- Email: [email protected]
Global implementation of human papillomavirus (HPV) vaccine: Lessons from hepatitis B vaccine
Gynecologic Oncology 117 (2010) S32–S35
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
Review
Global implementation of human papillomavirus (HPV) vaccine: Lessons from hepatitis B vaccine Mark A. Kane Consultant, Mercer Island, WA 98040, USA
a r t i c l e
i n f o
Article history: Received 19 January 2010 Available online 2 February 2010 Keywords: HPV vaccine HB vaccine Developing countries Costs Expanded Program for Immunization Immunization programs
a b s t r a c t Development of safe and effective vaccines against human papillomavirus (HPV)–the second vaccine against a major human cancer–is one of the most important medical and public health achievements of this century. As with all new vaccines, HPV is currently expensive and this cost precludes its use in the developing world, which has the greatest burden of disease from HPV-related cancers. Hepatitis B (HB) virus vaccine, which prevents chronic HB infection and related cirrhosis and liver cancer, has been successfully introduced as a routine vaccine for children in 89% of countries, including the poorest. The success of this vaccine provides a model for the introduction of HPV vaccine and control of cervical and other HPV-related cancers and genital warts. Lessons learned from HB vaccine introduction are relevant to our efforts to introduce HPV vaccine globally. As with HB vaccine, introduction of HPV vaccine into national immunization programs and routine use of this vaccine, funded by governments, will be needed to control HPV-related disease on a global basis. Global funding support will be needed to make control a reality for the poorest countries, and the program to accomplish this, the Global Alliance for Vaccines and Immunization (GAVI), has already expressed great interest in including HPV vaccine. For this to occur, the manufacturers will need to dramatically reduce the vaccine price for the poorest developing countries, and tier prices for wealthier developing countries not eligible for GAVI support. Countries will need to decide on the priority of HPV control in the context of other important new vaccines against pneumococcal pneumonia and rotavirus diarrhea. © 2010 Published by Elsevier Inc.
Introduction Human papillomavirus (HPV) vaccines (bivalent and quadrivalent) have been shown to be immunogenic, safe, and highly effective in preventing chronic infection and precancerous lesions in women [1,2], and the quadrivalent vaccine has been shown to prevent genital warts and chronic infection in men and women as well [3]. It is the second vaccine able to prevent a major human cancer (cervical cancer), as well as other less common cancers (vulvar, vaginal, anal, penile, and head and neck) in women and men. Currently, as with all modern vaccines, the price of the vaccine is high and precludes its introduction into public sector programs in most developing countries where the benefit of the vaccine will be maximal. However, the price of the vaccine will fall with time, and vaccine manufacturers have stated that they are willing to tier prices for developing countries and dramatically reduce prices for the poorest developing countries that get their newer vaccines through the Global Alliance for Vaccines and Immunization (GAVI) and the Pan American Health Organization (PAHO) Revolving Fund for Latin America. Hepatitis B (HB) vaccine, the first vaccine to prevent a major human cancer (primary liver cancer), can serve as a model for the introduction
E-mail address: [email protected]. 0090-8258/$ – see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.ygyno.2010.01.029
of HPV vaccine on a number of levels. First, the answer to the question “How can we deliver HPV vaccine to young people in the developing world?” is to integrate the vaccine into the World Health Organization (WHO) Expanded Program on Immunization (EPI) and all national immunization programs. Second, the HB model suggests that it may be possible to do more than protect immunized individuals: we may be able to reduce viral transmission and induce heard immunity to protect non-immunized individuals as well. Third, the HB model suggests that we may wish to investigate the immunization of children younger than is currently proposed in order to increase immunization coverage, and we may wish to re-examine the premise that this is a cost-effective vaccine primarily for adolescent females. Vaccines as a major tool in the prevention of cancer Cancer prevention activities have been dominated by issues such as smoking reduction, screening for breast, cervical, colon, and prostate cancer prevention or early detection, occupational exposures, and dietary factors. However, the cancer prevention community has been largely unaware that vaccines have emerged as a primary tool for cancer prevention, with HB and HPV vaccines as the first examples. Educating the cancer control community to get their powerful advocacy and funding support will help to generate the political will to undertake HPV control globally. As with HB vaccine, pediatricians and family practice
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35
S33
physicians need to realize that they are immunizing to prevent diseases of adults that they may not see. Pediatricians are important advocates for preventive medicine, but they may know little about HPV infection and cervical and other HPV-related cancers [4]. Conversely, the Ob/Gyn community knows about HPV and cervical cancer prevention, but often knows little about vaccines and immunization delivery. Bringing these communities together on these issues is beginning to happen in industrial countries, and this needs to happen in developing countries as well.
the age of sexual debut to see the impact, and the currently unknown duration of protection would have to be established, but doing preliminary safety and immunogenicity studies in this age group would allow health planners additional options to consider for longterm HPV control. Even if a booster dose were needed during early adolescence, this might be easier than giving the entire series during the pre-adolescent period.
