Abstract
Two licensed vaccines designed to prevent certain HPV infections are currently available (quadrivalent vaccine, Garadasil, Merck, New Jersey, USA; bivalent vaccine, Cervarix, GSK, Uxbridge, USA). They both contain viruslike particles that induce immunity against human papillomavirus (HPV) types 16 and 18, which are responsible for ~70% of cervical cancer worldwide, with the quadrivalent vaccine also including HPV types 6 and 11, the cause of nonmalignant genital warts. The principle of these prophylactic vaccines is the induction of neutralising antibodies that can intercept the virus before it can infect its target cell. Most studies have focussed on the prevention of cervical cancer as the focus of HPV vaccination and have concluded that with sufficient coverage of vaccination in adolescent girls before sexual activity, immunisation of boys would not be cost effective. However, prevention of genital warts is another matter, as the latter represents a significant burden on health care resources for both sexes. In respect of anogenital cancer, the data underwriting both vaccines’ licensing critically depended on demonstrations in stringently designed clinical trials of safety, immunogenicity and efficacy in preventing surrogate endpoints of cancer (mainly cervical cancer). Numerous studies, focussed on women aged 15–25/26 years without HPV infection, have established effective immunogenicity with virtually 100% protection against HPV 16 and 18 high-grade lesions for up 5 years for the quadrivalent vaccine and up to 6.4 years for the bivalent vaccine. Importantly, for both vaccines immuno-bridging studies have established higher levels of antibodies are induced in pre-adolescents, providing the basis for vaccination of sexually naive populations. Studies in women 15–55 years have confirmed bivalent vaccine immunogenicity and longevity of induced antibodies, whereas a recent clinical trial of the quadrivalent vaccine established immunogenicity and efficacy in women aged 24–45 years. Since naturally exposed women do not necessarily seroconvert and the induced levels may not be sufficient to provide protection against a subsequent infection, vaccination can also provide benefits in sexually active women who remain at risk of oncogenic HPV infection. Unfortunately, our knowledge of longevity of protection is still relatively limited and difficult to obtain, as it is problematic to conduct extended placebo controlled clinical trial studies especially when vaccination is available to protect against a significant proportion of HPV-associated cancer. A further complication is that the two vaccines cannot prevent all HPV driven cancer, which is associated with up to 14 oncogenic types. Ultimately, the impact on the prevention of cancer will only become apparent after more than 20 years following population-based vaccination. Studies on protection against genital warts by the quadrivalent vaccine have also shown safety, immunogenicity and 100% efficacy in per-protocol vaccinated women aged 15–26 for up to 4 years. The quadrivalent vaccine’s effectiveness in males was recently studied in a randomised trial of 4055 males aged 16 to 26 years old. The results showed that in men who were not infected by HPV types 6 and 11 at the start of the study, the quadrivalent HPV vaccine was nearly 90% effective in preventing genital warts caused by infection with HPV types 6 and 11 with 7–36 months follow-up. Simplistically, it would appear that if these vaccines were equal in their properties in preventing the disease associated with the individual vaccine HPV types (preferably 100% efficacy against the individual vaccine types) then it would be a simple matter to support the choice of the quadrivalent vaccine. The earlier licensing of the quadrivalent vaccine, plus local issues, ensured the commitment of Australia to use the quadrivalent vaccine for its national vaccination program. By contrast, both the quadrivalent and bivalent vaccines were available for comparison when the UK requested tenders for its national vaccination program and it selected the bivalent vaccine. The latter process was slightly more transparent than that used to make the decision in Australia but in each case, the available medical evidence was deemed sufficient to support the contemporaneous choices. However, the overwhelming justification for introducing HPV vaccination in both the developed and the developing world has been focussed on prevention of cancer and not genital warts. Importantly, recent data have highlighted potential differences in the properties of the two vaccines in respect of their inherent immunogenicity and cross protective efficacy against nonvaccine type infections and associated lesions with implications for the extent of potential protection against cervical cancer. The measurement of antibody levels was a necessary part of the licensing process for both vaccines but the dependency of the HPV life cycle on the differentiation of the target epithelium without any cell death limited the development of any direct assay of HPV neutralisation ex vivo. Unfortunately, the assays used to assess antibody levels induced by the two vaccines were CSIRO PUBLISHING Editorial
Published Version
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