Human papillomavirus vaccine: A boon or curse

Abstract

Cervical cancer is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime. Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions which need careful follow-up and often need excision. It was observed in a study, pre-adolescent vaccination alone reduced cancer incidence by 44% and was more effective than screening alone. A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. In April 2010, The Indian parliament's Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls.

Introduction

More than any other cancer, cervical cancer reflects striking global health inequity. Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020.¹

It is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Affecting relatively young women, it is the largest single cause of years of life lost to cancer in the developing world. The deaths of women who are in their most productive years have a devastating effect on the well-being of their families. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime.²

HPVs are nonenveloped, double-stranded DNA viruses in the family Papillomaviridae. Isolates of HPV are classified as “types,” and numbers are assigned in order of their discovery.³ Types are designated on the basis of the nucleotide sequence of specific regions of the genome. All HPVs have an 8 kb circular genome enclosed in a capsid shell composed of the major and minor capsid proteins L1 and L2, respectively.

Although the majority of infections cause no symptoms and are selflimited, persistent genital HPV infection can cause cervical cancer in women and other types of anogenital cancers and genital warts in both men and women.

Infections with low-risk types (e.g., types 6 and 11) can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. High risk HPV types act as carcinogens in the development of cervical cancer and other anogenital cancers.^4,5 High-risk types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82, can cause low-grade cervical cell abnormalities, high-grade cervical cell abnormalities that are precursors to cancer, and anogenital cancers.⁶

Need for Vaccine

Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions,⁷ which need careful follow-up and often need excision.⁸ Moreover, HPV infections that manifest as genital warts arise in 1–2% of young adults,⁹ for which treatment is expensive and painful, and recurrences are common.¹⁰ More than 35 types of HPV infect the genital tract.³ Of these, types 16 and 18 cause about 70% of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN); HPV 6 and 11 cause 90% of anogenital warts.¹⁰ A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPV-associated clinical diseases. HPV infections are not treated; treatment is directed at the HPV-associated lesions.

Condom use might reduce the risk for HPV and HPV-associated diseases (e.g., genital warts and cervical cancer). A study among newly sexually active college women demonstrated a 70% reduction in HPV infection when their partners used condoms consistently and correctly.¹¹ Abstaining from sexual activity (i.e., refraining from any genital contact with another persons) is the surest way to prevent genital HPV infection. For those who choose to be sexually active, a monogamous relationship with an uninfected partner is the strategy most likely to prevent future genital HPV infections.

The majority of cervical cancer cases and deaths can be prevented through detection of pre-cancerous changes in the cervix by cytology using the Pap test. Pap test screening includes a conventional Pap or a liquid-based cytology.¹² New options for cervical cancer prevention motivate important questions in low-income countries. Traditional cytology screening, conducted at frequent intervals and requiring multiple clinic visits for women with abnormal cytology (e.g., screening, diagnostic testing, and treatment), has been difficult to implement in India.¹³ Screening with HPV DNA testing and/or visual inspection with acetic acid (VIA) have been demonstrated to be acceptable and promising alternatives when embedded in a screening protocol that requires fewer visits^14,15 and utilises cryotherapy conducted by nurses to treat the majority of early cancer precursors. These strategies, less dependent on existing health system infrastructure and associated with greater rates of follow-up, are also expected to be cost-effective.¹⁶

Health and Economic Impact of HPV 16 and 18 Vaccination

Most recently, 2 new vaccines have been shown to be highly effective in preventing infection with HPV 16 and 18 in women without prior exposure to these types (FDA, 2006). Contemplating an HPV vaccination program adds complexity to decision making about India's national approach to cervical cancer control. The country will want to consider the burden of cervical cancer, the comparative effectiveness – and potential synergies – of vaccination and screening, the financial costs required to initiate and sustain programs, their cost-effectiveness, and the programmatic capacity and infrastructure necessary to effectively deliver a 3-dose pre-adolescent vaccine.

To provide insight to decision makers and stakeholders invested in reducing mortality from cervical cancer in India, the potential avertable burden of disease and cost-effectiveness associated with various vaccination and screening strategies should be assessed.

In a study by Diaz M et al.¹⁷ pre-adolescent vaccination alone reduced cancer incidence by 44% (range, 28–57%) and was more effective than screening alone (Fig. 1, upper panel).

Figure 1.

Effectiveness of preadolescent vaccination v/s screening.

A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone (Fig. 1, lower panel).

One vaccine (Gardasil) is a quadrivalent HPV-16/18 cervical cancer candidate vaccine that contains Virus Like Particle's (VLPs) from 2 oncogenic HPV types, HPV-16 and HPV-18, and also contains VLPs from HPV types 6 and 11, which are not involved in cervical cancer pathogenesis but are linked to benign genital warts. The second vaccine (Cervarix) is a bivalent HPV-16/18 cervical cancer candidate vaccine that contains VLPs only from the 2 oncogenic HPVtypes, HPV-16 and HPV-18. Virus like particle–based vaccines have been shown to provide near complete type-specific protection against infection with HPV types included in the vaccine in the initial years following vaccination.^18-20

Given that HPV infection depends on the viral genome being present in the epithelial basal cells that give rise to the cells in the higher layers of the epithelium and that the L1 protein is only expressed in these higher cell layers, it is not clear whether the vaccine induced immune response directed against L1 would have curative potential among infected individuals.²¹ Most HPV infections, regardless of type, clear spontaneously, typically within 6 months to 2 y²² Risk of progression to in situ disease and invasive cancer is highest among the small subset of women with persistent infections beyond this period.²³

Understanding whether vaccination provides any therapeutic benefit to infected women is of importance in countries where HPV DNA testing has been incorporated into cervical cancer screening programs.^24,25 Women in such programs who test positive for HPV might want to avail themselves of the vaccine instead of waiting several months to determine whether their infections clear or opting for treatments based on excision or ablation of the cervical transformation zone where cancers arise.

