Human Papillomavirus Vaccines: What Does the Future Hold for Preventing Cervical Cancer in Resource-Poor Settings Through Immunization Programs?

CERVICAL CANCER IS A MAJOR health problem, particularly in developing countries where over 80% of global incidence and deaths from the disease occur, with estimated age-standardized incidence rates as high as 61 per 100,000 compared with 11 per 100,000 in developed countries.1 A measurable reduction in cervical cancer incidence and mortality in developed countries over the last 30 years has been largely the result of widespread Pap-based screening and diagnostic biopsy followed by treatment of precursor lesions.2–6 However, the difficulties involved in establishing and maintaining high-quality conventional cytology-based services in developing countries,7,8 and the promising, yet preliminary results of studies of alternative screening strategies, mean that for many nations, the development of a vaccine against the types of human papillomavirus (HPV) that cause cervical cancer may hold the most potential in the long term for disease reduction. The results of the, multicenter, U.S.-based, double-blind, randomized, placebo-controlled HPV vaccine study published in 2002 showed for the first time that HPV vaccines have, in principle, the potential to reduce or prevent cervical cancer.9 This article reviews the current status of HPV vaccine development and highlights outstanding research questions. Furthermore, the article examines the reality of implementing HPV vaccination programs, the promise that HPV vaccines holds for reducing the incidence of cervical cancer around the world, and the continued role for cervical cancer screening and treatment programs in the context of an effective vaccine. Human Papillomavirus and Cervical Cancer Unlike other cancers, there is a wealth of evidence on the natural history of cervical cancer and how to prevent the disease. The major breakthrough in the understanding of the natural history of cervical cancer was the identification of certain types of HPV as the etiologic agent responsible for the disease.10–13 Genital HPV is thought to be the most common sexually transmitted infection. It is estimated that in the United States alone, there are 5.5 million new genital HPV infections per year, and prevalence rates ranging from 30% to 46% have been seen in young women.14,15 HPV resides in the skin and is easily transmitted by direct contact that occurs during sexual activity. Condoms provide limited protection against HPV infection because the virus is commonly found on the skin in areas not covered by a condom.16 Despite high prevalence rates, it appears that most infections are benign and transitory with spontaneous clearance of the HPV infection.15,17,18 Some infections persist, although we do not yet fully understand what environmental and host immunologic factors are associated with persistence. What is clear, however, is that persistent infection with high-risk HPV types, often over many years, increases the risk of development of precancerous lesions and progression of these lesions to cervical cancer.15,17,19–22 There are many different types of HPV, over 15 of which have been categorized as high-risk carcinogenic types.23 It appears that 4 types, HPV 16, 18, 31, and 45, are most prevalent, with HPV 16 estimated to be responsible for approximately half of all cases of cervical cancer worldwide.23,24 Of significance to vaccine development is the remarkable homogeneity of HPV types worldwide, and a vaccine covering 2 of the most common HPV types would cover approximately 70% of cancers.23,25,26 However, it is important to note that despite these generalities, there are some geographic variations in the distribution of HPV types associated with cervical cancer, and it appears there are countries where types other than HPV 16, 18, 31, and 45 play a role in cervical cancer.25,27–29 Human Papillomavirus Vaccines HPV vaccines hold great promise in reducing cervical cancer-associated mortality and morbidity. Several different vaccines, targeting specific HPV types, are in various stages of clinical trials.30,31 In a landmark proof-of-concept study of an HPV 16 vaccine published in late 2002, Koutsky et al.9 showed a significantly reduced persistent HPV infection rate in those fully vaccinated compared with the placebo controls. In line with these results are the recently published efficacy results of a bivalent prophylactic vaccine targeting HPV 16 and 18, which showed remarkable efficacy for incident and persistent infection as well as efficacy to prevent precursor lesions associated with HPV 16 and 18 infection.32 Both vaccines were generally well tolerated, and there were no serious vaccine-related adverse events.9,32 The HPV 16 and 18 study reported high antibody levels, which were higher than in women who had natural infection with the specific HPV types and stayed high even at 18 months after vaccination.32Table 1 shows the key results from both studies. In addition, new trials of a multivalent vaccine targeting 2 high-risk HPV types (16 and 18) and 2 HPV types associated with genital warts (6 and 11) have begun.13 These studies have created considerable optimism for the future of HPV vaccines. However, long-term follow up is needed to confirm that HPV vaccination can ultimately prevent