A Phase 1/2 Randomized, Observer-blinded, Multi-country Study to Evaluate Safety and Immunogenicity of Investigational Adjuvanted Human Papillomavirus Vaccine in Females (16 to 26 Years of Age)
Phase: PHASE1
Conditions: Cervical Intraepithelial Neoplasia
Sponsor: GlaxoSmithKline

TITLE PAGE 
Protocol Title: A Phase 1/2 randomized, observer-blinded, multi-country study to evaluate 
safety and immunogenicity of investigational adjuvanted human papillomavirus vaccine in 
females (16 to 26 years of age) 
Protocol Number: 213749 (HPV9-AS04-001) 
Amendment Number: 3 
Product: Investigational adjuvanted human papillomavirus vaccine 
Short Title: A study on the immune response and safety of an adjuvanted human papillomavirus 
vaccine when given to healthy women 16 to 26 years of age 
Study Phase: 1/2 
Sponsor Name: GlaxoSmithKline Biologicals SA 
Legal Registered Address: Rue de l’Institut, 89, 1330 Rixensart, Belgium 
EudraCT number: 2022-000090-15 
Date of Original Protocol: 13 December 2021 
Date of Original Protocol Version 2.0: 02 March 2022 
Date of Protocol Amendment 1/DEU-1: 23 June 2022 
Date of Protocol Amendment 2: 23 September 2022 
Date of Protocol Amendment 3: 08 June 2023 
 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 2 of 110 
SPONSOR SIGNATORY: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
 
 
 
Jasur Danier 
VP Clinical Science, Viral Cluster 
 
Date 
GlaxoSmithKline Biologicals SA 
 
 
Medical Monitor name and contact are provided in Study Reference Manual. 
Investigator Agreement Page is provided in Appendix 7. 
 
 
PPD

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 3 of 110 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Substantial 
Region 
Amendment 3 
08 June 2023 
No 
Global 
Amendment 2 
23 September 2022  
Yes 
Global 
Amendment 1/DEU-1 
23 June 2022 
Yes 
Local - Germany 
Version 2.0 
02 March 2022 
Yes 
Global 
Original Protocol 
13 December 2021 
- 
- 
Protocol Amendment 3:08 June 2023  
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study. 
Overall Rationale for Amendment 
The purpose of the Protocol Amendment 3 is to improve participant adherence to the vaccination 
schedule by increasing time interval between Visit 1 (first study vaccination) and Visit 5 (third 
study vaccination) that will allow participants to complete HPV vaccination series during the 
study period. Additionally, for the analysis of anti-HPV neutralizing antibody titers at Month 2, 
we increased the number of participants from 160 up to 384 to collect additional immunogenicity 
data after the first study vaccine administration. This change applies to samples already collected 
and no additional Month 2 blood samples will be collected from participants. Furthermore, a 
change has been made in the statistical section to obtain group data (i.e., HPV9High, HPVMed 
and HPVLow study groups) instead of pooled data on correlation between anti-HPV IgG 
antibody concentration and anti-HPV neutralizing antibody titers. 
Added text is bold italic and deleted text is strikethrough.  
Section and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
3.0 Objectives and endpoints, 
 
Edited text in footnote #3: 
Anti-HPV neutralizing antibody 
titers at Month 2 will be performed 
in a subset of 160 384 participants 
(at least 40 96 participants in each 
group) 
Increase the pool of 
immunogenicity data after the first 
vaccine administration 
1.3 Schedule of Activities 
Table 2 Intervals Between Study 
Visits 
Allowed Interval Range  
Visit 1 → Visit 5 180166-194 days 
Improve participants’ adherence to 
the vaccination schedule and ensure 
completion of a full HPV 
vaccination series 
4.1 Overall Design,  
Edited text:  
Increase immunogenicity data after 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 4 of 110 
Section and Name 
Description of Change 
Brief Rationale 
Appendix 3 
Pseudovirion-based neutralization 
assay (PBNA) at (…) Month 2 will 
be performed in a subset of 160 384 
participants (at least 40 96 
participants in each group) 
the first vaccine administration 
9.4.2.2.1 Within Groups 
Assessment 
Edited text: 
Pearson coefficient of correlation 
between anti-HPV IgG antibody 
concentration and anti-HPV 
neutralizing antibody titers with 
associated P-value will be 
calculated for eachpooled 
investigational adjuvanted vaccines 
group and Gardasil 9 group for 
each antigen for timepoint and 
overall. 
To obtain group data instead of 
pooled data on correlation between 
anti-HPV IgG antibody 
concentration and anti-HPV 
neutralizing antibody titers 
Signature page 
Updated Sponsor Signatory: 
Nadia Meyer 
Clinical and Epidemiology R&D 
Project Leader 
Jasur Danier 
VP Clinical Science, Viral Cluster 
Updated to current signatory for 
this study. 

TABLE OF CONTENTS 
TITLE PAGE ..........................................................................................................................1 
TABLE OF CONTENTS ........................................................................................................5 
TABLE OF TABLES .............................................................................................................10 
TABLE OF FIGURES ...........................................................................................................11 
1.
PROTOCOL SUMMARY ........................................................................................12 
1.1. 
Synopsis ...........................................................................................................12 
1.2. 
Schema ............................................................................................................15 
1.3. 
Schedule of Activities .....................................................................................15 
2.
INTRODUCTION......................................................................................................19
2.1. 
Background ....................................................................................................19 
2.2. 
Study Rationale ..............................................................................................20 
2.3. 
Benefit/Risk Assessment ................................................................................20 
2.3.1. 
Risk Assessment and Risk Mitigation Strategies ..............................20 
2.3.2. 
Benefit Assessment ...........................................................................22 
2.3.3. 
Overall Benefit/Risk Conclusion .......................................................22 
3.
OBJECTIVES AND ENDPOINTS ..........................................................................23 
4.
STUDY DESIGN ........................................................................................................25 
4.1. 
Overall Design ................................................................................................25 
4.2. 
Scientific Rationale for Study Design ...........................................................27 
4.2.1. 
Rationale for the use of a Comparator Vaccine and 
Randomization ...................................................................................27 
4.2.2. 
Selection of Study Population ...........................................................27 
4.2.3. 
Rationale for Blinding .......................................................................27 
4.3. 
End of Study Definition .................................................................................28 
5.
STUDY POPULATION ............................................................................................29 
5.1. 
Inclusion Criteria ...........................................................................................29 
5.2. 
Exclusion Criteria ..........................................................................................29 
5.2.1. 
Medical Conditions ...........................................................................30 
5.2.2. 
Prior/Concomitant Therapy ...............................................................30 
5.2.3. 
Prior/Concurrent Clinical Study Experience .....................................31 
5.2.4. 
Other Exclusions ...............................................................................31 
5.2.5. 
Lifestyle Considerations ....................................................................31 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 6 of 110 
5.3. 
Screen Failures ...............................................................................................31 
5.4. 
Criteria for Temporary Delay for Enrollment and/or Intervention 
Administration ...............................................................................................31 
6.
STUDY INTERVENTIONS .....................................................................................33 
6.1. 
Study Interventions Administered ...............................................................33 
6.2. 
Preparation/Handling/Storage/Accountability ...........................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding........................35 
6.3.1. 
Participant Identification ...................................................................35 
6.3.2. 
Randomization to Study Intervention ................................................35 
6.3.3. 
Intervention Allocation to the Participant .........................................35 
6.3.4. 
Allocation of Participants to Assay Subsets ......................................36 
6.3.5. 
Blinding and Unblinding ...................................................................36 
6.3.5.1. 
Blinding ...........................................................................36 
6.3.5.2. 
Emergency Unblinding ....................................................37 
6.3.5.3. 
Emergency Unblinding Prior to Regulatory 
Reporting of Serious Adverse Events ..............................37 
6.4. 
Study Intervention Compliance ....................................................................38 
6.5. 
Dose Modification ..........................................................................................38 
6.6. 
Continued Access to Study Intervention After the End of Study ..............38 
6.7. 
Treatment of Overdose ..................................................................................38 
6.8. 
Concomitant Medications/Products and Concomitant 
Vaccinations....................................................................................................38 
6.8.1. 
Recording of Concomitant Medications/Products and 
Concomitant Vaccinations .................................................................38 
6.8.2. 
Concomitant Medications/Products/Vaccines That May Lead 
to Elimination of a Participant From Per Protocol Analyses ............39 
6.9. 
Intercurrent Medical Conditions That May Lead to Elimination 
of a Participant From Per Protocol Analyses ..............................................39 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................40 
7.1. 
Discontinuation of Study Intervention .........................................................40 
7.2. 
Contraindications to Subsequent Study Intervention(s) 
Administration ...............................................................................................40 
7.3. 
Participant Discontinuation/Withdrawal From the Study ........................41 
7.4. 
Lost to Follow-up ...........................................................................................41 
8.
STUDY ASSESSMENTS AND PROCEDURES ....................................................42 
8.1. 
Immunogenicity Assessments .......................................................................42 
8.1.1. 
Biological Samples ............................................................................42 
8.1.2. 
Laboratory Assays for Immunogenicity ............................................43 
8.1.3. 
Immunological Correlates of Protection ...........................................44 
8.2. 
Safety Assessments .........................................................................................44 
8.2.1. 
Pre-Intervention Administration Procedures .....................................45 
8.2.1.1. 
Collection of Demographic Data .....................................45 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 7 of 110 
8.2.1. 
Pre-Intervention Administration Procedures .....................................45 
8.2.1.1. 
Collection of Demographic Data .....................................45 
8.2.1.2. 
Collection of Medical/Vaccination History .....................45 
8.2.1.3. 
Physical Examination/Vital Signs ...................................45 
8.2.1.4. 
Pregnancy Test ................................................................45 
8.2.1.5. 
Checking Contraindications, Warnings, and 
Precautions to Intervention Administration .....................46 
8.2.2. 
Clinical Safety Laboratory Tests .......................................................46 
8.2.3. 
Study Holding Rules and Safety Monitoring ....................................46 
8.2.3.1. 
Staggered Enrollment ......................................................46 
8.2.3.2. 
Safety Holding Rules .......................................................48 
8.2.3.3. 
iSRC Evaluation ..............................................................51 
8.3. 
Adverse Events ...............................................................................................52 
8.3.1. 
Time Period and Frequency for Collecting AEs/SAEs, 
pIMDs, and Pregnancy Information ..................................................52 
8.3.2. 
Method of Detecting AEs and SAEs, Pregnancies, and 
pIMDs ................................................................................................54 
8.3.3. 
Clinically Significant Abnormal Laboratory Findings ......................54 
8.3.4. 
Follow-up of AEs and SAEs, Pregnancies, and pIMDs ....................54 
8.3.5. 
Regulatory Reporting Requirements for SAEs, Pregnancies, 
and pIMDs .........................................................................................54 
8.3.6. 
Treatment of Adverse Events ............................................................55 
8.3.7. 
Participant Card .................................................................................55 
8.3.8. 
Medical Device Deficiencies .............................................................55 
8.3.8.1. 
Detection, Follow-up, and Reporting of Medical 
Device Deficiencies .........................................................56 
8.3.8.2. 
Regulatory Reporting of Medical Device 
Deficiency When Used as Combination Product ............56 
8.4. 
Study Procedures During Special Circumstances ......................................56 
9. 
STATISTICAL CONSIDERATIONS .....................................................................58 
9.1. 
Statistical Hypotheses ....................................................................................58 
9.2. 
Sample Size Determination ...........................................................................58 
9.2.1. 
Statistical Considerations on Safety Assessment ..............................58 
9.2.2. 
Statistical Considerations on Immunogenicity Assessment ..............59 
9.2.2.1. 
Exploratory Immunologic Non-Inferiority 
Analyses ..........................................................................59 
9.3. 
Populations for Analyses ...............................................................................60 
9.4. 
Statistical Analyses.........................................................................................61 
9.4.1. 
Primary Endpoints Analyses .............................................................61 
9.4.1.1. 
Analysis Related to Safety and Reactogenicity ...............61 
9.4.1.2. 
Immunogenicity Analyses ...............................................61 
9.4.1.2.1 Within Groups Assessment ..............................62 
9.4.2. 
Secondary Endpoints Analyses .........................................................62 
9.4.2.1. 
Analysis Related to Safety and Reactogenicity ...............62 
9.4.2.2. 
Immunogenicity Analyses ...............................................62 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 8 of 110 
                  9.4.2.2.1         Within Groups Assessment ......................62 
9.4.2.2.2 
Exploratory Between Group 
Assessment ..............................................63 
9.4.3. 
iSRC Analyses ...................................................................................63 
9.5. 
Interim Analyses ............................................................................................64 
9.5.1. 
Sequence of Analyses ........................................................................64 
9.5.2. 
Statistical Considerations for Interim Analyses ................................65 
10. 
REFERENCES ...........................................................................................................66 
11. 
APPENDICES ............................................................................................................68 
APPENDIX 1 
ABBREVIATIONS AND GLOSSARY OF 
TERMS 
 .........................................................................................68 
APPENDIX 2 
REGULATORY, ETHICAL, AND STUDY 
OVERSIGHT CONSIDERATIONS ............................................................74 
Regulatory and Ethical Considerations ............................................................74 
Financial Disclosure.........................................................................................74 
Insurance ..........................................................................................................75 
Informed Consent and Assent Process .............................................................75 
Data Protection.................................................................................................76 
Administrative Structure ..................................................................................76 
Medical Monitor ..............................................................................................76 
Dissemination of Clinical Study Data..............................................................76 
Data Quality Assurance ...................................................................................77 
Source Documents ...........................................................................................78 
Study and Study Center Closure ......................................................................78 
Publication Policy ............................................................................................79 
APPENDIX 3 
CLINICAL LABORATORY TESTS ..........................80 
Humoral Immunity...........................................................................................80 
Humoral Immunity: HPV IgG concentration by multiplex 
immunoassay (ECL) ........................................................80 
Humoral Immunity: HPV neutralizing assay (PBNA) ......................80 
APPENDIX 4 
ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING .............................................................82 
Definition of an AE ..........................................................................................82 
Events Meeting the AE Definition ....................................................82 
Events NOT Meeting the AE Definition ...........................................82 
Definition of an SAE .......................................................................................83 
Solicited Events ...............................................................................................84 
Unsolicited AEs ...............................................................................................84 
Adverse Events of Special Interest ..................................................................84 
Potential Immune-Mediated Diseases ...............................................84 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 9 of 110 
Clinical Laboratory Parameters and Other Abnormal Assessments 
Qualifying as AEs/SAEs ...................................................................94 
COVID-19 Cases .............................................................................................94 
Events or Outcomes Not Qualifying as AEs/SAEs: Pregnancy ......................94 
Assessment of Causality ..................................................................................94 
Medically Attended Visits ...............................................................................95 
Assessment of Intensity ...................................................................................95 
Maximum Intensity of Solicited Events ............................................95 
Maximum Intensity of Unsolicited AEs and SAEs ...........................95 
Assessment of Outcomes .................................................................................96 
Recording, Follow-up, and Assessment of AEs, SAEs, pIMDs, and 
Pregnancies ........................................................................................96 
Recording AEs and SAEs ..................................................................96 
Use of eDiary/app ..............................................................................97 
Follow-up of AEs, SAEs, and pIMDs, and Pregnancies ...................97 
Follow-up During the Study ..............................................................97 
Follow-up After the Participant is Discharged from the Study .........98 
Updating of SAE, pIMD, Pregnancy Information After 
Removal of Write Access to the Participant’s 
eCRF ................................................................................98 
Follow-up of Pregnancies ..................................................................98 
Events Requiring Expedited Reporting to IQVIA .............................98 
SAE Reporting to IQVIA via EDC ...................................................99 
Back-up SAE Reporting to IQVIA via Paper (in Case of 
EDC Failure) ...................................................................99 
Adverse Events Related to the Use of Medical Devices ..................................99 
Definitions of a Medical Device AE and Adverse Device 
Effect ...............................................................................99 
Definition of a Medical Device SAE, Serious Adverse 
Device Effect, and Unanticipated Serious 
Adverse Device Effect ...................................................100 
Serious Adverse Device Effect (SADE) Definition: .....................................100 
Assessment of Severity of a Medical Device AE ..........................................100 
Recording and Reporting of Medical Device AE, ADE, SADE, and 
USADE ............................................................................................101 
APPENDIX 5 
CONTRACEPTIVE GUIDANCE AND 
COLLECTION OF PREGNANCY INFORMATION.............................102 
Definitions......................................................................................................102 
Woman of Childbearing Potential ...................................................102 
Women of Non-Childbearing Potential ...........................................102 
Contraception Guidance .................................................................................102 
Female Participants who Become Pregnant ...................................................103 
APPENDIX 6 
PROTOCOL AMENDMENT HISTORY .................104 
Protocol Amendment 1/DEU-1: 23 June 2022 ..............................................106 
Protocol Version 2.0: 02 March 2022 ............................................................106 
APPENDIX 7 
SIGNATURE OF INVESTIGATOR .........................110 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 10 of 110 
 
TABLE OF TABLES 
Table 1 
Schedule of Activities ......................................................................................16 
Table 2 
Intervals Between Study Visits ........................................................................18 
Table 3 
Risk Assessment and Risk Mitigation Strategy ...............................................21 
Table 4 
Study Objectives and Endpoints ......................................................................23 
Table 5 
Study Groups, Vaccines, and Blinding ............................................................27 
Table 6 
Study Interventions Administered ...................................................................34 
Table 7 
Biological Samples ..........................................................................................43 
Table 8 
Humoral Immune Response .............................................................................43 
Table 10 
Hematology and Biochemistry Tests ...............................................................46 
Table 11 
Solicited Events to be Collected in Step 1 and 2 .............................................47 
Table 12 
Intensity Scales for Solicited Events ................................................................47 
Table 13 
Biochemistry and Hematology Parameters Grading Component ....................48 
Table 14 
Study Holding Rules for Step 1 to be Assessed Post-Dose 1 ..........................50 
Table 15 
Time Period and Frequency for Collecting AE/SAE and Pregnancy 
Information ......................................................................................................53 
Table 16 
Expedited Reporting of SAEs, Pregnancies, and pIMDs ................................55 
Table 17 
2-sided 95% Exact Confidence Intervals for the True Adverse Event 
Rate for Various Observed Adverse Event Rates (270 Participants per 
Group) ..............................................................................................................58 
Table 18 
Power to Show That the Lower Limit of the 2-sided 95% CI on Anti-
HPV IgG Antibody GMC ratio (HPV-9 Vaccine Group Divided by 
Gardasil 9 Group), 1 Month After Dose 3 is Not Less Than 0.5 ....................59 
Table 19  
Study Analyses Sets .........................................................................................60 
Table 20 
Study Administrative Structure ........................................................................76 
Table 21 
List of Potential Immune-Mediated Diseases ..................................................86 
Table 22 
Highly Effective Contraceptive Methods ......................................................103 
 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 11 of 110 
TABLE OF FIGURES 
Figure 1 
Study Design Overview ...................................................................................25 
Figure 2 
Probability of Not Meeting Holding Rules 1 and 2 for 12 Participants 
per Study Group in Step 1 ................................................................................51 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 12 of 110 
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1/2 randomized, observer-blinded, multi-country study to evaluate safety 
and immunogenicity of investigational adjuvanted human papillomavirus vaccine in females 
(16 to 26 years of age) 
Protocol Number: 213749 (HPV9-AS04-001) 
Protocol Amendment Number: 3 
Product: investigational adjuvanted human papillomavirus vaccine 
Short Title: A study on the immune response and safety of a human papillomavirus vaccine 
when given to healthy women 16 to 26 years of age. 
Rationale: GlaxoSmithKline Biologicals SA (GSK) is developing an investigational adjuvanted 
human papillomavirus (HPV) vaccine to protect against HPV types 6, 11, 16, 18, 31, 33, 45, 52, 
and 58. This study will evaluate the reactogenicity, safety, and immunogenicity of 3 formulations 
of GSK’s investigational adjuvanted HPV vaccine versus Gardasil 9, administered 
intramuscularly (IM) according to a 0, 2, 6 month vaccination schedule in females 16-26 years of 
age. 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and reactogenicity of 
GlaxoSmithKline Biologicals SA (GSK)’s 
investigational adjuvanted human papillomavirus 
(HPV) vaccine formulations 
Solicited events 
 
Percentage of participants reporting each solicited 
administration site event assessed as Grade 3 in 
terms of intensity within 7 days (Day 1 – Day 7) 
after each vaccine dose. 
 
Percentage of participants reporting each solicited 
systemic event assessed as Grade 3 in terms of 
intensity within 7 days (Day 1 – Day 7) after each 
vaccine dose. 
Unsolicited adverse events (AEs) 
 
Percentage of participants reporting unsolicited 
adverse event assessed as Grade 3 in terms of 
intensity classified by Medical Dictionary for 
Regulatory Activities (MedDRA) within 28 days 
(Day 1 – Day 28) after each vaccine dose.  
Serious adverse events (SAEs) 
 
Percentage of participants reporting SAEs classified 
by MedDRA from first vaccination up to study end. 
Safety laboratory parameters (Step 1 participants) 
 
Percentage of participants presenting clinically 
relevant abnormalities in each biochemical and 
hematological parameter at Day 7 post-dose 1. 
 
To evaluate the immune response to GSK’s 
investigational adjuvanted HPV vaccine 
 
Anti-HPV immunoglobulin G (IgG) antibody 
geometric mean concentrations (GMCs), 1 month 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 13 of 110 
Objectives 
Endpoints 
formulations  
after the third dose (Month 7). 
Secondary 
 
To evaluate the safety and reactogenicity of GSK’s 
investigational adjuvanted HPV vaccine 
formulations 
Solicited events 
 
Percentage of participants reporting each solicited 
administration site event within 7 days (Day 1 – 
Day 7) after each vaccine dose. 
 
Percentage of participants reporting each solicited 
systemic event within 7 days (Day 1 – Day 7) after 
each vaccine dose. 
Unsolicited AEs 
 
Percentage of participants reporting unsolicited 
symptoms within 28 days (Day 1 – Day 28) after 
each vaccine dose  
Potential immune-mediated disease (pIMDs) 
 
Percentage of participants reporting pIMDs from 
first vaccination up to study end. 
Pregnancy outcomes 
 
The percentage of participants who experienced 
pregnancy and their outcomes from Day 1 of 
pregnancy up to study end. 
 