How are vaccines delivered to children in the developing world?
The poorest 72 countries in the developing world receive most of their newer vaccines through GAVI, which has an international fund that helps to pay for the vaccines. GAVI receives major support from the International Finance Facility for Immunisation, the Bill and Melinda Gates Foundation, and support from many governments [14]. Countries in Latin America receive their vaccines through the PAHO Revolving Fund, under which countries pay for vaccines obtained at very low prices negotiated by the PAHO [15]. GAVI procurement of HB vaccine was crucial in the uptake of this vaccine in the poorest countries, and the PAHO Revolving Fund obtained it for Latin America. For countries to obtain the vaccine through GAVI, several steps will need to occur. First, the vaccine price would need to be dramatically reduced for GAVI country purchase. At least one vaccine manufacturer has announced that they will offer GAVI a “no profit” price, although this price has not been revealed [16]. Second, the GAVI Board would need to approve funding for HPV vaccine, and has decided to do so if it can raise the necessary funds [17]. Currently, the economic crisis is affecting the ability of GAVI to afford new vaccines, but this should change as economies improve. Third, GAVI-eligible countries would need to choose to take the vaccine, and there are several extremely attractive vaccines that could compete with HPV, including pneumococcal conjugate and rotavirus vaccines. If a country chose HPV vaccine, they would have to pay a small amount per dose (in the order of $0.50) and GAVI would pay the difference in cost up to the negotiated price with the manufacturer. The poorest countries, especially those affected by war or natural disasters, would pay nothing. Advocates of HPV immunization need to direct their efforts toward insuring that the GAVI Board makes favorable decisions with respect to HPV vaccine inclusion into GAVI programs, and that countries have the information they need to choose HPV immunization. It should be pointed out that about one third of children are born in China, India, and Indonesia. These countries have local vaccine production, and the vaccines used in their routine immunization programs are all locally produced. HPV vaccine producers need to explore partnering with local producers in these countries if routine use of HPV vaccine in those countries is to occur. Wealthier developing countries will need to purchase the vaccine for the public sector themselves or with the help of bilateral donors. Manufacturers have agreed to tier prices relative to the economic level of the country to help them afford the vaccine [18].
Every country has a national immunization program that routinely delivers vaccines to children. While many countries have a private market for vaccines where expensive new vaccines are first introduced, in most countries in both the developing and industrial world the public sector programs deliver vaccines to the great majority of children and adolescents. Even in the US, more than half of children and adolescents get their vaccines through the federally funded Vaccines for Children program [5]. All national immunization programs are part of the EPI network , which is coordinated by the WHO and United Nations Children's Fund (UNICEF). The EPI recommends immunization policy and provides technical information and technical assistance for national programs, and UNICEF purchases and ships vaccines to most developing countries. Introduction of HPV vaccine into the EPI will be a necessary step for global implementation, as it was for HB vaccine [6]. The WHO Scientific Advisory Group of Experts has recently issued recommendations for countries to use HPV vaccine for pre-adolescent females [7]. Recent data have shown that the quadrivalent HPV vaccine is highly effective in preventing genital warts and chronic HPV infection in males as well as females [3]. However, data are not yet available on the prevention of pre-cancerous lesions in males, and there is debate about the cost-effectiveness of male immunization, with some prominent health economists stating that male immunization is not, or not likely to be, cost-effective in industrial country settings [8,9]. However, most economic studies of HPV immunization have not fully studied male disease, and at least one study, done by Merck economists, has found male immunization more economically attractive [10]. The US Food and Drug Administration and the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) have approved the vaccine for use in males, but have not issued the strong programmatic recommendation for routine use (which is in place for females) [11]. Most national immunization programs, even in the poorest countries, are highly effective at reaching children below the age of 2 years, but most programs in the developing world do not effectively reach pre-adolescents, adolescents, and adults in routine programs [12]. However, most countries can reach these groups in campaignstyle programs such as polio eradication, measles campaigns, and neonatal tetanus vaccination programs for women of child-bearing age. Since the target group for HPV vaccine is currently pre-adolescent and adolescent girls, these immunization programs will need to be expanded to reach these children in a routine way. Several countries have also added adolescent HB immunization to their childhood programs to accelerate the pace of HB control. While expanding these programs will be difficult and expensive in some countries, these efforts will be needed for other future vaccines against HIV/AIDS, malaria, tuberculosis, epidemic influenza, and vaccines against sexually transmitted diseases [13]. An alternative to adolescent immunization should be explored with HPV vaccine, and that is to study the safety and immunogenicity of the vaccine in children receiving the other EPI vaccines at less than 2 years of age. The incorporation of HPV vaccine into the routine EPI, possibly as a component of combination vaccines, would guarantee very high rates of coverage. Of course, one would have to wait until
How are vaccines funded in the developing world?
