In 1990, in New Zealand, and 1991, in Australia, the introduction of a National Cervical Screening program revolutionised our specialty: the incidence and mortality of invasive cervical cancer were dramatically halved in only ten years.1 The lives of up to 300 Australian and New Zealand women per year were saved, and more were spared the potential morbidity associated with treatment of invasive cervical cancer. On a worldwide scale, cervical cancer is the fourth-most common cancer in women and the second-most common cause of cancer-related death.2 There are more than 500 000 new cases and approximately 266 000 deaths from cervical cancer each year. The greatest disease burden is in less-developed regions of the world, where more than 80 per cent of cervical cancer occurs. The cost and infrastructure required for a comprehensive screening program is prohibitive in many of these countries.
We are now watching a new revolution: the introduction of the human papillomavirus (HPV) vaccine to the national immunisation schedule is expected to decrease the incidence of invasive cervical cancer further, while simultaneously having an impact on the incidence of high-grade cervical dysplasia, treatment-related sequelae, the incidence of other anogenital cancers, and the suffering associated with genital warts. It is anticipated that prophylactic HPV vaccines for types 16 and 18 administered to young women before the onset of sexual activity can prevent 70 per cent of cervical cancer cases. There is hope that this strategy will become accessible to populations where screening has not been possible, so that the worldwide incidence of cervical cancer will also fall.
Harald zur Hausen’s pioneering research in the early 1980s isolated HPV-16 DNA from 50 per cent and HPV-18 DNA from 20 per cent of cervical cancers.3 HPV DNA was similarly isolated from precursor cervical lesions. A causal link in the development of cervical cancer was hypothesised, and confirmed by further research. In 2008, zur Hausen was awarded the Nobel Prize in Medicine for his role in these discoveries that greatly increased our understanding of HPV-mediated carcinogenesis and provided the foundation for the innovation of prophylactic vaccines for cervical cancer.
Cervical cancer was the first cancer acknowledged as virtually 100 per cent attributable to an infection.4 Until recently, neither treatment techniques nor screening strategies, to any extent, utilised this knowledge.5 However, following on from zur Hausen’s crucial studies, research groups all over the world recognised that a vaccine that induced neutralising antibodies to specific ‘high-risk’ HPV genotypes could theoretically prevent cervical cancer. The challenge was to create a vaccine against a virus that provokes a relatively subdued immunological response naturally and throws up additional obstacles such as using the differentiation of epithelium to regulate its lifecycle, preventing traditional approaches to the production of virus for vaccine in vitro.6
Jian Zhou and Ian Frazer’s 1991 breakthrough was to use recombinant DNA technology to create virus-like particles (VLPs) of the recombinant HPV-16 L1 capsid protein that mimic the papillomavirus structurally and elicit high titres of neutralising antibodies.7 After filing a patent application, Zhou and Frazer licensed their technology in 1995 to a pharmaceutical company to develop a prophylactic vaccine against HPV 16, 18, 6, 11. Within three years of development and testing, the first human trials successfully took place in 1998. In 2002, the first randomised placebo-controlled trial of the efficacy of a VLP-based HPV vaccine showed 100 per cent efficacy in preventing persistent HPV infection in young, previously uninfected women.8 Further randomised, double-blind, placebo-controlled trials of both the bivalent and quadrivalent prophylactic HPV vaccines followed.9 10 Efficacy rates in preventing persistent HPV infection and associated clinical lesions were found to be extremely impressive; the vaccines were found to be safe and well-tolerated. Cost-effectiveness and health economic impact studies were of additional importance to the growing literature.
By mid-2006 the quadrivalent vaccine (Gardasil) was registered by Australia’s Therapeutic Goods Administration (TGA) and the bivalent vaccine (Cervarix) was registered in 2007. Australia was the first country in the world to introduce a government-funded universal HPV vaccination program in 2007. The initial cohort was 12–13-year-old girls, alongside a two-year catch-up program for women up to 26 years old. In 2013, 12–13-year-old boys were added to the program. New Zealand commenced a national vaccination program in 2008.