To evaluate the immune response for all HPV 
vaccine types for all vaccines 
 
Anti-HPV IgG antibody concentration at Day 1, 
Month 2, Month 3, Month 6, Month 7 and 
Month 12.  
 
Anti-HPV IgG antibody seroconversion1 rate at 
Month 2, Month 3, Month 6, Month 7 and 
Month 12. 
 
Anti-HPV neutralizing antibody titers at Day 1, 
Month 3 and Month 72 in all participants, Month 23 
in a subset of participants. 
 
Anti-HPV neutralizing antibody seroconversion1 
rate at Month 3 and Month 72. 
 
Correlation between anti-HPV IgG antibody 
concentration and anti-HPV neutralizing antibody 
titers at Day 1, Month 2, Month 3 and Month 7. 
1 Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer greater than or equal to the 
cut-off value) in the serum of participants seronegative before vaccination. 
2 At least 150 participants in each group. In case of any delay, analysis may be performed for as many participants 
as possible with data available at the time of the analysis. Analysis for remaining participants will be performed 
at the time of the next analysis. 
3 384 participants (at least 96 participants in each group) 
Note: Tertiary objectives and endpoints are available in the main text of this protocol. 
 
Overall Design: This will be a phase 1/2 randomized, observer-blind, multi-country study with 
4 groups of females 16-26 years of age at the time of vaccine administration. Participants will be 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 14 of 110 
randomized in a 1:1:1:1 ratio to receive a series of 3 investigational adjuvanted intervention 
doses (3 different potencies [a high, medium, low potency]) or a series of the Gardasil 9 vaccine. 
The investigational adjuvanted intervention or Gardasil 9 vaccine will be administered 
intramuscularly (IM) at Day 1 (Month 0), Month 2, and Month 6. Blood sampling will be 
performed on Day 1, Month 2, Month 3, Month 6, Month 7, and Month 12 to assess for 
immunological response. In Germany, only adult participants between and including 18 years to 
26 years of age are to be included in this clinical study. 
This study is organized in to 2 steps. Forty-eight participants (12 per group) of the study Step 1 
(sentinel participants) will receive the initial assigned dose prior to participants in Step 2 of the 
study, and sentinel participants will have an additional blood sampling visit at Day 7 to assess for 
biochemical and hematological parameters. The internal Safety Review Committee (iSRC) will 
review the accumulated safety data up to 7 days post-dose 1 for the sentinel participants* to 
determine whether any of the pre-defined holding rules have been met. If no safety concerns 
were observed and no holding rules were met, the sentinel participants will continue with study 
visits and dosing as scheduled and the Step 2 participants will be initiated. Vaccination of Step 2 
participants with a second dose will not be initiated before all Step 1 participants have received 
their second vaccination dose.  
 
 
 
*In case not all 48 of the Step 1 participants are enrolled and vaccinated with a first dose of study 
vaccine by 30 September 2022, the iSRC will review the accumulated safety data up to 7 days 
post-dose 1 of all participants available by that date. If no safety signal is identified, these 
participants will be vaccinated with a second dose. To avoid any additional participants running 
out of the allowed interval range for their second vaccine dose, additional iSRC review(s) may 
need to be planned to review the safety data up to 7 days post-dose 1 of these participants, but 
only when all 48 Step 1 participants have been enrolled and their data have been reviewed by the 
iSRC, the iSRC will decide on the initiation of the vaccination of Step 2 participants. 
Number of Participants: Approximately 1080 participants will be randomly assigned to the 
4 study groups to provide approximately 270 participants per study group. 
Intervention Groups:  
Study groups 
Study Interventions 
Number of Participants 
HPV9High  
HPV9-High 
270 
HPV9Med 
HPV9-Medium 
270 
HPV9Low 
HPV9-Low 
270 
Gar9 
Gardasil 9 
270 
Duration: The duration of the intervention will be approximately 6 months. Participants will be 
monitored until Month 12. Monitoring of pregnancies (if any) can be beyond 12 months. 
Statistical Methods: Three analyses sets will be used in this study, the Enrolled Set, the 
Exposed Set, and the Per Protocol Set. The primary objective and all immunogenicity objectives 
will be evaluated descriptively.  Exploratory immunologic non-inferiority analyses will be 
performed, to help in decision making of the formulation selection for the further phase 3 clinical 
studies. 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 15 of 110 
Internal Safety Review Committee: An iSRC will be reviewing the accumulated safety data up 
to 7 days post-dose 1 for the sentinel participants to determine whether any of the pre-defined 
holding rules have been met in order to proceed with study schedule of activities. The iSRC will 
review the safety data on a monthly basis until safety data from 1-month post-dose 2 for all 
participants and data from 1-month post-dose 3 for Step 1 participants are reviewed. 
1.2. Schema 
See study schema in Figure 1. 
1.3. Schedule of Activities 
The schedule of activities is presented in Table 1.

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 16 of 110 
Table 1 
Schedule of Activities 
Age 
16 – 26 years of age at the time of study intervention administration* 
Notes 
Visit 
Visit 1  
Visit 2** Visit 3  
Visit 4   
Visit 5  
Visit 6  
Visit 7 
Time point 
Day 1 
Day 7 
Month 2 
Month 3 
Month 6 
Month 7 
Month 12 
Informed consent (and assent if applicable) 
● 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria 
● 
 
 
 
 
 
 
See Sections 5.1-5.2 
Collect demographic data 
● 
 
 
 
 
 
 
See Section 8.2.1.1 
Medical history 
● 
 
 
 
 
 
 
See Section 8.2.1.2 
Vaccination history 
○ 
 
 
 
 
 
 
See Section 8.2.1.2 
Physical examination/Vital signs 
● 
○ 
● 
○ 
● 
○ 
○ 
See Section 8.2.1.3 
Body temperature before study vaccination1 
● 
 
● 
 
● 
 
 
See Section 8.2.1.3 
Pregnancy test (urine) before study vaccination 
● 
 
● 
 
● 
 
 
See Section 8.2.1.4 
Randomization 
○ 
 
 
 
 
 
 
See Section 6.3.2 
Check contraindications, warnings, and precautions 
to study vaccine  
○ 
 
○ 
 
○ 
 
 
See Sections 5.4, 
7.2, 8.2.1.5 
Administration of study vaccine 
● 
 
● 
 
● 
 
 
 
Recording of administered study vaccination 
number 
● 
 
● 
 
● 
 
 
 
Distribute and instruct participant/participant’s 
parent(s)/LAR(s) on the use of eDiary for solicited 
AEs 
○ 
 
○ 
 
○ 
 
 
 
Distribute and instruct participants/participant’s 
parent(s)/LAR(s) on the use of Memory Aid for 
unsolicited AEs and concomitant 
medication/vaccination 
○ 
 
○ 
 
○ 
 
 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 17 of 110 
Age 
16 – 26 years of age at the time of study intervention administration* 
Notes 
Visit 
Visit 1  
Visit 2** Visit 3  
Visit 4   
Visit 5  
Visit 6  
Visit 7 
Time point 
Day 1 
Day 7 
Month 2 
Month 3 
Month 6 
Month 7 
Month 12 
Laboratory assessments2 
 
Blood sampling for antibody determination 
(~50 mL) 
● 
 
● 
● 
● 
● 
● 
See Section 8.1 
Blood sampling for any hematological/biochemical 
laboratory abnormality for Step 1 participants 
(~5 mL) 
● 
● 
 
 
 
 
 
See Section 8.2.2 
Safety assessments 
See Section 8.2 
Record any concomitant medications/vaccinations 
● 
● 
● 
● 
● 
● 
● 
See Section 6.8.1 
Record any intercurrent medical conditions 
 
● 
● 
● 
● 
● 
● 
See Section 6.9 
Review the solicited events (Days 1-7 post study 
vaccine administration) recorded by the 
participant/participant’s parent(s)/LAR(s) 
 
● 
 
● 
 
● 
 
 
Recording of unsolicited AEs (Days 1-28 post 
study vaccine administration) 
 
● 
● 
● 
● 
● 
 
 
Return of eDiaries/disable electronic application 
 
 
 
 
 
○ 
 
 
Return of Memory Aids 
 
○** 
○ 
○ 
 
○ 
 
 
Recording of all SAEs, including SAEs related to 
study intervention, to study participation, to a 
concurrent GSK medication/vaccine4 
● 
● 
● 
● 
● 
● 
● 
 
Recording of AEs/SAEs leading to withdrawal of a 
participant from the intervention/study 
● 
● 
● 
● 
● 
● 
● 
 
Recording of pregnancies and pregnancy outcomes5 
● 
● 
● 
● 
● 
● 
● 
 
Recording of pIMDs 
● 
● 
● 
● 
● 
● 
● 
See Table 21 
Study Conclusion 
 
 
 
 
 
 
● 
See Section 4.3 
(the table footnote continues on the next page) 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) − Amendment 3 
Page 18 of 110 
* 18-26 years of age for Step 1 participants.  
Note: In Germany, only adult participants between and including 18 to 26 years of age are to be included in this clinical study 
** For Step 1 participants only 
AE = adverse event; 
; D = day; eDiary = electronic diary; LAR = legally authorized representative; pIMD = potential 
immune-mediated disease; SAE = serious adverse event 
● is used to indicate a study procedure that requires documentation in the individual electronic case report form (eCRF) 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF 
1 
The preferred location for measuring the temperature is the axilla. Fever is defined as body temperature ≥37.5°C/99.5°F. 
2 
Blood samples should be collected prior to vaccine administration.  
3 
Only for 200 participants (50/group) at pre-selected sites. 
4 
The collection and reporting period starts once the participants’ informed consent (and assent, if applicable) is obtained. 
5 
Follow-up of pregnancy outcomes will be done beyond Month 12. 
Table 2 
Intervals Between Study Visits 
Interval 
Planned Visit Interval* 
Allowed Interval Range 
Visit 1→Visit 2** 
7 days 
7 – 12 days 
Visit 1→Visit 3 
60 days 
56 – 74 days 
Visit 3→Visit 4 
28 days 
28 – 44 days 
Visit 1→Visit 5  
180 days 
166 – 194 days 
Visit 5→Visit 6 
28 days 
28 – 44 days 
Visit 1→Visit 7 
360 days 
346 – 374 days 
*Number of days between the visits. 
**Visit 2 is for Step 1 participants only. 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 19 of 110 
2. INTRODUCTION 
2.1. Background 
Persistent infection with carcinogenic human papilloma virus (HPV) presents a serious risk of 
development of HPV-related cervical neoplasia. Of more than 100 identified HPV types, 13 are 
classified as oncogenic by the International Agency for Research on Cancer (HPV-16, 18, 31, 33, 
35, 39, 45, 51, 52, 56, 58, 59, and 68). While in low grade lesions HPV type distribution varies 
greatly, HPV types 16 and 18 are the predominant oncogenic types accounting for approximately 
70% of all cervical cancer cases. HPV types 31, 33, 45, 52, and 58 cause an additional 20% of all 
cervical cancer cases worldwide (Arbyn et al, 2014; Bruni et al, 2021). Over the last decade with 
the increased use of molecular diagnostic techniques, growing evidence suggests HPV 
involvement in different anatomical sites such as anal region and the oropharynx 
(Bray et al, 2018; Götz et al, 2019; Hartwig et al, 2012). The low risk (non-oncogenic) HPV 
types 6 and 11 cause 90% of genital warts and some low grade cervical intraepithelial neoplasia 
and are also linked to recurrent respiratory papillomatosis. 
Three HPV L1 virus-like particle (VLP) vaccines are licensed in the US, in EU and numerous 
countries worldwide: Cervarix (GSK’s HPV-16/18 AS04 adjuvanted vaccine), Gardasil (Merck 
Sharp and Dohme’s HPV-6/11/16/18 vaccine) and Gardasil 9 (Merck Sharp and Dohme’s 
HPV-6/11/16/18/31/33/45/52/58 vaccine). These vaccines have shown excellent safety and 
efficacy profiles.  
Over a decade after first HPV vaccines (Cervarix and Gardasil) were licensed and have been 
widely used, disease epidemiology has evolved. Population-level impact of vaccinating girls and 
women against HPV infections, anogenital warts, and cervical intraepithelial neoplasia 
demonstrates significant evidence of effectiveness of HPV vaccines across countries (Cervarix 
and Gardasil) in real-world settings (Drolet MM et al, 2019; Palmer et al, 2019) as well as 
long-term protection (Hoes et al, 2020; Mesher et al, 2018), even in reduced dose schedule 
(Pasmans et al, 2019) and among different at-risk populations (Woestenberg et al, 2020). 
As of 2020, less than 25% of low-income and less than 30% of lower-middle-income countries 
had introduced the HPV vaccine for the prevention of HPV diseases into their national 
immunization schedules, while more than 85% of high-income countries had done so 
(WHO, 2020). 
In 2020, the World Health Organization (WHO) adopted a global strategy to eliminate cervical 
cancer and called for concerted efforts between its partners and the private sector to reach the 
target of 90% HPV vaccination coverage by 2030 in girls by age 15 years. One of the actions to 
reach this target is to overcome vaccine supply constraints and to secure sufficient HPV vaccines 
(WHO, 2020). 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 20 of 110 
2.2. Study Rationale 
This project aims at developing a new GlaxoSmithKline Biologicals SA (GSK) 
AS04-adjuvanted HPV vaccine. The VLP type composition will include HPV types 6, 11, 16, 
18, 31, 33, 45, 52, and 58. This study will evaluate the reactogenicity, safety, and 
immunogenicity of 3 formulations of GSK’s investigational adjuvanted HPV vaccine versus 
Gardasil 9, administered intramuscularly (IM) according to a 0, 2, 6 month vaccination schedule 
in females 16-26 years of age (18-26 years of age in Germany). The aim of the study is to 
generate data to allow the selection of the investigational adjuvanted HPV vaccine formulation 
which will be used for the phase 3 studies. Participants who receive the selected formulation and 
Gardasil 9 will be invited to participate in an additional 4-year extension study with yearly visits, 
to generate long-term immunogenicity and safety data. 
2.3. Benefit/Risk Assessment 
2.3.1. Risk Assessment and Risk Mitigation Strategies 
Refer to the current Investigator’s Brochure (IB) for the detailed summary of potential risks and 
benefits of the investigational adjuvanted HPV vaccine. The investigational vaccine is expected 
to have a benefit risk profile similar to other known HPV vaccines. The most common side 
effects currently known following administration of HPV vaccines are pain, redness, or swelling 
at the location where the vaccine was administered, and fever, dizziness, syncope, nausea, 
headache, and muscle or joint pain (CDC, 2021). On very rare occasions, a person may 
experience allergic reaction (anaphylaxis). 
For the risks associated with administration of Gardasil 9 refer to the vaccine’s prescribing 
information/package insert. 
GSK/designee (IQVIA [see the study administrative structure in Table 20]) will immediately 
notify the investigators if any additional safety or toxicology information becomes available 
during the study. 
The risk assessment and mitigation strategy for this study are outlined in Table 3. In addition to 
these specific mitigation strategies, the study will be conducted in a staggered manner with 
safety evaluations by an internal Safety Review Committee (iSRC) (Section 8.2.3). Holding rules 
that have been established will be applied. The project Safety Review Team (SRT) will also 
review blinded data on a regular basis throughout the study. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 21 of 110 
Table 3 
Risk Assessment and Risk Mitigation Strategy 
Important Potential/Identified 
Risk 
Data/Rationale for Risk 
Mitigation Strategy 
All Study Vaccines 
Hypersensitivity reactions 
(including anaphylaxis). 
Acute allergic reactions such as a 
rare case of anaphylactic event 
may occur with any vaccine 
administration. These are serious, 
but rare occurrences estimated in 
the range of 1 to 10 cases per 
million of vaccinations, 
depending on the vaccine studied 
(Ruggerberg et al, 2007). 
Participants with known 
hypersensitivity to any component of 
the vaccine are excluded from 
enrollment. The onset of vaccine-related 
allergic symptoms occurs shortly after 
vaccination. In order to treat participants 
with a serious allergic reaction to 
vaccination, all participants will need to 
remain under observation (i.e., visibly 
followed; no specific procedure) at the 
study site for at least 60 minutes after 
vaccination. 
Syncope 
Syncope (fainting) can occur 
following or even before any 
vaccination as a psychogenic 
response to the needle injection.  
All participants will remain under 
observation at the vaccination center for 
at least 60 minutes after vaccination. 
Local inflammatory reaction due 
to intramuscular (IM) injection 
IM vaccination commonly 
precipitates a transient and 
self-limiting local inflammatory 
reaction. This may typically 
include pain at injection site, 
redness, and swelling. 
All participants will remain under 
observation at the vaccination center for 
at least 60 minutes after vaccination. 
Solicited local adverse events (AEs) will 
be collected and reviewed from Day 1 to 
Day 7 post study vaccine 
administration. 
GSK’s investigational adjuvanted HPV vaccine 
Theoretical risk of acquiring a 
vaccine-induced autoimmune 
disease after vaccination. 
Potential immune-mediated 
diseases (pIMDs) are a theoretical 
concern with adjuvanted vaccines 
(Tavares et al, 2013). 
During the informed consent process, 
participants will be informed of this 
theoretical risk and asked to report any 
AEs that they consider 
serious/significant and/or for which they 
received medical attention at any point 
during the study. 
Participants with a history or with a 
current diagnosis of an autoimmune 
disease will be excluded from the study 
A pIMD is an adverse event of special 
interest (AESI) and occurrence of 
pIMDs will be captured and described. 
pIMDs will be collected throughout the 
study. 
Study Procedures – Blood sampling 
Pain and bruising 
Pain or bruising at the site where 
blood is drawn.  
A topical analgesic may be applied to 
the site where blood will be collected. 
Syncope 
Syncope (fainting) can occur 
following or even before any 
blood draw as a psychogenic 
response to the needle injection. 
All participants will remain under 
observation at the clinical center for at 
least 60 minutes after vaccination. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 22 of 110 
2.3.2. Benefit Assessment 
An indirect benefit is that the information obtained in this study will aid the development of an 
HPV vaccine, which is intended to prevent cervical, vulvar, vaginal, anal and oropharyngeal 
cancers caused by high risk HPV types 16, 18, 31, 33, 45, 52, and 58 and genital warts caused by 
low risk HPV types 6 and 11. In addition, this vaccine aims to prevent precancerous or dysplastic 
lesions (cervical intraepithelial neoplasia, adenocarcinoma in situ, vulvar intraepithelial 
neoplasia, vaginal intraepithelial neoplasia, anal intraepithelial neoplasia) caused by HPV types 
6, 11, 16, 18, 31, 33, 45, 52, and 58. 
Another benefit for all study participants may include gaining of information and medical advice 
about their general health status through medical evaluations/assessments associated with this 
study (i.e., physical examinations and blood testing [hematology and biochemistry data]). 
2.3.3. Overall Benefit/Risk Conclusion 
The investigational adjuvanted HPV vaccine is currently in an early stage of clinical 
development and no vaccine efficacy has been demonstrated in humans. Taking into account the 
measures to minimize the risk to the participants, the potential risks are justified by the potential 
benefits linked to the development of this investigational adjuvanted HPV vaccine. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 23 of 110 
3. Objectives and Endpoints 
Table 4 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety and reactogenicity of 
GlaxoSmithKline Biologicals SA (GSK)’s 
investigational adjuvanted human papillomavirus 
(HPV) vaccine formulations. 
Solicited events 
 
Percentage of participants reporting each solicited 
administration site event assessed as Grade 3 in 
terms of intensity within 7 days (Day 1 – Day 7) 
after each vaccine dose. 
 
Percentage of participants reporting each solicited 
systemic event assessed as Grade 3 in terms of 
intensity within 7 days (Day 1 – Day 7) after each 
vaccine dose. 
Unsolicited adverse events (AEs) 
 
Percentage of participants reporting unsolicited 
adverse event assessed as Grade 3 in terms of 
intensity classified by Medical Dictionary for 
Regulatory Activities (MedDRA) within 28 days 
(Day 1 – Day 28) after each vaccine dose.  
Serious adverse events (SAEs) 
 
Percentage of participants reporting SAEs classified 
by MedDRA from first vaccination up to study end. 
Safety laboratory parameters (Step 1 participants) 
 
Percentage of participants presenting clinically 
relevant abnormalities in each biochemical and 
hematological parameter at Day 7 post-dose 1. 
 
To evaluate the immune response to GSK’s 
investigational adjuvanted HPV vaccine 
formulations. 
 
Anti-HPV immunoglobulin G (IgG) antibody 
geometric mean concentrations (GMCs), 1 month 
after the third dose (Month 7). 
Secondary 
 
To evaluate the safety and reactogenicity of GSK’s 
investigational adjuvanted HPV vaccine 
formulations. 
Solicited events 
 
Percentage of participants reporting each solicited 
administration site event within 7 days (Day 1 – 
Day 7) after each vaccine dose. 
 
Percentage of participants reporting each solicited 
systemic event within 7 days (Day 1 – Day 7) after 
each vaccine dose. 
Unsolicited AEs 
 
Percentage of participants reporting unsolicited 
symptoms within 28 days (Day 1 – Day 28) after 
each vaccine dose.  
Potential immune-mediated disease (pIMDs) 
 
Percentage of participants reporting pIMDs from 
first vaccination up to study end. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 24 of 110 
Objectives 
Endpoints 
Pregnancy outcomes 
 
The percentage of participants who experienced 
pregnancy and their outcomes from Day 1 of 
pregnancy up to study end. 
 
To evaluate the immune response for all HPV 
vaccine types for all vaccines. 
 
Anti-HPV IgG antibody concentration at Day 1, 
Month 2, Month 3, Month 6, Month 7, and 
Month 12.  
 
Anti-HPV IgG antibody seroconversion1 rate at 
Month 2, Month 3, Month 6, Month 7, and 
Month 12. 
 
Anti-HPV neutralizing antibody titers at Day 1, 
Month 3 and Month 72 in all participants, Month 23 
in a subset of participants. 
 