cervical cancer.TABLE 1: Human Papillomavirus (HPV) Vaccine Results From Published StudiesUnanswered Vaccine Development Questions Although promising, the current vaccine studies have yet to show long-term impact of vaccines on the disease burden. Most vaccines currently under development only target one or 2 of the carcinogenic HPV types, although some also include HPV 6 and 11 to offer protection against genital warts and encourage men to take the vaccine. In the absence of long-term results, modeling studies have been done to evaluate the impact of type-specific vaccines on cervical cancer. A modeling study conducted by Goldie et al.33 shows that if 100% of adolescents are fully vaccinated before their first exposure to HPV infection, an HPV 16 and 18 vaccine with 98% efficacy against persistent type-specific infection can lead to a similar reduction in 16 and 18-associated cervical cancer and approximately 51% reduction in the total burden of cervical cancer. Although 2 HPV types appear to be associated with the majority of cervical cancer worldwide, the geographic variability, described previously, means that a quadrivalent vaccine against HPV 16, 18, 31, and 45 will have a greater impact on disease globally. Even then, cervical cancer in some countries (predominantly those that have no leverage on research agendas) is associated with other types such as HPV 35, 51, and 58, so there may be less cause to be optimistic about the impact of vaccines in the reduction of cervical cancer in these countries. Ideally, to be useful globally, any vaccine must include protection against several of the many high-risk HPV types, but this might be associated with immunologic interference. More epidemiologic studies are necessary to provide the data needed to guide development of multivalent HPV vaccines and estimate the potential effect of vaccines with different combinations of HPV types in different countries and regions. It is unclear at this time what, if any, beneficial effect the HPV vaccines currently being studied would have on women who are already HPV-infected. A multivalent vaccine may protect women from getting infected with other HPV types than the one she already has. Unfortunately, animal studies are not particularly useful, because HPV does not cause disease in animals, further delaying research on which vaccines might be potentially useful. The results of the studies by Koutsky and Harper are based on a short follow up (median of 17 months), and the long-term vaccine immunity is yet unknown—a crucial question that needs to be answered. For maximum use, any vaccine needs to provide a long-lasting immune response, preferably lasting for as long as a woman is sexually active. The need for booster doses must be minimized, because the programmatic and cost implications of trying to achieve wide coverage will be overwhelming for many developing countries. Ideally, it is essential to know the duration of protection and the need for, required frequency of, and effectiveness of booster doses before advocating vaccines. Assembling these long-term data can take considerable time. Hepatitis B vaccines have been available for nearly 2 decades, yet the need for booster doses was hotly debated as recent as 2000.34 However, because current evidence from HPV vaccine studies show that the antibody titers in fully immunized women are higher than after natural infection, these antibodies may persist for several years, thereby reducing the need for booster doses.32 Gathering evidence on the duration of protection provided by HPV vaccines is essential and hence, projects should be designed to collect such long-term data. Information on the stability, shelf life, and storage requirements (including the need for a cold chain) for these vaccines is also important, because this will affect their use and effectiveness, especially in developing countries, and such information is vital to plan an effective vaccination program. Cost is another key consideration, particularly in developing countries where most cervical cancer occurs.35 There are currently over 20 vaccines being studied; however, many such as peptide vaccines and VLPs would be expensive.30 Developing a one-dose vaccine that does not require a complex cold chain would reduce program costs, as would developing more easily produced (in developing countries) or more easily administered vaccines.36–39 Vaccine Coverage Although vaccine effectiveness and ease of use are important, for any vaccine to achieve herd immunity and lead to a significant reduction in cervical cancer, wide coverage is crucial.33,40 Yet even with long established and proven vaccines, this is often challenging, especially in resource-poor settings. After years of programming and donor support, the worldwide coverage of the 6 key childhood vaccinations is reported to be currently 74%.41 In some developing countries, however, it is estimated to be much less, as low as 30%.41 Forty percent of children are thought not to have been vaccinated against measles,41 and more than 50% of the children in sub-Saharan Africa in 1999 had not received the DPT3 vaccination.42 Furthermore, the gap in the accessibility of the range of vaccines for children in rich and poor countries is widening; infants in the United States receive vaccines to prevent 11 diseases, whereas children