An Open-label Phase III Study to Investigate the Safety, Tolerability and Immunogenicity of a Nine-valent Human Papillomavirus (HPV) Vaccine (Gardasil®9) in Solid Organ Transplant Recipients and HIV-infected Patients
Phase: PHASE3
Conditions: Human Papilloma Virus, Hiv, Organ Transplants
Sponsor: Universitaire Ziekenhuizen KU Leuven

Product: V503 
 
Protocol 
An Open-label phase III study to investigate the safety, 
tolerability and immunogenicity of a nine-valent human 
papillomavirus (HPV) vaccine (Gardasil®9) in solid organ 
transplant recipients and HIV-infected patients 
13 November 2018 
Version 4 – Amendement 1 
Investigational Medicinal Product (i.e. Study Vaccine):  
GARDASIL®9 
EudraCT NUMBER: 
2017-004322-15  
NTC number: 
NCT03525210 
Sponsor: 
University hospitals of Leuven (UZ Leuven) 
Principal investigator:  
Prof. Dr. Corinne Vandermeulen 
Study coordinator: 
Lise Boey 
 
Leuven University Vaccinology Center (LUVAC) 
KU Leuven 
Herestraat 49 
3000 
Leuven 
 016/34 20 20 
email : corinne.vandermeulen@uzleuven.be 
email : lise.boey@kuleuven.be 
 
Sub-Investigators: 
Prof. dr. I. Derdelinckx 
Prof. dr. D. Kuypers 
Prof. dr. J. Van Cleemput 
Prof. dr. R. Vos 
 
University hospitals of Leuven 
Herestraat 49 
3000 
Leuven 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Table of contents 
 
Table of contents ........................................................................................................................ 2 
List of tables ............................................................................................................................... 4 
ABBREVIATIONS AND DEFINITIONS ..................................................................................... 7 
1. 
PROTOCOL SYNOPSIS .................................................................................................... 8 
1.1. 
Title .............................................................................................................................. 8 
1.2. 
Primary purpose of the study vaccine ......................................................................... 8 
1.3. 
Rationale ...................................................................................................................... 8 
1.4. 
Summary of study design ............................................................................................ 9 
1.5. 
Dosage/Dosage Form, Route, and Dose Regimen .................................................. 10 
1.6. 
Study flow chart ......................................................................................................... 10 
2. 
CORE PROTOCOL .......................................................................................................... 12 
2.1. 
Rationale .................................................................................................................... 12 
2.2 
Objectives and hypothesis ........................................................................................ 13 
2.2.1. Primary Objective: .................................................................................................. 13 
2.2.2. Secondary Objective(s): ......................................................................................... 13 
2.3. 
Subject inclusion criteria ............................................................................................ 14 
2.4. 
Subject exclusion criteria ........................................................................................... 15 
2.5. 
Study design and duration ......................................................................................... 17 
2.5.1. Study design summary ........................................................................................... 17 
2.5.2 Treatment plan ......................................................................................................... 18 
2.6. 
List of immunogenicity measures .............................................................................. 18 
2.7 
List of Safety Measurements ..................................................................................... 18 
2.8 
Data monitoring committee ....................................................................................... 19 
3.0. 
Protocol details .............................................................................................................. 20 
3.1. 
Study procedures ...................................................................................................... 20 
3.1.1. Identifying Study Subjects ...................................................................................... 20 
3.1.2. Informed Consent ................................................................................................... 20 
3.1.3. Subject Identification Card ...................................................................................... 20 
3.1.4. Concomitant Medication(s)/Treatment(s) ............................................................... 20 
3.1.5. Assignment of Allocation Number .......................................................................... 21 
3.1.7. Vaccination and Evaluation .................................................................................... 21 
3.1.8. Management of Pregnant Subjects ........................................................................ 21 
3.1.9. Dosage and Administration .................................................................................... 22 
3.1.10. Dispense Vaccination Diary.................................................................................. 23 
3.1.11. Blinding/Unblinding ............................................................................................... 23 
3.1.12. General Precautions for Administration of Study Vaccines ................................. 23 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
3.2 
Discontinuation/Withdrawal Criteria .......................................................................... 23 
3.2.1. Discontinuation of Vaccination ............................................................................... 23 
3.2.2. Withdrawal from the Study ..................................................................................... 24 
3.2.3. Lost to Follow-up .................................................................................................... 24 
3.3 
Immunogenicity Measurements ................................................................................ 24 
3.4 
Safety Measurements ................................................................................................ 25 
3.4.1 Clinical Measurements for Safety ............................................................................ 25 
3.4.2 Assessing and Recording Adverse Events ............................................................. 26 
3.5 
Statistical analysis plan ............................................................................................. 32 
3.5.1 In-house Blinding ..................................................................................................... 32 
3.5.2 Hypothesis/Estimation ............................................................................................. 32 
3.5.3 Analysis Endpoints .................................................................................................. 32 
3.5.4 Analysis Populations ................................................................................................ 33 
3.5.5 Statistical Methods ................................................................................................... 35 
3.5.6 Sample Size and Power Calculations ..................................................................... 39 
3.5.7 Interim Analysis ........................................................................................................ 40 
3.6 
DEFINITION OF COMPLIANCE MEASURE ............................................................ 40 
3.7 
Labeling, Packaging, Storage, Dispensing, and Return of Clinical Supplies ........... 40 
3.7.1 Product Description ................................................................................................. 40 
3.7.2 Packaging Information ............................................................................................. 40 
3.7.3 Clinical Supplies Disclosure .................................................................................... 41 
3.7.4 Shipment of Investigational Medicinal Product ....................................................... 41 
3.7.5 Storage and Handling Requirements ...................................................................... 41 
3.7.6 Accountability of Investigational Medicinal Product ................................................ 42 
3.7.7 Return of Investigational Medicinal Product ............................................................ 42 
3.8 
Data Management ..................................................................................................... 42 
3.9 
Study report ............................................................................................................... 42 
4.0. 
ADMINISTRATIVE AND REGULATORY DETAILS ..................................................... 43 
4.1. 
Confidentiality ............................................................................................................ 43 
4.1.1. Confidentiality of Subject Records ......................................................................... 43 
4.1.2. Confidentiality of IRB/IEC Information .................................................................... 43 
4.2. 
Compliance with Law, Audit and Debarment ............................................................ 43 
4.3. 
Compliance with Trial Registration and Results Posting Requirements .................. 44 
4.4 
Quality Management System .................................................................................... 44 
4.5 
Data Management ..................................................................................................... 45 
4.6 
Publications ............................................................................................................... 45 
5.0 
LIST OF REFERENCES ............................................................................................... 46 
6.0 
SIGNATURES ............................................................................................................... 47 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
List of tables  
Table 1: Vaccine Formulation (0.5 mL Dose) ...................................................................... 10 
Table 2: Guidelines for Pregnant Subjects: Managing Study Visits and Study 
Vaccinations ........................................................................................................... 19 
Table 3: Evaluating Adverse Events .................................................................................... 26 
Table 4: Acceptable Day ranges for Vaccination Visits .................................................... 30 
Table 5: Acceptable Day Ranges for Collection of Serum Samples ................................ 31 
Table 6: Analysis Strategy for Safety Parameters ............................................................. 33 
Table 7: Investigational medicinal product ......................................................................... 36 
 
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
RATIONALE for Amendment 1 
 
In the HIV group we anticipated a sample size of 140 patients which was deemed feasible 
since 471 HIV patients between 18 and 46 years of age were followed in the university 
hospitals of Leuven. However, at the start of study only a list of 366 eligible patients was 
available, of whom 69 have been enrolled in the study to date, 8 have discontinued treatment 
at the hospital, 105 patients will be approached in the near future and 198 had to be excluded 
during screening. The main reasons for exclusion were a history of condylomata (n = 56), a 
history of low grade vaginal, vulvar, cervix or anal neoplasia (n = 19), not deemed to be eligible 
by the treating physician, and no interest or no time. Based on the current response and 
eligibility rates, we estimate that in total about 70 patients can be included according to the 
current study protocol.  
 
Based on this finding, literature on HPV vaccination in HIV patients was looked into again and 
a recalculation of the initial sample size was done based on the following findings:  
- 
Prior to the start of the study, a sample size calculation was based on an expected 
seroconversion rate of 85%-91% for HPV type 18 (most stringent seroconversion rate) 
and allows to estimate the proportion of seroconverted patients with a margin of error 
(precision) of ±5.9% to ±4.7% (1). The expected seroconversion rates for types 6, 11, 
and 16 are higher (> 95%), and thus with a smaller margin of error (less then ±3.6%). 
- 
The expected seroconversion rates that were used for the sample size calculation were 
retrieved from published data of patients with a CD4-count of 200-350 cells/mm². 
However, 92% of the patients that are currently included have a CD4-count of >350 
cells/mm², which makes seroconversion rates in patients with more than 350 CD4+ 
cells/mm² more applicable (1). Published seroconversion rates in these patients are 
95%-99% for HPV types 6, 11 and 16 and 90% for HPV-18.  
- 
This sample size calculation does not take in to account that patients might be 
seropositive to certain HPV-types at baseline and that their data will be excluded for 
the analysis of the seroconversion outcome of the corresponding HPV-type. 
Seroprevalence to different HPV-types in previous studies on the safety and 
immunogenicity of the quadrivalent HPV-vaccine in HIV patients ranged from 13% to 
45% for the different vaccine HPV-types (1–3).  
- 
In order to maximize the number of eligible subjects, we amend the protocol to also 
include patients with a history of abnormal PAP-smears without treatment or 
genital warts. We believe that this allows us to reach a total sample size of at least 
100 HIV-patients. Patients who are seropositive for a given HPV-type at baseline will 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
still be excluded for the analysis of seroconversion of that particular type but will still be 
useful for the analysis of the other HPV-types. Knowing that in HIV-patients the 
expected seroconversion rate of HPV-18 is relatively lower than the seroconversion 
rates of HPV types 6, 11 and 16, maximizing the number of eligible subjects for the 
analysis of this type is especially beneficial in order to obtain a reasonable margin of 
error. Enrolling patients with history of genital warts, who are most likely seropositive 
to HPV types 6 or 11, still allows us to increase the number of HPV-18 seronegative 
patients. In addition, clinical presentation of HPV infection does not necessarily 
implicate seropositivity to HPV. 
- 
With a total sample size of n=100, a majority of whom will have no history of HPV-
lesions, we expect to be able to use the data of at least 80 patients for the analysis 
seroconversion of each HPV type under study. Seroconversion rates of 95-99% 
for HPV types 6, 11 and 16 can then be estimated with a margin of error of ±4.8% 
- 2.2%, and the anticipated seroconversion rate of 90% for HPV type 18 with a 
margin of error of ±6.6%. 
 
The amendment to the study protocol therefore includes an adaptation of the study 
protocol which consists of a reduction of the planned sample size (from 140 to 100), and 
a wider recruitment in order to fulfil the aims of the study.  
 
