Quadrivalent Human Papillomavirus (qHPV) Vaccine in Cancer Survivors: Cross Sectional Survey and Phase II Open-Label Vaccine Trial
Phase: PHASE2
Conditions: Cancer Survivor, Prevention of Human Papillomavirus Infection
Sponsor: University of Alabama at Birmingham

Official Title: Quadrivalent Human Papillomavirus (qHPV) Vaccine in Cancer Survivors: 
Cross Sectional Survey and Phase II Open-Label Vaccine Trial 
 
NCT Number: NCT01492582 
 
Document: Protocol 
 
Document Date: 3/2/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Human Papillomavirus (HPV) Vaccine in Cancer Survivors: 
Cross Sectional Survey and Phase II Open-Label Vaccine Trial 
 
 
PRINCIPAL INVESTIGATOR:  
 
Wendy Landier, PhD, RN (University of Alabama at Birmingham; UAB) 
 
CO-PRINCIPAL INVESTIGATOR: 
James Klosky, PhD (St. Jude Children’s Research Hospital; SJCRH) 
 
 
Co-Investigators: 
Smita Bhatia, MD, MPH (UAB)  
Saro Armenian, DO, MPH (City of Hope; COH) 
Rama Jasty-Rao, MD (University of Michigan; UM) 
Melissa Hudson, MD (SJCRH) 
Can-Lan Sun, PhD (COH) 
Karen Wasilewski-Masker, MD, MS (Emory University; EU) 
F. Lennie Wong, PhD, Biostatistician (COH) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
             
PARTICIPATING SITES: 
 
UNIVERSITY OF ALABAMA AT BIRMINGHAM (UAB) 
Wendy Landier, PhD, RN, site PI 
Yanjun Chen, MS, Biostatistician 
CITY OF HOPE (COH) 
Saro Armenian, DO, Site PI 
ST. JUDE CHILDREN’S RESEARCH HOSPITAL (SJCRH) 
James Klosky, PhD, Site PI 
Melissa Hudson, MD 
Daniel Green, MD  
Leslie Robison, PhD 
Kathryn Russell, PhD  
UNIVERSITY OF MICHIGAN (UM) 
Rama Jasty-Rao, MD, Site PI  
Marcia Leonard, RN, PNP  
EMORY UNIVERSITY SCHOOL OF MEDICINE (EU)  
Karen Wasilewski-Masker, MD, MS, Site PI  
 
SIGNIFICANT CONTRIBUTORS: 
Sharon Denison, Pharm D (COH) 
Anna Guiliano, PhD, H. Lee Moffitt Cancer Center 
John Zaia, MD (COH) 
 

 
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TABLE OF CONTENTS 
ABSTRACT ................................................................................................................................................................ 4 
STUDY SCHEMA (OVERVIEW) ................................................................................................................................ 6 
STUDY SCHEMA (DETAILED) ................................................................................................................................. 7 
1.0 
OBJECTIVES AND HYPOTHESES ........................................................................................................... 8 
2.0 
BACKGROUND .......................................................................................................................................... 8 
2.1.  
SIZE OF THE TARGETED CANCER SURVIVOR POPULATION ............................................................................... 8 
2.2.  
HUMAN PAPILLOMAVIRUS (HPV): PREVALENCE AND ASSOCIATED MALIGNANCIES .......................................... 8 
2.3.  
HPV IN IMMUNOCOMPROMISED PATIENTS ....................................................................................................... 9 
2.4.  
HPV VACCINE DEVELOPMENT AND TESTING IN THE GENERAL (IMMUNOCOMPETENT) POPULATION ................... 9 
2.5.  
VACCINATION IN POPULATIONS WITH ALTERED IMMUNE COMPETENCE ........................................................... 10 
2.6.  
PREVALENCEOF HPV VACCINE INITIATION .................................................................................................... 10 
2.7. 
FACTORS RELEVANT TO HPV VACCINE NON-INITIATION ................................................................................ 11 
2.8 
THEORETICAL MODEL/CONCEPTUAL FRAMEWORK ........................................................................................ 12 
2.9 
PRELIMINARY STUDIES ................................................................................................................................. 13 
2.10  
OVERALL SIGNIFICANCE OF THE STUDY ........................................................................................................ 13 
3.0 
ELIGIBILITY .............................................................................................................................................. 14 
3.1 
INCLUSION CRITERIA: AIM 1 (SURVEY) .......................................................................................................... 14 
3.2 
INCLUSION CRITERIA: AIM 2 (VACCINE EVALUATION) .................................................................................... 14 
3.3 
EXCLUSION CRITERIA: AIM 2 (VACCINE EVALUATION) ................................................................................... 15 
4.0 
METHODS: AIM 1 (SURVEY) ................................................................................................................... 15 
4.1 
STUDY DESIGN ............................................................................................................................................ 15 
4.2 
IDENTIFICATION/RECRUITMENT OF PARTICIPANTS ......................................................................................... 15 
4.3 
DATA ABSTRACTION .................................................................................................................................... 16 
4.4 
HPV VACCINATION SURVEY ......................................................................................................................... 16 
4.5 
SURVEY COMPLETION THANK YOU LETTER .................................................................................................. 19 
5.0  
METHODS: AIM 2 (VACCINE EVALUATION) ......................................................................................... 19 
5.1 
STUDY DESIGN ............................................................................................................................................ 19 
5.2 
IDENTIFICATION/RECRUITMENT OF PARTICIPANTS ......................................................................................... 19 
5.3 
DATA ABSTRACTION .................................................................................................................................... 20 
5.4 
VACCINATION PROTOCOL ............................................................................................................................. 20 
5.4.1 
    Quadrivalent and Nonavalent HPV Vaccine .................................................................................... 20 
5.4.2 
    Vaccine Supply and Storage ............................................................................................................ 21 
5.4.3 
    Vaccine Preparation and Administration .......................................................................................... 21 
5.4.4 
    Vaccine Administration Schedule ..................................................................................................... 21 
5.4.5  
Concurrent Therapies ....................................................................................................................... 22 
5.4.6  
Laboratory Studies ........................................................................................................................... 22 
5.4.7  
Vaccine Dose #1 .............................................................................................................................. 23 
5.4.8  
Vaccine Dose #2 .............................................................................................................................. 25 
5.4.9  
Vaccine Dose #3 .............................................................................................................................. 27 
5.4.10  
Month 7 (Follow-Up #1) .................................................................................................................... 29 
5.4.11  
Month 24 (Follow-Up #2) .................................................................................................................. 29 
5.4.12  
Premature Study Discontinuation Visit ............................................................................................. 30 
5.4.13  
End of Study ..................................................................................................................................... 30 
 
 

 
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6.0 
HUMAN SUBJECTS ISSUES ................................................................................................................... 31 
6.1 
POTENTIAL BENEFITS .................................................................................................................................. 31 
6.2 
POTENTIAL RISKS ........................................................................................................................................ 31 
6.3 
RISK TO BENEFIT RATIO ............................................................................................................................... 31 
6.4 
PRECAUTIONS ............................................................................................................................................. 32 
6.5 
ALTERNATIVES ............................................................................................................................................ 32 
6.6 
CONFIDENTIALITY ........................................................................................................................................ 32 
6.7 
FINANCIAL OBLIGATIONS AND COMPENSATION ............................................................................................. 32 
6.8 
INFORMED CONSENT PROCESS .................................................................................................................... 33 
7.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ............................................................ 33 
7.1 
EVALUABLE PATIENTS ................................................................................................................................. 33 
7.2 
PRIMARY ENDPOINTS ................................................................................................................................... 33 
7.3 
SCHEMA – AIM 1: SURVEY ........................................................................................................................... 33 
7.4 
SCHEMA – AIM 2:VACCINE EVALUATION ....................................................................................................... 34 
8.0 
STATISTICAL METHODS ........................................................................................................................ 35 
8.1 
SAMPLE SIZE ............................................................................................................................................... 35 
8.2 
DATA ANALYSIS .......................................................................................................................................... 36 
9.0 
DATA AND SAFETY MONITORING ........................................................................................................ 38 
9.1 
DEFINITION OF RISK LEVEL .......................................................................................................................... 38 
9.2 
MONITORING AND PERSONNEL RESPONSIBLE FOR MONITORING .................................................................... 38 
9.3 
ADVERSE EVENTS ........................................................................................................................................ 33 
9.4 
STUDY STOPPING RULES ............................................................................................................................. 39 
REFERENCES ......................................................................................................................................................... 46 
APPENDICES .......................................................................................................................................................... 52 

 
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ABSTRACT 
Advances in treatment for childhood cancer over the past five decades have resulted in a rapidly 
growing population of survivors.1 A substantial number of these survivors are adolescents and young 
adults – an age group that is at the highest risk for sexually transmitted infection (STI).2,3 Human 
papillomavirus (HPV) is the most common STI in the U.S. today,2 with prevalence rates in sexually 
active young individuals ranging from 44.8% in females4 to 51.2% in males5. Persistent infection with 
oncogenic strains of HPV (e.g., types 16 and 18) is strongly associated with the development of 
dysplasia and cancers affecting the genital tract and oropharyngeal mucosa.6-11 Non-oncogenic HPV 
types (primarily 6 and 11) are associated with genital warts, low-grade dysplasia and recurrent 
respiratory papillomatosis.4,8,12,13 Immunosuppression increases HPV persistence and risk of invasive 
HPV-related malignancies.6,14-18 Systemic treatment for cancer (chemotherapy, radiation, hematopoietic 
cell transplantation [HCT]) may result in prolonged immunosuppression,19-21 placing cancer survivors at 
higher risk for HPV-related morbidity.22-26 In fact, cervical cancer risk is increased 13-fold and oral 
cancer risk 17-fold in HCT survivors compared with the age- and sex-matched general population.23  
The quadrivalent HPV (qHPV) vaccine (HPV-6, -11, -16, -18; Gardasil; Merck Research 
Laboratories)27 was approved by the U.S. Food and Drug Administration (FDA) for females (in 2006) 
and for males (in 2009) 9 to 26 years of age, and has been used since that time for prevention of HPV-
related cancers and precancerous lesions in both genders.28 The safety, tolerability, immunogenicity, 
and efficacy of the qHPV vaccine have been demonstrated in healthy young individuals;29-32 the vaccine 
confers protection against HPV types 6, 11, 16, and 18, which together account for more than 70% of 
all new cervical cancers33 and 90% of genital warts.34  
The nonavalent form of the HPV vaccine (9vHPV; Gardasil 9) extends protection beyond that offered 
by the qHPV vaccine through inclusion of five additional oncogenic types (31, 33, 45, 52, and 58). A 
trial of 14,215 females between 16 and 26 years of age established efficacy of the 9vHPV vaccine 
against these 5 additional oncogenic HPV subtypes.35 Clinical trials involving 20,334 immunocompetent 
males and females between 9 and 26 years of age demonstrated that the 9vHPV vaccine is safe and 
generally well tolerated and provides comparable (i.e., non-inferior) immunogenicity against HPV types 
6, 11, 16, and 18 as compared to the qHPV vaccine.35,36 The FDA approved the 9vHPV vaccine for 
licensure on 12-10-14. On 2-26-15, the Centers for Disease Control (CDC) Advisory Committee on 
Immunization Practices (ACIP) added the 9vHPV vaccine to the recommended vaccines for females 
and males age 9-26 in the United States.37 During 2015-16, the 9vHPV vaccine has rapidly replaced 
the qHPV vaccine in clinical practice. However, studies of other vaccines, such as hepatitis B in 
immunocompromised populations including cancer survivors, have shown diminished immunogenicity 
and response persistence, requiring alteration of vaccine dose, schedule, or composition in order to 
improve immunological responses.21,38,39 Importantly, no studies to date have reported immunogenicity, 
or safety/ tolerability of the qHPV or 9vHPV vaccines in cancer survivors. 
Despite the excellent efficacy and safety profile of the qHPV vaccine in the general population, and 
2006 recommendation by the Advisory Committee on Immunization Practices (ACIP) for routine 
vaccination of young females, only 44.3% of the 13- to 17-year old females have initiated the HPV 
vaccine series and only 26.7% have received all three doses.40 There is paucity of data regarding HPV 
vaccine uptake in other age groups and none to date in males. Notably, there are no reports of the 
prevalence of HPV vaccine initiation or acceptability in cancer survivors. Despite their increased risk for 
HPV-related morbidity, it is possible that HPV vaccine uptake is even lower in cancer survivors than in 
the general population, due to reluctance on the part of patients/parents or clinicians when 
immunogenicity and safety/tolerability data for this population is lacking.  
This trial uses an approach that combines a cross-sectional survey, to determine vaccine initiation rates 
in cancer survivors between 9 and 26 years of age who are between 12 and 60 months post completion 
of systemic therapy, to identify predictors of vaccine non-initiation in these survivors; and among cancer 
survivors identified to be unimmunized, a single arm phase II open-label trial, to determine the 

 
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immunogenicity and safety/tolerability of the qHPV vaccine (HPV-6, -11, -16, -18; Gardasil; Merck 
Research Laboratories; for patients enrolled on or before 3-1-16) and the 9vHPV vaccine (HPV-6, -11, -
16, -18, -31, -33, -45, -52 and -58; Gardasil 9; Merck Research Laboratories; for patients enrolled after 
3-1-16),  and simultaneously explore response persistence. 
 
The primary aims of this study are to: 
1. Using a cross-sectional survey approach, estimate the prevalence of HPV vaccine initiation in 
cancer survivors ages 9 to 26 years 
a. Examine the sociodemographic, behavioral, and medical determinants of HPV vaccine 
non-initiation  
2.  Among cancer survivors identified to be non-immunized in Aim 1 and by additional methods, use 
a single-arm, phase II, open-label, prospective longitudinal trial design, to evaluate the 3-dose 
qHPV vaccine series (for patients enrolled on or before 3-1-16) and the 3-dose 9vHPV vaccine 
series (for patients enrolled after 3-1-16), and measure the following endpoints: 
 
a.  Determine immunogenicity following the third and final vaccine dose 
b.  Identify clinical/host factors influencing immunogenicity 
c.  Determine the safety/tolerability of the qHPV and 9vHPV vaccines in cancer survivors 
 
3. As an exploratory aim, evaluate persistence of antibody response at 2 years post-vaccine 
initiation and identify clinical/host factors influencing response persistence 
 
Cancer survivors between the ages of 9 and 26 years who are at least 12 months and no more than 60 
months following completion of systemic therapy will complete a survey (closed with protocol version 
03); unimmunized survivors will be offered the 3-dose qHPV vaccine series (for patients enrolled on or 
before 3-1-16) or the 3-dose 9vHPV series (for patients enrolling after 3-1-16); vaccine safety, 
tolerability, and immunogenicity will be determined according to the specified endpoint definitions. 
Findings will identify determinants of vaccine initiation, and provide evidence for immunogenicity, and 
safety/tolerability of the qHPV and 9vHPV vaccines, thus providing the needed evidence base for 
recommendations regarding HPV vaccination in cancer survivors.      

 
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STUDY SCHEMA (Overview) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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STUDY SCHEMA (Detailed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 7 
- HPV antibody titers (Window for testing: 4 - 8 weeks after Dose #3)  
- Complete Month 7 Visit Form (Follow-Up #1) 
- Complete detailed medical record chart abstraction per the Children’s Oncology Group Cancer 
Treatment Summary Form (modified version for 9vHPV patients)
- HPV antibody titers and HPV-specific total immunoglobulins 
 (Window for testing: 72 - 84 weeks after Dose #3) 
-  Complete Month 24 Visit Form (Follow-Up #2) 
Month 24 
Aim 1 
(Survey) 
(Protocol v3: 
Closed)
- Identify eligible study subjects  
- Explain nature of study and obtain informed consent 
- Administer survey to parent (age 9-17) or patient (age 18-26) 
- Complete Medical Record Review Form and Intensity of Treatment Rating Scale 2.0 
- HPV antibody titers  (Geometric Mean Titer + HPV type-specific seropositivity) 
- Quantitative Immunoglobulins 
- Targeted review of systems/screening for acute illness  
- Complete Vaccine Visit Form 
- Sexually active females must agree to use contraception from Day 1 until 4 weeks following Dose #3 
- HPV vaccine Dose #1 
- Adverse Events Diary x 7 days post vaccine (14 days for qHPV vaccine patients)  
Dose #1 
(Day 1) 
- Targeted review of systems/screening for acute illness  
- Complete Vaccine Visit Form  
- HPV vaccine Dose #2 (Window for administration: 8-12 weeks after Dose #1) 
- Adverse Events Diary x 7 days post vaccine (14 days for qHPV vaccine patients) 
Dose #2  
(8-12 weeks 
after Dose #1) 
Dose #3 
(24-32 weeks 
after Dose #1) 
- Targeted review of systems/screening for acute illness  
- Complete Vaccine Visit Form  
- HPV vaccine Dose #3 (Window for administration: 24-32 weeks after Dose #1, but no sooner 
    than 16 weeks after Dose #2) 
- Adverse Events Diary x 7 days post vaccine (14 days for qHPV vaccine patients) 
- Identify patients who have not yet initiated the HPV vaccine series  
   (per survey response or other methods such as clinician referral, chart review, etc.)  
- Obtain medical clearance for participation from patient’s treating clinician 
- Explain vaccine portion of study, and obtain informed consent
Aim 2 
(Vaccine) 
 
Enrollment stratified into 4 groups based on age (9-15, 16-26) and gender (male/female) 

 
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1.0 
OBJECTIVES AND HYPOTHESES 
 
Aim 1:     
Using a cross-sectional survey approach, estimate the prevalence of HPV vaccine non-initiation  
a. Examine sociodemographic, behavioral, and medical determinants of HPV vaccine non-
initiation  
Hypothesis 1: The HPV vaccine initiation rates for cancer survivors will be less than 40% (estimated rate in 
the general population); subgroups of cancer survivors with particularly low vaccine initiation rates will be 
identified. 
 
