Transmission Reduction and Prevention With HPV Vaccination (TRAP-HPV) Study
Transmission Reduction and Prevention With HPV Vaccination (TRAP-HPV) Study
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.
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 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. This interruption in
 study visits lead to slight alterations in the timing of vaccinations, which will be adjusted
 for in the final analyses as required.

 *Due to challenges with participant recruitment, we will complete the study with 500
 participants (250 couples), as opposed to the original target of 1000 participants (500
 couples). This sample size is achievable based on current recruitment rates and will maintain
 enough statistical precision for the 2x2 factorial design of the study.

 (full protocol available upon request)
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