GARDASIL 9: 3 Dose vs. 2 Dose With Delayed 3rd Dose
Phase: PHASE4
Conditions: Immunization, Efficacy, Human Papilloma Virus
Sponsor: The University of Texas Medical Branch, Galveston

 
 
 
 
GARDASIL 9: 3-Dose vs. 2-Dose with Delayed 3rd-Dose 
 
 
 
 
 
 
Abbey Berenson, MD, PhD, Professor 
 
OB/GYN, University of Texas Medical Branch 
 
CPRIT Funding ID # RP190022  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Cancer Prevention & Research Institute of Texas 
PO Box 12097, Austin, TX 78711 
Version 17 (February 13, 2025) 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
0.0 
Signature Page 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Study Product Description 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
8.0 
Study Withdrawal/Discontinuation 
9.0 
Statistical Considerations 
10.0 
Ethical Considerations and Privacy/Confidentiality Issues 
11.0 
Record Retention 
12.0 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Cancer Prevention & Research Institute of Texas 
PO Box 12097, Austin, TX 78711 
Version 17 (February 13, 2025) 
 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator:* 
 
 
Signed: 
 
 
 Date: 
 
 
 
Name, Title 
 
 
 
 
 
* The protocol should be signed by the local investigator who is responsible for the study 
implementation at his/her specific site; i.e., if Investigational New Drug study, the individual who 
signs the Form FDA 1572. 
 
 
 
 
 
 

 
Cancer Prevention & Research Institute of Texas 
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1.0 
Background 
 
The human papillomavirus (HPV) causes most cases of cervical, anal, vaginal, oropharyngeal, 
and penile cancers, and many vulvar cancers.1 Overall, 40% of women and 45% of men in the US 
have a genital HPV infection at any given time and more than 38,000 people in the US are 
diagnosed with an HPV-related cancer each year.2,3 Effective vaccines to prevent infection are 
available and widespread uptake could have dramatic effects. A systematic review determined 
that if 80% of girls and boys in high-income countries such as the US were vaccinated, then 
transmission of oncogenic HPV types could actually be eliminated.4 To achieve this, the 
Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination against 
HPV of all adolescents at 11–12 years of age.5  
 
However, only 34% of 13–17 year-old males and females in the US completed all required doses 
by 2016.6 For those not vaccinated at a younger age, catch-up vaccination can still occur through 
age 26.5 Few unvaccinated individuals over 17 years of age, however, seek out and obtain all 
required doses of the HPV vaccine. This low completion rate among older adolescents and young 
adults is concerning as they could derive substantial benefit from the vaccine even if they have 
already initiated sexual activity. This is a critical group to immunize as increasing vaccination 
rates among older adolescents and young adults will decrease the amount of time required to 
achieve herd immunity in the US.7  
 
One possible reason for the low completion rate among older adolescents and young adults is that 
finishing the series requires an additional dose if the first dose happens after age 14. When the 
HPV vaccine was first introduced 12 years ago, 3 doses were recommended for everyone. After a 
study demonstrated that a 2-dose schedule of Gardasil 9 elicited a sufficient antibody response in 
9–14 year olds, the recommendation was changed to only 2 doses for adolescents who began 
before 15 years old.5,8,9 However, 3 doses are still recommended for older patients as 
immunogenicity data are not available for a 2-dose schedule in this population.5  
 
To explore the immunogenicity of a 2-dose schedule in 15–26 year olds, the PI has already 
requested and obtained an exemption from the Food and Drug Administration’s Investigational 
New Drug requirements. On May 9, 2017 she was informed she could conduct the study. She has 
arranged for a laboratory at the Centers for Disease Control and Prevention (CDC) to perform all 
assays (see letter from CDC.) Third, she has obtained permission from the president of UTMB to 
conduct the trial in UTMB clinics (see letter from Dr. David Callender of UTMB).  
 
This study is testing an alternative dosing schedule of a vaccine currently given as standard of 
care. Actually, it is not uncommon for patients to receive one or more doses later than the 
recommended dosing schedule due to transportation issues, missed appointments, scheduling 
issues, etc. In these instances, it is recommended that patients of all ages and dosing schedules 
receive the vaccine at the next available opportunity as part of standard of care. Thus, this study is 
similar to standard care and presents minimal risks to participants.  
 