Because current management protocols often involve retesting HPV positive women within months of an initial HPV-positive result before treatment decisions are made, understanding the impact of vaccination on viral clearance in the first 6 to 12 months following an initial HPV-positive result would be informative. If effective at clearing established infections, it is reasonable to expect that vaccination would work within this time frame, given the near complete rate of seroconversion and high levels of immune response observed after 1 or 2 doses of vaccine.

From a population (or public health) perspective, however, it is unclear whether, among women infected with HPV, the residual benefit of preventing infection with HPV types contained in the vaccine to which the women have not yet been exposed would be sufficient to warrant vaccination. However, since HPVs are very common viruses to which women are typically exposed in the initial months or years following sexual debut,²³ vaccination of women after they have been exposed and infected (ie, after their peak period of exposure) is likely to be of less benefit than vaccination of women prior to initial exposure.

Examination of the level of benefit provided by HPV vaccination of women who are past their peak period of exposure is currently under evaluation in several ongoing clinical efficacy trials. It is also not clear whether vaccination would benefit women with prevalent infection by increasing their immunologic resistance against reappearance (via reactivation or reinfection) with the same viral type in the future. Because HPV-infected women who clear their infection have demonstrated immune-competence to handle an established HPV infection, these women might be expected to be capable of handling subsequent infections without the need for vaccination. In particular, it is possible to hypothesize that T-cell responses developed following an initial HPV infection that successfully clears would be capable of adequately eradicating subsequent viral infections. This remains an open issue for future investigation.

HPV Vaccine –A Boon or Bane

In a study by Hildesheim A et al. in women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treating prevalent infections. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls. Fortunately, for older women in developing countries there are new options for cervical-cancer screening that are likely to provide cost-effective strategies for reducing the risk of cancer.²⁶

Rights violation found in HPV vaccine studies in India – PATH & ICMR did demonstration project on the safety of the HPV vaccine in the states of Andhra Pradesh & Gujrat which was suspended by the Indian Govt. in response to demands from advocacy group. In April 2010, The Indian parliament's Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” In view of the reports finding of violation of human rights and clinical trial rules, the committee has recommended legal action against non-profit organization Program for Appropriate Technology in Health (PATH), which initiated the HPV project with the Indian Council of Medical Research (ICMR) in 2007, a year before marketing approval for HPV vaccines was given in India.

The trial's (by PATH & ICMR) purpose was to prepare ground for inclusion of the HPV vaccine in the Universal Immunization Program (UIP). The advocacy groups that pressured the Indian Government to halt and re-evaluate the HPV vaccine activities drew their information from many sources. They made fact-finding visits to study sites, combined with information from a US-based anti-HPV vaccination group, and additionally researched various public documents.²⁷

As far as these groups were concerned, their arguments were evidence-based. Some of the points made by the advocacy groups and a member of parliament are generally reasonable: calling for increased funds for health, maximising investment in priority health issues, ensuring the safety of health interventions, communicating clearly and honestly any risks, and conducting ethical processes in research. Beyond these broader demands, there was a mix of facts, misinformation, principles, anger at injustices, and anger at perceived interference by multinational companies, funders, and international non-governmental organisations in local concerns, and a final pointing to the government for its ultimate responsibility to protect people's health and wellbeing.

Consideration that the HPV-vaccine activities were in the interest of women's health could have been more loudly articulated, but that argument would need a different type of evidence and argument than that used by the advocacy groups. Reluctance by public health authorities to respond to issues of public distrust for fear that they will exacerbate the problem is dangerous.²⁸

Experience is increasingly showing that public distrust does not go away if unaddressed and can lead to program disruptions and even disease outbreaks. We need to find new ways to engage the public, early on, in health research and in the design and delivery of health programmes. That approach includes taking the time to listen to societal concerns, public emotions, and politics that can derail programmes or research. We might not always understand them, but we cannot ignore them.

Conclusion

The resources, infrastructure, and technological expertise required, together with the need for repeated screening at frequent intervals, have made conventional cytology-based screening prohibitively difficult in most poor countries. With the availability of an effective, safe vaccine, there is real hope for reducing the global burden of cervical cancer. Although achieving broad coverage of young adolescents, negotiating tiered pricing, and securing financing will be challenging, it is sobering to realize that with every 5-year delay in bringing vaccination to developing countries, 1.5 million to 2 million more women will die. Vaccination has the potential to save many lives. Let us hope that a committed global effort makes fulfillment of the promise of the new vaccine possible.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.