Information about HB vaccine HB vaccine was introduced in 1982 in industrial countries and primarily used at that time to immunize members of “high-risk” groups such as healthcare workers, hemophiliacs, certain ethnic groups from highly endemic areas, intravenous drug users, men who had sex with men, and heterosexuals with multiple partners [19]. The vaccine cost about $100 for three doses and at that price it was not possible to introduce the vaccine into public sector programs in the developing world. The strategy to immunize “high-risk” groups in general failed, with the exception of healthcare workers, who were usually required to take the vaccine provided by their employers or the government. With the discovery that the vaccine was protecting certain individuals (which was good) but not the community, the strategy shifted to preventing infection in everyone by using the
S34
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35
vaccine as a universal childhood vaccine of children and adolescents [20]. With this strategy, community rates of HB fell dramatically [21]. The lesson for HPV is clear. “Opportunistic” immunization of selected individuals will protect those individuals but has little impact on rates of HPV-related diseases in the community. Only routine immunization of pre-adolescents and adolescents in government-funded programs will lead to the community control of these diseases.
HB vaccine in the developing world As mentioned, the vaccine was initially too expensive for public sector programs in the developing world. Production of the vaccine in South Korea and later China, India, and Brazil, and the expiration of key patents reduced the price dramatically to about $1.00 per pediatric dose by the early 1990s [22]. The price of the vaccine for developing countries is now about $0.20 per dose. In 1992, the WHO called for all countries to add HB vaccine to their routine immunization schedule [23]. However, it took almost 20 years for the vaccine use in the developing world to reach levels comparable to the use in industrialized countries. Many of the poorest countries did not receive HB vaccine for the public sector until GAVI provided it for them free for 5 years. HB vaccine is now routinely used for children in 171 of 193 (89%) WHO member states including the poorest countries [24]. The global vaccine community has worked hard to shorten the gap between availability of newer vaccines in the industrial and developing worlds and it is hoped that HPV vaccine will become available in developing countries with much less delay than was seen with HB vaccine [6].
Impact on cancer As with HPV, HB carriers usually develop cancer following decades of chronic infection. Therefore, we do not expect dramatic falls in cancer rates for decades following immunization. Cancer epidemiologists and public health officials differ on how they conceptualize the situation: while cancer epidemiologists count impact when cancer rates fall, immunization experts measure impact when successful immunization is given preventing the chronic infection that causes the disease. Cases of liver cancer in adolescents and young adults are common enough in Taiwan to already directly measure a dramatic decrease in liver cancer, proving that prevention of chronic HB infection with vaccine prevents cancer. Liver cancer incidence in children and adolescents immunized at birth was one third of the incidence in unvaccinated children [32]. Conclusion HB immunization provides a useful model for introduction and possible impact of HPV vaccine implementation and gives us good reason to believe that global implementation of HPV immunization is possible and will probably have a major impact on cervical and other HPV-related cancers. Global funding of HPV vaccine through GAVI and inclusion of HPV vaccine into the EPI and national immunization programs are necessary steps for global introduction. With this introduction, the second major vaccine-preventable human cancer, cervical cancer, may be controlled on a global basis. This should be the goal of the public health community in all countries. Key points
HB vaccine impact Similar to HPV vaccine, HB vaccine is a “subunit” vaccine composed of spherical particles of HB surface antigen formerly called the Australia antigen. The alum-adjuvanted vaccine is highly immunogenic and highly effective in preventing HB infection. More than 90% of children will be protected from acquiring chronic HB infection, the precursor to liver cancer and cirrhosis. The duration of protection induced by HB vaccine is unknown but is at least 20 years [25]. Very importantly, the duration of protection lasts much longer (decades) than the duration of detectable antibody in many individuals, suggesting that the protection is provided by immune memory when detectable circulating antibody is no longer found. This may be an important model for the duration of protection from HPV vaccine, which is also not presently known [26]. HB immunization of children has been extremely effective in reducing the prevalence of chronic HB. In high-prevalence countries such as are found in Asia and Africa, prior to immunization 10% to 15% of children became chronic carriers of the HB virus. Following effective levels of immunization, many of these countries now have less than 1–2% carriers in immunized cohorts of children [27–29]. This is also true in China, where control of HB is one of the great public health achievements of the century [30]. In addition to the fall in carrier rates, clinical HB disease, a measure of the current infection pressure of the virus, has fallen dramatically in most countries using the vaccine routinely. This means that viral circulation in the population has been dramatically reduced. In the US, for example, the CDC estimates that in 1990 232,000 HB infections occurred in the US, and that this declined to 43,000 by 2007 [31]. Although adult carriers still carry the virus in their livers, the infectivity of adult carriers naturally declines significantly with time when they lose the HB “e” antigen, and viral titers decline. This combination of non-infectious children protected by vaccine and less infectious adult carriers lowers infection pressure on the population.
