A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity and Safety of 9- Valent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine (V503) in Chinese Females 9 to 45 Years of Age
Phase: PHASE3
Conditions: Papillomavirus Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03903562 
Document Date: 
09-Jan-2023
A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity 
and Safety of 9-Valent Human Papillomavirus (HPV) L1 Virus-Like 
Particle (VLP) Vaccine (V503) in Chinese females 9 to 45 Years 
of Age

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
This protocol amendment is applicable only to China.
Protocol Title: A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity and 
Safety of 9-Valent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine 
(V503) in Chinese females 9 to 45 Years of Age
Protocol Number: 024-02
Compound Number: V503
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER: To Be Determined
EudraCT NUMBER: Not Applicable
Approval Date:  09 January 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
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
V503-024-02
09-JAN-2023
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
V503-024-01
12-MAR-2020
To extend the visit window of Dose 3 vaccination.
V503-024-00
14-SEP-2018
Original version
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment [02]
Overall Rationale for the Amendment:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
Title Page
Section 10.1 
Appendix 1 Code 
of Conduct for 
Clinical Trials
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Protocol Summary .....................................................................................................12
Synopsis....................................................................................................................12
Schema .....................................................................................................................18
Schedule of Activities (SoA) ...................................................................................19
2.
Introduction................................................................................................................24
Study Rationale .......................................................................................................24
Background..............................................................................................................24
Pharmaceutical and Therapeutic Background .....................................................24
Benefit/Risk Assessment.........................................................................................25
3.
Objectives/Hypotheses and Endpoints.....................................................................25
Stage I in females 9 to 45 years of age (Day 1 to Visit 10)...................................26
Stage II in females 9 to 19 years of age (post Visit 10 to Visit 15) ......................30
4.
Study Design...............................................................................................................31
Overall Design .........................................................................................................31
Stage I ..................................................................................................................31
Stage II.................................................................................................................32
Scientific Rationale for Study Design....................................................................32
Rationale for Endpoints .......................................................................................33
Immunogenicity Endpoints...........................................................................33
Safety Endpoints...........................................................................................33
Justification for Dose ..............................................................................................34
Beginning and End of Study Definition ................................................................34
Clinical Criteria for Early Study Termination .....................................................34
5.
Study Population........................................................................................................34
Inclusion Criteria....................................................................................................34
Stage I ..................................................................................................................34
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Stage II.................................................................................................................35
Exclusion Criteria ...................................................................................................36
Lifestyle Considerations .........................................................................................38
Screen Failures ........................................................................................................38
Participant Replacement Strategy.........................................................................38
6.
Treatments..................................................................................................................38
Treatments Administered.......................................................................................39
Preparation/Handling/Storage/Accountability ....................................................41
Dose Preparation..................................................................................................41
Handling, Storage and Accountability.................................................................41
Measures to Minimize Bias: Randomization and Blinding.................................42
Method of Treatment Assignment .......................................................................42
Stratification..................................................................................................42
Blinding................................................................................................................42
Treatment Compliance...........................................................................................42
Concomitant Therapy.............................................................................................42
Rescue Medications and Supportive Care ...........................................................43
Dose Modification ...................................................................................................43
Treatment After the End of the Study ..................................................................43
Clinical Supplies Disclosure...................................................................................43
7.
Discontinuation of Study Treatment and Participant Withdrawal ......................43
Discontinuation of Study Treatment.....................................................................43
Participant Withdrawal From the Study..............................................................44
Lost to Follow-up ....................................................................................................44
8.
Study Assessments and Procedures..........................................................................45
Administrative and General Procedures ..............................................................46
Informed Consent/Assent.....................................................................................46
General Informed Consent/Assent................................................................46
Inclusion/Exclusion Criteria ................................................................................46
Participant Identification Card.............................................................................46
Medical History ...................................................................................................47
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Prior and Concomitant Medications Review .......................................................47
Prior Medications..........................................................................................47
Concomitant Medications.............................................................................47
Assignment of Screening Number.......................................................................48
Physical Examinations.........................................................................................48
Axillary Temperature and Blood Pressure Prior to Study Vaccination...............48
Pregnancy Testing Prior to Study Vaccination....................................................48
Assignment of Treatment/Randomization Number.............................................49
Treatment Administration....................................................................................49
Preparation of Study Vaccine for Administration ........................................49
Study Vaccine Administration......................................................................50
Timing of Dose Administration....................................................................50
Discontinuation and Withdrawal .........................................................................50
Participant Blinding/Unblinding..........................................................................51
Calibration of Equipment.....................................................................................51
Immunogenicity Assessments.................................................................................51
Serum for Anti-HPV Antibody Testing...............................................................51
Immunogenicity Measurements...........................................................................52
Safety Assessments..................................................................................................53
Vaccination Report Card and Patient Reported Outcome ...................................53
Post-vaccination Observation Period (30 minutes)..............................................54
Clinical Safety Laboratory Assessments..............................................................54
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .......................................................................................54
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..................................................................55
Method of Detecting AEs, SAEs, and Other Reportable Safety Events..............56
Follow-up of AE, SAE and Other Reportable Safety Event Information............57
Regulatory Reporting Requirements for SAE .....................................................57
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................57
Pregnancy and Exposure During Breastfeeding ..................................................57
Events of Clinical Interest (ECIs)........................................................................58
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Treatment of Overdose...........................................................................................58
Pharmacokinetics....................................................................................................58
Pharmacodynamics.................................................................................................58
Biomarkers ..............................................................................................................58
Future Biomedical Research Sample Collection..................................................58
Visit Requirements..................................................................................................58
Prerequisites for Vaccination Visits.....................................................................59
Discontinued Participants Continuing to be Monitored in the Study ..................59
9.
Statistical Analysis Plan ............................................................................................59
Statistical Analysis Plan Summary........................................................................60
Responsibility for Analyses/In-house Blinding.....................................................62
Hypotheses/Estimation ...........................................................................................62
Analysis Endpoints..................................................................................................62
Immunogenicity Endpoints..................................................................................62
Safety Endpoints ..................................................................................................63
Analysis Populations...............................................................................................63
Immunogenicity Analysis Populations ................................................................63
Safety Analysis Populations ................................................................................64
Statistical Methods..................................................................................................64
Statistical Methods for Immunogenicity Analyses..............................................64
Statistical Methods for Safety Analyses ..............................................................70
Summaries of Baseline Characteristics, Demographics, and other 
Analyses...............................................................................................................72
Interim Analyses .....................................................................................................72
Multiplicity ..............................................................................................................72
Sample Size and Power Calculations ....................................................................73
Sample Size and Power for Immunogenicity.......................................................73
Sample Size and Power for Safety.......................................................................76
Subgroup Analyses..................................................................................................76
Compliance (Medication Adherence)....................................................................76
Extent of Exposure..................................................................................................76
10.
Supporting Documentation and Operational Considerations...............................77
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Appendix 1:  Regulatory, Ethical and Study Oversight Considerations ...........77
Code of Conduct for Clinical Trials.................................................................................77
Financial Disclosure.........................................................................................................79
Data Protection.................................................................................................................79
Confidentiality of Data ....................................................................................................79
Confidentiality of Participant Records.............................................................................80
Confidentiality of IRB/IEC Information..........................................................................80
Committees Structure.......................................................................................................80
Executive Oversight Committee..................................................................................80
Data Monitoring Committee........................................................................................80
Publication Policy ............................................................................................................81
Compliance with Study Registration and Results Posting Requirements .......................81
Compliance with Law, Audit, and Debarment ................................................................81
Data Quality Assurance ...................................................................................................82
Source Documents ...........................................................................................................83
Study and Site Closure.....................................................................................................83
Appendix 2:  Contraceptive Guidance and Pregnancy Testing..........................84
Definitions........................................................................................................................84
Contraception Requirements............................................................................................84
Pregnancy Testing............................................................................................................86
Appendix 3: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting..............................................87
Definition of AE ..............................................................................................................87
Definition of SAE ............................................................................................................88
Additional Events Reported.............................................................................................89
Recording AE and SAE ...................................................................................................89
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor...............92
Appendix 4: Country-specific Requirements .......................................................93
Appendix 5: Abbreviations ..................................................................................100
11.
References.................................................................................................................103
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LIST OF TABLES
Table 1
Study Treatment....................................................................................................40
Table 2
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events............................................................................56
Table 3
Analysis Strategy for Immunogenicity Variables – Stage I .................................68
Table 4
Analysis Strategy for Immunogenicity Variables – Stage II................................70
Table 5
Analysis Strategy for Safety Parameters ..............................................................71
Table 6
Power for Non-Inferiority Comparison in 9-19yr Group vs. 20-26yr 
Group....................................................................................................................75
Table 7
Power for Non-Inferiority Comparison in 9-15yr Group vs. 20-26yr 
Group....................................................................................................................75
Table 8
Power for Non-Inferiority Comparison in 27-45yr Group vs. 20-26yr 
Group....................................................................................................................75
Table 9
Contraceptive Methods.........................................................................................85
Table 10
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations .........................................................................................................86
Table 11
Local Reactions Grading ......................................................................................94
Table 12
Vital Signs Grading ..............................................................................................95
Table 13
Systemic Reactions Grading.................................................................................96
Table 14
Blood Chemistry Measurements Grading ............................................................97
Table 15
Hematology Measurements Grading....................................................................97
Table 16
Urinalysis Measurements Grading .......................................................................98
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LIST OF FIGURES
Figure 1
Study Diagram......................................................................................................18
Figure 2
Multiple Strategies to Control Overall Type One Error Rate...............................73
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1. Protocol Summary
Synopsis
Protocol Title:
A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity and Safety of 
9-Valent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine 
(V503) in Chinese females 9 to 45 Years of Age
Short Title:
Immunobridging study of 9vHPV vaccine in Chinese females 9 to 45 years of age
Objectives/Hypotheses and Endpoints:
This study consists of two stages, i.e. Stage I and II. The study period of Stage I is from 
Day 1 through Visit 10 (1 month post Dose 3) and Stage II is post Visit 10 up to Visit 15. 
Stage I in females 9 to 45 years of age (Day 1 to Visit 10):
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that 
administration of the 9-valent human 
papillomavirus (9vHPV) vaccine
induces non-inferior geometric mean 
titers (GMTs) for serum anti-HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58 in 
females 9 to 19 years of age 
compared to females 20 to 26 years 
of age.
Hypothesis (H1): 9vHPV vaccine
induces non-inferior immune 
responses in females 9 to 19 years of 
age who are seronegative at Day 1 to 
the relevant HPV type compared to 
females 20 to 26 years of age who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
anti-HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 GMTs at 1 month post 
Dose 3. (Each vaccine component 
will be analyzed separately. The 
statistical criterion for non-inferiority 
requires that the lower bound of two-

Competitive Luminex Immunoassay
(cLIA) antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.
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sided 97.5% confidence interval of 
GMT ratio (females 9 to 19 years of 
age vs. females 20 to 26 years of 
age) be greater than 0.67 for each 
HPV type.)

Objective: To demonstrate that 
administration of the 9vHPV vaccine 
induces non-inferior seroconversion
percentages to HPV types 6, 11, 16, 
18, 31, 33, 45, 52, and 58 in females
27 to 45 years of age compared to 
females 20 to 26 years of age.
Hypothesis (H2): 9vHPV vaccine 
induces non-inferior immune 
responses in females 27 to 45 years 
of age who are seronegative at Day 1 
to the relevant HPV type compared 
to females 20 to 26 years of age who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
the seroconversion percentages to 
each of HPV types 6, 11, 16, 18, 31, 
33, 45, 52, and 58 at 1 month post 
Dose 3. (Each vaccine component 
will be analyzed separately. The 
statistical criterion for non-inferiority 
requires that the lower bound of two-
sided 97.5% confidence interval for 
the difference (females 27 to 45 
years of age minus females 20 to 26 
years of age) in seroconversion 
percentages be greater than -5% for 
each HPV type.)

cLIA antibody seroconversion to each of 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58.
Secondary

Objective: To demonstrate that 
administration of the 9vHPV vaccine 
induces non-inferior seroconversion 
percentages to HPV types 6, 11, 16, 
18, 31, 33, 45, 52, and 58 in females
9 to 19 years of age compared to
females 20 to 26 years of age.

cLIA antibody seroconversion to each of 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58.
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Hypothesis (H3): 9vHPV vaccine
induces non-inferior immune 
responses in females 9 to 19 years of 
age who are seronegative at Day 1 to 
the relevant HPV type compared to 
females 20 to 26 years of age who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
the seroconversion percentages to 
each of HPV types 6, 11, 16, 18, 31, 
33, 45, 52, and 58 at 1 month post
Dose 3. (Each vaccine component 
will be analyzed separately. The 
statistical criterion for non-inferiority 
requires that the lower bound of two-
sided 97.5% confidence interval for 
the difference (females 9 to 19 years 
of age minus females 20 to 26 years 
of age) in seroconversion 
percentages be greater than -5% for 
each HPV type.)

Objective: To demonstrate that 
administration of the 9vHPV vaccine
induces non-inferior GMTs for 
serum anti-HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 in females 9 to 15
years of age compared to females 20
to 26 years of age.
Hypothesis (H4): 9vHPV vaccine
induces non-inferior immune 
responses in females 9 to 15 years of 
age who are seronegative at Day 1 to 
the relevant HPV type compared to 
females 20 to 26 years of age who 
are seronegative at Day 1 to the 
relevant HPV type, as measured by 
anti-HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 GMTs at 1 month post 
Dose 3. (Each vaccine component 
will be analyzed separately. The 
statistical criterion for non-inferiority 
requires that the lower bound of two-

cLIA antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.
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sided 97.5% confidence interval of 
GMT ratio (females 9 to 15 years of 
age vs. females 20 to 26 years of 
age) be greater than 0.67 for each 
HPV type.)

Objective: To summarize immune 
responses induced by the 9vHPV 
vaccine in females 9 to 15 years of 
age as measured by anti-HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58 cLIA 
seroconversion percentages.

Objective: To summarize immune 
responses induced by the 9vHPV 
vaccine in females 27 to 45 years of 
age as measured by anti-HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58 cLIA
GMTs.

Objective: To summarize immune 
responses induced by the 9vHPV 
vaccine using the HPV total IgG 
Luminex immunoassay (IgG LIA) in 
females 9 to 19 years of age, 20 to 
26 years of age, and 27 to 45 years 
of age.

Objective: To evaluate the safety of 
the 9vHPV vaccine in females 9 to 
19 years of age, 20 to 26 years of 
age, and 27 to 45 years of age based 
on the proportions of participants 
experiencing solicited injection-site 
adverse events (AEs), solicited 
systemic AEs, and serious AEs.

cLIA antibody seroconversion to each of 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58.

cLIA antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.

IgG LIA antibody titer and 
seroconversion to each of HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58.

Participant experiencing solicited
injection-site AEs.

Participant experiencing solicited 
systemic AEs.

Participant experiencing serious AEs.
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Stage II in females 9 to 19 years of age (post Visit 10 to Visit 15):
Objective/Hypothesis
Endpoint
Primary 

Objective: To evaluate persistence 
of immune responses induced by the 
9vHPV vaccine in females 9 to 19
years of age.

cLIA antibody titer and seropositivity to 
each of HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58.

IgG LIA antibody titer and 
seropositivity to each of HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58.
Secondary

Objective: To evaluate the safety of 
the 9vHPV vaccine in females 9 to 
19 years of age based on the 
proportion of participants 
experiencing serious AEs.