 
 
 
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
ABBREVIATIONS AND DEFINITIONS 
9vHPV  
9-valent (6/11/16/18/31/33/45/52/58) human papillomavirus vaccine 
AE 
 
adverse event 
ANSS   
all type-specific naïve subjects with serology 
cLIA  
 
competitive Luminex® immunoassay 
CRF  
 
case report form 
CSP  
 
clinical study protocol 
CSR  
 
clinical study report 
EDC  
 
electronic data capture 
EU  
 
European Union 
GMT   
geometric mean titre 
HIV 
 
human immunodeficiency virus 
HPV  
 
human papillomavirus 
ICF  
 
informed consent form 
IEC  
 
independent ethics committee 
IMP 
 
investigational medicinal product 
IRT 
 
Interactive response technology 
mAbs   
monoclonal antibodies 
mMU/mL  
milli merck units per millilitre 
MSD 
 
Merck Sharp & Dohme Corp., a subsidiary of Merck&Co 
PPI  
 
per protocol immunogenicity 
qHPV   
quadrivalent human papillomavirus vaccine 
SAE  
 
serious adverse event 
SOT 
 
solid organ transplantation 
VLP  
 
virus-like particles 
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
1. PROTOCOL SYNOPSIS 
1.1. 
Title 
An Open-label phase III study to investigate the immunogenicity and tolerability of a nine-valent human 
papillomavirus (HPV) vaccine (Gardasil®9) in solid organ transplant recipients and HIV-infected patients 
 
1.2. 
Primary purpose of the study vaccine 
Prevention of cervical, vulvar, vaginal and anal cancers and related precancerous lesions, external 
genital lesions, pap test abnormalities, and persistent infection caused by Human papillomavirus (HPV) 
types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in transplant recipients and HIV-infected adults. 
 
1.3. 
Rationale  
Human papilloma virus (HPV) is the main cause of cervical malignancies (99%) and contributes to 90% 
of anal cancers, 40 % of vulvar, vaginal and penile cancers and causes in lower numbers oropharyngeal 
and mouth cancers (1). Up to 80% of women get infected with HPV during their lives, with the highest 
incidence 3 to 4 years after sexual onset (2). For men the risk of infection start shortly after sexual debut 
and remains high for the remainder of their life and about 30% of all HPV-related cancer occurs in men. 
In order to induce malignancies, persistent HPV infection is needed (3). In immunocompetent persons 
only 10% of the infections persist >6 months. 
However, in immunocompromised patients, including transplant recipients and HIV-infected patients, 
chronic HPV-infection is more prevailing (4). Consequently, they have an increased risk for HPV-related 
complications. In healthy populations, HPV vaccination is very efficacious in preventing HPV infections. 
Studies showed a suboptimal immunogenicity of HPV vaccination in adult transplant patients but better 
immunogenicity in paediatric patients and HIV-infected patients with reasonable CD4-counts (>200 
cells/mm² or CD4% ≥15) (5-13). However, in HIV and solid organ transplant patients, only a limited 
number of studies has been done with the bivalent and the quadrivalent vaccine, which comprises virus 
like particles (VLPs) of HPV types 16 and 18 and types 6, 11, 16 and 18 respectively.  
In this study, the immunogenicity of the nine-valent HPV vaccine will be investigated in HIV and solid 
organ transplant patients, who will be recruited in the university hospitals of Leuven.  
The nine-valent vaccine that will be used in this study comprises 5 additional VLPs of oncogenic HPV 
types 31, 33, 45, 52 and 58 compared to the quadrivalent vaccine and consequently has an additional 
preventive benefit, as it increases the coverage of all cervical cancers from 70% to 90% (14). In clinical 
trials in women and men (16 to 26 years of age) as well as in girls and boys (9 to 15 years of age), the 
9-valent vaccine was well tolerated and prevented infection and disease due HPV types included in the 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
vaccine (15-17). The Gardasil®9 1 was licensed in the US, Canada, Australia and Europe in respectively 
2014 and 2015. 
Gardasil®9 is currently approved for use in persons (boys and girls) as of nine years of age (Belgian 
SPC). Currently there are no data available for men or women above 26 years of age. Nevertheless, 
data are available on women 24 to 46 years of age for quadrivalent Gardasil®2 vaccine from the 
FUTURE III trial. By the end of this clinical trial, data of the V503-004 study which enrolled women 
between 16 and 45 years of age might be available. 
 
1.4. 
Summary of study design 
This is a single-center, open-label study on safety, tolerability and immunogenicity of Gardasil®9 in 18 
to 45 year-old HIV patients, in 18 to 55 year-old solid-organ transplant (SOT) patients. 
This study will enrol 100 HIV patients with CD4+ count of >200cells/mm² and 170 SOT patients, all of 
whom have not yet received a prophylactic HPV vaccine. The 170 SOT patients will be equally divided 
over 3 different SOT patient groups, namely heart, lung and kidney transplant patients. Therefore the 
target is to include approximately 57 heart transplant patients, 57 lung transplant patients and 57 kidney 
transplant patients. Enrolment in a SOT subgroup will be stopped when 57 patients have been included 
unless recruitment cannot be achieved within one of the other SOT-patient population.  
All enrolled subjects will receive a 3-dose regimen (Day 1, Month 2, and Month 6) of GARDASIL®9. 
Serum samples will be collected on Day 1 and Month 7 for anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 
antibody determination. The time point for comparison of immune responses will be Month 7, or approximately 
4 weeks after the administration of the third dose. The safety/tolerability profile of the vaccine will be evaluated 
in all subjects in the study. Safety information will be collected on Day 1 through 1 month following the third 
vaccination or for a total of approximately 7 months for each subject. 
The immunogenicity and the safety data will be analyzed per group of patients. More specifically a 
separate analysis of HIV and SOT patients is planned, since it is expected that the immunosuppressive 
therapy of SOT patients might have a more profound effect on immunogenicity following vaccination.  
This study will provide a comparison of immunogenicity of Gardasil ®9 in immunocompromised patients, 
with historical controls (15, 18). The number of subjects to be enrolled in the study was determined 
based on the primary immunogenicity objective. 
                                                 
1 GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary 
of Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A 
 
2 GARDASIL [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] is a registered trademark of Merck & Co., Inc., 
Whitehouse Station, New Jersey, U.S.A. GARDASIL is also known as SILGARD in some countries. SILGARD is a trademark of Merck & Co., 
Inc., Whitehouse Station, New Jersey, U.S.A. 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
1.5. 
Dosage/Dosage Form, Route, and Dose Regimen 
Subjects will receive GARDASIL®9 (HPV 9-valent vaccine [recombinant, adsorbed]) administered as a 
0.5-mL intramuscular injection on Day 1, Month 2 and Month 6. The vaccine formulation is summarized 
in Table 1. GARDASIL®9 is available as a suspension for injection. It appears as a clear liquid with 
white precipitate. 
 
Table 1: Vaccine Formulation (0.5 mL Dose) 
HPV 6 
(mcg) 
 
HPV 
11 
(mcg) 
 
HPV 
16 
(mcg) 
 
HPV 
18 
(mcg) 
 
HPV 
31 
(mcg) 
 
HPV 
33 
(mcg) 
 
HPV 
45 
(mcg) 
 
HPV 
52 
(mcg) 
 
HPV 
58 
(mcg) 
 
Total 
VLP 
(mcg) 
 
AAHS† 
(mcg) 
 
30 
40 
60 
40 
20 
20 
20 
20 
20 
270 
500 
† AAHS, Merck Aluminum Adjuvant (amorphous aluminum hydroxyphosphate sulfate) 
HPV, human 
 
 
1.6. 
Study flow chart  
Visit Windows (a) for SOT group 
 
Consent 
visit 
 
2 months 
after 
Day 1, 
±4 weeks 
6 months 
after 
Day 1, -1 
week / +4 
weeks 
 
3 to 
7 weeks 
after 
Month 6 
Visit Windows (a) for HIV group 
 
Consent 
visit 
 
2 months 
after 
Day 1, 
, -4 weeks 
/ +2 weeks 
6 months 
after 
Day 1, ±4 
weeks  
3 to 
7 weeks 
after 
Month 6 
Procedures 
Visit 1 
(Day 1/  
Month 0) 
Visit 2  
(Month 2) 
Visit 3  
(Month 6) 
Visit 4  
(Month 7)  
(b) 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Obtain informed consent form  
X 
 
 
 
Assign screening number  
X 
 
 
 
Review inclusion/exclusion criteria (c)  
X 
 
 
 
Collect medical history (past year) 
X 
 
 
 
Collect demographics 
X 
 
 
 
Collect weight/height 
X 
 
 
 
Update medical history (new conditions not yet 
recorded as medical history or adverse events (AEs) 
 
X 
X 
X 
Review medications and non-study vaccines (d) 
X 
X 
X 
X 
Pregnancy test (urine) (e) 
X 
X 
X 
X 
Collect oral/tympanic temperature (f) 
X 
X 
X 
 
Assign allocation number 
X 
 
 
 
Provide diary card 
X 
X 
X 
 
Review and collect vaccination diary data 
 
X 
X 
X 
Blood sample for anti-HPV antibody testing (including 
retention serum) (10 ml blood each time) (g) 
X 
 
 
X 
Vaccination (Intramuscular, prefer deltoid muscle of 
non-dominant arm; do not give into buttocks) 
X 
X 
X 
 
Provide vaccination diary 
X 
 
 
 
Review vaccination diary (h) 
 
X 
X 
X 
Review AE’s, clinical follow up for safety (i) 
X 
X 
X 
X 
(a) To calculate visit windows, assume 1 month equals 30 days and 1 week equals 7 days. 
(b) Whenever possible, when a subject discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study visit should 
be performed at the time of discontinuation except for serum collection for HPV testing. 
(c) A physical examination may be performed during Visit 1 if deemed necessary by the investigator to assess eligibility criteria. 
(d) See Section 3.2.4. for details of documentation times and time period restrictions for medications and non-study vaccines. If other non-study vaccines 
are administered at any time during the study, they should not be administered in the same limb as the study vaccine and must be appropriately 
documented. 
(e) The serum or urine pregnancy test will be performed per the manufacturer’s instructions. A pregnancy test will be performed before administration of 
each dose of the study vaccine and at the final Month 7 visit on all female subjects. The pregnancy test must be performed prior to serum collection for 
HPV testing at Day 1. 
(f) If the subject has a fever (defined as an oral temperature of ≥37.8°C) within the 24-hour period prior to receiving a study vaccination, the subject should 
not receive study vaccine, and the vaccination visit should be rescheduled until after the fever has resolved. Oral temperature will be measured prior to 
each vaccination 
(g) Blood sample for anti-HPV measurements must be collected prior to the first study vaccination. Serum must be shipped as specified by MSD. The 
retention serum vial must remain at the study site until the MSD notifies the study site to ship the samples 
(h) The investigator should instruct the subject to use the vaccination diary to document oral temperature in the evening after each study vaccination and 
daily, at the same time of day, for 4 days after each study vaccination. Additionally, injection-site and systemic adverse event(s) (AEs), concomitant 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
medications, and concomitant vaccinations are to be documented in the vaccination diary starting after each study vaccination for a total of 15 days, 
including the day of vaccination (Day 1 to Day 15). 
(i) Observe subjects for at least 15 minutes after each vaccination for immediate untoward effects. Serious adverse events (SAEs), pregnancy events, and 
lactation events should be reported to MSD Belgium, within 24 hours. Adverse events and SAEs will be followed for 15 days and during the whole study, 
respectively, after the last dose (i.e., after the third dose for subjects completing the vaccination schedule or after the last received dose in the event of 
the subject withdrawing). 
 