• The success of hepatitis B (HB) vaccine introduction provides a useful model for global human papillomavirus (HPV) vaccine introduction. • Inclusion of HPV vaccine into national immunization programs and the WHO Expanded Program on Immunization will be necessary to achieve global control. • The international community must agree to fund HPV vaccine for the poorest countries. The mechanism to do this is through the Global Alliance for Vaccines and Immunization (GAVI), which funds new vaccines for the 72 poorest countries. • Manufacturers must dramatically lower prices for GAVI purchase and tier prices for wealthier developing countries who are not GAVI eligible. Manufacturers have pledged to do this. • With GAVI support for the poorest countries, 177 (89%) countries now use HB vaccine as a routine immunization. • HB vaccine has had a major impact on the prevalence of chronic carriers and the rates of acute HB in the community, and a reduction in liver cancer is already measurable in Taiwan. Conflict of interest statement Dr. Kane is a member of the Merck Global Advisory Board for HPV and has given talks sponsored by Merck and GSK.
References [1] FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27. [2] Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;374:301–14. [3] Palefsky J, Giuliano A. Efficacy of the quadrivalent HPV vaccine against HPV 6/11/16/18-related genital infection in young men. Presented at the 2008 Conference of the European Research Organization on Genital Infection and Neoplasia (EUROGIN); 2008 Nov 12-15; Nice, France. Abstract PS 1-3a. [4] Esposito S, Bosis S, Pelucchi C, Begliatti E, Rognoni A, Bellasio M, et al. Pediatrician knowledge and attitudes regarding human papillomavirus disease and its prevention. Vaccine 2007;25:6437–46.
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35 [5] Centers for Disease Control and Prevention [homepage on the Internet]. Vaccines for Children Program (VFC). Available from: http://www.cdc.gov/vaccines/ programs/vfc/default.htm. [6] Kane MA, Sherris J, Coursaget P, Aguado T, Cutts F. Chapter 15: HPV vaccine use in the developing world. Vaccine 2006;24(Suppl 3):S132–9. [7] World Health Organization (WHO). Human papillomavirus vaccines. WHO position paper. Wkly Epidemiol Rec 2009;84:118-31. Available from: http:// www.who.int/wer/2009/wer8415.pdf. [8] Jit M, Choi YH, Edmunds WJ. Economic evaluation of human papillomavirus vaccination in the United Kingdom. BMJ 2008;a769:337. [9] Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ 2009;b3884:339. [10] Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007;13:28–41. [11] Infectious Diseases Society of America (IDSA) [homepage on the Internet]. Patient care and science. ACIP makes recommendations for HPV vaccine use in males. IDSA News 2009 October;19(10). Available from: http://news.idsociety.org/idsa/ issues/2009-10-31/3.html. [12] Brabin L, Greenberg DP, Hessel L, Hyer R, Ivanoff B, Van Damme P. Current issues in adolescent immunization. Vaccine 2008;26:4120-34. [13] WHO, UNICEF, World Bank. State of the world's vaccines and immunization. 3rd ed. Geneva: WHO; 2009. Available from: http://www.unicef.org/media/files/ SOWVI_full_report_english_LR1.pdf. [14] Gavi Alliance [homepage on the Internet]. Innovative funding. Available from: http://www.gavialliance.org/about/in_finance/index.php. [15] Andrus JK, Sherris J, Fitzsimmons JW, Kane MA, Aguado MT. Introduction of human papillomavirus vaccines into developing countries—international strategies for financing and procurement. Vaccine 2008;26(Suppl 10):K87–92. [16] Merck and Co., Inc. Merck's plan to accelerate access to vaccines in the developing world. 20951760(1) – 07/09. Available from: http://www.merck.com/corporate-responsibility/docs/DW_Backgrounder062909.pdf. [17] Medical News Today [homepage on the Internet]. Global Vaccine Alliance Board approves $3.5B investment strategy that includes HPV vaccine; 2008 Jun 27. Available from: http://www.medicalnewstoday.com/articles/113026.php. [18] International Federation of Pharmaceutical manufacturers and Associations (IFPMA). HPV vaccine and cervical cancer. Available from: http://www.ifpma. org/index.php?id=2134. [19] Goldstein ST, Alter MJ, Williams IT, Moyer LA, Judson FN, Mottram K, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982–1998: implications for vaccination programs. J Infect Dis 2002;85:713–9.
