HPV VACCINES: PROSPECTS FOR ERADICATING ANO‐GENITAL NEOPLASIA

Abstract

The ability to generate human papillomavirus (HPV) virus like particles (VLPs) by the synthesis and self‐assembly in vitro of the major virus capsid protein L1 has transformed our prospects for preventing cervical carcinoma in women. Immunisation with L1 VLPs provides type specific protection in all the animal infections so far tested. In Phase I trials in humans HPV L1 VLP vaccines are safe and highly immunogenic stimulating robust B and T cell responses and generating high titres of neutralising antibody. Phase II and Phase III trials are in progress with preliminary data suggesting that antibody levels persist at measurable levels for at least 48 months post vaccination. Phase II proof of principle efficacy trials are immensely encouraging with evidence that these vaccines protect against infection and data from Phase III trials confirms this and shows, importantly that these vaccines protect against the development of high grade intra epithelial cervical neoplasia. At present the assumption is that the protection achieved by these vaccines against incident HPV infection and HPV associated ano‐genital pathology is mediated via serum neutralising IgG. However, since there have been very few vaccine failures thus far, immune correlates of protection have not been established. The available evidence is that the immunodominant neutralising antibodies generated by L1 VLPs are type‐specific and are not cross‐neutralising although highly homologous HPV pairs share minor cross‐ neutralisation epitopes. Cross reactive and cross neutralising antibodies are generated in vaccinees but at significantly lower titres and the duration of any cross protection that might be elicited is uncertain. VLP vaccines are likely to be expensive, require a cold chain and medical or para medical personnel for delivery. Furthermore L1 vaccines must be delivered before the sexual debut to prepubertal females (or males) and social and cultural issues may be important in determining vaccine take‐up. L1 based vaccines are not protective against established infections and in post exposure HPV infection, cell mediated immunity is critical. Studies in animal papillomavirus infections suggest that immunisation with specific early proteins, particularly E1 and E2, could be effective and immunotherapies for established lesions such as ano‐genital warts and low‐grade intra‐epithelial lesions are realistic. Such vaccines are likely to be combined with immunomodulators such as cytokines in order to maximise the response. Prime/boost strategies combining DNA and/or protein and/or recombinant viruses look to have significant potential as immunotherapies for benign or low grade HPV induced disease. Immunotherapies for HPV associated high‐grade pre‐cancers and invasive cancers are problematic. There is increasing evidence that high grade CIN and invasive cervical carcinomas are characterised by an immunosuppressive cytokine milieu and dominated by regulatory T cells. To be effective immunotherapies must reverse this in favour of effective cell mediated immunity and this represents a major challenge. In order to maximise the response. Prime/boost strategies combining DNA and/or protein and/or recombinant viruses look to have significant potential as immunotherapies for benign or low grade HPV induced disease. Immunotherapies for HPV associated high‐grade pre‐cancers and invasive cancers are problematic. There is increasing evidence that high grade CIN and invasive cervical carcinomas are characterised by an immunosuppressive cytokine milieu and dominated by regulatory T cells. To be effective immunotherapies must reverse this in favour of effective cell mediated immunity and this represents a major challenge.Reference: Stanley MA Human papillomavirus vaccines Reviews in Medical Virology 2006 16 139–49