Participant experiencing serious AEs.
Overall Design:
Study Phase
Phase 3
Clinical Indication
Prevention of cervical, vulvar, vaginal, and anal cancers and 
related precancers, anogenital lesions, Pap test abnormalities, 
and persistent infection caused by human papillomavirus 
(HPV) 6, 11, 16, 18, 31, 33, 45, 52, and 58.
Population
Healthy Chinese females 9-45 years of age will be enrolled 
in this study.
Study Type
Interventional
Type of Design
Multi-site, Single-arm
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 66 months from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related telephone call or visit. 
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Number of Participants:
Approximately 1990 participants will be enrolled in the Stage I as described in Section 9.9.
Participants 9 to 19 years of age who are enrolled in the Stage I and have received 3 doses 
of study vaccination will be eligible for participation into the Stage II.
Treatment Groups and Duration:
Treatment 
Groups
All enrolled participants will intramuscularly receive a 3-dose 
regimen of 9vHPV vaccine (V503) at Visit 1, Visit 4, and Visit 
8.
Duration of 
Participation
A subset of 25 girls 9 to 15 years of age enrolled in Stage I will 
receive 2 doses of 9vHPV vaccine and be evaluated for safety 
from 1st dose through Day 15 following 2nd dose by a Data
Monitoring Committee (DMC). If safety evaluation is 
favorable, the 25 girls evaluated for safety will receive a 3rd
dose and enrollment of the rest of the participants 9 to 15 years 
of age will be initiated; participants 9 to 15 years of age will 
receive 3 doses of 9vHPV vaccine and will be followed up to 1 
month post Dose 3 (Visit 10) during Stage I.
Participants 16 to 45 years of age will be receiving 3 doses of 
9vHPV vaccine and will be followed up to Visit 10 during 
Stage I. 
After Visit 10, only participants 9 to 19 years of age who have 
received 3 doses of study vaccination will be eligible for 
participation into Stage II and will be followed up to Visit 15.
Study Governance:
Study Governance 
Committees
Committee
Included in this study?
Steering Committee
N
Executive Oversight 
Committee
Y
Data Monitoring 
Committee
Y
Clinical Adjudication 
Committee
N
Study governance considerations are outlined in Appendix 1.
A list of abbreviations used in this document can be found in Appendix 5.
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Schema
The study design is depicted in Figure 1.
*: Visit 6 (Month 2.5) is only applicable to the first 25 participants enrolled in the 9-15 years old group who will 
be evaluated for safety from 1st dose through Day 15 following 2nd dose by the Data Monitoring Committee 
(DMC). If safety evaluation is favorable, the 25 girls evaluated for safety will receive the 3rd dose and 
enrollment of the rest of participants 9 to 15 years of age will be initiated.
Figure 1
Study Diagram
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Schedule of Activities (SoA)
Study Period
Stage I
(Participants 9-45 years of age)
Stage II
(Participants 9-19 years of age)
Notes
Visit Number/Title
Visit 1
Day 1
Visit 
2
Day 9
Visit 
3
Mont
h 1
Visit 
4
Mont
h 2
Visit 
5
Day 
70
Visit 
6
Mont
h 2.5*
Visit 
7
Mont
h 3
Visit 8
Mont
h 6
Visit 9
Day 
192
Visit 
10
Month 
7
Visit 
11
Month 
12
Visit 
12
Month 
24
Visit 
13
Month 
36
Visit 
14
Month 
48
Visit 15
Month 
60
Scheduled Day
1
9
32
62
70
77
93
184
8 days 
post 
Visit 8
31 
days 
post 
Visit 8
183 
days 
post 
Visit 8
548 
days 
post 
Visit 8
913 
days 
post 
Visit 8
1278 
days 
post 
Visit 8
1643 
days 
post 
Visit 8
Scheduling 
Windows
± 0 day
8 to 
14
days 
after 
Dose 
1
31 to 
38 
days 
after 
Dose 
1
40 to 
82 
days 
after 
Dose 
1
8 to 
14
days 
after 
Dose 
2
15 to 
17
days 
after 
Dose
2
31 to 
38 
days 
after 
Dose 
2
155 to 
364 
days 
after 
Dose 
1
8 to 14
days 
after 
Dose 3
21 to 
49 
days 
after 
Dose 3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Administrative 
and General 
Procedures
Informed Consent/
Assent
X
The interval between the 
date of consent/assent and 
the date of the Day 1 visit 
should be no more than 14 
days apart. If the interval is 
15 days or longer, then the 
participant must be re-
consented.
Provide Participant 
Identification Card
X
Assign Screening 
Number
X
Review Inclusion/
Exclusion Criteria
X
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Study Period
Stage I
(Participants 9-45 years of age)
Stage II
(Participants 9-19 years of age)
Notes
Visit Number/Title
Visit 1
Day 1
Visit 
2
Day 9
Visit 
3
Mont
h 1
Visit 
4
Mont
h 2
Visit 
5
Day 
70
Visit 
6
Mont
h 2.5*
Visit 
7
Mont
h 3
Visit 8
Mont
h 6
Visit 9
Day 
192
Visit 
10
Month 
7
Visit 
11
Month 
12
Visit 
12
Month 
24
Visit 
13
Month 
36
Visit 
14
Month 
48
Visit 15
Month 
60
Scheduled Day
1
9
32
62
70
77
93
184
8 days 
post 
Visit 8
31 
days 
post 
Visit 8
183 
days 
post 
Visit 8
548 
days 
post 
Visit 8
913 
days 
post 
Visit 8
1278 
days 
post 
Visit 8
1643 
days 
post 
Visit 8
Scheduling 
Windows
± 0 day
8 to 
14
days 
after 
Dose 
1
31 to 
38 
days 
after 
Dose 
1
40 to 
82 
days 
after 
Dose 
1
8 to 
14
days 
after 
Dose 
2
15 to 
17
days 
after 
Dose
2
31 to 
38 
days 
after 
Dose 
2
155 to 
364 
days 
after 
Dose 
1
8 to 14
days 
after 
Dose 3
21 to 
49 
days 
after 
Dose 3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Review Medical 
History
X
At Day 1, any medical 
history for 5 years prior to 
Day 1 and lifetime major 
medical history prior to 
Day 1 is to be collected for 
all participants. For 
participants who have had 
sexual intercourse, the 
lifetime gynecologic 
history is to be collected at 
Day 1.
Record Medications 
and Non-study 
Vaccinations
X
X
X
X
X
X
X
Physical 
Examination 
X
X
Height and weight are only
to be measured at Day 1.
Urine or Serum 
Pregnancy Testing
in Participant of 
Childbearing 
Potential
X
X
X
The pregnancy testing must 
be sensitive to 25 mIU/mL 
β-hCG. Results should be 
negative prior to each 
vaccination.
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Study Period
Stage I
(Participants 9-45 years of age)
Stage II
(Participants 9-19 years of age)
Notes
Visit Number/Title
Visit 1
Day 1
Visit 
2
Day 9
Visit 
3
Mont
h 1
Visit 
4
Mont
h 2
Visit 
5
Day 
70
Visit 
6
Mont
h 2.5*
Visit 
7
Mont
h 3
Visit 8
Mont
h 6
Visit 9
Day 
192
Visit 
10
Month 
7
Visit 
11
Month 
12
Visit 
12
Month 
24
Visit 
13
Month 
36
Visit 
14
Month 
48
Visit 15
Month 
60
Scheduled Day
1
9
32
62
70
77
93
184
8 days 
post 
Visit 8
31 
days 
post 
Visit 8
183 
days 
post 
Visit 8
548 
days 
post 
Visit 8
913 
days 
post 
Visit 8
1278 
days 
post 
Visit 8
1643 
days 
post 
Visit 8
Scheduling 
Windows
± 0 day
8 to 
14
days 
after 
Dose 
1
31 to 
38 
days 
after 
Dose 
1
40 to 
82 
days 
after 
Dose 
1
8 to 
14
days 
after 
Dose 
2
15 to 
17
days 
after 
Dose
2
31 to 
38 
days 
after 
Dose 
2
155 to 
364 
days 
after 
Dose 
1
8 to 14
days 
after 
Dose 3
21 to 
49 
days 
after 
Dose 3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Axillary 
Temperature and 
Blood Pressure
Prior to Study 
Vaccination
X
X
X
Axillary temperature and 
blood pressure are taken 
prior to each vaccination. If 
the participant has a fever 
(defined as an axillary 
temperature ≥37.1°C) 
within the 24-hour period 
prior to vaccination, the 
vaccination should be 
rescheduled after the fever 
has resolved.
Assign Treatment/
Randomization 
Number
X
The treatment/
randomization number will 
be assigned by an 
interactive response 
technology (IRT) system.
Study Vaccine 
Administration
X
X
X
All the study-related 
procedures for Day 1 visit 
except informed 
consent/assent, screening
number assignment, 
participant identification 
card, should be performed 
on the same day as and 
prior to the first 
vaccination. All 3 doses 
should be administered 
within 1 year. The interval 
between Dose 2 and Dose 3 
should be at least 3 months.
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Study Period
Stage I
(Participants 9-45 years of age)
Stage II
(Participants 9-19 years of age)
Notes
Visit Number/Title
Visit 1
Day 1
Visit 
2
Day 9
Visit 
3
Mont
h 1
Visit 
4
Mont
h 2
Visit 
5
Day 
70
Visit 
6
Mont
h 2.5*
Visit 
7
Mont
h 3
Visit 8
Mont
h 6
Visit 9
Day 
192
Visit 
10
Month 
7
Visit 
11
Month 
12
Visit 
12
Month 
24
Visit 
13
Month 
36
Visit 
14
Month 
48
Visit 15
Month 
60
Scheduled Day
1
9
32
62
70
77
93
184
8 days 
post 
Visit 8
31 
days 
post 
Visit 8
183 
days 
post 
Visit 8
548 
days 
post 
Visit 8
913 
days 
post 
Visit 8
1278 
days 
post 
Visit 8
1643 
days 
post 
Visit 8
Scheduling 
Windows
± 0 day
8 to 
14
days 
after 
Dose 
1
31 to 
38 
days 
after 
Dose 
1
40 to 
82 
days 
after 
Dose 
1
8 to 
14
days 
after 
Dose 
2
15 to 
17
days 
after 
Dose
2
31 to 
38 
days 
after 
Dose 
2
155 to 
364 
days 
after 
Dose 
1
8 to 14
days 
after 
Dose 3
21 to 
49 
days 
after 
Dose 3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Immunogenicity 
Procedures
Blood Collection
X
X
X
X
X
X
X
The blood sample collected 
at Day 1 for anti-HPV 
antibody measurements 
must be collected before 
vaccination.
Safety Procedures
30-minute Post-
Vaccination 
Observation 
X
X
X
Provide 
Vaccination Report 
Card (VRC)
X
X
X
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Study Period
Stage I
(Participants 9-45 years of age)
Stage II
(Participants 9-19 years of age)
Notes
Visit Number/Title
Visit 1
Day 1
Visit 
2
Day 9
Visit 
3
Mont
h 1
Visit 
4
Mont
h 2
Visit 
5
Day 
70
Visit 
6
Mont
h 2.5*
Visit 
7
Mont
h 3
Visit 8
Mont
h 6
Visit 9
Day 
192
Visit 
10
Month 
7
Visit 
11
Month 
12
Visit 
12
Month 
24
Visit 
13
Month 
36
Visit 
14
Month 
48
Visit 15
Month 
60
Scheduled Day
1
9
32
62
70
77
93
184
8 days 
post 
Visit 8
31 
days 
post 
Visit 8
183 
days 
post 
Visit 8
548 
days 
post 
Visit 8
913 
days 
post 
Visit 8
1278 
days 
post 
Visit 8
1643 
days 
post 
Visit 8
Scheduling 
Windows
± 0 day
8 to 
14
days 
after 
Dose 
1
31 to 
38 
days 
after 
Dose 
1
40 to 
82 
days 
after 
Dose 
1
8 to 
14
days 
after 
Dose 
2
15 to 
17
days 
after 
Dose
2
31 to 
38 
days 
after 
Dose 
2
155 to 
364 
days 
after 
Dose 
1
8 to 14
days 
after 
Dose 3
21 to 
49 
days 
after 
Dose 3
± 28 
days
± 28 
days
± 28 
days
± 28 
days
± 28 
days
Review and Collect 
VRC data
X
X
X
X
X
X
X
Telephone contacts are to 
be done around every week 
between Visit 2 and Visit 3, 
Visit 5 and Visit 7
(telephone contacts are
done after Visit 6 for the 
first 25 participants in the 
9-15 years old group), Visit 
9 and Visit 10 to remind the 
participants to record the 
VRC and answer any 
questions related to VRC.
Collect New 
Medical Conditions
X
X
X
X
X
X
X
X
X
X
After Day 1, any new 
medical conditions not 
already recorded as medical 
history or adverse events 
are collected.
Clinical Follow-up 
for Safety
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review and follow AEs, 
SAEs and other reportable 
safety events.
See Section 8.4.1 for time 
period and frequency of 
safety events reporting 
during the study.
*: Visit 6 (Month 2.5) is only applicable to a subset of participants aged 9-15 years (N=25) who will be evaluated for safety from the 1st dose through Day 15 following the 2nd
dose by the Data Monitoring Committee (DMC). If the safety is favorable, this subset of participant will receive the 3rd dose and enrollment of the rest of participants in the 9-15 
years old group will be initiated.
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2. Introduction
Study Rationale 
Human papillomavirus (HPV) infection is a sexually transmitted disease. The incidence of 
HPV infection peaks soon after the onset of sexual activity. Adolescents are at risk of HPV 
infection immediately after sexual debut. In a survey covering approximately 22,300 girls 
and young women aged 15 to 24 years in China, it is reported that 97.2% of young women 
had their sexual debut after 17 years of age [Guo, W., et al 2012]. Therefore, virginal 
adolescents 17 years of age or younger represent a population at risk of HPV exposure in 
China who would benefit the most from prophylactic HPV vaccination. The prevalence of 
HPV infection peaked in the adolescent group ≤20 years old (38.18%) according to the study 
including 961,029 HPV tests during 2011-2015 in southeastern China [Chen, X., et al 2017]. 
In addition, Chinese mid-adult women also remain at risk of HPV infections and related 
diseases in their sexual lives. Bimodal distribution of HPV prevalence was observed in 
Chinese women with the second peak among rural women aged 35-39 years and urban 
women aged 40-44 years [Zhao, F. H., et al 2012].
Based on the clinical data of global studies, 9vHPV vaccine was approved in China in April 
2018 for the prevention against infections, precancerous or dysplastic lesions and cervical, 
vulvar, vaginal and anal cancers caused by vaccine HPV types in women 16 to 26 years of 
age. According to the post-marketing requirement of local regulatory authority, the efficacy, 
immunogenicity, and safety of the 9vHPV vaccine should be evaluated in Chinese women.
In this phase 3 study, the immunogenicity and safety of the 9vHPV vaccine will be evaluated
in Chinese females 9 to 45 years of age. This study consists of Stage I and Stage II. The dual-
primary objectives of Stage I are to demonstrate that immune responses induced by the 
9vHPV vaccine in females 9 to 19 years of age and females 27 to 45 years of age are non-
inferior to those in females 20 to 26 years of age. The immunogenicity data of Stage I will be 
submitted to local regulatory authority as soon as possible to support the extension of 
indication for females 9 to 15 years of age and females 27 to 45 years of age.
In the Stage II, female participants 9 to 19 years of age will continue to be followed to 
evaluate persistence of immune responses to the 9vHPV vaccine in this population.
Background
Refer to the Investigator’s Brochure (IB)/ approved labeling for detailed background 
information on V503 (9vHPV vaccine).
Pharmaceutical and Therapeutic Background
V503 (9vHPV vaccine) is a prophylactic 9-valent HPV (types 6, 11, 16, 18, 31, 33, 45, 52, 
and 58) vaccine that is comprised of VLPs of the 4 HPV types (type 6, 11, 16, and 18) 
represented in the quadrivalent HPV (types 6, 11, 16, and 18) vaccine (qHPV vaccine, 
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Gardasil®1), plus the VLPs of 5 additional oncogenic HPV types (type 31, 33, 45, 52, and 
58). This vaccine offers the potential of significant prophylactic cancer coverage in addition 
to that already provided by qHPV vaccine, with an increase in overall cervical cancer 
coverage from approximately 70% to 90% worldwide. Based on Chinese data, overall 
cervical cancer coverage will be increased from 69% to 92% by the 9vHPV vaccine
[Serrano, B., et al 2014]. This is in addition to the potential of coverage for genital warts 
provided by VLPs of HPV Types 6 and 11.
Benefit/Risk Assessment
As of March 2018, 9vHPV vaccine has been licensed in more than 70 countries worldwide to 
prevent cervical, vulvar, vaginal, and anal cancers and precancers and anogenital warts 
caused by HPV types covered by the vaccine. The United States Food and Drug 
Administration (FDA) and the European Medicines Agency (EMA) have both determined 
that the benefits of the 9vHPV vaccine outweigh the risks [Center for Drug Evaluation and 
Research 2014] [European Medicines Agency 2016].
The risk benefit was deemed acceptable for 16-26 years old women by local regulatory 
authority as the 9vHPV vaccine has been approved for this age group in China based on
global efficacy data. For 9-15 years old and 27-45 years old women, local clinical data are 
required to support the indication of these age groups in China.
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.
3. Objectives/Hypotheses and Endpoints
This study consists of two stages (Stage I and II). The study period of Stage I is from Day 1 
through Visit 10 (1 month post Dose 3) and Stage II is post Visit 10 up to Visit 15.
1Gardasil® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] is a registered 
trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A. Gardasil® is also known as SILGARDTM
in some countries. SILGARDTM is a trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A. 
Gardasil® will be hereafter referred to as the qHPV vaccine or V501.
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Stage I in females 9 to 45 years of age (Day 1 to Visit 10)
Objective/Hypothesis
Endpoint
Primary 

Objective: To demonstrate that 
administration of the 9-valent human 
papillomavirus (9vHPV) vaccine induces 
non-inferior geometric mean titers 
(GMTs) for serum anti-HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58 in females 9 to
19 years of age compared to females 20
to 26 years of age.
Hypothesis (H1): 9vHPV vaccine induces 
non-inferior immune responses in females 
9 to 19 years of age who are seronegative 
at Day 1 to the relevant HPV type 
compared to females 20 to 26 years of 
age who are seronegative at Day 1 to the 
relevant HPV type, as measured by anti-
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58
GMTs at 1 month post Dose 3. (Each 
vaccine component will be analyzed 
separately. The statistical criterion for 
non-inferiority requires that the lower 
bound of two-sided 97.5% confidence 
interval of GMT ratio (females 9 to 19 
years of age vs. females 20 to 26 years of 
age) be greater than 0.67 for each HPV 
type.)