S35
[20] Alter MJ, Hadler SC, Margolis HS, Alexander WJ, Hu PY, Judson FN, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies. JAMA 1990;263:1218–22. [21] Bonanni P, Pesavento G, Bechini A, Tiscione E, Mannelli F, Benucci C, et al. Impact of universal vaccination programmes on the epidemiology of hepatitis B: 10 years of experience in Italy. Vaccine 2003;21:685–91. [22] Kane MA, Brooks A. New immunization initiatives and progress toward the global control of hepatitis B. Curr Opin Infect Dis 2002;5:465–9. [23] Van Damme P, Kane M, Meheus A. Integration of hepatitis B vaccination into national immunisation programmes. Viral Hepatitis Prevention Board. BMJ 1997;314:1033–6. [24] World Health Organization [homepage on the Internet]. Immunization, vaccines and biologicals. Hepatitis B. Available from: http://www.who.int/immunization/ topics/hepatitis_b/en/index.html. [25] McMahon BJ, Bruden DL, Petersen KM, Bulkow LR, Parkinson AJ, Nainan O, et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Ann Intern Med 2005;142:333–41. [26] Bonanni P, Boccalini S, Bechini A. Efficacy, duration of immunity and cross protection after HPV vaccination: a review of the evidence. Vaccine 2009;27 (Suppl 1):A46–53. [27] Clements CJ, Baoping Y, Crouch A, Hipgrave D, Mansoor O, Nelson CB, et al. Progress in the control of hepatitis B infection in the Western Pacific Region. Vaccine 2006;24:1975–82. [28] van der Sande MA, Waight PA, Mendy M, Zaman S, Kaye S, Sam O, et al. Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence. PLoS One 2007; e753:2. [29] Chongsrisawat V, Yoocharoen P, Theamboonlers A, Tharmaphornpilas P, Warinsathien P, Sinlaparatsamee S, et al. Hepatitis B seroprevalence in Thailand: 12 years after hepatitis B vaccine integration into the national expanded programme on immunization. Trop Med Int Health 2006;11:1496–502. [30] Centers for Disease Control and Prevention (CDC). Progress in hepatitis B prevention through universal infant vaccination—China, 1997–2006. MMWR Morb Mortal Wkly Rep 2007;56:441–5. [31] Centers for Disease Control and Prevention (CDC). Hepatitis B Information for Health Professionals. Statistics and Surveillance. Available from: http://www.cdc. gov/hepatitis/HBV/StatisticsHBV.htm#section1. [32] Chang MH, You SL, Chen CJ, Liu CJ, Lee CM, Lin SM, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst 2009;101:1348–55.
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
Review
Global implementation of human papillomavirus (HPV) vaccine: Lessons from hepatitis B vaccine Mark A. Kane Consultant, Mercer Island, WA 98040, USA
a r t i c l e
i n f o
Article history: Received 19 January 2010 Available online 2 February 2010 Keywords: HPV vaccine HB vaccine Developing countries Costs Expanded Program for Immunization Immunization programs
a b s t r a c t Development of safe and effective vaccines against human papillomavirus (HPV)–the second vaccine against a major human cancer–is one of the most important medical and public health achievements of this century. As with all new vaccines, HPV is currently expensive and this cost precludes its use in the developing world, which has the greatest burden of disease from HPV-related cancers. Hepatitis B (HB) virus vaccine, which prevents chronic HB infection and related cirrhosis and liver cancer, has been successfully introduced as a routine vaccine for children in 89% of countries, including the poorest. The success of this vaccine provides a model for the introduction of HPV vaccine and control of cervical and other HPV-related cancers and genital warts. Lessons learned from HB vaccine introduction are relevant to our efforts to introduce HPV vaccine globally. As with HB vaccine, introduction of HPV vaccine into national immunization programs and routine use of this vaccine, funded by governments, will be needed to control HPV-related disease on a global basis. Global funding support will be needed to make control a reality for the poorest countries, and the program to accomplish this, the Global Alliance for Vaccines and Immunization (GAVI), has already expressed great interest in including HPV vaccine. For this to occur, the manufacturers will need to dramatically reduce the vaccine price for the poorest developing countries, and tier prices for wealthier developing countries not eligible for GAVI support. Countries will need to decide on the priority of HPV control in the context of other important new vaccines against pneumococcal pneumonia and rotavirus diarrhea. © 2010 Published by Elsevier Inc.