The vaccines were developed to target the two HPV genotypes that zur Hausen and international epidemiological studies11 12 had identified as causing approximately 70 per cent of cervical cancer – HPV-16 and 18. The prophylactic vaccines were actually registered by the TGA prior to the completion of extensive local epidemiological studies. However, a meta-analysis of 533 Australian cases of cervical cancers typed for HPV was published in 200813 and reported HPV-16 was present in 60.4 per cent, HPV-18 in 19.7 per cent and HPV-45 in 4.6 per cent of histologically confirmed cancers. Taking into account that 13 cancers had both HPV-16 and 18, the author surmised that the vaccine could have prevented 77.7 per cent of cervical cancers in Australian women. The same meta-analysis looked at a subset of 83 adenocarcinomas – typing demonstrated HPV-16 in 28 per cent, HPV-18 in 41 per cent, and HPV-45 in ten per cent. These regional data were consistent with the previously reported international data.
‘…we have entered a new era, where improved understanding of the pathogenesis of cervical cancer…allows us to tackle cervical cancer more cleverly.’
Given the 10–20 year latency between HPV infection and the development of cervical cancer, it will take time to demonstrate a reduction in cancer incidence owing to HPV vaccination, particularly as the early adopters have been countries with an already low incidence of invasive cervical cancer. Even now though, less than ten years after vaccination started, we have reason to be excited by the impact of the HPV vaccine on our practice. A 2011 study of first-time STI clinic attendees shows a 59 per cent drop in genital warts in vaccine-eligible women.14 The Australian Institute of Health and Welfare reports a 63 per cent drop in high-grade abnormalities by histology in women aged less than 20 years from 2007 to 2013.15 A less marked decrease is reported in women aged 20–24 years during the same period, while an increase is seen in all other screened age groups. Extrapolating from these statistics, significantly fewer young women have experienced the psychological distress associated with diagnosis and treatment of high-grade cervical lesions, as well as potential treatment-related sequelae, than in the decades before immunisation.
As with all new vaccines, a strategy for reporting adverse effects from the two prophylactic HPV vaccines has been in place since their introduction. This information, coupled with the initial safety studies, has shown that the vaccines are well-tolerated, with no increased risk of serious adverse events when compared with placebo. Local injection site discomfort, erythema and swelling are the commonest side effects. The occurrence of headache, fatigue, fever and myalgia are similar to occurrence with placebo, as is the rate of syncope. The incidence of anaphylaxis is approximately 2.6 cases per million doses, which is similar to other vaccines.
Research into the duration of the prophylactic effect of the bivalent and quadrivalent vaccines is ongoing, but seems to be sustained for at least ten years. Alternative dosing regimens have been investigated and the World Health Organization (WHO) recently changed its recommendation to a two-dose regimen for females under 15 years (0 and 6 months) based on non-inferiority studies, for reasons of cost-saving, programmatic advantages and to aid vaccine uptake.16 A third vaccine has recently been approved in the USA – a nonavalent HPV vaccine (Gardasil 9) protects against an additional five HPV types (HPV-31, 33, 45, 52, 58) and could potentially prevent up to 90 per cent of cervical cancer.
Population-based cytological cervical screening has been a powerful tool in the reduction of cervical cancer rates, but we have entered a new era, where improved understanding of the pathogenesis of cervical cancer – coupled with the research and innovation of Zhou and Frazer’s VLP technology – allows us to tackle cervical cancer more cleverly. Primary prevention with the HPV vaccines has the potential to decrease cervical cancer incidence not just in developed countries, but also on a worldwide scale. Although the principal target is cervical cancer, there will be an additional benefit of reduction of other HPV-related cancers (vulvar, vaginal, anal, oropharyngeal), genital warts and high-grade pre-invasive lesions. The stage is now set for a more refined HPV-based screening strategy that acknowledges the aetiology of cervical cancer and integrates synergistically with the preventative strategy.