Competitive Luminex Immunoassay
(cLIA) antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.
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Objective/Hypothesis
Endpoint

Objective: To demonstrate that 
administration of the 9vHPV vaccine 
induces non-inferior seroconversion 
percentages to HPV types 6, 11, 16, 18, 
31, 33, 45, 52, and 58 in females 27 to 45
years of age compared to females 20 to 
26 years of age.
Hypothesis (H2): 9vHPV vaccine induces 
non-inferior immune responses in 
females 27 to 45 years of age who are 
seronegative at Day 1 to the relevant 
HPV type compared to females 20 to 26 
years of age who are seronegative at Day 
1 to the relevant HPV type, as measured 
by the seroconversion percentages to 
each of HPV types 6, 11, 16, 18, 31, 33, 
45, 52, and 58 at 1 month post Dose 3. 
(Each vaccine component will be 
analyzed separately. The statistical 
criterion for non-inferiority requires that 
the lower bound of two-sided 97.5% 
confidence interval for the difference 
(females 27 to 45 years of age minus 
females 20 to 26 years of age) in 
seroconversion percentages be greater 
than -5% for each HPV type.)

cLIA antibody seroconversion to each 
of HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58.
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Objective/Hypothesis
Endpoint
Secondary

Objective: To demonstrate that 
administration of the 9vHPV vaccine 
induces non-inferior seroconversion 
percentages to HPV types 6, 11, 16, 18, 
31, 33, 45, 52, and 58 in females 9 to 19
years of age compared to females 20 to 
26 years of age.
Hypothesis (H3): 9vHPV vaccine induces 
non-inferior immune responses in females 
9 to 19 years of age who are seronegative 
at Day 1 to the relevant HPV type 
compared to females 20 to 26 years of 
age who are seronegative at Day 1 to the 
relevant HPV type, as measured by the 
seroconversion percentages to each of 
HPV types 6, 11, 16, 18, 31, 33, 45, 52,
and 58 at 1 month post Dose 3. (Each 
vaccine component will be analyzed 
separately. The statistical criterion for 
non-inferiority requires that the lower 
bound of two-sided 97.5% confidence 
interval for the difference (females 9 to 
19 years of age minus females 20 to 26 
years of age) in seroconversion 
percentages be greater than -5% for each 
HPV type.)

cLIA antibody seroconversion to each 
of HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58.
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Objective/Hypothesis
Endpoint

Objective: To demonstrate that 
administration of the 9vHPV vaccine
induces non-inferior GMTs for serum 
anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58 in females 9 to 15 years of age 
compared to females 20 to 26 years of 
age.
Hypothesis (H4): 9vHPV vaccine induces 
non-inferior immune responses in females 
9 to 15 years of age who are seronegative 
at Day 1 to the relevant HPV type 
compared to females 20 to 26 years of 
age who are seronegative at Day 1 to the 
relevant HPV type, as measured by anti-
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58
GMTs at 1 month post Dose 3. (Each 
vaccine component will be analyzed 
separately. The statistical criterion for 
non-inferiority requires that the lower 
bound of two-sided 97.5% confidence 
interval of GMT ratio (females 9 to 15 
years of age vs. females 20 to 26 years of 
age) be greater than 0.67 for each HPV 
type.)

cLIA antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.

Objective: To summarize immune 
responses induced by the 9vHPV vaccine 
in females 9 to 15 years of age as 
measured by anti-HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 cLIA seroconversion 
percentages.

cLIA antibody seroconversion to each 
of HPV 6, 11, 16, 18, 31, 33, 45, 52,
and 58.

Objective: To summarize immune 
responses induced by the 9vHPV vaccine 
in females 27 to 45 years of age as 
measured by anti-HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 cLIA GMTs.

cLIA antibody titer to each of HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 58.

Objective: To summarize immune 
responses induced by the 9vHPV vaccine 
using the HPV total IgG Luminex 
immunoassay (IgG LIA) in females 9 to 
19 years of age, 20 to 26 years of age, 
and 27 to 45 years of age.

IgG LIA antibody titer and 
seroconversion to each of HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58.
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Objective/Hypothesis
Endpoint

Objective: To evaluate the safety of the 
9vHPV vaccine in females 9 to 19 years 
of age, 20 to 26 years of age, and 27 to 
45 years of age based on the proportions 
of participants experiencing solicited 
injection-site adverse events (AEs), 
solicited systemic AEs, and serious AEs.

Participant experiencing solicited
injection-site AEs.

Participant experiencing solicited 
systemic AEs.

Participant experiencing serious AEs.
Exploratory

Objective: To summarize of immune 
responses to the 9vHPV vaccine using 
the pseudovirion-based neutralization 
assay (PBNA) in females 9 to 19 years of 
age, 20 to 26 years of age, and 27 to 45 
years of age.

PBNA antibody titer and 
seroconversion to each of HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58.
Stage II in females 9 to 19 years of age (post Visit 10 to Visit 15)
Objective/Hypothesis
Endpoint
Primary 

Objective: To evaluate persistence of 
immune responses induced by the 
9vHPV vaccine in females 9 to 19 years 
of age.

cLIA antibody titer and seropositivity to 
each of HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58.

IgG LIA antibody titer and 
seropositivity to each of HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58.
Secondary

Objective: To evaluate the safety of the 
9vHPV vaccine in females 9 to 19 years 
of age based on the proportion of 
participants experiencing serious AEs.

Participant experiencing serious AEs.
Exploratory

Objective: To summarize persistence of 
immune responses to the 9vHPV 
vaccine using PBNA in females 9 to 19 
years of age.

PBNA antibody titer and seropositivity 
to each of HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58.
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4. Study Design 
Overall Design 
This is a non-randomized, multi-site, open-label study to investigate the immunogenicity and
safety of the 9vHPV vaccine in healthy Chinese females 9 to 45 years of age to be conducted 
in conformance with Good Clinical Practices.
The study consists of Stage I (Day 1 to Visit 10) and Stage II (post Visit 10 to Visit 15). The 
dual-primary objectives of Stage I are to demonstrate that immune responses induced by the 
9vHPV vaccine in females 9 to 19 years of age and 27 to 45 years of age are non-inferior to 
those in females 20 to 26 years of age. The results of immunobridging analyses of Stage I
will be submitted to local regulatory authority as soon as possible to extend the indication of 
9vHPV vaccine to Chinese females 9 to 15 years of age and 27 to 45 years of age.
The objective of Stage II is to assess the immune persistence following 9vHPV vaccination 
in females 9 to 19 years of age. The data of immune persistence will be submitted to local 
regulatory authority after the data are available.
Stage I
Approximately 1990 female participants 9 to 45 years of age who meet eligibility will be 
enrolled in the study. Enrollment of participants will be stratified based on the following age 
strata: 9-19 years old (N=690), 20-26 years old (N=650), and 27-45 years old (N=650). 
Within each 9-19 years old group and 27-45 years old group, enrollment will be further 
stratified by the pre-defined age subgroups as described in Section 6.3.1.1.
For participants 9-15 years of age, a sequential enrollment will be applied. The 1st step is to 
enroll 25 participants 9-15 years of age and the safety data after Dose 1 through Day 15 post 
Dose 2 will be reviewed by a Data Monitoring Committee (DMC). If the safety data are 
judged to be acceptable in the opinion of the DMC, then the 25 participants 9 to 15 years of 
age enrolled initially will received a 3rd dose at Visit 8, and the enrollment will be initiated to 
the rest of participants 9-15 years of age. All participants 9 to 15 years of age enrolled in the 
2nd step of enrollment will receive one dose of 9vHPV vaccine at Visit 1, Visit 4, and Visit 8, 
respectively.
The enrollment of participants 16 to 45 years of age will be initiated at the same time as that 
of the first 25 participants 9-15 years of age. Safety review by the DMC is not necessary for 
participants 16 to 45 years of age. All enrolled participants 16 to 45 years of age will receive 
one dose of 9vHPV vaccine at Visit 1, Visit 4, and Visit 8, respectively.
Medical history and vital signs will be collected at Day 1 for all participants. Physical 
examination will be conducted at Day 1 for all participants, and at Visit 6 for the 25 
participants initially enrolled in the 9-15 years old group for whom the safety will be 
reviewed by the DMC.
Serum samples will be obtained from each participant at Day 1 prior to vaccination and 1 
month post Dose 3 (Visit 10) for measurement of anti-HPV antibodies for HPV 6, 11, 16, 18, 
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31, 33, 45, 52, and 58 by cLIA and IgG LIA. However, only serum samples from a subset of 
participants will be tested by PBNA (N=600 in total, i.e. 200 participants randomly selected 
from each age group) as an exploratory objective of this study.
The safety will be monitored for all participants from Day 1 through Visit 10. Vaccination 
Report Card (VRC) will be provided to each participant after vaccination for recording AE 
information within 30 days (Days 1-31) after study vaccination including the day of 
vaccination. Serious adverse events (SAEs), cancers, overdoses, pregnancy events, lactation 
events, and SAEs of infants born to participant who received the study vaccine or who were 
breastfed during the vaccination period will be collected during the entire period of Stage I.
As participants 20-45 years of age will not enter into Stage II, the last study visit for these 
participants will be the Visit 10.
Stage II
Participants who are enrolled in the 9 to 19 years age group and have completed 3 doses of 
study vaccination during Stage I will be eligible for participation into Stage II and followed 
up to Visit 15. Therefore, the last study visit for participants 9-19 years of age who will not 
enter into Stage II will be the Visit 10.
Serum samples will be obtained at the time points of Visit 11, Visit 12, Visit 13, Visit 14, and 
Visit 15. All the serum samples will be tested by cLIA and IgG LIA for measurement of anti-
HPV antibodies for HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58. As an exploratory objective, 
PBNA will be performed on serum samples collected from the same subset of participants in 
the 9-19 years old group selected for PBNA testing during Stage I.
SAEs, cancers, overdoses, pregnancy events, lactation events, and infant SAEs will be 
collected during the entire period of Stage II.
For the purposes of analysis and results reporting, the primary outcome of each stage will be 
defined as the Sponsor’s receipt of the last serological data in each stage.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
Scientific Rationale for Study Design 
This phase 3 study is to fulfill the post-marketing requirement of local regulatory authority to 
evaluate the immunogenicity and safety of the 9vHPV vaccine in Chinese females. The main 
purpose of this study is to demonstrate that immune responses to the 9vHPV vaccine in 
females 9 to 19 years of age and females 27 to 45 years of age are non-inferior to those in 
females 20 to 26 years of age. Persistence of immunogenicity of the vaccine will be 
evaluated up to Visit 15 in females 9 to 19 years of age in this study.
As participants who are seropositive to the vaccine HPV types at baseline will not be 
included in the final analyses of immunogenicity (see Section 9.5.1 for definitions of 
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immunogenicity analysis populations), the baseline seropositivity rates in the study 
population were estimated based on previous local and global HPV studies and were
considered as one of the assumptions for sample size calculation (see Section 9.9.1).
Rationale for Endpoints
Immunogenicity Endpoints
Competitive Luminex immunoassay (cLIA) is the primary assay to assess the
immunogenicity in the qHPV and 9vHPV vaccine programs. In Stage I, serum samples will 
be collected at Day 1 and 1 month post Dose 3 (Visit 10) for analysis of antibody responses 
to 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58) by cLIA to support the primary and 
secondary objectives of the study.
As described in Section 9.4.1, the primary immunogenicity endpoints are cLIA antibody titer
(for H1) and seroconversion (for H2) to each of 9 HPV types at 1 month post Dose 3. The 
secondary immunogenicity endpoints are cLIA antibody seroconversion (for H3) and titer 
(for H4) to each of 9 HPV types at 1 month post Dose 3.
Antibody titer is the primary endpoint for 9-19 years old group and antibody seroconversion 
is the primary endpoint for 27-45 years old group, which is consistent with regulatory 
precedent for HPV vaccine licensure in China.
Non-inferiority margins used in this study are consistent with prior HPV vaccine studies.
HPV total IgG Luminex immunoassay (IgG LIA) will be used as a secondary measurement 
to evaluate the immunogenicity of the 9vHPV vaccine. IgG LIA antibody titer and 
seroconversion to 9 vaccine HPV types at 1 month post Dose 3 will be summarized.
The detailed description of these two immunoassays are provided in Section 8.2.2.
Pseudovirion-based neutralization assay (PBNA) which is developed by the National 
Institutes for Food and Drug Control (NIFDC, Beijing, China) will be used as an exploratory 
measurement to characterize the immune responses induced by the 9vHPV vaccine in a 
subset of participants.
In Stage II, serum samples will be collected at Visit 11, Visit 12, Visit 13, Visit 14, and Visit 
15 to evaluate the persistence of immune responses. Anti-HPV antibody titer and 
seropositivity at Visit 11, Visit 12, Visit 13, Visit 14, and Visit 15 measured by cLIA and 
IgG LIA will be summarized. The exploratory endpoints for persistence of immune 
responses include PBNA antibody titer and seropositivity at Visit 11, Visit 12, Visit 13, Visit 
14, and Visit 15 in a subset of participants.
Safety Endpoints
The safety endpoints used in this study are selected based on the product’s safety profile 
demonstrated in prior clinical studies with the 9vHPV vaccine, and meet the vaccine clinical 
requirements in China. 
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A list of the safety endpoints to evaluate the safety of the 9vHPV vaccine in the study 
population is provided in Section 8.3.1 and 9.4.2.
Justification for Dose 
The dose formulation of 9vHPV vaccine (including dose of antigen and amount of adjuvant) 
was determined based on immunogenicity and safety results of Phase II studies 
[Luxembourg, A., et al 2015] [Pitisuttithum, P., et al 2015].
The efficacy of the 9vHPV vaccine was established in a clinical trial in young women 16 to 
26 years of age based on a dosing regimen of 0, 2, 6 months [Joura, E. A., et al 2015].
The formulation and regimen of 9vHPV vaccine are identical to those used in prior global 
studies, and the licensed 9vHPV vaccine in China.
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent/assent form. 
The overall study ends when the last participant completes the last study-related telephone
call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator). For purposes of analysis and reporting, the overall study
ends when the Sponsor receives the last assay results (eg, serum, swab, and biopsy) or 
participant data from the last study-related telephone call or visit.
Clinical Criteria for Early Study Termination
Enrollment and vaccination of girls 9 to 15 years of age may be terminated if the DMC
determines that the safety profile of the 9vHPV vaccine assessed in 25 girls 9 to 15 years of 
age after Dose 2 is not acceptable.
5. Study Population
Healthy Chinese females aged 9 and 45 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.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Stage I  
Type of Participant and Disease Characteristics
1. Only healthy participants are to be enrolled. A participant is judged to be in good 
physical health on the basis of medical history and physical examination.
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Demographics
2. Participant is female between the ages of 9 years and 0 days and 45 years and 364 
days on the day of Day 1 vaccination.
3. Participant is eligible to participate, if at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2
OR 
b.) A WOCBP has not had sex with males or has had sex with males and used 
effective contraception as defined in Appendix 2 since the first day of participant’s 
last menstrual period through Day 1. And the participant understands and agrees that 
during the Day 1 through 1 month post Dose 3 period, she should not have sexual 
intercourse with males without effective contraception, and that the use of the rhythm 
method, withdrawal, and emergency contraception are not acceptable methods per the 
protocol.
4. Participant has a lifetime history of 0 to 4 male and/or female sexual partners at the 
time of enrollment. Male partner is defined as someone with whom the participant has 
penile penetrative sexual intercourse. Female partner is defined as someone who has 
contacted, either by penetrative (with fingers or other objects) or non-penetrative 
means, the participant’s genitalia during sexual activity.
Informed Consent/Assent
5. (Participants 9-17 years of age only) Participant’s legally acceptable representative
provides written informed consent for the study. Participant provides written 
informed assent for the study. 
6. (Participants 18-45 years of age only) Participant provides written informed consent 
for the study. 
General
7. Participant agrees to provide study personnel with a primary telephone number as 
well as an alternate form of contact, if available, for follow-up purposes.
Stage II  
1. Participant is enrolled in the Stage I.
2. Participant is 9 to 19 years of age at the enrollment in the Stage I.
3. Participant has completed 3 doses of study vaccination.
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Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
The following exclusion criteria are only required for Stage I. 
No exclusion criteria are applicable for Stage II.
Medical Conditions
1. Participant has known allergy to any vaccine component, including aluminum, yeast, 
or BENZONASE™ (nuclease, Nycomed™ [used to remove residual nucleic acids 
from this and other vaccines]). For the purpose of this exclusion criterion, an allergy 
to vaccine components is defined as an allergic reaction that met the criteria for 
serious adverse event defined in Appendix 3.
2. Participant has a history of severe allergic reaction (e.g. swelling of the mouth and 
throat, difficulty breathing, hypotension, or shock) that required medical intervention.
3. Participant with known thrombocytopenia or any coagulation disorder that would 
contraindicate intramuscular injections.
4. Participant has a fever (defined as an axillary temperature ≥37.1°C) within 24 hours
prior to the Day 1 vaccination (if the participant meets this exclusion criterion, the 
Day 1 visit may be rescheduled for a time when this criterion is not met).
5. Participant has any history of abnormal Pap test showing squamous intraepithelial 
lesion (SIL) or atypical squamous cells – undetermined significance (ASC-US), 
atypical squamous cells – cannot exclude HSIL (ASC-H), atypical glandular cells, or 
biopsy showing cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ or 
cervical cancer.
6. Participant has a history of external genital wart, vulvar intraepithelial neoplasia 
(VIN), vaginal intraepithelial neoplasia (VaIN), vulvar cancer or vaginal cancer.
7. Participant has a history of a positive test for HPV.
8. Participant is currently immunocompromised or has been diagnosed as having 
congenital or acquired immunodeficiency, human immunodeficiency virus (HIV) 
infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), rheumatoid 
arthritis, juvenile rheumatoid arthritis (JRA), inflammatory bowel disease, or other 
autoimmune condition.
9. Participant has a history of splenectomy.
10. Participant has a history or current evidence of any condition, therapy, lab 
abnormality or other circumstance that might confound the results of the study, or 
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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.
11. Participant has donated blood within 1 week prior to the Day 1 vaccination, or intends 
to donate during Day 1 through 1 month post Dose 3 of the study (if the participant 
meets this exclusion criterion, the Day 1 visit may be rescheduled for a time when 
this criterion is not met).
12. Participant is expecting to donate eggs during Day 1 through 1 month post Dose 3 of 
the study.
13. Female participant of childbearing potential as defined in Appendix 2 is pregnant as 
determined by a urine or serum pregnancy testing that is sensitive to 25 mIU/mL beta 
human chorionic gonadotropin (-hCG).
Prior/Concomitant Therapy
14. Participant is receiving or has received in the year prior to Day 1 vaccination the 
following immunosuppressive therapies: radiation therapy, cyclophosphamide, 
azathioprine, methotrexate, any chemotherapy, cyclosporin, leflunomide (Arava™), 
TNF-α antagonists, monoclonal antibody therapies (including rituximab [Rituxan™]), 
intravenous gamma globulin (IVIG), antilymphocyte sera, or other therapy known to 
interfere with the immune response. With regard to systemic corticosteroids, a 
participant will be excluded if 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 (orally or parenterally) lasting at least 1 
week in duration in the year prior to Day 1 vaccination. Participants using inhaled, 
nasal or topical corticosteroids are considered eligible for the study.
15. Participant who has received immune globulin product (including RhoGAMTM
[Ortho-clinical Diagnostics]) or blood-derived product other than IVIG within 6 
months prior to Day 1 vaccination, or plans to receive any such product during Day 1 
through 1 month post Dose 3 of the study.
16. Participant has received a marketed HPV vaccine, or has participated in an HPV 
vaccine clinical trial and has received either active agent or placebo.
17. Participant has received inactivated or recombinant vaccines within 14 days prior to 
Day 1 vaccination or has received live vaccines within 21 days prior to Day 1 
vaccination (if the participant meets this exclusion criterion, the Day 1 visit may be 
rescheduled for a time when this criterion is not met).
Prior/Concurrent Clinical Study Experience
18. Participant is concurrently enrolled in clinical studies of interventional agents.
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Diagnostic Assessments
Not Applicable.
Other Exclusions
19. Participant 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 of time when study visits would need to be scheduled.
20. Participant is, at the time of signing informed consent, a user of recreational or illicit 
drugs or has had a recent history (within the last year) of drug or alcohol abuse or 
dependence. Alcohol abusers are defined as those who drink despite recurrent social, 
interpersonal, and/or legal problems as a result of alcohol use.
21. 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.
Lifestyle Considerations
No lifestyle restrictions are required.
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study vaccination or withdraws from the study will not 
be replaced.
6. Treatments
Study treatment is defined as any investigational treatment(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 treatment(s) provided by the Sponsor] will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
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Treatments Administered
The study treatment to be used in this study is outlined below in Table 1.
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Table 1
Study Treatment
Study 
Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Vaccination 
Regimen
Use
IMP/NIMP
Sourcing
9vHPV 
vaccine, also 
known as 
V503
Liquid in vial
HPV
6/11/16/18/31/
33/45/52/58
L1 VLP: 
30/40/60/40/
20/20/20/20/
20 mcg per 
dose
0.5 mL per 
dose
Intramuscular
injection
Day 1, Month 2,
and Month 6*
Experimental
IMP
Provided 
centrally by 
the Sponsor
Definition Investigational Medicinal Product (IMP) and Non- Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
*: For the first 25 participants enrolled in the 9-15 years old group, the safety from 1st dose through Day 15 following 2nd dose will be evaluated by a DMC. If the safety is 
favorable, this subset of participant will receive the 3rd dose and enrollment of the rest of participants in the 9-15 years old group will be initiated.
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All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible.
Refer to Section 8.1.11 for details regarding administration of the study treatment.
Preparation/Handling/Storage/Accountability
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
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Measures to Minimize Bias: Randomization and Blinding
Method of Treatment Assignment 
Participants participating in this study will be allocated by nonrandom assignment.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
Age: Enrollment of participants will be stratified into three age strata. A total of 1990 
participants will be enrolled, with 690 participants 9 to 19 years of age, 650 participants 20 to 
26 years of age and 650 participants 27 to 45 years of age.

