Background: Semen represents a reservoir for human papillomavirus (HPV), rising concern in couples eligible for assisted reproduction techniques (ART). Humoral immunity against HPV is considered to protect from reinfection. We investigated the impact of vaccination on virus clearance in a cohort of infertile male patients showing HPV semen infection.

Methods: 179 out of 619 infertile patients, showing HPV-DNA detection in semen by FISH analysis, were enrolled. Subjects were split into 91 vaccine-sensitive (VSPs) and 88 nonvaccine-sensitive patients (NVSPs) by INNO-LiPA. 19 VSPs showed vaccine-type specific seroconvesion at recruitment. All patients underwent specific counselling. 42 seronegative VSPs were randomly assigned to receive quadrivalent vaccination in 6 months, whilst 49 VSPs, 19 seroconverted and 30 seronegative, served as controls. The prevalence of HPV-DNA semen infection and serology was studied in a follow-up of 24 months.

Results: Compared to seronegative patients, VSP seroconverted at recruitment showed absence of multiple infections and reduced prevalence of HPV semen infection at 12 (P = 0.039), 18 (P = 0.034) and 24 months (P = 0.034) of follow-up. Vaccinated VSP showed improved healing (P = 0.001 at 6 months and P < 0.001 at 12 months vs seroconverted VSP), achieving clearance in 12 months.

Discussion: Humoral immunity has a major role in healing from HPV infection. Elder ART patients with HPV semen infection may benefit by the union of both specific counselling and available prophylactic vaccination.

•We evaluated whether seroconversion in males influences HPV semen infection.•Naturally seroconverted patients showed reduced prevalence of HPV semen infection.•Naturally seroconverted patients also showed virtual absence of HPV multiple infection.•Prophylactic HPV vaccination induced clearance within 12 months from recruitment.•Seroconversion represents a key process involved in the clearance of the HPV.Available prophylactic vaccinations are considered of protective value for genital condyloma and precancerous lesions in female, but cost-effectiveness of the use of HPV vaccine in males is largely underinvestigated. HPV detection in semen is also an emerging problem in couples eligible for assisted reproduction techniques, since persistent infections are not compatible with repeated 6-months counselling-cycles to allow any spontaneous clearance of the virus in older infertile couples.In this study, we provide evidence that the development of seroconversion in human males affected by HPV infection in the genito-urinary tract, detected by HPV-DNA presence in the semen, has beneficial effects on the clearance of a viral load. Moreover, administration of prophylactic vaccination to HPV infected-seronegative patients induced seroconversion within 6 months from the first dosage administration, achieving 10 folds-higher antibody titre compared to natural seroconversion. If vaccine administration ameliorates the clearance of HPV semen infection, this could be a potential benefit to overcome fertility problems related to persistent HPV infections in males, after an obvious cost-effectiveness analysis.