There is a general consensus that immunobiology of

There is a general consensus that immunobiology of HPV clearance in course of natural infection mainly relies on cell-mediated immunity (Stanley, 2006). In this context, the role of natural humoral immunity is believed to exert minor protective effects through the neutralization of functional epitopes on the virus surface, mediating internalization into basal epithelial cells, and preventing the primary entry or re-entry of virions (Carter et al., 1996). However, this model only partially explains major epidemiological and serological differences between genders. In fact, a peak in the prevalence of HPV infection features females at the age of 20–35years, approximately at the age of sexual debut, followed by a progressive decrease with age. In males, the detection of HPV-DNA in the genital area is observed at a lower prevalence that persists almost unvaried across ages (Giuliano et al., 2010; De Vuyst et al., 2009; Klinglmair et al., 2013). On the other hand, the overall seroprevalence among females appears very low until 15years and then undergoes a progressive increase to 29.3–32.5% until early 30s and subsequent slight reduction in older ages. In contrast, seroprevalence in males remains below 3% until the age of 19, undergoing a slight increase to 12.2–13.5% until about 20 to 24years of age, after which it is stabilized (Desai et al., 2011; Markowitz et al., 2009). These data suggest that, despite neutralizing CCT251545 analogue are not always developed during a natural viral load, they cannot be considered just as a serological marker of an ongoing or previous HPV infection, but a key tool involved in the healing process. This is in agreement with early observations in humans, showing that HPV-type-specific IgG antibodies are detectable in serum during spontaneous regression of warts, presumably resulting from exposure of virions to the immune system at the time of initial infection, or due to re-infection during productive phase of the disease (Greer et al., 1995; Wikström et al., 1995). In our cohort of HPV-positive infertile men, the seroprevalence toward HPV in the group of VSP is 20.8% (19/91), a higher value compared to seroprevalence reported for the general male population (Desai et al., 2011; Markowitz et al., 2009). This is likely to be ascribable to the widely reported higher percentages of semen infection in infertile subjects compared to fertile controls, as reviewed (Foresta et al., 2015). It has to be considered that, at enrolment, patients were counselled for the management of semen infection, posing a forced condition of limited re-infection probability that favours healing (Garolla et al., 2014). In this context, seroconverted patients at recruitment showed a higher prevalence of anti-sperm antibodies compared to the seronegative ones, reflecting an active ongoing immune response in the genito-urinary tract toward virus particles bound on sperm surface (Garolla et al., 2013b). As a counterpart, seroconverted patients showed a further improved clearance and a virtual absence of multiple infections compared to seronegative, even if with low levels of significance probably due to the low sample size of the cohort, reinforcing a role for humoral immunity in healing from viral infection and re-infection. In agreement with this hypothesis, we evaluated virus clearance in patients undergoing prophylactic treatment with quadrivalent vaccine. In order to exclude any confounding effect of viral re-infection with nonvaccine-sensitive HPV types, we specifically selected patients infected by vaccine-sensitive HPV types (Malagón et al., 2012) in the vaccine arm. Surprisingly, the prevalence of HPV infection underwent a strong reduction at each time point compared to the control arm, achieving almost abrogation within 9 to 12months. Moreover, within 6months after the first administration, seroconversion was detected in the whole vaccine arm, displaying an average antibody titre 10 folds higher than patients developing natural seroconversion, coherently with previous reports (Hillman et al., 2012). In this regard, curative effects of neutralizing antibodies against recombinant self-assembled virus-like particles were early suggested in animal models (Ghim et al., 2000; Suzich et al., 1995). These studies showed that protection from oral canine papillomavirus infection was provided by passive transfer of hyperimmune IgG collected from regressor animals, supporting a role for systemic humoral immunity in healing from oral papillomas (Ghim et al., 2000; Suzich et al., 1995). Furthermore recent data from mammalian models, assessing passive immunization with sera from animals immunized with the commercially available vaccines, showed that anti-HPV antibodies are protective even at low titres (Day et al., 2010). This evidence is of particular importance, accounting for the efficiency of cross-protecting anti-HPV antibodies toward non-vaccine types, despite they are generally under-represented compared to vaccine type ones. There is a general debate about the role of HPV on sperm quality (Foresta et al., 2015; Golob et al., 2014). In this regard, a main limitation of the present study is the lack of the investigation on the impact of HPV on sperm quality over the 2years study. We previously reported that the strict relationship among HPV semen infection, detection of anti-sperm antibodies and impaired sperm motility relies on an actual local immune response toward HPV particles bound to sperm surface (Garolla et al., 2013b, 2014). Accordingly, healing from viral infection was accompanied by a progressive improvement of both the prevalence of anti-sperm antibodies and sperm motility. If vaccination boosts the clearance of HPV by arousing local immune response in the genito-urinary tract, a temporary increase of the anti-sperm antibodies and consistent reduction of sperm motility should be expected, followed by a global improvement of sperm parameters at the achievement of clearance. However further studies will add further insight on this issue.