 
2.0 
Rationale and Specific Aims 
 
Hypothesis: A 2-dose schedule of the HPV vaccine administered at 0 and 6 months to males and 
females 15–26 years old will elicit a non-inferior immune response compared to 3 doses 
administered at 0, 2, and 6 months to females and males 15–26 years old.  

 
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Aim 1: Determine if a 2-dose schedule of Gardasil 9 administered at 0 and 6 months to females 
15–26 years old elicits a non-inferior type-specific antibody response to that generated in females 
15–26 years old who receive the currently recommended 3-dose schedule.  
Aim 2: Determine if a 2-dose schedule of Gardasil 9 administered at 0 and 6 months to males 15–
26 years old elicits a non-inferior type-specific antibody response to that generated in males 15–
26 years old who receive the currently recommended 3-dose schedule.  
Aim 3: Evaluate the persistence of the immune response by comparing antibody levels 6 months 
after the last dose in (a) females 15–26 years of age receiving 2 vs. 3 doses and (b) males 15–26 
years of age receiving 2 vs. 3 doses. 
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
 
1) Males and females 15–26 years old.  
2) Ability to give informed consent. All participants under 18 years of age must have the 
informed consent of a parent and must assent to participation. 
3) Has not received any prior doses of the HPV vaccine. We will ask the patient and his/her 
parent (if <18) about prior vaccination and check the state registry (Immtrac), as well as the 
UTMB electronic medical record (if previously seen at UTMB), We will check with their 
primary care provider, if feasible, for patients who are not a previously established UTMB 
patient. 
4) Identified source of funding for vaccine which may include Texas Vaccines for Children 
(VFC) program, Medicaid, the Children’s Health Insurance Plan (CHIP), Texas Healthy 
Women program, Merck Patient Assistance Program, or other public or private health 
insurance. 
5) Reliable telephone access. 
6) Participant and parent/ guardian (if <18) can read and speak either English or Spanish. 
 
Exclusion criteria: 
 
1) For females, currently pregnant or plans to become pregnant or donate eggs in next 12 
months. Sexually active females must report that they use regular birth control. All female 
subjects will be required to take a urine pregnancy test before each Gardasil 9 dose, unless it 
can be verified that she gave birth within the last week. Any subjects with positive tests at the 
initial visit will be disqualified from the study and advised to seek prenatal care. If a subject 
is pregnant when her follow-up visit window closes, she will be removed from the study. 
2) History of 6 or more lifetime sexual partners.  
3) History of any immunodeficiencies (HIV+, chemotherapy treatment, status splenectomy) or 
autoimmune disorders (lupus, thyroid disorder, psoriasis).  
4) History of bleeding or platelet disorders such as hemophilia. 
5) Currently taking medication which can suppress immune function including systemic 
corticosteroids, 
radiation 
therapy, 
cyclophosphamide, 
azathioprine, 
methotrexate, 
cyclosporine, leflunomid, TNF-alpha antagonists, monoclonal antibody therapies, or 
intravenous immunoglobulin treatment.  
6) Known allergies to any components of the vaccine, including aluminum, yeast or Benzonase.  
7) Febrile at ≥100°F in the 24 hours prior to vaccination. This will be reviewed before each 
Gardasil 9 dose.  

 
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8) Received any non-study inactive vaccines within the past 14 days or any live vaccines within 
the past 30 days. Those excluded for this reason will be re-screened under the same study 
number at a later date. 
9) Plan to move out of the Galveston/Houston area in the 13 months following study entry.  
 
4.0 
Enrollment/Randomization 
 
Recruitment:  
 
