Eleven years ago, on 29 August 2006, the first Human Papillomavirus (HPV) immunisation was administered in Australia. The opportunity to develop the vaccine resulted from the discovery of a linkage between HPV and cervical cancer, and an insightful funding body, the Australian Cancer Research Foundation.
In the early 1980s a research group headed by Harald Zur Hausen at the German Cancer Research institute discovered that cervical cancer was associated with infection with Human Papillomavirus (HPV). This discovery was later recognised by being awarded the Nobel Prize in Physiology or Medicine in 2008.
Subsequent careful epidemiological studies by many groups showed not only that all cervical cancer could be attributed to infection with this virus, but also that a limited subset of about 10 of the many different papillomaviruses, termed “high risk” were the culprits.
Two HPV types (HPV16 and HPV18) were responsible for about 70% of the cervical cancer burden worldwide, and also contributed to the risk of other cancers relating to the anus and genitals, and some cancers of the mouth and throat. These studies also showed that cancer was a rare consequence of persistence of infection, that infections are largely without symptoms, generally transmitted sexually, and very common.
These observations initiated a search by many research groups for vaccines to prevent HPV infection. Initial seed funding from the Australian Cancer Research Foundation helped to enable our research team at the Diamantina Institute in Queensland to achieve a breakthrough discovery and to attract more funding.
By mid-90s a technology for making a mimic of the virus, termed a virus like particle, had been shown to induce virus neutralising antibodies in animals, and was therefore a likely candidate for a vaccine.
Vaccine manufacturing companies subsequently developed methods for large scale production of the virus like particles. Early in the following decade, there were large scale clinical trials, that showed that vaccines based on these particles were safe and effective at preventing infection, and the subsequent development of cervical pre-cancer. By June 2006 the first vaccines were licensed for use, and deployment started in August 2006.
Over the past decade, HPV vaccine programs have been rolled out in many countries around the world. Australia was one of the first to adopt universal immunisation of school girls and young women, and also one of the first to add immunisation of school boys to the vaccine program. The vaccine used in Australia prevents infection with the two papillomaviruses most commonly responsible for cancer together with the two papillomaviruses that cause genital warts.
Over the past decade there has also been a dramatic reduction (over 80%) in new presentations with genital warts amongst young women and men. There has been a corresponding reduction in the presence of HPV in the cervix of young women undergoing pap smear screening for cervical cancer. These results have been achieved through immunisation of about 70% of the eligible females.
Recently, similar results have been demonstrated in immunised women in the USA, where immunisation rates are much lower. Currently vaccines are licensed for use in every country of the world that regulates vaccines. Canada, Mexico, Brazil, and most European countries now have some form of universal immunisation program, and China has recently licenced the vaccine with the intent to introduce universal immunisation, while funding from the Gates Foundation and the WHO have enabled limited demonstration and pilot programs of HPV immunisation in many countries with developing and emerging economies, including India, Bhutan, Thailand, Mexico, Kenya, Vietnam, Fiji and Vanuatu. The majority of the more than 250,000 annual deaths from cervical cancer occur in these developing economies.
Immunisation is most commonly offered to 10-12 year old girls, prior to the onset of sexual activity. Although there have been some attempts to discredit the safety, the utility, or the moral justification of the vaccine programs, they have generally proven safe and well accepted. Over 150 million doses of vaccine have been delivered worldwide to date.
One future challenge is to develop effective means of delivering universal vaccination in the countries of the developing world, where cervical cancer incidence is high and where strategies for prevention of cervical cancer are non-existent or ineffective.
Barriers to all universal immunisation programs include vaccine cost, development of infrastructure for vaccine delivery and education to raise vaccine awareness, and the HPV vaccine is no different.
The relatively high cost of the vaccine itself in the developed world, which pays for the 15 year development program, has been sharply reduced by the manufacturing companies for the developing world. A further subsidised cost is available to those countries with with annual GDP of less than US$1580 per person. Nevertheless this vaccine is expensive in comparison with others.
Further, there are few countries that routinely deliver public health measures, including immunisation, to teenage and pre-teen girls, further hindering effective delivery. Considerable education about safety, efficacy, and purpose is necessary to ensure community acceptance of universal immunisation.
The current two virus type (Cervarix, GSK – HPV16, HPV18) and four virus type (Gardasil, Merck HPV 16 , HPV 18, HPV 6 and HPV11) have proven equally effective in preventing cervical HPV infections. Gardasil also protects against genital warts. A new virus like particle vaccine (Gardasil-9) includes seven of the most common cervical cancer HPV types plus HPV6 and 11. This is now being made available and is likely to replace the others, at least in the developed world.
Alternative and potentially cheaper vaccine products, some with broader coverage against HPV types are being developed. These are made in bacteria rather than yeast or insect cells and, if effective, may replace the current technologies. However, these are still in early development and it is unlikely that they will have much impact within the next 10 years.
Over the past ten years, the original vaccine delivery schedule of three doses over six months has been shown effective in extensive clinical trials at an individual and population level. However, data from subsequent trials suggests that two vaccine doses delivered over the same period gives comparable immune responses in younger people and two doses may therefore be as effective in preventing infection.
Data on the duration and individual and population efficacy of two dose regimens will need to be gathered over the next decade. Ideally, the HPV vaccine might be given with other routine childhood vaccines to preschool children, perhaps topped up with a single booster shot in adolescence. Studies are underway to determine whether this strategy for delivery will prove effective.
Use of the current vaccines may turn out to prevent other cancers caused by HPV infection. There is particular interest in head and neck cancers, where a formal clinical trial is unlikely because of the long lag time between infection and disease.
One area of particular research interest is whether immunisation against HPV might prevent reinfection after successful treatment for HPV associated disease, and therefore avoid the need for ongoing surveillance in women treated for the infection.
The current vaccines do not cure people already infected with HPV. Mostly, current infections cure themselves, but if they don’t, then the vaccines do not diminish the future risk of cancer.
Therapeutic vaccines that might cure people of cancer or at least of persisting infection are therefore under development, with a number of strategies showing some evidence of efficacy. However, none have proven 100% effective and all are still at the stage of early phase clinical trials.
Observations from over the past ten years are that the HPV vaccines, if delivered effectively to the majority of 10-12 year old girls in the developing world from today forward, should lead to the global elimination of new cervical and other HPV associated cancers by 2050.
Article author, Professor Ian Frazer is the Chair of the Medical Research Advisory Committee at the Australian Cancer Research Foundation.
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