Cervical cancer is the second largest cause of
cancer-related death in women worldwide, and it occurs following
persistent infection, sometimes for decades, with a specific subset of human papillomavirus (HPV) types; the approximately 13 oncogenic subtypes. Prophylactic
vaccines against
HPV infections hold promise for cost-effective reductions in the incidence of
cervical cancer, but this may not be enough. Two prophylactic
HPV vaccines are presently available and both contain L1 virus-like particles (VLPs) derived from the HPV subtypes most frequently associated with
cervical cancer, HPV-16 and -18. Since the L1-VLP
vaccines can only effectively prevent
infection by the specific HPV subtype against which the
vaccine was developed,
cervical cancers caused by high-risk HPV subtypes other than HPV-16 and -18 may still occur in recipients of the current
HPV vaccines. Furthermore, HPV vaccination coverage for adolescents is insufficient in most countries and therefore even HPV-16 and -18
infections are unlikely to be fully eradicated using the existing strategies. The development of HPV therapeutic
vaccines remains essential. Many therapeutic
vaccines aimed at clearing HPV-related cervical lesions have been developed and tested in patients with HPV16-positive cervical intraepithelial lesions (CIN) or
cervical cancers. To date, definitive clinical efficacy and appropriate immunological responses have never been demonstrated for cervical
neoplasia although promising results have been reported in patients with vulvar intraepithelial
neoplasia. Here we discuss shortcomings of previous HPV therapeutic
vaccine candidates and propose a novel vaccination strategy that leverages newly gained knowledge about mucosal immunity and the induction of mucosal immune responses.