800 males and females 15–26 years of age will be recruited to participate. We will collaborate 
with physicians in pediatric, family medicine, and women’s health clinics/hospitals within the 
UTMB Health System and ask them if they will allow us to directly recruit their patients. Directly 
recruiting in the clinics will give us a place to properly store vaccine doses, vaccinate patients, 
draw blood, and prepare serum samples. Signs will be posted in the clinic informing patients 
about the study and how to enroll. Clinical personnel (eg, nurses, physicians, patient navigators) 
will also assist by asking eligible patients and parents whose medical record indicates they or 
their child are unvaccinated if they are interested in participating. If they agree, they will be 
screened using a standardized form to determine if they meet all inclusion and exclusion criteria. 
Permission will be obtained from parents to query minors in private about their sexual history. 
We will also place flyers and announcements at UTMB and advertise at non-UTMB 
college/university campuses. If necessary, we will expand our advertising to newspapers and 
social media. Flyers will be displayed in public areas in the community, including but not limited 
to schools, churches, community centers/events, and local retail establishments. Flyers will be 
sent by mail to patients whose providers have given us permission to contact them, and postcards 
or flyers will be mailed to local residents using a commercially available mailing list. Flyers will 
also be emailed/mailed to School of Nursing (SON) students at UTMB so as to inform them of 
the study and to provide contact information should they desire additional information or wish to 
enroll. Participants recruited in this way will be able to attend one of our recruitment clinics for 
study procedures. This combination of recruitment sources is needed to ensure that we will meet 
our goal of 800 participants.  
EPIC will also be used to identify eligible patients who previously indicated their interest in (and 
consent to be contacted about) participating in research projects at UTMB.  
For those who agree to participate and meet all inclusion and exclusion criteria, written informed 
consent will be obtained. For those <18 years of age, a parent/guardian will provide written 
consent and the adolescent will provide written assent. Screening and recruiting procedures will 
occur in a private space whenever available. We will devote adequate time to explain the study to 
participants and parents of minors using terminology they can understand in English or Spanish, 
when needed. Potential participants who do not meet study criteria will be directed to their 
physician or a facility that can provide the HPV vaccine to them. To increase efficiency and 
decrease patient burden, the patient record numbers of those who decline will be recorded so that 
they are not approached again in future visits. 
To clarify, a) permission to contact patients to participate was obtained from their individual 
providers and b) a waiver of consent was requested in order to pre-review patient medical records 
for eligibility to participate in this study. 
 
Randomization: 
 
After obtaining informed consent, enrolled participants will be randomized in a 1:1 ratio to either 
the 2-dose study group or the 3-dose standard care group. The UTMB Office of Biostatistics 

 
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(OBIOS) will generate the randomization scheme. The scheme will be centralized on a secure 
website to facilitate access to study personnel and eliminate selection bias. At the time that a 
participant has signed informed consent and met all eligibility criteria, study personnel will utilize 
REDCap, which has been programmed to randomize patients as described above, to obtain the 
study allocation information. Study personnel will be required to enter information including the 
protocol number, the site number, and participant’s age and sex to receive the participant 
identification number and study assignment for the 2-dose study group or the 3-dose standard 
care group. The PI has previously used these techniques in randomized trials conducted in UTMB 
clinics with excellent success. 
 
 
 
5.0 
Study Procedures 
 
Baseline visit:  
Project staff will follow standardized instructions to ensure unbiased and systematic data 
collection. At the baseline visit, all participants will have their blood drawn (B1; see Figure 1), 
which will be processed and later sent to the CDC lab to determine their baseline levels of 
antibodies for the 9-valent HPV types. After the blood draw, participants will be randomized to 
either the 3-dose standard care group or the 2-dose experimental group. All participants will 
receive the first dose of the HPV vaccine (V1) at this time (T0). They will be observed for up to 15 
minutes after the injection to ensure they do not have any adverse reactions to the vaccine. 
Participants will be scheduled for their next visit before leaving the clinic. 
Demographics (i.e., date of birth, age, ethnicity, race, marital status) and other information (i.e., 
height, weight, coverage, and clinic site) will be collected by project staff (via the EMR and 
subjects’ self-reports) utilizing internal-use documents previously approved by the IRB.  
An appointment reminder handout will be distributed to all subjects. It will specify when they are 
scheduled to receive follow up doses and state that they are in a clinical trial and thus should not 
receive the HPV vaccine at a regular clinic visit.  
 
 
 
 
 
 
Figure 1: Dosing and Sampling Schedule: Gray boxes indicate windows of time during which a participant 
can return for a follow-up vaccination or blood draw. The windows of time for the Month 6 vaccination (T2) 
and second blood draw (B2) overlap in the figure; however, per participant, the window for B2 will be set by T2. 
See text for details. 

