Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study

Abstract

IntroductionHuman papillomaviruses (HPVs) are responsible for one-third of all cancers caused by infections. Most HPV studies focus on chronic infections and cancers, and we know little about the early stages of the infection. Our main objective is to better understand the course and natural history of cervical HPV infections in healthy, unvaccinated and vaccinated, young women, by characterising the dynamics of various infection-related populations (virus, epithelial cells, vaginal microbiota and immune effectors). Another objective is to analyse HPV diversity within hosts, and in the study population, in relation to co-factors (lifestyle characteristics, vaccination status, vaginal microbiota, human genetics).Methods and analysisThe PAPCLEAR study is a single center longitudinal study following 150 women, aged 18–25 years, for up to 2 years. Visits occur every 2 or 4 months (depending on HPV status) during which several variables are measured, such as behaviours (via questionnaires), vaginal pH, HPV presence and viral load (via qPCR), local concentrations of cytokines (via MesoScale Discovery technology) and immune cells (via flow cytometry). Additional analyses are outsourced, such as titration of circulating anti-HPV antibodies, vaginal microbiota sequencing (16S and ITS1 loci) and human genotyping. To increase the statistical power of the epidemiological arm of the study, an additional 150 women are screened cross-sectionally. Finally, to maximise the resolution of the time series, participants are asked to perform weekly self-samples at home. Statistical analyses will involve classical tools in epidemiology, genomics and virus kinetics, and will be performed or coordinated by the Centre National de la Recherche Scientifique (CNRS) in Montpellier.Ethics and disseminationThis study has been approved by the Comité de Protection des Personnes Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016–488) and by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007). Results will be published in preprint servers, peer-reviewed journals and disseminated through conferences.Trial registration numberNCT02946346; Pre-results.

HPV cervical infections and serological status in vaccinated and unvaccinated women

“…Analysing the interaction between HPVs and the immune response (e.g. cytokines, immune cells) via longitudinal follow-up may help understand this epidemiological finding [11].…”

“…Here, we analyse data from the inclusion visit (Visit 1) and the result visit (Visit 2) for N = 149 participants (one was removed after realising she did not meet one of the inclusion criteria). The detailed protocol of the study is described elsewhere [11]. In short, during the inclusion visit, a gynaecologist or mid-wife performed a cervical smear in PerservCyt medium for squamous intraepithelial screening via liquid cytology.…”

Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation

“…Clinically, after a primary infection, the manifestations of infection are not perceptible early; this makes acute HPV infection very poorly documented. The anti-HPV antibody kinetics have not yet been determined because the prodromes associated with HPV acute infection occur very late after infection; however, studies are underway ( 118 ). Moreover, from available data, about 98% of women are exposed to HPV infection, and about 30% ( 119 ) to 40% ( 120 ) are susceptible to infection.…”

Cytokine response following perturbation of the cervicovaginal milieu during HPV genital infection

“…17–20 The challenges are numerous and at various scales, ranging from cellular heterogeneity of solid tissue and non-detectability, to demographic and behavioral determinants. The PAPCLEAR cohort 12 had been set up prospectively to yield a fairly homogeneous study population in terms of age, sexual activity and thus exposure history prior to enrollment. Incidentally, it also turned out to be well-balanced in terms of HPV infections such that it constitutes an opportunity to measure local immune mediators, such as cytokines, taking also into account covariates pertaining to microbial perturbations of the cervicovaginal environment.…”