Anti-HPV neutralizing antibody seroconversion1 
rate at Month 3 and Month 72. 
 
Correlation between anti-HPV IgG antibody 
concentration and anti-HPV neutralizing antibody 
titers at Day 1, Month 2, Month 3, and Month 7. 
Tertiary 
1 Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer greater than or equal to the 
cut-off value) in the serum of participants seronegative before vaccination. 
2 At least 150 participants in each group. In case of any delay, analysis may be performed for as many participants 
as possible with data available at the time of the analysis. Analysis for remaining participants will be performed 
at the time of the next analysis. 
3 384 participants (at least 96 participants in each group) 
4 
 
 
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 25 of 110 
4. STUDY DESIGN 
4.1. Overall Design 
The study design diagram is provided in Figure 1. 
Study groups are presented in Table 5. 
Figure 1 
Study Design Overview 
 
 
D = day; iSRC = internal Safety Review Committee; M = month; IgG = immunoglobulin G; 
 
; pIMD = potential immune-mediated disease; V = visit 
^V2 is only for Step 1 participants 
*Pregnancy test before study vaccine administration 
$Pseudovirion-based neutralization assays at D1, M2 (subset), M3 and M7  
#
 
+Post study vaccine administration 
&iSRC reviews Sentinel participants post-dose 1 safety data, then iSRC reviews the data on monthly basis until 
safety data from 1-month post-dose 2 for all participants and data from 1-month post-dose 3 for Step 1 participants 
are reviewed 
%Blood sampling for biochemistry and hematology is only for Step 1 participants.
CCI
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 26 of 110 
Recruitment: 
A staggered enrollment will be used: 
 In Step 1, 48 participants (12 per group) aged 18-26 years will be enrolled and vaccinated 
with the first dose, with an interval of at least 60 minutes between participants to allow sites 
to efficiently put on hold study vaccination in case of any safety concern. 
 Unblinded safety data up to 7 days post-dose 1 in Step 1 will be reviewed by iSRC. Holding 
rules will apply (refer to Section 8.2.3).  
 If no safety concern is identified, Step 1 participants will be allowed to complete the 
vaccination schedule (doses 2 and 3*), and the remaining 1032 participants aged 
16-26 years** will be enrolled at the same time (Step 2).  
*In case not all 48 of the Step 1 participants are enrolled and vaccinated with a first dose of 
study vaccine by 30 September 2022, the iSRC will review the accumulated safety data up to 
7 days post-dose 1 of all participants available by that date. If no safety signal is identified, 
these participants will be vaccinated with a second dose. To avoid any additional participants 
running out of the allowed interval range for their second vaccine dose, additional iSRC 
review(s) may need to be planned to review the safety data up to 7 days post-dose 1 of these 
participants, but only when all 48 Step 1 participants have been enrolled and their data have 
been reviewed by the iSRC, the iSRC will decide on the initiation of the vaccination of 
Step 2 participants. 
** In Germany, only adult participants between and including 18 to 26 years of age will 
be included in this clinical study. 
Vaccination schedule: 
A 0-2-6 month vaccination schedule will be followed. 
Blood sample collection: 
 A 5 mL blood sample will be drawn from Step 1 (Sentinel) participants at Visit 1 (Day 1) and 
Visit 2 (Day 7) to assess biochemical and hematological parameters. 
 For assessment of immune response, blood samples (~50 mL) will be drawn at Day 1, 
Month 2, Month 3, Month 6, Month 7 and Month 12 in all participants. Immunoglobulin G 
(IgG) antibody determination will be performed for these timepoints in all participants. 
Pseudovirion-based neutralization assays will be performed. Blood samples drawn at Day 1 
(all participants), Month 2 (at least 96 participants in each group), Month 3 (all participants) 
and Month 7 (at least 150 participants in each group) will be tested. 
 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 27 of 110 
Table 5 
Study Groups, Vaccines, and Blinding 
Study 
groups 
Number of 
participants 
Age 
(Min-Max) 
Study 
vaccinations 
Blinding* 
Visit 1 to Visit 7 (Observer-
Blind) 
HPV9High  
270 
16-26 years of age 
HPV9-High 
X 
HPV9Med 
270 
16-26 years of age 
HPV9-Medium 
X 
HPV9Low 
270 
16-26 years of age 
HPV9-Low 
X 
Gar9 
270 
16-26 years of age 
Gardasil 9 
X 
HPV = human papillomavirus 
*This study is observer-blinded (double-blinded for the 3 formulations of the investigational adjuvanted HPV 
vaccine and observer-blinded for the investigational adjuvanted HPV vaccine vs Gardasil 9)  
Note : In Germany, only adult participants between and including 18 to 26 years of age will be included in this 
clinical study. 
 
4.2. Scientific Rationale for Study Design 
4.2.1. Rationale for the use of a Comparator Vaccine and Randomization 
This study is an active controlled study. Gardasil 9 will be used as comparator. It has proven 
effectiveness, is approved for routine vaccinations in many countries and it is the only HPV 
vaccine marketed in the United States of America. It will allow the generation of data to compare 
the immunologic profile of the 3 investigational formulations to the one of Gardasil 9.  
The participants will be randomized in the study in order to reduce bias of selection. 
4.2.2. Selection of Study Population 
The study will enroll healthy females 16-26 years of age (18-26 years of age in Germany), which 
is the gender and age cohort in which the efficacy of HPV vaccines has been demonstrated, at the 
time of the first dose, who have a lifetime history of 0-4 sexual partners and use adequate 
contraception. The exclusion criteria such as previous exposure to HPV vaccine or components 
of the investigational vaccine, history of previous HPV infection or of external genital/vaginal 
warts and any immunocompromised or autoimmune conditions, aim at avoiding potential 
immunological or clinical bias. 
4.2.3. Rationale for Blinding 
The study will be conducted in an observer-blind manner in order to reduce the risk of biased 
study outcomes. There will be a double-blind for the 3 formulations of the investigational 
adjuvanted HPV vaccine and an observer-blind for the investigational adjuvanted HPV vaccine 
versus Gardasil 9. A full double blinding is not possible because of the difference in the 
presentation of the investigational adjuvanted HPV vaccine formulations and Gardasil 9. 
See the definitions of double blinding and observer-blind in Glossary of Terms and refer to 
Section 6.3.5.1 for details. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 28 of 110 
4.3. End of Study Definition 
A participant is considered to have completed the study if she returns for the last visit/contact or 
is available for the last scheduled procedure/contact as described in the protocol. 
The end of study (EoS) is defined as the date of the Last Participant Last Visit (LPLV) or date of 
last testing results released whichever comes last. In the latter, EoS must be achieved no later 
than 8 months after the LPLV. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 29 of 110 
5. STUDY POPULATION 
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. Deviations 
from these criteria can jeopardize the scientific integrity, regulatory acceptability of the study or 
safety of the participant. 
5.1. Inclusion Criteria 
All participants must satisfy ALL the following criteria at study entry: 
1. Healthy participants as established by medical history and clinical examination before 
entering into the study  
2. For Step 1 only: Female between and including 18 and 26 years of age at the time of the 
first study intervention administration 
3. For Step 2: Female between and including 16 and 26 years of age at the time of the first 
study intervention administration 
4. Note: German Participants: In Germany, only adult participants between and including 
18 to 26 years of age are to be included in this clinical study. Written informed consent 
obtained from the participant prior to performance of any study-specific procedure (for 
participants below the legal age of consent as per local regulations, written informed 
consent must be obtained from the participant/participant’s parent[s]/legally acceptable 
representatives [LAR{s}] and, in addition, the participant should sign and personally date 
a written informed assent). 
5. Participants and/or participants’ parent(s)/LAR(s) who, in the opinion of the investigator, 
can and will comply with the requirements of the protocol (e.g., completion of the 
electronic diary [eDiary], return for follow-up visits). 
6. Female participant with no more than 4 lifetime sexual partners prior to enrollment. 
7. Female participants of non-childbearing potential may be enrolled in the study. 
Female participants of childbearing potential may be enrolled in the study if the 
participant: 
 has practiced adequate highly effective contraception for at least 1 month prior to 
study intervention administration, and 
 has a negative pregnancy test on the day of study intervention administration, and 
 has agreed to continue adequate contraception during the entire intervention period 
and for 2 months after completion of the study intervention administration series. 
See Appendix 5 for the definition of women of childbearing potential and acceptable 
contraception requirements. 
5.2. Exclusion Criteria  
The following criteria should be checked at the time of study entry. The potential participant 
shall not be included in the study if any of exclusion criterion applies. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 30 of 110 
5.2.1. Medical Conditions 
1. Pregnant or lactating female. 
2. Female planning to become pregnant or planning to discontinue contraceptive precautions. 
3. History of any reaction or hypersensitivity likely to be exacerbated by any component of the 
study intervention(s). 
4. History or current diagnosis of autoimmune disease. 
5. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on 
medical history and physical examination (no laboratory testing required). 
6. Hypersensitivity to latex. 
7. Major congenital defects, as assessed by the investigator. 
8. History of abnormal Papanicolaou test or abnormal cervical biopsy result. 
9. History of external genital/vaginal warts. 
10. History of positive HPV test. 
11. Acute or chronic clinically significant pulmonary, cardiovascular, neurologic, hepatic or 
renal functional abnormality, as determined by physical examination or laboratory tests.  
12. Any other clinical condition that, in the opinion of the investigator, might pose additional risk 
to the participant due to participation in the study. 
Refer to Section 5.4 for criteria for the conditions for the temporary delay or enrollment and/or 
intervention. 
5.2.2. Prior/Concomitant Therapy 
13. Previous vaccination against HPV. 
14. Previous exposure to monophosphoryl lipid A or AS04 adjuvant. 
15. Use of any investigational or non-registered product (drug, vaccine or medical device) other 
than the study intervention(s) during the period beginning 30 days before the first dose of 
study intervention(s) (Day -29 to Day 1), or their planned use during the study period. 
16. Planned administration/administration of a vaccine not foreseen by the study protocol in the 
period starting 30 days before each dose and ending 30 days after each dose of study 
interventions administration* 
*In case emergency mass vaccination for an unforeseen public health threat (e.g., a 
pandemic) is organized by public health authorities outside the routine immunization 
program, the time period described above can be reduced if necessary for that vaccine, 
provided it is licensed and used according to its Product Information. 
17. Administration of long-acting immune-modifying drugs at any time during the study period 
(e.g., infliximab). 
18. Use of systemic cytotoxic agents within the previous 3 months prior to randomization into 
this study or at any time during the study period. 
19. Chronic administration (defined as more than 14 days in total) of immunosuppressants or 
other immune-modifying drugs during the period starting 3 months prior to the first study 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 31 of 110 
intervention dose(s). For corticosteroids, this will mean prednisone equivalent ≥20 mg/day 
for adult participants or ≥0.5 mg/kg/day with maximum of 20 mg/day for participants under 
18 years of age. Inhaled and topical steroids are allowed.  
20. Administration of systemic immunoglobulins and/or any blood products or plasma
derivatives during the period starting 3 months before the administration of the first dose of
study interventions or planned administration during the study period.
5.2.3. Prior/Concurrent Clinical Study Experience 
21. Concurrently participating in another clinical study, at any time during the study period, in
which the participant has been or will be exposed to an investigational or a
non-investigational intervention (drug/invasive medical device [see the definition in 
Glossary of Terms]).
5.2.4. Other Exclusions 
22. History of /current chronic alcohol consumption and/or drug abuse.
23. Any study personnel or their immediate dependants, family, or household members.
24. Child in care.
5.2.5. Lifestyle Considerations 
No restrictions pertaining to lifestyle and/or diet apply. 
5.3. Screen Failures 
Not applicable as there is no screening phase of the potential participants as part of this study. 
5.4. Criteria for Temporary Delay for Enrollment and/or Intervention Administration 
Enrollment and/or study intervention administration may be postponed within the permitted time 
interval until transient circumstances cited below are resolved and the participant stays eligible: 

Acute disease and/or fever at the time of enrollment and/or study intervention administration.
Fever is defined as temperature ≥37.5°C/99.5°F. The preferred location for measuring
temperature will be the axilla.

Participants with a minor illness (such as mild diarrhea, mild upper respiratory infection)
without fever may be enrolled and/or dosed at the discretion of the investigator.

Use of antipyretics and/or analgesics and/or antibiotics within 3 days prior to study
intervention administration.

Participants with symptoms suggestive of active Coronavirus Disease 2019 (COVID-19)
infection (e.g., fever, cough, etc.) until they are free of symptoms for at least 14 days.

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 32 of 110 
 Enrollment and/or study intervention administration of participants with known 
COVID-19-positive contacts within the past 14 days should be delayed for at least 14 days 
since the exposure and if the participant remains free of symptoms. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 33 of 110 
6. STUDY INTERVENTIONS 
6.1. Study Interventions Administered 
The details on the vaccines administered in this study are provided in Table 6. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 34 of 110 
Table 6 
Study Interventions Administered 
Study vaccines 
HPV9-High formulation 
HPV9-Medium formulation 
HPV9-Low formulation 
Gardasil 9 
Study vaccines 
formulation 
GSKVx000000031357 (Dose Aa 
GSKVx000000031397); 
GSKVx000000031399 (Dose Ba 
GSKVx000000031400); 
GSKVx000000031402 (Dose Ca 
GSKVx000000031327); 
GSKVx000000031328 (Dose Da 
GSKVx000000031408); 
GSKVx000000031409 (Dose Ea 
GSKVx000000031427); 
GSKVx000000031407 (Dose Fa 
GSKVx000000031360); 
GSKVx000000031429 (Dose Ga 
GSKVx000000031384); 
GSKVx000000031361 (Dose Ha 
GSKVx000000031371); 
GSKVx000000031363 (Dose Ia 
GSKVx000000031434); Excipients; Water for 
injections q.s. 0.5 mL 
GSKVx000000031398 (Dose Ab 
GSKVx000000031397); 
GSKVx000000031382 (Dose Bb 
GSKVx000000031400); 
GSKVx000000031403 (Dose Cb 
GSKVx000000031327); 
GSKVx000000031405 (Dose Db 
GSKVx000000031408); 
GSKVx000000031410 (Dose Eb 
GSKVx000000031427); 
GSKVx000000031428 (Dose Fb 
GSKVx000000031360); 
GSKVx000000031430 (Dose Gb 
GSKVx000000031384); 
GSKVx000000031362 (Dose Hb 
GSKVx000000031371); 
GSKVx000000031433 (Dose Ib 
GSKVx000000031434); Excipients; 
Water for injections q.s. 0.5 mL 
GSKVx000000031358 (Dose Ac 
GSKVx000000031397); 
GSKVx000000031401 (Dose Bc 
GSKVx000000031400); 
GSKVx000000031404 (Dose Cc 
GSKVx000000031327); 
GSKVx000000031406 (Dose Dc 
GSKVx000000031408); 
GSKVx000000031426 (Dose Ec 
GSKVx000000031427); 
GSKVx000000031359 (Dose Fc 
GSKVx000000031360); 
GSKVx000000031383 (Dose Gc 
GSKVx000000031384); 
GSKVx000000031432 (Dose Hc 
GSKVx000000031371); 
GSKVx000000031364 (Dose Ic 
GSKVx000000031434); Excipients; 
Water for injections q.s. 0.5 mL 
HPV6 L1 (30 µg)¹; HPV11 
L1 (40 µg)¹; HPV16 L1 (60 
µg)¹; HPV18 L1 (40 µg)¹; 
HPV31 L1 (20 µg)¹; HPV33 
L1 (20 µg)¹; HPV45 L1 (20 
µg)¹; HPV52 L1 (20 µg)¹; 
HPV58 L1 (20 µg)¹; ¹ 
adsorbed on amorphous 
aluminum hydroxyphosphate 
sulfate; Amorphous 
aluminum hydroxyphosphate 
sulfate (0.5 mg Al³⁺); Water 
for injections q.s. 0.5 mL 
Dose form 
(Presentation) 
Suspension for injection (syringe) 
Suspension for injection (syringe) 
Suspension for injection (syringe) 
Suspension for injection 
(syringe) 
Type 
Biologic/Combination Product 
Biologic/Combination Product 
Biologic/Combination Product 
Biologic/Combination 
Product 
Route of administration 
Intramuscular 
Intramuscular 
Intramuscular 
Intramuscular 
Location 
Deltoid 
Deltoid 
Deltoid 
Deltoid 
Directionality 
Upper 
Upper 
Upper 
Upper 
Laterality* 
Nondominant 
Nondominant 
Nondominant 
Nondominant 
Number of doses to be 
administered 
3 
3 
3 
3 
Volume to be 
administered 
0.5 mL 
0.5 mL 
0.5 mL 
0.5 mL 
Packaging, labeling and 
trademark 
Refer to the Study Reference Manual for 
details 
Refer to the Study Reference Manual 
for details 
Refer to the Study Reference Manual 
for details 
Refer to the Study Reference 
Manual for details 
Manufacturer 
GlaxoSmithKline Biologicals SA (GSK) 
GSK 
GSK 
Merck & Co. 
*The nondominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the nondominant arm, an injection in the dominant arm may be performed. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 35 of 110 
6.2. Preparation/Handling/Storage/Accountability 
The study vaccines must be stored at the respective label storage temperature conditions in a safe 
and locked place. Access to the storage space should be limited to authorized study personnel. 
The storage conditions will be assessed during pre-study activities under the responsibility of 
IQVIA. The storage temperature should be continuously monitored with calibrated (if not 
validated) temperature monitoring device(s) and recorded. Refer to the Study Reference Manual 
(SRM)/pharmacy manual for more details on storage of the study intervention(s). 
6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Participant Identification 
Participant identification numbers (IDs) will be assigned sequentially to the participants who 
have consented or provided assent with consent from each participant’s parent(s)/LAR(s) to 
participate in the study, according to the range of participant IDs allocated to each study center. 
The participant IDs will be documented in the electronic Case Report Form (eCRF). 
The eligibility of the participant will be determined based on the inclusion and exclusion criteria 
listed in Section 5. The participant ID will be the participant’s unique identification number for 
all eCRFs and associated study documentation that will be used for duration of the study. If the 
participant is terminated from the study, her participant ID cannot be re-assigned. 
6.3.2. Randomization to Study Intervention 
All eligible participants will be centrally randomized to the study group at a 1:1:1:1 ratio using 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS) 
randomization (refer to Glossary of Terms for a definition of IVRS/IWRS). At study initiation, 
log in information and directions for the IVRS will be provided to each study center. The study 
and the center will be used as a minimization factor for randomization in Step 1 and the study, 
the center and 
 will be used as a minimization factor for randomization in 
Step 2.  
The participants will receive a unique treatment number (refer to Glossary of Terms for a 
definition of a treatment number). Once a treatment number has been assigned, it cannot be 
re-assigned. 
6.3.3. Intervention Allocation to the Participant 
Allocation of the participant to an intervention group at the study center will be performed using 
IVRS/IWRS through Interactive Response Tool (IRT) operated at the study level, before the first 
vaccination and after assessment of eligibility. 
The actual randomization assignment that the participant received (to one of the groups) will be 
identifiable in IRT in case of unblinding. 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 36 of 110 
After obtaining the signed and dated Informed Consent Form (ICF) (and informed assent form 
[IAF] if applicable) from the participant/participant’s parent(s)/LAR(s) and having checked the 
eligibility of the participant, the delegated clinical study staff will access IVRS/IWRS. Upon 
entering the participant ID, the randomization system will determine the intervention group and 
provide the treatment number. 
For all subsequent doses or replacement, new treatment numbers will be obtained through the 
IVRS/IWRS. 
Refer to the IVRS/IWRS user guide or the SRM for specific instructions related to instances 
when IVRS/IWRS is not available. 
Refer to the SRM for additional information related to the treatment number allocation. 
6.3.4. Allocation of Participants to Assay Subsets  
Immunogenicity assessments are planned as outlined in Section 8.1.  
Refer to Section 9.3 for descriptions of analysis populations. 
6.3.5. Blinding and Unblinding 
6.3.5.1. Blinding 
This study is observer-blind (double-blind for the 3 formulations of the investigational 
adjuvanted HPV vaccine and observer-blind for the investigational adjuvanted HPV vaccine 
versus Gardasil 9). 
By observer-blind, it is meant that during the study, the vaccine recipient and those responsible 
for the evaluation of any study endpoint will be unaware of which vaccine was administered. To 
do so, vaccine preparation and administration will be done by a third party which will be a study 
center staff member who will not participate in any of the study clinical evaluation assays. The 
third party will know if the vaccine to dispense is the investigational adjuvanted HPV vaccine 
formulation or Gardasil 9. However, they will not know which one of the 3 investigational 
adjuvanted HPV vaccine formulations is dispensed (double-blind for the 3 formulations of the 
investigational adjuvanted HPV vaccine). 
A blinded observer will participate in the participant’s post injection assessments, perform 
clinical evaluations and record the clinical data. 
The laboratory in charge of sample testing will be blinded to the study intervention assignment. 
Codes will be used to link the participant and study to each sample. There will be no link 
between the study intervention groups and the identity of the participant. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 37 of 110 
Unblinded monitors and in the event of a quality assurance audit, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that 
randomization/dispensing has been done accurately. 
6.3.5.2. Emergency Unblinding 
Unblinding a participant’s individual intervention number should occur ONLY in case of a 
medical emergency when knowledge of the intervention is essential for the clinical management 
or welfare of the participant. 
In case of emergency, the investigator will have unrestricted, immediate, and direct access to the 
participant’s individual study intervention through IVRS/IWRS. At activation, the study centers 
will be provided instructions and/or other applicable information for emergency unblinding in 
the SRM or other sources. The IRT used by the IVRS/IWRS provider will be programmed with 
blind-breaking instructions. In case of an emergency, the investigator has the sole responsibility 
for determining if unblinding of a participant’s intervention is warranted. The participant’s safety 
must always be the first consideration in making such a determination. 
If a participant’s intervention assignment is unblinded, the Medical Monitor (see the definition in 
Glossary of Terms) must be notified WITHIN 24 HOURS after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation (see the 
definition in Glossary of Terms) and eCRF, as applicable. The participant may continue in the 
study. 
In the event of a Quality Assurance audit, the auditor(s) may be allowed access to unblinded 
study intervention information records to verify that vaccine dispensing has been done 
accurately. 
A non-investigator physician (e.g., physician from emergency room) or participant/participant’s 
parent(s)/LAR(s)/caregiver (see Glossary of Terms for a definition of a caregiver)/family 
member may also request emergency unblinding. Instructions for this will be provided to the 
participant/participant’s parent(s)/LAR(s) at enrollment. 
6.3.5.3. Emergency Unblinding Prior to Regulatory Reporting of Serious Adverse Events 
GSK policy (which incorporates the International Council for Harmonisation [ICH] E2A 
guideline, European Union Clinical Study Directive, and the United States Federal Regulations) 
is to unblind the report of any unexpected serious adverse event (SAE) that is 
attributable/suspected to be attributable to the investigational vaccine prior to regulatory 
reporting. 
IQVIA will follow these policies along with IQVIA’s standard procedures and will be 
responsible for unblinding the intervention assignment in accordance with the specified time 
frames for expedited reporting of SAEs. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 38 of 110 
In addition, IQVIA may unblind the intervention assignment for any participant with a Suspected 
Unexpected Serious Adverse Reaction or an SAE that is fatal or life-threatening. If the SAE 
requires an expedited regulatory report be sent to 1 or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or GSK’s policy. 
6.4. Study Intervention Compliance 
When participants are dosed at the site, they will receive the study intervention directly from the 
investigator or designee, under medical supervision. The date of administration of each study 
intervention dose will be recorded in the source documents. 
6.5. Dose Modification 
Not applicable. 
6.6. Continued Access to Study Intervention After the End of Study 
GSK will not be providing to the participants the continuing access to either study vaccine after 
the conclusion of the study.  
6.7. Treatment of Overdose 
Any dose of either study vaccine greater than the dose advised as per protocol is considered an 
overdose. All cases of vaccine overdose should be reported as adverse events (AEs) (or SAEs, if 
SAE criteria are met) and followed accordingly. 
6.8. Concomitant Medications/Products and Concomitant Vaccinations 
At each study visit/contact, the investigator or designee should question the participant or 
participant’s parent(s)/LAR(s) about any medications/products taken and vaccinations received 
by the participant, whether prescribed or over the counter. Memory aids used by 
participant/participant’s parent(s)/LAR(s) will be reviewed for any additional medication(s) and 
vaccination(s), which will be transcribed in eCRFs. 
6.8.1. Recording of Concomitant Medications/Products and Concomitant Vaccinations  
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the eCRF: 
 All concomitant medications/products, except vitamins and dietary supplements, 
administered during the 28-day period following each dose of study vaccine. 
 Any concomitant vaccination administered in the period starting from the first dose of study 
vaccine and ending at the last study visit. 
 All concomitant medication associated with AE, including vaccines/products, except 
vitamins and dietary supplements, administered after the first dose of study intervention. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 39 of 110 
 All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines (refer to Section 5.2.2 and 
Section 9.3 for further details). 
 Prophylactic medication (i.e., medication administered in the absence of ANY symptom and 
in anticipation of a reaction to the vaccination). 
For example, an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring 
 Any concomitant medications/products/vaccines relevant to an SAE/potentially 
immune-mediated response (pIMD) to be reported as per protocol or administered during the 
study period for the treatment of an SAE/pIMD. In addition, concomitant medications 
relevant to SAEs and pIMD need to be recorded on the expedited AE report. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The record of a concomitant medication should include at a minimum the reason for use, dates of 
administration including start and end dates, dosage information including dose and frequency. 
6.8.2. Concomitant Medications/Products/Vaccines That May Lead to Elimination of a 
Participant From Per Protocol Analyses 
The use of the concomitant medications/products/vaccines listed in Section 5.2.2 will not require 
withdrawal of the participant from the study but may determine a participant’s evaluability in the 
per protocol analysis. See Section 9.3 for cohorts to be analyzed. 
6.9. Intercurrent Medical Conditions That May Lead to Elimination of a Participant From 
Per Protocol Analyses 
At each study visit subsequent to the first vaccination, it must be verified if the participant has 
experienced or is experiencing any intercurrent medical condition (refer to Glossary of Terms for 
the definition of intercurrent medical condition). If it is the case, the condition(s) must be 
recorded in the AE section of the eCRF. 
At the time of analysis, participants may be eliminated from the per protocol cohort for 
immunogenicity if, during the study, they incur a condition that has the capability of altering 
their immune response or are confirmed to have an alteration of their initial immune status. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 40 of 110 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
7.1. Discontinuation of Study Intervention 
Discontinuation of study intervention refers to any participant who has not received all planned 
doses of study intervention. A participant who discontinued study intervention may continue 
other study procedures (e.g., safety or immunogenicity), planned in this protocol at the discretion 
of the investigator.  
The primary reason for premature discontinuation of the study intervention will be documented 
on the eCRF and may include (but not be limited to), the following: 
 Adverse event requiring expedited reporting to IQVIA 
 Pregnancy 
 Unsolicited non-serious AE 
 Solicited AE 
 Not willing to be vaccinated 
 Other (specify) 
7.2. Contraindications to Subsequent Study Intervention(s) Administration 
The eligibility for subsequent study intervention administration must be confirmed before 
administering any additional dose. 
All exclusion criteria have to be re-checked to ensure that the participant is still eligible. In 
addition, participants who meet any of the criteria listed below should not receive additional dose 
of study intervention. 
 Study participants who experience any SAE judged to be possibly or probably related to 
study intervention or non-study concomitant vaccine/product, including hypersensitivity 
reactions. 
 Study participants who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the participant if she continues to participate in the study. 
 Anaphylaxis following the administration of study intervention. 
 Any condition that in the judgment of the investigator would make intramuscular injection 
unsafe. 
 Occurrence of a new pIMD (see Table 21 for the list of pIMDs) or the exacerbation of an 
existing pIMD that, in the opinion of the investigator, expose the participant to unacceptable 
risk from subsequent vaccination. In such cases, the investigator should use his/her clinical 
judgment prior to administering the next dose of study intervention.  
The participants who have become ineligible for subsequent study intervention administration 
should be encouraged to continue other study procedures, at the investigators’ discretion. All 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 41 of 110 
relevant criteria for discontinuation of study intervention administration must be recorded in the 
eCRF. 
7.3. Participant Discontinuation/Withdrawal From the Study 
A participant is considered to have withdrawn from the study if no new study procedure has been 
performed or no new information has been collected for her since the date of withdrawal/last 
contact. 
From an analysis perspective, a study “withdrawal” refers to any participant who did not return 
for the concluding visit.  
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
All data and samples collected up to and including the date of withdrawal of/last contact with the 
participant will be included in the study analyses. 
The primary reason for study withdrawal will be documented in the eCRF based on the list 
below: 
 AEs requiring expedited reporting to IQVIA  
 Unsolicited non-serious AEs 
 Solicited AE 
 Withdrawal by participant, not due to an AE* 
 Migrated/moved from the study area 
 Lost to follow-up 
 Sponsor study termination 
 Other (specify) 
*If a participant is withdrawn from the study because she withdrew consent and the reason for 
withdrawal was provided, the investigator must document this reason in the eCRF. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will follow 
participants who are withdrawn from the study due to an AE/SAE until the event is resolved. 
7.4. Lost to Follow-up 
A participant will be considered “lost to follow-up” if she fails to return for scheduled visits and 
is unable to be contacted by the study center. Refer to the SRM for a description of the actions to 
be taken before considering the participant as lost to follow-up. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 42 of 110 
8. STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are only permitted when necessary for the management of 
immediate safety concerns for the participant. 
Immediate safety concerns should be discussed with IQVIA as soon as they occur or when the 
study team becomes aware of them. The purpose of this communication is to determine if the 
participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the schedule of activities (SoA) 
(Section 1.3). 
All eligibility evaluations must be completed, and the results reviewed before confirming that 
potential participants meet all eligibility criteria. 
The SRM provides the investigator and study center personnel with detailed administrative and 
technical information that does not impact the participant safety. 
8.1. Immunogenicity Assessments  
8.1.1. Biological Samples 
Collected biological samples will be used for protocol-mandated research and purposes related to 
the improvement, development and quality assurance of the laboratory tests described in this 
protocol. 
Additional serological assays may be performed in the future to further characterize the disease 
and/or the immunological response elicited by study intervention. These assays may not be 
represented in the objectives/endpoints of the study protocol. 
Findings in this or future studies may make it desirable to use samples acquired in this study for 
research not planned in this protocol. In this case, all participants in countries where this is 
allowed will be asked to give consent to allow GSK or a contracted partner, to use the samples 
for further research. The further research will be subject to prior IEC/IRB approval, if required 
by local legislation. 
Information on further investigations and their rationale can be obtained from GSK. 
Sample testing will be done in accordance with the recorded consent of the individual 
participant/participant’s parent(s)/LAR(s). 
Collected samples will be stored for a maximum of 20 years. This storage period begins when 
the last participant performed the last study visit, unless local rules, regulations or guidelines 
require different timeframes or procedures, which would then be in line with participant consent. 
These extra requirements need to be communicated formally to and discussed and agreed with 
GSK. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 43 of 110 
Blood samples will be collected from participants as described in Table 7. 
Table 7 
Biological Samples 
Sample Type 
Quantity 
Time 
point 
Time 
Point 
Time 
Point 
Time 
Point 
Time 
Point 
Time 
Point 
Time 
Point 
Subset 
Name 
Blood sampling for 
antibody determination  
Approximately 
50 mL 
Visit 1 
Day 1 
 