Among cancer survivors identified to be non-immunized in Aim 1, and among additional non-
immunized cancer survivors meeting study eligibility criteria: 
Aim 2:   
Using a single-arm, phase II, open-label, prospective longitudinal trial design, to evaluate the 3-
dose qHPV (for patients enrolled on or before 3-1-16) or 9vHPV (for patients enrolled after 3-1-16) 
vaccine series and measure the following endpoints: 
 
 
a.  Determine immunogenicity following the third and final vaccine dose 
b.  Identify clinical/host factors influencing immunogenicity 
c.  Determine the safety/tolerability of the qHPV and 9vHPV vaccine in cancer survivors 
 
Hypothesis 2: Immunogenicity to the qHPV and 9vHPV vaccines will be heterogeneous among cancer 
survivors, with subpopulations that received the most intense therapy demonstrating inferior immunogenicity. 
The qHPV and 9vHPV vaccines will be safe and well-tolerated by cancer survivors. 
 
Exploratory sub-aim:  
Evaluate the persistence of antibody response at 2 years post vaccine initiation and identify 
clinical/host factors influencing response persistence. 
 
2.0 
BACKGROUND 
 
2.1.  
Size of the Targeted Cancer Survivor Population 
Commensurate with the improvement in survival rates over the past five decades, the number of long-
term survivors has increased substantially. Five year survival is estimated at 82.5% for children 
diagnosed between 0-14 years of age, 82.8% for those diagnosed between 15-19 years of age, and 
85.1% for those diagnosed between 20-24 years of age.3 There are over 325,000 long-term survivors 
of childhood/adolescent cancers (diagnosed at ages 0-19 years) in the U.S.;1 73,563 young cancer 
survivors are currently 10-19 years of age, while 156,152 are 20-29 years of age.3 Thus, there are 
substantial numbers of survivors in the age group at highest risk for HPV infection, and who fall within 
the targeted age range for HPV vaccination (9 to 26 years).  
 
2.2.  
Human Papillomavirus (HPV): Prevalence and Associated Malignancies 
HPV is a double-stranded DNA virus enclosed in a non-enveloped capsid that infects cutaneous or 
mucosal epithelial surfaces.41,42 Over 100 types of HPV have been identified, based on genetic 
sequence of the outer capsid L1 protein.42 Over 40 HPV types are associated with infection of the 
anogenital and oropharyngeal epithelium.10 HPV types are categorized as low or high risk based on 
their oncogenic potential. Persistent infection with high-risk HPV types is strongly associated with 
development of high-grade squamous intraepithelial neoplasia and cancers affecting the uterine cervix, 
vulva, vagina, penis, and anogenital and oropharyngeal mucosa.7,14 Approximately 70% of cervical 

 
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cancer is caused by HPV types 16 and 18;9-11 90% of anal cancers, 40-50% of vulvar, vaginal, and 
penile cancers, 33-72% of oropharyngeal cancers, and 10% of laryngeal cancers are attributable to 
high-risk HPV infection.8,43-45 Low-risk HPV types (primarily types 6 and 11) are associated with 
anogenital warts, low-grade dysplasia, and respiratory papillomatosis.4, 12,13  
An estimated 6.2 million new cases of HPV infection occur annually in the U.S.42 Prevalence of HPV 
infection is highest within the first few years following sexual debut.46-49 Prior to widespread availability 
of the prophylactic HPV vaccine, the overall prevalence of HPV infection among females between 14 
and 59 years of age was 26.8%, and the burden was highest among women age 20-24 (44.8%); 
prevalence among females age 14-19 was 24.5%.4 In a recent study of 463 asymptomatic males age 
18-40 years, 51% were positive for at least one HPV subtype.5 In 2010, 12,200 women were diagnosed 
with cervical cancer and 4,210 died from the disease.3 Total healthcare costs of HPV-related disease in 
the U.S. are estimated at $4 billion annually,50 exceeding the economic burden of all other STIs with the 
exception of human immunodeficiency virus (HIV).  
 
2.3.  
HPV in Immunocompromised Patients 
Immunosuppression increases HPV persistence and is associated with an increased risk for developing 
HPV-related neoplasia in both males and females.6,7,14,15,51 Immunosuppressed solid organ transplant 
recipients are at increased risk for HPV infection17, HPV-associated cervical intraepithelial neoplasia 
(CIN),18 squamous cell carcinoma of the skin,52 and anogenital cancers53-56 compared to the general 
population. Women infected with HIV have an increased prevalence of cervical HPV infection, a higher 
prevalence of CIN, and higher grades of CIN compared to the general population.57 Additionally, the 
prevalence of cervical HPV infection, and higher grade of CIN increases with diminishing immune 
status.58 Cervical cancer is known to occur at high rates in the HIV-positive population, and is an AIDS-
defining illness.59 Both men and women who are HIV positive are at increased risk for anal HPV 
infection, anal cancer,60 and oropharyngeal cancer61 than the general population. Hodgkin lymphoma is 
associated with deficits in cellular immunity that often persist long after treatment ends,62 suggesting an 
increased vulnerability to HPV-related infection and cervical and anal cancer.22 Pelvic irradiation is 
associated with impaired genital track epithelial cell function63 and HPV-related dysplasia and 
carcinomas of the genital tract.64-66 Patients who have undergone HCT for hematologic malignancies 
are at significantly increased risk for cervical and other HPV-associated cancers than the general 
population.23-25 In addition to the 13-fold increased risk for cervical cancer and 17-fold increased risk for 
oral cancer reported in HCT survivors noted above,23 the risk for cervical pathology is higher among 
allogeneic HCT recipients.25 Prolonged immunodeficiency in combination with HPV exposure explains 
the elevated risks.23,25  
 
2.4.  
HPV Vaccine Development and Testing in the General (Immunocompetent) Population  
Vaccines against HPV are composed of noninfectious virus-like particles (VLPs) made of recombinant 
viral L1 protein identical to the naturally occurring viral capsid.67 qHPV vaccine: The quadrivalent HPV 
(qHPV) vaccine (HPV-6, -11, -16, -18; Gardasil; Merck Research Laboratories)27 is currently 
approved by the FDA for administration to both males and females between 9 and 26 years of age28 
and is indicated for prevention of HPV-16 and -18 related cervical, vulvar, vaginal, and anal cancers in 
females and HPV-16 and -18 related anal cancer in males, with additional indications in both genders 
for protection against HPV-6, -11, -16, and -18 precancerous or dysplastic lesions and HPV-6 and -11 
related genital warts. In clinical trials with healthy females, the qHPV vaccine demonstrated 98% 
efficacy in protecting HPV-naïve recipients from acquiring HPV vaccine types68 and 100% efficacy for 
prevention of vaccine-type HPV-associated vaginal, vulvar, perineal and perianal intraepithelial lesions 
or warts and CIN grades 1 to 3 or adenocarcinoma in situ associated with vaccine-type HPV.27 In 
healthy males, the qHPV vaccine demonstrated ~90% efficacy against external genital lesions including 
genital warts.32  9vHPV vaccine: The nonavalent HPV (9vHPV) vaccine (HPV-6, -11, -16, -18, -31, -33, 
-45, -52, -58; Gardasil 9; Merck Research Laboratories)69 is currently approved by the FDA for 

 
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administration to both males and females between 9 and 26 years of age70 and is indicated for 
prevention of HPV-16, -18, -31, -33, -45, -52, and -58 related cervical, vulvar, vaginal, and anal cancers 
in females and HPV-16, -18, -31, -33, -45, -52, and -58 related anal cancer in males, with additional 
indications in both genders for protection against HPV-16, -18, -31, -33, -45, -52, and -58 precancerous 
or dysplastic lesions and HPV-6 and -11 related genital warts.69 The 9vHPV vaccine extends protection 
beyond that offered with the qHPV vaccine through inclusion of five additional oncogenic types (31, 33, 
45, 52, and 58). A trial of 14,215 females between 16 and 26 years of age established efficacy of the 
HPV-9 vaccine against these 5 additional oncogenic subtypes.35 The qHPV vaccine provides protection 
against approximately 70% of cervical cancers, 70-75% of vulvar cancers, 65% of vaginal cancers, and 
85-90% of anal cancers. The 9vHPV vaccine targets 5 additional oncogenic subtypes, which account 
for approximately 15-20% of cervical cancers, 10-15% of vulvar cancers, 20% of vaginal cancers, and 
5-10% of anal cancers; thus, the 9vHPV vaccine provides protection against 85-90% of the oncogenic 
HPV subtypes associated with cervical cancer, 85-90% of vulvar cancers, 80-85% of vaginal cancers, 
and 90-95% of anal cancers.69 
2.4.1. Immunogenicity: The qHPV and 9vHPV vaccines are highly immunogenic in males and females 
in the general population,29-31,35,36 and are primarily dependent on humoral immune response.71 
Immunogenicity varies by age and gender; the most robust responses are seen in younger individuals 
and in males.30,69 There is paucity of data regarding the immunogenicity of the qHPV and 9vHPV 
vaccines in immunocompromised populations. In HIV-infected children 7-12 years of age who received 
the qHPV vaccine, >96% of vaccine recipients seroconverted to all 4 vaccine antigens (i.e. negative 
anti-HPV antibody titers at baseline and positive titers one month after completing vaccine series); 
however geometric mean titers (GMT) against vaccine subtypes 6 and 18 were 30-50% lower than 
those of age-matched historical controls.27,72  
 
2.4.2. Safety: qHPV vaccine: The qHPV vaccine has been safe and well-tolerated in 5 clinical trials 
enrolling 21,480 subjects73 and in post-licensure safety monitoring.74 The most common adverse 
reactions were headache (vaccine, 28.2%; placebo 28.4%); fever (13.0% vs. 11.2%), and nausea 
(6.7% vs. 6.5%). The rates of serious adverse events (AEs) were comparable between vaccine and 
placebo groups28 and occurred at 50% the rate reported for licensed vaccines. Severe injection site 
reactions were slightly higher in the vaccine group (2.2%) compared to placebo (0.9%).73,74 In post-
licensure monitoring, AEs were consistent with pre-licensure data with the exception of disproportional 
reporting (per 100,000 doses of qHPV vaccine distributed) of syncope (8.2/100,000) and venous 
thromboembolic events (VTE) (0.2/100,000); 94% of syncopal episodes were classified as non-serious 
and 90% of patients with VTE had a known risk factor.74 9vHPV vaccine: In clinical trials involving 
20,334 immunocompetent males and females between 9 and 26 years of age, the 9vHPV vaccine has 
been shown to be safe and generally well tolerated compared to the qHPV vaccine. Females age 16-26 
who received 9vHPV were more likely to report mild to moderate injection site adverse events 
compared to those who received qHPV (90.7% vs. 84.9%), with the most common events being pain, 
swelling, erythema, and pruritis. Adverse event reports in males were lower than in females and were 
similar to qHPV. There was no increase in reported serious adverse events for 9vHPV compared to 
qHPV.36,69 
 
2.5.  
Vaccination in Populations with Altered Immune Competence 
The success of active vaccination relies on an intact immune system. Inactive or recombinant subunit 
vaccines (qHPV and 9vHPV) rely primarily on the humoral component.42,71  
 
2.5.1. Vaccination of young cancer survivors: Current clinical practice arbitrarily calls for initiation of 
vaccination (of any type) at least 6-12 months after completion of cancer treatment in order to allow 
sufficient recovery of the immune system and avoid inferior responses generally observed when 
vaccines are given in the early months following cancer therapy.75 However, there is lack of consensus 

 
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regarding vaccine re-initiation following successful completion of cancer treatment.76,77 Impairment of 
immunity is seen to varying degrees after completion of cancer therapy, and is dependent on intensity 
of chemotherapy, radiation and other immunosuppressive agents;78 immune competence can be 
particularly impaired following HCT, especially in patients with chronic graft-versus-host disease 
(GvHD).79 Studies of hepatitis B, pneumococcal and Haemophilus influenzae type b (Hib) vaccines 
have shown diminished immunogenicity and response persistence in cancer survivors, requiring 
alteration of vaccine dose, schedule, timing, or composition in order to improve immunological 
responses.21,38,39,80,81  
 
2.5.2. Use of the qHPV and 9vHPV vaccine in cancer survivors: Since the qHPV and 9vHPV vaccines 
are subunit vaccines, they do not contain viral DNA, and hence cannot impart a risk of vaccine-
associated transmission of HPV infection. However, there is lack of information regarding 
immunogenicity of the qHPV and 9vHPV vaccines in cancer survivors. Cancer survivors who are at 
least one year following completion of systemic therapy generally have normal or near-normal 
measures of humoral immunity (i.e., quantitative immunoglobulins [Quant Ig]) for the most part.19,82,83 
Therefore, it is conceivable that survivors will mount an immunogenic response to qHPV and 9vHPV 
vaccines similar to that observed in the general population. However, subsets of survivors may not 
respond adequately,79,84 since immune recovery following cancer treatment may be variable,19,20 and in 
particular, immune reconstitution following HCT may vary based on donor source and presence of 
chronic GvHD.85 Data regarding the immunogenicity and safety/tolerability of qHPV and 9vHPV 
vaccines in cancer survivors are needed in order to determine whether the 3-dose schedule 
recommended for the general population is appropriate for this population.  
2.6. 
Prevalence of HPV Vaccine Initiation 
Although adolescent females in the general population report high levels of acceptance regarding HPV 
vaccination, rates of actual vaccine initiation are low, ranging from 5-45%.40,86,87 The U.S. Centers for 
Disease Control and Prevention reported that only 44.3% of 13-17 year old females in the general 
population had initiated the HPV vaccine series and only 26.7% had received all 3 doses.40 Importantly, 
all reported HPV vaccination rates to date are significantly lower than the 90% target established by the 
Healthy People 2010 initiative.88 There are no data regarding the prevalence of HPV vaccine initiation 
in the cancer survivor population. Furthermore, there are no studies regarding HPV vaccine uptake in 
males in any population.  
 
2.7. 
Factors Relevant to HPV Vaccine Non-Initiation 
2.7.1 Sociodemographic factors: Cervical cancer is associated with lower education, lower household 
income, and Hispanic ethnicity.89 Socioeconomic differences in sexual behavior resulting in increased 
transmission of oncogenic HPV types, coupled with lack of access to cervical cancer screening, have 
been suggested as potential explanations for these findings.45 Among childhood cancer survivors, 
women who are college educated, medically insured and older are more likely to have undergone 
Papanicolaou (Pap) testing for cervical cancer within the previous 3 years compared to survivors who 
are less educated, without insurance, and younger.90 Childhood cancer survivors are more likely to 
report unemployment and lower educational attainment and income compared to their siblings,91 and 
may therefore be at risk for suboptimal cervical cancer screening. Similar demographic findings have 
been reported specific to HPV vaccine initiation; for example, among healthy females there are several 
key factors that discriminate those who have or have not initiated HPV vaccination: socioeconomic 
status and education,92-95 age,40, 92,95,96 race, 97,98 and geographic region.40 
 
2.7.2 Behavioral factors:  
Vaccine acceptability – adolescent attitudes: Despite relatively low rates of HPV vaccine initiation, 
between 66 and 74% of adolescent/young adult females have reported intention to receive the 

 
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vaccine.99,100 Studies of adolescent attitudes toward STI vaccination indicate high levels of acceptance, 
influenced by perceptions of vaccine characteristics (low cost, efficacy), health beliefs, provider 
recommendations, perceived increased susceptibility to STIs such as HIV, and perceived benefits of 
vaccination. 101-105 In contrast, greater perceived obstacles (e.g., difficulty keeping clinic appointments), 
fear of the vaccine causing infection, lower perceived risk, and fear of needles are related to lower 
acceptability.101 Despite reports of generally high levels of HPV vaccination acceptance and intentions, 
actual vaccination rates remain low to date.86   
Parental attitudes toward vaccination: Parents are also accepting of HPV vaccination, with 55-100% of 
parents indicating a willingness to vaccinate.92,106,107 Factors associated with increased acceptance 
include parental history of HIV testing, higher number of lifetime sexual partners, older age of child at 
time of vaccination, having had a family member with cancer, and belief that the vaccine would be 
accepted by the parent’s peers/partners.106,108,109 A belief in the protective effects of childhood vaccines 
in general, and specifically in the protection offered by HPV vaccination, correlate with parental HPV 
vaccine acceptability.110 Mothers willing to discuss cervical cancer, sex, STIs, or HPV with their 
daughters at earlier ages are more likely to accept HPV vaccination.108 Perceived physician 
encouragement and HPV-related knowledge also appear to be associated with positive parental 
attitudes toward vaccination.92 In contrast, parental anxiety regarding vaccine safety, conservative 
religious/cultural views, belief that vaccination encourages sexual activity, lack of disease-specific 
knowledge, risk of unknown harmful side effects, and low concern for child’s HPV acquisition have 
characterized the opposition that some parents have to HPV vaccination.92-94,111,112  
 
