; HPV=human papillomavirus
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/assent, but before allocation/randomization, must be reported 
by the investigator if they cause the participant to be excluded from the study, or are the 
result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, placebo, or a procedure.
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All AEs that occur from the time of allocation/randomization through 28 days following the 
first vaccination(s) and from the time of any subsequent vaccination(s) through 28 days 
thereafter, must be reported by the investigator. All MAAEs, SAEs, and other reportable 
safety events that occur from the time of allocation/randomization throughout the duration of 
the individual’s participation in the study, must be reported by the investigator, regardless of 
whether the events are considered to be vaccine-related by the investigator.
In this study, myocarditis and pericarditis are always considered to be SAEs that meet the 
“Other important medical events” criteria detailed in Section 10.3.2 (the investigator should 
also assess whether other criteria might apply). Definitions of myocarditis and pericarditis 
are provided in Section 10.3.1.
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 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent/Assent 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
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Type of Event
Reporting Period:
Consent/Assent 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
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
ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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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.
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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest
There are no 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 an eVRC 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 6.
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Table 6
Solicited Adverse Events
Type of Solicited 
Adverse Event
Predefined Solicited Adverse Events
(Preferred Term)
Solicited Time Period
Injection Site
Left arm (postvaccination with 9vHPV vaccine)
Injection-site pain/tenderness
Injection-site swelling
Injection-site redness (erythema)
Right arm (postvaccination with mRNA-1273 
vaccine)
Injection-site pain/tenderness
Injection-site swelling
Injection-site redness (erythema)
Underarm gland swelling or tenderness 
(lymphadenopathy)
Day 1 to Day 7 
postvaccination
Systemic
Headache
Fatigue
Muscle aches all over the body (myalgia)
Joint aches in several joints (arthralgia)
Nausea
Vomiting
Chills
Day 1 to Day 7 
postvaccination
All solicited injection-site AEs will be considered related to study intervention.
In addition, the investigator will review all solicited AEs for the following:
•
Is the event a symptom of another diagnosis?
•
Is the event ongoing at the end of the solicited period?
•
Does the event meet serious criteria?
A solicited AE that meets any of the above criteria must also be reported on the appropriate 
eCRF as specified in the data entry guidelines.
8.4.9.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 6, or 
2) predefined in Table 6 but reported at any time outside the solicited time period.
As detailed in Section 8.4, the investigator will assess unsolicited AEs that meet the 
definition of an AE or SAE with respect to seriousness, intensity, and causality.
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8.5
Treatment of Overdose
In this study, an overdose is defined as a participant receiving >1 dose of any individual 
study vaccine in a 24-hour period or >2 doses of any individual study vaccine throughout the 
study.
Sponsor does not recommend specific treatment for an overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Study File Binder (or equivalent).
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent/assent for FBR, the following 
specimens will be obtained as part of FBR:
•
DNA for future research
•
Leftover main study serum from anti-HPV antibody testing stored for future research
•
Leftover main study serum from SARS-CoV-2 spike protein-specific binding antibody 
testing stored for future research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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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
The Screening Visit or the last Screening Visit (for rescreening) should be on the same day of 
enrollment and the first dose of vaccination. Potential participants will be evaluated to 
determine that they fulfill the entry requirements as provided in Section 5. Screening 
procedures may be repeated after consultation with the Sponsor.
8.11.2
Intervention and Follow-up Periods
Requirements during the intervention and follow-up periods are outlined in Section 1.3.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study vaccination but continue in the study will attend study 
visits as provided in Section 1.3; however, serum will not be collected.
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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 final database lock, changes are made to primary hypotheses, or 
the statistical methods related to those hypotheses, then the protocol will be amended 
(consistent with ICH Guideline E-9). Changes to exploratory or other nonconfirmatory 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in an sSAP and referenced in the CSR for the study. Posthoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
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Study Design Overview
A Phase 3, Multicenter, Open-Label Study to Evaluate the Safety and 
Immunogenicity of 2-dose Regimens of 9vHPV and mRNA-1273 SARS-
CoV-2 Vaccines Where the First Dose of Each Vaccine Are Given 
Concomitantly in Boys and Girls 9 to 11 Years of Age
Treatment Assignment
Study participants will be randomized in a 1:1 ratio between the 
Concomitant and Nonconcomitant Groups. No stratification will be 
implemented during randomization.
Analysis Populations
Immunogenicity: Per-protocol population
Safety: APaT population
Primary Endpoint(s)
Immunogenicity:
1.
cLIA anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 titers.
2.
SARS-CoV-2 spike protein-specific binding antibody concentration.
Safety:
1.
Solicited injection-site AEs Day 1 through Day 7 postvaccination.
2.
Solicited systemic AEs Day 1 through Day 7 postvaccination.
3.
SAEs Day 1 through Day 28 postvaccination.
4.
Vaccine-related SAEs observed any time during the study.
Key Secondary Endpoints
Immunogenicity:

Seroconversion to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 
based on cLIA.