Visit 3 
Month 
2 
Visit 4 
Month 
3 
Visit 5 
Month 
6 
Visit 6 
Month 7 
Visit 7 
Month 
12 
All 
participant
s 
Blood sampling for any 
hematological/biochemical 
laboratory abnormality  
Approximately 
5 mL 
Visit 1 
Day 1 
Visit 
2*  
Day 7 
 
 
 
 
 
Step 1 
participant
s 
 
*Visit 2 is for Step 1 participants only. 
8.1.2. Laboratory Assays for Immunogenicity 
The laboratory tests for immunogenicity are listed in Table 8 and Table 9. All laboratory testing 
will be performed at GSK laboratory or in a laboratory designated by GSK. Refer to Appendix 3 
for a brief description of the assays. 
Table 8 
Humoral Immune Response 
Assay type 
System Component 
Method 
Humoral Immunity 
(Antibody 
determination) 
Serum 
Anti-HPV-6 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-11 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-16 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-18 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-31 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-33 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-45 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-52 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-58 L1 VLP Ab IgG 
ECL 
Serum 
Anti-HPV-6 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-11 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-16 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-18 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-31 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-33 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-45 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-52 PSV L1/L2 neutralizing Ab 
PBNA 
Serum 
Anti-HPV-58 PSV L1/L2 neutralizing Ab 
PBNA 
Ab = antibody; ECL= electrochemiluminescence assay; HPV = human papilloma virus; IgG = immunoglobulin G; 
PBNA = pseudovirion-based neutralization assay; PSV = pseudovirion; VLP = virus-like particle 
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 44 of 110 
Further laboratory testing related to the investigational adjuvanted vaccine formulations and/or 
HPV disease may be performed if deemed necessary or if assay(s) become available. 
The addresses of clinical laboratories used for sample analysis will be provided in a separate 
document accompanying this study protocol. 
GSK clinical laboratories have established a Quality System supported by procedures. The 
activities of GSK clinical laboratories are audited regularly for quality assessment by an internal 
(GSK-dependent) but laboratory-independent Quality Department. 
8.1.3. Immunological Correlates of Protection 
There is no established correlate of protection with the assay(s) to be used in this study for any of 
the vaccines administered in the frame of this study. 
8.2. Safety Assessments  
The investigator and his/her designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE. The investigator and designees are responsible 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 45 of 110 
for following up AEs that are serious, considered related to the study intervention or the study, or 
that caused the participant’s withdrawal from the study intervention or study. 
8.2.1. Pre-Intervention Administration Procedures 
8.2.1.1. Collection of Demographic Data  
Demographic data such as age in years, race, and ethnicity (with attention to local ethical 
considerations) will be collected from each participant and recorded in the eCRF. 
8.2.1.2. Collection of Medical/Vaccination History 
The medical and vaccination history should be checked by interviewing the 
participant/participant’s parent(s)/LAR(s) and/or review of the participant’s medical records. It 
should be verified that none of the exclusion criteria related to medical and vaccination history 
(Section 5.2) are met. Any pre-existing conditions or signs and/or symptoms present in a patient 
prior to the first study vaccination will be recorded in the eCRF.  
8.2.1.3. Physical Examination/Vital Signs 
On Day 1, a history directed physical examination (including the injection site examination) will 
be performed for each participant as per the standard of care.  Physical examination at each study 
visit after the first study intervention administration will be performed only if the 
participant/participant’s parent(s)/LAR(s) indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the investigator or delegate. Collected 
information needs to be recorded in the eCRF. 
On Day 1 and at each vaccination, vital signs (including temperature, systolic/diastolic blood 
pressure, heart rate, and respiratory rate after at least 10 minutes of rest) will be collected. Vital 
signs are to be taken before blood collection for laboratory tests. Collected information needs to 
be recorded in the eCRF 
Treatment of any abnormality observed during this examination has to be performed according 
to local medical practice outside this study or by referral to an appropriate healthcare provider. 
If the investigator determines that the participant’s health on the day of study intervention 
administration (Visit 1 [Day 1], Visit 3 [Month 2] and Visit 5 [Month 6]) temporarily precludes 
dosing, the visit will be rescheduled. Refer to Section 5.4 for the list of criteria for the temporary 
delay of study intervention administration. 
8.2.1.4. Pregnancy Test 
All study participants must perform a high sensitivity urine pregnancy test prior to each study 
vaccine administration. Pregnancy testing must be performed even if the participant is denying 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 46 of 110 
any sexual activity, menstruating at the time of visit, or is considered infertile. The study vaccine 
may only be administered after the pregnancy test is negative. 
Refer to Appendix 5 for the contraceptive guidance and information on study continuation for a 
participant who becomes pregnant during the study. 
8.2.1.5. Checking Contraindications, Warnings, and Precautions to Intervention 
Administration 
Warnings and precautions to administration of study intervention must be checked at each visit 
with planned administration of study intervention. Refer to Section 7.2 for contraindications to 
subsequent study intervention administration and to Section 5.4 for criteria for temporary delay 
for enrollment and/or intervention administration.  
8.2.2. Clinical Safety Laboratory Tests 
Blood sampling for any hematological/biochemical laboratory abnormality for Step 1 
participants will be collected at Visits 1 and 2. Hematology and biochemistry tests performed in 
the local laboratories are listed in Table 10. The volumes of blood to be collected are shown in 
Table 7. 
Table 10 
Hematology and Biochemistry Tests 
Assay type 
System 
Component 
Method 
Hematology 
Whole Blood  
Leukocytes (white blood cells) 
As per local laboratory 
procedures 
Whole Blood 
Neutrophils* 
Whole Blood  
Lymphocytes* 
Whole Blood  
Basophils* 
Whole Blood  
Monocytes* 
Whole Blood  
Eosinophils* 
Whole Blood  
Hemoglobin 
Thrombocytes 
Platelets 
Red Blood Cells 
Erythrocytes (red blood cells) 
Biochemistry 
Serum 
Blood urea nitrogen 
As per local laboratory 
procedures 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
*For white blood cell differential count. 
8.2.3. Study Holding Rules and Safety Monitoring 
8.2.3.1. Staggered Enrollment 
As this will be the first time that these investigational adjuvanted HPV vaccine formulations will 
be administered in humans, the enrollment will be staggered (refer to Section 8.2.3.3 for details). 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 47 of 110 
In Step 1, 48 participants (12 per group) aged 18-26 years will be enrolled and vaccinated with 
the first dose with an interval of at least 60 minutes between participants. Safety data from Step 1 
participants will be reviewed 7 days post-dose 1 by an unblinded iSRC (independent of the study 
team). 
The solicited administration site and systemic events that will be collected during the 7-day 
follow-up period following each vaccination are presented in Table 11. The intensity of the 
solicited AEs will be assessed as described in Table 12. 
Table 11 
Solicited Events to be Collected in Step 1 and 2  
Event 
Symptoms 
Solicited administration site events 
Pain 
Redness 
Swelling 
Solicited systemic events 
Fever 
Headache 
Myalgia 
Arthralgia 
Fatigue 
Note: participants/participants’ parent(s)/LAR(s) will be instructed to measure and record the axillary temperature in 
the evening. If additional temperature measurements are taken at other times of the day, participants/participants’ 
parent(s)/LAR(s) will be instructed to record the highest temperature in the electronic Diary. 
Table 12 
Intensity Scales for Solicited Events 
Event  
Intensity grade  
Parameter  
Pain 
1 (Mild) 
Mild: Any pain neither interfering with nor 
preventing normal everyday activities.  
2 (Moderate) 
Moderate: Painful when limb is moved and 
interferes with everyday activities.  
3 (Severe) 
Severe: Significant pain at rest. Prevents normal 
everyday activities.  
Redness and Swelling at 
administration site (Greatest surface 
diameter in mm)  
1 (Mild) 
>0 mm to ≤20 mm  
2 (Moderate) 
>20 mm to ≤50 mm 
3 (Severe) 
>50 mm 
Temperature* in °C 
1 (Mild) 
≥37.5°C (99.5°F) to ≤38.0°C (100.4°F) 
2 (Moderate) 
>38.0°C (100.4°F) to ≤39.0°C (102.2°F) 
3 (Severe) 
>39.0°C (102.2°F)  
Headache 
1 (Mild) 
Headache that is easily tolerated 
2 (Moderate) 
Headache that interferes with normal activity 
3 (Severe) 
Headache that prevents normal activity 
Fatigue 
1 (Mild) 
Fatigue that is easily tolerated 
2 (Moderate) 
Fatigue that interferes with normal activity 
3 (Severe) 
Fatigue that prevents normal activity 
Arthralgia 
1 (Mild) 
Arthralgia that is easily tolerated 
2 (Moderate) 
Arthralgia that interferes with normal activity 
3 (Severe) 
Arthralgia that prevents normal activity 
Myalgia 
1 (Mild) 
Myalgia that is easily tolerated 
2 (Moderate) 
Myalgia that interferes with normal activity 
3 (Severe) 
Myalgia that prevents normal activity 
SoA = schedule of activities  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 48 of 110 
*Refer to the SoA (Table 1) for the definition of fever and the preferred location for temperature measurement.
Biochemistry and hematology parameters will be collected in Step 1 participants (refer to 
Table 10). The intensity of these parameters will be assessed as described in Table 13. 
Table 13 
Biochemistry and Hematology Parameters Grading Component 
Grade 1 
Grade 2 
Grade 3 
Grade 4** 
Hematology 
Hemoglobin (g/dL) female 
12-11
10.9-9.5 
9.4-8 
<8 
Hemoglobin change from baseline female (g/dL) <1.5 
1.6-2 
2.1-5 
>5
WBC (cell/mm3) increase 
10,800-
15,000 
15,001-
20,000 
20,001-
25,000 
>25,000
WBC (cell/mm3) decrease 
3,500-2,500 
2,499-1,500 
1,499-1,000 
<1,000 
Lymphocyte (cell/mm3) decrease 
1,000-750 
749-500
499-250
<250 
Neutrophils (cell/mm3) decrease 
2,000-1,500 
1,499-1,000 
999-500
<500 
Eosinophils (cell/mm3)  
650-1,500
1,501-5,000 
>5,000
hypereosinophilic 
syndrome 
Platelet (cell/mm3) decrease 
140,000-
125,000 
124,000-
100,000 
99,000-
25,000 
<25,000 
Biochemistry 
ALT (increase by factor) 
1.1-2.5×ULN 2.6-5×ULN 
5.1-10×ULN >10×ULN
AST (increase by factor) 
1.1-2.5×ULN 2.6-5×ULN 
5.1-10×ULN >10×ULN
Blood Urea Nitrogen 
BUN mg/dL 
23-26
27-31
>31
Requires dialysis
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; FDA = Food and 
Drug Administration; ULN = upper limit of normal; WBC = white blood cells 
Note: The laboratory values provided in the table are taken from the FDA Guidance for Industry “Toxicity Grading 
Scale for Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” dated 
September 2007. These laboratory values serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
**The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as potentially life-threatening (Grade 4). 
Besides the standard AE collection (solicited AEs, unsolicited AEs, SAEs), the study will also 
collect pIMDs (see Table 21) throughout the study due to presence of the adjuvant AS04. 
8.2.3.2. Safety Holding Rules 
The safety holding rules for the vaccination phases of the study are defined in Table 14. 
For participants enrolled in Step 1, holding rules 1a-1d from Table 14 will be assessed by the 
investigator on a continuous basis, and meeting any of these holding rules will trigger a hold of 
vaccination irrespective of number of participants enrolled and/or timing of the event relative to 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 49 of 110 
vaccination. Holding rules 2a-2c from Table 14 will be assessed by the iSRC during the safety 
evaluations on unblinded data. 
These holding rules have been written under the assumption that the safety data from all 
participants will be available. If the data from all Step 1 participants are not available (i.e., in 
case a participant is lost to follow-up), then the holding rules will be assessed on a pro-rata basis 
(expressed as percentage of participants to be evaluated) i.e., 3 out of 12 participants per arm or 
25% per arm. 
Of note, no formal holding rules will be applied for other safety data such as non-life-threatening 
SAEs, missed visits due to study intervention-related AEs, Grade 1 and Grade 2 solicited and 
unsolicited AEs in the 7-day follow-up period and unsolicited AEs collected from Day 8 to Day 
30 after study intervention administration. However, if available, these data will also be reviewed 
by the iSRC to allow an overall assessment of the benefit/risk ratio of study intervention 
administration. 
If the investigator becomes aware of a holding rule being met, they must suspend administration 
of the study intervention and inform IQVIA immediately (e.g., holding rules 1a-d). IQVIA will 
inform the investigator if holding rules 2a-c are met. Investigators will be responsible to inform 
the IRB/IEC if a holding rule has been met. 
The following communication sequence must be followed: 
 The concerned site staff will put study intervention administration and enrollment on hold. 
 The concerned site staff will immediately inform IQVIA’s safety team (i.e., the events to be 
reported via an Electronic Data Capture system [EDC]). 
 Enrollment and intervention allocation through IVRS/IWRS will then be stopped on a study 
level. 
 IQVIA will inform all investigators about the stopping of enrollment and intervention.  
 IQVIA will also provide the blinded data to GSK’s Clinical Research and Development Lead 
and Safety Lead for further SRT and GSK Global Safety Board review. 
 IQVIA will forward the relevant unblinded safety information to iSRC for evaluation. 
 Based on the recommendation from iSRC, GSK’s Global Safety Board will make the 
decision whether the study can resume, be modified, or stopped. GSK will notify IQVIA on 
this decision. 
 IQVIA will notify all investigators on this decision. 
 Depending on the outcome of the safety evaluation, the study will be re-started, terminated, 
or resumed under a protocol amendment. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 50 of 110 
Table 14 
Study Holding Rules for Step 1 to be Assessed Post-Dose 1 
Holding 
Rule 
Event 
Number of 
participants/group 
Step 1  
1a 
Death or any life-threatening serious adverse event (SAE) 
≥1 
1b 
Any non-life-threatening SAE that cannot be reasonably attributed to a 
cause other than intervention as per Investigator or Sponsor assessment 
≥1 
1c 
Any withdrawal from the study (by investigator or participant request) 
following a Grade 3 adverse event (AE) 
≥1 
1d 
Any administration site or systemic solicited AE leading to 
hospitalization, or fever > 40°C (104°F), or necrosis at the injection 
site, each with an event onset within the 7-day (days 1-7) 
post-intervention period 
≥1 
2a 
Any Grade 3 solicited administration site events (lasting 48 hours or 
more as Grade 3), with an event onset within the 7-day (days 1-7) 
post-intervention period 
≥3/12 (≥25%) 
2b 
Any Grade 3 solicited systemic events (lasting 48 hours or more as 
Grade 3), with an event onset within the 7-day (days 1-7) 
post-intervention period  
≥3/12 (≥25%) 
2c 
Any Grade 3 unsolicited AE, that can be reasonably attributed to the 
vaccination as per Investigator or Sponsor assessment, with an event 
onset within the 7-day (days 1-7) post-vaccination period OR  
Any Grade 3 or above abnormality in pre-specified hematological or 
biochemical laboratory parameters with an event onset within the 
7-day (days 1-7) post-intervention period 
≥3/12 (≥25%) 
Note: by Sponsor, it means GlaxoSmithKline Biologicals SA’s designee for AE recording and assessment, IQVIA 
Risk Assessment for Step 1 
As shown in Figure 2, with 12 participants per study group: 
 Each holding rule 1a-1d has more than 89% chance of not being met for vaccination with a 
true incidence rate corresponding to the occurrence of holding rule event below 1%, and has 
more than 70% chance of being met for vaccination with a true incidence rate above 10%. 
 Each holding rule 2a-2c has more than 89% chance of not being met for vaccination with a 
true incidence rate below 10% and more than 60% chance of being met for vaccination with 
a true incidence rate above 25%. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 51 of 110 
Figure 2 
Probability of Not Meeting Holding Rules 1 and 2 for 12 Participants per 
Study Group in Step 1 
 