2. CORE PROTOCOL 
2.1. 
Rationale 
Human papilloma virus (HPV) is the main cause of cervical malignancies and contributes to 90% of anal 
cancers, 40 % of vulvar, vaginal and penile cancers and causes in lower amounts oropharyngeal and 
mouth cancers (1). Up to 80% of women get infected with HPV during their lives, with the highest 
incidence 3 to 4 years after sexual onset (2). For men the risk of infection start shortly after sexual debut 
and remains high for the remainder of their life and about 30% of all HPV-related cancer occurs in men. 
In order to induce malignancies, persistent HPV infection is needed (3). In immunocompetent persons 
only 10% of the infections persist >6 months. 
However, in immunocompromised patients, including transplant recipients and HIV-infected patients, 
chronic HPV-infection is more prevailing (4). Consequently, they have an increased risk for HPV-related 
complications. In healthy populations, HPV vaccination is very efficacious in preventing HPV infections. 
Studies showed a suboptimal immunogenicity of HPV vaccination in adult transplant patients but better 
immunogenicity in paediatric patients and HIV-infected patients with reasonable CD4-counts (>200 
cells/mm² or CD4% ≥15) (5-13). However, in HIV and solid organ transplant patients, research has only 
been done with the bivalent and the quadrivalent vaccine, which comprises virus like particles (VLPs) of 
HPV types 16 and 18 and types 6, 11, 16 and 18 respectively.  
In this study, the immunogenicity of the nine-valent HPV vaccine will be investigated in HIV and solid 
organ transplant patients, who will be recruited in the university hospitals of Leuven. This tertiary hospital 
is large hospital located in the center of Belgium and is a reference center where patients from all over 
the country are treated. Approximately 415 heart, 590 lung and 700 kidney transplant patients are 
followed in the hospital, of whom approximately 160, 210 and 350 are between 18 and 55 years of age, 
respectively. About 900 HIV patients are equally followed in the university hospital of whom 470 are 
between 18 and 45 years old. 
The nine-valent vaccine that will be used in this study comprises 5 additional VLPs of oncogenic HPV 
types 31, 33, 45, 52 and 58 compared to the quadrivalent vaccine and consequently has an additional 
preventive benefit, as it increases the coverage of all cervical cancers from 70% to 90% (14). In clinical 
trials in women and men (16 to 26 years of age) as well as in girls and boys (9 to 15 years of age), the 
9-valent vaccine was well tolerated and prevented infection and disease due HPV types included in the 
vaccine (15-17). The Gardasil®9 was licensed in the US, Canada, Australia and Europe in respectively 
2014 and 2015.Gardasil®9 is currently approved for use in persons (boys and girls) as of nine 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
years of age (Belgian SPC). Currently there are no data available for men or women above 26 
years of age. Nevertheless, data are available on women 24 to 46 years of age for quadrivalent 
Gardasil® vaccine from the FUTURE III trial. By the end of this clinical trial, data of the V503-004 
study which enrolled women between 16 and 45 years of age might be available 
 
2.2 
Objectives and hypothesis 
2.2.1. Primary Objective Immunogenicity:  
To determine the immunogenicity of Gardasil®9 with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52 
and 58 in adult HIV (age: 18-45 years) and transplant patients (age: 18-55 years). 
Hypothesis: GARDASIL®9 induces in 18-45-year-old HIV patients (>200 CD4 T cells/mm²) 
seroconversion rates for HPV 6, 11 16, 18, 31, 33, 45, 52, and 58 at 4 weeks after Dose 3 that are 
similar to those induced in historical controls (healthy persons between 18 and 45 years of age. If the 
proposed control data are not available, immunogenicity will be compared to data from male and 
female healthy persons between 18 and 26 years of age and previous data from the immunogenicity 
of Gardasil® in HIV patients). The seroconversion rate for each of the HPV types 6, 11, 16, 18, 31, 
33, 45, 52, and 58 will be tested separately. 
Hypothesis: GARDASIL®9 induces in 18-55-year-old solid organ transplant patients 
seroconversion rates for HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 4 weeks after Dose 3 that are 
similar to those induced in historical controls (healthy persons between 18 and 45 years of age. If the 
proposed control data are not available, immunogenicity will be compared to data from male and 
female healthy persons between 18 and 26 years of age). The seroconversion rate for each of the 
HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 will be tested separately. 
(Seroconversion is defined as changing serostatus from seronegative at Day 1 to seropositive 
(antibody titer above seroconversion cut-off) by 4 weeks after Dose 3) 
 
2.2.2. Secondary Objective(s):  
SAFETY 
To determine the safety and tolerability of Gardasil®9 with respect to HPV types 6, 11, 16, 18, 31, 33, 
45, 52 and 58 in adult HIV (age: 18-46 years) and solid organ transplant patients (age: 18-55 years). 
 
Hypothesis: GARDASIL®9 is well tolerated 18-45-year-old HIV patients compared to healthy 
subjects as evaluated by the occurrence of local and systemic reactions following vaccination. 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Hypothesis: GARDASIL®9 is well tolerated by 18-55-year-old solid organ transplant patients 
compared to healthy subjects as evaluated by the occurrence of local and systemic reactions 
following vaccination. 
 
IMMUNOGENICITY 
 
2.3. 
Subject inclusion criteria 
To be included in the study and to receive the first study vaccination, subjects must meet all inclusion 
criteria. For items with an asterisk (*), if the subject does not meet these inclusion criteria, the Day 1 visit 
may be rescheduled to a time when these criteria can be met. 
1. Independent Ethics Committee (IEC)-approved written informed consent form (ICF) must be 
obtained from the subject prior to any study-related procedure (including discontinuation of 
prohibited medication, if applicable) as required by local law.  
2. Subject (man or woman) is between the age of 18 years and 0 days and 45 years and 365 days 
for HIV patients, between 18 years and 0 days and 55 years and 365 days for transplant patients 
at time of signing the ICF. 
3. Subject is able to understand and adhere to the study procedures (e.g., is not planning to relocate 
far from the investigational centre during the study period); is able to read, understand, and 
complete the vaccination diary; is able to understand the risks involved with the study; and 
voluntarily agrees to participate in the study by giving written informed consent.  
4. * Since the first day of their last menstrual period through Day 1, female subjects have not had sex 
with males or has had sex with males and used effective contraception with no failures (an example 
of a failure is a male condom that ruptures during sexual intercourse). Effective contraception is 
defined as a marketed, approved contraceptive product that the subject has used per the 
manufacturer’s instructions with every act of sexual intercourse. The subject understands and 
agrees that during the Day 1 through Month 7 period, she should not have sexual intercourse with 
males without effective contraception. The use of the rhythm method alone, withdrawal alone, and 
emergency contraception, are not acceptable methods per the protocol. Subjects who have 
reached menopause, undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation 
are eligible without the use of contraceptives. Postmenopausal status is defined as: (1) No menses 
for >1 year but <3 years and confirmed by follicle stimulating hormone (FSH) levels elevated into 
the postmenopausal range, or (2) no menses for at least 3 years. 
5. * Subject has had no temperature ≥37.8°C within 24 hours prior to the first injection. 
6. Patient considerations 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
- 
HIV patients: have CD4+ T cell count of >200 cells/mm² at the last control (less than 16 
months ago). 
- 
SOT patients received their organ transplantation ≥12 months prior to vaccination and has 
been stable in the past 6 months (i.e. no acute rejection or other immunological reactions). 
7. Apart from having HIV or received a solid organ transplant, the subject is in stable condition (i.e. 
no graft-versus-host disease or other immunological reactions) and is judged to be in good physical 
health on the basis of medical history, physical examination (if deemed necessary), and laboratory 
testing 
8. Subject agrees to provide study personnel with a primary telephone number as well as an alternate 
telephone number for follow-up purposes. 
 
2.4. 
Subject exclusion criteria 
To be included and receive the first study vaccination, subjects should not have any exclusion criteria. 
For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 visit may be 
rescheduled for a time when these criteria are not met. 
 
1. 
Subject has a history of an abnormal Pap test or abnormal cervical biopsy results (showing 
cervical intraepithelial neoplasia or worse) or cervical disease (i.e., surgical treatment for cervical 
lesions). 
2. 
Patient medical history regarding HPV lesions: 
a. Exclusion criterion for HIV patients: Subject has history of high grade Anal Intraepithelial 
Neoplasia, high grade Vulvar Intraepithelial Neoplasia or high grade Vaginal Intraepithelial 
Neoplasia. 
• 
history of anal or peri-anal condyloma is allowed 
 
b. Exclusion criterion for SOT patients: Subject has history genital warts, Anal Intraepithelial 
Neoplasia, Vulvar Intraepithelial Neoplasia or Vaginal Intraepithelial Neoplasia. 
3. 
Subject has a history of known prior vaccination with an HPV vaccine, i.e., received a marketed 
HPV vaccine, or has participated in an HPV vaccine clinical study and has received either active 
agent or placebo. 
4. 
Subject is pregnant (as determined by serum or urine pregnancy test). 
5. 
Subject is, at the time of signing ICF, a user of recreational or illicit drugs or has had a recent 
history (within the last year) of drug or alcohol abuse or dependence. Alcohol abusers are defined 
as those who drink despite recurrent social, interpersonal, and/or legal problems as a result of 
alcohol use. 

 
 
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6. 
Subject has a history of severe allergic reaction, including known allergy to any vaccine 
component, including aluminum, yeast, or BENZONASE® (nuclease, Nycomed [used to remove 
residual nucleic acids from this and other vaccines]) (e.g., swelling of the mouth and throat, 
difficulty breathing, hypotension or shock) that met the criteria for serious adverse experiences 
defined in this protocol. 
7. 
Patient’s condition 
a. Exclusion criterion only for HIV patients: Subject has had a splenectomy, or has been 
diagnosed as having a congenital immunodeficiency, lymphoma, leukaemia, systemic lupus 
erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel 
disease, or other autoimmune or immunosuppressive condition, or has a history of any 
disease, which, in the investigator’s opinion, may confound the results of the study or pose 
an additional risk to the subject. 
b. Exclusion criterion only for SOT patients: Subject has had a splenectomy, or has been 
diagnosed as having a congenital or acquired immunodeficiency, HIV infection, lymphoma, 
leukaemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, 
inflammatory bowel disease, or other autoimmune or immunosuppressive condition, or has 
a history of any disease, which, in the investigator’s opinion, may confound the results of the 
study or pose an additional risk to the subject. 
8. Patient’s medication 
a. Exclusion criterion only for HIV patients: Subject is receiving or has received in the year 
prior to enrolment the following immunosuppressive therapies: radiation therapy, 
cyclophosphamide, azathioprine, methotrexate, any chemotherapy, cyclosporin, leflunomide 
(tumour necrosis factor-α antagonists, monoclonal antibody therapies (including rituximab 
[Rituxan]), intravenous gamma globulin, antilymphocyte sera, or other therapy known to 
interfere with the immune response. With regard to systemic corticosteroids, a subject will 
be excluded if she is currently receiving steroid therapy, has recently (defined as within 2 
weeks of enrolment) received such therapy, or has received 2 or more courses of high dose 
corticosteroids (≥20mg/day of prednisone [or equivalent] orally or parenterally) lasting at 
least 1 week in duration in the year prior to enrolment. Subjects using inhaled, nasal, or 
topical corticosteroids are considered eligible for the study 
b. Exclusion criterion only for SOT patients: Subject is receiving or has received in the year 
prior to enrolment the following immunosuppressive therapies: radiation therapy, 
cyclophosphamide,  methotrexate, any chemotherapy, leflunomide (tumour necrosis factor-
α antagonists, monoclonal antibody therapies (including rituximab [Rituxan]) ,intravenous 
gamma globulin or antilymphocyte sera. 
9. Subject has received any immune globulin or blood-derived product within the 3 months prior to 
the Day 1 vaccination, or plans to receive any such product during Day 1 through Month 7 of 
the study. 