Seroresponse to SARS-CoV-2 based on SARS-CoV-2 ECL assay.
Statistical Methods for Key 
Immunogenicity Analyses
Evaluation of primary and secondary objectives will be performed
separately for each immunogenicity parameter. Analysis of variance 
modeling will be used. The response variable is the natural logarithm of 
the relevant antibody titers and an indicator variable representing the 
concomitant vaccination group will be a fixed effect. Point estimates of the 
GMTs/GMC and corresponding within-group 95% CIs as well as 
geometric mean ratio and corresponding 95% CI of the geometric mean 
ratio will be derived from the estimate of the fixed effect.
Statistical Methods for Key 
Safety Analyses
By-treatment group summaries of safety endpoints will be provided in 
terms of treatment group-specific counts and proportions (or percent) of 
participants who are cases of particular safety endpoints. Confidence 
intervals of risk difference (difference in percent or proportions), when 
provided, will be calculated using the M&N method [Miettinen, O. and 
Nurminen, M. 1985].
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 
The expected total sample size is approximately 160 participants. 
Participants are to be randomly assigned in a 1:1 ratio to the Concomitant 
Group and Nonconcomitant Group.
Immunogenicity:
This is an estimation study. There are no hypotheses to be evaluated.
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. 
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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 is being conducted as a randomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the randomized allocation schedule for 
study treatment assignment. The algorithm for the randomized allocation of subjects will be 
implemented in an interactive response technology by a study vendor.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study, and no formal 
hypothesis testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints that will be evaluated for between-treatment 
differences are listed below.
9.4.1
Immunogenicity Endpoints
Primary immunogenicity analysis endpoints include:
•
GMTs of anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 measured by cLIA at 4 weeks 
Postdose 2 of 9vHPV vaccine.
•
GMCs of SARS-CoV-2 spike protein-specific binding antibodies at 4 weeks Postdose 2
of mRNA-1273 vaccine.
Secondary immunogenicity analysis endpoints include:
•
Seroconversion to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 4 weeks Postdose 2 
of 9vHPV vaccine. Seroconversion is defined as changing from cLIA anti-HPV 
seronegative prevaccination with 9vHPV vaccine to seropositive at 4 weeks Postdose 2 of 
9vHPV vaccine.
•
Seroresponse to SARS-CoV-2 at 4 weeks Postdose 2 of mRNA-1273 vaccine. 
Seroresponse is defined as ≥4-fold rise in SARS-CoV-2 spike protein-specific binding 
antibody concentration from baseline to 4 weeks Postdose 2 of mRNA-1273 vaccine. If 
the baseline SARS-CoV-2 spike protein-specific binding antibody concentration is less 
than the LLOQ of the SARS-CoV-2 ECL assay, a ≥4-fold rise is defined as SARS-CoV-2 
spike protein-specific binding antibody concentration ≥4 × LLOQ of the SARS-CoV-2 
ECL assay.
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9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and body temperature measurements postvaccination.
The safety analysis endpoints that address the primary objective include:
•
Solicited injection-site AEs Days 1 through 7 postvaccination
•
Solicited systemic AEs Days 1 through 7 postvaccination
•
SAEs Days 1 through 28 postvaccination
•
Serious vaccine-related AEs observed any time during the study
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Population
The PPI population will serve as the primary population for the analysis of immunogenicity 
relating to 9vHPV vaccination. The PPI population is HPV type-specific. The PPI population 
consists of all randomized participants who:
1. Have received all vaccinations planned within the context of the study with the correct 
dose of the 9vHPV vaccine and each vaccination visit has occurred within day ranges 
acceptable for statistical analysis (see Table 7 for vaccination visits day ranges acceptable 
for statistical analysis).
2. Were seronegative by HPV-9 cLIA to the appropriate HPV type pre-9vHPV vaccination 
(see Table 8 for serum collection day ranges acceptable for statistical analysis).
3. Have evaluable serology results based on serum sample collected within 21 to 49 days 
Postdose 2 of 9vHPV vaccination.
4. Have no protocol deviations that could interfere with the evaluation of participant’s 
immune response to 9vHPV vaccination.
The mRNA-1273 per-protocol (mRNA-1273-PP) population will serve as the primary 
population for the analysis of immunogenicity relating to mRNA-1273 vaccination. This 
population consists of all randomized participants who:
1. Have received all vaccinations planned within the context of the study with the correct 
dose of mRNA-1273 and each vaccination visit has occurred within day ranges 
acceptable for statistical analysis (see Table 7 for vaccination visits day ranges acceptable 
for statistical analysis).
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2. Have evaluable serology results based on serum sample collected within 21 to 42 days 
Postdose 2 of mRNA-1273 vaccine.
3. Have no protocol deviations that could interfere with the evaluation of participant’s 
immune response to mRNA-1273 vaccine.
Table 7
Acceptable Day Ranges for Vaccination Visits
Vaccination Dose
Vaccination Visit Window as 
Specified in the SoA
(Relative to Vaccination Dose 1)
Day Range for Inclusion in
Statistical Analysis
(Relative to Vaccination Dose 1)
Dose 1
9vHPV vaccine
0
0
mRNA-1273
0
0
Dose 2
9vHPV vaccine
6 months 4 weeks
148 to 218 days
mRNA-1273
28 to 42 days
21 to 42 days
HPV=human papillomavirus; RNA=ribonucleic acid; SoA=schedule of activities
Table 8
Acceptable Day Ranges for Collection of Serum Samples
Study Time
Target Collection Day
Day Range for Inclusion in
Statistical Analysis
Predose 1 (target collection days and day ranges are relative to vaccination dose 1)
9vHPV vaccine
0
–14 to 0
mRNA-1273
0
–14 to 0
Postdose 2 (target collection day and day range are relative to vaccination dose 2)
9vHPV vaccine
28 days
21 to 49 days
mRNA-1273
28 days
21 to 42 days
HPV=human papillomavirus; RNA=ribonucleic acid; SoA=schedule of activities
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of any study vaccine. Participants will be included 
in the treatment group corresponding to the study vaccine they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who received incorrect vaccination regimen for 
the entire vaccination period; such participants will be included in the treatment group 
corresponding to the vaccination regimen actually received.
9.6
Statistical Methods
9.6.1
Immunogenicity Analysis Methods
9.6.1.1
Estimation of Immune Response Relating to HPV
Anti-HPV titers reported as less than the HPV type-specific LLOQ will be replaced by a 
numeric value equal to half of the HPV type-specific LLOQ in analyses of immunogenicity.
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For each of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58, the primary objective relating to 
response to HPV vaccination at 4 weeks Postdose 2 will be evaluated. Separately for each 
HPV type, the GMTs with 2-sided within-group 95% CIs and GMT ratio with corresponding 
2-sided 95% CI will be calculated using an analysis of variance model with a response of log 
individual anti-HPV titers and a fixed effect for the vaccination groups (Table 9).
9.6.1.2
Estimation of Immune Response Relating to SARS-CoV-2
The primary objective relating to response to mRNA-1273 vaccination at 4 weeks Postdose 2 
will be evaluated. The analysis methods are the same as those that will be used for primary 
objective 1 (see Section 9.6.1.1).
SARS-CoV-2 spike protein-specific binding antibody concentrations reported as less than the 
LLOQ of the ECL assay will be replaced by a numeric value equal to half of the LLOQ in 
analyses of immunogenicity.
9.6.1.3
Estimation of Percent Seroconversion and Percent Seroresponse
The seroconversion percentages with respect to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 
58, and seroresponse percentage with respect to SARS-CoV-2, will be evaluated by 
computing point estimates and corresponding 2-sided 95% CIs. Calculation of the CI will be 
based on the exact binomial method proposed by Clopper and Pearson [CLOPPER, C. J. and 
PEARSON, E. S. 1934] (Table 9).
Table 9
Strategy for Analysis of Immunogenicity Endpoints
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Immunogenicity Objectives and Hypotheses
GMTs of anti-HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 measured by cLIA at 
4 weeks Postdose 2 of 9vHPV vaccine
P
Point estimate, 
95% CI by 
ANOVA
Per-protocol
Observed data 
only
GMCs of SARS-CoV-2 spike protein-
specific binding antibodies at 4 weeks 
Postdose 2 of mRNA-1273 vaccine
P
Point estimate, 
95% CI by 
ANOVA
Per-protocol
Observed data 
only
Secondary Immunogenicity Objectives
Seroconversion to HPV Types 6, 11, 
16, 18, 31, 33, 45, 52, and 58 at 4 
weeks Postdose 2 of 9vHPV vaccine
P
Point estimate, 
95% CI value by 
Clopper and 
Pearson
Per-protocol
Observed data 
only
Seroresponse to SARS-CoV-2 at 
4 weeks Postdose 2 of mRNA-1273 
vaccine
P
Point estimate, 
95% CI value by 
Clopper and 
Pearson
Per-protocol
Observed data 
only
ANOVA=analysis of variance; CI=confidence interval; cLIA=competitive Luminex Immunoassay; GMC=geometric 
mean concentration; GMT=geometric mean titer; HPV=human papillomavirus; P=primary; RNA=ribonucleic acid; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
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9.6.2
Safety Analysis Methods
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs and postvaccination body temperature measurements.
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) are either prespecified as “Tier 1” endpoints or will be classified as belonging to 
“Tier 2” or “Tier 3” based on the observed number of participants with an event.
Tier 1 Events
Safety parameters or AEs of special interest identified a priori that will be subject to 
inferential testing for statistical significance constitute “Tier 1” safety endpoints. There are 
no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the M&N method [Miettinen, O. and 
Nurminen, M. 1985]. Membership in Tier 2 requires that at least 4 participants in any 
vaccination group exhibit the event. The threshold of at least 4 participants was chosen 
because the 95% CI for the between-group difference in percent incidence will always 