2.7.3 Medical factors:  
Healthcare provider recommendation: Although 90% of pediatricians endorse HPV vaccination, many 
report parental barriers to HPV vaccine administration, including concerns regarding vaccine safety, 
reluctance to discuss sexuality and HPV transmission, belief that the child receives too many vaccines, 
denial that the child may be at risk for HPV, and concerns that vaccination would lead to riskier 
adolescent behaviors.113,114 Nonetheless, medical providers have considerable influence regarding 
vaccination decisions for their patients.103,115 Healthcare provider recommendation of HPV vaccine to 
cancer survivors may maximize the likelihood of vaccination; the current study will provide evidence to 
endorse such recommendations.  
Cancer diagnosis and treatment history: Patients who have received more therapy that is 
immunosuppressive may experience a prolonged recovery period. Patients with hematological 
malignancies are more likely to require more intense therapies, including allogeneic HCT, which may 
result in chronic GvHD requiring ongoing immunosuppression.116 Thus, cancer diagnosis and 
treatment-related factors may play a significant role in decisions related to vaccine initiation in the 
cancer survivor population; there is currently very little data to support this, resulting in a critical gap in 
the literature that this study will address. 
2.8 
Theoretical Model/Conceptual Framework 
An integrative framework guided by the Health Belief Model (HBM),117,118 and Theory of Planned 
Behavior (TPB),119 will provide the theoretical basis for testing our predictive models of HPV vaccination 
initiation and intent. The HBM postulates that a health behavior (e.g., initiating HPV vaccination) is 
influenced by perceptions of both the threat posed by a health problem (e.g., HPV-related cancers) and 
the value of actions aimed at reducing the threat (e.g., HPV vaccination as a means of reducing risk of 
HPV-related cancers). The HBM includes 6 primary factors (perceived susceptibility, severity, barriers, 
benefits, cues to action, and self efficacy)118 that explain a significant proportion of the variance 
regarding decision to engage in a health-promoting behavior. TPB posits that an individual’s attitudes 
regarding a behavior, perceptions of the beliefs of significant others (norms), and perceived control over 
a behavior influence behavioral intent, which in turn drives engagement in the actual behavior.119 This 
theory assumes that behavioral intention is the most significant determinant of engaging in a behavior, 

 
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with intent initially influenced by personal evaluation of a behavior and personal beliefs regarding 
whether important people would approve or disapprove of the behavior.120 Thus, multiple factors 
influence HPV vaccine intent, which subsequently predicts initiation of HPV vaccine. In this aim, the 
primary dependent variable will be HPV vaccine non-initiation prior to study participation; by collecting 
survey data regarding vaccine intention and key factors influencing health behaviors informed through 
HBM and TPB (Table 1), we will identify potentially modifiable barriers to HPV vaccine initiation in 
cancer survivors, setting the stage for development of interventions to improve uptake of the HPV 
vaccine in this vulnerable population. 
 
2.9 
Preliminary 
Studies  
“HPV among Survivors 
of 
Childhood 
Cancer” 
(SJCRH-HPV-1; 
PI 
Klosky; 
Co-Investigator 
Hudson) 
is 
an 
IRB-
approved 
and 
institutionally-funded 
exploratory 
study 
conducted at St. Jude 
Children’s 
Research 
Hospital. This pilot study 
aimed to estimate the 
prevalence 
of 
HPV 
vaccination and examine 
predictors of vaccine initiation and intent in a cohort of cancer survivors from a single institution. As of 
3-4-11, 220 parents (of female patients age 9-17) and 75 female cancer survivors (age 18-26) have 
been approached for participation in this study. Overall consent rate is 94.2% (95% for ages 9-17; 90% 
for ages 18-26) with an 86% survey completion rate. Reasons for non-participation (n=17) include “not 
interested” (88.2%) and “tired of filling out questionnaires” (11.8%). Self-/parent-reported HPV vaccine 
initiation rates in this cohort are 33.3% overall (33.1% for age 9-17; 38.9% for age 18-26), with lower 
vaccine initiation rates in patients with leukemia/lymphoma (29.0%) compared with solid tumors 
(38.2%). Vaccine initiation rates by race are 31.4% for Caucasians compared with 40.7% for all other 
races combined; initiation rates by religious preference are: Protestant 39.1%, Catholic 22.2%, Other 
30%; and by annual income: <$20K: 50%, $20-99K:25.8%, >$100K: 40%. When unimmunized 
survivors were asked how likely they were to initiate the vaccine in the future, 46.0% indicated 
“likely/very likely/definitely will”, 21.9% indicated “unlikely/very unlikely/definitely will not,” and 32.1% 
were “unsure”. When unimmunized survivors were asked about their willingness to receive the HPV 
vaccine in the setting of a clinical trial, 62.8% indicated willingness, 17.2% indicated unwillingness, 
20.0% were unsure.  
In the current study, we will expand upon this pilot initiative across geographically and racially/ethnically 
diverse populations in order to collect data that is generalizable to the broader cancer survivor 
population; and, for the first time, to include both males and females. Finally, we plan to explore 
predictors of vaccine refusal in unimmunized survivors (i.e., unimmunized participants will be offered 
the HPV vaccine after survey completion, and reasons for refusal will allow examination of translation of 
intent into action vs. refusal).   
  
2.10  Overall Significance of the Study 
2.10.1 Importance of the Problem: This study will address high priority areas identified by NIH 
Table 1. Theoretical Basis for Testing Predictive Model 
PROPOSED PREDICTORS OF HPV VACCINE INITIATION
SURVEY ITEMS ELICITING PREDICTORS
†Perceived susceptibility to HPV-related disease 
D1a-e 
†Perceived severity of HPV-related disease 
D2a-h 
†Perceived barriers to HPV vaccination 
D3a-l 
†Perceived benefits/efficacy of the HPV vaccine 
D4a-g 
†Cues to action 
C1, C2a-m 
†Self-efficacy 
D5a-f, D6 
Knowledge of HPV and related health risks 
B1-10 
Heath behaviors 
G1-17 
Demographic factors 
A1-9 
Sexual relationships/communication 
H1a-t; I1-5; J1-13 
§Attitude toward vaccine-related decision-making 
C6-10; F1a-j 
§Social and environmental influences on decision 
E1a-q, E2-3 
§Healthcare provider recommendation 
C2c,d; E1a; G6,8,18 
§Intention to vaccinate 
C5a-d 
OUTCOME OF INTEREST: HPV VACCINE INITIATION 
Vaccination status 
C3-4 
†Component of Health Belief Model    §Component of Theory of Planned Behavior 
 
 

 
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(NINR/NCI): (1) health promotion; (2) cancer prevention; and, (3) cancer survivorship. Several factors 
combine to make this research compelling: (1) availability of a licensed vaccine that is indicated for 
prevention of HPV-infection in females and now also in males and that is safe, highly immunogenic and 
efficacious in the general population; (2) the large and continually expanding population of young 
cancer survivors at risk for HPV-related infection and neoplasms; (3) the high burden of 
morbidity/mortality due to HPV infection in the cancer survivor population; and (4) the critical need to 
develop evidence to inform optimal utilization of the HPV vaccine in cancer survivors in order to 
optimize health promotion and disease prevention in this vulnerable population. 
2.10.2 Gaps in Scientific Knowledge to be Addressed:  The study will address the following important 
gaps in scientific knowledge relevant to health promotion and disease prevention among young cancer 
survivors: (1) prevalence and determinants of HPV vaccine initiation among cancer survivors; (2) 
adequacy of the 3-dose qHPV and the 3-dose 9vHPV vaccine series in inducing immunogenicity in 
individuals treated for cancer; (3) impact of humoral immune competence and therapeutic exposures on 
qHPV and 9vHPV vaccine immunogenicity; and (4) safety and tolerability of the qHPV and 9vHPV 
vaccines among cancer survivors. If the rates of HPV vaccine initiation are low among cancer survivors, 
and qHPV and 9vHPV vaccines are immunogenic, safe, and tolerable in cancer survivors, then, this 
study would provide strong rationale for developing intervention programs to improve HPV vaccine 
uptake in cancer survivors. Importantly, this research will inform development of these interventions, 
since we will determine facilitators and barriers in cancer survivors and identify subgroups of survivors 
at particularly high risk for poor vaccine uptake (and therefore likely to derive the most benefit from 
targeted interventions). Additionally, this research will inform recommendations for HPV vaccination of 
this vulnerable population. We will also identify clinical factors associated with inadequate immunogenic 
response to the vaccine, and the impact of humoral competence on this response, providing a 
foundation for future development of alternative vaccination strategies (e.g., alterations in timing, dose 
and/or schedule) in any subgroups that are unable to mount an adequate response to the standard 3-
dose vaccine series. Given the large and ever-increasing number of young cancer survivors in the U.S., 
this research could potentially result in substantial benefits to this vulnerable population, including 
primary prevention of HPV-related malignancies and their associated morbidity and mortality. 
Additionally, this study will form the basis for future investigations aimed at determining the efficacy of 
the 9vHPV vaccine in reducing HPV-related morbidity in this population.     
 
 
 
3.0 
ELIGIBILITY 
 
3.1 
Inclusion Criteria: Aim 1 (Survey)  
[Protocol v3, 8/17/15: Accrual goal for Aim 1 met, enrollment to survey closed] 
3.1.1  Cancer survivor (9 to 26 years of age at study participation) 
 
3.1.2 Between 12 and 60 months after completion of cancer therapy  
(chemotherapy, radiation, HCT)  
3.1.3 Scheduled for a return clinic visit at one of the participating institutions 
(An estimated 60%-80% of patients that are 12-60 months from therapy end are regularly followed in the 
clinic; sociodemographic and clinical characteristics will be compared between participants and non-
participants to determine evidence of participation bias)  
3.1.4 English or Spanish-speaking  
3.1.5 Willing to provide informed consent/assent for study participation.  
3.2 
Inclusion Criteria: Aim 2 (Vaccine Evaluation) 
3.2.1  Cancer survivor (9 to 26 years of age at study participation) 

 
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3.2.2.   Between 12 and 60 months after completion of cancer therapy  
(chemotherapy, radiation, HCT) 
3.2.3 Survey response indicated no prior history of HPV vaccination OR patient has no prior 
history of HPV vaccination by self- or parent/caregiver-report 
3.2.4.   English or Spanish-speaking 
3.2.5 Medical clearance from treating clinician for study participation  
3.2.6 Agrees to return to participating institution for 3 HPV vaccine injections 
3.2.7 Willing to provide informed consent/assent for study participation 
 
3.3 
Exclusion Criteria: Aim 2 (Vaccine Evaluation) 
 
3.3.1 Allergy to any component of the HPV vaccine including yeast and aluminum 
3.3.2 Thrombocytopenia (platelet count <50K) or coagulation disorder that would 
contraindicate intramuscular injection 
3.3.3 Transfusion of blood products or intravenous immune globulin within 3 months of study 
entry 
3.3.4 Female, and a) currently pregnant or lactating, or b) of childbearing potential and 
unwilling  to avoid pregnancy during the vaccine phase of study (beginning at Day 1 and 
continuing until at least 4 weeks after all 3 vaccine doses have been administered). 
4.0 
METHODS: AIM 1 (SURVEY)  
[Protocol v3, 8/17/15: Accrual goal for Aim 1 met, enrollment to survey closed] 
4.1 
Study Design 
The study design for Aim 1 is a cross-sectional survey to determine vaccine initiation rates and identify 
predictors of vaccine non-initiation in cancer survivors 
 
4.2 
Identification/Recruitment of Participants  
This study will be conducted at the University of Alabama at Birmingham (UAB) and at 4 institutions 
affiliated with the Consortium for Pediatric Interventional Research (CPIR), including St. Jude Children’s 
Research Hospital (SJCRH), City of Hope (COH), University of Michigan (UM), and Emory 
University/Children’s Healthcare of Atlanta (EU/ CHOA). The coordinating center for this study is the 
University of Alabama at Birmingham (UAB), Birmingham, AL. The CPIR has established infrastructure 
to perform interventional research aimed at reducing morbidity among childhood cancer survivors.  
The number of potentially eligible participants at each site is shown in Table 2.   
Table 2. Potentially Eligible Participants by Institution 
Institution 
Male
Female
Total
#HCT
% HCT
City of Hope 
137 
116 
253
116 
45.8 
Emory Univ - Children’s Healthcare Atlanta 
241 
170 
411
34 
08.3 
St. Jude Children’s Research Hospital 
524 
411 
935
159 
17.0 
C. S. Mott Children’s Hospital – Univ Mich 
99 
63 
162
42 
25.9 
University of Alabama at Birmingham (UAB) 
220 
180 
400
60 
15.0 
Total 
1221 
940 
2161
411
19.0
The study team at each site includes the consortium site principal investigator (PI), co-investigators, 
participating clinicians, and the protocol nurse and/or clinical research assistant (CRA). The study team 
will use patient rosters, cancer registry data, or similar methods to identify patients eligible for the Aim 1 
(Survey) who have an upcoming clinic appointment at the participating site. Eligible patients >18 years 
of age (or parents of patients <18) will be approached by a study team member, who will fully explain 

 
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the study, including all risks,  benefits and alternatives. Informed consent will be obtained in the 
patient/parent’s preferred language. Assent, along with parental consent, will be obtained from minors 
according to the policies at the participating institutions. To reduce any potential recruitment bias, 
patients will be approached consecutively in order of scheduled medical visits. For eligible patients who 
refuse study participation, reasons for refusal will be documented.  
 
4.3 
Data Abstraction 
The Medical Record Review Form and Intensity of Treatment Rating Scale 2.0 will be completed for all 
patients enrolled  in  Aim 1 (Survey). 
 
Medical Record Review Form: This form captures data elements abstracted from the medical record, 
including diagnosis, date of birth, date of diagnosis, time from diagnosis, treatment modalities (surgery, 
chemotherapy, radiation, HCT), and date of treatment completion (see Appendix 1). 
 
Intensity of Treatment Rating Scale 2.0 (ITR-2): The ITR-2121 (see Appendix 2) is a validated tool that 
uses cancer diagnosis, stage or risk level, and treatment modalities to produce an overall rating of 
cancer treatment intensity with 4 levels (least to most intensive); inter-rater reliability of this tool is .87.  
The two instruments provide a concise record of the diagnosis and treatment intensity. Ten percent of 
randomly selected records will be rated independently by two reviewers to establish inter-rater 
reliability.  
 
4.4 
HPV Vaccination Survey  
The patient (if 18 years or older) or parent (of patients 9-17 years of age) will be asked to complete a 
survey that elicits demographic information, current HPV vaccine status (including number of doses 
received, if any), knowledge regarding HPV,112 patient/parent perspectives regarding HPV 
vaccine,93,96,112,122 health-related practices,95 HPV vaccine intent,93 and standardized questions 
assessing health beliefs,123 cues to action and self-efficacy,96,106 sexual communication,124-126 and 
sexual behavior.127 The instrument is available in paper and HIPAA-compliant electronic formats in 
English/Spanish, Male/Female and Parent/Patient Versions (see Appendix 3). Participants may also 
complete the questionnaire via interview (in person or by phone) if preferred. Completion time is 
approximately 15 to 20 minutes. Derivation of questionnaire items is reviewed below and in Table 3, 
which summarizes the variables to be studied, the questionnaire item numbers and the participants 
queried, and the source(s) that guided development of the items. 
 
4.4.1 Health Beliefs 
The HPV Vaccine Health Beliefs Questionnaire123 is a validated instrument designed to measure the 
parental health belief constructs of perceived severity, perceived vulnerability, perceived barriers, and 
perceived benefits/efficacy as it relates to the HPV vaccine. The questionnaire’s instructions direct 
participants to respond to items on a Likert-type rating scale which ranges from “Strongly Disagree” to 
“Strongly Agree.” The internal reliabilities (Cronbach’s alpha coefficients) for the 4 scales are as follows: 
Perceived Severity (.84), Perceived Barriers (.89), Perceived Vulnerability (.70) and Perceived Vaccine 
Benefits/Efficacy (.90). The predictive validity of these health belief factors has been established in their 
relationships with HPV vaccination acceptability among mothers of girls aged 11-16.123 Additional 
scales measuring vaccine-related Cues to Action and Self-Efficacy are also included as part of the 
study questionnaire, with these scales having been adapted from previously validated surveys.86,96,106  
 
4.4.2 Sexual Communication 
For parents, the Mother-Adolescent Sexual Communication (MASC) Instrument is used to measure 
parental-adolescent communication regarding sexual behavior and development.124 Exploratory factor 
analyses of this 18 item measure resulted in 4 primary factors including Content, Context, Timing and 
Style of communications with internal reliabilities (Cronbach’s alpha coefficients) of .87, .90, .82, and 

 
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.71 for these four factors respectively. Convergent validity for this instrument is found in its relationships 
with subscales from the Parent-Child Relationship Questionnaire,128 while discriminant validity has been 
established in its low association with the Family Impact Questionnaire.129  Questions have been 
adapted to allow for inclusion of male participants. 
 