 
 
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10. Subject has thrombocytopenia or other coagulation disorder that would contraindicate 
intramuscular injections.  
11. * Subject has received inactivated vaccines within 14 days prior to the Day 1 vaccination or has 
received replicating (live) vaccines within 28 days prior to the Day 1 vaccination. The 
administration of the inactivated influenza vaccine is allowed 7 days prior to or after each study 
vaccine. 
12. Subject is concurrently enrolled in a clinical study of investigational agent. 
13. Subject has a history or current condition of which the investigator believes that it might interfere 
with the study vaccines. 
14. Subject has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might confound the results of the study, or interfere with the subject’s 
participation for the full duration of the study, such that it is not in the best interest of the subject 
to participate. 
15. Subject is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this trial. 
 
2.5. 
Study design and duration  
2.5.1. Study design summary  
This is a single-center, open-label study on immunogenicity and tolerability of Gardasil®9 in 18 to 45 
year-old HIV patients, in 18 to 55 year-old solid-organ transplant (SOT) patients. 
This study will enrol 100 HIV patients with CD4+ count of >200cells/mm² and 170 SOT patients, all of 
whom have not yet received a prophylactic HPV vaccine. The 170 SOT patients will be equally divided 
over 3 different SOT patient groups, namely heart, lung and kidney transplant patients. Therefore the 
target is to include approximately 57 heart transplant patients, 57 lung transplant patients and 57 kidney 
transplant patients. Enrolment in a SOT subgroup will be stopped when 57 patients have been included 
unless recruitment cannot be achieved within one patient population.  
All enrolled subjects will receive a 3-dose regimen (Day 1, Month 2, and Month 6) of GARDASIL®9. 
Serum samples will be collected on Day 1 and Month 7 for anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 
antibody determination. The time point for comparison of immune responses will be Month 7, or approximately 
4 weeks after the administration of the third dose. The safety/tolerability profile of the vaccine will be evaluated 
in all subjects in the study. Safety information will be collected on Day 1 through 1 month following the third 
vaccination or for a total of approximately 7 months for each subject. 
The immunogenicity and the safety data will be analyzed per group of patients. More specifically a 
separate analysis of HIV and SOT patients is planned, since it is expected that the immunosuppressive 
therapy of SOT patients might have a more profound effect on immunogenicity following vaccination.  

 
 
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This study will provide a comparison of immunogenicity of Gardasil ®9 in immunocompromised patients, 
with historical controls (15, 18).The number of subjects to be enrolled in the study was determined based 
on the primary immunogenicity objective. 
2.5.2 Treatment plan 
All enrolled 100 HIV patients and 170 SOT patients will receive GARDASIL®9 as a 3-dose regimen of 
0.5-mL intramuscular injections administered on Day 1, Month 2, and Month 6. Study vaccine must be 
stored in a refrigerator that has a temperature between 2 °C and 8°C. If the refrigerator in which the 
study vaccine is stored deviates from the 2°C to 8°C range, study vaccinations should be suspended 
and MSD should be contacted immediately so that an investigation can be conducted. 
 
2.6. 
List of immunogenicity measures  
Serum will be collected for analysis of anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 responses by 
competitive Luminex® immunoassay (cLIA). Serum will be analysed to support the primary objective. 
At Day 1, blood samples will be collected prior to the first study vaccination to identify subjects who have 
been exposed to study vaccine HPV types prior to enrolment. Serology results at Day 1 are not part of 
the inclusion/exclusion criteria; thus, no subject will be excluded from the study based on these results. 
After Day 1, serum specimens will be collected at the Month 7 study visit as specified in the Study Flow 
Chart (Section 1.6). 
 
2.7 
List of Safety Measurements 
Each subject will receive a vaccination diary at the Day 1, Month 2, and Month 6 study vaccination visits. 
In the diary, the subject will be asked to record oral temperature in the evening after each study 
vaccination and daily, at the same time of the day, for 4 days after each vaccination, starting at the day 
of vaccination, for the purpose of identifying febrile events. In addition, beginning after each study 
vaccination and for a total of 15 days including the day of vaccination (Day 1 to Day 15), the subject will 
be asked to record injection-site and systemic adverse events (AEs), concomitant medications, and 
concomitant vaccinations on the vaccination diary. Serious adverse events (SAEs), pregnancy 
information, and lactation information will also be collected as described in Section 3.4. In addition, new 
medical conditions not present at baseline and not reported as an AE (i.e., incident medical conditions 
occurring outside of a Day 1 to Day 15 period post-vaccination and not considered SAEs) will be 
collected throughout the study. In case of pregnancy, the pregnancy and any serious adverse 
experiences in study subjects and their infants must be followed to outcome. In addition, if subjects 
receive study vaccine while breastfeeding during the Day 1 through Month 7 period, any serious adverse 
experiences in the study subjects and their infants must be followed to outcome. 

 
 
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2.8 
Data monitoring committee 
Since its market introduction in 2006, over 183 million doses of GARDASIL® have been distributed (as 
of April 2015). The safety profile is well characterized and continuously monitored by routine post-
marketing surveillance activities. In June 2015, GARDASIL®9 (V503) was granted marketing 
authorization in Europe. Previous studies with Gardasil® in immunocompromised patients did not reveal 
any specific safety issues. Gardasil®9 is also an inactivated vaccine and not a live vaccine. Therefore 
the need for a Data Monitoring Committee was not deemed necessary in this context. 
 
 

 
 
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3.0. 
Protocol details  
3.1. 
Study procedures 
3.1.1. Identifying Study Subjects 
Subject identification will be done in collaboration with the different clinical treating specialists (infectious 
disease specialists and transplant specialists) in order to include patients who comply with all in- and 
exclusion criteria. The patients will be informed about the possibility to participate in the current study 
by the treating specialist during a routine medical check- up. A dedicated person will then inform the 
patient about the objectives, obligations, possible benefits and risks of the study. The investigator will 
mention that the participation is voluntary and that withdrawal from the study or non-participation in the 
study will have no effect on the care to which the subject is otherwise entitled.  
3.1.2. Informed Consent 
Written informed consent will be obtained prior to any study procedure is started. The patient will be 
given sufficient time to consider participation in this clinical trial and will be given the opportunity (if 
necessary) to discuss his participation with his GP. Consent must be documented by the subject’s dated 
signature on a consent form along with the dated signature of the person conducting the consent 
discussion. A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. The initial informed consent form, any subsequent revised written informed 
consent form and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject should be informed in a timely manner if new 
information becomes available that may be relevant to the subject’s willingness to continue participation 
in the trial. The communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature. If there are 
changes to the subject’s status during the trial (e.g., health or age of majority requirements), the 
investigator or qualified designee must ensure the appropriate consent is in place.  
3.1.3. Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a research trial. 
The card will contain trial site contact information (including direct telephone numbers) to be utilized in 
the event of an emergency. The investigator or qualified designee will provide the subject with a Subject 
Identification Card immediately after the subject provides written informed consent. At the time of 
treatment allocation, site personnel will add the allocation number to the Subject Identification Card.  
3.1.4. Concomitant Medication(s)/Treatment(s) 
See the exclusion criteria for specific restrictions for prior and concomitant medications at Day 1. Use 
of medicines and non-study vaccines will be reviewed at each visit and should be documented in the 
individual subject’s Case Report Form (CRF) in the following manner: 
- 
“Special Medications” (corticosteroids, immunosuppressives, immune globulins, and blood 
products) from 3 days prior to Day 1 through Month 7; 

 
 
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- 
“Other Medications” from 3 days prior to each study vaccination through 1 5 days (Day 1 to Day 
15) after each study vaccination; 
- 
“Non-Study Non-Replicating (Inactive) Vaccines” for 14 days prior to each study vaccination 
through 15 days (Day 1 to Day 15) after each study vaccination; and 
- 
“Non-Study Replicating (Live) Vaccines” for 28 days prior to each study vaccination through 28 
days (Day 1 to Day 28) after each study vaccination. 
If possible, the subject should not receive special medications or non-study vaccines within the time 
periods given above. Subjects may receive allergen desensitization therapy and tuberculin skin testing 
while participating in the study. 
3.1.5. Assignment of Allocation Number 
All consented subjects will be given a unique allocation number that will be used to identify the subject 
for all procedures that occur prior to vaccine allocation. Each subject will be assigned only one allocation 
number, corresponding to the subject’s condition (HIV vs SOT; (001) (002 -004)). Allocation numbers 
must not be re-used for different subjects. Any subject who is screened multiple times will retain the 
original allocation number assigned at the initial screening visit. The allocation number also identifies 
the subject for all procedures occurring after screening.  
3.1.7. Vaccination and Evaluation 
All subjects will receive vaccination at the Day 1, Month 2 and Month 6 visit. Subject will be observed 
for 15 minutes after vaccination for any untoward adverse event.  
3.1.8. Management of Pregnant Subjects 
All female subjects will have a urine pregnancy test performed before administration of each dose of the 
study vaccine and at the final Month 7 visit per the manufacturer’s instructions. Any subject with a 
positive pregnancy test at Day 1 will not be vaccinated and will not be allowed to participate in the study. 
For subjects who become pregnant after receiving one or two study vaccinations, study visits and 
vaccinations will be paused until resolution of the pregnancy (e.g. term, elective termination, 
spontaneous abortion). Study visits and study vaccination in pregnancy subjects will be handled as 
described in Table 2. Breastfeeding is not a contraindication to receiving study vaccinations. Pregnancy 
and breast-feeding in study subjects and infant serious adverse experiences (SAEs) must be reported 
as described in Section 3.4. 
 
 

 
 
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Table 2: Guidelines for Pregnant Subjects: Managing Study Visits and Study Vaccinations 
Time When Pregnancy is Detected 
Action 
Day 1 (before first vaccination) 
Do not vaccinate subject 
Between Day 1 and Month 2 
 
(After study vaccine dose 1 and 
before study vaccine dose 2 
was administered) 
- 
No scheduled visits until resolution of the 
pregnancy (e.g., term, elective termination, 
spontaneous abortion). 
- 
The Month 2 study vaccination should be 
administered at least 4 weeks following 
resolution 
of 
pregnancy 
and 
after 
normalization of β-hCG levels. 
- 
The Month 6 study vaccination should be 
administered 4 months after the Month 2 
study vaccination.  
- 
The Month 7 visit should be conducted 1 
month after the Month 6 study vaccination.  
Between Month 2 and Month 6 
 
(After study vaccine dose 2 and 
before study vaccine dose 3 
was administered) 
- 
No scheduled visits until resolution of the 
pregnancy (e.g., term, elective termination, 
spontaneous abortion). 
- 
The Month 6 study vaccination should be 
administered at least 4 weeks following 
resolution of pregnancy and after 
normalization of β-hCG levels. 
- 
The Month 7 visit should be conducted 1 
month after the Month 6 study vaccination. 
After Month 6 
 
(After study vaccine dose 3 was 
administered) 
- 
Continue with scheduled study visits during 
the pregnancy. 
- 
Safety follow-up will be conducted after 
resolution of the pregnancy (e.g., term, 
elective termination, spontaneous abortion). 
 