 
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Follow-up visits:  
Participants will be screened during each follow-up vaccination visit to ensure they continue to 
meet those inclusion and exclusion criteria required for safe vaccination, including whether they 
have developed any new allergies to the vaccine’s components. Febrile patients or those who 
received another vaccine will be rescheduled, if possible, to do so within the allowed window for 
vaccination (±4 weeks). Study personnel may call participants who miss a scheduled visit (due to 
transportation issues or scheduling conflicts) prior to withdrawing them from the study. These 
participants will be offered a home visit to receive the time-sensitive follow up study procedure 
(i.e., vaccination, urine pregnancy test, or blood draw) that they need to stay within their allowed 
window and remain in the study. 
Participants will also be screened to determine if they received the vaccine at another location. 
Those who receive HPV vaccination doses outside the study or do not meet the study parameters 
will be excluded. In an effort to prevent doses being administered by clinic personnel outside of 
the study, the project manager will post notices at the clinic prompting nurses to check the FYI 
flags in EPIC and/or will attend one or more of the clinics’ in-service events to remind them in 
person. Which option to be utilized will be determined by each clinic manager’s preference.   
Participants who are pregnant when their follow-up visit window closes will be removed from the 
study.  
At T1, only participants in the standard 3-dose arm of the study will need to return to the clinic. 
Two months ±4 weeks after T0, 3-dose arm participants will receive a second dose of the HPV 
vaccine (V2) (Figure 1). The window of time for vaccination is similar to that used in the 2-dose 
study in 9–14 year olds by Iveresen et al.8 Participants in the experimental group will not receive 
a vaccine dose at 2 months and therefore will not need to attend clinic at T1.  
 
Six months after enrollment (T2), the third dose of Gardasil 9 (V3) will be administered to the 
standard 3-dose group and the second dose (V2) will be administered to the experimental 2-dose 
group. Participants will have a window of 6 months ±4 weeks after T0 to receive their final dose  
 
The second blood (B2) draw will be done at T3, which will be timed to 3–7 weeks after T2 when 
the final HPV dose was administered. The third and final blood draw (B3) will be done at T4, 6 
months ±4 weeks after T2. Participants will be reimbursed for their time and effort at the time of 
each blood draw: $50 for B1 and B2 and $75 for B3. After the B3 blood draw, we will administer 
the 3rd dose to participants in the 2-dose arm with their consent.  
We considered collecting blood specimens at more or less frequent intervals. Timing of collection 
of blood specimens was carefully considered, and we chose a sampling scheme that would limit 
the number of blood draws while still allowing us to achieve the aims of the study. We also 
considered collecting all information via self-report, such as vaccination history. However, the 
literature demonstrates that patients often forget whether they were vaccinated, and therefore, 
accessing past vaccination records to improve reliability of vaccination history is necessary.  
 
Handling of blood samples:  
Study personnel will verify the participant’s identity before drawing the blood sample. Five mL 
of whole blood will be collected by venipuncture and will be collected in a red-top Vacutainer 
tube using standard procedures. 
 
 

 
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Home Visits 
 
Licensed phlebotomists or medical assistants on the study staff will transport the vaccine in a 
cooler with icepacks to keep it at 0°C and 2°C. Vaccine syringes will be prepared during the 
home visit. Female participants will need a urine pregnancy test prior to vaccination; a specimen 
cup will be provided. Study staff will also bring a caddy that contains additional supplies needed 
(alcohol wipes, gauze, bandages, butterfly needles, red top tubes, small test tube rack, gloves, 
biohazard disposable bin, tourniquet, absorbent pads, thermometer, etc.). A transportable table 
and chair will also be utilized. 
With each shipment/delivery of serum aliquots to the Galveston UTMB campus, a data file with 
the Sample IDs, sample locations in the box, collection dates, and other relevant information will 
be sent to the Project Manager via e-mail. Each sample will be checked against the worksheet for 
correct sample label ID when it arrives at UTMB Galveston. Samples will not be labeled with 
participant name or identifying information in order to protect confidentiality of participants and 
to mask the study group of the participants from lab personnel. One aliquot of serum per 
participant per blood draw will be sent to the CDC for analysis. The CDC lab will record serology 
results in an Excel spreadsheet. Data will be transferred to the PI at completion of testing and 
quality control validation of results. Methods for this immunoassay have been developed by the 
CDC.10 Assays will be performed at CDC laboratory facilities.  
 
