A Study to Assess the Reduction of Human Papillomavirus (HPV) Viral Infectivity and Transmission in HPV-Positive Women After Vaccination With 9vHPV (RIFT-HPV)

Summary

This is a non-randomized, open label study to assess the reduction of Human Papillomavirus (HPV) infectivity and transmission in women positive for HPV16 and/or 18 in a cervical, oral and anal sample and vaccinated with 9vHPV/Gardasil-9™.

The primary objective of the study is to demonstrate that vaccination with a 3-dose regimen of 9vHPV will reduce viral infectivity in HPV 16/18/16+18-positive women. This objective rests upon the hypothesis that, since vaccination with 9vHPV triggers the production of type-specific HPV antibodies which are exudated to the cervical and other infected mucosae, these antibodies adhere to and neutralize newly produced HPV 16/18 viral particles also present in the mucosae, thus reducing HPV's infective capacity and transmission to sexual partners.

Secondary objectives of the study are:

* To determine HPV antibody levels before and after vaccination for each of the 9vHPV-covered HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58), to distinguish an induced antibody production due to 9vHPV vaccination from a natural response to an HPV infection (when antibody production is expected to be lower).
* To demonstrate viral infectivity reduction in HPV 16/18/16+18 after vaccination with 1-dose or 2-dose regimen of 9vHPV. Since antibody production after administration of 2 vaccine doses is not inferior to 3 doses, infectivity reduction is expected to be detected after 2 doses, and at least partially after one dose.

The main endpoint of the study is the evaluation of the HPV infective capacity in cervical, anal and oral samples from HPV 16, 18 or 16+18-positive women, using a cellular assay that models in-vitro the cervical mucosa. In brief, the specific HPV biomarker E1\^E4 is measured in HaCaT keratinocytes after being cultured with study samples and thus, exposed to HPV16/18 viral particles. A reduction in E1\^E4 expression is expected for keratinocytes exposed to samples taken after vaccination with 9vHPV, since the specific HPV antibodies also present in these samples would bind HPV viral particles and prevent infection of cultured keratinocytes.

Other endpoints included in the study are:

* Detection of antibodies against HPV types covered by 9vHPV (6/11/16/18/31/33/45/52/58) by specific immunoassays (ELISA, cLIA).
* HPV16/18 virion detection using ELISA and electronic microscopy.
* HPV DNA detection and genotyping, using Anyplex HPV28. These endpoints are performed in cervical, anal and oral samples from HPV 16, 18 or 16+18-positive women
* Titration of antibodies against HPV types covered by 9vHPV in serum samples from HPV 16, 18 or 16+18-positive women using ELISA or cLIA.

A minimum of 39 and 30 women will be enrolled in two different study population cohorts, respectively:

* RIFT-HPV 1 cohort: non-vaccinated adult women aged 35 years or older, positive for HPV16-, 18-, or double positive for 16 and 18, without lesion or with cervical intraepithelial neoplasia (CIN) 1/2 lesion eligible for conservative treatment.
* RIFT-HPV 2 cohort: non-vaccinated adult women aged 27 years or older, positive for HPV16-, 18-, or double positive for 16 and 18, with multiple cervical, vulvar and/or anal lesions, with cervical lesions eligible for conservative treatment.

Candidates to participate in the study are selected according to the HPV DNA test result in a cervical sample taken in their routine cervical cancer screening visit or in their routine gynaecological follow-up visit.

There is no control group in this study: all participants are expected to complete all the per-protocol procedures in a total of 4 study visits within an average of 7 months' duration: Visit 1/ Day1, Visit 2/Month 2, Visit 3/Month 6, and Visit 4/Month 7.

The study procedures are the following:

* Pregnancy test on a urine sample in Visit 1 (pregnant women are excluded from the study).
* Completion of a questionnaire about the participant's health status, use of oral contraception and sexual activity in Visits 1 and 4.
* Cervical, anal oral and blood sample collection Visits 1, 2 and 3 before receiving 9vHPV vaccination, and in Visit 4.
* Intramuscular administration of 9vHPV in a three-dose regimen in Visits 1, 2 and 3.

Regarding data analysis for primary objective assessment, differences in the infectivity rate before (Day 1/ Visit 1) and after vaccination with 3 doses of 9vHPV (Month 7/ Visit 4) will be compared in cervical, anal and oral samples using non-parametric Wilcoxon signed rank test. The same assessment will be done in 1- or 2-dose vaccination scenario.

Antibody production before and after vaccination will be summarized for each of the 9vHPV-covered HPV types.

Conditions

• Cervical Intraepithelial Neoplasia Grade I/ II/ III (CIN I/II/III)
• Human Papillomavirus (HPV) Infections
• High-risk HPV
• HPV-16/ 18

Interventions

BIOLOGICAL

Nonavalent HPV vaccine (9vHPV/Gardasil-9™).

Sterile suspension, 0.5 ml dose, intramuscular administration in a 3 dose-regimen (Day 1, Month 2, Month 6), prepared from the highly purified virus-like particles (VLPs) of the major capsid L1 protein from 9 HPV types: 6/11/16/18/31/33/45/52/58. 9vHPV is currently indicated in the EU in individuals from 9 years of age for the prevention of diseases caused by vaccine's 9 HPV types: genital warts (HPV6 and 11) and premalignant lesions and cancers affecting the cervix, vulva, vagina and anus (HPV16, 18, 31, 22, 45, 52 and 58). It was authorized for marketing in the EU on June 9th, 2015.

Sponsors & Collaborators

• Hospital del Mar

  collaborator OTHER

• Catalan Institute of Health

  collaborator OTHER_GOV

• Miquel Angel Pavon Ribas

  lead OTHER

Principal Investigators

• Miquel Àngel Pavón Ribas, PhD · Cancer Epidemiology Research Program (PREC), Catalan Institute of Oncology (ICO-Hospitalet)/Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain.

• Francesc Xavier Bosch José, PhD - MD · Cancer Epidemiology Research Program (PREC), Catalan Institute of Oncology (ICO-Hospitalet)/Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain.

Study Design

Allocation

NA

Purpose

PREVENTION

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-09-13

Primary Completion

2026-12-31

Completion

2026-12-31

FDA Drug

Yes

Countries

• Spain

Study Locations