include zero when vaccination groups of equal size each have less than 4 participants and 
thus would add little to the interpretation of potentially meaningful differences. The 95% CIs 
for Tier 2 events will be provided without adjustment for multiplicity, thus the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences with respect to the Tier 
2 events.
In addition to individual events that occur in ≥4 participants in any vaccination group, the 
broad AE categories consisting of the proportion of participants with SAEs during Days 1 
through 28 postvaccination, AEs of special interest (see Section 10.3.1), MAAEs, and 
vaccine-related SAEs reported any time during the study, and elevated temperatures 
(≥37.8°C or ≥100.0°F) will be considered Tier 2 endpoints. The proportion of participants 
with solicited injection-site AEs and solicited systemic AEs during Days 1 through 7 
postvaccination, and severe injection-site AEs during Days 1 through 28 postvaccination will 
also be included in Tier 2 endpoints. Detailed endpoints and day ranges are summarized in 
Table 10.
The day ranges (Days 1 through 7 and Days 1 through 28) associated with some Tier 2 
endpoints are consistent with those used in clinical studies of the mRNA-1273 vaccine.
Tier 3 Events
Safety endpoints that are not Tier 2 events are considered Tier 3 events. Only point estimates 
(counts and percentages) by vaccination group are provided for Tier 3 safety parameters.
Safety analyses will be based on the observed data (ie, with no imputation of missing data).
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The day ranges (Days 1 through 5 and Days 1 through 15) associated with some Tier 3 
endpoints are consistent with those used in clinical studies of the 9vHPV vaccine. Summaries 
for these endpoints are planned to be provided for comparability with summaries in previous 
9vHPV vaccine clinical studies.
Table 10
Strategy for Analysis of Safety Endpoints
Safety 
Tier
Safety Endpointa
95% CI for 
Comparison of 
Concomitant and 
Nonconcomitant 
Groups
Descriptive 
Statistics
Tier 2
Solicited injection-site AEs, Days 1 through 7 
postvaccination
X
X
Severe injection-site AEs, Days 1 through 28 
postvaccination
X
X
Unsolicited injection-site AEs observed in ≥4 participants 
in either vaccination group, Days 1 through 28 
postvaccination
X
X
Solicited systemic AEs (headache, fatigue, myalgia, 
arthralgia, nausea, vomiting, and chills), Days 1 through 7 
postvaccination
X
X
Unsolicited systemic AEs observed in ≥4 participants in 
either vaccination group, Days 1 through 28 
postvaccination
X
X
Elevated temperaturesa, Days 1 through 7 postvaccination
X
X
Serious AEs, Days 1 through 28 postvaccination
X
X
Serious vaccine-related AEs reported any time during the 
study
X
X
AEs of special interest reported any time during the study
X
X
MAAEs reported any time during the study
X
X
Tier 3
Solicited injection-site AEs, Days 1 through 5 
postvaccination
X
Severe injection-site AEs, Days 1 through 15 post 
vaccination
X
Unsolicited injection-site AEs observed in ≥4 participants 
in either vaccination group, Days 1 through 15 
postvaccination
X
Systemic (solicited or unsolicited) AEs observed in ≥4 
participants in either vaccination group, Days 1 through 15 
postvaccination
X
Elevated temperaturesa, Days 1 through 5 postvaccination
X
Serious AEs, Days 1 through 15 postvaccination
X
AEs by SOC
X
Maximum intensity rating for each category of injection-
site AEs
X
Maximum intensity rating, overall systemic AEs
X
Maximum temperatures
X
AE=adverse event; CI=confidence interval; MAAE=medically attended adverse event; SOC=system organ class; 
X=indicating summary statistic will be provided
a
Defined as maximum (over the follow-up period) temperature ≥37.8°C (≥100°F, oral equivalent).
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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
This is an estimation study. The study is expected to enroll approximately 160 participants 
(80 per group). The estimated half-widths of 2-sided 95% CIs for GM Ratios between the 
Concomitant versus Nonconcomitant Groups for each serotype range between 0.279 to 0.494 
(Table 11), corresponding to a sample size of 80 per group. There is no corresponding power 
since no hypothesis will be tested.
Table 11
Half-widths of 2-sided 95% CIs for Geometric Mean Ratios by Serotype
Serotype
Expected 
Coefficient of 
Variationa
Expected Number of 
Participants 
Enrolled
(per group)
Expected Exclusion 
from Per-Protocol 
Populationa
Half-width of 
95% CI for GM 
Ratiob
HPV 6
1.11
80
13%
0.300
HPV 11
1.16
80
13%
0.309
HPV 16
1.17
80
9%
0.304
HPV 18
1.35
80
9%
0.334
HPV 31
1.21
80
10%
0.313
HPV 33
1.20
80
9%
0.309
HPV 45
1.38
80
9%
0.338
HPV 52
1.03
80
9%
0.279
HPV 58
1.10
80
10%
0.293
SARS-CoV-2
2.91c
80
10%
0.494
CI=confidence interval; GM=geometric mean; HPV=human papillomavirus; SARS-CoV-2=severe acute respiratory 
syndrome coronavirus 2
a The HPV-specific expected values are based on data from study NCT01984697 (EudraCT: 2013-001314-15).
b The half-width of 95% CI for GM ratio is calculated at 1-sided Type I error α=0.025 under the assumption that the ratio 
of geometric means in the Concomitant and Nonconcomitant Groups is 1.0.
c The standard deviation of the SARS-CoV-2 spike protein-specific binding antibody concentrations in natural-logarithm 
scale was estimated as 1.5. The corresponding coefficient of variation of concentrations in the untransformed scale was 
calculated as square-root(exp[1.5*1.5] – 1).
9.9.2
Sample Size for Safety Analysis
The probability of observing at least 1 vaccine-related SAE depends on the number of 
participants vaccinated and the underlying incidence rate in the study population. In this 
study with 80 participants in each vaccination group, there is ≥0.90 probability of observing 
at least 1 vaccine-related SAE in a vaccination group if the incidence of a SAE is ≥2.84% 
(Table 12).
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Table 12
Probability of Observing At Least 1 Vaccine-related Serious Adverse Event in 
a Group With 80 Participants
Incidence Rate
Probability of ≥1 Participant Out of 80 With 
Vaccine-related SAE
2.84% (1 of every 35 participants)
0.90
3.68% (1 of every 27 participants)
0.95
8.27% (1 of every 12 participants)
0.99
SAE=serious adverse event
If no vaccine-related SAE is observed among the approximately 80 participants in a 
vaccination group, this study will provide 97.5% confidence that the underlying incidence 
rate of vaccine-related SAE in that vaccination group is ≤4.51% (10 of every 222
individuals).
9.10
Subgroup Analyses
There is no subgroup analysis planned to be conducted.
9.11
Compliance (Medication Adherence)
Compliance in this study is defined as receipt of 2 doses of 9vHPV vaccine and mRNA-1273 
vaccine in the context of the study. To summarize compliance, the numbers of participants 
who receive each vaccination will be tabulated. For each vaccination dose, histograms of the 
time of administration of the vaccine relative to the target vaccination visit will be provided.
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of study 
participants administered the 9vHPV vaccine and mRNA-1273 vaccine.
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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 Interventional 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 
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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 
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 prespecified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
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authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III. Participant Protection
A. 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 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Not applicable.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
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.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, 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.
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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.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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.
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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 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor 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
All female participants will have a serum or urine pregnancy test (sensitive to at least 
25 mIU/mL β-hCG) performed at each vaccination visit.
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 individual’s participation in the study.
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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 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.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
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.
Definition of Solicited and Unsolicited AE
•
Solicited AEs are predefined local (at the injection site) and systemic events for which 
the participant is specifically questioned, and which are noted by the participant in their 
VRC.
•
An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant who has provided documented informed consent/assent. Unsolicited AEs 
include serious and nonserious AEs.
Definition of MAAE
•
AEs in which medical attention is received during an unscheduled, nonroutine outpatient 
visit, such as an emergency room visit, office visit, or an urgent care visit with any 
medical personnel for any reason. Routine visits are not considered MAAEs. Examples of 
routine visits include physical examination, wellness visits, or vaccinations.
•
Note: Determination of MAAEs is the responsibility of the investigator or a qualified 
designee. Once identified, MAAEs should be reported to the Sponsor per the timeline for 
NSAE/SAEs reporting.
Definition of AEs of Special Interest
•
AEs of special interest (serious and nonserious AEs) for this study are scientific and 
medical concerns specific to the mRNA-1273 vaccine per regulatory requirements. The 
list of AEs of special interest is provided below.
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Medical Concept
Additional Notes
Anosmia, ageusia
New onset COVID-associated or idiopathic events without other etiology excluding 
congenital etiologies or trauma.
Subacute thyroiditis
Including but not limited to events of atrophic thyroiditis, autoimmune thyroiditis, 
immune-mediated thyroiditis, silent thyroiditis, thyrotoxicosis, and thyroiditis.
Acute pancreatitis