3.1.9. Dosage and Administration 
Study vaccine will be administered at Day 1, Month 2, and Month 6. At each visit, subjects will receive 
GARDASIL®9 as a 0.5-mL intramuscular injection using a syringe. Injections should be administered at 
a 90° angle into the muscle tissue using a needle long enough to ensure intramuscular deposition of 
vaccine. The deltoid muscle of the non-dominant arm is the preferred site of vaccination. Study vaccines 

 
 
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should not be administered into the buttocks area. Injections should not be given within 2 cm of a tattoo, 
scar, or skin deformity. The subject should be afebrile (oral temperature <37.8ºC) for 24 hours prior to 
each vaccination. If the subject reports having been febrile within this 24-hour pre-vaccination period, 
no vaccination will be administered to the subject. The subject should be rescheduled to return for the 
vaccination visit once the fever has been resolved for at least 24 hours. If other non-study vaccinations 
are administered at any time during the study, they should not be administered in the same limb as the 
study vaccine and must be appropriately documented. The injection site for these non-study vaccines 
must also be documented. 
3.1.10. Dispense Vaccination Diary  
The investigator or delegate will train the subject or subject’s parent/legal guardian in the use of the 
vaccination diary prior to dispensing it at Visit 1. Oral temperatures, injection-site AEs, prompted 
systemic complaints, other complaints or illnesses, and medications will be recorded in the vaccination 
diary throughout the study. The study site personnel will review the data captured in the vaccination 
diary with the subject at Visit 2 through Visit 4.  
3.1.11. Blinding/Unblinding 
Not applicable. This is an open-label study. 
3.1.12. General Precautions for Administration of Study Vaccines 
Adequate treatment provisions, including epinephrine, should be available for immediate use should 
any anaphylactic or anaphylactoid reactions occur. The subject should stay at least 15 minutes at the 
investigator's office to detect any immediate AE. A sterile syringe and needle should be used for the 
vaccination injection for each subject. Needles should not be recapped. Safe disposal procedures 
should be followed. 
 
3.2 
Discontinuation/Withdrawal Criteria 
3.2.1. Discontinuation of Vaccination 
Discontinuation of study vaccination does not represent withdrawal from the study.  
As certain data on clinical events beyond study vaccination discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study vaccination. Therefore, all participants who discontinue study vaccination prior 
to completion of the vaccination period, will still continue to participate in the trial. 
Participants may discontinue study vaccination at any time for any reason or be dropped from the study 
vaccination at the discretion of the investigator should any untoward effect occur. In addition, a 
participant may be discontinued from study vaccination by the investigator if study vaccination is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
A participant must be discontinued from study vaccination but continue to be monitored in the study for 
any of the following reasons: 

 
 
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- 
The participant requests to discontinue study vaccination. 
For participants who are discontinued from study vaccination but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed , except for serum 
collection for HPV testing at the final visit. 
Participants may be allowed to begin study vaccination again if deemed medically appropriate. 
3.2.2. Withdrawal from the Study 
A participant must be withdrawn from the study if the participant withdraws consent from the study. If a 
participant withdraws from the study, they will no longer receive study vaccination or be followed at 
scheduled protocol visits. When a subject discontinues/withdraws from participation in the trial, all 
applicable activities scheduled for the final trial visit should be performed except for serum collection for 
HPV testing at the time of discontinuation. Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements outlined in 
Section 3.4.2 - Assessing and Recording Adverse Events. 
3.2.3. Lost to Follow-up 
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to contact the 
subject, the following procedures are to be performed: 
- 
The site must attempt to contact the subject and reschedule the missed visit. If the subject is 
contacted, the subject should be counselled on the importance of maintaining the protocol-
specified visit schedule. 
- 
The investigator or designee must make every effort to regain contact with the subject at each 
missed visit (e.g. phone calls and/or a certified letter to the subject’s last known mailing address 
or locally equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
- 
Note: A subject is not considered lost to follow up until the last scheduled visit for the individual 
subject. The amount of missing data for the subject will be managed via the pre-specified data 
handling and analysis guidelines. 
 
3.3 
Immunogenicity Measurements 
The assay used in this study is the 9-valent HPV cLIA. The purpose of the assay is to detect antibodies 
to HPV VLPs types 6, 11, 16, 18, 31, 33, 45, 52, and 58, before and after vaccination with GARDASIL®9. 
Tests will be performed by Focus Diagnostics, Inc. (California, U.S.A) to measure HPV antibodies at 
baseline and evaluate the serological response after vaccination. Yeast-derived VLPs are coupled to a 
set of 9 distinct fluorescent Luminex microspheres. Antibody titres are determined in a multiplexed, 
competitive format in which known HPV type-specific, phycoerythrin-labelled, neutralising monoclonal 
antibodies (mAbs) compete with the subject’s serum antibodies for binding to type-specific 
conformationally sensitive, neutralizing epitopes on the VLPs. The fluorescent signals from the bound 

 
 
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HPV –specific detection mAbs are inversely proportional to the subject’s neutralizing antibody titres. 
Results for the assay are reported as a concentration of antibody in arbitrary milli-Merck Units per 
millilitre (mMU/mL). The HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 cLIA is performed in a 96-well 
microtitre plate. A 12-point standard curve using reference serum pool from adult females immunized 
with 9 -vHPV vaccine, 4 controls, and 16 samples are added to the plate in duplicate. Samples are 
tested at a 1:4 and a 1:40 dilution. The detection antibodies followed by the VLP-microspheres for types 
6, 11, 16, 18, 31, 33, 45, 52, and 58 are added to each well. The plates are sealed with foil covers and 
incubated for 15 to 25 hours. Following incubation, the plates are washed and then analysed on a 
BioPlex (Luminex) instrument. The seropositivity cutoffs for HPV types are assessed using a panel of 
sera from subjects that are highly likely to be HPV naïve (children), and from subjects who are likely to 
be seropositive. Any sample being tested for a specific HPV type with a cLIA titre lower than the cutoff 
corresponding to that HPV type is considered seronegative for that HPV type.  
 
3.4 
Safety Measurements 
3.4.1 Clinical Measurements for Safety 
All subjects will be observed for at least 15 minutes after each study vaccination for any untoward effects, 
including allergic reactions. This observation period will be documented in the individual subject’s source 
documents. 
Each subject will receive a vaccination diary at the Day 1, Month 2, and Month 6 study vaccination visits. 
In the vaccination diary, the subject will be asked to record oral temperature in the evening after each 
study vaccination and daily, at the same time of day, for 4 days after each study vaccination for the 
purpose of identifying febrile events. They will also be asked to record any injection-site reactions 
prompted in the vaccination diary, i.e., injection-site tenderness, swelling, or redness occurring after 
each study vaccination and daily for 4 days after each study vaccination (solicited injection-site 
reactions). In addition to injection-site reactions prompted in the vaccination diary, the subject will be 
asked to assess the presence of other injection-site reactions and systemic AEs starting after each study 
vaccination for a total of 15 days. The subject will be asked to record injection-site and systemic AEs, 
concomitant medications, and concomitant vaccinations on the vaccination diary.  
The information on the vaccination diary should be generated only by the subject. The subject will be 
expected to bring the vaccination diary to the study site at the next scheduled visit. In case of 
hospitalization or visit to another physician, the subject should be informed to contact the investigator 
immediately. 
The study site personnel will review the data captured in the vaccination diary with the subject or 
subject’s parent/legal guardian at Visit 2 through Visit 4.  
All vaccination diary information will be recorded in the individual subject’s CRF. The investigator/sub-
investigator will determine causality of systemic AEs recorded on the vaccination diary using the 
guidelines given in Section 3.4.2.4 and will classify each event as an SAE or non-serious AE. If an oral 

 
 
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temperature indicates a fever (defined as an oral temperature of ≥37.8°C), the AE of “fever” must be 
documented in the individual subject’s CRF. 
At the time of vaccination diary review at the next scheduled visit, subjects will be questioned regarding 
any new medical conditions that occurred beyond Day 15 (after dosing). The investigator/sub-
investigator will determine if the medical condition is to be reported as an SAE using the reporting 
guidelines provided below. 
3.4.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product or protocol - specified procedure, whether or not considered related 
to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant 
adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated 
with the use of the study vaccine, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency or 
severity from expected levels are not to be considered adverse events. Examples of this may include, 
but are not limited to, teething, typical crying in infants and children and onset of menses or menopause 
occurring at a physiologically appropriate time. 
Adverse events may occur during the course of the use of the study vaccine during the clinical trial or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose 
(whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre -allocation baseline period as a 
result of a protocol-specified intervention or a procedure. 
All adverse events will be collected from the time the consent form is signed through 14 days following 
the first vaccination(s) and from the time of any subsequent vaccination(s) through 14 days thereafter, 
and such events will be recorded at each examination on the Adverse Event case report 
forms/worksheets. 
3.4.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
In this trial, an overdose is any dose higher than 0.75 mL of vaccine in any one dose or receiving >4 
doses (0.5mL each dose). 
If an adverse event(s) is associated with (“results from”) the overdose of the study vaccine, the adverse 
event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of study vaccine meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” 

 
 
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All reports of overdose with and without an adverse event must be reported within 24 hours to MSD 
either by electronic media or paper.  
3.4.2.2 Reporting of Pregnancy and Lactation to MSD 
Although not considered an adverse event, it is the responsibility of the investigators or their designees 
to report any pregnancy in a subject (spontaneously reported to them or detected by urine or serum 
pregnancy test per protocol) that occurs during the trial through 1 month following the last vaccination. 
If a subject becomes pregnant during the trial, including subjects who never received vaccine allocation 
and had a positive pregnancy test at Day 1, all related information must be reported to MSD. For subjects 
who become pregnant with LMP prior or equal to Day 30 following the final vaccination, the pregnancy 
will be collected in MSD’s global safety database. Furthermore, all fetal loss pregnancy outcomes 
(ectopic pregnancy, elective termination, spontaneous abortion, late fetal death) must be reported as a 
Serious Adverse Experience (Other Important Medical Event). All subjects who receive study vaccine, 
including discontinued subjects who agree to provide further information, must be followed to the 
completion/termination of the pregnancy. In addition, if the pregnancy continues to term, the outcome 
(health of the infant) must be reported. If a subject receives study vaccine while breastfeeding all related 
information, including outcome, must be reported to MSD. Infant serious adverse experiences (SAEs) 
for all infants born to subjects who received study vaccine must be reported to the MSD. 
All pregnancy, lactation, and infant SAE events must be reported within 24 hours to MSD either by 
electronic media or paper. MSD contact information can be found in the Investigator Trial File Binder. 
Refer to Data Entry Guidelines (DEGs) for instructions for reporting these events. 
3.4.2.3 Immediate Reporting of Adverse Events to the Sponsor 
3.4.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of the study 
vaccine that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a cancer; 
• 
Is associated with an overdose; 
• 
Is another important medical event 
Refer to Table 3 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause, 
that occurs to any subject from the time the consent is signed through 1 month following the last 
vaccination, whether or not related to the study vaccine, must be reported within 24 hours to MSD either 

 
 
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by electronic media or paper. MSD’s contact information can be found in the Investigator Trial File 
Binder. 
Additionally, any serious adverse event brought to the attention of an investigator who is a qualified 
physician at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to MSD if the event is either: 
• 
A death that resulted in the subject discontinuing the trial or 
• 
A serious adverse event that is considered by an investigator who is a qualified physician to be 
vaccine related. All subjects with serious adverse events must be followed up for outcome. 
3.4.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 
24 hours to MSD either by electronic media or paper. MSD’s contact information can be found in the 
Investigator Trial File Binder. 
Events of clinical interest for this trial include: 
• 
An overdose of study vaccine, as defined in Section 3.4.2.1- Definition of an Overdose for This 
Protocol and Reporting of Overdose to MSD, that is not associated with clinical symptoms or 
abnormal laboratory results. 
3.4.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events with respect to the elements 
outlined in Table 3.The investigator’s assessment of causality is required for each adverse event. Refer 
to Table 3 for instructions in evaluating adverse events. 
 