Within 9-19 years old stratum, approximately 2:1 allocation will be applied based on 
two age subgroups: 9-15 years old and 16-19 years old.

Within 27-45 years old stratum, approximately 1:1 allocation will be applied based on 
two age subgroups: 27-35 years old and 36-45 years old.
Blinding 
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the vaccine administered.
Treatment Compliance
Interruptions from the protocol specified vaccination schedule (i.e. administration of 3 doses
at scheduled time points) for reasons not defined per protocol require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medication or vaccination specifically prohibited, discontinuation 
from study treatment 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 treatment requires the mutual 
agreement of the investigator, the Sponsor and the participant.
See the exclusion criteria for specific restriction for prior and concomitant medications at 
Day 1 (Section 5.2) and prerequisites for other vaccination visits (Section 8.10.1).
The participant should not receive systemic corticosteroids, immunosuppressive therapies, 
immune globulin or blood-derived products during Day 1 through 1 month post Dose 3 (Visit 
10) of the study, non-study inactivated or recombinant vaccines within 14 days prior to or 14 
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days after any dose of study vaccination, non-study live vaccines within 21 days prior to or 
14 days after any dose of 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 documented as described in 
Section 8.1.5.
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
Dose Modification  
Not Applicable.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment. Therefore, all participants who 
discontinue study treatment prior to completion of vaccination regimen will still continue to 
participate in the study as specified in Section 1.3 and Section 8.10.2.
Participants may discontinue study treatment at any time for any reason or be discontinued 
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.1.12.
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A participant must be discontinued from study treatment 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 treatment.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, see Section 1.3 and Section 8.10.2 for those procedures to be completed at each 
specified visit.
Participants may be allowed to begin study treatment again if deemed medically appropriate
with consultation from the Clinical Director.
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.12. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
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 assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent, and assent if 
applicable, be obtained from the participant. In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
The total maximum amount of blood collected from each participant for the immunogenicity 
objectives over the duration of Stage I, including any extra assessments that may be required, 
will not exceed approximately 20 mL.
The total maximum amount of blood collected from each participant for the immunogenicity 
objectives over the duration of Stage II, including any extra assessments that may be 
required, will not exceed approximately 50 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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Administrative and General Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical study. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
consent/assent is in place. 
General Informed Consent/Assent
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the participant must receive the
Institutional Review Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable 
opinion in advance of use. The participant 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 dated signature 
or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent/assent form 
template at the protocol level. 
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable, will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
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.
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 utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
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Card immediately after the participant provides written informed consent/assent. At the time 
of treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
At the Day 1 visit, the participant’s medical history for 5 years prior to Day 1 and lifetime
major medical history prior to Day 1 will be collected. The major medical history is defined 
as a medical condition in which emergency room visit, hospitalization and/or surgery were 
needed. For the participants who have had sexual intercourse prior to Day 1, lifetime 
gynecologic history will be collected at the Day 1 visit.
Other documentation, such as demographics, sexual history, pregnancy history, and 
contraceptive use, will be collected in the data collection system, as instructed in the 
electronic case report form entry guidelines.
Prior and Concomitant Medications Review
Prior Medications
See the exclusion criteria for specific restrictions for prior and concomitant medications at 
Day 1 (Section 5.2). Prior and concomitant use of medicines and non-study vaccines will be
reviewed at the specified study visits of Stage I (see Section 1.3) and should be documented
in the data collection system by the investigator or qualified designee in the following 
manner:

“Special medications” (corticosteroids, immunosuppressive therapies, immune 
globulins, and blood-derived products) from the year prior to Day 1 through Visit 
10.

“Other medications” from 3 days prior to each study vaccination through 14 days 
after each study vaccination.

“Non-study inactivated or recombinant vaccines” from 14 days prior to each 
study vaccination through 14 days after each study vaccination.

“Non-study live vaccines” from 21 days prior to each study vaccination through 
14 days after each study vaccination.
Concomitant Medications
The investigator or qualified designee will record concomitant medication, if any, taken by 
the participant during the study as outlined above.
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For the specific case where a participant mistakenly receives a non-study HPV vaccine at any 
time during the study, the non-study HPV vaccine should be documented in the data 
collection system.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation. Each 
participant will be assigned only one screening number. Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Physical Examinations
A physical examination will be conducted at Day 1 for all participants, and at Visit 6 (Month 
2.5) for the first 25 participants enrolled in the 9-15 years old group, for whom the safety will 
be reviewed by the DMC. Height and weight will only be measured at Day 1.
Physical examination details will be documented in the participant’s study chart and any 
medical condition will be documented in the data collection system. Height and weight will 
be documented in the data collection system.
Axillary Temperature and Blood Pressure Prior to Study Vaccination
Axillary temperature and blood pressure will be taken before study vaccination at Visit 1, 
Visit 4, and Visit 8.
If the participant has a fever (defined as an axillary temperature of ≥37.1°C) within the 24-
hour period prior to vaccination, the vaccination should be rescheduled after the fever has 
resolved.
Axillary temperature will be documented in the data collection system and blood pressure
will be documented in the participant’s study chart.
Pregnancy Testing Prior to Study Vaccination
All female participants of childbearing potential will have a urine or serum pregnancy testing
at each vaccination visit (i.e. Visit 1, Visit 4, Visit 8) (see Section 10.2 - Appendix 2). 
The pregnancy testing results must be obtained prior to each study vaccination (on the day 
the participant is vaccinated). Any participant found to be pregnant at the Day 1 visit will not 
be allocated and will not participate in the study.
Management of study visits and study vaccination for enrolled participants who become 
pregnant after the Day 1 visit is summarized in Table 10 (see Section 10.2 - Appendix 2).
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Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Although 
treatment is allocated by non-random assignment, the numbers assigned are called 
“treatment/randomization numbers” in the protocol. The treatment allocation will occur 
centrally using an interactive response technology (IRT) system. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Study vaccine(s) should be prepared and administered by appropriately qualified members of 
the study personnel (e.g. physician, nurse, physicians' assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local, state country and intuitional guidance.
Study vaccine should not be used for any purpose other than that stated in the protocol.
The first dose of study vaccine will be administered at Day 1 (Visit 1), which should be the 
day of allocation. The second and third (final) doses of study vaccine will be administered 
subsequently at Visit 4 and Visit 8, respectively. All 3 doses should be administered within 1 
year as shown in the SoA (Section 1.3).
All the study-related procedures for Day 1 visit except informed consent/assent, baseline 
number assignment, participant identification card, should be performed on the same day as
and prior to the first study vaccination.
The interval between the date of consent and the date of the Day 1 visit should be no more 
than 14 days apart. If the interval is 15 days or longer, then the participant must be re-
consented. 
Participants should not be enrolled or vaccinated if protocol requirements are not met. At 
Day 1, study vaccine should be administered after the blood draw for anti-HPV antibody 
testing (see Section 8.2.1). Section 8.10.1 provides additional information on other 
prerequisites for vaccination visits.
Preparation of Study Vaccine for Administration
The study vaccine may be removed from the refrigerator and allowed to sit at room 
temperature for no longer than 15 minutes prior to administration. 
Study vaccine must be used as supplied (no dilution before administration). Prior to
administration, mix the contents of the vial thoroughly by rolling the vial between the palms
of both hands for 30 seconds. Withdraw a 0.5-mL dose from the vial, which contains
approximately 0.75 mL of study vaccine. After mixing, the study vaccine will appear as a
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whitish, semi-translucent suspension. If the appearance is otherwise, do not administer and
contact the Sponsor immediately.
Study Vaccine Administration
At each vaccination visit, participants will receive study vaccine as a 0.5-mL intramuscular 
injection. The deltoid muscle of the nondominant arm is the preferred site of vaccination. 
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 
administered in the deltoid muscle with the following needle length and gauge specifications: 
1-inch needle, 22 to 23 gauge, for participants weighing < 90 kg; 1½-inch needle, 22 to 23 
gauge, for participants weighing ≥90 kg. If the injection is given in the thigh, a 1½ -inch 
needle, 22 to 23 gauge should be used.
Study vaccination should not be administered in the buttocks area. Injections should not be 
given within 2 cm of a tattoo, scar, or skin deformation.
All participants will be observed for at least 30 minutes after each vaccination. This 
observation period will be documented for any immediate reaction with particular attention 
to any evidence of allergic phenomena.
Timing of Dose Administration
Study vaccine will be administered at Visit 1, Visit 4, and Visit 8, as shown in the SoA (See 
Section 1.3).
Acceptable day ranges for vaccination visits are as follows: 

Dose 1: Day 1 (±0 days)

Dose 2: 40 to 82 days after Dose 1

Dose 3: 155 to 364 days after Dose 1 (The interval between Dose 2 and Dose 3 
should be at least 3 months.)
The Day 1 visit is defined as the day that the first study vaccination is given (i.e., the date 
when Dose 1 of 9vHPV vaccine is injected).
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the vaccination regimen
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (Visit 10 is the final visit for Stage I, and Visit 15 is the 
final visit for Stage II) (exception for Stage I: serum collection should not be done at the final 
visit if the participant has not received all 3 doses of study vaccine) should be performed (at 
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the time of withdrawal). Any AEs which are present at the time of withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8.4 .
The final visit assessment for participant withdraws from the study can be done via a phone 
call.
Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Critical Equipment for this study includes:

Refrigerator equipped with an appropriate temperature monitoring device to ensure 
the temperature is maintained at 2°C to 8°C for storage of study vaccines.

Non frost-free freezer with an appropriate temperature monitoring device to ensure 
serum samples are stored at -20°C or colder until shipped to the Sponsor-designated
Central Laboratory.