 
6.0 
Study Product Description 
 
Gardasil 9 is a non-infectious recombinant 9-valent vaccine prepared from the purified virus-like 
particles of the major capsid (L1) protein of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. 
Gardasil 9 is a vaccine indicated in girls, boys, women and men 9 through 45 years of age.   
Gardasil 9 is a sterile suspension for intramuscular administration. The dosage form is a 0.5-mL 
suspension for injection as a single-dose vial and prefilled syringe. Gardasil 9 should be 
administered as soon as possible after being removed from refrigeration. Gardasil 9 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. After thorough agitation, 
Gardasil 9 is a white, cloudy liquid. 
Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a 
previous dose of Gardasil 9 or Gardasil (4, 11), is a contraindication to the receipt of vaccine.  
 
Modification of Study Intervention/Investigational Product for a Participant 
 
The individual dose will not be modified, just the dosing schedule. If patient has a 
contraindication, no dose will be administered.  
 
Accountability Procedures for the Study Intervention/Investigational Product(s) 
 
As the intervention under study is a change in the dosing regime of an existing, recommended 
vaccine, standard procedures for distribution and storage of doses are already in place.  
 
 

 
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Assessment of Subject Compliance with Study Intervention/Investigational Product  
 
Study personnel will review the medical records of every participant prior to each dose 
administration to check for exclusion criteria including: history of immunodeficiency or 
autoimmune disorder, medication that can suppress immune function, allergies to vaccine 
components, recent receipt of non-study vaccines (within 14 days for inactive vaccines and within 
30 days for live vaccines).  
The oral or tympanic temperature of all patients will be determined before each dose of Gardasil 
9 is administered. All female subjects will be required to take a urine pregnancy test before each 
Gardasil 9 dose, unless it can be verified that she has given birth within the last week. Any 
subjects with positive tests will be disqualified from the study and advised to seek prenatal care.  
Compliance will be determined by and limited to receipt of all required doses of Gardasil 9. 
 
Concomitant Medications/Treatments 
 
All drugs and/or treatments are permitted except: 
1. Medications that suppress immune function including systemic corticosteroids, radiation 
therapy, cyclophosphamide, azathioprine, methotrexate, cyclosporine, leflunomid, TNF-alpha 
antagonists, monoclonal antibody therapies, or intravenous immunoglobulin treatment.  
2. Non-study inactive vaccines within past 14 days or live vaccines within past 30 days.  
 
 
7.0 
Adverse Events/Unanticipated Problems involving Risk  
 
The risks of this study are similar to those currently experienced in the general population, as the 
vaccine has already been approved by the FDA and is administered as a routine vaccine in males 
and females 9–26 years old. We will not be administering the vaccine to any age or sex groups 
for which it is not approved or recommended.  
 
Syncope has been reported, but is not common for the HPV vaccine. It has been reported in 8 out 
of 100,000 doses of Gardasil.11 Observation for up to 15 minutes after administration is 
recommended. Anaphylactic reactions occur in approximately 1 in 1,000,000 doses following 
administration of Gardasil.12  Appropriate medical treatment and supervision will be available in 
case this unlikely event occurs. 
 
Injection-site reactions (pain, swelling, and erythema) and oral temperature recorded for five days 
after each injection of Gardasil 9 among females 16–26 years of age during the clinical studies 
showed that any pain was reported by up to 89.9% after any dose although severe pain was 
reported by only 4.3%.13 Any swelling was reported by 40.0% with severe swelling by 3.8%. Any 
injection-site redness was reported by 34% with severe erythema by 1.6%. Fever greater than or 
equal to 102◦F was reported by 1.0%. Injection-site pruritus was reported by 5.5%. Headache 
occurred in 14.6%, pyrexia in 5.0%, nausea in 4.4% dizziness in 3.0% and fatigue in 2.3%, 
diarrhea in 1.2%, oropharyngeal pain in 1.0%, myalgia in 1.0%, upper abdominal pain in 0.7%, 
and upper respiratory tract infection in 0.1%.  
Among males 16–26 years of age receiving Gardasil 9 in clinical studies, any injection-site pain 
was reported by up to 63.4% after any dose; severe pain was reported by only 0.6%.13 Any 
swelling was reported by 20.2% with severe swelling by 1.1%. Any injection-site redness was 
reported by 20.7% with severe erythema by 0.4%. Fever greater than or equal to 102◦F was 

 
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reported by 0.6%. Injection-site pruritus was reported by 1.0%, headache by 7.3%, pyrexia by 
2.4%, nausea by 1.0%, dizziness by 1.0%, fatigue by 1.4%, and nausea by 1.0%.  
 