Young adult participants complete The Miller Sexual Communication Scale.125 This scale consists of 
two subscales assessing the content and process of sexual communication between adolescents/ 
young adults and their parents.  The Parent-Adolescent Sexual Topic Discussion subscale consists of 
ten questions addressing sexual topics such as contraception and coping with sexual aspects of their 
romantic relationships. Response choices are offered to a four-point Likert scale ranging from one 
(strongly disagree) to four (strongly agree) to correspond with the second subscale. This scale has 
been demonstrated to be internally valid with a reported alpha coefficients ranging from 0.72 - 0.78.126 
A second 10 item subscale is included which is labeled the Open Sexual Communication subscale. 
This subscale measures the process of sexual communication between adolescents/young adults and 
their parents.  Higher scores on both subscales indicate greater communication on sex-related topics 
between adolescents/young adults and parents, with negatively worded items reverse-scored. The 
internal consistency of this subscale has been reported to be 0.86.126  Questions have been adapted to 
allow for inclusion of male participants. 
 
4.4.3. General Knowledge of HPV and Related Risk Factors 
Knowledge of HPV, cervical cancer, and HPV vaccination is measured by a scale adapted from Brabin 
and colleagues.112 Ten multiple choice items are used to assess knowledge of HPV-related health risks. 
Participants receive a score of 1 or 0 for each response and the number of correct answers is summed 
to create a knowledge score for each participant. Higher scores represent more accurate responses 
and greater levels of HPV-related knowledge. The content of the questionnaire was abstracted  from 
the CDC’s website for HPV vaccination information122 as well as items previously formulated by Brabin 
and colleagues.112 
 
4.4.4. Socio-Environmental Factors 
Participants are asked to rate potential influences on their HPV vaccine decision-making. Twelve items 
are used to provide an overall measure of important influences on decision-making. Responses range 
from 1 (not at all important) to 4 (very important). One open-ended qualitative item also allows 
participants to comment on any other influences on the decision regarding HPV vaccination. Items 
regarding social influences on vaccine decision-making were adapted from questions used in previous 
studies.93,96,112  
 
4.4.5. Medical Care and Demographic Factors 
All participants are asked to provide demographic information including age, race/ethnicity, marital 
status, religious preference, education level, and annual household income. Parents are asked to 
provide their relationship to the patient, and their child’s age and grade in school. Items were adapted 
from previous research instruments.93,96,112  Medical background questions include relevant parental 
and patient health history (STI, HPV infection, genital warts, abnormal Pap smears, cervical cancer) 
and 
health 
behaviors 
(healthcare 
visits, 
vaccine 
history, 
and 
for 
females, 
history 
of 
obstetric/gynecologic care, mammography, and Pap smears).  Items were adapted from previous self-
report questionnaires.95 
 
4.4.6. Current Vaccination Status (Primary Dependent Variable) 
The patient’s HPV vaccination status is determined by one item, the dependent variable for Primary 
Aim #1. The item reads “Have you (your son/daughter) received the HPV vaccination?” Brand name 
prompts (Gardasil – males and females, and Cervarix – females only) are included in the item. 

 
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Response choices include 4 options: “I (my son/daughter) have received… A) 0 of the 3 shot series 
(has not started the vaccine, B) 1 of the 3 shot series, C) 2 of the 3 shot series, and D) 3 of the 3 shot 
series (has completed the vaccine).”  Responses will be dichotomized to reflect those who have and 
have not initiated HPV vaccination. An additional item for those who indicate prior initiation of the HPV 
vaccine series captures the age of the patient at the time of the first HPV vaccine dose. 
 
4.4.7. HPV Vaccination Intent 
For those participants who indicate that they (or their son/daughter) have not yet initiated the HPV 
vaccine series, 4 additional items assess HPV vaccine intent.  Each item allows for responses that 
range from “Definitely Will Not” (0) to “Definitely Will” (6), generating scores ranging from 0 - 24, with 
higher scores indicating greater likelihood that the patient will receive the HPV vaccine in the future. 
Items regarding vaccinate intent were adapted from questions used in previous research.93 
 
4.4.8. Sexual Behavior 
Because HPV is a sexually transmitted infection, it is important that risky sexual behavior be considered 
among the factors influencing vaccination decisions. Parental perception of their child’s dating/sexual 
activity are assessed with four items with response choices ranging from 1 (not at all true for him/her) to 
4 (very true for him/her). Higher scores reflecting greater perceived sexual activity. One item will be 
reverse coded.  Additionally, young adult participants are queried regarding their sexual behavior. The 
11 questions included on the young adult version of the questionnaire are empirically validated items 
which query safe sexual practices (e.g. type and frequency of contraceptive use) and sexual 
history.127,130,131  
 
Table 3. Derivation of Questionnaire Items 
Variables  
Questionnaire Items/Participants Queried
Source or Adapted Source
Demographic 
A1-9 (parent) 
A1-6 (patient) 
Brabin, et al., 2006112 
Constantine & Jerman, 200793 
Dempsey, et al., 200696 
Knowledge of HPV & Related 
Health Risks 
B1-10 (all) 
Brabin, et al., 2006112 
CDC, 2007122 
Vaccination Status 
C3-4 (all) 
Investigator-developed for this study 
Intent to Vaccinate 
IC5a-d (all) 
Constantine & Jerman, 200793 
Vaccine Attitudes/Beliefs 
C6a-d (all) 
C7-10 (all) 
Cox, et al., 2010123 
Brabin, et al., 2006112 
Health Belief Factors 
  Perceived susceptibility 
  Perceived severity 
  Perceived barriers 
  Perceived benefits 
 
D1a-d (males)/D1a-e (females) 
D2a-g (males)/D2a-h (females) 
D3a-l (all) 
D4a-g (all) 
 
Cox, et al., 2010123 
Dempsey, et al., 200696 
Gerend, et al., 2007106 
 
Cues to Action 
C1, C2a-l (parents)/a-m (patients) 
G8 (parents of males), 18 (parents of females) 
G6 (male patients), 11 (female patients) 
Dempsey, et al., 200696 
Gerend, et al., 2007106 
Kahn, et al., 200886 
Self-Efficacy 
D5a-g (all) 
Kahn, et al., 200886 
Socio-Environmental 
Influences 
D6 (all) 
E1a-l (male patients/parents of males) 
E1a-n (parents of females) 
E1a-p (female patients) 
E2-3 (all) 
Brabin, et al., 2006112 
Constantine & Jerman, 200793 
Dempsey, et al., 200696 
HPV Vaccine Decision-Making 
F1a-j (all) 
Brabin, et al., 2006112 
Medical Factors 
G1-3 (male patients/parents of males) 
G1-9 (parents of females) 
G6-7 (parents of males) 
G15-17 (parents of females) 
G 4-7 (female patients) 
Rosenthal, et al., 200895 

 
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Variables  
Questionnaire Items/Participants Queried
Source or Adapted Source
Health behaviors 
G4-5 (male patients/parents of males) 
G1-3, 8-10 (female patients) 
G 10-14 (parents of females) 
Rosenthal, et al., 200895 
Sexual relationships/ 
communication 
 
H1a-r (parents) 
H1a-t (patients) 
J1a-f  (all) 
J2-13 (patients) 
Cox, Fasolino, & Tavakoli, 2008124 
Miller, et al., 1998125 
Gomez & Marin, 1996127 
Kelly et al., 1992130 
Kelly et al., 1997131 
HPV Communication 
I1a-e (all) 
I2-5 (parents) 
Brabin, et al., 2006112 
 
4.5 
Survey Completion Thank You Letter 
A Thank You Letter (Appendix 4) will be sent to each subject who completes the survey portion of the 
study. 
 
5.0  
METHODS: AIM 2 (VACCINE EVALUATION) 
 
5.1 
Study Design  
The study design for Aim 2 (Vaccine Evaluation) is a single arm phase II open-label trial, to determine 
the immunogenicity and safety/tolerability of the quadrivalent HPV vaccine (HPV-6, -11, -16, -18; 
Gardasil; Merck Research Laboratories; for patients enrolled on or before 3-1-16), and the nonavalent 
HPV vaccine (HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58; Gardasil 9; Merck Research 
Laboratories; for patients enrolled after 3-1-16) among those cancer survivors identified to be 
unimmunized, and to explore response persistence to the qHPV and 9vHPV vaccines. 
 
5.2 
Identification/Recruitment of Participants  
Eligible patients for Aim 2 (Vaccine Evaluation) will be identified by Aim 1 survey responses that 
indicate non-initiation of the HPV vaccine series (i.e., patients who have not received any HPV vaccine 
doses). Additionally, potentially eligible patients may be identified at the participating sites through 
patient rosters, cancer registry data, clinician referrals, databases, and/or medical records, or by similar 
methods. Patients may also be self- or parent- referred to the study. The study may be publicized via 
flyers or brochures placed in clinic, and/or distributed at institutional events that eligible patients and/or 
their parents are likely to attend, such as health fairs, holiday, or survivorship events. Additionally, 
information about the study may be included in institution-affiliated newsletters and/or websites, and in 
announcements such as “call on hold” messages recorded for the institution’s telephone system (see 
Appendix 5 for sample recruitment materials). Potentially eligible patients (or parents of patients under 
the age of 18) will be contacted by a study team member, who will confirm eligibility, including self- or 
parent-reported non-initiation of the HPV vaccine series, and will fully explain the study, including all 
risks, benefits and alternatives. Informed consent will be obtained in the patient/parent’s preferred 
language. Assent, along with parental consent, will be obtained from minors according to the policies at 
the participating institutions. For eligible patients who are approached and refuse study participation, 
reasons for refusal will be documented. Prior to enrollment, the treating clinician of each eligible patient 
will be contacted by a member of the institutional study team to obtain medical clearance for the 
patient’s participation. Patients who become 18 years of age during the study period will be re-
consented at the first visit following their 18th birthday, and will sign a new consent form at that time.  
Participants will be stratified based on age and gender due to difference in vaccine immunogenicity 
between males and females, and in younger (age 9-15) vs. older (age 16-26) cohorts within the general 
population.30 The coordinating center (UAB) will track enrollment to each of four age/gender-based 
strata. Strata will close to enrollment once each stratum has attained the targeted number of 
participants; additional participants will be enrolled as necessary to replace any non-evaluable 
participants. An Appointment Reminder Letter (Appendix 6) may be sent to study participants to 

 
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facilitate scheduling of vaccine and follow-up laboratory appointments. 
 
5.3 
Data Abstraction 
In addition to the medical record data abstraction described in Section 4.3 (demographics, diagnosis, 
standardized intensity of treatment rating), the study team will abstract detailed data regarding the 
patient’s medical history and therapeutic exposures (e.g., names of surgeries, chemotherapy, radiation, 
and related dates), according to the Children’s Oncology Group’s Cancer Treatment Summary Form 
(see Appendix 7; modified version applies to patients enrolled after 3-1-16),132 including details such as 
cumulative doses of selected chemotherapy, radiation, and immunosuppressive agents; and if 
applicable, date and type of HCT; presence and extent of chronic GvHD; and dose and duration of 
selected immunosuppressive agents post-HCT.  
 
5.4 
Vaccination Protocol 
5.4.1  
Quadrivalent HPV Vaccine (for patients enrolled on or before 3-1-16): The qHPV vaccine (HPV-6, -
11, -16, -18 vaccine, recombinant; Gardasil; Merck Research Laboratories) is a non-infectious 
recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major 
capsid (L1) protein of HPV types 6, 11, 16, and 18. The L1 proteins are produced by separate 
fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The 
fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which 
include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast 
cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs 
are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate 
Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining 
the adsorbed VLPs of each HPV type and additional amounts of aluminum-containing adjuvant and the 
final purification buffer.  
Each 0.5 ml dose of the vaccine contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 
11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein. The vaccine also 
contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate 
adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of 
sodium borate, less than 7 mcg yeast protein/dose, and water for injection. The vaccine does not 
contain preservatives (including thimerosal) or antibiotics. 
Nonavalent HPV Vaccine (for patients enrolled after 3-1-16): The 9vHPV vaccine (HPV-6, -11, -16, -
18, -31, -33, -45, -52, -58) vaccine, recombinant; Gardasil 9; Merck Research Laboratories) is a non-
infectious recombinant nonavalent vaccine prepared from the purified virus-like particles (VLPs) of the 
major capsid (L1) protein of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The L1 proteins are 
produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled 
into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined 
fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs 
are released from the yeast cells by cell disruption and purified by a series of chemical and physical 
methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous 
Aluminum Hydroxyphosphate Sulfate). The nonavalent HPV VLP vaccine is a sterile liquid suspension 
that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of 
aluminum-containing adjuvant and the final purification buffer.  
Each 0.5 ml dose of the vaccine contains approximately 30 mcg of HPV 6 L1 protein, 40 mcg of HPV 
11 L1 protein, 60 mcg of HPV 16 L1 protein, 40 mcg of HPV 18 L1 protein, 20 mcg of HPV Type 31 L1 
protein, 20 mcg of HPV Type 33 L1 protein, 20 mcg of HPV Type 45 L1 protein, 20 mcg of HPV Type 
52 L1 protein, and 20 mcg of HPV Type 58 L1 protein. The vaccine also contains approximately 500 

 
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mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium 
chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, less than 7 mcg 
yeast protein/dose, and water for injection. The vaccine does not contain preservatives (including 
thimerosal) or antibiotics. 
    
5.4.2 Vaccine Supply and Storage 
HPV vaccine for this study will be dispensed from a single lot (or if not possible due to expiration dates, 
from subsequent similar lots) by Merck Research Laboratories to the Investigational Pharmacist at each 
participating site.  The Pharmacist at each site is required to maintain complete records of all study 
vaccines received from Merck Research Laboratories and subsequently dispensed, discarded, or 
returned. All unused vaccines must be destroyed on-site at the Investigational Pharmacy after the study 
is completed or terminated. Damaged or expired study vaccines are to be handled in the same manner. 
The vaccine should be kept refrigerated at 2C to 8C (36F to 46F), protected from light, and should 
not be frozen. Any vaccine that becomes inadvertently frozen must be discarded. 
Additional storage considerations for 9vHPV vaccine: The 9vHPV vaccine should be administered 
as soon as possible after being removed from refrigeration. The 9vHPV vaccine can be administered 
provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8C 
and 25C) does not exceed 72 hours. Cumulative multiple excursions between 0C and 2C are also 
permitted as long as the total time between 0C and 2C does not exceed 72 hours. These are not, 
however, recommendations for storage. 
5.4.3 Vaccine Preparation and Administration 
The qHPV and 9vHPV vaccines are supplied in 0.5 ml single-dose vials. The vaccine vial should be 
agitated thoroughly immediately prior to administration to obtain a uniform suspension. After thorough 
agitation, the vaccine appears as a white, cloudy suspension. The vaccine should be used as supplied. 
No dilution or reconstitution is necessary. The vaccine should not be mixed in the same syringe or 
injected at the same site as other vaccines, and should not be injected intravenously or intradermally. 
0.5 ml of the vaccine should be withdrawn from the single-dose vial using a sterile needle and syringe 
free of preservatives, antiseptics, and detergents. The vaccine should be administered intramuscularly 
in the deltoid region of the upper arm (preferred site) preferably in the nondominant arm, or in the 
higher anterolateral area of the thigh (if the deltoid site is contraindicated). A 22 to 23 gauge needle 
long enough to ensure intramuscular deposition of the vaccine should be used, based on the patient’s 
gender, weight, and site of administration (see Table 4 for preferred needle lengths). As with all 
vaccines, a solution of 1:1000 epinephrine will be available for injection should an anaphylactic reaction 
occur.  
Table 4. Preferred needle length based on patient gender, weight, and administration site 
Gender 
Weight 
Deltoid: 
Needle length 
Anterolateral Thigh: 
Needle Length 
Male or female 
<60 kg 
5/8” to 1” 
 
 
All patients: 
1 to 1-1/2” 
 
Male or female 
60-70 kg 
1” 
Female 
>70-90 kg 
1” to 1-1/2” 
Male 
>70-118 kg 
1” to 1-1/2” 
Female 
>90 kg 
1-1/2” 
Male 
>118 kg 
1-1/2” 
 
5.4.4 Vaccine Administration Schedule 
Each participant will receive three doses of HPV quadrivalent vaccine (HPV-6, -11, -16, -18; Gardasil; 
Merck & Co, Inc.; patients enrolled on or before 3-1-16) or the 9vHPV vaccine (HPV-6, -11, -16, -18, -
31, -33, -45, -52 and -58; Gardasil 9; Merck Research Laboratories; patients enrolled after 3-1-16), 
according to the FDA-recommended 3-dose schedule: Dose #1: Day 1; Dose #2: 8 weeks after first 

 
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dose; Dose #3: 24 weeks after first dose.  All attempts should be made for participants to receive 
vaccine at the designated time points (Day 1, Week 8, Week 24). Vaccine should not be given sooner 
than the following required minimum time intervals between doses: Dose 1 to Dose 2: 8 weeks; Dose 2 
to Dose 3: 16 weeks. Acceptable windows for vaccine administration are indicated in Table 5. If vaccine 
administration is delayed, participants should continue on study and an attempt should be made to 
delay subsequent vaccine visits, if possible, while maintaining the acceptable windows. For example, if 
vaccine Dose #2 is delayed from Week 8 to Week 12, all subsequent visits should be delayed by 4 
weeks, if possible, so that vaccine Dose #3 will occur at Week 28 (Week 24 + 4 weeks), and the 4-
week post-vaccine Dose #3 visit will occur at Week 32 (Week 28 + 4 weeks) and so on, while 
maintaining the acceptable windows for vaccine administration and laboratory studies specified in 
Tables 5 and 6.  
 