Including but not limited to events of autoimmune pancreatitis, 
immune-mediated pancreatitis, ischemic pancreatitis, edematous 
pancreatitis, pancreatitis, acute pancreatitis, hemorrhagic pancreatitis, 
necrotizing pancreatitis, viral pancreatitis, and subacute pancreatitis.

Excluding known etiologic causes of pancreatitis (alcohol, gallstones, 
trauma, recent invasive procedures).
Appendicitis
Include any event of appendicitis.
Rhabdomyolysis
New onset rhabdomyolysis without known etiology such as excessive exercise or 
trauma.
Acute respiratory 
distress syndrome
Including but not limited to new events of acute respiratory distress syndrome and 
respiratory failure.
Coagulation disorders
Including but not limited to thromboembolic and bleeding disorders, disseminated 
intravascular coagulation, pulmonary embolism, deep vein thrombosis.
Acute cardiovascular 
injury
Including but not limited to myocarditis, pericarditis, microangiopathy, coronary 
artery disease, arrhythmia, stress cardiomyopathy, heart failure, or acute myocardial 
infarction.
In addition, investigators will be asked to report as a related AE of special interest if 
within 7 days of any mRNA-1273 vaccination, clinical signs/symptoms consistent 
with the CDC case definition of myocarditis and/or pericarditis 
(https://www.cdc.gov/mmwr/volumes/70/wr/mm7027e2.htm#T1_down) [Gargano, 
J. W., et al 2021].
Participants who meet criteria for both myocarditis and pericarditis may be 
described under myopericarditis.
Myocarditis Case Definition
Presence of ≥1 new or worsening of the following clinical symptoms:

Chest pain/pressure/discomfort

Dyspnea/shortness of breath/pain with breathing

Palpitations

Syncope
OR
Presence of ≥2 of the following:

Irritability

Vomiting

Poor feeding

Tachypnea

Lethargy
AND
For PROBABLE CASE:
≥1 new finding of:

Troponin level above upper limit of normal (any type of troponin)

Abnormal electrocardiogram ECG or EKG or rhythm monitoring findings 
consistent with myocarditis

To meet the ECG or rhythm monitoring criterion, must include at least one 
of:
o
ST segment or T-wave abnormalities
o
Paroxysmal or sustained atrial, supraventricular, or ventricular 
arrhythmias
o
AV nodal conduction delays or intraventricular conduction defects
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Medical Concept
Additional Notes

Abnormal cardiac function or wall motion abnormalities on 
echocardiogram

cMRI finding consistent with myocarditis [Ferreira, V. M., et al 2018]

For CONFIRMED CASE:

Histopathologic confirmation of myocarditis (using Dallas criteria) [Aretz, 
H. T. 1987]
OR

Troponin level above upper limit of normal (any type of troponin) AND 
cMRI findings consistent with myocarditis
AND

No other identifiable cause of the symptoms and findings
Pericarditis Case Definition
Presence of ≥2 new or worsening of the following clinical features:

Acute chest pain

(Typically described as made worse by lying down, deep inspiration, or 
cough; and relieved by sitting up or leaning forward, although other types 
of chest pain may occur)

Pericardial rub on examination

New ST-elevation or PR-depression on EKG, or

New or worsening pericardial effusion on echocardiogram or MRI
Acute kidney injury

Include events with idiopathic or autoimmune etiologies

Exclude events with clear alternate etiology (trauma, infection, tumor, or 
iatrogenic causes such as medications or radiocontrast agents, etc)

Include all cases that meet the following criteria:
o
Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 
hours; OR
o
Increase in serum creatinine to ≥1.5 × baseline, known or presumed to 
have occurred within prior 7 days; OR
o
Urine volume ≤0.5 mL/kg/hour for 6 hours.
Acute liver injury

Include events with idiopathic or autoimmune etiologies

Exclude events with clear alternate etiology (trauma, infection, tumor, etc)

Include all cases that meet the following criteria:
o
>3-fold elevation above the upper normal limit for ALT or AST OR
o
>2-fold elevation above the upper normal limit for total serum 
bilirubin or gamma glutamyl transferase or alkaline phosphatase.
Dermatologic 
findings

Chilblain-like lesions;

Single organ cutaneous vasculitis;

Erythema multiforme;

Bullous rashes;

Severe cutaneous adverse reactions including but not limited to: Stevens-
Johnson syndrome, toxic epidermal necrolysis, drug reaction with 
eosinophilia, and systemic symptoms, and fixed drug eruptions.
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Additional Notes
Multisystem 
inflammatory 
disorders

MIS-C

Kawasaki’s disease

HLH
MIS-C Case Definition
Investigators will be asked to report, as AE of special interest, clinical 
signs/symptoms consistent with the CDC case definition of MIS-C 
(https://emergency.cdc.gov/han/2020/han00432.asp):

An individual aged <21 years presenting with fever, laboratory evidence of 
inflammation, and evidence of clinically severe illness requiring 
hospitalization, with multisystem (>2) organ involvement (cardiac, renal, 
respiratory, hematologic, gastrointestinal, dermatologic or neurological);
AND