Centrifuge for processing of blood samples.
Immunogenicity Assessments 
Serum for Anti-HPV Antibody Testing
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. For collection of the serum samples, the study sites must follow 
instructions provided by the Sponsor-designated Central Laboratory and must use the 
materials provided by the Sponsor-designated Central Laboratory. Samples should be 
shipped, labeled, and handled as instructed by the Sponsor/Central Laboratory. Specimen 
collection supplies provided by the Sponsor/Central Laboratory must be used by the site 
without substitution.
An approximate 10-mL blood sample will be collected from each participant at the scheduled 
time points (see Section 1.3) and serum will be separated for anti-HPV antibody 
measurements. 
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Immunogenicity Measurements
The 9-valent HPV competitive Luminex immunoassay (HPV-9 cLIA) will be used for the 
primary and secondary objectives of the study.
The purpose of the HPV-9 cLIA assay is to quantify the antibodies specific to the 
neutralizing epitopes of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. This assay is used by 
the Testing Laboratory to evaluate the serological response before and after vaccination with 
the 9vHPV vaccine and to measure HPV infection-induced antibodies for sero-epidemiology 
studies.
HPV virus-like particles (VLPs) derived from yeast for each of the 9HPV types are coupled 
to one of 9 distinct fluorescent Luminex MagPlex® magnetic microspheres. Each 
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 a human serum sample. HPV type-specific neutralizing monoclonal antibodies 
conjugated with phycoerythrin (PE-mAb conjugate) compete with the antibodies in the 
serum sample for binding to the neutralizing epitopes of the VLPs coupled to the 
microspheres. After incubation with PE-mAb conjugate and sample serum, the microspheres 
are washed and the fluorescent signal from the PE-mAb conjugate is read. The fluorescence 
signal is inversely proportional to the HPV antibody concentration of the serum sample 
tested. 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 
nine HPV types. A standard curve for each HPV type is calculated using a weighted 4-
parameter logistic curve fit. Antibody concentration results are expressed as milliMerck 
Units/mL (mMU/mL).
In this study, the 9-valent HPV total IgG Luminex immunoassay (HPV-9 IgG LIA) will be 
used as a secondary measurement, complementary to the cLIA. 
Yeast-derived VLPs are coupled to a set of 9 distinct fluorescent Luminex microspheres. 
Antibody concentrations are determined in a multiplexed, direct binding format by measuring 
the amount of VLP-specific IgG bound to VLP-microspheres on the Luminex platform. 
Following incubation with human serum, fluorescent signal from an anti-human IgG 
detection antibody that binds directly to serum IgG and equally to each IgG subclass (1-4) is 
directly measured on the Luminex or Bioplex instrument. The fluorescent signal from the 
IgG-bound fluorescent detection antibody is proportional to the individual’s HPV type-
specific anti-VLP IgG antibody levels. Results for the assay are reported as concentration of 
antibody in mMU/mL.
cLIA and IgG LIA will be performed at the Sponsor-designated Central Laboratory in China.
PBNA developed by NIFDC (Beijing, China) will be used in the exploratory analysis to 
characterize the immune responses to the 9 types of HPV vaccine following study 
vaccination. PBNA is an assay that functionally measures the full spectra of neutralizing 
antibodies to HPV. HPV pseudovirions are produced by co-transfecting the 293TT or 293FT 
human embryonic kidney cell line with an expression plasmid encoding the HPV L1 and L2 
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capsid genes and another encoding reporter gene. Pseudovirions of L1/L2 self-assemble and 
package a reporter plasmid within. Pseudovirions are incubated with 293TT or 293FT cell 
and when pseudovirions enter cells, report gene will be expressed. If neutralizing antibodies 
are present in the test sera, infection of cells by pseudovirions and subsequent expression of 
reporter gene is inhibited. The serum neutralization titers are defined as the 50% maximal 
inhibitory concentration (IC50).
Serum samples collected from a subset of participants will be tested by PBNA as described 
in Section 4.1 at NIFDC.
All the immunoassays listed above will be used for immunogenicity analyses through Stage I
and II.
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.
Vaccination Report Card and Patient Reported Outcome
All participants will receive a VRC at each study vaccination visit (Visit 1, Visit 4, and Visit 
8).
Using the VRC, participant or participant’s legally acceptable representative will be asked to 
record the following safety information: axillary temperature in the evening after each study 
vaccination and daily, at the same time of day whenever possible, for 7 days after each study 
vaccination; solicited injection-site AEs (injection-site redness, swelling, induration, and 
pain) from Day 1 through Day 8 after each study vaccination; any AEs from Day 1 through 
Day 31 after each study vaccination. Participant or participant’s legally acceptable 
representative will be asked to record concomitant medications and concomitant vaccinations 
for 15 days following each study vaccination on VRC. Medications taken by participants due 
to AEs during Day 16 through Day 31 after each study vaccination will also be collected on 
VRC.
VRCs will be returned for review on Day 9 (i.e. Visit 2, Visit 5, and Visit 9) and Day 32 (i.e. 
Visit 3, Visit 7, and Visit 10) after each study vaccination, respectively. The first 25 
participants enrolled in the 9-15 years old group will have an additional VRC return visit 
(Visit 6) to collect the safety data through Day 15 following the 2nd dose. 
Except Visit 10 (1 month post Dose 3) at which visit blood samples will be collected, the 
purpose of other VRC return visits is to review the VRCs, so out of windows will not be 
considered as protocol deviation for Visit 2, Visit 3, Visit 5, Visit 6, Visit 7, and Visit 9.
However, Visit 10 sample collection out of windows will be considered as a protocol 
deviation.
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Telephone contacts will be done around every week between Visit 2 and Visit 3, Visit 5 and 
Visit 7 (telephone contacts will be done after Visit 6 for the first 25 participants in the 9-15 
years old group), Visit 9 and Visit 10 until the VRCs are returned to remind the participants 
to record the VRC and answer any questions related to VRC.
SAEs, cancers, overdoses, pregnancy events, lactation events, and infant SAEs will be 
collected during the entire study period as instructed in the Section 8.4.
In addition, new medical conditions will be collected after the Day 1 visit throughout the end 
of study. At the specified visits, participants will be questioned regarding any new medical 
conditions that occurred since the last scheduled visit. The new medical conditions are any 
medical events which occur after entry into the study and have not been reported as an 
adverse event (i.e., events that occur outside of the period of 31 days after each vaccination 
and are not reported as SAEs). A condition reported as medical history at Day 1 is not 
reportable as new medical condition. However, a medical condition which has been reported 
as medical history at Day 1 but aggravates during the study and is not reported as an AE or 
SAE should be reported as new medical condition. Unlike AE, relationship to study vaccine 
will not be evaluated for new medical conditions.
Post-vaccination Observation Period (30 minutes)
All participants will be observed for at least 30 minutes after each study vaccination for any 
immediate untoward effects with particular attention to any evidence of allergic phenomena. 
This observation period will be documented in the participant’s study chart.
Clinical Safety Laboratory Assessments
●
There are no protocol specified laboratory assessments in this study.
●
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).
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Section 10.3 - Appendix 3.
AE, 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 AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization must be reported by the investigator if they cause the 
participant to be excluded from the study, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
From the time of allocation/randomization through 30 days following the first vaccination(s) 
and from the time of any subsequent vaccination(s) through 30 days thereafter, all AEs, 
SAEs and other reportable safety events must be reported by the investigator. 
SAEs (regardless of causality) at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor. Other reportable safety events 
(cancer, pregnancy, breastfeeding exposure, and overdose) at any time outside of the time 
period specified in the previous paragraph should also be reported to the Sponsor. In 
addition, SAEs of infants born to participants who received the study vaccine or who were 
breastfed during the study are reportable for the entire study period.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment 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 2.
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Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Time Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
After the 
Protocol 
Specified 
Follow-up 
Period
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report all
Within 24 hours of 
learning of event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Report all
Within 24 hours of 
learning of event
Event of Clinical 
Interest
There are no ECIs for this study
Not applicable
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Report all
Within 5 calendar 
days of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Report all
Within 5 calendar 
days of learning of 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
A VRC will be used by the participant to document any AEs within 30 days (Days 1-31) 
following each study vaccination.
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Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy (if the participant received at least 1 vaccine dose) and exposure during 
breastfeeding, Cancer and Overdose will be followed until resolution, stabilization, until the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
7.3). In addition, the investigator will make every attempt to follow all nonserious AEs that 
occur in randomized participants for outcome. Further information on follow-up procedures 
is given in Section 10.3 - Appendix 3. Both Sponsor’s criteria (Section 10.3 - Appendix 3)
and CFDA (China Food and Drug Administration)’s criteria (Section 10.4 - Appendix 4) will 
be applied to assess the intensity/toxicity of adverse events by investigator.
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment 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 treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable to this study.
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 (in participants who received at least 1 vaccine dose) must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
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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.
All participants of childbearing potential will undergo a urine or serum pregnancy testing
prior to each study vaccination (see Section 1.3, Section 10.2 - Appendix 2). Participants 
found to be pregnant at Day 1 are not eligible to participate in the study (Section 5.2). 
Participants who inadvertently become pregnant before receiving all 3 doses of vaccine do 
not receive additional doses until ≥4 weeks after resolution of pregnancy and normalization 
of β-hCG levels as described in Table 10 (Section 10.2 - Appendix 2). Breastfeeding is not a 
contraindication to enrollment or to receiving study vaccinations. Pregnancy and 
breastfeeding in study participants and SAEs of infants born to participants who received the 
study vaccine or who were breastfed within the protocol pre-defined period must be reported 
as described in Section 8.4.1.
Events of Clinical Interest (ECIs)
There are no ECIs for this study.
Treatment of Overdose
In this study, an overdose is defined as a participant receiving >1 dose of study vaccine in a 
24-hour period or >3 doses of study vaccine throughout the study. 
Sponsor does not recommend specific treatment for an overdose.
Pharmacokinetics
PK parameters will not be evaluated in this study.
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Biomarkers
Biomarkers are not evaluated in this study.
Future Biomedical Research Sample Collection 
Future biomedical research samples will not be collected in this study.
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
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Prerequisites for Vaccination Visits
This section summarizes prerequisites for visits with study vaccinations and specimen 
collection. Deviations from these prerequisites require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision.
See the inclusion/exclusion criteria for specific restrictions at Day 1 (see Section 5.1.1 and
Section 5.2). At the Dose 2 and Dose 3 study vaccination visits (Visit 4 and Visit 8), study 
personnel should verify by questioning the participant and/or by examination that: 
1. The participant has not had a fever (defined as an axillary temperature of ≥37.1°C) 
within the 24-hour period prior to the Dose 2 or Dose 3 study vaccination visit.
2. The participant has not received any systemic (oral or parenteral) corticosteroids 
within 2 weeks prior to the Dose 2 or Dose 3 study vaccination visit.
3. The participant has not received a non-study inactivated or recombinant vaccine 
within 14 days prior to the Dose 2 or Dose 3 study vaccination visit or a non-study 
live vaccine within 21 days prior to the Dose 2 or Dose 3 study vaccination visit.
4. The participant of childbearing potential is not pregnant as determined by a urine or 
serum pregnancy testing (see Section 10.2 - Appendix 2).
If the participant does not meet the requirements listed above, the study visit (including 
specimen collection and study vaccination) should be rescheduled.
Discontinued Participants Continuing to be Monitored in the Study
During Stage I, participants who discontinue study vaccinations but continue in the study 
may attend study visits per the SoA (Section 1.3). However, serum samples will not be 
collected at Visit 10 from participants who did not complete the 3-dose regimen of study 
vaccination.
Participants 9 to 19 years of age who did not complete the 3-dose regimen of study vaccine 
will not be eligible for participation into Stage II (see Section 5.1.2 for Inclusion Criteria of 
Stage II).
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any final database lock, changes made to primary (H1/H2)
and/or secondary (H3/H4) 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 non-confirmatory analyses made after the protocol has been finalized, 
but prior to final database lock, will be documented in a supplemental Statistical Analysis 
Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design 
Overview
A Phase 3 Open-Label Clinical Trial to Study the Immunogenicity 
and Safety of a 9-Valent Human Papillomavirus (HPV) L1 Virus-
Like Particle (VLP) Vaccine (V503) in Chinese females 9 to 45 
Years of Age
Treatment
Assignment
All enrolled participants will receive a 3-dose regimen of 9vHPV 
vaccine. The first 25 participants enrolled in the 9-15 years old 
group will receive Dose 3 if the safety from Dose 1 through 15 
days post Dose 2 is acceptable by DMC. Stratification factors are 
provided in Section 6.3.1.1.
Analysis 
Populations
Immunogenicity: Per-protocol immunogenicity (PPI) population
Safety: All Participants as Treated (APaT) population
Primary 
Endpoint(s)
Stage I:
(1) H1 (9-19 years old vs. 20-26 years old): cLIA antibody titer 
to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58;
(2) H2 (27-45 years old vs. 20-26 years old): cLIA antibody 
seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58.
Secondary 
Endpoints
Stage I:
(1) H3 (9-19 years old vs. 20-26 years old): cLIA antibody 
seroconversion to each of HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58;
(2) H4 (9-15 years old vs. 20-26 years old): cLIA antibody titer to 
each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58.
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Statistical 
Methods for Key 
Immunogenicity 
Analyses
Stage I:
(1) H1: 9vHPV vaccine induces non-inferior immune responses 
in females 9 to 19 years of age who are seronegative at Day 1 
to the relevant HPV type compared to females 20 to 26 years 
of age who are seronegative at Day 1 to the relevant HPV 
type, as measured by anti-HPV 6, 11, 16, 18, 31, 33, 45, 52,
and 58 GMTs at 1 month post Dose 3. (Each vaccine 
component will be analyzed separately. The statistical 
criterion for non-inferiority requires that the lower bound of 
two-sided 97.5% confidence interval of GMT ratio (females 9 
to 19 years of age vs. females 20 to 26 years of age) be greater 
than 0.67 for each HPV type.)
(2) H2: 9vHPV vaccine induces non-inferior immune responses 
in females 27 to 45 years of age who are seronegative at Day 
1 to the relevant HPV type compared to females 20 to 26 
years of age who are seronegative at Day 1 to the relevant 
HPV type, as measured by the seroconversion percentage to 
each of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 1 
month post Dose 3. (Each vaccine component will be 
analyzed separately. The statistical criterion for non-
inferiority requires that the lower bound of two-sided 97.5% 
confidence interval for the difference (females 27 to 45 years 
of age minus females 20 to 26 years of age) in seroconversion 
percentages be greater than -5% for each HPV type.)
Statistical 
Methods for Key 
Safety Analyses
Safety assessments will be descriptive in nature and will include 
calculation of proportions of participants with adverse events as 
well as 95% CI.
Interim Analyses
One interim analysis will be performed to evaluate the safety of the 
9vHPV vaccine in 25 participants aged 9-15 years from Dose 1 
through Day 15 post Dose 2. The safety data will be reviewed by a
DMC. If the safety data are judged to be acceptable, then 
enrollment will be initiated to the rest of participants in the 9-15
years old group.
Multiplicity
•
For the dual-primary hypotheses (H1 and H2), Bonferroni 
method is used to control overall one-sided type I error at level 
of 0.025. Each of the dual-primary hypotheses has a 0.0125 
one-sided type I error. Success criterion of the study is the 
success on either of the dual-primary hypotheses;
•
Fixed sequence testing strategy is used to control multiplicity
between primary hypothesis and secondary hypotheses.
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Sample Size and 
Power 
The planned sample size is 1990 female participants (9-19 years 
old: 690; 20-26 years old: 650; 27-45 years old: 650). The overall
power to claim the study success based on the dual-primary 
hypotheses is >0.999.
•
Approximately an overall 99.1% power for H1 to 
demonstrate that females aged 9-19 years is non-inferior to 
females aged 20-26 years in terms of cLIA GMTs at 1 month 
post Dose 3 at an overall one-sided 1.25% alpha-level; 
•
Approximately an overall 92.9% power for H2 to demonstrate 
that females aged 27-45 years is non-inferior to females aged 
20-26 years in terms of cLIA seroconversion percentages at 1 
month post Dose 3 at an overall one-sided 1.25% alpha-level.
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 is a non-randomized, open-label study, therefore participants, investigators, and 
SPONSOR personnel will be aware of participant treatment assignments when each 
participant is enrolled and treatment is assigned.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Analysis Endpoints
Immunogenicity Endpoints
Stage I (Day 1 to Visit 10)
The primary immunogenicity endpoints are cLIA antibody titer (for H1) and seroconversion 
(for H2) at 1 month post Dose 3 to each of 9 HPV types. Seroconversion is defined as
participant’s serostatus changing from seronegative at Day 1 to seropositive at 1 month post
Dose 3. A participant with a cLIA titer at or above the serostatus cutoff value for a given 
HPV type is considered seropositive for that type. The cLIA antibody titers at Day 1 will also 
be summarized.
The secondary immunogenicity endpoints are cLIA antibody seroconversion (for H3) and 
titer (for H4) to each of 9 HPV types.  
Anti-HPV antibody titer and seroconversion to each of 9 HPV types measured by IgG LIA 
will be summarized as secondary analyses of immunogenicity.
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The exploratory endpoints for immunogenicity include antibody titer and seroconversion to 
each of 9 HPV types measured by PBNA, which was developed and performed by NIFDC.
Stage II (post Visit 10 to Visit 15)
For the second stage of study, anti-HPV antibody titer and seropositivity at Visit 11, Visit 12, 
Visit 13, Visit 14, and Visit 15 measured by cLIA and IgG LIA will be summarized to
describe the persistence of the serum antibody responses to the 9 vaccine HPV types.
The exploratory endpoints for immunogenicity include PBNA antibody titer and 
seropositivity at Visit 11, Visit 12, Visit 13, Visit 14, and Visit 15.
Safety Endpoints
The key safety endpoints used to evaluate the safety of the 9vHPV vaccine will include 
proportions of participants with solicited injection-site AEs from Day 1 through Day 8 
following any study vaccination, solicited systemic AE (elevated axillary temperature (≥37.1
ºC)) from Day 1 through Day 8 following any study vaccination, proportions of participants 
with systemic AEs from Day 1 through Day 31 following any study vaccination, and 
proportion of participants experiencing SAEs at any time during the study. Pregnancy 
outcomes during the study will be summarized. Non-serious and serious adverse events and 
new medical conditions considered potentially indicative of autoimmune disorders will be 
analyzed as Conditions of Particular Attention (CPA) in this study as was done in previous 
9vHPV vaccine studies [Moreira, E. D., et al 2016].
Analysis Populations
Immunogenicity Analysis Populations
Per-Protocol Immunogenicity Population
The per-protocol immunogenicity (PPI) population will serve as the primary population for 
analysis of immune responses to the 9vHPV vaccine. To be included in this population, 
participants must:
(1) Have received all 3 study vaccinations with the correct dose of the correct clinical 
material, and each vaccination visit must occur within the vaccination visit window 
specified in Section 1.3 – SoA.
(2) Be seronegative at Day 1 for the HPV type being analyzed. In the analysis of HPV 
types 6 and 11, the participant must be seronegative to both HPV 6 and 11.
(3) Have provided post Dose 3 serum samples within the visit (i.e., Visit 10) window 
specified in Section 1.3 – SoA.
(4) Have no other protocol violation that could interfere with the evaluation of 
participant’s immune response to the study vaccine.
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All Type-Specific Naïve Participants with Serology Population
A supportive immunogenicity analysis will be carried out on the all type-specific naïve 
participants with serology (ANPS) population. To be included in this population, participants 
must:
(1) Have received all 3 study vaccinations.
(2) Be seronegative at Day 1 for the HPV type being analyzed. In the analysis of HPV 
types 6 and 11, the participant must be seronegative to both HPV 6 and 11.
(3) Have provided post Dose 3 serum samples.
Unlike the PPI population, the ANPS population will include participants who meet any 
exclusion criteria that were deemed to potentially interfere with the evaluation of immune 
responses to the 9vHPV vaccine. In addition, no day ranges on the timing of the vaccination
and post Dose 3 serum sample collection will be applied. 
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety 
data. The APaT population consists of all participants who received at least one dose of study 
vaccination and have clinical follow-up for safety.
Statistical Methods
This study composed of two stages with different objectives. Database will be locked and 
analysis will be conducted after completion of each stage. The immunobridging analysis of 
Stage I will be conducted when the last serological results at Day 1 and 1 month post Dose 3
of Stage I are available. The persistence of immunogenicity will be analyzed once the last 
serological results of Stage II are available. A separate report will be generated for Stage I 
and Stage II, respectively.
Statistical Methods for Immunogenicity Analyses
Stage I (Day 1 to Visit 10):
Two dual-primary hypotheses, H1 and H2 will share a one-sided alpha level 0.025. The 
success criterion of the study is the success on either of the dual-primary hypotheses. 
To test H1, the immune responses as measured by anti-HPV cLIA GMTs at 1 month post 
Dose 3 will be analyzed separately for each of 9 HPV types. The statistical criterion for non-
inferiority requires that the lower bound of two-sided 97.5% confidence interval of GMT 
ratio (9 to 19 years of age vs. 20 to 26 years of age) be greater than 0.67 for each HPV type. 
The primary hypothesis H1 will be considered a success if the non-inferiority criteria for 
GMTs are met for all 9 HPV types in the comparisons between females 9 to 19 years of age
vs. females 20 to 26 years of age. 
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For each HPV type, the hypothesis to be tested at α=0.0125 level (1-sided) are 
H0: GMT1/GMT2 ≤ 0.67
Ha: GMT1/GMT2 > 0.67
where GMT1 and GMT2 represent the GMTs at 1 month post Dose 3, in the 9-19 years old 
group and in the 20-26 years old group, respectively. The point estimate of GMT will be 
calculated by taking the anti-natural-logarithm of the arithmetic mean of the natural-
logarithm-transformed anti-HPV titers. The test above will be conducted using an ANOVA 
model with a response of log individual titers and a fixed effect for comparison group. 
To test H2, cLIA seroconversion percentages at 1 month post Dose 3 will be analyzed 
separately for each of 9 HPV types. The statistical criterion for non-inferiority requires that 
the lower bound of two-sided 97.5% confidence interval of seroconversion percentages (27
to 45 years of age minus 20 to 26 years of age) be greater than -5% for each HPV type. The 
primary hypothesis H2 will be considered a success if the non-inferiority criteria for 
seroconversion percentages are met for all 9 HPV types in the comparisons between 27 to 45
years of age vs. 20 to 26 years of age. 
The point estimate of seroconversion percentage for a particular HPV type is the ratio of the 
number of PPI-eligible participants for that particular HPV type who seroconverted to the 
relevant HPV type over the total number PPI-eligible participants for that particular HPV 
type.
For each HPV type, the hypothesis to be tested at α=0.0125 level (1-sided) are
H0: p1-p2 ≤ -0.05
Ha: p1-p2 > -0.05
where p1 is the proportion of participants who seroconvert by 1 month post Dose 3 in the 27-
45 years old group and p2 is the proportion of participants who seroconvert by 1 month post 
dose 3 in the 20-26 years old group. 
The tests above will be conducted using the method of Miettinen and Nurminen [Miettinen, 
O. and Nurminen, M. 1985]. The statistical criterion for non-inferiority requires that the 
lower bound of two-sided 97.5% confidence interval for the difference (27-45 years of age
minus 20-26 years of age) in seroconversion percentages being greater than -5 percentage 
points for each HPV type.
Anti-HPV GMTs and seroconversion percentages measured by IgG LIA will be summarized 
as secondary objective of immunogenicity.
PBNA results (GMTs and seroconversion percentages) will be summarized as exploratory 
objective and will be provided in a supplemental report after the data are available.
The extended visit window of study vaccination may result in different intervals between 
doses, which has real potential to alter the read-out of the anti-HPV titers compared to the 
read-out expected from the original designated regimen (0, 2, 6 months). Besides, It is not 
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guaranteed that the effect that the time interval between doses will have on anti-HPV titer 
read-outs will be the same in each of the age groups.  There is a real possibility that the 
variability of anti-HPV titers in each age group will affect the resulting GMTs in each age 
group in a way that the resulting GMT ratio is now different from the assumed GMT ratio 
used to power the non-inferiority hypothesis testing. If the shift in GMT ratio is in the 
direction greater than 1.0, the altered time interval between doses biased the hypothesis 
testing in favor of the age group represented by the numerator of the GMT ratio (i.e. 9-19 
years old or 27-45 years old group). If the shift in GMT ratio is in the direction less than 1.0, 
then there is a risk that the hypothesis test will become underpowered. And the other 
situation would be no meaningful shift in the GMT ratio between age groups. So to 
investigate the potential impact, a supportive analysis on PPI population will be performed 
by HPV type using the following stepwise regression models.