8.2.3.3. iSRC Evaluation 
The iSRC will review the accumulated safety data up to 7 days post-dose 1 of sentinel 
participants in Step 1*. The iSRC will have access to the participant randomization list and will 
review unblinded data. The iSRC members will determine whether any of the pre-defined 
holding rules are met (refer to Section 8.2.3) or if there is any other safety signal. If no safety 
signal is observed, vaccination of the “Step 1” participants will continue, and vaccination of the 
remaining participants (“Step 2” participants) will be initiated. 
Following this initial review(s), the iSRC will review all available safety data on a regular basis 
(monthly) until data from 1-month post-dose 2 for all participants and data from 1-month 
post-dose 3 for Step 1 participants are reviewed. During these reviews, monitoring of safety 
events will be done with no holding rules assessment (refer to the iSRC charter for details). It 
will be up to iSRC to trigger a study hold or study change if deemed necessary. In addition to the 
iSRC, the project SRT will review blinded data on a regular basis throughout the study. 
*In case not all 48 of the Step 1 participants are enrolled and vaccinated with a first dose of study 
vaccine by 30 September 2022, the iSRC will review the accumulated safety data up to 7 days 
post-dose 1 of all participants available by that date. If no safety signal is identified, these 
participants will be vaccinated with a second dose. To avoid any additional participants running 
out of the allowed interval range for their second vaccine dose, additional iSRC review(s) may 
need to be planned to review the safety data up to 7 days post-dose 1 of these participants, but 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 52 of 110 
only when all 48 Step 1 participants have been enrolled and their data have been reviewed by the 
iSRC, the iSRC will decide on the initiation of the vaccination of Step 2 participants. 
8.3. Adverse Events 
The definitions and details on recording, evaluating, and reporting of AEs, SAEs, pIMDs, and 
also pregnancies are provided in Appendix 4. 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study intervention or study procedures, or that caused 
the participant to discontinue the study/study intervention (see Section 7).  
8.3.1. Time Period and Frequency for Collecting AEs/SAEs, pIMDs, and Pregnancy 
Information 
Collection of AEs, SAEs, pregnancies, and pIMDs will be performed at the time points and 
periods specified in Table 15. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the medical history section of the eCRF, not the AE section. 
All SAEs will be recorded and reported to IQVIA within 24 hours. The investigator will submit 
any updated SAE data to IQVIA within 24 hours of it being available through the Expedited 
Report Form. 
Investigators are not obligated to actively seek AE or SAE after the participant concluded the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after the participant has been discharged from the study, and the event is considered 
reasonably related to the study intervention, the investigator must notify IQVIA. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 53 of 110 
Table 15 
Time Period and Frequency for Collecting AE/SAE and Pregnancy Information 
 
Visit 1 
Visit 2 
 
 
Visit 3 
 
Visit 4 
 
Visit 5 
 
Visit 6 
Visit 7 
Event 
Day 1 
Day 7 
 
 
Month 
2 
 
Month 3 
 
Month 
6 
 
Month 7 
Month 12 
Dose 1 
7 days 
post-
Dose 1 
28 days 
post-
Dose 1 
 
Dose 2 
7 days 
post-
Dose 2 
28 days 
post-
Dose 2 
 
Dose 3 
7 days 
post-
Dose 3 
28 days 
post-
Dose 3 
Study 
conclusion 
Administration site and 
systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs (all, fatal, related) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or 
concurrent GSK 
medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies/pregnancy 
outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; SAE = serious adverse event; pIMD = potentially immune-mediated disease 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 54 of 110 
8.3.2. Method of Detecting AEs and SAEs, Pregnancies, and pIMDs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. Memory aids used by participant/participant’s parent(s)/LAR(s), will be 
reviewed for health-related issues of participants and for potential AEs, which will be transcribed 
in eCRFs. 
8.3.3. Clinically Significant Abnormal Laboratory Findings 
The investigator must record any clinically relevant changes occurring during the study in the 
AE section of the eCRF. All clinically significant abnormal laboratory test values should be 
repeated until the values return to normal/baseline, or until they are no longer considered 
significantly abnormal by the investigator. If such values do not return to normal/baseline after 
an interval judged reasonable by the investigator, the etiology of the abnormal value should be 
identified, and the sponsor notified. In any case, the investigator should document they reviewed 
the laboratory report. 
8.3.4. Follow-up of AEs and SAEs, Pregnancies, and pIMDs  
After the initial AE/SAE/pIMD, or pregnancy report, the investigator is required to proactively 
follow each participant at subsequent visits/contacts. All SAEs and pIMDs will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
8.3.5. Regulatory Reporting Requirements for SAEs, Pregnancies, and pIMDs 
Once an investigator becomes aware that a study participant has experienced SAE, pIMD, or 
pregnancy during the study, they or designated study staff must report it to IQVIA within the 
timeframes provided in Table 16 via an electronic Expedited AE Report or Expedited Pregnancy 
Report. If the complications fulfill serious criteria, an SAE report should additionally be 
completed within 24 hours. This is essential for meeting legal obligations and ethical 
responsibilities for participant safety and the safety of a study intervention under clinical 
investigation. 
For SAEs/pIMDs, the investigator will always provide an assessment of causality at the time of 
the initial report. 
Follow-up of relevant information on a pregnancy should be submitted the same way within 
2 weeks once this information becomes available. Pregnancy outcome should be reported within 
2 weeks. 
Local regulatory requirements and GSK’s policy for the preparation of an investigator safety 
report for Suspected Unexpected Serious Adverse Reactions must be followed. These reports 
will be forwarded to investigators as necessary. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 55 of 110 
GSK/IQVIA has a legal responsibility to notify local authorities and other regulatory agencies 
about the safety of a study intervention under clinical investigation. GSK/IQVIA will comply 
with country-specific regulatory requirements related to safety reporting to the regulatory 
authority, IRB/IEC, and investigators. 
Table 16 
Expedited Reporting of SAEs, Pregnancies, and pIMDs 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAE 
24 hours1,2,3 
electronic Expedited 
AE Report 
24 hours1 
electronic Expedited AE 
Report 
Pregnancy 
2 weeks1 
electronic Pregnancy 
Report 
2 weeks 
electronic Pregnancy 
Report  
pIMD 
24 hours2,4 
electronic Expedited 
AE Report 
24 hours1 
electronic Expedited AE 
Report 
AE = adverse event; pIMD = potentially immune-mediated disease; SAE = serious adverse event 
1 Timeframe allowed after receipt or awareness of the information by the investigator/study center staff. 
2 The investigator will confirm review of the SAE/pIMD causality by ticking the “reviewed” box in the electronic 
Expedited AE Report within 72 hours of submission of the SAE/pIMD. 
3 For coronavirus disease 2019 (COVID-19) related SAEs, reports should be submitted following routine 
procedures for SAEs. 
4 Timeframe allowed once the investigator determines that the event meets the protocol definition of an pIMD. 
8.3.6. Treatment of Adverse Events 
Any medication administered for the treatment of an AE should be recorded in the Expedited AE 
Report of the participant’s eCRF. 
8.3.7. Participant Card 
The investigator or investigator’s designee must provide the participant/participant’s 
parent(s)/LAR(s) with a “participant card” containing information about the clinical study. The 
participant/participant’s parent(s)/LAR(s) must be instructed to keep the participant card in 
her/their possession at all times throughout the study. In an emergency, this card serves to inform 
the responsible attending physician/LAR/caregiver/family member that the participant is in a 
clinical study and that relevant information may be obtained by contacting the investigator or 
his/her back-up. 
8.3.8. Medical Device Deficiencies 
This clinical study will collect information of any device deficiencies associated with the study 
interventions that are combination products. Refer to Glossary of Terms for the definition of a 
combination product and a medical device deficiency. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 56 of 110 
8.3.8.1. Detection, Follow-up, and Reporting of Medical Device Deficiencies 
The investigator is responsible for the detection, documentation and prompt reporting of any 
medical device deficiency occurring during the study to IQVIA. Device deficiencies should be 
reported within 24 hours after the investigator determines that the event meets the protocol 
definition of a device deficiency. New or updated information will be recorded on the originally 
completed form with all changes signed and dated by the investigator and reported to IQVIA 
within 24 hours. 
Refer to Appendix 4 for details on recording and reporting of medical device deficiencies. 
The investigator will ensure to follow the participants with reported device deficiencies and 
perform any additional investigations to determine the nature and/or causality of the deficiency. 
8.3.8.2. Regulatory Reporting of Medical Device Deficiency When Used as Combination 
Product 
The investigator will promptly report all device deficiencies occurring with any medical device 
provided for use in the study in order for IQVIA to fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety information relating to 
medical devices being used in clinical studies. Refer to Appendix 4 for details of reporting. 
The investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to the 
reporting of device deficiencies to the IRB/IEC. 
8.4. Study Procedures During Special Circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from local 
public health and other competent authorities regarding the protection of individuals’ welfare 
must be followed. For the duration of such special circumstances, the following measures may be 
implemented for enrolled participants: 
 Safety follow-up may be made by a phone call, other means of virtual contact, or home visit, 
if appropriate. 
 If the eDiary device was provided to the participant/participant’s parent(s)/LAR(s), it may be 
returned to the study center by conventional mail after the end of the relevant data collection 
period. If the application (app) was provided to the participants’ parent(s)/LAR(s) for use on 
their personal device, the app can be disabled remotely. 
 Biological samples may be collected at a different location* other than the study center or at 
participant’s home. Biological samples should not be collected if they cannot be processed in 
a timely manner or appropriately stored until the intended use. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 57 of 110 
*Note: It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH Good Clinical Practice (GCP) requirements, 
such as adequate facilities to perform study procedures, appropriate training of the staff, and 
documented delegation of responsibilities in this location. This alternate location may need to be 
covered by proper insurance for the conduct of study on participants by investigator and study 
center staff other than the designated study center. 
Any impact of the above-mentioned measures on the study data analysis and results will be 
determined on a case-by-case basis and reported upon the study completion. 
The impact on the Per Protocol Set (PPS) for immunogenicity will be determined on a 
case-by-case basis. Any impact of the above-mentioned measures on the study results will be 
described in the Clinical Study Report. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 58 of 110 
9. STATISTICAL CONSIDERATIONS 
9.1. Statistical Hypotheses 
The primary objective of the study will be evaluated descriptively. 
In this study, exploratory immunologic non-inferiority analyses will be performed, to help in 
decision making of the formulation selection for phase 3. 
9.2. Sample Size Determination 
The target enrollment is 1080 participants (270 participants in each group). 
The enrollment to the study will be performed in 2 steps. In Step 1, 48 participants (12 per 
group) will be enrolled and vaccinated. If no safety concern is identified, the remaining 
1032 participants will be enrolled and vaccinated in Step 2 to reach 1080 participants. 
9.2.1. Statistical Considerations on Safety Assessment 
In Step 1, the sample size of 12 participants per group would provide a probability of at least 
80% to observe at least 1 AE, if the true AE rate is equal to or greater than 12.6%. 
The sample size of 270 participants per group would provide a probability of at least 93% to 
observe at least 1 Grade 3 AE, if the true Grade 3 AE rate is equal to or greater than 1.0%. 
Table 17 provides the 2-sided 95% exact confidence interval (CI) for a range of AE rates 
(270 participants per group). 
Table 17 
2-sided 95% Exact Confidence Intervals for the True Adverse Event Rate for 
Various Observed Adverse Event Rates (270 Participants per Group) 
Participants 
vaccinated 
Observed number 
participants 
reporting the 
adverse events 
Observed 
percentage of 
participants with 
the adverse events  
2-sided 95% exact confidence interval 
Lower limit 
Upper limit 
 270 
0 
0.0 
0.0% 
1.4% 
1 
0.4 
0.0% 
2.0% 
10 
3.7 
1.8% 
6.7% 
27 
10.0 
6.7% 
14.2% 
30 
11.1 
7.6% 
15.5% 
50 
18.5 
14.1% 
23.7% 
100 
37.0 
31.3% 
43.1% 
150 
55.6 
49.4% 
61.6% 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 59 of 110 
If the true Grade 3 AE rate is 10%, with the sample size of 270 participants per group, the 
incidence of Grade 3 AEs above 14.2% with 97.5% confidence (14.2%=upper limit for 2-sided 
95% CI) will be ruled out. 
9.2.2. Statistical Considerations on Immunogenicity Assessment 
All the immunogenicity objectives in the study will be evaluated descriptively. 
Considering a 20% rate of non-evaluable participants, it is assumed that approximately 
864 evaluable participants (216 participants in each group) will be available for the evaluation of 
the primary immunogenicity objective. 
9.2.2.1. Exploratory Immunologic Non-Inferiority Analyses 
Exploratory immunologic non-inferiority analyses will be performed in the study, to help in 
decision making of the formulation selection for phase 3 (Table 18). 
The estimated sample size of 216 evaluable participants in each group provides at least 94% 
power to evaluate non-inferiority of a formulation in terms of antibody geometric mean 
concentrations (GMCs) measured by the electrochemiluminescence (ECL) assay. 
In order to control the global type I error to below 7.5%, Bonferroni correction will be applied. 
The non-inferiority of each of the investigational formulations will be assessed at 2.5% type I 
error. That is, the non-inferiority in terms of antibody GMC for the investigational formulation 
will be reached, if the lower limit of the 2-sided 95% CI for the antibody GMC ratio 
(investigational group/Gardasil 9 group) is not less than 0.5 for each of the 9 HPV types. To 
account for the multiplicity of comparison for 9 HPV types, the global type II errors are 
conservatively estimated as the sum of individual type II errors. 
Table 18 
Power to Show That the Lower Limit of the 2-sided 95% CI on Anti-HPV 
IgG Antibody GMC ratio (HPV-9 Vaccine Group Divided by Gardasil 9 
Group), 1 Month After Dose 3 is Not Less Than 0.5 
Standard deviation 
(Log10 [concentration]) 
N evaluable 
(in each group) 
Type II error for each HPV type 
Overall Power 
0.7 
216 
0.6% 
94.6% 
CI = confidence interval; GMC = geometric mean concentration; HPV = human papillomavirus virus; 
IgG = immunoglobulin G 
Power was obtained using PASS 2019, non-inferiority test for 2 means, under the alternative of equal means and 
variances. 
Since there are no immunogenicity data generated with the assay that will be used in this study, 
several studies with various multivalent HPV formulations in the age group 16-26 years were 
reviewed and a conservative standard deviation for log10 transformed antibody concentrations of 
0.7 for each of the 9 HPV types is used for the computation of power. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 60 of 110 
If the standard deviation for log10 transformed antibody concentrations is 0.47, the sample size 
of 216 evaluable participants in each group provides at least 73% power to assess the 
non-inferiority of a formulation in terms of antibody GMCs with a non-inferiority margin of 
0.67. 
The study also evaluates the immune responses using a neutralization assay as a secondary 
endpoint. If the standard deviation for log10 transformed antibody titers is around 0.6 as observed 
in HPV-019 (109823) study assessing GSK’s bivalent HPV-16/18 AS04-adjuvanted vaccine: 
 the sample size of at least 150 participants to obtain 120 evaluable participants at Month 7 
provides at least 74% power to assess the non-inferiority of a formulation to Gardasil 9 in 
terms of neutralizing antibody geometric mean titers (GMTs) with a non-inferiority margin 
of 0.5. 
 the sample size of at least 270 participants to obtain 216 evaluable participants provides at 
least 98% power to show the non-inferiority of a formulation to Gardasil 9 in terms of 
neutralizing antibody GMTs with a non-inferiority margin of 0.5. 
However, note that this does not take into account the multiplicity due to comparisons performed 
for antibody concentrations measured by ECL assay. 
9.3. Populations for Analyses 
Populations for analyses in this study are defined in Table 19. 
Table 19  
Study Analyses Sets 
Analysis set 
Description 
Enrolled set  
Participants who received a study vaccine or had a blood draw before study vaccine 
administration or were randomized. Note as per Good Clinical Practice (GCP) enrolled 
participants should have completed the informed consent process and participants should 
be eligible before initiating any study procedure. 
Exposed set (ES) 
All participants who received a study vaccine. Analysis per group is based on the study 
vaccine administered. 
A safety analysis based on the ES will include all vaccinated participants. 
An immunogenicity analysis based on ES will include all vaccinated participants for 
whom immunogenicity data are available. 
Per Protocol set (PPS) 
The per protocol set for analysis of immunogenicity will be defined by time point (to 
include all eligible participants’ data up to the time of important protocol deviations).  
The PPS will include all evaluable participants in the ES: 
 
Meeting all eligibility criteria. 
 
For whom the administration route of the vaccine was as according to protocol. 
 
For whom the study vaccine was administered as per protocol. 
 
Who did not receive a concomitant medication/product leading to exclusion 
from a PP analysis, as described in the protocol. 
 
Who did not present with a intercurrent medical condition leading to exclusion 
from a PP analysis, as described in the protocol. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 61 of 110 
Analysis set 
Description 
 
Who complied with the vaccination schedule, as specified in Table 1. 
 
Who complied with the timings of the post-vaccination blood sampling for 
immune response evaluation, as specified in Table 1. 
 
For whom post-vaccination immunogenicity results are available for at least 
one antigen at the corresponding time points. 
For discontinuation of study intervention and participant discontinuation/withdrawal details, see 
Section 7. 
9.4. Statistical Analyses 
The statistical analysis plan will be prepared and will include a more technical and detailed 
description of the statistical analyses including the supportive analyses and demography 
summaries. This section is a summary of the planned statistical analyses of the most important 
endpoints i.e., the primary and secondary endpoints. The safety analysis for the iSRC will be 
described separately. 
Unless otherwise mentioned, for all the planned analysis with CI, a 95% CI will be computed. 
9.4.1. Primary Endpoints Analyses 
9.4.1.1. Analysis Related to Safety and Reactogenicity 
The safety analysis will be based on the Exposed Set (ES). 
The percentage of participants reporting each solicited administration site event and systemic 
event assessed as Grade 3 in intensity during the solicited follow-up period (Day 1 – Day 7 after 
vaccine administration) will be tabulated, per dose and over the whole vaccination course, with 
exact 95% CI. 
The percentage of participants with at least 1 report of unsolicited AE assessed as Grade 3 in 
intensity classified by the Medical Dictionary for Regulatory Activities (MedDRA) reported up 
to 28 days after vaccination will be tabulated with exact 95% CI. 
The percentage of participants with at least 1 report of a SAEs classified by MedDRA from first 
vaccination up to Month 12, will be tabulated with exact 95% CI. 
The percentage of participants in Step 1 outside the defined normal ranges for each biochemical 
and hematological parameter measured in the study at Day 7 post-dose 1 will be tabulated with 
exact 95% CI. 
9.4.1.2. Immunogenicity Analyses 
The immunogenicity analysis for primary endpoints will be based on PPS for analysis of 
immunogenicity. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 62 of 110 
 
Within Groups Assessment 
For each group at Month 7 (1-month post-dose 3), antibody GMC with 95% CI and range of 
antibody concentrations will be tabulated for each antigen. 
9.4.2. Secondary Endpoints Analyses 
9.4.2.1. Analysis Related to Safety and Reactogenicity 
The safety analysis will be based on the ES. 
The percentage of participants reporting each solicited administration site event and systemic 
event during the solicited follow-up period (Day 1 – Day 7 after vaccine administration) will be 
tabulated, per dose and over the whole vaccination course, with exact 95% CI. 
The percentage of participants with at least 1 report of unsolicited AEs classified by MedDRA 
reported up to 28 days after vaccination will be tabulated with exact 95% CI. 
The percentage of participants with at least 1 report of a pIMD classified by MedDRA from first 
vaccination up to study end, will be tabulated with exact 95% CI. 
The percentage of participants who experienced pregnancy during the entire study period will be 
reported. The percentage of pregnancies and their outcomes will be reported. 
Pregnancies and their outcomes will be described in detail. 
SAEs and pIMDs will be described in detail. 
9.4.2.2. Immunogenicity Analyses 
The immunogenicity analysis for secondary endpoints will be based on PPS for analysis of 
immunogenicity. 
 