No alternative plausible diagnoses;
AND

Positive for current or recent SARS-CoV-2 infection by RT-PCR, 
serology, or antigen test; or COVID-19 exposure within the 4 weeks prior 
to the onset of symptoms:
o
Fever ≥38.0°C/≥100.4ºF for ≥24 hours, or report of subjective fever 
lasting ≥24 hours
o
Including, but not limited to, one or more of the following: an elevated 
C-reactive protein, erythrocyte sedimentation rate, fibrinogen, 
procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase, or 
interleukin 6, elevated neutrophils, reduced lymphocytes, and low 
albumin
Some individuals may fulfill full or partial criteria for Kawasaki disease but should 
be reported if they meet the case definition for MIS-C. Consider MIS-C in any 
pediatric death with evidence of SARS-CoV-2 infection.
Thrombocytopenia

Platelet counts <150 ×109 per mm3

Including but not limited to immune thrombocytopenia, platelet production 
decreased, thrombocytopenia, thrombocytopenic purpura, thrombotic 
thrombocytopenic purpura, or HELLP syndrome.
Acute aseptic arthritis

New onset aseptic arthritis without clear alternate etiology (eg, gout, 
osteoarthritis, and trauma).
New onset of or 
worsening of 
neurologic disease

Including but not limited to
o
Guillain-Barre syndrome
o
Acute disseminated encephalomyelitis
o
Peripheral facial nerve palsy (Bell’s palsy)
o
Transverse myelitis
o
Encephalitis/encephalomyelitis
o
Aseptic meningitis
o
Febrile seizures
o
Generalized seizures/convulsions
o
Stroke (hemorrhagic and nonhemorrhagic)
o
Narcolepsy
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Medical Concept
Additional Notes
Anaphylaxis
Anaphylaxis is an acute hypersensitivity reaction with multiorgan system
involvement that can present as, or rapidly progress to, a severe life-threatening 
reaction. It may occur following exposure to allergens from a variety of sources.
Anaphylaxis is a clinical syndrome characterized by the following:

Sudden onset AND

Rapid progression of signs and symptoms AND

Involves 2 or more organ systems, as follows:
o
Skin/mucosal: urticaria (hives), generalized erythema, angioedema, 
generalized pruritus with skin rash, generalized prickle sensation, and 
red and itchy eyes.
o
Cardiovascular: measured hypotension, clinical diagnosis of 
uncompensated shock, loss of consciousness or decreased level of 
consciousness, and evidence of reduced peripheral circulation.
o
Respiratory: bilateral wheeze (bronchospasm), difficulty breathing, 
stridor, upper airway swelling (lip, tongue, throat, uvula, or larynx), 
respiratory distress, persistent dry cough, hoarse voice, sensation of 
throat closure, sneezing, and rhinorrhea.
o
Gastrointestinal: diarrhea, abdominal pain, nausea, and vomiting.
Other syndromes

Fibromyalgia

Postural orthostatic tachycardia syndrome

Chronic fatigue syndrome (includes myalgic encephalomyelitis and 
postviral fatigue syndrome)

Myasthenia gravis
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AV=atrioventricular; 
CDC=Centers for Disease Control and Prevention; cMRI=cardiac magnetic resonance imaging; COVID-19=Coronavirus 
disease caused by severe acute respiratory syndrome coronavirus 2; ECG/EKG=electrocardiogram; HELLP=hemolysis, 
elevated liver enzymes, and low platelets; MIS-C=multisystem inflammatory syndrome in children; MRI=magnetic 
resonance imaging; RT-PCR=reverse transcription polymerase chain reaction; SARS-CoV-2=severe acute respiratory 
syndrome coronavirus 2
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.
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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.
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.
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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 
Vaccinea
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
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
Lymphadenopathyb
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
ER visit or 
hospitalization
Any injection-site reaction that begins ≥8 days after receipt of study vaccine
Pain/Tenderness
Erythema/Redness
Swelling/
Lymphadenopathyb
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 upon information provided by the participant on the eVRC and verbally during eVRC review. For the 
injection-site redness and swelling: >0 to 5 cm (0 to 2 inches) will be categorized as mild, >5 cm to 10 cm (>2 
inches to 4 inches) will be categorized as moderate, and >10 cm (>4 inches) will be categorized as severe. If the 
participant has an ER 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.
b
Axillary lymphadenopathy ipsilateral to the side of mRNA-1273 vaccine injection
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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
Requires ED 
visit or 
hospitalization
ED=emergency department
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].
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.
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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?
-
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.
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(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 his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a 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.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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•
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,
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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.
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.
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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
Not applicable as participants enrolled are boys and girls 9 to 11 years of age who have not 
yet had coitarche and do not plan on becoming sexually active during the vaccination period.
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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.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical 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.
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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 
(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 
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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.
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.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International 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
ACIP
Advisory Committee on Immunization Practices
AE
adverse event
APaT
All-Participants-as-Treated
β-hCG
β-human chorionic gonadotropin
CDC
Centers for Disease Control and Prevention
CI
confidence interval
cLIA
competitive Luminex Immunoassay
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
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
ECL
electrochemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection
EEA
European Economic Area
EMA
European Medicines Agency
EUA
Emergency Use Authorization
eVRC
electronic Vaccination Report Card
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSR
First Site Ready
GCP
Good Clinical Practice
GMC
geometric mean concentration
GMT
geometric mean titer
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HLH
hemophagocytic lymphohistiocytosis
HPV
human papillomavirus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IM
intramuscular
IRB
Institutional Review Board
IRT
interactive response technology
IVRS
interactive voice response system
IWRS
integrated web response system
LLOQ
lower limit of quantitation
MAAE
medically attended adverse event
MIS-C
Multisystem Inflammatory Syndrome in Children
mIU
milli international units
mL
milliliter
M&N
Miettinen and Nurminen
NSAE
nonserious AE
PP
per-protocol
PPI
per-protocol immunogenicity
PQC
product quality complaint
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
US
United States
VLP
vaccine-like particle
VSD
Vaccines Sciences Department
WHO
World Health Organization
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11
REFERENCES
[Aretz, H. T. 1987]
Aretz HT. Myocarditis: the Dallas 
criteria. Hum Pathol. 1987 Jun;18(6):619-
24.
[06FD2H]
[Baden, L. R., et al 2021]
Baden LR, El Sahly HM, Essink B, 
Kotloff K, Frey S, Novak R, et al. 
Efficacy and safety of the mRNA-1273 
SARS-CoV-2 vaccine. N Engl J Med. 
2021 Feb 4;384(5):403-16.
[05QRLQ]
[Centers for Disease Control 
and Prevention 2015]
Centers for Disease Control and 
Prevention. Epidemiology and prevention 
of vaccine-preventable diseases. 13th ed. 
Hamborsky J, Kroger A, Wolfe S, 
editors. Washington (DC): Department of 
Health and Human Services (HHS); 
c2015. Chapter 6, Vaccine 
administration; p. 79-106.
[0508PV]
[Centers for Disease Control 
and Prevention 2022]
Centers for Disease Control and 
Prevention. Summary document for 
interim clinical considerations: for use of 
COVID-19 vaccines currently authorized 
or approved in the United States. 
Washington (DC): Department of Health 
and Human Services (HHS); 2022 Jun 
23. 5 p.
[08350X]
[CLOPPER, C. J. and 
PEARSON, E. S. 1934]
Clopper CJ, Pearson ES. The use of 
confidence of fiducial limits illustrated in 
the case of the binomial. Biometrika 
1934;26(4):404-13.
[03RRVC]
[Cull, B. 2022]
Cull B, Harris M. Children and COVID-
19: state data report. Itasca, IL: American 
Academy of Pediatrics (AAP); 2022 May 
12. 42 p. Joint publication of Children's 
Hospital Association (CHA), Lenexa, 
KS.
[082NKL]
08M7H8