Introduction Human papillomavirus (HPV) vaccines (bivalent and quadrivalent) have been shown to be immunogenic, safe, and highly effective in preventing chronic infection and precancerous lesions in women [1,2], and the quadrivalent vaccine has been shown to prevent genital warts and chronic infection in men and women as well [3]. It is the second vaccine able to prevent a major human cancer (cervical cancer), as well as other less common cancers (vulvar, vaginal, anal, penile, and head and neck) in women and men. Currently, as with all modern vaccines, the price of the vaccine is high and precludes its introduction into public sector programs in most developing countries where the benefit of the vaccine will be maximal. However, the price of the vaccine will fall with time, and vaccine manufacturers have stated that they are willing to tier prices for developing countries and dramatically reduce prices for the poorest developing countries that get their newer vaccines through the Global Alliance for Vaccines and Immunization (GAVI) and the Pan American Health Organization (PAHO) Revolving Fund for Latin America. Hepatitis B (HB) vaccine, the first vaccine to prevent a major human cancer (primary liver cancer), can serve as a model for the introduction
E-mail address: [email protected]. 0090-8258/$ – see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.ygyno.2010.01.029
of HPV vaccine on a number of levels. First, the answer to the question “How can we deliver HPV vaccine to young people in the developing world?” is to integrate the vaccine into the World Health Organization (WHO) Expanded Program on Immunization (EPI) and all national immunization programs. Second, the HB model suggests that it may be possible to do more than protect immunized individuals: we may be able to reduce viral transmission and induce heard immunity to protect non-immunized individuals as well. Third, the HB model suggests that we may wish to investigate the immunization of children younger than is currently proposed in order to increase immunization coverage, and we may wish to re-examine the premise that this is a cost-effective vaccine primarily for adolescent females. Vaccines as a major tool in the prevention of cancer Cancer prevention activities have been dominated by issues such as smoking reduction, screening for breast, cervical, colon, and prostate cancer prevention or early detection, occupational exposures, and dietary factors. However, the cancer prevention community has been largely unaware that vaccines have emerged as a primary tool for cancer prevention, with HB and HPV vaccines as the first examples. Educating the cancer control community to get their powerful advocacy and funding support will help to generate the political will to undertake HPV control globally. As with HB vaccine, pediatricians and family practice
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35
S33
physicians need to realize that they are immunizing to prevent diseases of adults that they may not see. Pediatricians are important advocates for preventive medicine, but they may know little about HPV infection and cervical and other HPV-related cancers [4]. Conversely, the Ob/Gyn community knows about HPV and cervical cancer prevention, but often knows little about vaccines and immunization delivery. Bringing these communities together on these issues is beginning to happen in industrial countries, and this needs to happen in developing countries as well.
the age of sexual debut to see the impact, and the currently unknown duration of protection would have to be established, but doing preliminary safety and immunogenicity studies in this age group would allow health planners additional options to consider for longterm HPV control. Even if a booster dose were needed during early adolescence, this might be easier than giving the entire series during the pre-adolescent period.
How are vaccines delivered to children in the developing world?
The poorest 72 countries in the developing world receive most of their newer vaccines through GAVI, which has an international fund that helps to pay for the vaccines. GAVI receives major support from the International Finance Facility for Immunisation, the Bill and Melinda Gates Foundation, and support from many governments [14]. Countries in Latin America receive their vaccines through the PAHO Revolving Fund, under which countries pay for vaccines obtained at very low prices negotiated by the PAHO [15]. GAVI procurement of HB vaccine was crucial in the uptake of this vaccine in the poorest countries, and the PAHO Revolving Fund obtained it for Latin America. For countries to obtain the vaccine through GAVI, several steps will need to occur. First, the vaccine price would need to be dramatically reduced for GAVI country purchase. At least one vaccine manufacturer has announced that they will offer GAVI a “no profit” price, although this price has not been revealed [16]. Second, the GAVI Board would need to approve funding for HPV vaccine, and has decided to do so if it can raise the necessary funds [17]. Currently, the economic crisis is affecting the ability of GAVI to afford new vaccines, but this should change as economies improve. Third, GAVI-eligible countries would need to choose to take the vaccine, and there are several extremely attractive vaccines that could compete with HPV, including pneumococcal conjugate and rotavirus vaccines. If a country chose HPV vaccine, they would have to pay a small amount per dose (in the order of $0.50) and GAVI would pay the difference in cost up to the negotiated price with the manufacturer. The poorest countries, especially those affected by war or natural disasters, would pay nothing. Advocates of HPV immunization need to direct their efforts toward insuring that the GAVI Board makes favorable decisions with respect to HPV vaccine inclusion into GAVI programs, and that countries have the information they need to choose HPV immunization. It should be pointed out that about one third of children are born in China, India, and Indonesia. These countries have local vaccine production, and the vaccines used in their routine immunization programs are all locally produced. HPV vaccine producers need to explore partnering with local producers in these countries if routine use of HPV vaccine in those countries is to occur. Wealthier developing countries will need to purchase the vaccine for the public sector themselves or with the help of bilateral donors. Manufacturers have agreed to tier prices relative to the economic level of the country to help them afford the vaccine [18].