Product: V503 
Table 3: Evaluating Adverse Events  
Maximum Intensity 
Mild 
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated) 
Moderate 
 
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong) 
Severe 
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities) 
Injection site redness or swelling from the day of vaccination through Day 4 post-vaccination will be evaluated by maximum 
size. 
Seriousness 
A serious adverse event (AE) is any adverse event occurring at any dose that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a pre-existing 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or 
Is a cancer; or 
Is associated with an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event 
when,based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause the test vaccine to be discontinued? 
Relationship to test 
vaccine 
Did the test vaccine cause the adverse event? The determination of the likelihood that the test vaccine caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test vaccine and the adverse event based upon the available 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
information. The following components are to be used to assess the relationship between the test vaccine and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the test vaccine caused the adverse event: 
Exposure 
 
Is there evidence that the subject was actually exposed to the test vaccine such as: reliable history, acceptable compliance 
assessment (e.g., diary), seroconversion or identification of vaccine virus in bodily specimen? 
Time Course 
 
Did the AE follow in a reasonable temporal sequence from administration of the test vaccine? 
Is the time of onset of the AE compatible with a vaccine-induced effect? 
Likely Cause 
 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors 
Relationship to test 
vaccine (continued) 
The following components are to be used to assess the relationship between the test vaccine and the AE: (continued) 
Dechallenge 
(not applicable for vaccines) 
Rechallenge 
 
Was the subject reexposed to the test vaccine in this trial? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose 
vaccine trial.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE TEST VACCINE, OR IF REEXPOSURE TO THE TEST VACCINE POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE. 
 
Consistency with Trial 
Vaccine Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test vaccine or vaccine class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the 
following: 
Use the following criteria as guidance (not all criteria must be present to be indicative of a vaccine relationship). 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Yes, there is a reasonable possibility of vaccine 
relationship 
There is evidence of exposure to the test vaccine. The temporal sequence of the AE onset relative to the administration of the test 
vaccine is reasonable. The AE is more likely explained by the test vaccine than by another cause. 
No, there is not a reasonable possibility of vaccine 
relationship 
Subject did not receive the test vaccine OR temporal sequence of the AE onset relative to administration of the test vaccine is not 
reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) 
 

Product: V503 
3.4.2.5 Sponsor Responsibility for Reporting Adverse Events and Patient/Device Events and Incidents 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations.  
 
3.5 
Statistical analysis plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the study has 
begun, but prior to database lock, changes are made to primary hypotheses, or the statistical methods 
related to those hypotheses, then the protocol will be amended (consistent with International Conference 
on Harmonisation [ICH] Guideline E-9). Changes to exploratory or other non-confirmatory analyses 
made after the protocol has been finalized, along with an explanation as to when and why they occurred, 
will be listed in the clinical study report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR. All statistical analyses specified in this protocol will be conducted using R. version 
3.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2013). 
3.5.1 In-house Blinding  
All subjects in this study will receive GARDASIL®9; the study is thus open-label.  
3.5.2 Hypothesis/Estimation 
Objectives and hypotheses of the study are stated in Section 2.1.  
3.5.3 Analysis Endpoints 
3.5.3.1 Immunogenicity 
The immunogenicity endpoints are: 
• 
The cLIA GMTs to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 at 4 weeks after Dose 3.  
• 
The cLIA seroconversion percentages to HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 by 4 weeks 
after Dose 3.  
A subject with a cLIA titre at or above the serostatus cutoff for a given HPV type (see Section 3.3) is 
considered seropositive for that type. Seroconversion is defined as changing serostatus from 
seronegative at Day 1 to seropositive, by 4 weeks after Dose 3. 
3.5.3.2 Safety 
Safety assessment will focus on injection-site adverse reactions and elevated temperatures Day 1 to 
Day 5 post-vaccination and systemic AEs Day 1 to Day 15 post-vaccination, reported on the vaccination 
diary. In addition, SAEs and pregnancy will be collected from the time the ICF is signed through 1 month 
following the last vaccination. 
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
3.5.4 Analysis Populations 
3.5.4.1 Immunogenicity Analysis Populations 
Per Protocol Immunogenicity Population 
The per-protocol immunogenicity (PPI) analysis populations will serve as the primary populations of 
subjects for the analysis of immune responses to each of the 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, 
and 58). The PPI analysis populations are HPV type-specific, i.e., each HPV type has its own PPI 
analysis population. To be included in a particular HPV type-specific PPI analysis population, subjects 
must: 
• 
Have received all 3 vaccinations of the correct dose of GARDASIL®9 within acceptable day 
ranges (See Table 4). 
• 
Have evaluable serology results at Day 1 and Month 7 based on serum samples collected 
within acceptable day ranges (See Table 5). 
• 
Be seronegative to the appropriate HPV type at Day 1. 
• 
Have no protocol deviations that could interfere with the evaluation of subject's immune 
response to GARDASIL®9. 
To be included in the PPI analysis population for any vaccine HPV type, subjects need to be 
seronegative to that specific type at Day 1. The final determination of protocol deviation categories 
deemed as having potential to interfere with evaluation of immune response to GARDASIL®9 will be 
made prior to database lock and will be recorded in a separate study document. 
Table 4: Acceptable Day ranges for Vaccination Visits  
Dose of 
9vHPV 
Vaccine 
Scheduled 
for Injection 
Protocol Specified Visit Window 
for SOT group 
Day Range 
for 
Inclusion in 
Statistical 
Analysis for 
SOT group 
(Relative to 
Day 1†) 
Protocol Specified Visit Window 
for HIV group 
Day Range 
for 
Inclusion in 
Statistical 
Analysis for 
HIV group 
(Relative to 
Day 1†) 
Dose 1 
Dose 
2Dose 3 
Day 1† 
Month 2 ± 4 weeks 
Month 6 (-1 week / +4 weeks) 
0 
30 to 90 
170 to 210 
Day 1† 
Month 2 (-4 weeks / +2 weeks) 
Month 6 ± 4 weeks 
0 
30 to 75 
150 to 210 
† Day 1 refers to the date when Dose 1 of the study vaccine is injected. For vaccinations after Day 1, the day ranges for inclusion in the 
statistical analysis are wider than the protocol-specified visit windows primarily to account for differences at the study sites in counting 
months (e.g., 1 calendar month versus 30 days versus 4 weeks). 
9vHPV, 9-valent human papillomavirus. 
 

 
 
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Table 5: Acceptable Day Ranges for Collection of Serum Samples 
Study Visit 
Target Collection Day 
(Relative to Day 1†) 
Day Range for Inclusion in 
Statistical Analysis† 
Day 1 
0 
–14 to 0 (Relative to Day 1)‡ 
Month 7 
30 days after Dose 3 
21 to 49 after Dose 3§ 
† Day 1 refers to the date when dose 1 of study vaccine is injected. For Month 7, indicated target collection/day range is 
relative to date of injection of Dose 3 of study vaccine. 
‡ Applies to both the PPI and ANSS analysis populations. 
§ Applies to the PPI analysis population only. The day range for the ANSS analysis population is 21 to 105 days after dose 3. 
ANSS = All type-specific naïve subjects with serology; PPI = Per-protocol immunogenicity. 
 
All Type-Specific Naïve Subjects with Serology Population 
A supportive immunogenicity analysis will be carried out on the all type-specific naïve subjects with 
serology (ANSS) analysis population. The ANSS analysis populations are HPV type-specific similar to 
the PPI analysis populations. To be included in these sets of subjects, subjects must: 
• 
Have received all 3 vaccinations of GARDASIL®9; 
• 
Have evaluable serology results at Day 1 and Month 7 based on serum samples collected within 
acceptable day ranges (See Table 5); 
• 
Be seronegative to the appropriate HPV type at Day 1. 
To be included in the ANSS analysis population for HPV 6 and 11, subjects must be seronegative to 
both HPV 6 and 11 at Day 1. To be included in the ANSS analysis population for any other vaccine HPV 
type, subjects need to be seronegative to that specific type at Day 1. 
Unlike the PPI analysis populations, ANSS analysis populations will not exclude subjects who had 
protocol deviations deemed as having potential to interfere with evaluation of immune response to 
GARDASIL®9. In addition, no day ranges on the timing of the vaccination will be applied. 
The seropositive or GMT population 
The seropositive or GMT analysis population will include subjects who were seropositive at day 1 for a 
given HPV type. An increase in antibody titers pre- and postvaccination will be analysed for each of the 
9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58). The seropositive analysis populations are HPV type-
specific, i.e., each HPV type has its own seropositive analysis population. To be included in a particular 
HPV type-specific seropositive analysis population, subjects must: 
• 
Have received all 3 vaccinations of the correct dose of GARDASIL®9 within acceptable day 
ranges (See Table 4). 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
• 
Have evaluable serology results at Day 1 and Month 7 based on serum samples collected 
within acceptable day ranges (See Table 5). 
• 
Be seropositive to the appropriate HPV type at Day 1. 
• 
Have no protocol deviations that could interfere with the evaluation of subject's immune 
response to GARDASIL®9. 
 
3.5.4.2 Safety Analysis Population 
The all subjects as-treated (ASaT) analysis population, comprised of subjects who received at least 1 
dose of GARDASIL®9 and had at least 1 study visit with safety follow-up, will be the primary population 
for safety analyses. 
 
3.5.5 Statistical Methods 
3.5.5.1 Immunogenicity Analyses 
The primary analyses of immunogenicity will be conducted in the Per Protocol Immunogenicity (PPI) 
population as defined in Section 3.5.4.1. Immunogenicity data will be analysed separately for HIV and 
SOT patients. The potential influence of factors such as immunosuppressive therapy and time after 
transplantation for SOT patients and CD4-count and antiretroviral therapy for HIV patients will be 
estimated. 
• 
Seroconversion 
The primary outcome, seroconversion, defined as changing serostatus from seronegative at Day 1 to 
seropositive (antibody titre above seroconversion cut-off) by 4 weeks after Dose 3, will be described 
with 95% CI. Differences with historical controls will be determined with a test for binary (seroconversion 
or not) proportions. 
• 
GMT 
All titers will be log transformed and the antilog of the mean will be calculated to obtain the GMT. GMT 
will be described with 95%CI. GMTs of immunocompromised patients will be compared with GMTs of 
historical controls with a one sample t-test, comparing month 7 GMTs for each component. 
 