Across clinical studies of Gardasil 9, no deaths occurred that were assessed as vaccine-related.13  
 
In all of the clinical trials with Gardasil 9 subjects were evaluated for new medical conditions 
potentially indicative of a systemic autoimmune disorder. In total, 2.2% (351/15,703) of Gardasil 
9 recipients reported new medical conditions potentially indicative of systemic autoimmune 
disorders, which were similar to rates reported following saline placebo in historical clinical 
trials. 
 
Serious Adverse Event (SAE):  
 
An SAE is defined as an AE that meets one of the following conditions that occur within six 
weeks of vaccination and is possibly related to the vaccine: 
 
• 
Death during the period of protocol defined surveillance  
• 
Life-threatening event (defined as a subject at immediate risk of death at the time of the 
event) 
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization 
during the period of protocol defined surveillance  
• 
Results in a persistent or significant disability/incapacity 
• 
Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based 
upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an 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. 
 
All SAEs will be: 
• 
recorded on the UTMB External SAE Reporting log followed through resolution by a 
study clinician 
• 
reviewed and evaluated by a study clinician 
• 
reported to the PI, IRB, and the Vaccine Adverse Event Reporting System (VAERS) 
Serious Adverse Events 
 
Any AE which occurs within 6 weeks of vaccination considered serious by the PI or Sub 
investigator or which meets the aforementioned criteria must be submitted on the SAE form to 
the IRB in accordance with IRB policies and procedures. SAEs will also be reported to VAERS if 
possibly related to the study procedures. 
 
 
All SAEs will be followed until satisfactory resolution or until the PI,Sub investigator, or 
patient’s physician deems the event to be chronic or the patient to be stable.  
Procedures to be followed in the Event of Abnormal Laboratory Test Values or Abnormal 
Clinical Findings 
 
This study does not include any physical exams or safety laboratory tests.  

 
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Reporting Procedures 
The most common adverse reactions to Gardasil 9 are injection-site pain, injection-site swelling, 
erythema, and headaches. Study personnel will counsel subjects to report adverse reactions to 
their health care provider. All serious adverse events will be reported to the VAERS system 
(www.vaers.hhs.gov). 
  
 
8.0 
Study Withdrawal/Discontinuation 
 
Reasons for Withdrawal 
 
A study subject will be discontinued from participation in the study if any of the following occur: 
• 
Inability of study personnel to contact subjects for follow-up vaccinations 
• 
Excessive appointment cancellations (> 6) by the subject 
• 
Subject withdrawals consent to continue in the research for any reason 
• 
An unanticipated/unacceptable toxicity or adverse event (AE)  
 
 
Handling of Withdrawals 
 
There is minimal risk involved in this study. As the intervention under investigation is a reduced 
schedule of a currently used vaccine, patients who choose to withdraw will not be under any 
additional risk beyond that of normal patient care. Patients who choose to withdraw will not be 
contacted any further after notifying study staff. However, the data that they have provided up to 
the point of withdrawal will be retained and possibly used for research purposes.  
 
Termination of Study  
 
This is a minimal risk study with no foreseeable reasons for potential termination.  
 
 
 
 
9.0 
Statistical Considerations 
 
Data Analysis: We will compare the immunogenicity of the 2-dose experimental group to the 3-
dose standard care group for the corresponding sex. Participants will be required to 1) have 
received all injections of the vaccine within the predetermined time ranges, 2) have an adequate 
serum sample collected at the appropriate time intervals, and 3) be seronegative at T0 for the HPV 
type that will be analyzed. Results of this experiment will be analyzed using intention-to-treat 
analyses, as these are the standard for non-inferiority trials.  
Aim 1. Determine if a 2-dose schedule of the HPV vaccine administered at 0 and 6 
months to females 15–26 years old elicits a non-inferior type-specific antibody 
response to that generated in females 15–26 years old who receive the currently 
recommended 3-dose schedule. 
Ha: Two-dose 9-valent HPV vaccination immunogenicity levels among females are non-
inferior to 3-dose 9-valent HPV vaccination immunogenicity levels among females. 
H0: Two-dose 9-valent HPV vaccination immunogenicity levels are inferior to 3-dose 9-
valent HPV vaccination immunogenicity levels among females. 