Table 5: Acceptable windows for vaccine administration
Interval 
Dose 1
Dose 2
Dose 3 
Minimum interval between vaccine doses 
-- 
8 weeks 
16 weeks 
Maximum interval between vaccine doses 
-- 
12 weeks 
24 weeks 
Acceptable vaccine administration window 
Day 1 
8-12 weeks after 
Dose 1 
24-32 weeks after Dose 1, but no 
sooner than 16 weeks after Dose 2 
5.4.5  Concurrent Therapies 
Medications that may interfere with evaluation of the safety and tolerability of the vaccine should not be 
administered during the indicated timeframes unless medically necessary. Medications in this category 
include: 
- 
Any live attenuated vaccine administered within 28 days before or after any HPV vaccine injection 
- 
Any subunit or killed vaccines (e.g., influenza, pneumococcal, antigen injections for allergy 
treatment) within 14 days before or after any HPV vaccine injection 
All vaccines and immunosuppressive agents (e.g., corticosteroids, calcineurin inhibitors) taken within 
28 days of Dose #1, between Doses #1 and #2, between Doses #2 and #3, and 28 days after Dose #3 
will be elicited by the study team and recorded on the Vaccine Visit Form (Appendix 8; completed at 
Dose 1, Dose 2, and Dose 3) or the Month 7 Visit Form (Appendix 9, completed at Month 7) and if 
applicable, on the Premature Study Discontinuation (PSD) Form (Appendix 10, completed at PSD visit 
or at declaration of loss to follow-up, see Section 5.4.13).  
 
5.4.6  Laboratory Studies 
Quantitative immunoglobulins: A 6 ml blood specimen for Quantitative Ig (immunoglobulin subsets), 
collected in a tube supplied by the institution’s laboratory, will be drawn on Day 1 (prior to the first 
vaccine dose). Specimens for Quantitative Ig will be processed and run in the CLIA-approved clinical 
laboratories at each participating institution and the results reported to the coordinating center.   
Anti-HPV -6, -11, -16, -18 (4cLIA; for patients enrolled on or before 3-1-16):  A 10 ml blood specimen 
will be obtained in a non-additive, non-serum separator (non-SST) red top tube on Day 1 and at Months 
7 and 24 (designated time windows in Table 6) to measure serum neutralizing antibodies to the 4 
vaccine types (HPV-6, -11, -16, -18) using competitive Luminex immunoassays (cLIA). Geometric 
Mean Titers (GMT) for anti-HPV-6, -11, -16, -18 responses will be reported in milli-Merck Units per 
milliliter (mMU)/ml.133,134  
Anti-HPV -6, -11, -16, -18, -31, -33, -45, -52, -58 (9cLIA; for patients enrolled after 3-1-16):  A 10 ml 
blood specimen will be obtained in a non-additive, non-serum separator (non-SST) red top tube on Day 
1 and at Months 7 and 24 (designated time windows in Table 6) to measure serum neutralizing 
antibodies to the 9 vaccine types (HPV-6, -11, -16, -18, -31, -33, -45, -52, -58) using competitive 
Luminex immunoassays (cLIA). Geometric Mean Titers (GMT) for anti-HPV-6, -11, -16, -18, -31, -33, -

 
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45, -52, -58 responses will be reported in milli-Merck Units per milliliter (mMU)/ml.133,134  
HPV-specific total  immunoglobulins:  HPV-specific total immunoglobulins (9 IgG) testing will be done 
using the same 10 ml specimen collected for Anti-HPV-6, -11, -16, -18 (for patients enrolled on or 
before 3-1-16) or for Anti-HPV-6, -11, -16, -18, -31, -33, -45, -52, -58 (for patients enrolled after 3-1-16) 
at the Month 24 time point only.  
Specimens for Anti-HPV (4cLIA or 9cLIA) and HPV-specific total immunoglobulins (9 IgG) will be 
processed immediately, frozen, and subsequently shipped on dry ice to UAB where they will be stored 
frozen and batch-shipped to the PPD Vaccines and Biologics Laboratory, Merck Laboratory, and/or 
Focus Diagnostics Laboratory. Refer to Appendix 11 for detailed instructions regarding specimen 
collection, labeling, processing, shipping, and storage. Samples will be tested at PPD Vaccines and 
Biologics Laboratory, Merck Laboratory, and/or Focus Diagnostics Laboratory in 4cLIA or 9cLIA and 
9IgG assays for immunogenicity measurements, and data results will be transferred on quality assured 
CD. After testing, samples will be stored at PPD Vaccines and Biologics Laboratory, Merck Laboratory, 
and/or Focus Diagnostics Laboratory at -20°C or lower for 3 months.  
 
Table 6: Acceptable windows for laboratory studies 
Study Time Point 
Day 1
Month 7 
Month 24
Acceptable window when 
laboratory studies can be drawn 
Day 1 
4-8 weeks after Vaccine 
Dose #3 
72-84 weeks after 
Vaccine Dose #3 
Studies to be drawn 
Quantitative Immunoglobulins 
(Quant Ig);  
Anti-HPV (4cLIA for patients 
enrolled on or before 3-1-16; 
9cLIA for patients enrolled after 
3-1-16) 
Anti-HPV (4cLIA for 
patients enrolled on or 
before 3-1-16; 9cLIA for 
patients enrolled after 3-
1-16) 
Anti-HPV (4cLIA for 
patients enrolled on or 
before 3-1-16; 9cLIA for 
patients enrolled after 3-
1-16);  HPV-specific total 
immunoglobulin (9 IgG) 
Specimen requirement 
6 ml in tube supplied by 
institution’s clinical lab 
10 ml in non serum-separating 
(non-SST) red top tube  
10 ml in non-SST red top 
tube 
10 ml in non-SST red top 
tube 
5.4.7  Vaccine Dose #1 (Day 1) 
5.4.7.1  
Participants will be provided with education regarding HPV and the HPV vaccine 
using the most recent versions of the Centers for Disease Control (CDC) fact sheet as 
posted at www.cdc.gov/std/hpv/STDFact-HPV.htm or other age- and sex-appropriate 
materials from the CDC, such as materials posted at www.cdc.gov/vaccines/teens or 
www.cdc.gov/vaccines/who/teens/vaccines/hpv.html (samples in Appendix 12) and 
the most recent version of the Gardasil® (for patients enrolled on or before 3-1-16) or 
Gardasil 9 (for patients enrolled after 3-1-16) Vaccine Information Statement (VIS) 
as posted at www.cdc.gov/vaccines/pubs/vis/default.htm (sample in Appendix 13). 
 
5.4.7.2 
Sexually active female participants of childbearing potential will be instructed to use 
contraception beginning with first vaccine dose and continuing until at least 4 weeks 
after all 3 vaccine doses have been administered. Participants will be queried prior to 
each dose to determine if there is a possibility of pregnancy. If there is any possibility 
of pregnancy, a pregnancy test (urine or blood as per local institutional preference 
and procedures) will be obtained prior to vaccine administration and if positive, the 
vaccine will be withheld and the participant withdrawn from receiving further vaccine 
on the study. The vaccine will not be administered to sexually active females who 
refuse contraception.  
5.4.7.3  
The following blood specimens will be drawn: 
 - Quantitative immunoglobulins (6 ml whole blood in tube supplied by institution’s 

 
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clinical laboratory) – this specimen will be processed and analyzed by the clinical 
laboratories at the participating institution and results will be submitted to the 
coordinating center. 
 - Anti-HPV: 4cLIA for patients enrolled on or before 3-1-16; 9cLIA for patients 
enrolled after 3-1-16 (10 ml whole blood in non SST red top tube) 
 - Specimens (other than for Quantitative immunoglobulins) will be processed and 
shipped to the coordinating center according to the instructions in Section 5.4.6. and 
Appendix 11.  
 
5.4.7.4 
Targeted review of systems/ screening for acute illness and medication review will be 
performed. Vaccine administration must be rescheduled if any of the following are 
present: 
 
- Serious active infection (afebrile upper respiratory infection is not considered a 
serious infection) 
 
- Fever >100F or >37.8C (oral) within 24 hours prior to the visit 
 
- Receipt of any vaccines within 2-4 weeks prior to visit (as per Section 5.4.5)  
 
- Receipt of any blood products or transfusions within 3 months prior to visit 
 
- If acute or chronic medical or surgical conditions or contraindications not described 
above are present, the site investigator should consult with the coordinating center PI 
to obtain clearance to administer the vaccine 
 
 
 
Vaccine Visit Form (Appendix 8) will be completed and submitted.  
 
5.4.7.5 
HPV Vaccine Dose #1 (Gardasil for patients enrolled on or before 3-1-16; Gardasil 
9 for patients enrolled after 3-1-16) will be administered (0.5 ml IM per instructions in 
Section 5.4.3). Syncope has been reported following vaccine administration and may 
result in falling with injury; participant will be observed for 30 minutes following 
vaccine administration to assess for any adverse reactions. As with all vaccines, a 
solution of 1:1000 epinephrine will be available for injection in the event an 
anaphylactic reaction were to occur. 
 
5.4.7.6 
Participant will be provided with a Vaccine Report Card Kit (thermometer, metric tape 
measure, and Vaccine Report Card [adverse events diary]) and asked to record oral 
temperature 4 hours after the vaccine injection and then daily for 5 days following 
vaccine administration, and to record any adverse symptoms in the diary daily for 7 
days (for patients enrolled after 3-1-16) or 14 days (for patients enrolled on or before 
3-1-16) post vaccine administration (Appendix 14). The patient or parent/caregiver will 
be instructed to report any unusual reactions immediately; participants reporting any 
grade 3 or higher symptoms will be instructed to return to the clinic within 24 hours for 
evaluation and management. An Adverse Events/Research-Related Problems 
Reporting Form (AERF – Appendix 15) will be completed and submitted for all 
adverse events or unanticipated problems requiring expedited reporting (as defined in 
Section 9.3.2).  
 
5.4.7.7 
For patients enrolled on or before 3-1-16: Study team member will contact patient 
(or parent/caregiver) 2 to 3 days following vaccine administration (if unable to reach, 
regular attempts will continue to be made to contact the patient or parent/caregiver on 
business days up to 1 week post visit), and again 2 weeks (preferred timeframe: 15-
20 days) following vaccine administration (if unable to reach, regular attempts will 

 
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continue be made to contact the patient or parent/caregiver on business days up to 3 
weeks post visit and then weekly thereafter),to evaluate for any vaccine-related 
complications. If the patient or parent/caregiver does not respond, they will be asked 
to provide the information from their Vaccine Report Card at the next scheduled study 
visit. Data may continue to be collected outside of the suggested timeframes, if 
necessary. Each item on the Vaccine Report Card form (Appendix 14) will be 
reviewed with the patient or parent/caregiver and the information recorded by the 
study team member onto the electronic Vaccine Report Card form within the study 
database. The Vaccine Report Card completed by the study team member during the 
follow-up contacts, will be submitted to the study coordinating center via database 
export. An Adverse Events/Research-Related Problems Reporting Form (AERF – 
Appendix 15) will be completed and submitted to the coordinating center for all 
adverse events or unanticipated problems identified during these contacts that meet 
criteria for expedited reporting (as defined in Section 9.3.2) within 2 business days of 
becoming aware of the event/problem .  
 
 
For patients enrolled after 3-1-16: The patient (or parent/caregiver) will be 
instructed to contact their healthcare provider (and, when feasible, notify the study 
team) should they experience any severe symptoms (as defined on the Vaccine 
Report Card) within 2 weeks of vaccine receipt. A study team member will contact the 
patient (or parent/caregiver) one week (i.e., Day 8, or the first business day after Day 
8) following vaccine administration (if unable to reach, regular attempts will continue 
to be made to contact the patient or parent/caregiver on business days up to 2 weeks 
post visit) to evaluate for any vaccine-related complications. If the patient or 
parent/caregiver does not respond, they will be asked to provide the information from 
their Vaccine Report Card at the next scheduled study visit. Data may continue to be 
collected outside of the suggested timeframes, if necessary. Each item on the 
Vaccine Report Card form (Appendix 14) will be reviewed with the patient or 
parent/caregiver and the information recorded by the study team member onto the 
electronic Vaccine Report Card form within the study database. The Vaccine Report 
Card completed by the study team member during the follow-up contact, will be 
submitted to the study coordinating center via database export. An Adverse 
Events/Research-Related Problems Reporting Form (AERF – Appendix 15) will be 
completed and submitted to the coordinating center for all adverse events or 
unanticipated problems identified during this contact that meet criteria for expedited 
reporting (as defined in Section 9.3.2), within 2 business days of becoming aware of 
the event/problem.  
 
5.4.8  Vaccine Dose #2 
Note: this visit must be conducted no less than 8 weeks after Vaccine Dose #1, and no later 
than Week 12 
5.4.8.1 
Sexually active female participants of childbearing potential will be instructed to use 
contraception beginning with first vaccine dose and continuing until at least 4 weeks 
after all 3 vaccine doses have been administered. Participants will be queried prior to 
each dose to determine if there is a possibility of pregnancy. If there is any possibility 
of pregnancy, a pregnancy test (urine or blood as per local institutional preference 
and procedures) will be obtained prior to vaccine administration and if positive, the 
vaccine will be withheld and the participant withdrawn from receiving further vaccine 
on the study. The vaccine will not be administered to sexually active females who 
refuse contraception.  

 
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5.4.8.2 
Targeted review of systems/ screening for acute illness and medication review will be 
performed. Vaccine administration must be rescheduled if any of the following are 
present: 
 
- Serious active infection (afebrile upper respiratory infection is not considered a 
serious infection) 
 
- Fever >100F or >37.8C (oral) within 24 hours prior to the visit 
 
- Receipt of any vaccines within 2-4 weeks prior to visit (as per Section 5.4.5)  
 
- If acute or chronic medical or surgical conditions or contraindications not described 
above are present, the site investigator should consult with the coordinating center PI 
to obtain clearance to administer the vaccine. 
 
 
 
Vaccine Visit Form (Appendix 8) will be completed and submitted.  
 
 
The most recent version of the Gardasil® (for patients enrolled on or before 3-1-16) or 
Gardasil 9 (for patients enrolled after 3-1-16) Vaccine Information Statement (VIS), 
as posted at www.cdc.gov/vaccines/pubs/vis/default.htm (sample in Appendix 13), will 
be given to the patient/parent. 
 
5.4.8.3 
HPV Vaccine Dose #2 (Gardasil for patients enrolled on or before 3-1-16; Gardasil 
9 for patients enrolled after 3-1-16) will be administered (0.5 ml IM per instructions in 
Section 5.4.3). Syncope has been reported following vaccine administration and may 
result in falling with injury; participant will be observed for 30 minutes following 
vaccine administration to assess for any adverse reactions. As with all vaccines, a 
solution of 1:1000 epinephrine will be available for injection in the event an 
anaphylactic reaction were to occur. 
 
5.4.8.4 
 Participant was provided with a Vaccine Report Card Kit (thermometer, metric tape 
measure) on Day 1; this will be re-supplied if necessary. The participant will be given 
a Vaccine Report Card [adverse events diary] and asked to record oral temperature 4 
hours after the vaccine injection and then daily for 5 days following vaccine 
administration, and to record any adverse symptoms in the diary daily for 7 days (for 
patients enrolled after 3-1-16) or 14 days (for patients enrolled on or before 3-1-16) 
post vaccine administration (Appendix 14). The patient or parent/caregiver will be 
instructed to report any unusual reactions immediately; participants reporting any 
grade 3 or higher symptoms will be instructed to return to the clinic within 24 hours for 
evaluation and management. An Adverse Events/Research-Related Problems 
Reporting Form (AERF – Appendix 15) will be completed and submitted for all 
adverse events or unanticipated problems requiring expedited reporting (as defined in 
Section 9.3.2).  
 
5.4.8.5 
 For patients enrolled on or before 3-1-16: Study team member will contact patient 
(or parent/caregiver) 2 to 3 days following vaccine administration (if unable to reach, 
regular attempts will continue to be made to contact the patient or parent/caregiver on 
business days up to 1 week post visit), and again 2 weeks (preferred timeframe: 15-
20 days) following vaccine administration (if unable to reach, regular attempts will 
continue be made to contact the patient or parent/caregiver on business days up to 3 
weeks post visit and then weekly thereafter),to evaluate for any vaccine-related 
complications. If the patient or parent/caregiver does not respond, they will be asked 

 
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to provide the information from their Vaccine Report Card at the next scheduled study 
visit. Data may continue to be collected outside of the suggested timeframes, if 
necessary. Each item on the Vaccine Report Card form (Appendix 14) will be 
reviewed with the patient or parent/caregiver and the information recorded by the 
study team member onto the electronic Vaccine Report Card form within the study 
database. The Vaccine Report Card completed by the study team member during the 
follow-up contacts, will be submitted to the study coordinating center via database 
export. An Adverse Events/Research-Related Problems Reporting Form (AERF – 
Appendix 15) will be completed and submitted to the coordinating center for all 
adverse events or unanticipated problems identified during these contacts that meet 
criteria for expedited reporting (as defined in Section 9.3.2) within 2 business days of 
becoming aware of the event/problem .  
 