3.5.5.2 Statistical Methods for Safety Analyses 
All subjects who received at least 1 dose of GARDASIL®9 and have safety follow-up data will be 
included in the analysis of safety.  
Prevalence of safety measures will be described with 95% CI and will be compared to the prevalence 
in historical controls with a test for proportions. Regardless of incidence, all AEs will be summarized as 
frequencies and percentages by vaccination visit, and across all vaccination visits. Specific AEs for 
which summaries will be provided are identified in Table 6. Incidence is defined as (number of subjects 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
with the indicated endpoint divided by the total number of subjects with follow-up over the relevant 
period) × 100%. Confidence intervals (95%) and 2-sided p-values will be provided without adjusting for 
multiplicity. Treatment administration data will be summarized for including number of vaccine injections 
received. Imputation methods will not be used to replace missing safety data. Safety data for HIV 
patients and SOT patients will be analysed separately. 
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Table 6: Analysis Strategy for Safety Parameters 
Adverse Event Endpoint 
Follow-Up Period 
Summaries/Analyses 
After Any 
Vaccination 
Visit 
Any 
Time 
During 
Study 
Incidence 
Risk 
Difference 
and 95% CI 
(b) 
p-Value 
Day 1 
to Day 
5 (a) 
Day 1 
to Day 
15 (a) 
Clinical AE 
 
 
 
 
 
 
• 
Any AE 
• 
Death 
 
• 
 
 
 
• 
 
• 
 
• 
 
 
 
• 
Injection-site adverse events (c) 
 
 
 
 
 
 
• 
Injection-site 
pain/tenderness,swelling, and 
redness 
• 
Other injection-site adverse 
reactions 
• 
Severe injection-site adverse 
reactions 
• 
Number (%) of subjects by 
maximum intensity rating, over 
all injection-site adverse 
reactions 
• 
Number (%) of subjects by 
maximum intensity rating, within 
each of the categories of 
injection-site adverse reactions 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
• 
 
 
• 
(d) 
 
• 
 
 
 
 
 
 
• 
 
Systemic AEs  
 
 
 
 
 
 
• 
Systemic AEs  
• 
Number (%) of subjects by 
maximum intensity rating, over 
all systemic AEs  
 
• 
 
• 
 
 
• 
 
• 
 
• 
(e) 
 
Temperatures 
 
 
 
 
 
 
Elevated temperatures (f) 
Maximum temperatures (g) 
 
• 
 
• 
 
 
 
• 
 
• 
 
• 
 
• 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
AEs of special interest 
 
 
 
 
 
 
• 
Serious AEs  
• 
Serious VR AEs 
• 
New medical conditions 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
(a) The day of vaccination is counted as Day 1. 
(b) Defined as the difference in incidence between the comparison groups (SOT and HIV patients versus historical 
controls). 
(c) For the injection-site redness and swelling 0 to 2.5 cm (0 to 1 inch) will be categorized as mild, >2.5 to 5 cm (>1 
inch to 2 inches) will be categorized as moderate, and >5 cm (>2 inches) will be categorized as severe. 
(d) Only for injection-site adverse reactions occurring in ≥1% of subjects in either group. 
(e) Only for systemic AEs occurring in ≥1% of subjects in either group. 
(f) Defined as maximum (over the follow-up period) temperature ≥37.8°C. 
(g) Distribution of maximum temperatures over the relevant follow-up period. 
AEs, adverse events; VR, vaccine-related. 
 
3.5.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses 
Baseline characteristics and demographic variables will be summarized for HIV and SOT patients using 
descriptive statistics or categorical tables on all subjects enrolled in the study and on all PPI eligible 
subjects (i.e., subjects belonging to at least one PPI analysis populations). No formal statistical testing 
of differences with census data from patient populations with respect to these characteristics will be 
performed.  
Quantitative variables (except antibody titres) will be displayed using descriptive statistics by way of 
sample size, mean, standard deviation, median, minimum, and maximum. Antibody titres will be 
displayed using descriptive statistics by way of sample size, GMT s, and two-sided 95% CIs.  
Categorical variables will be displayed using descriptive statistics by way of sample size, count by 
category, and proportion by category. Missing data will be counted but not included in the calculation of 
proportions. 
Subject Accounting 
The number and percentage of subjects screened (ICF signed), enrolled (allocation number assigned), 
vaccinated (at least once and at each vaccination time point), discontinued, and the primary reason for 
discontinuation will be displayed for HIV and SOT patients. Reasons for subjects excluded from the PPI 
analysis populations will be summarized and displayed in subject accounting tables.  
 
 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
Subject Characteristics 
Demographic variables and other baseline characteristics such as age, vital signs (height, weight, and 
oral temperature), and country of origin will be summarized for both HIV and SOT patients.  
Baseline HPV Status 
A serum sample will be collected from all subjects at the Day 1 visit for the purpose of assessing baseline 
HPV serostatus to the 9vHPVvaccine HPV types (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58). A subject 
will be considered seropositive to a given HPV type at Day 1 if the subject’s anti-HPV titre is greater 
than or equal to the corresponding serostatus cutoff for that HPV type or seronegative to a given HPV 
type at Day 1 if the subject’s anti-HPV titre is less than the corresponding serostatus cutoff for that HPV 
type. For each HPV type, the proportions of subjects who are seronegative or seropositive will be 
summarized for both HIV and SOT patients. 
Prior and Concomitant Medications 
The number and percentage of subjects with prior medications or vaccinations prior to each study 
vaccination will be summarized for both HIV and SOT patients. The relevant pre-injection day ranges 
for summarization will be 3 days for medications, 14 days for non-live virus vaccines, and 28 days for 
live virus vaccines. 
Similarly, the number and percentage of subjects with concomitant medications or vaccinations within 
15 days (Day 1 to Day 15) following any study vaccination will be summarized for each age group. The 
number of subjects with “Special Medications” (corticosteroids, immunosuppressives, immune globulins, 
and blood products [Section3.2.4]) will be summarized for both HIV and SOT patients throughout the 
study period. 
New Medical Conditions: New medical conditions occurring during the study (i.e., incident medical 
conditions occurring outside of a Day 1 to Day 15 period post -vaccination and not considered SAEs) 
will be summarized for both HIV and SOT patients. 
3.5.6 Sample Size and Power Calculations 
Based on an expected seroconversion rate of 80%, a sample size of 170 transplant patients allows to 
estimate the proportion of protected transplant patients with precision (95% confidence interval) of ±6% 
(10).  
Furthermore, based on an expected seroconversion rate 85-91%, a sample size of 140 HIV-patients 
allows to estimate the proportion of protected patients with precision (95% confidence interval) of ±6% 
and 5% respectively (7). Based on expected differences in GMT to healthy populations, a sample size 
of 140 HIV-patients allows to estimate the GMTs HPV type 6, 11, 16 and 18 with a power of 0.38, 0.82, 
1 and 1, respectively (7, 19). 
Due to difficulties in the recruitment of HIV patients without genital warts a recalculation of the sample 
size was done. With a total sample size of n=100, a majority of whom will have no history of HPV-
lesions, we expect to be able to use the data of at least 80 patients for the analysis seroconversion of 
each HPV type under study. Seroconversion rates of 95-99% for HPV types 6, 11 and 16 can then be 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
estimated with a margin of error of ±4.8% - 2.2%, and the anticipated seroconversion rate of 90% for 
HPV type 18 with a margin of error of ±6.6%. 
 
3.5.7 Interim Analysis 
No interim analysis is planned. 
3.6 
DEFINITION OF COMPLIANCE MEASURE 
Compliance is defined in this study as receipt of all scheduled study vaccinations. To summarise 
compliance, the numbers of subjects who receive each vaccination will be tabulated. Compliance with 
the planned vaccination schedule (Day 1, Month 2, and Month 6) will be described by histograms of 
actual intervals between vaccinations relative to the expected interval in the CSR. 
 
3.7 
Labeling, Packaging, Storage, Dispensing, and Return of Clinical Supplies 
3.7.1 Product Description 
Investigational Medicinal Product (IMP) will be provided by MSD as summarized in 
Table 7. 
Table 7: Investigational medicinal product 
Product name 
Potency 
Dosage Form/ Content s/ 
Route of Administration 
Storage Conditions  
GARDASIL®9 
V503 (9-Valent 
HPV L1 VLP) Vaccine 
(Recombinant, 
adsorbed) 
HPV Types (L1 protein) 
6/11/16/18/31/33/45/52/58 
 
30/40/60/40/20/20/20/20/20 
mcg 
Adsorbed on AAHS 500 
mcg 
Sterile suspension for 
intramuscular injection  
1 dose (0.5 mL) 
 
Shake well before use. 
Store at 2.0 to 8.0°C  
Do not freeze. Protect 
from light. 
AAHS, Merck Aluminum Adjuvant (amorphous aluminum hydroxyphosphate sulfate); HPV, human papillomavirus; 
VLP, virus-like particle. 
 
GARDASIL®9 is available as a suspension for injection. It appears as a clear liquid with white 
precipitate. 
3.7.2 Packaging Information 
Supplies will be labelled in accordance with local regulatory requirements. 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
3.7.3 Clinical Supplies Disclosure 
Not applicable. This study is open-label. 
3.7.4 Shipment of Investigational Medicinal Product 
The IMP will be shipped to the study site, refrigerated and stored at 2.0°C to 8.0°C following the 
guidelines on transport on commercial goods. Upon receipt at the study site, the vaccine should be 
removed from the outer secondary shipping box and placed immediately into the refrigerator. 
Upon arrival of the shipment at the study site, the person responsible will verify that the content of the 
shipment corresponds to the order and that the products arrived in good condition. He/she will 
acknowledge receipt to MSD Belgium by email.  
3.7.5 Storage and Handling Requirements 
The clinical supplies storage area at the study site must be monitored by the site staff for temperature 
consistency with the acceptable storage temperature range specified in this protocol or in the product 
label attached to the protocol. Documentation of temperature monitoring should be maintained. Supplies 
should be stored in the original nested box with the lid closed to minimize exposure to light. If the 
refrigerator in which the study vaccine is stored deviates from the 2.0°C to 8.0°C range, study 
vaccinations should be suspended and MSD should be contacted immediately. Vaccine must NOT be 
frozen. 
A daily refrigerator temperature log must be maintained at the study site. The refrigerator must be 
equipped with an appropriately calibrated min/max thermometer and/or circular chart temperature 
recorder. The temperature log will be reviewed by the investigator (or designee). An appropriate back 
up system (i.e., alarm or generator) and study site personnel telephone numbers should be in place in 
the event of a refrigerator failure. 
In case of a cold chain break (i.e., if the temperature of the refrigerator is lower than 2.0°C or exceeds 
8.0°C): 
• 
The investigator (or designee) at the site should follow the current clinical complaint process to 
file an excursion 
• 
The investigator (or designee) must wait for further instructions from MSD, as to whether or not 
the study vaccines can be used. The investigator is not allowed to use the study vaccines before 
getting MSD approval to do so.  
• 
The cold chain break must be documented in the Investigator site file and the Trial Master File. 
The IMP must be received by a designated person at the study site, handled and stored safely and 
properly, and kept in a secured location to which only the investigator and designated assistants have 
access. IMP is to be administered only in accordance with the protocol. 
Any concerns raised about the manufacturing, packaging, labelling, or distribution of IMP supply which 
could potentially impact its suitability for use should be immediately reported to MSD. The IMP must be 
quarantined until the MSD’s feed-back is received as to whether or not the vaccine can be used. 