PRODUCT: V503
113
PROTOCOL/AMENDMENT NO.: 076-03
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15-FEB-2023
[Ferreira, V. M., et al 2018]
Ferreira VM, Schulz-Menger J, 
Holmvang G, Kramer CM, Carbone I, 
Sechtem U, et al. Cardiovascular 
magnetic resonance in nonischemic 
myocardial inflammation: expert 
recommendations. J Am Coll Cardiol. 
2018 Dec 18;72(24):3158-76.
[06FD2D]
[Food and Drug 
Administration 2007]
Food and Drug Administration. Guidance 
for industry: toxicity grading scale for 
healthy adult and adolescent volunteers 
enrolled in preventive vaccine clinical 
trials. Rockville, MD. Sep 2007.
[05B4S4]
[Gargano, J. W., et al 2021]
Gargano JW, Wallace M, Hadler SC, 
Langley G, Su JR, Oster ME, et al. Use 
of mRNA COVID-19 vaccine after 
reports of myocarditis among vaccine 
recipients: update from the advisory 
committee on immunization practices -
United States, June 2021. MMWR Morb 
Mortal Wkly Rep. 2021 Jul 9;70(27):977-
82.
[06F5FS]
[Giuliano, A. R., et al 2019]
Giuliano AR, Joura EA, Garland SM, 
Huh WK, Iversen OE, Kjaer SK, et al. 
Nine-valent HPV vaccine efficacy against 
related diseases and definitive therapy: 
comparison with historic placebo 
population. Gynecol Oncol. 
2019;154:110-7.
[05J2TJ]
[Huh, W . K., et al 2017]
Huh WK, Joura EA, Giuliano AR, 
Iversen OE, de Andrade RP, Ault KA, et 
al. Final efficacy, immunogenicity, and 
safety analyses of a nine-valent human 
papillomavirus vaccine in women aged 
16-26 years: a randomised, double-blind 
trial. Lancet. 2017 Nov 
11;390(10108):2143-2159.
[04TDZJ]
08M7H8

PRODUCT: V503
114
PROTOCOL/AMENDMENT NO.: 076-03
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15-FEB-2023
[Iversen, O. E. 2016]
Iversen OE, Miranda MJ, Ulied A, 
Soerdal T, Lazarus E, Chokephaibulkit K, 
et al. Immunogenicity of the 9-Valent 
HPV Vaccine Using 2-Dose Regimens in 
Girls and Boys vs a 3-Dose Regimen in 
Women. JAMA. 2016 Dec 
13;316(22):2411-2421.
[04SJ7X]
[Joura, E. A., et al 2015]
Joura EA, Giuliano AR, Iversen OE, 
Bouchard C, Mao C, Mehlsen J, et al. A 
9-valent HPV vaccine against infection 
and intraepithelial neoplasia in women. N 
Engl J Med. 2015 Feb 19;372(8):711-23.
[044RDM]
[Kjaer, S. K., et al 2001]
Kjaer SK, Chackerian B, van den Brule 
AJC, Svare EI, Paull G, Walboomers 
JMM, et al. High-risk human 
papillomavirus is sexually transmitted: 
evidence from a follow-up study of 
virgins starting sexual activity 
(intercourse). Cancer Epidemiol 
Biomarkers Prev 2001;10:101-6.
[03R70S]
[Kosalaraksa, P., et al 2015]
Kosalaraksa P, Mehlsen J, Vesikari T, 
Forsten A, Helm K, Van Damme P, et al. 
An open-label, randomized study of a 9-
valent human papillomavirus vaccine 
given concomitantly with diphtheria, 
tetanus, pertussis and poliomyelitis 
vaccines to healthy adolescents 11-15 
years of age. Pediatr Infect Dis J. 2015 
Jun;34(6):627-34.
[04GZWH]
[Lazarus, R., et al 2021]
Lazarus R, Baos S, Cappel-Porter H, 
Carson-Stevens A, Clout M, Culliford L, 
et al. Safety and immunogenicity of 
concomitant administration of COVID-19 
vaccines (ChAdOx1 or BNT162b2) with 
seasonal influenza vaccines in adults in 
the UK (ComFluCOV): a multicentre, 
randomised, controlled, phase 4 trial. 
Lancet. In press 2021.
[07X6ZY]
08M7H8