Step 1: A no-intercept regression model will be fitted on the natural logarithm of anti-
HPV cLIA titers at 1 month post dose 3 (as dependent variable Y) with the following 
independent variables:
o
X1: Indicator for 9-19 years of age (X1=1 if 9-19 year-old, X1=0 if otherwise)
o
X2: Indicator for 20-26 years of age (X2=1 if 20-26 year-old, X2=0 if 
otherwise)
o
X3: Indicator for 27-45 years of age (X3=1 if 27-45 year-old; X3=0 if 
otherwise)
o
X4: Time (in months) from Dose 1 to Dose 2
o
X5: Time (in months) from Dose 2 to Dose 3

The regression coefficients associated with X1, X2, and X3 represent the expected 
GMTs in natural logarithm scale (or log-GMT) in each of the 3 age groups.

The regression coefficients associated with X4 and X5 represents the contribution of 
time interval between vaccinations on the expected log-GMTs.

The association of log-GMT with X4 and X5, in addition to (or over and above) the 
association of log-GMT with the protocol-specified age groupings will be evaluated 
as follows:
o
The partial correlation coefficient associated with X4 and X5, given X1, X2, 
and X3 are already in the model, will be calculated and provided.
o
The nominal statistical significance of X4 and X5, given X1, X2, and X3 are 
already in the model, will be evaluated. 

If X4 and X5 are nominally statistically significant (p-value ≤0.05), 
Step 2 outlined below will be performed.
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
If X4 and X5 are not nominally statistically significant (p-value > 0.05), Step 2 
outlined below will not be performed, and is an indication that there is no association 
between dosing interval and expected log-GMT. Step 2: The following explanatory 
variables will be added to the regression model specified in Step 1:
o
X1*X4: Time (in months) from Dose 1 to Dose 2 among 9-19 year-olds
o
X3*X4: Time (in months) from Dose 1 to Dose 2 among 27-45 year-olds
o
X1*X5: Time (in months) from Dose 2 to Dose 3 among 9-19 year-olds
o
X3*X5: Time (in months) from Dose 2 to Dose 3 among 27-45 year-olds

These 4 explanatory variables provide insight on whether the effect of dosing interval 
varies by age group. 

The association of log-GMT with X1*X4, X3*X4, X1*X5, and X3*X5, in addition to 
(or over and above) the association of log-GMT with the protocol-specified age 
groupings and dosing intervals, will be evaluated as follows:
o
The partial correlation coefficient associated with X1*X4, X3*X4, X1*X5, 
and X3*X5, given X1, X2, X3, X4, and X5 are already in the model, will be 
calculated and provided.
o
The nominal statistical significance of X1*X4, X3*X4, X1*X5, and X3*X5, 
given X1, X2, X3, X4, and X5 are already in the model, will be evaluated. 

A result indicating that X1*X4, X3*X4, X1*X5, and X3*X5 are 
nominally statistically significant at p-value ≤0.05 suggests that the 
effect of dosing interval on the expected cLIA anti-HPV GMT at 1 
month post dose 3 varies by age group.
Table 3 summarizes the immunobridging analyses for Stage I.
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Table 3
Analysis Strategy for Immunogenicity Variables – Stage I
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objectives
Anti-HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 cLIA GMTs at 1
month post Dose 3 (9-19yr vs. 
20-26yr). (Each type will be 
tested separately.)
P
Point and 97.5% CI 
estimations as well as 
statistical testing will 
be performed by using 
an ANOVA model.
PPI
Observed data 
only
cLIA % seroconversion to HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 
58 at 1 month post Dose 3 (27-
45yr vs. 20-26yr). (Each type 
will be tested separately.)
P
Point and 97.5% CI 
estimations as well as 
statistical testing of 
binomial proportion 
are based on 
Miettinen &
Nurminen method.
PPI
Observed data 
only
Anti-HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 cLIA GMTs at 
Day 1 and 1 month post Dose 3
(9-19yr vs. 20-26yr).
S
Point and 95% CI 
estimations will be 
provided by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
ANPS
Observed data 
only
cLIA % seroconversion to HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 
58 at 1 month post Dose 3 (27-
45yr vs. 20-26yr).
S
Point and 95% CI 
estimations are based 
on exact method; no 
statistical testing and 
between group 95% 
CI will be given.
ANPS
Observed data 
only
Secondary Objectives
cLIA % seroconversion to HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 
58 at 1 month post Dose 3 (9-
19yr vs. 20-26yr). (Each type 
will be tested separately.)
P
Point and 97.5% CI 
estimations as well as 
statistical testing of 
binomial proportion is 
based on Miettinen &
Nurminen method.
PPI
Observed data 
only
Anti-HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 cLIA GMTs at 1 
month post Dose 3 (9-15yr vs. 
20-26yr). (Each type will be 
tested separately.)
P
Point and 97.5% CI 
estimations as well as 
statistical testing will 
be performed by using 
an ANOVA model.
PPI
Observed data 
only
cLIA % seroconversion to HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 
58 at 1 month post Dose 3 (9-
15yr vs. 20-26yr).
S
Point and 95% CI 
estimations are based 
on exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Anti-HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 cLIA GMTs at 
Day 1 and 1 month post Dose 3
(27-45yr vs. 20-26yr).
S
Point and 95% CI 
estimations will be 
provided by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
Anti-HPV 6, 11, 16, 18, 31, 33, 
45, 52, and 58 IgG LIA GMTs 
at Day 1 and at 1 month post 
Dose 3.
S
Point and 95% CI 
estimations will be 
performed by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
IgG LIA % seroconversion to 
HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 at 1 month post 
Dose 3.
S
Point and 95% CI 
estimations are based 
on exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
Impact of the time between 
Vaccination 2 and 3 on anti-HPV 
6, 11, 16, 18, 31, 33, 45, 52, 
and 58 cLIA GMTs at 1 month 
post Dose 3 by HPV type
S
Stepwise regression 
models
PPI
Observed data 
only
  † P=Primary approach; S=Supportive approach.
ANPS = all type-specific naïve participants with serology; CI = confidence interval; GMT = geometric mean 
titer; PPI = per-protocol immunogenicity.
Stage II (post-Visit 10 to Visit 15):
In the second stage of study, participants 9 to 19 years of age enrolled in the Stage I who 
have completed 3 doses of study vaccination will be followed up to Visit 15 to evaluate the 
persistence of the serum antibody titers for each of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 
at Visit 11, Visit 12, Visit 13, Visit 14, and Visit 15. Both cLIA and IgG LIA will be used to 
measure GMTs and seropositivity percentages.
Table 4 summarizes the immunogenicity persistence analyses for Stage II.
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Table 4
Analysis Strategy for Immunogenicity Variables – Stage II
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
cLIA GMTs to HPV 6, 11, 16, 
18, 31, 33, 45, 52, and 58 at 
Visit 11, Visit 12, Visit 13, 
Visit 14, and Visit 15
P
Point and 95% CI 
estimation will be 
performed by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
cLIA % seropositivity to HPV 6, 
11, 16, 18, 31, 33, 45, 52, and 
58 at Visit 11, Visit 12, Visit 
13, Visit 14, and Visit 15
P
Point and 95% CI 
estimation based on 
exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
IgG LIA GMTs to HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58 at 
Visit 11, Visit 12, Visit 13, 
Visit 14, and Visit 15
P
Point and 95% CI 
estimation will be 
performed by using an 
ANOVA model; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
IgG LIA % seropositivity to 
HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 at Visit 11, Visit 12, 
Visit 13, Visit 14, and Visit 15
P
Point and 95% CI 
estimation based on 
exact method; no 
statistical testing and 
between group 95% 
CI will be given.
PPI
Observed data 
only
  † P=Primary approach.
ANPS = all type-specific naïve participants with serology; CI = confidence interval; GMT = geometric mean 
titer; PPI = per-protocol immunogenicity.
PBNA results (GMTs and seropositivity percentages) will be summarized as exploratory 
objective and will be provided in a supplemental report after the data are available.
Statistical Methods for Safety Analyses
Safety will be assessed by statistical and clinical review of all safety data collected 
throughout the study. All participants who are vaccinated and who have safety follow-up data 
will be included in the safety analyses and summaries. To provide an overall assessment, 
safety measures that occurred in the pre-defined time interval during the study will be 
summarized, such as the incidence of
1. any adverse events;
2. any injection-site adverse events;
3. any systemic adverse events; 
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4. any serious adverse events;
5. any vaccination-related adverse events;
6. any vaccination-related serious adverse events;
7. conditions of particular attention (CPA*); 
8. pregnancy outcomes;
9. new medical conditions.
*: More details about CPA will be provided in the sSAP.
Stage I (Day 1 to Visit 10):
Summary statistics, counts and percentages and 95% confidence interval will be provided by 
age groups: (1) 9- to 19-year-old group; (2) 20- to 26-year-old group; and (3) 27- to 45-year-
old group which are summarized in Table 5.
Table 5
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 
95% CI
Descriptive 
Statistics
Injection-site adverse events prompted for on the VRC occurring 
Day 1 to Day 8 following any vaccination
×
×
Solicited systemic AE (elevated axillary temperature (≥37.1ºC))
from Day 1 through Day 8 following any vaccination
×
×
Injection-site adverse events not prompted for on the VRC occurring 
Day 1 to Day 8 following any vaccination in ≥1% of participants in 
any age group
×
×
Systemic adverse events in ≥1% of participants in any age group 
within 30 days following any vaccination
×
×
Serious adverse events at any time during study
×
×
Vaccination-related serious adverse events observed at any time 
during the study
×
×
Injection-site severe or more adverse events (by CFDA grading 
scale) occurring Day 1 to Day 8 following any vaccination
×
×
Injection-site severe adverse events (by Merck grading scale) 
occurring Day 1 to Day 8 following any vaccination
×
×
Systemic severe or more adverse events (by CFDA grading scale) 
within 30 days following any vaccination
×
×
Systemic severe adverse events (by Merck grading scale) within 30 
days following any vaccination
×
×
Conditions of particular attention
×
×
All injection-site adverse events occurring Day 1 to Day 8 following 
any vaccination
×
All systemic adverse events within 30 days following any 
vaccination
×
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Both Sponsor’s criteria (Section 10.3 – Appendix 3) and CFDA’s criteria (Section 10.4 -
Appendix 4) will be applied to assess the intensity/toxicity of adverse events by investigator. 
The incidence of greatest intensity/toxicity based on the two criteria will be tabulated for
injection-site AEs and systemic AEs.
All pregnancy outcomes and infant SAEs will be summarized.
Stage II (post-Visit 10 to Visit 15):
Summary statistics, including counts and proportions of participants with SAEs during the 
entire period of Stage II will be summarized for 9-19 years old participants.
In addition, all pregnancy outcomes and infants SAEs will be summarized.
Summaries of Baseline Characteristics, Demographics, and other Analyses
Baseline characteristics, demographic variables, medical history, prior and concomitant 
therapies of females 9 to 45 years of age will be summarized using descriptive statistics or 
categorical tables. No statistical hypothesis tests will be performed on these characteristics. 
The number and percentage of participants screened, allocated, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. 
New medical conditions will be collected during the entire period of the study. However, the 
data of new medication conditions will be separately summarized for Stage I and Stage II. 
Interim Analyses
One interim analysis will be performed in this study to evaluate the safety of the 9vHPV 
vaccine from Dose 1 through Day 15 following Dose 2 in a subset of 25 participants aged 9-
15 years. The safety data will be reviewed by a DMC. If the safety data are judged to be 
acceptable in the opinion of the DMC, then these 25 participants will receive the 3rd dose at 
Visit 8 and the enrollment will be initiated to the rest of participants in the 9-15 years old 
group. Available safety data from the 16-26 years old group will be provided along with the 
subset of 25 participants in the 9-15 years old group in order for the DMC to complete their 
safety evaluation.
This study is composed of two stages. Database will be locked and analyses will be 
conducted after completion of each stage. A full CSR will be generated for Stage I and a 
supplemental statistical report will be generated for Stage II.
Multiplicity
Figure 2 shows the multiplicity strategy for the study. 
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Figure 2
Multiple Strategies to Control Overall Type One Error Rate
For the dual-primary hypotheses (H1 and H2), Bonferroni method is used to control overall 
one-sided type I error at level of 0.025. Each of the dual-primary hypotheses has a 0.0125 
one-sided type I error. The study would be successful if either H1 or H2 are met. If H1 is not 
met then no further testing (H3, H4) will be completed.
Fix sequence testing strategy is used to control multiplicity between dual-primary hypothesis 
(H1) and secondary hypotheses (H3 and H4). The testing order is as follows: H1 (GMT, 9-
19yr vs.20-26yr) will be tested firstly and if H1 wins H3 (seroconversion percentages, 9-19yr
vs. 20-26yr) will then be tested; if H3 wins H4 (GMT, 9-15yr vs. 20-26yr) will be tested.
Each one will be tested at a level of 0.0125. If anyone failed to reject null the subsequent
ones would not be tested.  
Furthermore, success is required on all 9 HPV types for hypotheses testing GMT and 
seroconversion percentages, so no multiplicity adjustment is needed to account for the 
multiple HPV types.
Sample Size and Power Calculations
Sample Size and Power for Immunogenicity
Approximately 1990 participants will be enrolled in the study with the following allocated 
sample sizes for each age group as: 690 participants in 9-19yr age group (460 in 9-15yr and 
230 in 16-19yr), 650 participants in 20-26yr age group, and 650 participants in 27-45yr age 
group. The overall power to claim the study success based on the dual-primary hypotheses is 
>0.999.
Two dual-primary hypotheses (H1 and H2) and two secondary hypotheses (H3 and H4) are 
considered when determine overall sample size and the sample sizes allocated to each age 
group. The calculations are based on the following assumptions: 
1) HPV Types 6, 11, 16, 18, 31, 33, 45, 52, 58 responses are identical in 9-15yr, 9-19yr,
and 20-26yr age groups;
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2) HPV Types 6, 11, 16, 18, 31, 33, 45, 52, 58 seroconversion percentages are identical 
in 9-19yr, 20-26yr, and 27-45yr age groups; 
3) The overall percentages of participants not eligible for per-protocol analyses for each 
HPV type are 15% in 9-15yr age group, 9-19yr age group, 30% in 20-26yr and 27-
45yr age groups which are calculated based on:

percentage of the participants are initially seropositive to each HPV type

expected attrition rate through 1 month post Dose 3 (Visit 10)

expected percentage of participants excluded due to vaccinations or serology 
samples out of range
4) The standard deviations of the natural logarithm of the Visit 10 titers are no more 
than 1.2 for each HPV type when expressed as mMU/mL, the unitage used in 
previous HPV vaccine studies;
5) Regarding to the dual-primary hypotheses (H1 and H2), Type I error will be 
controlled by Bonferroni Method, i.e. one-sided 0.0125 for each hypothesis.
The estimates of exclusion rates and standard deviation are based on the data from previous 
qHPV vaccine and 9vHPV vaccine studies.
The overall power to establish the non-inferiority of the dual-primary endpoints: (1) cLIA
GMTs in 9-19 yr vs. 20-26 yr; and (2) cLIA seroconversion percentages in 27-45yr vs. 20-
26yr will be at least 99.1% and 92.9% respectively, at a level of 0.0125. 
The overall power to establish the non-inferiority of the secondary endpoints: (1) cLIA
seroconversion percentages in 9-19yr vs. 20-26yr and (2) cLIA GMTs in 9-15yr vs. 20-26y 
will be at least 98.4% and 95.8% respectively, at a level of 0.0125. 
The detailed sample size and power results for immunogenicity endpoints are presented in 
Table 6, Table 7, and Table 8 by age groups.
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Table 6
Power for Non-Inferiority Comparison in 9-19yr Group vs. 20-26yr Group
GMT ratio (Dual-primary, H1)
Antigen
Assumed 
SD
Enrolled Sample Size
(9-19yr/20-26yr) 
Effective Sample Size
(9-19yr/20-26yr)
Power
Overall 
Power†
Each HPV 
Type
1.2
690/650
586/455
0.999
0.991
Seroconversion percentage difference (Secondary, H3)
Antigen
SR
Enrolled Sample Size 
(9-19yr/20-26yr) 
Effective Sample Size 
(9-19yr/20-26yr)
Power
Overall 
Power†
Each HPV 
Type
98%
690/650
586/455
0.998
0.984
Note: Non-inferiority margin for GMT ratio is 0.67; non-inferiority margin for seroconversion rate is -5%.
† Overall power is calculated by multiplying the power for each HPV type.  
Table 7
Power for Non-Inferiority Comparison in 9-15yr Group vs. 20-26yr Group
GMT ratio (Secondary, H4)
Antigen
Assumed 
SD
Enrolled Sample Size 
(9-15yr/20-26yr) 
Effective Sample Size 
(9-15yr/20-26yr)
Power
Overall 
Power†
Each HPV 
Type
1.2
460/650
391/455
0.995
0.958
Note: Non-inferiority margin for GMT ratio is 0.67.
† Overall power is calculated by multiplying the power for each HPV type.  
Table 8
Power for Non-Inferiority Comparison in 27-45yr Group vs. 20-26yr Group
Seroconversion percentage difference (Dual-primary, H2)
Antigen
SR
Enrolled Sample Size 
(27-45yr/20-26yr) 
Effective Sample Size 
(27-45yr/20-26yr
Power
Overall 
Power†
Each HPV 
Type
98%
650/650
455/455
0.992
0.929
Note: Non-inferiority margin for seroconversion percentage is -5%;
† Overall power is calculated by multiplying the power for each HPV type.  
The original GMT values are log transformed before analysis. As such, the CI for the means 
and the non-inferiority margin will be constructed on the natural log scale. The calculations
are based on two-sample t-test and are carried out using PASS 2008. The minimum criterion 
for success is that the lower bound of two-sided 97.5% CI of difference between natural-log-
transformed GMTs > log (0.67). Given the assumed SD of the natural-log-transformed titers
at 1 month post Dose 3, this may occur when the observed difference between treatment 
groups is approximately log (0.82) or larger. 
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The calculations of power and sample sizes for seroconversion percentages are based on an 
asymptotic method proposed by Miettinen and Nurminen (1985) [Miettinen, O. and 
Nurminen, M. 1985] and are carried out using PASS 2008. The minimum criterion for 
success is that the lower bound of two-sided 97.5% CI of difference > -5%. Given the 
assumed seroconversion percentage 98%, this may occur when the observed difference in 
response rates is approximately -3% or larger. 
Sample Size and Power for Safety
The probability of observing a specific AE in this study depends on the number of vaccinated 
participants with safety follow-up and the underlying incidence of that specific AE in the 
study population. 
Across seven clinical studies in the 9vHPV vaccine program, 356 of 15,778 (2.3%) 
individuals who were administered vaccine and had safety follow-up reported a SAE; 
0.044% (7 out of 15,778) reported at least one SAE determined to be vaccine related 
[Moreira, E. D., et al 2016]. 
Assuming that all 650 participants enrolled in this study will have safety follow-up, then 
there is a greater than 99.9% chance of observing at least one SAE; and 24.9% chance of 
observing at least one vaccine related SAE, on at least one of the 650 participants. If no 
vaccine-related SAEs are observed among the 650 participants, this study will provide 95% 
confidence that the underlying percentage of participants with vaccine-related SAE is 
<0.46% (1 in every 217 participants) among vaccinated participants. This is based on 
calculation of a 1-sided 97.5% upper confidence limit of a binomial proportion using the 
exact binomial method of Clopper and Pearson [Clopper, C. J. 1934].
Subgroup Analyses
Age groups, 9-19yr, 20-26yr and 27-45yr will be subgroup factors for this study. Age group 
9-15 yr will also be analyzed for the secondary immunogenicity and safety objectives.
Compliance (Medication Adherence)
Compliance is defined in this study as receipt of all scheduled study vaccinations. To 
summarize compliance, the numbers of participants who receive each vaccination will be 
tabulated. Compliance with the planned vaccination schedule (Visit 1, Visit 4 and Visit 8) 
will be described by histograms of actual intervals between vaccinations relative to the 
expected interval.
Extent of Exposure
As indicated in Section 8.1.11, each study participant is planned to be administered 0.5 mL 
of 9vHPV vaccine at each vaccination visit. Thus, each participant is expected to be 
administered a total of 1.5 mL of 9vHPV vaccine.
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10. Supporting Documentation and Operational Considerations
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to 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 
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reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. 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.
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.
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B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (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.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which 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.
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 
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considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
Confidentiality of 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 in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the study.
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (see Section 9.7
Interim Analyses) and recommend to the EOC whether the study should continue in 
accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
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Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and 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.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
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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. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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Appendix 2:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described Table 9 in consistently and correctly from Day 1 
through 1 month post Dose 3 (Visit 10).
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Table 9
Contraceptive Methods
Acceptable Contraceptive Methods  
Failure rate of >1% per year when used consistently and correctly. 
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b 
●
Intrauterine hormone-releasing system (IUS)  
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) Typical use failure rates are higher than perfect-use failure rates (i.e., when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
All female participants of childbearing potential will have a urine or serum pregnancy testing
(sensitive to 25 mIU/mL beta human chorionic gonadotropin [β-hCG]) performed at each 
vaccination visit (i.e. Visit 1, Visit 4, Visit 8) per the manufacturer’s instructions. 
The pregnancy testing results must be obtained prior to each study vaccination (on the day 
the participant is vaccinated). Any participant found to be pregnant at the Day 1 visit will not 
be allocated and will not participate in the study. 
For enrolled participants who become pregnant after receiving one or two study vaccination, 
study visits and vaccination will be paused until resolution of the pregnancy (e.g. term, 
elective termination, spontaneous abortion). Study visits and study treatment in pregnant 
participants will be handled as described in Table 10.
Table 10
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations
Visit where pregnancy is 
detected
Action
Day 1
(before first vaccination)

Do not enroll participant.
Between Day 1 and Visit 4
(After study vaccine Dose 1 
and before study vaccine Dose 
2 was administered)

No scheduled visits (excluding VRC return visits) until 
resolution of the pregnancy (e.g., term, elective termination, 
spontaneous abortion).

The Dose 2 study vaccination should be administered at least 
4 weeks following resolution of pregnancy and after 
normalization of β-hCG levels.

The Dose 3 study vaccination should be administered 4 
months after the Dose 2 study vaccination.

Visit 10 should be conducted 1 month after the Dose 3 study 
vaccination.
Between Visit 4 and Visit 8
(After study vaccine Dose 2 
and before study vaccine Dose 
3 was administered)

No scheduled visits (excluding VRC return visits) until 
resolution of the pregnancy (e.g., term, elective termination, 
spontaneous abortion).

The Dose 3 study vaccination should be administered at least 
4 weeks following resolution of pregnancy and after 
normalization of β-hCG levels.

Visit 10 should be conducted 1 month after the Dose 3 study 
vaccination.
After Visit 8
(After study vaccine Dose 3 
was administered)

Continue with scheduled study visits during the pregnancy.

