Therapeutic Human Papillomavirus (HPV) Vaccines: A Novel Approach

Abstract

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.

Keywords: E7-expressing lactobacillusbases vaccine.; HPV therapeutic vaccine; cervical mucosal immune system; mucosal vaccination.

Fig. (1)

HPV subtype distribution in cervical neoplastic lesions in Japan [18]. HPV16 and 18 are the most common subtypes found in invasive cervical cancer (ICC) but more than 40% of invasive lesions are associated with other oncogenic subtypes in Japan. HPV52 is the most common HPV subtype present among Japanese women with with normal cervical cytology [19].

Fig. (2)

Mucosal immune system in cervix. GALT is thought to act as the inductive site for cervical IELs. GALT and cervical mucosal connect through mucosa-specific T cells which express homing receptors, integrin α4β7 and/or CCR9. Integrin α4β7+ T cells can differentiate into αEβ7+ T cells upon exposure to TGF-β and expression of integrin αEβ7 facilitates retention of lymphocytes in the epithelium via interactions with E-cadherin. Integrin αEβ7 is a specific marker of IELs residing in mucosal epithelia and those cells expressing this antigen on their surface were initially educated in the gut. Oral administration of the therapeutic vaccine can stimulate directly to the inductive site. LPL: lamina propria lymphocytes.