 
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Non-inferiority of antibody GMTs at 1 month after the last dose is administered will be tested by 
developing 2-sided 95% confidence intervals for the ratio of GMTs drawn at T3, as is consistent 
with the power analyses of non-inferiority trials in the literature.8 This will be equivalent to the 
lower bound of a 1-sided 97.5% confidence interval (1-sided test, α=0.025). The ratio will be 
developed using antibody GMTs in 15–26 year old females in the 2-dose study group relative to 
antibody GMTs among 16–26-year-old females in the 3-dose standard care group. In order to 
reject the null hypothesis, the lower bound of the ratio of antibody GMTs in females who 
received 2 doses should be 0.5 or greater for each of the 9 vaccine types.17-26 If inferior 
immunogenicity is noted for any of the 9 vaccine types for the 2-dose experimental group, then 
H0 will not be rejected. 
Aim 2. Determine if a 2-dose schedule of the HPV vaccine administered at 0 and 6 
month to males 15–26 years old elicits a non-inferior type-specific antibody response 
to that generated in males 15–26 years old who receive the currently recommended 
3-dose schedule. 
Ha: Two-dose Gardasil 9 immunogenicity levels among males are non-inferior to 3-dose 
9-valent HPV vaccine immunogenicity levels among males. 
H0: Two-dose Gardasil 9 immunogenicity levels among males are inferior to 3-dose 9-
valent HPV vaccine immunogenicity levels among males. 
Non-inferiority of antibody GMTs at 1 month after the last dose is administered will be tested 
similar to the analysis plan presented for Aim 1. Two-sided 95% confidence intervals for the ratio 
of antibody GMTs drawn at T3 will be developed. The ratio will consist of antibody  
GMTs in 15–26-year-old males as compared to 15–26-year-old males in the 3-dose standard care 
group. In order to reject the null hypothesis, the lower bound of the 95% confidence interval for 
the ratio of antibody GMTs in males should be 0.5 or greater for each of the 9 vaccine-type 
HPVs. If inferior immunogenicity is noted for any of the 9 vaccine types, then H0 will not be 
rejected. 
Secondary analyses: We will also compare immunogenicity of the experimental 2-dose group in 
males with the immunogenicity of the 3-dose standard care group in females. This will allow us 
to compare the immunogenicity of the 2-dose schedule in males to that of the standard schedule 
in females, the population originally studied in efficacy trials.14,15 Non-inferiority at T3 will be 
tested by constructing 2-sided 95% confidence intervals for the ratio of antibody GMTs among 
the 2-dose 15–26-year-old male experimental group as compared to the 3-dose 15–26-year-old 
female group. To determine non-inferiority between the 2 groups, the lower bound of the ratio of 
antibody GMTs in males should be 0.5 or greater for each of the 9 vaccine types. We will also 
determine whether the level of immunogenicity for each type is above naturally-acquired 
immunity among males at T3.  
Aim 3: Evaluate the persistence of the immune response by comparing antibody 
levels 6 months after the last dose in (a) females 15–26 years of age receiving 2 vs 3 
doses and (b) males 15–26 years of age receiving 2 vs 3 doses. 
Ha: Two-dose Gardasil 9 immunogenicity levels are non-inferior to 3-dose 9-valent HPV 
vaccine immunogenicity among females and males at 6 months after the last dose. 
H0: Two-dose Gardasil 9 immunogenicity levels are inferior to 3-dose 9-valent HPV 
vaccine immunogenicity among females and males at 6 months after the last dose. 
 

 
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Non-inferiority of antibody GMTs at 6 months after T2 will be tested by constructing two-sided 
95% confidence intervals for the ratio of antibody GMTs drawn at T4. The ratios will consist of 
antibody GMTs in 15–26-year–old females in the 2-dose group as compared to 15–26-year-old 
females in the 3-dose standard care group. Likewise, ratios of antibody GMTs in 15–26-year-old 
males in the 2-dose experimental group as compared to 15–26-year-old males in the 3-dose 
standard care group will be constructed. In order to reject the null hypothesis, the lower bound of 
the 95% confidence interval for the ratio of antibody GMTs in both comparisons should be 0.5 or 
greater for each of the Gardasil 9 types. If inferior immunogenicity is noted for any HPV type for 
either sex, then H0 will not be rejected. 
 
 
 
Sample Size Justification:  
 
The sample size determined for this study takes into account the need to recruit a sufficient 
number of participants who 1) could be included in assessments for the 9 HPV types that the 
vaccine protects against, considering that some may have been exposed before baseline, and 2) to 
account for loss to follow-up. Power analysis calculations were performed using estimates from 
published clinical trials and HPV prevalence rates in the age groups that will be included in this 
study. It was estimated that up to 15% of study participants will be seropositive for 1 or more 
vaccine types.16 We then assumed an attrition rate of 15% at the 12-month follow-up point. 
 