Safety follow-up will be conducted after resolution of the 
pregnancy (e.g., term, elective termination, spontaneous 
abortion).
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Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment 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 
treatment 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 
of study treatment without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to Section 8.4.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of an MSD product and is documented in the patient’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) which 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
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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 one 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.
Additional Events Reported
Additional events which 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.
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.
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Assessment of intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. (for pediatric studies, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. (for pediatric studies, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric studies, extremely distressed or unable to do usual activities).
●
Injection site redness or swelling within 7 days post each vaccination will be 
evaluated by maximum size.
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE will 
be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialled document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test 
product and the AE based upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor's product caused the AE:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily 
specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a vaccine-induced effect?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
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●
Rechallenge: Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF 
REQUIRED, THE IRB/IEC. 
●
Consistency with Study treatment Profile:
Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable. 
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
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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.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
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 Trial File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 4: Country-specific Requirements
China Food and Drug Administration (CFDA)’s Criteria on Assessment of Toxicity of 
Adverse Events
Guideline of the Grading Standards for Adverse Events Toxicity in Clinical Trials on 
Prophylactic Vaccines
Foreword
Vaccines are a class of special drugs usually used in healthy population to prevent diseases. 
Healthy subjects are selected for the clinical trials at different stages on the majority of 
prophylactic vaccines, and most prophylactic vaccines are used in healthy children. 
Therefore, safety concerns in the process of clinical studies of prophylactic vaccines are 
particularly important, and the requirements should be higher than those for general 
therapeutic drugs. 
Standardized standards for the evaluation and grading of adverse events have been gradually 
widely used in the evaluation of safety of therapeutic drugs in patients with specific diseases, 
but these grading standards apply to patients who may experience adverse events mild, 
moderate or severe clinical or laboratory abnormalities in the disease process, so the 
parameters may not be suitable for healthy volunteers. The aim of this guideline in 
formulating grading standards for the adverse events of prophylactic vaccines is to minimize 
the risks for healthy subjects in clinical trials. The defined values of parameters adopted in 
such adverse events grading standards are based on experience obtained from clinical trials 
on already marketed vaccines and information that has been made public in combination with 
consideration of the current reality of China.  
1. Overview
This Guideline applies to innovative prophylactic vaccines, and is applicable to the 
evaluation of severity of clinical and laboratory abnormalities (i.e. strength of adverse 
reactions) occurring in clinical trials in which the subjects are healthy adults and adolescents. 
Meanwhile, it can serve as the unblinding standards stipulated in the design of clinical trials 
on general prophylactic vaccine, as well as the reference for whether to terminate clinical
studies. In addition, the uniform adverse events grading standards provided by this guideline 
are conducive for comparison of safety data of prophylactic vaccines between different 
treatment groups in the same clinical trial or between different clinical trials. 
Clinical trials on prophylactic vaccines should strictly comply with the Good Clinical 
Practices (GCP) and meet relevant regulatory requirements. Management regulations require 
that adverse events occurring in clinical studies of vaccines should be inspected by related 
regulatory authorities and monitored by related main bodies (registration applicant, ethics 
committee and investigators), and appropriately reported for filing. 
Investigators of clinical trials on prophylactic vaccines must timely, comprehensively, 
objectively and accurately record all safety observation values and related data for evaluation 
of adverse events or adverse reactions; registration applicants must monitor the entire process 
of clinical studies. These adverse reaction grading standards are conducive for safety 
monitoring, timely judgment and appropriate reporting as required.
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The aim of this Guideline and guidelines related to clinical trials on vaccines that have been 
issued are to provide references for the evaluation of safety of prophylactic vaccines for 
clinical trials, and the classification and grading standards for adverse reactions here provide 
supplements to the integrity of safety data in clinical studies.
2. Basic Contents
The grading indicators for adverse reactions in clinical trials on prophylactic vaccines
provided by this Guideline include two parts (see details in the toxicity grading table). One 
part is clinical indicators (local reactions, systemic reactions, vital sign measurements), and 
the other part is laboratory indicators (blood chemistry, hematology and urinalysis), but not 
all safety indicators to be observed in clinical trials on prophylactic vaccines have been 
covered herein. For some special vaccines in the process of development, additional 
monitoring indicators may need to be added, or the specific defined values of parameters in 
the tables should be modified. For example, extra parameters are based on safety suggestions 
in pre-clinical toxicological studies or experience from previously marketed similar products.
Appropriate observation indicators may be selected from the adverse reactions grading tables 
herein according to the characteristics of different vaccines for clinical trials, and reasonable
safety monitoring and evaluation should be performed according to the respective 
characteristics of vaccines and disease prevalence.
(1) Adverse reactions grading tables
a. Clinical observation indicators (Table 11~Table 13)
Table 11
Local Reactions Grading
Local 
reactions
Mild 
(Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-threatening
(Grade IV)
Pain
Does not affect 
activities
Affects activities 
or requires 
repeated use of 
non-narcotic 
analgesics
Affects activities 
or requires 
repeated use of 
narcotic 
analgesics
Emergency treatment or 
hospitalization
Skin and 
mucosa
Redness and 
itching
Diffuse, 
maculopapular 
rash, dryness, 
desquamation
Blisters, 
dampness, 
desquamation or 
ulceration
Peeling dermatitis, mucosal 
involvement, or erythema 
multiforme, or suspected 
Stevens-Johnsons syndrome
Induration *
<15 mm
15~30 mm
>30 mm
Gangrene or exfoliative 
dermatitis
Redness*
<15 mm
15~30 mm
>30 mm
Gangrene or exfoliative 
dermatitis
Swelling**
<15 mm and 
does not affect 
activities
15~30 mm or 
affects activities
>30 mm or 
restrains daily 
activities 
Gangrene
Rash 
(injection site)
<15 mm
15~30 mm
>30 mm
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Local 
reactions
Mild 
(Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-threatening
(Grade IV)
Pruritus
Mild pruritus at 
the injection 
site
Moderate pruritus
of the injection 
limb
Systemic pruritus
* In addition to the grading and evaluation of local reactions by most directly measuring the diameter, the
development of and changes in the measurements should also be recorded. 
** The evaluation and grading of swelling should be based on the functional grades and actual measurements.
Table 12
Vital Signs Grading
Vital signs*
Mild 
(Grade I)
Moderate 
(Grade II)
Severe 
(Grade III)
Potentially life-threatening 
(Grade IV)
Fever, axillary 
temperature*
37.1~37.5°C
37.6~39.0°C
>39.0°C
Oral temperature
**
37.7~38.5
38.6~39.5°C
39.6~40.5°C
>40°C
Tachycardia 
(beats/min)
101~115
116~130
>130
Emergency treatment or 
hospitalization due to 
arrhythmia
Bradycardia 
(beats/min)
50~54
45~49
<45
Emergency treatment or 
hospitalization due to 
arrhythmia
Hypertension 
(systolic blood 
pressure 
mmHg)***
141~150
151~155
>155
Emergency treatment or 
hospitalization due to severe 
hypertension
Hypertension 
(diastolic blood 
pressure 
mmHg)***
91~95
96~100
>100
Emergency treatment or 
hospitalization due to severe 
hypertension
Hypotension 
(systolic blood 
pressure mmHg) 
***
85~89
80~84
<80
Emergency treatment or 
hospitalization due to 
hypotensive shock  
Respiratory 
frequency 
(times/min)
17~20
21~25
>25
Requires intubation
* It is cited from China’s Prophylactic Vaccination Manual. The subjects should be tested in a stationary state. 
** Oral temperature; the subjects should not drink cold or hot beverage or smoke before the detection. 
*** It is necessary to compare with baseline blood pressure value before the use of vaccines in order to 
determine blood pressure abnormalities for specific analysis.
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Table 13
Systemic Reactions Grading 
Systemic reactions
Mild (Grade I)
Moderate 
(Grade II)
Severe (Grade III)
Potentially life-
threatening (Grade IV)
Hypersensitivity
Itching without 
rash
Local urticaria
Extensive urticaria, 
angioedema
Severe
hypersensitivity
Headache
Does not affect 
activities and
require no 
treatment
Transient, slightly 
affects activities 
and requires 
treatment 
(repeated use of 
non-narcotic 
analgesics)
Significantly 
affects daily 
activities, with 
response to initial 
anesthetic 
treatment
Refractory, requires 
repeated anesthetic 
treatment. Emergency 
treatment or 
hospitalization
Fatigue, weakness
Normal activities 
were weakened 
for<48, and it 
does not affect 
activities
Normal activities 
were weakened by 
20%~50% for >48 
hours, and it 
slightly affects 
activities
Normal activities 
were weakened 
by>50%, and it 
significantly affects 
daily activities, 
making the subject 
unable to work
The subject cannot 
take care of 
himself/herself. 
Emergency treatment 
or hospitalization
Nausea, vomiting
Once to twice per 
24 hours, normal 
intake, does not 
affect activities
2~5 times/24 
hours, 
significantly 
decreased intake 
or restrained 
activities
> 6 times within 24 
hours, no significant 
intake, requires 
intravenous infusion 
Requires 
hospitalization or 
nutrition through other 
means due to 
hypotensive shock 
Diarrhea
Mild or transient, 
loose stool 2~3 
times/day, or 
mild diarrhea 
lasting < 1 week 
Moderate or 
continuous, 
4~5 times/day, or 
diarrhea lasting > 
1 week 
Watery stool > 6 
times/day, or 
bloody diarrhea, 
orthostatic 
hypotension, 
electrolyte 
imbalance, requires 
intravenous 
infusion > 2L
Hypotensive shock, 
requires 
hospitalization for 
treatment 
Myalgia
Does not affect 
daily activities
Muscle tenderness 
not at the injection 
site, slightly 
affects daily 
activities
Severe muscle 
tenderness, 
significantly affects 
daily activities
Significant symptoms, 
muscle necrosis, 
requires emergency 
treatment or 
hospitalization
Cough
Transient, does 
not require 
treatment
Persistent cough, 
and treatment is 
effective
Paroxysmal cough 
which cannot be 
controlled by 
treatment
Emergency treatment 
or hospitalization
Other discomfort 
or clinical adverse 
reactions 
(according to the 
corresponding 
determination 
standards) 
Does not affect 
activities
Slightly affects 
activities and does 
not require  drug 
treatment 
Significantly 
affects daily 
activities and 
requires  drug 
treatment
b. Laboratory indicators (Table 14~Table 16) 
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Since all laboratory indicators as reference standards must be determined according to the 
stipulated normal values, the range of stipulated normal values should be provided to prove 
their reasonableness and feasibility. The following indicators are for reference only. 
Table 14
Blood Chemistry Measurements Grading
Serum
Mild (Grade I)
Moderate (Grade II)
Severe (Grade III)
Potentially life-
threatening 
(Grade IV)
Liver function—
elevated ALT 
and AST caused 
by influencing 
factors
1.25~2.5 ×ULN*
2.6~5 
×ULN
5.1~10
×ULN
>10×ULN
Creatinine
1.1~1.5×ULN
1.6~3.0×ULN
3.1~6×ULN
>6×ULN
BUN
1.25~2.5×ULN
2.6~5×ULN
5.1~10×ULN
>10×ULN
Bilirubin: 
elevated due to 
influencing 
factors, but 
functional  test 
proves normal 
1.1~1.5×ULN
1.6~2.0×ULN
2.0~3.0×ULN
>3.0×ULN
Bilirubin: 
elevated due to 
influencing 
factors 
accompanied by 
elevated 
indicators for 
liver function test
1.1~1.25×ULN
1.26~1.5×ULN
1.51~1.75×ULN
>1.75×ULN
Pancreatic 
enzymes—
amylase, lipase
1.1~1.5×ULN
1.6~2.0×ULN
2.1~5.0×ULN
>5.0×ULN
CPK-mg/dL
1.25~1.5×ULN
1.6~3.0×ULN
3.1~10×ULN
>10×ULN
*“ULN”: Refers to the upper limit of normal
Table 15
Hematology Measurements Grading
Blood
Mild (Grade I)
Moderate 
(Grade II)
Severe (Grade 
III)
Potentially life-threatening 
(Grade IV)
Hemoglobin 
(female) (g/dL)
12.0~13.0
10.0~11.9
8.0~9.9
<8.0
Hemoglobin 
(female) and 
changes (gm/dL) 
compared to before 
trial
Growth~1.5
1.6~2.0
2.1~5.0
>5.0
Hemoglobin (male) 
(g/dL)
12.5~14.5
10.5~12.4
8.5~10.4
<8.5
Hemoglobin (male) 
and changes 
(gm/dL) compared 
to before trial
Growth~1.5
1.6~2.0
2.1~5.0
>5.0
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Blood
Mild (Grade I)
Moderate 
(Grade II)
Severe (Grade 
III)
Potentially life-threatening 
(Grade IV)
Leukocytosis 
(number/mm3)
>13,000/mm3
13,000~
15,000/mm3
15,000~
30,000/mm3
>30,000 
Leukopenia
(number/mm3)
2500~3500
1500~2499
1000~1499
<1000
Clotting time—
prolongation caused 
by influencing 
factors
1.0~1.10×ULN
1.11~1.20×ULN
1.21~1.25×ULN
>1.25×ULN
Partial 
thromboplastin 
time—prolongation 
caused by 
influencing factors
1.0~1.2×ULN
1.21~1.4×ULN
1.41~1.5×ULN
>1.5×ULN
“ULN”: Refers to the upper limit of normal 
Table 16
Urinalysis Measurements Grading
Urine
Mild 
(Grade I)
Moderate 
(Grade II)
Severe
(Grade III)
Potentially life-
threatening 
(Grade IV)
Protein
Trace
1+
2+
>2+
Urine glucose
Trace
1+
2+
>2+
Blood cells 
(microscopy)
number of red blood 
cells under each high-
power field (rbc/hpf)
1~10
11~50
>50 or/and 
densely 
distributed red 
blood cells
Hospitalization for 
treatment or requires 
infusion of blood cell 
concentrates
Grading indicators in the tables above are not recommended for safety monitoring of healthy 
volunteers in clinical trials on all vaccines, and do not include all safety monitoring 
indicators. It is recommended to select monitoring indicators to be used in subjects in clinical 
trials on the corresponding prophylactic vaccines.
Whereas some physiological indicators for healthy infants and young children are 
significantly different from those for adults, it is recommended to make appropriate
adjustments to such indicators combined with the specific conditions of clinical trials for 
specific applications. 
(2) General evaluation principles for the grading of adverse reactions 
For clinical abnormalities not involved in the above grading tables, adverse reactions should 
be graded and evaluated according to the following standards: 
Grade I, mild, short-term discomfort (<48 hours), requiring no medical treatment;
Grade II, moderate, mildly to moderately restrain daily activities, requiring no or only a little 
medical intervention; 
Grade III, severe, significantly restrains daily activities, requiring care of daily life and 
medical treatment, or maybe hospitalization;
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Grade IV, life-threatening, extremely restrains daily activities, significantly requiring care of 
daily life, medical treatment and hospitalization;
(3) Severe or life-threatening adverse reactions
In clinical studies of prophylactic vaccines, the strength of any clinical events identified by 
clinical physicians as severe or life-threatening should be considered as Grade IV, including 
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse 
bruising, numbness or paralysis, acute psychosis, severe depression, etc.
The discovery of severe or rare adverse reactions usually requires clinical studies with large 
sample sizes, and sometimes such reactions need to be further evaluated after marketing. 
However, in pre-marketing clinical studies, the sample size should be enlarged as much as 
possible in order to find uncommon or rare severe adverse reactions. For vaccines whose 
primary applicable population is healthy individuals including infants and young children, 
their safety requirements are stricter than those for other drugs, and more cautious 
considerations should be taken into account. If necessary, clinical studies with safety 
observation indicators as the clinical evaluation endpoints may be carried out, and the 
minimal sample size should meet the statistical requirements. 
The China Food and Drug Administration will make timely modifications and improvements 
to this Guideline according to the status of clinical studies of prophylactic vaccines.
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Appendix 5: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
all participants as treated
ASC-H
atypical squamous cells – cannot exclude HSIL
ASC-US
atypical squamous cells – undetermined significance
ANPS
all type-specific naïve participants with serology
-hCG
beta human chorionic gonadotropin
CAC
Clinical Adjudication Committee
CIN
cervical intraepithelial neoplasia
cLIA
competitive Luminex Immunoassay
CONSORT
Consolidated Standards of Reporting Trials
CPA
Conditions of Particular Attention
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
eCTA
exploratory Clinical Trial Application
CTFG
Clinical Trial Facilitation Group 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GMT
geometric mean titer
9vHPV
9-valent human papillomavirus
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Abbreviation
Expanded Term
qHPV
quadrivalent human papillomavirus
HIV
human immunodeficiency virus
HPV
human papillomavirus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVIG
intravenous gamma globulin
JRA
juvenile rheumatoid arthritis
NDA
New Drug Application 
NIFDC
National Institutes for Food and Drug Control
NIMP
Non-Investigational Medicinal Product
PBNA
pseudovirion-based neutralization assay
PK
pharmacokinetic
PPI
per-protocol immunogenicity
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SIL
squamous intraepithelial lesion
SLE
systemic lupus erythematosus
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
UDS
urine drug screen
VaIN
vaginal intraepithelial neoplasia
VIN
vulvar intraepithelial neoplasia
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Abbreviation
Expanded Term
VLP
virus-like particle
VRC
vaccination report card
WOCBP
woman/women of childbearing potential 
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11.
References
[Center for Drug 
Evaluation and Research 
2014]
Center for Drug Evaluation and Research 
(CDER). Summary basis for regulatory action -
Gardasil 9 [Internet]. Maryland: Department of 
Health and Human Services, Food and Drug 
Administration; 2014. Available from: 
http://www.fda.gov/downloads/BiologicsBloodV
accines/Vaccines/ApprovedProducts/UCM42823
9.pdf .
[04LNXC]
[Chen, X., et al 2017]
Chen X, Xu H, Xu W, Zeng W, Liu J, Wu Q, et 
al. Prevalence and genotype distribution of 
human papillomavirus in 961,029 screening tests 
in southeastern China (Zhejiang Province) 
between 2011 and 2015. Sci Rep. 2017 Nov 
1;7(1):14813.
[04V4HF]
[Clopper, C. J. 1934]
Clopper CJ, Pearson ES. The use of confidence 
or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
[03Q0LW]
[European Medicines 
Agency 2016]
European Medicines Agency. Gardasil 9 -
Human papillomavirus 9-valent vaccine 
(recombinant, adsorbed) (EMA/192711/2016) 
[Internet]. London: European Medicines 
Agency; 2016. 4 p. Available from: 
http://www.ema.europa.eu/docs/en_GB/docume
nt_library/EPAR_-
_Summary_for_the_public/human/003852/WC5
00189114.pdf .
[04LNX8]
[Guo, W., et al 2012]
Guo W, Wu Z, Qiu Y, Chen G, Zheng X. The 
timing of sexual debut among Chinese youth. Int 
Perspect Sex Reprod Health. 2012 
Dec;38(4):196-204.
[04V4JB]
[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]
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Product: V503 
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[Luxembourg, A., et al 
2015]
Luxembourg A, Brown D, Bouchard C, Giuliano 
AR, Iversen OE, Joura EA, et al. Phase II studies 
to select the formulation of a multivalent HPV
L1 virus-like particle (VLP) vaccine. Hum 
Vaccin Immunother. 2015 Apr 27:0. [Epub 
ahead of print].
[045TBW]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative analysis 
of two rates. Statistics in Medicine 1985;4:213-
26.
[03NTPN]
[Moreira, E. D., et al 
2016]
Moreira ED Jr, Block SL, Ferris D, Giuliano 
AR, Iversen OE, Joura EA, et al. Safety Profile 
of the 9-Valent HPV Vaccine: A Combined 
Analysis of 7 Phase III Clinical Trials. 
Pediatrics. 2016 Aug;138(2). pii: e20154387.
[04HBHT]
[Pitisuttithum, P., et al 
2015]
Pitisuttithum P, Velicer C, Luxembourg A. 9-
Valent HPV vaccine for cancers, pre-cancers and 
genital warts related to HPV. Expert Rev 
Vaccines. 2015 Sep 14:1-15.
[047XK8]
[Serrano, B., et al 2014]
Serrano B, Alemany L, de Ruiz PA, Tous S, 
Lima MA, Bruni L, et al. Potential impact of a 9-
valent HPV vaccine in HPV-related cervical 
disease in 4 emerging countries (Brazil, Mexico, 
India and China). Cancer Epidemiol. 2014 
Dec;38(6):748-56.
[04V4H8]
[Zhao, F. H., et al 2012]
Zhao FH, Lewkowitz AK, Hu SY, Chen F, Li 
LY, Zhang QM, et al. Prevalence of human 
papillomavirus and cervical intraepithelial 
neoplasia in China: a pooled analysis of 17 
population-based studies. Int J Cancer. 2012 
Dec;131(12):2929-38.
[04V56G]
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