Human papillomavirus is a leading cause of cervical cancer

Chronic viral infections are responsible for up to 12% of cancers worldwide, with human papillomaviruses (HPV), a common sexually transmitted infection, contributing to 5.2% of human malignancy. The human papillomavirus infection has been well established as a causal agent for cervical cancer.

Cancer of the cervix uteri is the second most common cancer among women today. In 2008, an estimated 529,828 new cases of cervical cancer were reported, resulting in 275,128 deaths.

HPV16 and HPV 18 account for 71% of invasive cervical cancers today, whereas HPV16, 18, 31, 33, 35, 45, 52, and 58 account for more than 90% of cases. Furthermore, it is causally associated with a proportion of anal, penile, oropharangeal, vaginal and vulval cancers, accounting for 97,215 non-cervical cancer cases among men and women.

With the rising trends of oropharangeal, anal and tonsillar cancers, the non-cervical-related cancers are projected to rise. But the causal role that HPV plays for a significant proportion of cancer is its Achilles heel.

How human papillomavirus vaccines work to control infection

The most effective control of viral infections is prophylactic vaccination. The development of prophylactic HPV vaccines is one of the scientific triumphs of the past 20 years. The overarching aim of HPV vaccination is to eliminate cervical cancer and its effects on women, their families, community and country.

The current HPV prophylactic vaccine is based on L1 capsid proteins, which pose no infection risk. In essence, the vaccine simulates ‘L1 viraemia’, resulting in L1-specific immune responses being generated. In vaccinees, the systemic antibody levels are 50 times higher than after natural infection.

Immunisation with HPV virus-like particles predominantly produces type-specific, virus-neutralising antibodies, although some cross-protection against other related HPV types is observed.

The current assumption is that the protection afforded by these vaccines is mediated by the neutralising antibodies that are effective in preventing HPV particles from infecting the basal keratinocyte. This prohibits the establishment of a productive life-cycle by the virus and hence prevents infection.

Despite its effectiveness, no immunological measurements (including antibody levels) can be correlated to protection. Prophylactic vaccines are most effective when given before exposure to HPV, hence the recommendation of vaccinating adolescents.

It is important for clinicians to understand that these vaccines are not meant to be used to treat women with existing cervical intraepithelial neoplasia. More comprehensive discussions on the mechanisms of HPV vaccination can be found in Chapter 1.

How human papillomavirus vaccines work to control infection

The most effective control of viral infections is prophylactic vaccination. The development of prophylactic HPV vaccines is one of the scientific triumphs of the past 20 years. The overarching aim of HPV vaccination is to eliminate cervical cancer and its effects on women, their families, community and country.

The current HPV prophylactic vaccine is based on L1 capsid proteins, which pose no infection risk. In essence, the vaccine simulates ‘L1 viraemia’, resulting in L1-specific immune responses being generated. In vaccinees, the systemic antibody levels are 50 times higher than after natural infection.

Immunisation with HPV virus-like particles predominantly produces type-specific, virus-neutralising antibodies, although some cross-protection against other related HPV types is observed.

The current assumption is that the protection afforded by these vaccines is mediated by the neutralising antibodies that are effective in preventing HPV particles from infecting the basal keratinocyte. This prohibits the establishment of a productive life-cycle by the virus and hence prevents infection.

Despite its effectiveness, no immunological measurements (including antibody levels) can be correlated to protection. Prophylactic vaccines are most effective when given before exposure to HPV, hence the recommendation of vaccinating adolescents.

It is important for clinicians to understand that these vaccines are not meant to be used to treat women with existing cervical intraepithelial neoplasia. More comprehensive discussions on the mechanisms of HPV vaccination can be found in Chapter 1.

Global uptake of human papillomavirus vaccines

Two prophylactic HPV vaccines are currently licensed: a quadrivalent (Gardasil ^® ) and a bivalent (Cervarix™) vaccine. Both vaccines have been shown to be immunogenic, safe, and highly effective in preventing persistent infection and pre-cancerous lesions in women.