Every country has a national immunization program that routinely delivers vaccines to children. While many countries have a private market for vaccines where expensive new vaccines are first introduced, in most countries in both the developing and industrial world the public sector programs deliver vaccines to the great majority of children and adolescents. Even in the US, more than half of children and adolescents get their vaccines through the federally funded Vaccines for Children program [5]. All national immunization programs are part of the EPI network , which is coordinated by the WHO and United Nations Children's Fund (UNICEF). The EPI recommends immunization policy and provides technical information and technical assistance for national programs, and UNICEF purchases and ships vaccines to most developing countries. Introduction of HPV vaccine into the EPI will be a necessary step for global implementation, as it was for HB vaccine [6]. The WHO Scientific Advisory Group of Experts has recently issued recommendations for countries to use HPV vaccine for pre-adolescent females [7]. Recent data have shown that the quadrivalent HPV vaccine is highly effective in preventing genital warts and chronic HPV infection in males as well as females [3]. However, data are not yet available on the prevention of pre-cancerous lesions in males, and there is debate about the cost-effectiveness of male immunization, with some prominent health economists stating that male immunization is not, or not likely to be, cost-effective in industrial country settings [8,9]. However, most economic studies of HPV immunization have not fully studied male disease, and at least one study, done by Merck economists, has found male immunization more economically attractive [10]. The US Food and Drug Administration and the Advisory Committee on Immunization Practices (ACIP) of the US Centers for Disease Control and Prevention (CDC) have approved the vaccine for use in males, but have not issued the strong programmatic recommendation for routine use (which is in place for females) [11]. Most national immunization programs, even in the poorest countries, are highly effective at reaching children below the age of 2 years, but most programs in the developing world do not effectively reach pre-adolescents, adolescents, and adults in routine programs [12]. However, most countries can reach these groups in campaignstyle programs such as polio eradication, measles campaigns, and neonatal tetanus vaccination programs for women of child-bearing age. Since the target group for HPV vaccine is currently pre-adolescent and adolescent girls, these immunization programs will need to be expanded to reach these children in a routine way. Several countries have also added adolescent HB immunization to their childhood programs to accelerate the pace of HB control. While expanding these programs will be difficult and expensive in some countries, these efforts will be needed for other future vaccines against HIV/AIDS, malaria, tuberculosis, epidemic influenza, and vaccines against sexually transmitted diseases [13]. An alternative to adolescent immunization should be explored with HPV vaccine, and that is to study the safety and immunogenicity of the vaccine in children receiving the other EPI vaccines at less than 2 years of age. The incorporation of HPV vaccine into the routine EPI, possibly as a component of combination vaccines, would guarantee very high rates of coverage. Of course, one would have to wait until
How are vaccines funded in the developing world?
Information about HB vaccine HB vaccine was introduced in 1982 in industrial countries and primarily used at that time to immunize members of “high-risk” groups such as healthcare workers, hemophiliacs, certain ethnic groups from highly endemic areas, intravenous drug users, men who had sex with men, and heterosexuals with multiple partners [19]. The vaccine cost about $100 for three doses and at that price it was not possible to introduce the vaccine into public sector programs in the developing world. The strategy to immunize “high-risk” groups in general failed, with the exception of healthcare workers, who were usually required to take the vaccine provided by their employers or the government. With the discovery that the vaccine was protecting certain individuals (which was good) but not the community, the strategy shifted to preventing infection in everyone by using the
S34
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35
vaccine as a universal childhood vaccine of children and adolescents [20]. With this strategy, community rates of HB fell dramatically [21]. The lesson for HPV is clear. “Opportunistic” immunization of selected individuals will protect those individuals but has little impact on rates of HPV-related diseases in the community. Only routine immunization of pre-adolescents and adolescents in government-funded programs will lead to the community control of these diseases.