 
For patients enrolled after 3-1-16: The patient (or parent/caregiver) will be 
instructed to contact their healthcare provider (and, when feasible, notify the study 
team) should they experience any severe symptoms (as defined on the Vaccine 
Report Card) within 2 weeks of vaccine receipt. A study team member will contact the 
patient (or parent/caregiver) one week (i.e., Day 8, or the first business day after Day 
8) following vaccine administration (if unable to reach, regular attempts will continue 
to be made to contact the patient or parent/caregiver on business days up to 2 weeks 
post visit) to evaluate for any vaccine-related complications. If the patient or 
parent/caregiver does not respond, they will be asked to provide the information from 
their Vaccine Report Card at the next scheduled study visit. Data may continue to be 
collected outside of the suggested timeframes, if necessary. Each item on the 
Vaccine Report Card form (Appendix 14) will be reviewed with the patient or 
parent/caregiver and the information recorded by the study team member onto the 
electronic Vaccine Report Card form within the study database. The Vaccine Report 
Card completed by the study team member during the follow-up contact, will be 
submitted to the study coordinating center via database export. An Adverse 
Events/Research-Related Problems Reporting Form (AERF – Appendix 15) will be 
completed and submitted to the coordinating center for all adverse events or 
unanticipated problems identified during this contact that meet criteria for expedited 
reporting (as defined in Section 9.3.2), within 2 business days of becoming aware of 
the event/problem. 
5.4.9  Vaccine Dose #3 
Note: this visit must be conducted no earlier than 16 weeks after Vaccine Dose #2 and no later 
than Week 32 
5.4.9.1 
Sexually active female participants of childbearing potential will be instructed to use 
contraception beginning with first vaccine dose and continuing until at least 4 weeks 
after all 3 vaccine doses have been administered. Participants will be queried prior to 
each dose to determine if there is a possibility of pregnancy. If there is any possibility 
of pregnancy, a pregnancy test (urine or blood as per local institutional preference 
and procedures) will be obtained prior to vaccine administration and if positive, the 
vaccine will be withheld and the participant withdrawn from receiving further vaccine 
on the study. The vaccine will not be administered to sexually active females who 
refuse contraception.   
 
5.4.9.2 
Targeted review of systems/ screening for acute illness and medication review will be 
performed. Vaccine administration must be rescheduled if any of the following are 

 
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present: 
 
- Serious active infection (afebrile upper respiratory infection is not considered a 
serious infection) 
 
- Fever >100F or >37.8C (oral) within 24 hours prior to the visit 
 
- Receipt of any vaccines within 2-4 weeks prior to visit (as per Section 5.4.5)  
 
- If acute or chronic medical or surgical conditions or contraindications not described 
above are present, the site investigator should consult with the coordinating center PI 
to obtain clearance to administer the vaccine 
 
Vaccine Visit Form (Appendix 8) will be completed and submitted.  
 
 
 
The most recent version of the Gardasil® (for patients enrolled on or before 3-1-16) or 
Gardasil 9 (for patients enrolled after 3-1-16) Vaccine Information Statement (VIS), 
as posted at www.cdc.gov/vaccines/pubs/vis/default.htm (sample in Appendix 13), will 
be given to the patient/parent. 
 
5.4.9.3 
 HPV Vaccine Dose #3 (Gardasil for patients enrolled on or before 3-1-16; Gardasil 
9 for patients enrolled after 3-1-16) will be administered (0.5 ml IM per instructions in 
Section 5.4.3). Syncope has been reported following vaccine administration and may 
result in falling with injury; participant will be observed for 30 minutes following 
vaccine administration to assess for any adverse reactions. As with all vaccines, a 
solution of 1:1000 epinephrine will be available for injection in the event an 
anaphylactic reaction were to occur. 
 
5.4.9.4 
 Participant was provided with a Vaccine Report Card Kit (thermometer, metric tape 
measure) on Day 1; this will be re-supplied if necessary. The participant will be given 
a Vaccine Report Card [adverse events diary] and asked to record oral temperature 4 
hours after the vaccine injection and then daily for 5 days following vaccine 
administration, and to record any adverse symptoms in the diary daily for 7 days (for 
patients enrolled after 3-1-16) or 14 days (for patients enrolled on or before 3-1-16) 
post vaccine administration (Appendix 14). The patient or parent/caregiver will be 
instructed to report any unusual reactions immediately; participants reporting any 
grade 3 or higher symptoms will be instructed to return to the clinic within 24 hours for 
evaluation and management. An Adverse Events/Research-Related Problems 
Reporting Form (AERF – Appendix 15) will be completed and submitted for all 
adverse events or unanticipated problems requiring expedited reporting (as defined in 
Section 9.3.2).  
 
5.4.9.5 
 For patients enrolled on or before 3-1-16: Study team member will contact patient 
(or parent/caregiver) 2 to 3 days following vaccine administration (if unable to reach, 
regular attempts will continue to be made to contact the patient or parent/caregiver on 
business days up to 1 week post visit), and again 2 weeks (preferred timeframe: 15-
20 days) following vaccine administration (if unable to reach, regular attempts will 
continue be made to contact the patient or parent/caregiver on business days up to 3 
weeks post visit and then weekly thereafter),to evaluate for any vaccine-related 
complications. If the patient or parent/caregiver does not respond, they will be asked 
to provide the information from their Vaccine Report Card at the next scheduled study 
visit. Data may continue to be collected outside of the suggested timeframes, if 
necessary. Each item on the Vaccine Report Card form (Appendix 14) will be 
reviewed with the patient or parent/caregiver and the information recorded by the 

 
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study team member onto the electronic Vaccine Report Card form within the study 
database. The Vaccine Report Card completed by the study team member during the 
follow-up contacts, will be submitted to the study coordinating center via database 
export. An Adverse Events/Research-Related Problems Reporting Form (AERF – 
Appendix 15) will be completed and submitted to the coordinating center for all 
adverse events or unanticipated problems identified during these contacts that meet 
criteria for expedited reporting (as defined in Section 9.3.2) within 2 business days of 
becoming aware of the event/problem .  
 
 
For patients enrolled after 3-1-16: The patient (or parent/caregiver) will be 
instructed to contact their healthcare provider (and, when feasible, notify the study 
team) should they experience any severe symptoms (as defined on the Vaccine 
Report Card) within 2 weeks of vaccine receipt. A study team member will contact the 
patient (or parent/caregiver) one week (i.e., Day 8, or the first business day after Day 
8) following vaccine administration (if unable to reach, regular attempts will continue 
to be made to contact the patient or parent/caregiver on business days up to 2 weeks 
post visit) to evaluate for any vaccine-related complications. If the patient or 
parent/caregiver does not respond, they will be asked to provide the information from 
their Vaccine Report Card at the next scheduled study visit. Data may continue to be 
collected outside of the suggested timeframes, if necessary. Each item on the 
Vaccine Report Card form (Appendix 14) will be reviewed with the patient or 
parent/caregiver and the information recorded by the study team member onto the 
electronic Vaccine Report Card form within the study database. The Vaccine Report 
Card completed by the study team member during the follow-up contact, will be 
submitted to the study coordinating center via database export. An Adverse 
Events/Research-Related Problems Reporting Form (AERF – Appendix 15) will be 
completed and submitted to the coordinating center for all adverse events or 
unanticipated problems identified during this contact that meet criteria for expedited 
reporting (as defined in Section 9.3.2), within 2 business days of becoming aware of 
the event/problem. 
 
5.4.10  Month 7: 4-8 Weeks Following Final Vaccine Dose 
Note: this visit must be conducted no earlier than 4 weeks and no later than 8 weeks after 
Vaccine Dose #3 
 
5.4.10.1  The following blood specimens will be drawn: 
 - Anti-HPV 4cLIA for patients enrolled on or before 3-1-16 or 9cLIA for patients 
enrolled after 3-1-16: 10 ml whole blood in non-SST red top tube 
 
Specimens will be processed and shipped to the coordinating center according to the 
instructions in Section 5.4.6. and Appendix 11.  
5.4.10.2 Month 7 Visit Form (Follow-Up #1; Appendix 9) will be completed and submitted.  
 
5.4.11  Month 24: 72-84 Weeks (~ 2 Years) Following Vaccine Dose #1 
Note: this visit must be conducted no less than 72 weeks and no later than 84 weeks after 
Vaccine Dose #3. 
5.4.11.1 The following blood specimens will be drawn: 
- Anti-HPV 4cLIA for patients enrolled on or before 3-1-16 or 9cLIA for patients 
enrolled after 3-1-16, and HPV-specific total immunoglobulin (9 IgG): 10 ml whole 

 
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blood in non-SST red top tube 
 
Specimens will be processed and shipped to the coordinating center according to the 
instructions in Section 5.4.6. and Appendix 11.  
5.4.11.2   Month 24 Visit Form (Follow-Up #2; Appendix 16) will be completed and submitted.  
 
5.4.12  Premature Study Discontinuation Visit 
Administration of the study vaccine must stop permanently and a Premature Study 
Discontinuation Visit scheduled if any of the following occur: 
- 
A confirmed Grade > 3 toxicity that is deemed possibly, probably, or definitely vaccine-
related and not resolved to < Grade 1 by the next due date for vaccine administration  
- 
A Grade >3 toxicity recurs after the next administration of the study vaccine 
- 
A Grade 4 life-threatening toxicity whose relationship to the vaccine is possibly, 
probably, or definitely related 
- 
The investigator determines that receipt of additional study vaccines would be 
detrimental to the participant’s health or well-being 
- 
The participant becomes pregnant 
- 
The participant withdraws consent 
- 
The participant fails to comply with study requirements so as to cause harm to 
herself/himself or seriously interfere with the validity of the study results 
- 
The subject is unable to continue participation due to circumstances preventing 
completion of study procedures 
- 
The study is stopped by a government agency, such as the National Institutes of Health 
(NIH) 
- 
The study is stopped for other administrative reasons 
Participants who are to be permanently discontinued from the study will complete a final 
premature study discontinuation visit before going off study, at which time the following data will 
be collected: 
5.4.12.1  The following blood specimens will be drawn: 
- Anti-HPV 4cLIA for patients enrolled on or before 3-1-16 or 9cLIA for patients 
enrolled after 3-1-16: 10 ml whole blood in non-SST red top tube 
 
Specimens will be processed and shipped to the coordinating center according to the 
instructions in Section 5.4.6. and Appendix 11.  
5.4.12.2 Premature Study Discontinuation Form (Appendix 10) will be completed and submitted.  
5.4.13  End of Study 
For patients completing the study prematurely (e.g., due to withdrawal), a Premature Study 
Discontinuation Form (Appendix 10) will be completed and submitted. For subjects who are lost 
to follow-up prior to Month 24, the Premature Study Discontinuation Form will be completed at 
the time the subject is deemed by the site PI to have ended their participation in the study. For 
subjects who complete all study time points, no study completion form is required.  A Thank You 
Letter (Appendix 17) will be sent to each subject that completes the Month 24 time point. 
 
 

 
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6.0 
HUMAN SUBJECTS ISSUES 
 
6.1 
Potential Benefits 
Aim 1 (Survey): There are no potential benefits to survey participation; however, benefits to future 
patients may occur, including increased knowledge regarding prevalence and determinants of HPV 
vaccine initiation among cancer survivors, which could potentially inform future interventions to improve 
HPV vaccine uptake among cancer survivors. 
 
Aim 2 (Vaccine Evaluation): Potential benefits to the participant include the administration of the HPV 
vaccine, which has been shown in the general population to be highly protective for HPV infection. The 
3-dose vaccine series will be provided at no charge to the participant. Additionally, benefits to future 
patients may potentially occur as a result of the increased knowledge gained from this study regarding 
safety, tolerability, and immunogenicity of the quadrivalent and nonavalent HPV vaccine in cancer 
survivors. 
 
 
6.2 
Potential Risks 
Aim 1 (Survey): It is possible that some participants may be uncomfortable answering questions 
regarding their sexual history and activity; however, these questions are considered part of standard 
adolescent/young adult health care. Nevertheless, participants will be informed that if they do not want 
to answer any questions for any reason, they may skip those questions. 
Aim 2 (Vaccine Evaluation): The primary risk associated with Aim 2 are the risks associated with 
administration of the HPV vaccine, which is believed to be safe when administered in the general 
population, but which has not been studied in cancer survivors. Common side effects reported in the 
general population have included skin redness, pain, swelling, and/or muscle soreness at the injection 
site. Syncope has been reported following vaccine administration and may result in falling with injury; 
participants will therefore be observed for 30 minutes in the clinic following vaccine administration. 
Some patients may experience mild to moderate fever, chills, nausea, fatigue, or headache following 
the vaccine. These symptoms are usually transient and resolve without intervention. Although rare, 
serious side effects can occur and may include rash, urticaria, dyspnea, stridor, wheezing, edema of 
the face, lips, or throat, pruritis, seizures, tachycardia, hypotension, and shock, or other side effects that 
are currently unknown in this population. As with all vaccines, a solution of 1:1000 epinephrine will be 
available for injection should an anaphylactic reaction occur. Since the HPV vaccine has not been 
tested in cancer survivors, severity of side effects could potentially be increased in this patient 
population and side effects that are currently unknown could potentially occur. Additionally, the drawing 
of blood specimens may cause local discomfort, bleeding, or bruising; rarely a small clot or infection 
can occur at the site of the venipuncture.  
 
6.3 
Risk to Benefit Ratio 
Aim 1 (Survey): The primary risks associated with survey completion include participant discomfort 
regarding answering questions regarding their sexual history and activity; however, these questions are 
considered part of standard adolescent/young adult health care. There is no direct benefit to 
participation; however, there is potential benefit in regard to knowledge gained that may be of benefit to 
future patients.  
 
Aim 2 (Vaccine Evaluation): 
The primary risk associated with Aim 2 are the risks associated with administration of the HPV vaccine, 
which is believed to be safe when administered in the general population, but which has not been 

 
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studied in cancer survivors. Reactions to the vaccine may include pain, swelling, muscle soreness 
and/or skin redness at the site of the injection, fever, chills, nausea, fatigue, and headache. Although 
rare, serious side effects can occur and may include rash, urticaria, dyspnea, stridor, wheezing, edema 
of the face, lips, or throat, pruritis, seizures, tachycardia, hypotension, and shock, or other side effects 
that are currently unknown in this population. Additionally, the drawing of blood specimens may cause 
local discomfort, bleeding, or bruising; rarely a small clot or infection can occur at the site of the 
venipuncture. Benefits include potential protection against the HPV vaccine subtypes, including the 
highly oncogenic subtypes 16 and 18, which currently are known to cause 70% of all cervical cancers 
and protection against subtypes 6 and 11, which are currently known to cause 90% of genital warts;29 
Additionally, patients enrolled after 3-1-16 will receive the nonavalent vaccine, which has been shown 
in the general population to provide protection against 85-90% of the oncogenic HPV subtypes 
associated with cervical cancer, 85-90% of vulvar cancers, 80-85% of vaginal cancers, and 90-95% of 
anal cancers. Therefore, if the vaccine is adequately immunogenic in this population, participants may 
potentially receive the significant benefit of protection against cervical, penile, anal, and orophyrangeal 
cancers and genital warts. Additionally, future patients may benefit from the determination of the safety, 
immunogenicity, and optimal timing of HPV vaccine administration among cancer survivors. 
 
6.4 
Precautions 
Protection against Risk. In order to protect participants from any potential risks associated with the 
current study, the following assurances will be adhered to: (1) participation is voluntary and consent to 
participate can be withdrawn at any point within the study without penalty, (2) prospective participants 
who do not wish to volunteer for the current study will not lose their access to medical services at their 
treating institution (3) all participants will be informed of foreseeable benefits and risks, (4) all data 
collected from participants or via medical chart review will be stored on a secure computer and/or 
locked file cabinet(s). In addition, participants will be informed that they have the right to refuse to 
continue their participation without penalty for any personal reason. If participants indicate that they are 
experiencing emotional or psychological issues related to topics raised by the study questionnaire, they 
will be evaluated by a nurse or social worker. Referrals to a psychologist will be available if applicable.  
If significant reactions to the study vaccine occur, the treating clinician, site PI, and/or the study PI may 
remove a participant from the study. 
Safety Monitoring: Participant safety will be monitored as outlined in Section 9.0 (Data Safety and 
Monitoring Plan).  
 
6.5 
Alternatives 
The patient may choose (or for minors the parent/guardian may choose for the patient) not to 
participate in the study.  
 
6.6 
Confidentiality 
All data collected by the researchers will remain confidential. Study information will be made as 
anonymous as possible through the use of codes, files will be stored in locked cabinets, and all 
database records will require a password in order to access study data.  Only personnel directly 
involved with the study will have access to the study data, including the primary investigator, co-
investigators, research assistants, and study personnel.  Patient data in published study results will not 
include personal identifying information such as name.   
 
6.7 
Financial Obligations and Compensation 
There is no charge for participation in this study. Vaccines and related preparation and administration 
charges and all study-related labs will be provided without cost to the participant.  To compensate Aim 
2: Vaccine Evaluation participants for their time and transportation expenses related to study 
participation, participants will receive $100 (or equivalent voucher/gift card) at Month 7 and $75 (or 

 
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equivalent voucher/gift card) at Month 24.  
 