Within Groups Assessment 
For each group at each time point for which a blood sample result is available, the following 
analyses will be conducted: 
 Seroconversion and seropositivity rates for each antigen (with exact 95% CI) will be 
calculated. 
 Seroconversion is defined as the appearance of antibodies (i.e., concentrations/titer 
greater than or equal to the cut-off value) in the serum of participants seronegative 
before vaccination. 
 Antibody GMCs/GMTs with 95% CI and range of antibody concentrations/titers will be 
tabulated for each antigen. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 63 of 110 
 The antibody GMCs will be derived considering log-transformed concentrations are 
normally distributed with unknown variance. Concentration below the assay cut-off 
will be assigned half the cut-off for the purpose of antibody GMC computation. 
 The distribution of antibody concentrations/titers for each antigen will be displayed using 
reverse cumulative curves for the sub-cohort of initially seronegative participants. 
 Pearson coefficient of correlation between anti-HPV IgG antibody concentration and 
anti-HPV neutralizing antibody titers with associated P-value will be calculated for each 
investigational adjuvanted vaccines group and Gardasil 9 group for each antigen for 
timepoint and overall. The Pearson correlation coefficient is computed by log10 
transformation of specific antibody concentrations. Scatter plots will be generated. 
 
For each HPV type, the functional relationship between the pair of assay methods 
(pseudovirion-based neutralization assay [PBNA] versus ECL) will be estimated by 
timepoint using the Deming’s regression model (Brown et al, 2014).  
 
Exploratory Between Group Assessment 
For each HPV antigen, antibody GMC ratios and the 2-sided 95% CIs of antibody GMC ratios 
will be computed using an analysis of variance model on the log10 transformation of the 
antibody concentration adjusted for country effect. This analysis will be performed at Month 3 
(1-month post-dose 2) and at Month 7 (1-month post-dose 3) time points. The non-inferiority of 
different vaccine formulations to the control group will be assessed if the lower limit of the 
2-sided 95% CI is not less than the defined non-inferiority limit. 
Additional exploratory group comparisons may be performed to facilitate the formulation 
selection. 
9.4.3. iSRC Analyses 
The analysis will be based on the ES. The analyses will be further described in detail in the 
statistical analysis plan. 
 Demographic characteristics, baseline general medical and vaccination history, withdrawals 
from the study. 
 Study intervention exposure by group and by intervention.  
 Summary tables containing information on any events considered in the holding rules and 
other events (SAE, any withdrawal due to intervention-related AE, any AEs causing 
withdrawal from the study). 
 Incidence of solicited administration site AEs (pain, redness, swelling): any grade, Grade 3 
(2-days or more after Dose 1, 7-day follow-up period after intervention), any solicited 
administration site AEs leading to hospitalization within 7 days (Day 1 – Day 7) after each 
vaccine dose. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 64 of 110 
 Incidence of solicited systemic AEs (fever, headache, fatigue, myalgia, and arthralgia): any 
grade, Grade 3, any related, Grade 3 related (2-days or more after Dose 1, 7-day follow-up 
period after each intervention), any solicited systemic AEs leading to hospitalization, fever 
>40°C (104°F), within 7 days (Day 1 – Day 7) after each vaccine dose). 
 Incidence of unsolicited AEs: any, Grade 3, any related, Grade 3 related (7-day and 30-day 
follow-up period after each intervention). 
 Any, Grade 3 or above abnormality in pre-specified hematology and biochemistry parameters 
with an event onset within 7 days (Day 1 – Day 7) after each vaccine dose.  
 Incidence of SAEs: Any, any related, fatal, fatal related.  
 Incidence of pIMDs: Any, any related. 
 Any medically attended events. 
 Any pregnancy and pregnancy outcomes, overall and pregnancy exposures (i.e., exposures 
during pregnancy). 
 Summary tables containing information on concomitant medication/product during the 7-day 
follow-up period and during the 30-day follow-up period of each intervention. 
 Safety narratives, patient profiles and laboratory reports, if required. 
 Other information as deemed necessary by the iSRC. 
9.5. Interim Analyses 
9.5.1. Sequence of Analyses 
The analyses will be performed stepwise: 
 In preparation of the planned iSRC evaluations, analyses of all available safety data (as clean 
as possible) will be performed. The blinded and unblinded summaries will be generated. The 
unblinded analyses will be done by an Independent External Statistician to maintain the study 
blind and will be shared with iSRC members through a secured folder (refer to the iSRC 
charter). The outcome of the iSRC reviews will be communicated to the study team. 
 A first analysis will be performed on all data available, for primary and secondary endpoints 
up to Month 3 (1-month post-dose 2). This includes all safety data up to 1-month 
post-dose 2 for all participants, anti-HPV IgG data up to 1-month post-dose 2 for all 
participants* and anti-HPV neutralizing titers data up to 1-month post-dose 2 with at least 
150* participants/group for 1-month post-dose 2 timepoint. A clinical study report will be 
written. The investigators and the study team will not be provided with the individual data 
listings or with the randomization listings until the end-of-study analysis. 
 A second analysis will be performed on all available data, for primary and secondary 
endpoints up to Month 7 (1-month post-dose 3). This includes all safety data up to 1-month 
post-dose 3 for all participants, anti-HPV IgG data up to 1-month post-dose 3 for all 
participants and anti-HPV neutralizing titers data up to 1-month post-dose 3 with at least 
150* participants/group for 1-month post-dose 3 timepoint. Analysis will be documented in a 
statistical report. No clinical study report will be written. The investigators and the study 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 65 of 110 
team will not be provided with the individual data listings or with the randomization listings 
until the end-of-study analysis. 
 The final end-of-study-analysis will be performed when all data for primary and secondary 
endpoints up to study conclusion are available (Month 12). Individual listings will only be 
provided at this stage. 
 An integrated 
clinical study report containing all available data will be written. 
*In case of visit delay, analysis may be performed for as many participants as possible with data 
available at the time of the analysis. Analysis for remaining participants will be performed at the 
time of the next analysis. 
9.5.2. Statistical Considerations for Interim Analyses 
All analyses will be conducted on final data and therefore no statistical adjustment for interim 
analyses is required. 
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 66 of 110 
10. REFERENCES 
Arbyn M, Tommasino M, Depuydt C, et al. Are 20 human papillomavirus types causing cervical 
cancer? J Pathol. 2014 Dec;234(4):431-5. 
Bruni L, Albero G, Serrano B, et al. ICO/IARC. Information Centre on HPV and Cancer (HPV 
Information Centre). Human Papillomavirus and Related Diseases in the World. Summary 
Report 22 October 2021. Accessed 3 December 2021. 
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates 
of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 
2018;68(6):394-424. 
Brown D, Müller M, Sehr P, et al. Concordance assessment between a multiplexed competitive 
Luminex immunoassay, a multiplexed IgG Luminex immunoassay, and a pseudovirion-based 
neutralization assay for detection of human papillomaviruse types 16 and 18. Vaccine. 2014; 
32(44): 5880-5887 
Centers for Disease Control and Prevention (CDC). Human Papillomavirus (HPV). Last 
reviewed: July 23, 2021. https://www.cdc.gov/hpv/index.html. Accessed: 1 November 2021 
Drolet M, Bénard E, Pérez N, Brisson M, on behalf of the HPV Vaccination Impact Study 
Group. Population-level impact and herd effects following the introduction of human 
papillomavirus vaccination programmes: updated systematic review and meta-analysis. The 
Lancet, 2019; 394 (10197): 497-509. 
Götz C, Bischof C, Wolff KD, et al. Detection of HPV infection in head and neck cancers: 
Promise and pitfalls in the last ten years: A meta-analysis. Mol Clin Oncol. 2019; 10(1): 17-28 
Hartwig S, Syrjanen S, Dominiak-Felden G, et al. Estimation of the epidemiological burden of 
human papillomavirus-related cancers and non-malignant diseases in men in Europe: a review 
BMC Cancer. 2012 Jan 20;12:30. 
Hoes J, Pasmans H, Knol MJ, et al. Persisting Antibody Response 9 Years After Bivalent 
Human Papillomavirus (HPV) Vaccination in a Cohort of Dutch Women: Immune Response and 
the Relation to Genital HPV Infections. J Infect Dis. 2020; 221(11):1884-1894. 
ICH Harmonised Tripartite ICH Guideline for Good Clinical Practices E6 (R1). 1997 Federal 
Register, 62 (90):25691-25709 
Mesher D, Panwar K, Thomas SL, et al. The Impact of the National HPV Vaccination Program 
in England Using the Bivalent HPV Vaccine: Surveillance of Type-Specific HPV in Young 
Females, 2010-2016. J Infect Dis. 2018;218(6):911-921. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 67 of 110 
Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, Cruickshank M. 
Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-
13 in Scotland: retrospective population study. BMJ. 2019; 365: l1161. 
Pasmans H, Schurink-van't Klooster T, Bogaard M, van Rooijen D, de Melker H, Welters M, et 
al. Long-term HPV-specific immune response after one versus two and three doses of bivalent 
HPV vaccination in Dutch girls. Vaccine. 2019; 37(49):7280-88. 
Ruggerberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines for data 
collection, analysis, and presentation of immunization safety data. Vaccine. 2007; 25(31): 5675-
84. 
Tavares Da Silva F, De Keyser F, Lambert PH, et al. Optimal approaches to data collection and 
analysis of potential immune-mediated disorders in clinical trials of new vaccines. Vaccine 2013; 
31(14): 1870-1876. 
WHO Global strategy to accelerate the elimination of cervical cancer as a public health problem. 
Geneva: World Health Organization; 2020. License: CC BY-NC-SA 3.0 IGO. 
Woestenberg PJ, King AJ, van Benthem BHB, et al. (2018) Bivalent Vaccine Effectiveness 
Against Type-Specific HPV Positivity: Evidence for Cross-Protection Against Oncogenic Types 
Among Dutch STI Clinic Visitors. J Infect Dis. 2020. 217(2):213-22. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 68 of 110 
11. APPENDICES 
APPENDIX 1 
ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Definition 
ADE 
Adverse device effect 
AE 
Adverse event 
AESI 
Adverse event of special interest 
app 
Application 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
eCRF 
Electronic case report form 
ECL 
Electrochemiluminescence 
EDC 
Electronic Data Capture system  
eDiary 
Electronic diary 
EoS 
End of study 
ES 
Exposed set 
FSH 
Follicle stimulating hormone  
GCP 
Good Clinical Practice 
GMC 
Geometric mean concentration 
GSK 
GlaxoSmithKline Biologicals SA 
HPV 
Human papillomavirus 
HRT 
Hormonal replacement therapy  
IAF 
Informed assent form 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS 
Intracellular cytokine staining 
ID number 
Identification number 
IEC 
Independent Ethics Committee 
igG 
Immunoglobulin G 
IM 
Intramuscularly 
IRB 
Institutional Review Board 
IRT 
Interactive Response Tool 
iSRC 
Internal Safety Review Committee  
IVRS 
Interactive Voice Response System  
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 69 of 110 
IWRS 
Interactive Web Response System  
LAR 
Legally acceptable representative 
LPLV 
Last participant last visit 
MedDRA 
Medical Dictionary for Regulatory Activities  
PBNA 
Pseudovirion-based neutralization assay 
pIMD  
Potential immune-mediated disease 
PPS 
Per protocol set 
QTL 
Quality tolerance limit 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SoA 
Schedule of activities 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
USADE 
Unanticipated serious adverse device effect 
VLP 
Virus-like particle 
WHO 
World Health Organisation 
Glossary of Terms 
Blinding 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an acceptable 
level of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In a 
double-blind trial, the participant, the investigator and 
sponsor staff who are involved in the treatment or clinical 
evaluation of the participants and the review or analysis of 
data are all unaware of the intervention assignment. In an 
observer-blind study, the participant, the study center and 
sponsor or sponsor’s designee’s personnel involved in the 
clinical evaluation of the participants are blinded while 
other study personnel may be aware of the treatment 
assignment.  
Caregiver 
In the context of a clinical study, a caregiver could include 
an individual appointed to oversee and support the 
participant's compliance with protocol specified 
procedures. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 70 of 110 
Child in care 
A child who has been placed under the control or 
protection of an agency, organization, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted. 
Combination product 
Combination product comprises any combination of 
 drug 
 device 
 biological product 
Each drug, device, and biological product included in a 
combination product is a constituent part. 
Eligible (participant) 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrolled (participant) 
“Enrolled” means a participant’s/participant’s 
parent(s)’/LAR(s)’ agreement to participate in a clinical 
study following completion of the informed consent 
process. Potential participants who are evaluated for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the 
data produced. 
Evaluable (participant) 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per protocol analysis. 
Immunological correlate 
of protection 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
Intercurrent medical 
Conditions 
A condition that has the capability of altering a 
participant’s immune response including an 
immunodeficiency condition diagnosed during the study. 
Intervention 
Term used throughout the clinical study to denote a set of 
investigational product or marketed product or placebo 
intended to be administered to a participant. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 71 of 110 
Invasive medical device 
A device which, in whole or in part, penetrates inside the 
body, either through a body orifice or through the surface 
of the body. 
Investigational 
vaccine/product 
A pharmaceutical form of an active ingredient being 
tested in a clinical study, including a product with a 
marketing authorization when used in a way different 
from the approved form, or when used for an unapproved 
indication, or when used to gain further information about 
an approved use. 
Investigator 
A person responsible for the conduct of the clinical study 
at a study center. If a study is conducted by a team of 
individuals at a study center, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study center to qualified 
individual or party to perform those study-related duties 
and functions. 
Interactive voice/web 
response system 
The software that enables the randomizing of participants 
into clinical trials and allocation of the study product to 
them in a blinded fashion. This technology allows study 
centers to interact with a database by following voice/web 
prompts in order to enter the information. 
Legally acceptable 
representative 
An individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective 
participant, to the participant's participation in the clinical 
study. 
The terms legal representative, legally authorized 
representative are used in some settings. 
Medically attended AEs 
Symptoms or illnesses requiring hospitalization, or 
emergency room visit, or visit to/by a health care 
provider.  
Medical device deficiency 
A device deficiency is an inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, 
safety, or performance. Device deficiencies include 
malfunctions, use errors and information supplied by the 
manufacturer. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 72 of 110 
Medical Monitor 
IQVIA’s delegate providing significant scientific 
contribution to the conduct of the study. 
Study/Site Monitor 
An individual assigned by the sponsor or sponsor’s 
designee and responsible for assuring proper conduct of 
clinical studies at 1 or more study centers. The terms 
Clinical Research Monitor and Clinical Research 
Associate are used in some settings. 
Participant 
Term used throughout the protocol to denote an individual 
who has been contacted to participate or participates in the 
clinical study, either as a recipient of the 
vaccine(s)/product or as a control. 
Synonym: subject 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Solicited event 
Events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the participant or an observer 
during a specified post-vaccination follow-up period. 
Source data 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data are 
contained in source documents (original records or 
certified copies). A certified copy is a copy (irrespective 
of the type of media used) of the original record that has 
been verified (i.e., by a dated signature or by generation 
through a validated process) to have the same information, 
including data that describe the context, content, and 
structure, as the original. 
Source documents 
Original legible documents, data, and records (e.g., 
hospital records, clinical and office charts, laboratory 
notes, memoranda, participants' diaries, memory aids, or 
evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate 
copies, microfiches, photographic negatives, microfilm or 
magnetic media, X-rays, participant files, and records kept 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 73 of 110 
at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical 
study). 
Treatment number 
A number identifying intervention given to a participant, 
according to intervention allocation. 
Unsolicited adverse event 
Any AE reported in addition to those solicited during the 
clinical study. Also, any “solicited” symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited AE. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 74 of 110 
APPENDIX 2 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisation of Medical 
Sciences International Ethical Guidelines 
 Applicable ICH GCP Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF and IAF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the study 
is initiated. 
 Any protocol amendments will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
 IQVIA will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 Notifying the IRB/IEC of SAE(s) or other significant safety findings as required by 
IRB/IEC procedures. 
 Providing oversight of the conduct of the study at the study center and adherence to 
requirements of Code of Federal Regulations (CFR) Title 21, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
 After reading the protocol, each investigator will sign the protocol signature page 
(Appendix 7) and send a copy of the signed page to IQVIA. The study will not start at 
any study center at which the investigator has not signed the protocol. 
Financial Disclosure 
Investigators and sub-investigators will provide IQVIA with sufficient, accurate financial 
information as requested to allow GSK or IQVIA to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing financial interest information prior to initiation of the study center. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 75 of 110 
Investigators are responsible for providing the financial information update if their financial 
interests change at any point during their participation in a study and for 1 year after completion 
of the study. 
Insurance 
GSK will provide insurance in accordance with local guidelines and requirements as a minimum 
for the participants in this study. The terms of the insurance will be kept in the study files. 
Informed Consent and Assent Process 
 The investigator or his/her representative must fully explain the nature of the study to the 
participant/participant’s parent(s)/LAR(s) and answer all questions regarding the study. 
 Participant/participant’s parent(s)/LAR(s) must be informed that their participation is 
voluntary.  
 Freely given and written/witnessed/thumb printed informed consent must be obtained 
from each participant/participant’s parent(s)/LAR(s)/witness and participant informed 
assent as appropriate, prior to participation in the study. 
 The content of the ICF must meet the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
 The medical record must include a statement that informed consent and assent (if 
applicable) was obtained before the participant was enrolled in the study and the date the 
written consent and assent (if applicable) was obtained. The authorized person obtaining 
the informed consent and assent (if applicable) must also sign the ICF (and IAF if 
applicable). 
 Participants must be re-consented to the most current version of the ICF(s) (and IAFs if 
applicable) during their participation in the study. 
 Re-consent must be obtained in accordance with local laws and regulations for 
participants who become legally emancipated during the study, i.e., reach the legal age of 
consent. The participant can provide consent by signing/witnessing/thumb printing an 
ICF (and IAF if applicable), similar to that provided to the parent(s)/LAR(s) at study 
start, which summarizes the study and includes a consent statement and documents that 
the participant agrees to continue participating in the study. 
 A copy of the ICF(s) (and IAF[s]if applicable) must be provided to the 
participant/participants’ parent(s)/LAR(s). 
 The study investigator is encouraged to obtain IAF from the minor in addition to the ICF 
provided by the parent(s)/LAR(s) when a minor can assent to decisions about her 
participation in the study. The investigator is also accountable for determining a minor's 
capacity to assent to participation in a research study according to the local laws and 
regulations. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 76 of 110 
Data Protection 
Participants will be assigned a unique identifier. Any participant records or datasets transferred 
to IQVIA/GSK will contain only the identifier. Name and any other information which would 
identify the participant will not be transferred.  
The participants/participants’ parent(s)/LAR(s) must be informed that: 
 The participant’s study-related data will be used by IQVIA/GSK in accordance with local 
data protection law. 
 The participant’s medical records may be examined by Clinical Quality Assurance auditors 
or other authorized personnel appointed by GSK/IQVIA, by appropriate IRB/IEC members, 
and by inspectors from regulatory authorities. 
 IQVIA/GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study, in accordance 
with the Data Privacy Notice that will be sent to the site staff.  
 The participants/participants’ parent(s)/LAR(s) must be notified about their rights regarding 
the use of their personal data in accordance with the data privacy section of the ICF (and IAF 
if applicable). 
Administrative Structure 
Table 20 
Study Administrative Structure 
Function 
Responsible Organization 
Study Operations Management, Medical Monitoring, Study Master File 
IQVIA 
Randomization, Blinding, Unblinding 
Cenduit 
Clinical Supply Management, Quality Assurance Auditing 
GSK 
Biostatistics, Medical Writing 
IQVIA 
Laboratory Assessments 
GSK 
Internal Safety Review Committee and Safety Review Team 
GSK 
Medical Monitor 
Refer to the SRM. 
Dissemination of Clinical Study Data 
 The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study register in compliance with the 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 77 of 110 
 Where required by regulation, summaries will also be posted on applicable national or 
regional clinical study registers. 
 Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. IQVIA will also provide the investigator 
with the full summary of the study results. The investigator is encouraged to share the 
summary results with the study participants and/or participant’s parent(s)/LAR(s), as 
appropriate. 
 IQVIA will provide the investigator with the randomization codes for their study center 
only after completion of the full statistical analysis. 
 GSK intends to make anonymized patient-level data from this study available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by study 
participants are used to maximum effect in the creation of knowledge and understanding. 
Data Quality Assurance 
 The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents (see Glossary of Terms for definitions of 
essential documents and source documents). The storage system used during the study 
and for archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
 Essential study documents may be added or removed where justified (in advance of study 
initiation) based on their importance and relevance to the study. When a copy is used to 
replace an original document (e.g., source documents, eCRF), the copy should fulfill the 
requirements for certified copies.  
 All participant data relating to the study will be recorded on eCRF (or printed Case 
Report Form in case of an EDC failure) unless transmitted to GSK or IQVIA 
electronically (e.g., laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF.  
 The investigator must maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s participants 
that supports information entered in the eCRF.  
 The completion of the eDiary will be checked by the investigator/designee at the study 
visits and these checks will be documented as applicable. The instructions on the review 
of the eDiary will be provided to the site separately (e.g., eDiary manual or SRM). 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection.  
 IQVIA is responsible for the data management of this study including quality checking of 
the source data.  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 78 of 110 
 Study/Site Monitors (see the definition in Glossary of Terms) will perform ongoing 
source data verification to confirm that data entered into the eCRF by authorized study 
center personnel are attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry, and should be fully explained if necessary (e.g., via an audit trail). The safety and 
rights of participants must be protected and study be conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
 Quality Tolerance Limits (QTLs) will be pre-defined to identify systematic issues that 
can impact participant safety and/or the reliability of study results. These pre-defined 
parameters will be monitored during the study. Important deviations from the QTLs and 
remedial actions taken will be summarized in the Clinical Study Report. 
 Study records and source documents, including signed ICF and IAF (as applicable), 
pertaining to the conduct of this study must be retained by the investigator for 25 years 
from the issue of the final Clinical Study Report/equivalent summary unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval from GSK. No records 
may be transferred to another location or party without written notification to 
GSK/IQVIA. 
Source Documents 
 Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of the data collected. Investigator should maintain a record of 
the location(s) of their source documents.  
 Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any 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. 
 Definition of what constitutes source data and source documents is provided in  
Glossary of Terms. 
Study and Study Center Closure 
GSK/IQVIA reserves the right to close the study center or terminate the study at any time for any 
reason at the sole discretion of GSK, provided there is sufficient notice given to account for 
participant’s safe exit from study participation. Study center regular closure will occur upon 
study completion. A study center is considered closed when all required data/documents and 
study supplies have been collected and a study center closure visit has been performed.  
The investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 79 of 110 
Reasons for the early closure of a study center by IQVIA/GSK or investigator may include but 
are not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, GSK/IQVIA’s procedures, or GCP guidelines 
 Inadequate recruitment of participants by the investigator 
 Discontinuation of further study intervention development 
 Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, IQVIA shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, for the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participants and should assure appropriate participant therapy and/or 
follow-up. 
Publication Policy 
GSK aims to submit for publication the results of the study in searchable, peer reviewed 
scientific literature within 18 months from LPLV for interventional studies and follows 
authorship and other guidance from the International Committee of Medical Journal Editors. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 80 of 110 
APPENDIX 3 
CLINICAL LABORATORY TESTS 
For assessment of immune response, blood sample will be drawn at Day 1, Month 2, Month 3, 
Month 6, Month 7 and Month 12 in all participants. IgG antibody determination by ECL 
multiplex methodology will be performed for all timepoints in all participants. 
Pseudovirion-Based Neutralization Assays (PBNA) will be performed on the following subsets: 
Day 1 (all participants), Month 2 (in a subset of 384 participants from Step 2 [96 participants in 
each group]), Month 3 (all participants) and Month 7 (at least 150 participants in each group 
from Step 2). 
 
