Transmission Reduction and Prevention With HPV Vaccination (TRAP-HPV) Study

Phase 4

Completed

Conditions: Human Papillomavirus Infection

Interventions: Biological: Hepatitis A vaccine
Biological: HPV vaccine, Gardasil 9

Registration Number: NCT01824537

Lead Sponsor: McGill University

Brief Summary: Human papillomavirus (HPV) is a member of the Papillomaviridae family of DNA viruses that is capable of infecting humans. HPV infection can cause cancers of the cervix, vulva, vagina, and anus in women or cancers of the anus and penis in men. Two prophylactic vaccines have been proven to be highly effective in preventing the acquisition of HPV infection and the genital precancerous lesions caused by it. However, we do not know yet if a previously infected individual, once vaccinated, would be less infective to her or his sexual partner. We plan to conduct a study, called Transmission Reduction And Prevention with HPV vaccination (TRAP-HPV) study to answer this question. It will include 500 sexually active couples\* (total of 1000 individuals) in university student health clinics in Montreal (age 18-45 years). It will be a randomized placebo-controlled, double-blinded intervention trial. Study participants will be followed up to 12 months. Behavioural and biological data will be collected at the time of study enrolment, then at months 2, 4, 6, 9 and 12 post-enrolment. The results of this trial will be invaluable in informing policies regarding vaccination of women and men.

Detailed Description: Two prophylactic vaccines (Gardasil by Merck, and Cervarix by GlaxoSmithKline) have been proven in randomized controlled trials (RCT) to be highly effective in preventing infection against the target HPV types (HPV-6, 11, 16 and 18, for Gardasil, and HPV-16/18, for Cervarix) and the cervical precancerous lesions caused by them. These vaccines have shifted the paradigm of prevention and are expected to have a major impact in reducing the burden of cervical cancer and of other HPV-associated malignancies, such as vulvar, vaginal, penile, anal, and oropharyngeal cancers, as well as benign HPV-associated conditions (in the case of Gardasil), such as anogenital warts and respiratory papillomatosis. However, little is known about the extent with which vaccination may reduce transmission between sexual partners; i.e. much remains to be understood on the effects of HPV vaccine in preventing transmission of target HPV types to sexual partners of vaccinated individuals and its impact on herd immunity.

The investigators propose to conduct a placebo-controlled, double-blinded RCT to measure the impact of vaccination in preventing HPV transmission within young (age 18-45) heterosexual couples at McGill and Concordia Universities in Montreal, Canada. Individual partners in 500 couples\* will be randomized to a treatment (Gardasil 9) or a control vaccine (Avaxim, a hepatitis A vaccine). This control vaccine provides a similar health benefit incentive as HPV vaccination while preserving the scientific cogency of a "placebo" comparator. Risk factor data will be collected via computerized questionnaires at enrolment (time 0), 2, 4, 6, 9 and 12 months\*. At all time points, the investigators will measure HPV DNA infection status by polymerase chain reaction (PCR) in both partners in exfoliated penile, and oral samples from men and vaginal, oral samples from women. Assessing pre-enrolment humoral immune response to HPV infection with a competitive Luminex immunoassay (CLIA) will be done in an enrolment blood sample from all study participants.

The primary outcome will be the reduction of HPV DNA positivity for the target HPV vaccine types (types 6, 11, 16 and 18) in multiple anatomic sites in Avaxim-treated sexual partners of participants who received Gardasil 9. The investigators hypothesize that HPV vaccination is effective in reducing the risk of HPV transmission to their sexual partners. They will use the Kaplan-Meier technique and logrank tests to compare the cumulative probability of HPV infection in sexual partners of vaccinated versus unvaccinated individuals against follow-up time, and Cox proportional hazards regression to estimate the effect of vaccination and other covariates on transmission of HPV to sexual partners. Statistical analyses will follow an intention-to-treat approach but additional regression models will examine the role of several candidate determinants in mediating transmission and the protective effects. Mixed-effects models will also be used to take advantage of the repeated measurements across visits, HPV types, and anatomical sites for the same subject.