6.8 
Informed Consent Process 
Informed consent will be obtained from each patient (of age of majority) according to the approved 
procedures of the institutional review board (IRB) or Ethics Committee at each participating institution. 
Consent of the parent/guardian and assent of the patient will be obtained for each minor participant 
according to the policies and procedures in place at each participating institution and according to the 
laws in the state where the informed consent is being signed. The original consent form will be placed 
in the medical record. A copy will be given to the participant and a copy will be filed with the research 
record. 
 
7.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
7.1 
Evaluable Patients 
Aim 1 (Survey): A subject will be considered evaluable if they complete the survey item indicating HPV 
vaccine initiation/non-initiation and for whom medical record abstraction data is submitted as described 
in Section 4.3. 
Aim 2 (Vaccine Evaluation): A subject will be considered evaluable for the primary (immunogenicity) 
aim if they are seronegative for HPV-16 and/or HPV-18 at baseline, complete all 3 HPV vaccine doses 
within the specified administration windows (Section 5.4.4), have evaluable Month 7 Anti-HPV 4cLIA 
(for patients enrolled on or before 3-1-16) or 9cLIA (for patients enrolled after 3-1-16) results that were 
drawn within the acceptable window (Section 5.4.6), and for whom medical record abstraction data is 
submitted as described in Section 5.3. Safety data will be reported on all eligible subjects who receive 
at least one dose of vaccine, regardless of whether they are evaluable for the additional study aims.  
7.2 
Primary Endpoints 
Aim 1 (Survey):  
1. HPV vaccine non-initiation  
Aim 2 (Vaccine Evaluation): 
1. HPV antibody titers (Anti-HPV 4cLIA [for patients enrolled on or before 3-1-16] or 9cLIA [for 
patients enrolled after 3-1-16]  [Geometric Mean Titers; Seropositivity]  
(Day 1, Month 7, and Month 24) [Immunogenicity] 
2.  Vaccine Report Card (participant/parent diary of adverse events, collected for 7 days (for 
patients enrolled after 3-1-16) or 14 days (for patients enrolled on or before 3-1-16) following 
each vaccine dose, and Adverse Events/Research-Related Problems Reporting Forms 
[Safety/tolerability]  
 
7.3 
Schema – Aim 1: Survey 
Aim 1: Survey 
[Protocol v3, 8/17/15: Accrual goal for Aim 1 met, enrollment to survey closed] 
 
Requirement 
Pre-Entry
Study Entry 
Verification of eligibility (Protocol Section 3.1) 
X
 
Informed consent/assent 
X 
Registration 
X 
Medical record abstraction: 
- Medical Record Review Form (Appendix 1)  
- Intensity of Treatment Rating Scale (Appendix 2) 
X 
Survey completion (Appendix 3) 
X 
 
 
 

 
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7.4 
Schema – Aim 2:Vaccine Evaluation 
Aim 2: Vaccine Evaluation 
Requirement 
Pre-
entry 
Day 
1 
Dose
#2 
Dose  
#3 
Month  
7  
Month 
24 
PSD* 
 
Verification of eligibility (Protocol Sections 3.2 and 3.3)  
X 
 
 
 
 
 
 
Permission for participation from treating clinician 
X 
 
 
 
 
 
 
Informed consent/assent 
 
X 
 
 
 
 
 
Medical record abstraction:  
Cancer Treatment Summary Form (Appendix 7) 
 
 
 
 
X 
 
 
Patient/parent education (Appendix 12, 13) 
 
X 
X 
X 
 
 
 
Targeted review of systems 
Screening for acute illness  
Screening for pregnancy (if indicated)  
Vaccine Visit Form (Appendix 8) 
 
X 
X 
X 
 
 
 
HPV Vaccine 
Dose 
#1 
Dose 
#2 
Dose  
#3 
 
Vaccine Report Card (Appendix 14)  
x 7 days (if enrolled after 3-1-16) or 14 days (if enrolled 
on or before 3-1-16) post each vaccine dose, including 
home temperature monitoring 4 hours after each vaccine 
dose, then daily x 5 days  
 
X 
X 
X 
 
 
 
Quantitative Ig [humoral immunity]  
 
X 
 
 
 
 
 
Anti-HPV 4cLIA (if enrolled on or before 3-1-16) or 9cLIA 
(if enrolled after 3-1-16) [geometric mean titers and 
HPV type-specific seropositivity] 
 
X 
 
 
X 
X 
X 
HPV-specific total immunoglobulin [qualitative aspects of 
HPV-specific humoral response] 
 
 
 
 
 
X 
 
Adverse Events/Research-Related Problems Form 
(AERF; Appendix 15) 
 
 
 
 
 
 
 
Month 7 Visit Form (Follow-Up #1) (Appendix 9) 
 
 
 
 
X 
 
 
Month 24 Visit Form (Follow-Up #2) (Appendix 16) 
 
 
 
 
 
X 
 
Premature Study Discontinuation (PSD) Form  
(Appendix 10)† 
 
 
 
 
 
 
X 
*PSD = Premature Study Discontinuation (collected at PSD clinic visit or when deemed lost to follow-up; see Section 5.4.12) 
 = AERF to be completed as needed at any study time point 
†PSD Form will also be completed as needed at any time point that participation is terminated prematurely 

 
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8.0 
STATISTICAL METHODS 
8.1 
Sample Size 
Aim 1 (Survey): A sample size of 1090 eligible subjects is required to address Specific Aim 1. We have 
chosen this sample size based on our preliminary study (Section 2.9), from which we can assume that 
90% (n=981) of those approached will participate in the survey. A sample of 981 survey participants for 
Specific Aim 1 will provide 80% power to reject the null hypothesis that the prevalence (p) of HPV 
vaccine initiation is ≤0.4 if the true p is at least 0.44 (one-sided test, Type I error=0.05). It will also 
provide a 2-sided 95% confidence interval (CI) of sample p±.061 if true p=0.4.  
 [Protocol v3, 8/17/15: Accrual goal for Aim 1 met, enrollment to survey closed] 
 
Aim 2 (Vaccine Evaluation):  
 
qHPV Vaccine Cohort (patients enrolled on or before 3-1-16): Based on national vaccine initiation 
rates and our preliminary data (Section 2.9),40 we conservatively assume that 60% (n=589) of the 981 
survey participants will have not initiated the HPV vaccine. Based on our data (Section 2.9) and prior 
trials,30,31,135 we conservatively assume that of the non-vaccinated survey participants, 60% (n=353) will 
agree to receive the vaccine, 96% (n=339) will be seronegative at baseline (Intent to Treat [IT] sample), 
and 92% (n=312) will complete all 3 doses, yielding 312 (Per-Protocol [PP]) subjects who will have 
received all 3 doses of qHPV vaccine for examining Aim 2.1. This sample size was calculated using the 
mean GMT and SD reported by Merck & Co.28 for healthy males and females aged 9-15 years and 16-
26 years as the historical healthy population. The following assumptions were made: i) cancer survivors 
were similarly distributed in regard to immunogenicity with the same SD as in this healthy population; ii) 
margin of equivalence (E) was ½ of the mean GMT of the healthy population (Table 7).  Using the 
method of Korn and Freidlin136 for sample size calculations using historical controls, a total of 312 
subjects (72 younger females, 77 older females, 82 younger males, and 81 younger males) will provide 
80% power to demonstrate non-inferiority with respect to anti-HPV-16, and/or -18 GMT in cancer 
survivors compared to the healthy population assuming a one-sided t-test, Type I error =0.00312 (for 
an overall Type I error =0.025), and margin of equivalence (E) shown in Table 7 by sex and age for 
each vaccine type.  
 
Table 7. Sample Size for Aim 2 (Vaccine Evaluation)
 
Females
Anti-
HPV 
9-15y (younger) 
16-26y (older)
Healthy 
Cancer 
E 
SD
N
Healthy
Cancer
E
SD 
N 
16 
4918.5 
2459.3 
2459.25 
5585.26 
72 
2411.3 
1205.65 
1205.65 
2915.77 
77 
18 
1042.6 
521.3 
521.30 
1161.91 
69 
475.6 
237.80 
237.80 
500.01 
58 
 
 
Males
16 
6056.5 
3028.3 
3028.25 
6895.81 
72 
2401.5 
1200.75 
1200.75 
2747.45 
72 
18 
1357.4 
678.7 
678.70 
1641.08 
82 
402.6 
201.30 
201.30 
489.9 
81 
Sample size required = 312 
 
The coordinating center will track enrollment to each stratum (Younger Females, Older Females, 
Younger Males, Older Males), and will close enrollment to each stratum once the targeted number of 
evaluable participants has been reached. 
 
9vHPV Vaccine Cohort (patients enrolled after 3-1-16):  Results of interim data analysis on the 
qHPV vaccine cohort (performed in January 2016 with data from patients who had a Month 7 sample 
available for analysis on or before 8-28-15; N=133) indicate that the cohort enrolled on or before 3-1-16 
(N=254) who have received/are receiving the qHPV vaccine will be more than sufficient to address non-
inferiority (i.e., lower limit of the multiplicity-adjusted 95% confidence intervals for the ratio of the mean 
geometric mean titer for anti-HPV-16 and -18 in the cancer vs. healthy population >0.5 for each 

 
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age/gender group) of the qHPV vaccine in cancer survivors. We are therefore extending the study to 
evaluate non-inferiority of the 9vHPV vaccine; interim data analysis results from the qHPV vaccine 
cohort indicate that an additional 200 patients will be sufficient to perform this evaluation in cancer 
survivors.  
 
8.2 
Data Analysis 
8.2.1.  Aim 1 (Survey) 
8.2.1.1. Estimate the prevalence of HPV vaccine initiation in cancer survivors ages 9 to 
26 years. Examine the sociodemographic, behavioral, and medical determinants of HPV 
vaccine non-initiation  
The outcome is HPV vaccine initiation status (Yes: received at least one dose/ No: never 
received any doses) at the time of survey completion. The prevalence (p) of qHPV 
vaccine initiation among 981 survey participants and its 2-sided 95% CI will be 
calculated. A one-sided t-test of Ho: p≤0.4 will be conducted using Type I error=0.05. 
Significant predictors of vaccine initiation will be identified using logistic regression. We 
will consider predictors relevant to vaccine acceptance or refusal, including 
sociodemographic (e.g., age, sex, education, race/ethnicity, income), medical (e.g., 
cancer diagnosis, intensity of treatment, conventional treatment vs. HCT), and behavioral 
(e.g., perceived susceptibility to HPV, perceived severity of consequences of HPV 
infection, 
attitudes 
toward 
vaccination, 
attitudes 
toward 
healthcare 
provider 
recommendation of vaccine, engagement in health promotion behaviors, knowledge 
regarding association of HPV with cancer, familial decision-making style). A sample size 
of 981 will provide 80% power at 5% significance level to detect an odds ratio of 1.45 to 
2.0 for a dichotomous variable with 50% of the sample in one group. 
 
8.2.2.  Aim 2 (Vaccine Evaluation) 
8.2.2.1.  Determine immunogenicity of qHPV and 9vHPV vaccine 1 month following the 
third and final vaccine dose 
The primary analytic approach will be per-protocol (PP)30 analysis; intention to treat 
analysis will also be conducted. The evaluation will be completed separately for the qHPV 
and 9vHPV cohorts. The sample size is powered to determine whether vaccine-induced 
anti-HPV-16 and -18 neutralizing antibody response in cancer survivors is comparable to 
the age- and sex-matched general population (Table 7); PP immunogenicity population 
includes participants who are seronegative for the oncogenic vaccine components of 
primary interest (HPV-16, -18) on Day 1, complete all three vaccine doses within the 
protocol-specified time frames, and have immunogenicity data available at the time of 
analysis. Each vaccine component will be analyzed separately, and we will adjust for 
intensity of treatment. Anti-HPV-6 and -11 (and in the 9vHPV cohort, Anti-HPV-31, -33, -
45, -52, and -58) response will also be explored. The primary outcome of interest is GMT. 
We will also assess seropositivity rates among cancer survivors. Seropositivity (binary 
variable) is defined as: qHPV cohort: Anti-HPV-6, -11, -16, and -18 titer > 20, 16, 20, and 
24 mMU/ml respectively;30 9vHPV cohort: Anti-HPV-6, -11, -16, -18, -31, -33, -45, -52, 
and -58 titer > 30, 16, 20, 24, 10, 8, 8, 8, and 8 mMU/ml, respectively.69 
Outcome measure (GMT): Using the historical healthy population for qHPV28 and 
9vHPV69 respectively,  a multiplicity-adjusted 95% 2-sided confidence intervals for the 
ratio of mean GMT for HPV-16 and -18 in the cancer and healthy population will be 
computed. If the lower 95% limit is greater than 0.5, immunogenicity in cancer survivors 
will be considered non-inferior.30  

 
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Outcome measure: (seropositivity) [Exploratory only; study is not powered for this]: The 
percent of seropositive participants at Month 7 will be compared to the percent of age-
and sex-matched seroconverted individuals in the historical healthy population for each of 
2 vaccine components. Two one-sided tests of noninferiority (for each of 2 HPV types) 
will be conducted for each age-sex group at the 0.025 level (multiplicity adjusted) 
according to the methods of Miettinen and Nurminen.137 Seroconversion in cancer 
survivors will be considered non-inferior if the lower 95% CI for the difference in percent 
seropositive between the healthy and cancer population is <5 percentage points.30 The 
above analyses will be conducted for PP and IT samples. Although not powered to detect 
non-inferiority for HPV-6 and -11 (and in the 9vHPV cohort, HPV-31, -33, -45, -52, and -
58), we will also conduct similar analyses for GMT and seropositivity for these types. 
 
8.2.2.2.  Identify clinical/host factors influencing immunogenicity in cancer survivors 
Subjects whose GMT at Month 7 is less than ½ of the mean GMT of the corresponding 
age-sex matched health population will be classified as having lowered immunogenicity. 
Logistic regression will be used to identify significant predictors of lowered 
immunogenicity. Potential predictors include sex, primary diagnosis, current age, age at 
diagnosis/HCT, prior therapy (all therapeutic exposures, including cumulative doses of all 
immunosuppressive agents), intensity of therapy (conventional therapy vs. HCT), time 
from completion of therapy, presence/extent of chronic GvHD, dose/duration of 
immunosuppressive agents post-HCT, and Day 1 Quant Ig. This analysis will be 
conducted for HPV-16 and -18. At Type I error=0.5,  
312 subjects will achieve 80% power 
to detect odds ratios of 2.0 to 3.2 
depending on the hypothesized and  
true proportions of subjects with 
lowered immunogenicity (Table 8) or a 
dichotomized covariate with 50% of 
the sample in each group. 
 
8.2.2.3. 
Determine 
the 
safety/ 
tolerability of the qHPV and 9vHPV 
vaccine in cancer survivors 
In the IT sample, the number of 
vaccine-associated AE within 7 (for 
9vHPV) or 14 (for qHPV) days of each dose will be compared to those reported for the 
age- and sex-matched general population: % of subjects with injection site AEs (e.g., 
pain, erythema), % of subjects with systemic AEs (e.g., fever, syncope, headache, hives, 
rashes, diarrhea), % of subjects with serious AEs (e.g., life-threatening, result in 
persistent disability or death). Overall cohort: % of subjects who discontinue vaccine 
related to AE. AEs will be summarized descriptively as frequencies and percentages by 
type (injection site, systemic, serious), by vaccine dose (i.e., #1, #2, #3), and across all 
vaccine doses. Chi-square and exact tests will be used for comparison depending on the 
rarity of events. Our smallest PP subsample of 72 young females will provide 80% power 
to detect a difference of 0.0485 in AE rates if true rate=0.01, and a difference of 0.1068 if 
the true rate=0.85. For the largest PP subsample of 82 young males, the corresponding 
detectable differences are 0.0415 and 0.1021. For the entire PP sample of 312, the 
corresponding differences are 0.0189 and 0.0534. Type I error=.05 is assumed for each 
comparison. 
 