We calculated the sample size for the hypothesis: Ha: Antibody response to 2 doses will be non-
inferior to the antibody response to 3 doses of Gardasil 9 for females (Aim 1) and males (Aim 2). 
The GMTs will be non-inferior if the true ratio between each study group (female 2-dose and 
male 2-dose) and the 3-dose standard care groups (female 3-dose and male 3-dose) are equal to 
1.2, with a standard deviation of 1.2 consistent with the power analyses conducted by a previous 
clinical trial.8 The inferiority margin was set at 0.5, which is the standard in HPV vaccine clinical 
trials17-26. The statistical criterion for non-inferiority will be determined to be null when the lower 
bound of the 97.5% confidence interval for the GMT is 0.5 or greater for any of the vaccine 
types. A sample size of 91 in each group who are naïve to at least 1 of the vaccine types is 
required to reach 90% power to detect non-inferiority of the 2-dose compared to the 3-dose 
regimen at T3. Based on estimates of 15% of the baseline samples testing seropositive for at least 
one of the types, a sample size of 108 is required in each group for comparisons of T3 antibody 
titers.  
 
We also calculated the sample size for the hypothesis: Ha: Two-dose 9-valent HPV vaccine 
immunogenicity levels are non-inferior to 3-dose Gardasil 9 immunogenicity among females and 
males at 6 months after the last dose. Between T0 and T4, we assumed an attrition rate of 15%. 
Therefore, each comparison group requires a total sample size of 128 per group to achieve at least 
90% power to determine non-inferiority of the 2-dose experimental groups compared to the 3-
dose standard care groups at T4. The total sample size required is 800. All calculations were made 
using statistical software PASS, version 15. 
 
10.0 
Ethics and the Protection of Human Subjects 
 
Discussion of risks and possible benefits of Gardasil 9 will be provided to the subjects and their 
families. Consent forms describing in detail the study interventions/products, study procedures, 
and risks will be given to the subject and written documentation of informed consent obtained 
prior to administering Gardasil 9. Consent forms will be IRB-approved and the subject will be 

 
Cancer Prevention & Research Institute of Texas 
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Version 17 (February 13, 2025) 
asked to read and review the document. Upon reviewing the document, study personnel will 
explain the research study to the subject and answer any questions that may arise. The subject 
will sign the informed consent document prior to any procedures being done specifically for the 
study. The subject may withdraw consent at any time throughout the course of the trial. A copy of 
the informed consent document will be given to subjects for their records. The rights and welfare 
of the subjects will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997).   
Privacy/Confidentiality Issues 
 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to 
the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the Principal investigator. 
Individuals authorized to view study records will be identified to the study subject on the 
informed consent but may include a study monitor or other authorized representatives of agencies 
that regulate research including representatives from the Office of Human Research Protections 
or the Institutional Review Board. Study records may also be made available for internal 
compliance reviews and quality assurance representatives. 
These individuals may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the subjects in this study. The clinical study site will permit access to such 
records. 
In accordance with the Food and Drug Administration Amendment Act of 2007 (FDAAA) and 
The International Committee of Medical Journal Editors (ICMJE) member journals trials-
registration policy as a condition for publication, this study will be registered in the public trials 
registry ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Results will 
be published to ClinicalsTrial.gov when available but will not identify individual subjects. 
 
11.0 
Record Retention 
 
The investigator shall retain records required to be maintained under 21 CFR 312.62 for a period 
of 3 years following the date the investigation is discontinued. There will be no marketing 
application for a new drug as a result of this study as the intervention of study uses an FDA-
approved vaccine.  
Consent forms that include the HIPAA Authorization will be retained for a minimum of 3 years 
from the date of the authorization.  
For pediatric subjects, records shall be maintained until 3 years after completion of the research. 
Research records will be maintained in accordance with the current version of the Texas Health 
Records Table 17-III Record Retention Schedule, Human Subject Research Records and 
Documents.   

 
Cancer Prevention & Research Institute of Texas 
PO Box 12097, Austin, TX 78711 
Version 17 (February 13, 2025) 
 
12.0 
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