In addition, the quadrivalent vaccine has also been shown to prevent other premalignant conditions of the anogenital area caused by HPV16 and 18, genital warts and persistent infection in men and women.

To date, immunogenicity of the bivalent vaccine has been demonstrated up to 8.4 years. Model predictions based on conservative mathematical assumptions suggests that protection will last up to 20 years. This can be supported by observations from the smallpox and hepatitis B vaccine. Therefore, robust and reassuring data on safety, efficacy and duration of protection are available for currently available prophylactic vaccines.

Since its approval by the US Food and Drug Administration in 2006, the quadrivalent vaccine has been licensed in more than 109 countries worldwide, whereas the bivalent vaccine has been licensed in 64 countries since its introduction in 2007.

In the European Union, as of July 2010, 18 countries have incorporated a national HPV vaccination programme. Austria was the first country to initiate this in 2006, and the Netherlands, Latvia and Slovenia started their national immunisation programmes in 2009.

Coverage for routine vaccination with three doses varied between 17% and 81% in 2010. Three countries reached a vaccination coverage between 17% and 30% (France, Luxemburg and Norway), two at 56% and 58% (Denmark and Italy), and two at 80% and 81% (Portugal and the UK).

In South-East Asia, Malaysia is the first country to offer all 13-year-old girls free HPV vaccinations as part of a government-funded ,school-based immunisation programme.

In Australia, an excellent uptake of the quadrivalent vaccine has been reported since its introduction in July 2007. This resulted in a precipitous drop in the frequency of genital warts in young Australian women within 2 years. This drop was attributed to the high vaccine coverage. It is hoped that this short-term outcome of HPV vaccinations will be reflected in similar reductions of HPV-related malignancies in the longer term.

As these two licensed vaccines are projected to prevent cancers attributed to HPV16 and HPV 18, opportunities still exist for the pharmaceutical industry to develop a second-generation polyvalent HPV vaccine. With population trends indicating a rise in HPV infections and HPV-related cancers, HPV vaccination is expected to have a greater effect than merely preventing cervical cancer alone.

As with all modern vaccines, the current price of the HPV vaccine remains high, and this precludes its introduction into public-sector programmes in most developing countries, where the benefit of the vaccine will be maximal. It is expected, however, that the price of the vaccine will fall over time, and vaccine manufacturers have stated that they are willing to tier prices for developing countries.

Barriers to human papillomavirus vaccination in resource-constrained countries

Women living in poverty are willing to vaccinate their children, recent studies show, if recommended by their healthcare provider. This is despite having limited knowledge of issues around HPV and cervical cancer. These studies also highlight the gaps in education and access to healthcare.

The observations and lessons learned from efforts to curb the HIV and AIDS epidemic provide policy makers and stakeholders with further insights into the profound challenges of cervical cancer prevention.

Despite millions of dollars spent on programmes to modify behaviour, the annual incidents of HIV and sexually transmitted infections have not declined significantly. In part, this is because the approaches used in prevention presumed a degree of individual control in decision making that does not reflect the reality of women’s and girls’ circumstances in countries entrenched in economic and gender inequities.

Lack of attention paid to the critical characteristics of poverty and disadvantaged women are mirrored by the strategies that do not lead to transformation. In these circumstances, it is vital to look beyond the biology of disease and human behaviour. Interventions must aim to enhance women’s access to education, training, employment, minimise migration and, at the same time, promote gender-equitable norms.

It is now recognised that gender inequality and poverty must be addressed in order to provide quality services, whether it be improving maternal and childhood mortality or preventing genital fistula, female genital mutilation, HIV, sexually transmitted infections and cervical cancer, or making family planning more accessible. Multilevel, multi-sector and integrated strategies are needed to tackle these root problem.