In addition to the findings on protection to unvaccinated partners, it is expected that this study will provide valuable insights as to whether protection may exist for a vaccine recipient in preventing infection in an anatomical site in which a target type has not yet established infection. These findings will generate key parameter data to inform the extent of herd immunity in cost-effectiveness models of HPV vaccination. Such models are essential to arrive at rational science-driven policies of HPV vaccination in girls and boys in Canada.

As of March 13, 2020, study visits were temporarily suspended due to the COVID-19 pandemic. With university approval, study visits were resumed as of May 26, 2020. Precautionary measures were put in place to minimize the risks related to exposure to the coronavirus. This included minimizing the number of participants present at the study site, using COVID-19 screening questionnaires prior to the visit, wearing personal protective equipment, disinfecting hands and common areas, and maintaining safe distancing. Transportation (by Taxi or Uber) or parking fees were also paid for to ensure safe distancing while traveling to the study site. The interruption in study visits due to the COVID-19 pandemic led to slight alterations in the timing of vaccinations, which will be adjusted for in the final analyses as required.

\*With the slow accrual rates exacerbated by the COVID-19 pandemic, it was estimated that the target sample would not be reached within a reasonable timeframe. Therefore, we completed the study with 188 couples, before reaching the original target of 500 couples (1000 participants) and the interim target of 250 couples (500 participants) in order to maintain the scientific value of the study. In addition, we proposed to make the fifth time point the final visit. This shortened follow-up duration affected only three couples. Such protocol amendments were approved by the Institutional Review Boards.

Published protocol is available at PMID: 32788190

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 372

Inclusion Criteria

Couple must have been in a new relationship that started no more than six months prior to study entry
Both partners plan on remaining in Montreal for at least 1 year
Plan on having continued sexual contact with partner
Be willing to comply with study procedures

Exclusion Criteria

Volunteers must not have been vaccinated against HPV-Gardasil-9 (both partners)
Any history of cervical, penile, oral or anal cancers
Being pregnant or plan on immediately becoming pregnant

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Hepatitis A vaccine	Hepatitis A vaccine	The placebo comparator will be Avaxim, by Sanofi Pasteur. This control vaccine was chosen because hepatitis A immunization provides a similar health prevention incentive as HPV vaccination to study participants while preserving the scientific cogency of a "placebo" comparator. Gardasil 9 requires administration of 3 doses, while Avaxim only requires 2 doses. For this reason, a placebo injection (saline solution) will be added in between the Avaxim vaccination regimen. Consequently, both treatment and control vaccines will have similar regimens, i.e., study entry, 2 months, and 6 months.
HPV vaccine, Gardasil 9	HPV vaccine, Gardasil 9	HPV vaccine intervention: The intervention vaccine will be Gardasil 9, a 9-valent vaccine by Merck. This vaccine was chosen because it allows for the observation of 9 HPV outcomes (HPV 6, 11, 16 and 18) (the other available vaccine, Cervarix, protects against HPVs 16 and 18, only).

Primary Outcome Measures

Name	Time	Method
HPV Incidence Rates, Expressed as Incident Infections/1000 Infection-months at Risk. These Were Calculated Separately for Females and Males Across the Four Vaccine Assignment Groups.	Up to 12 months	Participants (n=308) from new (≤6 months) heterosexual couples aged 18+ in Montreal, Canada, were randomized into 4 groups: Group 1: 40 males and 40 females; Group 2: 31 males and 31 females; Group 3: 39 males and 39 females; Group 4: 44 males and 44 females. Genital samples, collected at 0, 2, 4, 6, 9, and 12 months, were genotyped for 36 HPV types. For females and males separately within each of the 4 groups, we calculated, via time-to-event analyses, the incidence rates (and their jackknife 95% confidence intervals, CI) as the number of incident infections/1000 infection-months at risk. We used type-specific HPV infections as the unit of analysis; that is, each participant could contribute time at risk for up to the 9 vaccine-targeted (i.e., HPVs 6, 11, 16, 18, 31, 33, 45, 52, and 58) type-specific HPV-level infections. Participants contributed time at risk for incidence of type-specific HPV-level infections if they had not previously tested positive for that HPV type.

Secondary Outcome Measures