Table 8. Proportion of Subjects with Lowered 
Immunogenicity and Associated Odds Ratios 
P0
P1 
OR
0.05 
0.143 
3.18 
0.1 
0.215 
2.47 
0.2 
0.34 
2.06 
0.3 
0.453 
1.93 
0.4 
0.558 
1.89 
0.5 
0.656 
1.91 
0.6 
0.748 
1.98 
P0 = Hypothesized proportion of subjects with lowered 
immunogenicity 
P1 = True proportion of subjects with lowered immunogenicity 
OR = Odds Ratio

 
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8.2.2.4. (Exploratory sub-aim): Evaluate the persistence of antibody response at 2 years 
post vaccine initiation and identify clinical/host factors influencing response persistence. 
Outcome measure (GMT): We will calculate mean GMT and 2-sided 95% CI for HPV-16 
and -18 at Month 24 following vaccine initiation for PP subjects and compare them to 
age-, sex, and time-matched means in the historical healthy population.28 Cancer 
survivors will be considered to have non-inferior persistence of antibody response to a 
subtype at a time point if the lower 95% confidence limit for the ratio of GMT in cancer 
survivors to historical healthy population is >50%.30  
Outcome measure (seropositivity): Seropositivity is defined as: qHPV cohort: Anti-HPV-6, 
-11, -16, and -18 titer > 20, 16, 20, and 24 mMU/ml respectively;30 9vHPV cohort: Anti-
HPV-6, -11, -16, -18, -31, -33, -45, -52, and -58 titer > 30, 16, 20, 24, 10, 8, 8, 8, and 8 
mMU/ml, respectively.69 Among PP participants, the percent seropositive to each vaccine 
subtype will be computed and compared to age-and sex-matched seropositive rates at 
Month 24 in the healthy population.28  One-sided tests of noninferiority for each HPV type 
will be conducted at the 0.025 (multiplicity adjusted) level according to the methods of 
Miettinen and Nurminen.137 For each subtype and time point, persistence of seropositivity 
will be considered non-inferior in cancer survivors if the lower 95% CI for the difference in 
percent seropositivity between the healthy and cancer population is less than 5 
percentage points. To identify factors associated with response persistence at each time 
point, we will classify cancer survivors as having impaired response persistence if their 
GMT is lower than ½ of the mean GMT in the age-sex-time matched healthy population. 
Logistic regression will be conducted at each time point to identify significant predictors of 
impaired response persistence. Potential predictors include sex, primary diagnosis, 
current age, age at diagnosis/HCT, prior therapy (all therapeutic exposures, including 
cumulative doses of all immunosuppressive agents), intensity of therapy (conventional 
therapy vs. HCT), time from completion of therapy, presence and extent of chronic GvHD, 
and Day 1 Quant Ig. In this exploratory sub-aim, we will also measure HPV-specific total 
immunoglobulin (total Ig) at Month 24 to better characterize the qualitative aspects of the 
HPV-specific humoral immune response.138,139  We recognize that we may not have 
sufficient power to test persistence of response to qHPV or 9vHPV vaccine; as such, this 
aim is exploratory. 
 
9.0 
DATA AND SAFETY MONITORING 
 
9.1 
Definition of Risk Level 
This is a Risk Level 3 study, because it includes a phase II clinical trial where the risks are at least 
balanced by the potential benefit to subjects and the importance of the knowledge that may result. This 
study involves open-label administration of 3 doses of the quadrivalent (for patients enrolled on or 
before 3-1-16) or nonavalent (for patients enrolled after 3-1-16) HPV vaccine. While the vaccine has not 
been studied in the targeted population of cancer survivors, and its immunogenicity and safety profile 
are unknown in this group, the vaccine is FDA-approved for administration to males and females 
between 9 and 26 years of age, including immunocompromised individuals. 
 
9.2 
Monitoring and Personnel Responsible for Monitoring 
The UAB DSMC (UAB CTMC-Clinical Trials Monitoring Committee) will serve as the safety board of 
record for this study.  
The Protocol Management Team (PMT), consisting of the co-PIs, co-investigators, CRA, protocol 
nurse, and statistician, is responsible for monitoring the data and safety of this study, including 
implementation of any stopping rules for safety and efficacy.  

 
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Data and safety will be reported to the UAB DSMC. Protocol-specific data collection will include the 
following items: Target and actual accrual by site, aggregate demographics and demographics by site, 
data completeness for Aim 1 (survey) and Aim 2 (vaccine evaluation), and the following safety 
reporting: Aim 1 (survey): % of subjects with unexpected adverse events; Aim 2 (vaccine evaluation): % 
of subjects with injection site adverse events (e.g., pain, erythema), % of subjects with systemic 
adverse events (e.g., fever, syncope, headache, hives, rashes, diarrhea), % of subjects with serious 
adverse events (e.g., life-threatening, result in persistent disability or death), % of subjects who 
discontinue vaccine related to adverse events, and number of subjects who become pregnant during 
the vaccine administration phase of the study. Adverse events will be summarized descriptively as 
frequencies and percentages by type (injection site, systemic, serious), by vaccine dose (i.e., #1, #2, 
#3), and across all vaccine doses.  The Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Biologics Evaluation and Research, September 
2007 (Tables 9.3.2, 9.3.3, and 9.3.4) will be used to assess toxicity and stopping rules (see Sections 
9.3 and 9.4 respectively). The study will utilize the Vaccine Adverse Event Reporting System (VAERS – 
www.vaers.hhs.gov) for AE reporting (see Appendix 18 for VAERS Reporting Form). For reporting 
purposes, attribution is defined as the assessment of the likelihood that an AE is caused by the 
research agent or protocol intervention. The attribution is assigned by the Principal Investigator after 
considering the clinical information, the medical history of the subject, and past experience with the 
research agent/intervention. The attribution is subject to change as follow-up information becomes 
available and it can be changed by the DSMC or by the IRB during the process of review. 
Reporting of data and safety to the DSMC will occur at the time of enrollment of 981 subjects to Aim 1, 
at the time of enrollment of 353 subjects to Aim 2, and if 2 or more cases of the same grade 3-4 toxicity 
with probable attribution that do not resolve in 72 hours are reported in separate patients enrolled on 
Aim 2 (see Section 9.4), or at least every 6 months, using the PMT report (Appendix 19). 
 
9.3  
Adverse Events 
9.3.1. Definitions 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention. 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32]  - A serious adverse event (SAE) is defined as 
any expected or unexpected adverse event that results in any of the following outcomes: 
 Death 
 Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
 A persistent or significant disability/incapacity 

 
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 A congenital anomaly/birth defect 
 Secondary malignancy, or 
 Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse). 
Unanticipated Problem (UP) – Any incident, experience or outcome that meets all three of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by 
the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
 
9.3.2. Reporting of Unanticipated Problems and Adverse Events: 
Unanticipated Problems (UP): Unanticipated problems must be reported by the study coordinating 
center site personnel to the UAB DSMC and IRB within 5 calendar days of receiving notification 
from 
the 
participating 
sites 
according 
to 
definitions 
and 
guidelines 
at 
http://www.uab.edu/policies/content/Pages/UAB‐RA‐PRO‐0000293.aspx. Any unanticipated problem that 
occurs during the study conduct will be reported to the DSMC and the central (UAB) IRB. 
Serious Adverse Events (SAE) - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and guidelines 
at http://www.uab.edu/policies/content/Pages/UAB‐RA‐PRO‐0000293.aspx and Table 9.3.1 below.  
Those SAEs that require expedited reporting will be submitted via fax or electronic transmission. 
Adverse Events (AE) - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems will be reported only in the protocol 
continuation reports and PMT report (see Table 9.3.1 below). 
 
 
 
 

 
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Table 9.3.1. Adverse Event and Unanticipated Problem Reporting Timelines for the DSMC and IRB 
 
Required Reporting Timeframe to DSMC  
Attribution 
UNEXPECTED 
EXPECTED 
 
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 
 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar  days 
No reporting required* 
Unlikely, Unrelated 
No reporting required* 
No reporting required* 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
5 calendar days 
5 calendar days 
 
Grade 1 and 2 AND resulting in hospitalization# 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
*Such events are not required to be reported to the DSMC.  These events should be included with the SAE/AE 
summary provided to the DSMC in the PMT reports and to the IRB in the Annual Continuation reports. 
 
# Hospitalization = Unplanned admission equal to or greater than 24 hours 
 
Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
9.3.2.1. Additional reporting requirements 
 
9.3.2.1.1. Expedited reporting by participating sites. All participating sites will submit Adverse 
Events/Research-Related Problems Reporting Forms (AERF - Appendix 15) to the coordinating center 
when reporting Adverse Events or Unanticipated Problems requiring expedited reporting (i.e., requiring 
reporting to the DSMC and/or central [UAB] IRB more frequently than every 6 months) and the events 
will be reported by the study coordinating center. Adverse events that do not require expedited 
reporting will be reported by the participating sites to the coordinating center on a quarterly basis and 
will be reported in aggregate at the time of protocol continuation reports and PMT report (per the 
requirements outlined in Table 9.3.1).    

 
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9.3.2.1.2. Additional reporting to be done by the study coordinating center.  
 
Merck Sharp & Dohme Corp. (Attn: Worldwide Product Safety; FAX 215 993-1220) will be provided with 
copies of all serious adverse experiences, regardless of causality, within two working days.  
Additionally, any pregnancy occurring in association with use of a Merck Product will be reported to 
Merck Sharp & Dohme Corp. (Attn: Worldwide Product Safety; FAX 215-993-1220).  
 
To the extent required by applicable law, a copy of all 15 Day Reports  and Annual Progress Reports 
will be submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices 
agency (PMDA) or other local regulators by the investigator. This submission will be cross referenced 
according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the 
time of submission.  Additionally, a copy of these reports will be submitted to Merck Sharp & Dohme 
Corp. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
The coordinating center will also notify VAERS (www.vaers.hhs.gov) within 2 business days of 
receiving notification from the participating sites of any vaccine-related Adverse Event requiring 
expedited reporting (as defined above and in Table 9.3.1).  
 
A summary table of potential adverse events and adverse event reporting requirements for this study is 
included in Appendix 20. 
 
 
 
9.3.3.  Toxicity Management 
Any symptoms that occur will be managed according to good medical practices and clinical judgment of 
the site investigator. Toxicities related to the vaccine will be monitored using the Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for Biologics 
Evaluation and Research, September 2007 (Tables 9.3.2, 9.3.3, and 9.3.4). Toxicities will generally be 
considered potentially vaccine-associated if their onset occurs within 7 days after receipt of a study 
vaccine dose. If evaluated, the toxicity should be documented on the Adverse Events/Research-
Related Problems Reporting Form (AERF) within 2 working days of the evaluation. All subjects will be 
followed for the reporting of toxicities for 14 days following each vaccine dose. In addition, any severe 
or unexplained toxicity occurring after the 14 days of follow-up brought to the attention of the 
investigator will be evaluated for possible vaccine-association, and documented on the AERF within 2 
working days of the evaluation if found to be possibly, probably, or definitely related to the vaccine. 
Toxicities will not be considered vaccine-associated AEs if clearly recognized alternative etiologies are 
identified. Alternative explanations for clinical abnormalities must be sought prior to study vaccine 
discontinuation. 
Therapeutic interventions that may interfere with evaluation of the safety/tolerability of the vaccine 
should be avoided during the indicated timeframes unless medically necessary. These include a) any 
live attenuated vaccine administered within 28 days of any HPV vaccine dose; b) any subunit or killed 
vaccines (e.g., influenza, pneumococcal, antigen injections for allergy treatment) within 14 days of any 
HPV vaccine dose. 
General toxicity management: 
- If a subject develops a persistent > Grade 3 clinical toxicity, the subject will not be permitted to 
participate in this study until the toxicity has resolved to < Grade 1. 
- All > Grade 3 clinical toxicities occurring within 14 days following any vaccine dose, and their 

 
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proposed management, must be reported to the coordinating center using the AERF within 2 business 
days of the site’s awareness of the event, regardless of relatedness. Clinical toxicities not identified in 
Tables 9.3.2, 9.3.3, and 9.3.4 should be graded according to the Common Terminology Criteria for 
Adverse Events v4.0 (http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx). 
9.3.4. Pregnancy: Sexually active females of childbearing potential will be instructed to use 
contraception throughout the 6-month period when the vaccine is administered. Participants will be 
queried prior to each dose to determine if there is a possibility of pregnancy; if so, a pregnancy test 
(urine or blood as per local institutional preference) will be obtained prior to vaccine administration. If 
positive, the participant will be withdrawn from receiving further vaccine on the study. Any pregnancy 
occurring during the vaccine phase of the study (i.e., Vaccine Day 1 through 4 weeks after all 3 vaccine 
doses have been administered) will be reported to the study coordinating center. There are no data 
indicating an association of adverse pregnancy outcomes or adverse effects of the developing fetus 
with the vaccine. Thus, if a vaccine dose is administered during pregnancy, no intervention is indicated 
other than withholding further doses and reporting as specified. The patient should be followed by the 
participating site for pregnancy outcome data (e.g., termination, miscarriage, pre-term or full-term 
delivery, fetal death/stillbirth, complications, single vs multiple birth, condition of infant(s), presence of 
congenital anomalies, etc.), which should be reported to the study coordinating center when available. 
The study coordinating center will report the pregnancy, and later the pregnancy outcome (with de-
identified subject information only), as follows: qHPV vaccine recipients (patients enrolled on or 
before 3-1-16): Merck Worldwide Product Safety; Fax 215-993-1220. 9vHPV vaccine recipients 
(patients enrolled after 3-1-16): Gardasil ®9 Pregnancy Registry maintained by Merck (URL: 
www.merckpregnancyregistries.com/gardasil9; Phone: 1-800-986-8999; Fax 215-993-1220) and Merck 
Worldwide Product Safety; Fax 215-993-1220.   
 
9.3.5. Grading of Clinical Abnormalities 
The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials, U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Biologics Evaluation and Research, September 2007 (Tables 9.3.2, 9.3.3, and 9.3.4) will be used to 
assess toxicity and stopping rules outlined in Sections 9.3 and 9.4 respectively.  
 
Table 9.3.2.  Local Injection Site Reaction 
 
Local Reaction to 
Injectable Product 
Mild  
(Grade 1) 
Moderate
 (Grade 2) 
Severe
 (Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Pain 
Does not interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
>24 hours or interferes 
with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Emergency room (ER) 
visit or hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant discomfort 
at rest 
ER visit or hospitalization 
Erythema/Redness* 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or exfoliative 
dermatitis 
Induration/Swelling** 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with activity 
>10 cm or prevents 
daily activity 
Necrosis 
*   In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as 
a continuous variable. 
**  Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 

 
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Table 9.3.3. Systemic Reaction -  Vital Signs 
 
Vital Signs* 
Mild
(Grade 1) 
Moderate
(Grade 2) 
Severe
(Grade 3) 
Potentially Life 
Threatening (Grade 4) 
Fever (C)** 
           (F)** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9  
101.2 – 102.0 
39.0 – 40 
102.1 - 104 
>40 
>104 
Tachycardia – beats per minute 
101-115 
116 – 130 
>130 
ER visit or hospitalization 
for arrhythmia 
Bradycardia – beats per minute*** 
50 – 54 
45 – 49 
<45 
ER visit or hospitalization 
for arrhythmia 
Hypertension (systolic) – mmHg 
141 – 150 
151 – 155 
>155 
ER visit or hospitalization 
for malignant hypertension 
Hypertension (diastolic) – mmHg 
91 – 95 
96 – 100 
>100 
ER visit or hospitalization 
for malignant hypertension 
Hypotension (systolic) – mmHg 
85 – 89 
80 – 84 
<80 
ER visit or hospitalization 
for hypotensive shock 
Respiratory Rate ( breaths per minute) 
17 – 20 
21 – 25 
>25 
Intubation 
*   Subject should be at rest for all vital sign measurements. 
**  Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 and 100 beats per minutes. Use clinical judgment when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes. 
 
Table 9.3.4. Systemic Reaction – General 
 
Systemic (General) 
Mild (Grade 1) 
Moderate (Grade 2)
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference with 
activity or 1 – 2 
episodes/24 hours 
Some interference with 
activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 – 3 loose stools or 
<400 gms/24 hours 
4 – 5 stools or 400 – 
800 grams/24 hours 
6 or more watery 
stools or >800 
gms/24 hours or 
requires outpatient 
IV hydration 
 
ER visit or 
hospitalization 
Headache 
No interference with 
activity 
Repeated use of non-
narcotic pain reliever 
>24 hours or some 
interference with 
activity 
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity 
ER visit or 
hospitalization 
Fatigue 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
 
ER visit or 
hospitalization 
Myalgia 
No interference with 
activity 
Some interference with 
activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference with 
activity 
Some interference with 
activity not requiring 
medical intervention 
Prevents daily 
activity and requires 
medical intervention 
ER visit or 
hospitalization 
 
From: Food and Drug Administration. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Biologics Evaluation and Research, September 2007. 

 
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9.4 
Study Stopping Rules 
 
If two or more cases of the same grade 3-4 toxicity with probable attribution that do not resolve in 72 
hours are reported in separate patients, accrual will be held until further review by the UAB Clinical 
Trials Monitoring Committee to determine whether or not the study should be stopped based on the 
data available at that time. 
 

 
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APPENDICES 
 
Appendix 
Content 
1 
2 
3 
 
 
 
 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
 
 
Medical Record Review Form 
Intensity of Treatment Rating Scale 2.0 
HPV Vaccination Survey 
- Parent/caregiver version – male patient (age 9-17) 
- Parent/caregiver version – female patient (age 9-17) 
- Patient version - male (age 18-26) 
- Patient version – female (age 18-26) 
Thank You Letter – Survey 
Sample Patient Recruitment Materials 
Appointment Reminder Letter - Vaccine 
Children’s Oncology Group Cancer Treatment Summary Form  
Vaccine Visit Form 
Month 7 Visit Form (Follow-Up #1) 
Premature Study Discontinuation (PSD) Form 
Blood Specimen Collection, Processing, Storage, and Shipping Guidelines 
Sample CDC Teaching Tools: Human Papillomavirus 
Sample VIS: HPV vaccine 
Vaccine Report Card (7- and 14-day versions) 
Adverse Events/Research-Related Problems Reporting Form (AERF) 
Month 24 Visit Form (Follow-Up #2) 
Thank You Letter - Vaccine 
VAERS Reporting Form 
PMT Report 
Summary of Potential Adverse Events/Research-Related Problems Reporting 
Requirements