Although it is assumed that the cost of HPV vaccines is the biggest hurdle of population vaccination in the developing world, equally prohibitive are social barriers and the lack of infrastructure to deliver the vaccines to the adolescent population.

For example, the cost of vaccines needs to take into account transportation and freight charges, storage at 4 °C, vaccine wastage, immunisation and administrative support. This in turn is dependent on existing facilities and infrastructure for that particular country.

For countries with a gross domestic product of less than USD 1,000 per capita, the per dose cost may need to be as low as USD 1 to 2 to make vaccination both cost-effective and affordable. Therefore, objectively defining the effect of HPV vaccination for a specific population is complex and difficult to generalise.

Making HPV16 and 18 vaccine accessible to 70% of young adolescent girls in 72 of the poorest countries, along with China, Thailand, and all of Latin America and the Caribbean, has been estimated to prevent future deaths of more than four million women over the next decade.

Experience from other universal vaccination programmes indicate that, for global HPV vaccination to affect incidence of cervical cancer, a co-ordinated strategy will most likely succeed. This should incorporate education (individuals targeted for vaccination, their parents or guardians, educators, community leaders) and innovative partnerships between organisations and individuals, without diverting resources from cervical screening.

Barriers to human papillomavirus vaccination in resourced countries

Patients and policy makers in developed countries, however, ask a different set of questions. With good access to health care, economic and quality-of-life issues are often the issues that come to the forefront.

The annual healthcare costs of HPV-related conditions in the USA was estimated to range from USD 2.25 to4.6 billion (£1.1 to 2.3 billion). In the UK, the estimated costs for national cervical cytology screening, management of abnormal and inadequate findings were £138.5 million. In addition to that, another £46.8 million was spent per annum on management costs for incident and prevalent cervical cancer cases.

Although the disease and economic burden are substantial and can be measured, the significant psycho–social and emotional effects of HPV-related disease are more difficult to quantify.

The problem with access to universal uptake of HPV vaccination in these countries is not so much the cost. For example, in the US, uptake of HPV vaccination has been reported to vary between 9.4% and 17% among young adult women. In some states, the purported interference in family life and sexual mores led to political efforts to forestall HPV vaccination programmes.

In a recent survey conducted in the US, where 80% of the respondents were fully insured and had access to healthcare, only 30% of them felt that HPV vaccination was important to them. The reasons given were the perceived lack of need and concerns about the vaccine. Geographical variation and area-level effects of poverty were also a documented phenomenon on HPV vaccine uptake in the USA.

In contrast, Denmark experienced a different set of barriers to HPV vaccination compared with the US. A significant discord was found between the intention of getting vaccinated and actually being vaccinated among the 16–26 year-old women. Cost and the lack of information on the benefits of HPV vaccination among sexually active women were the most significant barriers.

On the other hand, in British Columbia, where publicly funded school-based HPV vaccination programme exists (i.e. no financial or healthcare barriers), uptake of the vaccine was still suboptimal. Unlike the USA or Denmark, the low uptake in British Columbia was due to parental objection.

These cases exemplify the statement that ‘not all rich countries are the same…… each community within each country also differs.’

In developed countries, civil societies also have an increasingly influential role in setting vaccination policies. (Civil societies are defined as those parts of society that consists of organisations that look after people, their health and rights, excluding the government or the family.) Such groups have the capability of personalising risks and benefits, often embracing new social networking tools (e.g. Facebook, MySpace), as well as using public awareness talks and other media, to achieve their agenda.

The implementation of HPV vaccination at the European level is one example of this. Civil society advocacy at the European level supported key resolutions and white papers, which in turn informed national recommendations on cervical cancer vaccination.

This means the corollary of this is also true. Civil society organizations that oppose vaccination can similarly achieve a disproportionate voice in public discussions. These groups, as evident in Europe, can also have a negative effect on the uptake of HPV vaccination by providing an inaccurate but experiential interpretation against the vaccine.