PRODUCT: V503
115
PROTOCOL/AMENDMENT NO.: 076-03
V503-076-03 FINAL PROTOCOL
15-FEB-2023
[Lessler, J., et al 2021]
Lessler J, Grabowski MK, Grantz KH, 
Badillo-Goicoechea E, Metcalf CJE, 
Lupton-Smith C, et al. Household 
COVID-19 risk and in-person schooling. 
Science. 2021 Jun 4;372:1092-7.
[06DVYV]
[Malagon, T., et al 2019]
Malagon T, Louvanto K, Wissing M, 
Burchell AN, Tellier PP, El-Zein M, et al. 
Hand-to-genital and genital-to-genital 
transmission of human papillomaviruses 
between male and female sexual partners 
(HITCH): a prospective cohort study. 
Lancet Infect Dis. 2019 Mar;19:317-26.
[05QG4Z]
[Meites, E., et al 2016]
Meites E, Kempe A, Markowitz LE. Use 
of a 2-dose schedule for human 
papillomavirus vaccination - updated 
recommendations of the advisory 
committee on immunization practices. 
MMWR Morb Mortal Wkly Rep. 2016 
Dec 16;65(49):1405-8.
[04ZQNC]
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O, Nurminen M. Comparative 
Analysis of Two Rates. Stat Med 
1985;4:213-26.
[03QCDT]
[Moderna, Inc. 2021]
Moderna Messenger Therapeutics 
[Internet]. Cambridge (MA): Moderna, 
Inc.; c2021. Moderna announces positive 
top line data from phase 2/3 study of 
COVID-19 vaccine in children 6 to 11 
years of age [press release]. 2021 Oct 25 
[cited 2021 Dec 2]; 2 p. Available from: 
https://investors.modernatx.com/news/ne
ws-details/2021/Moderna-Announces-
Positive-Top-Line-Data-from-Phase-23-
Study-of-COVID-19-Vaccine-in-
Children-6-to-11-Years-of-Age-10-25-
2021/default.aspx.
[07XPCM]
[Opalka, D., et al 2010]
Opalka D, Matys K, Bojczuk P, Green T, 
Gesser R, Saah A, et al. Multiplexed 
serologic assay for nine anogenital 
human papillomavirus types. Clin 
Vaccine Immunol. 2010 May;17(5):818-
27.
[04K86F]
08M7H8

PRODUCT: V503
116
PROTOCOL/AMENDMENT NO.: 076-03
V503-076-03 FINAL PROTOCOL
15-FEB-2023
[O'Shaughnessy, J. A. 2022]
O'Shaughnessy JA (Acting Chief 
Scientist, Food and Drug Administration, 
Silver Spring, MD). Letter to: M. Olsen 
(ModernaTX, Inc., Cambridge, MA). 
2022 Jun 17. 25 p. SPIKEVAX (COVID-
19 Vaccine, (mRNA) EUA.
[08350S]
[Roberts, C., et al 2014]
Roberts C, Green T, Hess E, Matys K, 
Brown MJ, Haupt RM, et al. 
Development of a human papillomavirus 
competitive luminex immunoassay for 9 
HPV types. Hum Vaccin Immunother. 
2014;10(8):2168-74.
[056DRN]
[Schilling, A., et al 2015]
Schilling A, Parra MM, Gutierrez M, 
Restrepo J, Ucros S, Herrera T, et al. 
Coadministration of a 9-Valent Human 
Papillomavirus Vaccine With 
Meningococcal and Tdap Vaccines. 
Pediatrics. 2015 Sep;136(3):e563-72.
[04H0T4]
[U.S. Food and Drug 
Administration 2009]
U.S. Food and Drug Administration 
(CDER, CBER, CDRH). Guidance for 
industry patient-reported outcome 
measures: use in medical product 
development to support labeling claims 
[Internet]. Washington: U.S. Department 
of Health and Human Services; 2009. 
Available from: 
https://www.fda.gov/downloads/drugs/gu
idances/ucm193282.pdf
[04MG9J]
[Van Damme, P., et al 2015]
Van Damme P, Olsson SE, Block S, 
Castellsague X, Gray GE, Herrera T, et 
al. Immunogenicity and Safety of a 9-
Valent HPV Vaccine. Pediatrics. 2015 
Jul;136(1):e28-39.
[04885H]
08M7H8

PRODUCT: V503
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PROTOCOL/AMENDMENT NO.: 076-03
V503-076-03 FINAL PROTOCOL
15-FEB-2023
[Wallace, M., et al 2021]
Wallace M, Woodworth KR, Gargano 
JW, Scobie HM, Blain AE, Moulia D, et 
al. The Advisory Committee on 
Immunization Practices interim 
recommendation for use of Pfizer-
BioNTech COVID-19 vaccine in 
adolescents aged 12-15 years - United 
States, May 2021. MMWR Morb Mortal 
Wkly Rep. 2021 May 21;70(20):749-52.
[06DVFT]
[World Health Organization 
2014]
World Health Organization. Vaccins 
contre le papillomavirus humain: note de 
synthese de l'OMS, octobre 2014 [Human 
papillomavirus vaccines: WHO position 
paper, October 2014]. Wkly Epidemiol 
Rec. 2014 Oct 24;89(43):465-92.
[05HG9V]
[World Health Organization 
2017]
World Health Organization. Human
papillomavirus vaccines: WHO position 
paper, May 2017. Wkly Epidemiol Rec. 
2017 May 12;92(19):241-68.
[0558D4]
08M7H8