For these participants 
collection of an additional blood sample is foreseen at Day 1 and one month after the third dose 
(Month 7). 
Humoral Immunity 
Humoral Immunity: HPV IgG concentration by multiplex immunoassay (ECL) 
The anti-HPV-6/11/16/18/31/33/45/52/58 IgG response will be measured using the ECL 
multiplex technology from
 
 
  
The HPV9-AS04 ECL assay will be qualified prior the clinical testing of this study, meaning that 
the assay performance characteristics will be assessed, including limit of detection, precision, 
linearity, accuracy, specificity, robustness and stability.  
The assay qualification report and assay Standard Operation Procedure will be submitted to the 
Investigational New Drug application when available. 
The assay will be performed at GSK, Clinical Laboratory Sciences (Rixensart/Wavre, Belgium). 
Humoral Immunity: HPV neutralizing assay (PBNA) 
The neutralizing antibodies will be determined by the PBNA for HPV-
6/11/16/18/31/33/45/52/58 performed at the 
 
 with some adaptations (secondary 
endpoint). 
  
The PBNAs for the 9 HPV types will be qualified at 
 prior the clinical testing 
of the phase 1/2 study, meaning that assay performance characteristics including limit of 
detection, precision, linearity, specificity, robustness and stability will be assessed.  
The assay qualification report and assay Standard Operation Procedure will be submitted to the 
IND when available. 
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 81 of 110 
The assay will be performed by 
, Germany. 
 
CCI
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 82 of 110 
APPENDIX 4 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
Definition of an AE 
An AE is any untoward medical occurrence (an unfavorable/unintended sign - including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical study 
participant that is temporally associated with the study intervention. The AE may or may not be 
considered related to the study intervention. 
Events Meeting the AE Definition 
 Significant or unexpected worsening or exacerbation of the condition/indication under 
study. 
 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 vaccine(s)/product administration even 
though they may have been present prior to the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
vaccine(s)/product or a concurrent medication (overdose per se should not be reported as 
an AE/SAE). 
 Signs or symptoms temporally associated with study vaccine(s)/product administration. 
 Signs, symptoms that require medical attention (e.g., hospital stays, physician visits and 
emergency room visits). 
 Significant failure of an expected pharmacologic or biological action.  
 Pre- or post-intervention events that occur as a result of protocol-mandated procedures 
(i.e., invasive procedures, modification of participant’s previous therapeutic regimen). 
 Clinically significant abnormal laboratory findings or other abnormal assessments that are 
present at baseline and significantly worsen following the start of the study will also be 
reported as AEs or SAEs. 
 AEs to be recorded as solicited AEs are described in the Table 11. All other AEs will be 
recorded as UNSOLICITED AEs. 
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
 Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital, admission for routine examination). 
 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.  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 83 of 110 
 Pre-existing conditions or signs and/or symptoms present in a participant prior to the first 
study vaccination. These events will be recorded in the medical history section of the 
eCRF. 
 Hospitalization for elective treatment of a pre-existing condition (known or diagnosed 
prior to informed consent signature) that did not worsen from baseline. 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant’s condition. 
Definition of an SAE  
An SAE is any untoward medical occurrence that: 
a) Results in death 
b) Is life-threatening 
Note: 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, had it been more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or in an outpatient 
setting. Complications that occur during hospitalization are also considered as AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event will also 
be considered serious. When in doubt as to whether “hospitalization” occurred, or was 
necessary, the AE should be considered serious. 
d) Results in disability/incapacity  
Note: 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 
like illness, and accidental trauma (e.g., sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect in the offspring of a study participant  
f) Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g) Other situations 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events are 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. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Solicited Events 
Solicited events (systemic and administration site events) will include the events listed in 
Table 11. 
Unsolicited AEs 
An unsolicited AE is an AE that was not included in the list of solicited using an eDiary and that 
was spontaneously communicated by a participant/participant’s parent(s)/LAR(s) who has signed 
the informed consent. Unsolicited AEs include serious and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses requiring a 
hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participants/participants’ parents/LARs will be instructed to contact the study center as soon as 
possible to report medically attended events, as well as any events that, though not medically 
attended, are of participant/parental/LAR’s concern. Detailed information about reported 
unsolicited AEs will be collected by qualified study center personnel and documented in the 
participant’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant/participant’s parent(s)/LAR(s) will be collected during an interview with the 
participants/participant’s parent(s)/LAR(s) and by review of available medical records at the next 
visit. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are pre-defined (serious or non-serious) AEs of 
scientific and medical concern specific to the product or program, for which ongoing monitoring 
and rapid communication by the investigator to the sponsor can be appropriate, because such an 
event might warrant further investigation in order to characterize and understand it. 
Potential Immune-Mediated Diseases 
pIMDs are a subset of AESIs that include autoimmune diseases and other inflammatory and/or 
neurologic disorders of interest which may or may not have an autoimmune etiology. AEs that 
need to be recorded and reported as pIMDs include those listed in Table 21. 
The investigator must exercise their medical and scientific judgment to determine whether other 
diseases have an autoimmune origin (i.e., pathophysiology involving systemic or organ-specific 
pathogenic autoantibodies) and should also be recorded as a pIMD. 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard questionnaire 
and a list of MedDRA preferred term codes corresponding to the above diagnoses will be 
available to investigators at study start.  
Page 84 of 110 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 85 of 110 
When there is enough evidence to make any of the pIMD diagnoses, the AE must be reported as 
pIMD. Symptoms, signs, or conditions which might (or might not) lead to one of these 
diagnoses, should be recorded and reported as AEs but not as pIMDs until the final or definitive 
diagnosis has been made, and alternative diagnoses eliminated or shown to be less likely. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 86 of 110 
Table 21 
List of Potential Immune-Mediated Diseases 
Medical Concept 
Additional Notes 
Blood disorders and coagulopathies 
Antiphospholipid syndrome 
 
Autoimmune aplastic anemia 
 
Autoimmune hemolytic anemia 
 
Includes warm antibody hemolytic anemia and cold antibody hemolytic anemia 
Autoimmune lymphoproliferative syndrome 
(ALPS) 
 
Autoimmune neutropenia  
 
Autoimmune pancytopenia 
 
Autoimmune thrombocytopenia 
 
Evans syndrome 
 
Pernicious anemia 
 
Thrombosis with thrombocytopenia 
syndrome (TTS) 
 
Thrombotic thrombocytopenic purpura 
 
Cardio-pulmonary inflammatory disorders 
Idiopathic Myocarditis/Pericarditis 
 
Autoimmune / Immune-mediated myocarditis 
 
Autoimmune / Immune-mediated pericarditis 
 
Giant cell myocarditis 
Idiopathic pulmonary fibrosis 
Including but not limited to: 
 
Idiopathic interstitial pneumonia (frequently used related terms include “Interstitial lung disease”, 
“Pulmonary fibrosis”, “Immune-mediated pneumonitis”) 
Pulmonary alveolar proteinosis (PAP) 
 
Pleuroparenchymal fibroelastosis (PPFE) 
 
Endocrine disorders 
Addison’s disease 
 
Autoimmune / Immune-mediated thyroiditis  
Including but not limited to: 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 87 of 110 
Medical Concept 
Additional Notes 
 
Hashimoto thyroiditis (autoimmune hypothyroidism, lymphocytic thyroiditis) 
 
Atrophic thyroiditis  
 
Silent thyroiditis  
 
Thyrotoxicosis 
Autoimmune diseases of the testis and ovary 
 
Autoimmune hyperlipidemia 
 
Autoimmune hypophysitis 
 
Diabetes mellitus type I 
 
Grave's or Basedow’s disease 
 
Includes Marine Lenhart syndrome and Graves' ophthalmopathy, also known as thyroid eye disease 
(TED) or endocrine ophthalmopathy 
Insulin autoimmune syndrome 
 
Polyglandular autoimmune syndrome 
 
Includes Polyglandular autoimmune syndrome type I, II and III 
Eye disorders 
Ocular Autoimmune / Immune-mediated 
disorders 
Including but not limited to: 
 
Acute macular neuroretinopathy (also known as acute macular outer retinopathy) 
 
Autoimmune / Immune-mediated retinopathy  
 
Autoimmune / Immune-mediated uveitis, including idiopathic uveitis and sympathetic ophthalmia  
 
Cogan's syndrome: an oculo-audiovestibular disease 
 
Ocular pemphigoid 
 
Ulcerative keratitis 
 
Vogt-Koyanagi-Harada disease 
Gastrointestinal disorders 
Autoimmune / Immune-mediated 
pancreatitis 
 
Celiac disease 
 
Inflammatory Bowel disease  
Including but not limited to:  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 88 of 110 
Medical Concept 
Additional Notes 
 
Crohn’s disease  
 
Microscopic colitis  
 
Terminal ileitis 
 
Ulcerative colitis  
 
Ulcerative proctitis 
Hepatobiliary disorders 
Autoimmune cholangitis 
 
Autoimmune hepatitis 
 
Primary biliary cirrhosis 
 
Primary sclerosing cholangitis 
 
Musculoskeletal and connective tissue disorders  
Gout 
 
Includes gouty arthritis 
Idiopathic inflammatory myopathies 
Including but not limited to: 
 
Dermatomyositis 
 
Inclusion body myositis 
 
Immune-mediated necrotizing myopathy 
 
Polymyositis 
Mixed connective tissue disorder 
 
Polymyalgia rheumatica (PMR) 
 
Psoriatic arthritis (PsA) 
 
Relapsing polychondritis 
 
Rheumatoid arthritis  
Including but not limited to: 
 
Rheumatoid arthritis associated conditions 
 
Juvenile idiopathic arthritis 
 
Palindromic rheumatism 
 
Still's disease 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 89 of 110 
Medical Concept 
Additional Notes 
 
Felty’s syndrome 
Sjögren’s syndrome 
 
Spondyloarthritis 
Including but not limited to:  
 
Ankylosing spondylitis 
 
Juvenile spondyloarthritis 
 
Keratoderma blennorrhagica 
 
Psoriatic spondylitis  
 
Reactive Arthritis (Reiter's Syndrome) 
 
Undifferentiated spondyloarthritis 
Systemic Lupus Erythematosus  
 
Includes lupus associated conditions (e.g., cutaneous lupus erythematosus, lupus nephritis, etc.) or 
complications such as shrinking lung syndrome (SLS) 
Systemic Scleroderma (Systemic Sclerosis) 
 
Includes Reynolds syndrome (RS), systemic sclerosis with diffuse scleroderma and systemic sclerosis 
with limited scleroderma (also known as CREST syndrome) 
Neuroinflammatory/neuromuscular disorders 
Acute disseminated encephalomyelitis 
(ADEM) and other inflammatory-
demyelinating variants  
Includes the following: 
 
Acute necrotizing myelitis 
 
Bickerstaff's brainstem encephalitis  
 
Disseminated necrotizing leukoencephalopathy (also known as Weston-Hurst syndrome, acute 
hemorrhagic leuko-encephalitis, or acute necrotizing hemorrhagic encephalomyelitis)  
 
Myelin oligodendrocyte glycoprotein antibody-associated disease 
 
Neuromyelitis optica (also known as Devic’s disease) 
 
Noninfective encephalitis / encephalomyelitis / myelitis 
 
Postimmunization encephalomyelitis  
Guillain-Barré syndrome (GBS) 
 
Includes variants such as Miller Fisher syndrome and the acute motor and sensory axonal neuropathy 
(AMSAN) 
Idiopathic cranial nerve palsies/paresis and 
inflammations (neuritis) 
Including but not limited to: 
 
Cranial nerve neuritis (e.g., optic neuritis) 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 90 of 110 
Medical Concept 
Additional Notes 
 
Idiopathic nerve palsies/paresis (e.g., Bell’s palsy) 
 
Melkersson-Rosenthal syndrome 
 
Multiple cranial nerve palsies/paresis  
Multiple Sclerosis (MS) 
Includes the following: 
 
Clinically isolated syndrome (CIS)  
 
Malignant MS (the Marburg type of MS)  
 
Primary-progressive MS (PPMS) 
 
Radiologically isolated syndrome (RIS) 
 
Relapsing-remitting MS (RRMS) 
 
Secondary-progressive MS (SPMS) 
 
Uhthoff's phenomenon  
Myasthenia gravis 
 
Includes ocular myasthenia and Lambert-Eaton myasthenic syndrome 
Narcolepsy 
 
Includes narcolepsy with or without presence of unambiguous cataplexy 
Peripheral inflammatory-demyelinating 
neuropathies and plexopathies 
Including but not limited to: 
 
Acute Brachial Radiculitis (also known as Parsonage-Turner Syndrome or neuralgic amyotrophy) 
 
Antibody-mediated demyelinating neuropathy 
 
Chronic idiopathic axonal polyneuropathy (CIAP) 
 
Chronic Inflammatory-Demyelinating Polyradiculoneuropathy (CIDP), including atypical CIDP 
variants (e.g., multifocal acquired demyelinating sensory and motor neuropathy also known as Lewis-
Sumner syndrome) 
 
Multifocal motor neuropathy (MMN)  
Transverse myelitis (TM) 
 
Includes acute partial transverse myelitis (APTM) and acute complete transverse myelitis (ACTM) 
Renal disorders 
Autoimmune / Immune-mediated 
glomerulonephritis  
Including but not limited to: 
 
IgA nephropathy 
 
IgM nephropathy 
 
C1q nephropathy 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 91 of 110 
Medical Concept 
Additional Notes 
 
Fibrillary glomerulonephritis 
 
Anti-glomerular basement membrane disease 
 
Glomerulonephritis rapidly progressive 
 
Membranoproliferative glomerulonephritis 
 
Membranous glomerulonephritis 
 
Mesangioproliferative glomerulonephritis 
 
Tubulointerstitial nephritis and uveitis syndrome 
Skin and subcutaneous tissue disorders 
Alopecia areata 
 
Autoimmune / Immune-mediated blistering 
dermatoses  
Including but not limited to:  
 
Bullous Dermatitis 
 
Bullous Pemphigoid  
 
Dermatitis herpetiformis  
 
Epidermolysis bullosa acquisita (EBA)  
 
Linear IgA-mediated bullous dermatosis (LABD), also known as Linear IgA disease 
 
Pemphigus  
Erythema multiforme 
 
Erythema nodosum 
 
Interstitial granulomatous dermatitis 
 
Lichen planus 
 
Includes lichen planopilaris 
Localized Scleroderma (Morphoea) 
 
Includes Eosinophilic fasciitis (also called Shulman syndrome) 
Palisaded neutrophilic granulomatous 
dermatitis 
 
Psoriasis 
 
Pyoderma gangrenosum 
 
Stevens-Johnson Syndrome (SJS) 
Including but not limited to:  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 92 of 110 
Medical Concept 
Additional Notes 
 
 
Toxic Epidermal Necrolysis (TEN)  
 
SJS-TEN overlap 
Sweet’s syndrome 
 
Includes Acute febrile neutrophilic dermatosis 
Vitiligo 
 
Vasculitis 
Large vessels vasculitis  
Including but not limited to: 
 
Arteritic anterior ischemic optic neuropathy (AAION or arteritic AION) 
 
Giant cell arteritis (also called temporal arteritis)  
 
Takayasu's arteritis  
Medium sized and/or small vessels vasculitis  
Including but not limited to: 
 
Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type unspecified)  
 
Behcet's syndrome  
 
Buerger’s disease (thromboangiitis obliterans) 
 
Churg–Strauss syndrome (allergic granulomatous angiitis)  
 
Erythema induratum (also known as nodular vasculitis) 
 
Henoch-Schönlein purpura (also known as IgA vasculitis) 
 
Microscopic polyangiitis 
 
Necrotizing vasculitis 
 
Polyarteritis nodosa 
 
Single organ cutaneous vasculitis, including leukocytoclastic vasculitis, hypersensitivity vasculitis and 
acute hemorrhagic edema of infancy (AHEI) 
 
Wegener's granulomatosis  
Other (including multisystemic) 
Anti-synthetase syndrome 
 
Capillary leak syndrome 
 
Goodpasture syndrome 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 93 of 110 
Medical Concept 
Additional Notes 
Immune-mediated enhancement of disease 
 
Includes vaccine associated enhanced disease (VAED and VAERD). Frequently used related terms 
include “vaccine-mediated enhanced disease (VMED)”, “enhanced respiratory disease (ERD)”, 
“vaccine-induced enhancement of infection”, “disease enhancement”, “immune enhancement”, and 
“antibody-dependent enhancement (ADE)” 
Immunoglobulin G4 related disease 
 
Langerhans' cell histiocytosis 
 
Multisystem inflammatory syndromes 
Including but not limited to: 
 
Kawasaki’s disease 
 
Multisystem inflammatory syndrome in adults (MIS-A) 
 
Multisystem inflammatory syndrome in children (MIS-C)  
Overlap syndrome 
 
Pulmonary renal syndrome 
 
Raynaud’s phenomenon 
 
Sarcoidosis 
 
Includes Loefgren syndrome 
Susac's syndrome 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 94 of 110 
Clinical Laboratory Parameters and Other Abnormal Assessments Qualifying as 
AEs/SAEs 
In the absence of a diagnosis, abnormal laboratory findings, assessments, or other abnormal 
results the investigator considers clinically significant will be recorded as an AE or SAE, if they 
meet the definition of an AE or SAE. The investigator must exercise his/her medical and 
scientific judgment in deciding whether an abnormal laboratory finding, or other abnormal 
assessment is clinically significant. 
COVID-19 Cases 
Diagnosis of COVID-19 should be made in accordance with the World Health Organization case 
definition. Cases should be categorized as AEs or SAEs, and routine procedures for recording, 
evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance with 
the time period set out in the protocol. 
Events or Outcomes Not Qualifying as AEs/SAEs: Pregnancy 
Female participants who become pregnant after the first study intervention dose must not receive 
subsequent doses of the study intervention but may continue other study procedures at the 
discretion of the investigator. 
Assessment of Causality 
All solicited administration site and systemic events will be considered causally related to 
administration of the study interventions. The complete list of these events is provided in 
Table 11. 
The investigator must assess the relationship between study vaccines interventions and the 
occurrence of each unsolicited AE/SAE using clinical judgment.  
Alternative plausible possible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the study 
vaccines interventions will be considered and investigated. The investigator will also consult the 
IB and/or the Summary of Product Characteristics and/or Prescribing Information for marketed 
products to assist in making his/her assessment. 
Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the study 
intervention? 

YES: There is a reasonable possibility that the study intervention contributed to the AE.

NO: There is no reasonable possibility that the AE is causally related to the administration of
the study intervention. There are other, more likely causes and administration of the study
intervention is not suspected to have contributed to the AE.