 
 
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Unused study vaccines taken out from the stock at study site are considered to be unusable and cannot 
be returned to the stock. They must be quarantined and returned back to MSD as soon as possible. 
3.7.6 Accountability of Investigational Medicinal Product 
For the accountability procedure, please refer to Guidelines for IMP Management on site. 
3.7.7 Return of Investigational Medicinal Product 
All empty primary containers will be destroyed at the study site according to local regulations. Supplies 
will need to be returned to the depot of origin if destruction is not possible locally. 
Empty boxes of study vaccines must be kept at study site to enable verification of the vaccine 
accountability and can be destroyed on site after study has been completed. The following should be 
returned to the distributor according to the procedures detailed in the Investigator Site File: 
• 
Study vaccines unusable following a cold chain deviation, as soon as possible; 
• 
Study vaccines expiring within the current month, immediately; 
• 
Unused study vaccines which remain in stock at study site after the last administration to the 
last subject of the corresponding study site, after verification of vaccine accountability; 
• 
Study vaccines concerned by a batch recall, immediately. 
For the return procedure, please refer to Guidelines for IMP Management on site. The distributor will 
confirm the receipt of each study vaccine returned (at unit level). 
 
3.8 
Data Management 
Study data will be acquired via electronic format. As part of their responsibilities, the principal 
investigator or sub-investigator agree to maintain adequate source documents for the subjects treated 
as part of the research under this protocol. The principal investigator or sub-investigator agree to 
maintain source documentation (e.g., laboratory reports), to enter subject data into the individual 
subject’s CRF as accurately as possible. 
Each CRF will allow data entry by study site staff that can add and edit data, identify and resolve 
discrepancies, and view records. This system detection of discrepancies, enabling study site 
coordinators to resolve and manage discrepancies in a timely manner. 
The electronic database will be password protected. A quality review of the data will be performed by 
the study site by an independent person through risk-based source data verification of essential data. 
3.9 
Study report 
A clinical study report will be provided in which the study results will be compared with historical controls. 
 
 

 
 
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4.0. 
ADMINISTRATIVE AND REGULATORY DETAILS 
 
4.1. 
Confidentiality 
4.1.1. Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that IRB/ERC, or regulatory authority representatives 
may consult and/or copy trial documents in order to verify worksheet/case report form data. By signing 
the consent form, the subject agrees to this process. If trial documents will be photocopied during the 
process of verifying worksheet/case report form information, the subject will be identified by unique code 
only; only serum samples will be transmitted to MSD, which will only have a unique code.. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in connection 
with this trial in accordance with all applicable privacy laws, rules and regulations. 
4.1.2. Confidentiality of IRB/IEC Information 
The Sponsor is required to record the name and address of each IRB/IEC that reviews and approves 
this trial. The Sponsor, in collaboration with the relevant investigator  is also required to document that 
each IRB/IEC meets regulatory and ICH GCP requirements by requesting and maintaining records of 
the names and qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies. 
 
4.2. 
Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent manner 
and in conformance with this protocol, ICH GCP guidelines, the EU Clinical Trial Directive (as it may be 
amended or superseded from time to time), the latest version of the Declaration of Helsinki ; and all 
applicable federal and local laws, rules and regulations relating to the conduct of the clinical trial. 
The investigator also agrees to allow monitoring, audits, IRB/IEC review and regulatory authority 
inspection of trial-related documents and procedures and provide for direct access to all trial-related 
source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or from 
government programs for procedures included as part of the trial reimbursed to the investigator by the 
Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in compliance 
with Good Clinical Practice standards and applicable federal and local laws, rules and regulations.  
The investigator must maintain copies of all documentation and records relating to the conduct of the 
trial in compliance with all applicable legal and regulatory requirements. This documentation includes, 
but is not limited to, the protocol, worksheets/case report forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with regulatory authorities and IRBs/ERCs, 
consent forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 

 
 
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certification or quality control procedures and laboratory director curriculum vitae. By signing this 
protocol, the investigator agrees that documentation shall be retained at least 20 years the study was 
concluded.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary 
physician about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
The investigator will promptly inform Sponsor of any regulatory authority inspection conducted for this 
trial. Persons debarred from conducting or working on clinical trials by any court or regulatory authority 
will not be allowed to conduct or work on this trial. The investigator will immediately disclose in writing 
to the IRB/IEC if any person who is involved in conducting the trial is debarred or if any proceeding for 
debarment is pending or, to the best of the investigator’s knowledge, threatened.  
In addition, the investigator will review the trial report that summarizes the trial results and will describe 
the conduct and results of the trial [Clinical Study Report (CSR)] accurately to the best of his/her 
knowledge.  
 
4.3. 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the 
Sponsor of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialsregister.eu or other 
local registries. The Sponsor of this trial, will review this protocol and submit the information necessary 
to fulfil these requirements. Sponsor entries are not limited to FDAAA or the EMA clinical trial directive 
mandated trials. Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information. By signing this protocol, the investigator 
acknowledges that the statutory obligations under the EMA clinical trials directive or other locally 
mandated registries are that of the Sponsor and agrees not to submit any information about this trial or 
its results to those registries. 
 
4.4 
Quality Management System 
By signing this protocol, the Investigator agrees to be responsible for implementing and maintaining a 
quality management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented, 
and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical trial. 

 
 
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Protocol V503-IC – Date: 13-nov-2018- version 4 – Am1 
4.5 
Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy of subject 
data.  
4.6 
Publications 
This trial is intended for publication. Publication may include any or all of the following: posting of a 
synopsis online, abstract and/or presentation at a scientific conference, or publication of a full 
manuscript. The authors will submit a manuscript describing trial results within 12 months after the last 
data become available, which may take up to several months after the last subject visit in some cases 
such as vaccine trials. The investigator will post a synopsis of trial results on www.clinicaltrials.gov by 
12 months after the last data have become available . Authors of the primary results manuscript will be 
provided the complete results from the Clinical Study Report.  
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for 
important intellectual content; and 3) final approval of the version to be published. Authors must meet 
conditions 1, 2 and 3. Significant contributions to trial execution may also be taken into account to 
determine authorship, provided that contributions have also been made to all three of the preceding 
authorship criteria. Although publication planning may begin before conducting the trial, final decisions 
on authorship and the order of authors’ names will be made based on participation and actual 
contributions to the trial and writing, as discussed above. The first author is responsible for defending 
the integrity of the data, method(s) of data analysis and the scientific content of the manuscript. MSD 
will receive the opportunity to review all proposed abstracts, manuscripts or presentations regarding this 
trial 30 days prior to submission for publication/presentation. Any information identified by the MSD as 
confidential will be deleted prior to submission; this confidentiality does not include efficacy and safety 
results. MSD review can be expedited to meet publication timelines. 
  
 
 

 
 
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5.0 
LIST OF REFERENCES  
1. 
Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. 2006;24 Suppl 
3:S3/11-25. 
2. 
Moscicki AB, Hills N, Shiboski S, Powell K, Jay N, Hanson E, et al. Risks for incident human 
papillomavirus infection and low-grade squamous intraepithelial lesion development in young 
females. Jama. 2001;285(23):2995-3002. 
3. 
Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N, et al. The natural history of 
human papillomavirus infection as measured by repeated DNA testing in adolescent and young 
women. J Pediatr. 1998;132(2):277-84. 
4. 
Moscicki AB, Ellenberg JH, Crowley-Nowick P, Darragh TM, Xu J, Fahrat S. Risk of high-grade 
squamous intraepithelial lesion in HIV-infected adolescents. J Infect Dis. 2004;190(8):1413-21. 
5. 
Weinberg A, Song LY, Saah A, Brown M, Moscicki AB, Meyer WA, 3rd, et al. Humoral, mucosal, 
and cell-mediated immunity against vaccine and nonvaccine genotypes after administration of 
quadrivalent human papillomavirus vaccine to HIV-infected children. J Infect Dis. 
2012;206(8):1309-18. 
6. 
Kahn JA, Xu J, Kapogiannis BG, Rudy B, Gonin R, Liu N, et al. Immunogenicity and safety of the 
human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. Clin Infect Dis. 
2013;57(5):735-44. 
7. 
Kojic EM, Kang M, Cespedes MS, Umbleja T, Godfrey C, Allen RT, et al. Immunogenicity and 
safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis. 
2014;59(1):127-35. 
8. 
Denny L, Hendricks B, Gordon C, Thomas F, Hezareh M, Dobbelaere K, et al. Safety and 
immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South 
Africa: a partially-blind randomised placebo-controlled study. Vaccine. 2013;31(48):5745-53. 
9. 
MacIntyre CR, Shaw P, Mackie FE, Boros C, Marshall H, Barnes M, et al. Immunogenicity and 
persistence of immunity of a quadrivalent Human Papillomavirus (HPV) vaccine in 
immunocompromised children. Vaccine. 2016;34(36):4343-50. 
10. 
Kumar D, Unger ER, Panicker G, Medvedev P, Wilson L, Humar A. Immunogenicity of 
quadrivalent human papillomavirus vaccine in organ transplant recipients. Am J Transplant. 
2013;13(9):2411-7. 
11. 
Gomez-Lobo V, Whyte T, Kaufman S, Torres C, Moudgil A. Immunogenicity of a prophylactic 
quadrivalent human papillomavirus L1 virus-like particle vaccine in male and female adolescent 
transplant recipients. Pediatr Transplant. 2014;18(3):310-5. 
12. 
Levin MJ, Moscicki AB, Song LY, Fenton T, Meyer WA, 3rd, Read JS, et al. Safety and 
immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-
infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010;55(2):197-204. 
13. 
Toft L, Tolstrup M, Muller M, Sehr P, Bonde J, Storgaard M, et al. Comparison of the 
immunogenicity of Cervarix(R) and Gardasil(R) human papillomavirus vaccines for oncogenic 
non-vaccine serotypes HPV-31, HPV-33, and HPV-45 in HIV-infected adults. Hum Vaccin 
Immunother. 2014;10(5):1147-54. 
14. 
Zhai L, Tumban E. Gardasil-9: A global survey of projected efficacy. Antiviral Res. 2016;130:101-
9. 
15. 
Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-valent HPV vaccine 
against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711-23. 
16. 
Luxembourg A, Moreira ED, Jr., Samakoses R, Kim KH, Sun X, Maansson R, et al. Phase III, 
randomized controlled trial in girls 9-15 years old to evaluate lot consistency of a novel nine-valent 
human papillomavirus L1 virus-like particle vaccine. Hum Vaccin Immunother. 2015;11(6):1306-
12. 
17. 
Vesikari T, Brodszki N, van Damme P, Diez-Domingo J, Icardi G, Petersen LK, et al. A 
Randomized, Double-Blind, Phase III Study of the Immunogenicity and Safety of a 9-Valent 
Human Papillomavirus L1 Virus-Like Particle Vaccine (V503) Versus Gardasil(R) in 9-15-Year-
Old Girls. Pediatr Infect Dis J. 2015;34(9):992-8. 
18. 
Van Damme P, Meijer CJ, Kieninger D, Schuyleman A, Thomas S, Luxembourg A, et al. A phase 
III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV 
vaccines in men. Vaccine. 2016;34(35):4205-12. 
19. 
Castellsague X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, et al. End-of-study 
safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant 
vaccine in adult women 24-45 years of age. Br J Cancer. 2011;105(1):28-37. 
 

 
 
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6.0 
SIGNATURES 
As principal investigator, I agree to conduct this clinical trial in accordance with the design outlined in 
this protocol and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol). I agree to conduct the trial in accordance with generally accepted 
standards of Good Clinical Practice. I also agree to report all information or data in accordance with the 
protocol and, in particular, I agree to report any serious adverse events as defined in Section 3.4.2 – 
TRIAL PROCEDURES (Assessing and Recording Adverse Events) to MSD. I also agree to handle all 
study vaccines provided by MSD and collect and handle all clinical specimens in accordance with the 
protocol.  
 
Name Principal Investigator 
 
Title 
 
Signature 
 
Date signed