in low-income countries receive vaccines against 7.43 Adding new and more vaccines will challenge health services in developing countries even more, although the delivery issues might be different if the HPV vaccine is not, at the outset, a childhood immunization. The experience of establishing hepatitis B vaccination programs might serve as an example of the challenges to introduce a new vaccine. Hepatitis B infection is reported to cause 600,000 deaths per year.43,44 The recombinant hepatitis B vaccine has been available since the mid-1980s and universal vaccination has been recommended by the World Health Organization (WHO) since 1992. However, by 1996, only 80 to 90, mostly developed, countries had adopted national or regional policies for universal infant or adolescent hepatitis B immunizations,43,45 with few programs in sub-Saharan Africa, Latin America, or in Eastern and Central Europe doing so.46 In low-income countries, it was estimated in 1999 that only 6% of children had been immunized.43 Even in developed countries with universal and free hepatitis B programs, uptake is suboptimal. In a recent study, it was found that in one region of Canada, hepatitis B infant coverage (completing all 3 shots) was only 73%. Both physician and parental lack of awareness and lack of acceptance of the hepatitis B program were the main reasons for the poor coverage.47 Data from studies in the United Kingdom, United States, and Israel show hepatitis B acceptance rates among healthcare workers ranging from 36% to 89%.48 However, with extensive staff orientation and education, financial and administrative support, and careful advance planning, another U.S. study demonstrated much higher acceptance rates of 90% full coverage of health workers.49 Some countries are slow to approve vaccines, and even then, it often takes years for programs to develop. In India, the hepatitis B vaccine was approved for use several years ago, yet it was only in 2002 that the government of India included it as part of their routine immunization program. It is now being introduced in a phased manner, but only in 10 states. Targeting Adolescents To be most effective in preventing HPV infection, a prophylactic HPV vaccine will need to be administered before the onset of sexual activity, although as yet, we are not certain of how long before. Knowledge of the optimal age for HPV vaccination is crucial but is as yet unknown. Before introducing an HPV vaccination program, it is important to define and identify the target age group and to plan and implement appropriate strategies to reach the target population who are not yet infected but imminently at risk. Decision on the target age group will depend on the average age of sexual debut which, in the United States is around 16 years and is estimated to be lower in many developing countries. Hence, it is likely that early adolescents would be the first target group. Countries with national immunization programs extending to adolescents can incorporate HPV vaccination into the same program. However, the strategy of targeting early adolescents has several implications. First, it is important to find a conduit for programming and ensure youth accessibility. In developing countries, schools are often used as a focus for adolescent vaccination; nevertheless, this can be problematic because many adolescents in the developing world are not in school. For example, in Ethiopia, a country with an age-standardized cervical cancer incidence rate of 35 per 100,000, only 28% to 33% of children aged 6 to 10 years of age and 10% to 13% of children aged 11 to 15 years of age are in school.50 In India, with an age-standardized cervical cancer incidence rate of 31 per 100,000, it is reported that less than 50% of school-aged girls are attending school in some states.51 In addition, in less developed countries, girls often leave school early; for example, there are almost twice as many out-of-school girls in the 12- to 17-year age group compared with the 6- to 11-year age group in Southern Asia.52 Second, adolescent vaccination will also need to take into consideration the lack of understanding among youth of the need for protection against HPV related to their feelings of invulnerability and low risk. In a study of parents and adolescents, perception of risk was an important factor for the parents accepting hepatitis B vaccination for their adolescent children, but anticipating future medical consequences was not an important factor in the decision-making process for the adolescents.53 Third, if the vaccination program also wants to target boys, it is unlikely to garner much support among adolescent males, perhaps their parents as well, unless it contains protection against pathologies that may affect them such as genital warts. It is not clear, however, how much of an incentive that protection would be for acceptance of an HPV vaccine by boys and their parents. Another potential barrier to adolescent HPV vaccination in many settings may be parental opposition. Where parents are the decision-makers about immunizations, the association of HPV with sexual activity could cause low uptake as a result of parental concerns that providing vaccines against a sexually transmitted disease would appear to condone sexual activity. 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