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 95 of 110 
If an event meets the criteria to be determined as “serious”, additional examinations/tests will be 
performed by the investigator to determine ALL possible contributing factors for each SAE. 
Possible contributing factors include: 
 Medical history. 
 Other medication. 
 Protocol required procedure. 
 Other procedure not required by the protocol. 
 Lack of efficacy of the study interventions, if applicable. 
 An error in study intervention administration. 
 Other cause (specify). 
There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to IQVIA. However, it is very important to record an assessment of 
causality for every event before submitting the Expedited Adverse Events Report to IQVIA. 
Missing causality assessment by default to be considered as possibly related to the study 
intervention. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. The investigator may change their opinion of causality after receiving additional 
information and update the SAE information accordingly. 
Medically Attended Visits 
For each solicited and unsolicited AE the participant experiences, the participant/participant’s 
parent(s)/LAR(s) will be asked if the participant received medical attention defined as 
hospitalization, or an otherwise unscheduled visit to or from medical personnel for any reason, 
including emergency room visits. This information will be recorded in the eCRF/eDiary. 
Assessment of Intensity 
Maximum Intensity of Solicited Events 
The intensity of solicited AEs will be assessed as described in Table 12.  
Maximum Intensity of Unsolicited AEs and SAEs  
The investigator will assess the maximum intensity that occurred over the duration of the event 
for all unsolicited AEs (including SAEs) recorded during the study. The assessment will be 
based on the investigator’s clinical judgment. 
The intensity should be assigned to 1 of the following categories: 
 1 (mild): An AE which is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 96 of 110 
 2 (moderate): An AE which is sufficiently discomforting to interfere with normal everyday 
activities. 
 3 (severe): An AE which prevents normal, everyday activities (in adults/adolescents, such an 
AE would, for example, prevent attendance at work/school and would necessitate the 
administration of corrective therapy). 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 3 is a 
category used for rating the intensity of an event; and both AEs and SAEs can be assessed as 
Grade 3. An event is defined as “serious” when it meets 1 of the outcomes that define an SAE 
(see Definition of an SAE). 
Assessment of Outcomes 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) recorded during 
the study as: 
 Recovered/resolved. 
 Recovering/resolving. 
 Not recovered/not resolved. 
 Recovered with sequelae/resolved with sequelae. 
 Fatal (SAEs only) 
Recording, Follow-up, and Assessment of AEs, SAEs, pIMDs, and Pregnancies 
Recording AEs and SAEs 
All AEs and SAEs should be recorded into the appropriate section of the eCRF, irrespective of 
intensity or whether or not they are considered intervention-related. 
The participant/participants’ parent(s)/LAR(s) will be instructed to contact the investigator 
immediately should the participants manifest any signs or symptoms they perceive as serious. 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory and diagnostics reports) relative to the event. The 
investigator will then record all relevant information regarding an AE/SAE in the eCRF. The 
investigator is not allowed to send photocopies of the participant’s medical records to either GSK 
or IQVIA instead of appropriately completing the eCRF. However, there may be instances when 
copies of medical records for certain cases are requested by GSK or IQVIA. In this instance, all 
participant identifiers will be blinded on the copies of the medical records prior to submission to 
GSK or IQVIA. 
The investigator will attempt to establish a diagnosis pertaining to the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE/SAE and not the individual signs/symptoms. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 97 of 110 
Use of eDiary/app 
An eDiary/smartphone app will be used in this study to capture solicited administration site or 
systemic events. At the next visit after the end of reporting period, the investigator should check 
with the participant the solicited AEs entered by the participant and, if error, to correct them. The 
participants’/participants’ parent(s)/LAR(s) should be trained on how and when to complete the 
eDiary/enter information into the app. 
The eDiary/app may be completed in by a minor participant under the supervision of the 
participant’s parent(s)/LAR(s) provided the minor is capable of assessing and reporting the 
information to be recorded on eDiary. The ultimate accountability for completion of the eDiary 
remains with the participant’s parent(s)/LAR(s). The investigator should discuss this 
accountability with the participant’s parent(s)/LAR(s). If the eDiary has been completed in by a 
minor participant, the investigator or designee should verify the reported information during a 
discussion with the minor participant preferably in the presence of her parent(s)/LAR(s). 
Anyone who will evaluate administration site or systemic events and record the event in the 
eDiary/app should be trained on using the eDiary/app. This training must be documented in the 
participant’s source documents. If any individual other than the participants/participant’s 
parent(s)/LAR(s) is making entries in the eDiary/app, their identity must be documented in the 
eDiary/app/participant’s source documents. 
See Table 15 for the time period and frequency on collecting AEs/SAEs, pIMDs and 
pregnancies. 
Follow-up of AEs, SAEs, and pIMDs, and Pregnancies 
After the initial AE/SAE/pIMD/pregnancy or any other event of interest for the study, the 
investigator is required to proactively follow each participant at subsequent visits/contacts. All 
SAEs/pIMDs will be followed until the event is resolved, stabilized, or otherwise explained or 
the participant is lost to follow-up. 
Other non-serious AEs must be followed until the last contact or until the participant is lost to 
follow-up. 
Follow-up During the Study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until the last visit/contact of 
the participant. 
If the participant dies during participation in the study or during a recognized follow-up period, 
IQVIA will be provided with any available post-mortem findings, including histopathology. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 98 of 110 
Follow-up After the Participant is Discharged from the Study 
The investigator will provide any new or updated relevant information on previously reported 
SAE to IQVIA using electronic Expedited AE Report as applicable. The investigator is obliged 
to perform or arrange for the conduct of supplemental clinical examinations/tests and/or 
evaluations to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
Updating of SAE, pIMD, Pregnancy Information After Removal of Write Access to the 
Participant’s eCRF 
When additional SAE, pIMD, and pregnancy information is received after removal of write 
access to the participant’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The updated 
report should be faxed to IQVIA within the timeframe specified in Table 16. 
Follow-up of Pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the end of 
the pregnancy, whether full-term or premature, information on the status of the mother and child 
will be forwarded to IQVIA using the pregnancy follow-up report and the Expedited AE Report 
if applicable. Generally, the follow-up period does not need to be longer than 6 to 8 weeks after 
the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an SAE, it 
should always be reported as such. 
Furthermore, if the investigator becomes aware of any SAE occurring as a result of a post-study 
pregnancy AND it is considered by the investigator to be reasonably related to the study 
intervention, they must report this information to IQVIA. 
Events Requiring Expedited Reporting to IQVIA 
Once an investigator becomes aware that an SAE has occurred in a study participant, the 
investigator or investigator’s designee must complete information in the electronic Expedited AE 
Report WITHIN 24 HOURS. The report will always be completed as thoroughly as possible 
with all available details of the event. The report allows to specify that the event is serious or 
non-serious. 
Even if the investigator does not have all information regarding an SAE, the report should still be 
completed WITHIN 24 HOURS. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. The investigator will always provide an assessment of 
causality at the time of the initial report. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 99 of 110 
The investigator will be required to confirm the review of the SAE causality by ticking the 
“reviewed” box in the electronic Expedited AE Report within 72 hours of submission of the 
SAE. 
Refer to Table 15 for the details on timeframes for reporting of SAEs. 
SAE Reporting to IQVIA via EDC 
 The primary mechanism/tool for reporting an SAE to IQVIA will be the EDC. 
 If the EDC is unavailable for more than 24 hours, then the study center will use the paper 
Expedited AE Report. 
 The study center staff will enter the SAE data into the EDC as soon as it become available. 
 After the study is completed at a given site, the EDC will be taken offline to prevent the entry 
of new data or changes to existing data. 
 If a study center receives a report of a new SAE, pIMD, pregnancy from a participant or 
receives updated data on a previously reported SAE after the EDC has been taken offline, 
then the study center can report this information on a paper Expedited AE Report (see the 
next section) or to the Medical Monitor by phone. 
Contacts of the Medical Monitor for SAE reporting can be found in the SRM. 
Back-up SAE Reporting to IQVIA via Paper (in Case of EDC Failure) 
 Fax transmission of the SAE paper Expedited AE Report is the preferred method to transmit 
this information to the Medical Monitor. 
 In rare circumstances and in the absence of fax equipment, notification by phone is 
acceptable with a copy of the Expedited AE Report sent by overnight mail or courier service. 
 Initial notification via phone does not replace the need for the investigator to complete and 
sign the Expedited AE Report within the designated reporting timeframes. 
Contacts of the Medical Monitor for SAE reporting can be found in the SRM. 
Adverse Events Related to the Use of Medical Devices 
Definitions of a Medical Device AE and Adverse Device Effect 
 A medical device AE is any untoward medical occurrence, in a clinical study participant, 
users, or other persons, temporally associated with the use of study intervention whether or 
not considered related to a medical device. 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 medical device. This definition includes 
events related to the medical device or comparator and events related to the procedures 
involved. 
 An adverse device effect (ADE) is an AE related to the use of a medical device. This 
definition includes any AE resulting from: 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 100 of 110 
 insufficient or inadequate instructions for use (i.e., user error), or 
 any malfunction of a medical device, or 
 intentional misuse of the medical device. 
Definition of a Medical Device SAE, Serious Adverse Device Effect, and Unanticipated 
Serious Adverse Device Effect 
A Medical Device SAE is Any SAE That: 
a. 
Led to death 
b. Led to serious deterioration in the health of the participant, that either resulted in: 
 A life-threatening illness or injury. 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. 
 A permanent impairment of a body structure or a body function. 
 Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
 Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect  
d. Is a suspected transmission of any infectious agent via a medicinal product 
Serious Adverse Device Effect (SADE) Definition: 
A SADE is defined as an ADE that has resulted in any of the consequences characteristic of a 
serious adverse event. 
Any device deficiency that might have led to an SAE if appropriate action had not been taken 
or circumstances had been less fortunate. 
Unanticipated SADE (USADE) Definition 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a SADE that by its 
nature, incidence, severity or outcome has not been identified in the current version of the IB. 
Assessment of Severity of a Medical Device AE 
Severity of medical device AE will be assessed as: 
 Mild: Minor discomfort noticed but does not interfere with normal daily activity. 
 Moderate: Discomfort reducing or affecting normal daily activity. 
 Severe: Incapacitating with inability to work or perform normal daily activity. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 101 of 110 
Recording and Reporting of Medical Device AE, ADE, SADE, and USADE 
Device deficiencies must be reported to IQVIA within 24 hours after the investigator determines 
that the event meets the definition of a device deficiency. 
Fax transmission of the paper device deficiency/incident report form is the preferred method to 
transmit this information to IQVIA. 
In rare circumstances and in the absence of fax equipment, notification by phone is acceptable 
with a copy of the device deficiency/incident report form sent by overnight mail or courier 
service. 
Details of this process will be provided to the study centers separately (e.g., in the SRM). 
IQVIA will review all device deficiencies and determine and document in writing whether they 
could have led to an SAE. These device deficiencies will be reported to the regulatory authorities 
and IRBs/IECs as required by national regulations. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 102 of 110 
APPENDIX 5 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women of Non-Childbearing Potential 
 
Premenarchal 
Menarche is the first onset of menses in a young woman. Menarche is normally preceded by 
several changes associated with puberty including breast development and pubic hair 
growth. 
Additional evaluation should be considered if a participant’s fertility status is unclear (e.g., 
amenorrhea in adolescents or athletes) and a menstrual cycle cannot be confirmed before 
first dose of study intervention. 
 
Premenopausal woman with ONE of the following: 
 
Documented hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview. 
 
Postmenopausal woman 
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 hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
 
Women on HRT and whose menopausal status is in doubt will be required to use a 
non-hormonal, highly effective contraception method 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 Guidance 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective contraceptive method consistently and correctly according to the methods listed 
in GSK’s list of highly effective contraceptive methods (Table 22). 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 103 of 110 
Table 22 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent* 
Failure rate of <1% per year when used consistently and correctly 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
 
Oral 
 
Intravaginal 
 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
 
Injectable 
 
Oral 
Highly Effective Methods That Are User-Independent 
 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
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 female participant of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Male partner sterilization prior to the female participant’s entry into the study, and this male is 
the sole partner for that participant, 
The information on the male sterility can come from the site personnel’s review of the participant’s 
medical records; medical examination and/or semen analysis, or medical history interview provided by 
her or her partner. 
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 drug. 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. 
*Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Female Participants who Become Pregnant 
Refer to Section 8.3 and Appendix 4 for the information on detection, recording, reporting and 
follow-up of pregnancies. 
Any female participant who becomes pregnant during the study will need to discontinue further 
vaccination but may continue other study procedures at the discretion of the investigator. 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 104 of 110 
APPENDIX 6 
PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents. 
Protocol Amendment 2: 23 September 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for Amendment 
The purpose of the Protocol Amendment 2 is to allow for additional iSRC review(s) in case of 
enrollment delay to mitigate the risk that the iSRC for all 48 Step 1 participants may occur after 
the allowed interval range for their second vaccination dose. Additionally, the country-specific 
amendment for Germany (Protocol Amendment 1/DEU-1) to clarify that only adults between 
and including 18 to 26 years of age will be included in the study in Germany was incorporated. 
Further updates (as summarized below) were made to clarify the study procedures. 
Added text is bold italic and deleted text is strikethrough.  
Section and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
4.1 Overall Design  
8.2.3.3 iSRC Evaluation  
Added note: 
*In case not all 48 of the Step 1 
participants are enrolled and 
vaccinated with a first dose of 
study vaccine by 
30 September 2022, the iSRC will 
review the accumulated safety data 
up to 7 days post-dose 1 of all 
participants available by that date. 
If no safety signal is identified, 
these participants will be 
vaccinated with a second dose. To 
avoid any additional participants 
running out of the allowed interval 
range for their second vaccine 
dose, additional iSRC review(s) 
may need to be planned to review 
the safety data up to 7 days 
post-dose 1 of these participants, 
but only when all 48 Step 1 
participants have been enrolled 
and their data have been reviewed 
by the iSRC, the iSRC will decide 
on the initiation of the vaccination 
of Step 2 participants. 
To allow for additional iSRC 
review(s) in case of enrollment 
delay to mitigate the risk that the 
iSRC for all 48 Step 1 participants 
may occur after the allowed interval 
range for their second vaccination 
dose. 
1.1. Synopsis 
 
In Overall Design, 
the note was added: 
Vaccination of Step 2 participants 
with a second dose will not be 
Clarification to the study protocol 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 105 of 110 
Section and Name 
Description of Change 
Brief Rationale 
initiated before all Step 1 
participants have received their 
second vaccination dose. 
8.2.3.3 iSRC Evaluation 
Edited text: 
Following this first initial 
review(s), the iSRC will review all 
available safety data on a regular 
basis (monthly) until data from 
1-month post-dose 2 for all 
participants and data from 1-month 
post-dose 3 for Step 1 participants 
are reviewed. 
Clarification to the procedures 
associated with iSRC review 
1.3 Schedule of Activities 
Added footnote: 
2Blood samples should be collected 
prior to vaccine administration.  
The footnotes were renumerated 
accordingly along with the 
associated bookmarks. 
Clarification of study procedures 
order 
  
4.1 Overall Design 
 
Figure 1: Updated Solicited events 
(7 days) and Unsolicited events (28 
days) by moving from Visit 6 to 
Visit 5. 
Correction to align with study 
procedures 
6.1 Study Interventions 
Administered 
 
Footnote added to Table 6: 
*The nondominant arm is the 
preferred arm of injection. In case 
it is not possible to administer the 
vaccine in the nondominant arm, 
an injection in the dominant arm 
may be performed. 
Clarification to allow for flexibility 
in the laterality of study vaccines 
administration 
8.2.1.3 Physical Examination/Vital 
Signs 
On Day 1, a history directed physical 
examination will be performed for each 
participant. On Day 1, a history 
directed physical examination 
(including the injection site 
examination) will be performed for 
each participant as per the standard of 
care. 
Clarification of study procedure. 
Summary of Changes 
Summary of Changes table was 
added to document the most recent 
updates made to the protocol.   
Version control 
Appendix 6 
Appendix 6 was added to include 
the previous history of changes to 
the protocol. The Signature of 
Investigator was moved to 
Appendix 7. 
Version control 
Global document updates 
Minor clarifications, grammar 
corrections, version updates have 
been made.  
Minor edits are not summarized. 
1.1 Synopsis 
The note added: 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 106 of 110 
Section and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
4.1. Overall Design 
5.1. Inclusion Criteria 
 
In Germany, only adult 
participants between and including 
18 years to 26 years of age are to 
be included in this clinical study. 
Revision to address the request of 
health authority of Germany 
2.2. Study Rationale 
4.2.2. Selection of Study Population 
The note added: 
(18-26 years of age in Germany) 
 
Protocol Amendment 1/DEU-1: 23 June 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
This amendment applies only to Germany. 
Overall Rationale for the Amendment: 
This is a country-specific amendment for Germany to clarify that only adults between and 
including 18 to 26 years of age will be included in the study in this country. 
 
Added text is bold italic 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3. Schedule of 
Activities 
4.1. Overall Design 
5.1. Inclusion Criteria 
 
The note added: 
In Germany, only adult 
participants between and 
including 18 years to 26 
years of age are to be 
included in this clinical 
study. 
Revision to address the request of 
health authority 
2.2. Study Rationale 
4.2.2. 
Selection of 
Study Population 
The note added: 
(18-26 years of age in 
Germany) 
Protocol Version 2.0: 02 March 2022 
Overall Rationale for the Protocol Version 2.0 
The purpose of the Protocol Version 2.0 is to increase the volume of blood sample collected for 
antibody determination to enable the development and quantification of laboratory assays. 
Further, several clarifications of the study procedures as summarized below are included. 
Added text is bold italic and deleted text is strikethrough.  

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 107 of 110 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Added activity to Visits 1, 3, and 5: 
Distribute and instruct 
participants/participant’s 
parent(s)/LAR(s) on the use of 
Memory Aid for unsolicited AEs and 
concomitant medication/vaccination 
Clarification of study procedures 
 
Added activity to Visits 3, 4, and 6: 
Return of Memory Aids 
Clarification of study procedures 
1.3 Schedule of Activities  
(Table 1) 
8.1.1 Biological Samples 
Table 7 
Blood sampling for antibody 
determination (~20 50 mL) 
 
 
 
Higher volume of blood sample is 
needed for laboratory assays 
development and qualification 
1.3 Schedule of Activities  
(Table 1 and Table 2) 
8.1.1 Biological Samples 
(Table 7) 
Footnote added for Visit 2**: 
** Visit 2 is for Step 1 participants 
only 
Clarification of study procedures 
4.1 Overall Design 
Edited Figure 1 Footnote: 
&iSRC reviews Sentinel participants 
post-dose 1 safety data, then iSRC 
reviews the data on monthly basis until 
safety data from one1-month post-dose 
2 for all participants and data from 1-
month post-dose 3 for Step 1 
Clarification of data reviewed by 
the iSRC 
 
6.3.2 Randomization to Study 
Intervention 
The study and the center will be used 
as a minimization factor for 
randomization in Step 1 and the study, 
the center and 
 will 
be used as a minimization factor for 
randomization in Step 2. 
Clarification of minimization 
factors for randomization  
CCI
CCI

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 108 of 110 
6.8 Concomitant 
Medications/Products and 
Concomitant Vaccinations 
Memory aids used by 
participant/participant’s 
parent(s)/LAR(s) will be reviewed for 
any additional medication(s) and 
vaccination(s), which will be 
transcribed in eCRFs. 
Clarification of study procedures 
8.2.2.3 iSRC Evaluation 
Following this first review, the iSRC 
will review all available safety data on 
a regular basis (monthly) until data 
from 1-month post-dose 2 for all 
participants and data from 1-month 
post-dose 3 for Step 1 participants are 
reviewed. 
Clarification of data reviewed by 
the iSRC 
8.3.2 Method of Detecting AEs 
and SAEs, Pregnancies, and 
pIMDs 
Memory aids used by 
participant/participant’s 
parent(s)/LAR(s), will be reviewed for 
health-related issues of participants 
and for potential AEs, which will be 
transcribed in eCRFs. 
Clarification of study procedures 
9.4.3 iSRC Analyses 
The analysis will be based on the ES. 
The analyses will be further described 
in detail in the statistical analysis plan. 
Demographic characteristics, baseline 
general medical and vaccination 
history, withdrawals from the study. 
[…] 
Summary tables containing information 
on any events considered in the holding 
rules and other events (SAE, any 
withdrawal due to intervention-related 
AE, any AEs causing study withdrawal 
from the study). 
Incidence of solicited local 
administration site AEs (pain, redness, 
swelling): any grade, Grade 3 (2 -day 
period days or more after Dose 1, 7-day 
follow-up period after intervention), 
any solicited administration site AEs 
leading to hospitalization within 7 
days (Day 1 – Day 7) after each 
vaccine dose. 
Incidence of solicited general 
AEsystemic AEs (fever, headache, 
fatigue, myalgia, and arthralgia): any 
grade, Grade 3, any related, Grade 3 
related (2 days or more after Dose 1, 7-
day follow-up period after each 
intervention), any solicited systemic 
AEs leading to hospitalization, fever 
>40°C (104°F), within 7 days (Day 1 – 
Day 7) after each vaccine dose). 
[…] 
Clarification of the analyses 
performed for the iSRC to align 
with the iSRC charter 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 109 of 110 
Any, Grade 3 or above abnormality in 
pre-specified hematology and 
biochemistry parameters with an event 
onset within 7 days (Day 1 – Day 7) 
after each vaccine dose.  
Incidence of SAEs: Any, any related, 
fatal, fatal related.  
Incidence of pIMDs: Any, any related. 
[…] 
Any pregnancy and pregnancy 
outcomes, overall and pregnancy 
exposures (i.e., exposures during 
pregnancy). 
[…] 
Safety narratives, patient profiles and 
laboratory reports, if required. 
Other information as deemed 
necessary by the iSRC. 
Global document updates 
Minor clarifications, grammar 
corrections, version updates have been 
made to this document.  
Minor edits are not summarized. 
 

CONFIDENTIAL 
Protocol 213749 (HPV9-AS04-001) - Amendment 3 
Page 110 of 110 
APPENDIX 7 
SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: A Phase 1/2 randomized, observer-blinded, multi-country study to 
evaluate safety and immunogenicity of investigational adjuvanted human papillomavirus vaccine 
in females (16 to 26 years of age) 
PROTOCOL NO: 
213749 (HPV9-AS04-001) 
VERSION:   
       Amendment 3 
This protocol is a confidential communication of GSK. I confirm that I have read this protocol, I 
understand it, and I will work according to this protocol. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
Good Clinical Practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from GSK. 
Instructions to the Investigator:  Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to IQVIA. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
 
Signature of Investigator:       ________________________________ Date:  _______________ 
Investigator Name:                 _____________________________________________________ 
Investigator Title:                   _____________________________________________________ 
 
Name/Address of Center:       _____________________________________________________ 
 
 
 
 
                   _____________________________________________________ 
 
 
 
 
                   _____________________________________________________