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.

Timeline

Start

2022-09-13

Primary completion

2026-12

Completion

2026-12

Publications

• Background Bosch FX, Broker TR, Forman D, Moscicki AB, Gillison ML, Doorbar J, Stern PL, Stanley M, Arbyn M, Poljak M, Cuzick J, Castle PE, Schiller JT, Markowitz LE, Fisher WA, Canfell K, Denny LA, Franco EL, Steben M, Kane MA, Schiffman M, Meijer CJ, Sankaranarayanan R, Castellsague X, Kim JJ, Brotons M, Alemany L, Albero G, Diaz M, de Sanjose S; ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Comprehensive control of human papillomavirus infections and related diseases. Vaccine. 2013 Dec 30;31 Suppl 6:G1-31. doi: 10.1016/j.vaccine.2013.10.002.
• Background Schiffman M, Doorbar J, Wentzensen N, de Sanjose S, Fakhry C, Monk BJ, Stanley MA, Franceschi S. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers. 2016 Dec 1;2:16086. doi: 10.1038/nrdp.2016.86.
• Background Castle PE, Rodriguez AC, Bowman FP, Herrero R, Schiffman M, Bratti MC, Morera LA, Schust D, Crowley-Nowick P, Hildesheim A. Comparison of ophthalmic sponges for measurements of immune markers from cervical secretions. Clin Diagn Lab Immunol. 2004 Mar;11(2):399-405. doi: 10.1128/cdli.11.2.399-405.2004.
• Background Schwarz TF, Kocken M, Petaja T, Einstein MH, Spaczynski M, Louwers JA, Pedersen C, Levin M, Zahaf T, Poncelet S, Hardt K, Descamps D, Dubin G. Correlation between levels of human papillomavirus (HPV)-16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Hum Vaccin. 2010 Dec;6(12):1054-61. doi: 10.4161/hv.6.12.13399. Epub 2010 Dec 1.
• Background Parker KH, Kemp TJ, Pan Y, Yang Z, Giuliano AR, Pinto LA. Evaluation of HPV-16 and HPV-18 specific antibody measurements in saliva collected in oral rinses and merocel(R) sponges. Vaccine. 2018 May 3;36(19):2705-2711. doi: 10.1016/j.vaccine.2018.03.034. Epub 2018 Apr 6.
• Background Dillner L, Bekassy Z, Jonsson N, Moreno-Lopez J, Blomberg J. Detection of IgA antibodies against human papillomavirus in cervical secretions from patients with cervical intraepithelial neoplasia. Int J Cancer. 1989 Jan 15;43(1):36-40. doi: 10.1002/ijc.2910430109.
• Background Wang Z, Hansson BG, Forslund O, Dillner L, Sapp M, Schiller JT, Bjerre B, Dillner J. Cervical mucus antibodies against human papillomavirus type 16, 18, and 33 capsids in relation to presence of viral DNA. J Clin Microbiol. 1996 Dec;34(12):3056-62. doi: 10.1128/jcm.34.12.3056-3062.1996.
• Background Cameron JE, Snowhite IV, Chaturvedi AK, Hagensee ME. Human papillomavirus-specific antibody status in oral fluids modestly reflects serum status in human immunodeficiency virus-positive individuals. Clin Diagn Lab Immunol. 2003 May;10(3):431-8. doi: 10.1128/cdli.10.3.431-438.2003.
• Background MacCosham A, El-Zein M, Burchell AN, Tellier PP, Coutlee F, Franco EL. Transmission reduction and prevention with HPV vaccination (TRAP-HPV) study protocol: a randomised controlled trial of the efficacy of HPV vaccination in preventing transmission of HPV infection in heterosexual couples. BMJ Open. 2020 Aug 11;10(8):e039383. doi: 10.1136/bmjopen-2020-039383.
• Background Ozbun MA. Infectious human papillomavirus type 31b: purification and infection of an immortalized human keratinocyte cell line. J Gen Virol. 2002 Nov;83(Pt 11):2753-2763. doi: 10.1099/0022-1317-83-11-2753.
• Lopez-Codony V, de Andres-Pablo A, Ferrando-Diez A, Fernandez-Montoli ME, Lopez-Querol M, Tous S, Ortega-Exposito C, Torrejon-Becerra JC, Perez Y, Ferrer-Artola A, Sole-Sedeno JM, Grau C, Ruperez B, Saumoy M, Sanchez M, Peremiquel-Trillas P, Bruni L, Alemany L, Bosch FX, Pavon MA. Assessing the reduction of viral infectivity in HPV16/18-positive women after one, two, and three doses of Gardasil-9 (RIFT): Study protocol. PLoS One. 2024 May 20;19(5):e0304080. doi: 10.1371/journal.pone.0304080. eCollection 2024.

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