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Frazer: Prevention of cervical cancer through vaccination

Infection with one of ten genotypes of human papillomavirus (HPV), including, in particular, HPV16 and HPV18, constitutes 5% of the global cancer burden. The major cancer caused by these viruses, cervical cancer, is a late consequence of persisting infection with HPV, as are many anogenital (vulvar, anal, penile) and oropharyngeal cancers in younger men and women. Infection with the relevant papillomaviruses is extremely common, with over 50% of young men and women acquiring asymptomatic infection within 3 years of commencing sexual activity. However, 98% of infections resolve spontaneously in individuals with a competent immune system. The genetic and environmental determinants of persisting infection are otherwise largely unknown, though there is evidence that the immune response to HPV infection is to some extent genetically determined; therefore, programmes for prevention of cervical cancer must be provided globally as a public health measure if we are to prevent approximately 250 000 deaths each year from cervical cancer.

Vaccines to prevent HPV-associated cancers, based on HPV-like particles, are produced using genetically engineered yeast or genetically modified baculovirus-infected insect cells, which express the L1 major capsid protein of HPV16 and HPV18 [Cervarix® (GlaxoSmithKline, London, UK) and Gardasil® (Sanofi Pasteur MSD, Maidenhead, UK)], and also of HPV6 and HPV11 (Gardasil®). Conformational determinants that induce virus-neutralizing antibodies require a capsomer or capsid structure. Vaccines consisting of HPV capsids are near 100% effective at preventing HPV-associated disease, provided that they are given before infection with the virus. They are generally regarded as protecting against only the HPV genotypes in the vaccine. The current vaccines therefore have the potential to prevent about 70% of cervical cancer and are now approved for clinical practice in most countries. Vaccines incorporating more HPV genotypes are in the development pipeline and have shown good efficacy in phase III clinical trials.

Universal vaccine programmes were initiated in 2006 in Australia and have succeeded in sharply reducing the burden of HPV infection and associated disease over the last 8 years. The vaccine programmes were initially instigated for only girls and young women, but have effectively reduced the burden of infection equally in young men through herd immunity, suggesting that full coverage of the entire population may not be necessary to control disease burden on a global basis. Vaccine programmes have, to varying extents, been introduced across the developed world, and the major challenge now is to achieve delivery of these vaccines to the developing world, where the majority of cervical cancer occurs and no screening programmes for prevention are available. Programmes have been initiated through Gavi (the Vaccine Alliance) to ensure affordable availability of vaccines for countries that can put programmes in place to deliver vaccines to young women before the onset of sexual activity. Roll-out in the developing world has been facilitated by data suggesting that short- to medium-term protection from infection with HPV can be achieved by two immunisations one year apart, though the longer term comparable efficacy of two- and the standard three-dose regiments is not yet established.

Immunotherapy to prevent progression to cancer for the 2% of people who cannot clear their HPV infection is highly desirable, but many clinical trials have shown that conventional vaccines do not assist in achieving clearance of infection. Studies in animal models suggest that HPV infection-induced epithelial proliferation initiates local immunosuppression, and strategies to overcome this local immune suppression are now being developed.

Conflict of interest

Professor Frazer receives royalties on HPV vaccine sales from CSL Ltd. He also consults for Admedus Vaccines developing HPV therapeutic vaccines.

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