HB vaccine in the developing world As mentioned, the vaccine was initially too expensive for public sector programs in the developing world. Production of the vaccine in South Korea and later China, India, and Brazil, and the expiration of key patents reduced the price dramatically to about $1.00 per pediatric dose by the early 1990s [22]. The price of the vaccine for developing countries is now about $0.20 per dose. In 1992, the WHO called for all countries to add HB vaccine to their routine immunization schedule [23]. However, it took almost 20 years for the vaccine use in the developing world to reach levels comparable to the use in industrialized countries. Many of the poorest countries did not receive HB vaccine for the public sector until GAVI provided it for them free for 5 years. HB vaccine is now routinely used for children in 171 of 193 (89%) WHO member states including the poorest countries [24]. The global vaccine community has worked hard to shorten the gap between availability of newer vaccines in the industrial and developing worlds and it is hoped that HPV vaccine will become available in developing countries with much less delay than was seen with HB vaccine [6].
Impact on cancer As with HPV, HB carriers usually develop cancer following decades of chronic infection. Therefore, we do not expect dramatic falls in cancer rates for decades following immunization. Cancer epidemiologists and public health officials differ on how they conceptualize the situation: while cancer epidemiologists count impact when cancer rates fall, immunization experts measure impact when successful immunization is given preventing the chronic infection that causes the disease. Cases of liver cancer in adolescents and young adults are common enough in Taiwan to already directly measure a dramatic decrease in liver cancer, proving that prevention of chronic HB infection with vaccine prevents cancer. Liver cancer incidence in children and adolescents immunized at birth was one third of the incidence in unvaccinated children [32]. Conclusion HB immunization provides a useful model for introduction and possible impact of HPV vaccine implementation and gives us good reason to believe that global implementation of HPV immunization is possible and will probably have a major impact on cervical and other HPV-related cancers. Global funding of HPV vaccine through GAVI and inclusion of HPV vaccine into the EPI and national immunization programs are necessary steps for global introduction. With this introduction, the second major vaccine-preventable human cancer, cervical cancer, may be controlled on a global basis. This should be the goal of the public health community in all countries. Key points
HB vaccine impact Similar to HPV vaccine, HB vaccine is a “subunit” vaccine composed of spherical particles of HB surface antigen formerly called the Australia antigen. The alum-adjuvanted vaccine is highly immunogenic and highly effective in preventing HB infection. More than 90% of children will be protected from acquiring chronic HB infection, the precursor to liver cancer and cirrhosis. The duration of protection induced by HB vaccine is unknown but is at least 20 years [25]. Very importantly, the duration of protection lasts much longer (decades) than the duration of detectable antibody in many individuals, suggesting that the protection is provided by immune memory when detectable circulating antibody is no longer found. This may be an important model for the duration of protection from HPV vaccine, which is also not presently known [26]. HB immunization of children has been extremely effective in reducing the prevalence of chronic HB. In high-prevalence countries such as are found in Asia and Africa, prior to immunization 10% to 15% of children became chronic carriers of the HB virus. Following effective levels of immunization, many of these countries now have less than 1–2% carriers in immunized cohorts of children [27–29]. This is also true in China, where control of HB is one of the great public health achievements of the century [30]. In addition to the fall in carrier rates, clinical HB disease, a measure of the current infection pressure of the virus, has fallen dramatically in most countries using the vaccine routinely. This means that viral circulation in the population has been dramatically reduced. In the US, for example, the CDC estimates that in 1990 232,000 HB infections occurred in the US, and that this declined to 43,000 by 2007 [31]. Although adult carriers still carry the virus in their livers, the infectivity of adult carriers naturally declines significantly with time when they lose the HB “e” antigen, and viral titers decline. This combination of non-infectious children protected by vaccine and less infectious adult carriers lowers infection pressure on the population.
• The success of hepatitis B (HB) vaccine introduction provides a useful model for global human papillomavirus (HPV) vaccine introduction. • Inclusion of HPV vaccine into national immunization programs and the WHO Expanded Program on Immunization will be necessary to achieve global control. • The international community must agree to fund HPV vaccine for the poorest countries. The mechanism to do this is through the Global Alliance for Vaccines and Immunization (GAVI), which funds new vaccines for the 72 poorest countries. • Manufacturers must dramatically lower prices for GAVI purchase and tier prices for wealthier developing countries who are not GAVI eligible. Manufacturers have pledged to do this. • With GAVI support for the poorest countries, 177 (89%) countries now use HB vaccine as a routine immunization. • HB vaccine has had a major impact on the prevalence of chronic carriers and the rates of acute HB in the community, and a reduction in liver cancer is already measurable in Taiwan. Conflict of interest statement Dr. Kane is a member of the Merck Global Advisory Board for HPV and has given talks sponsored by Merck and GSK.
References [1] FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27. [2] Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;374:301–14. [3] Palefsky J, Giuliano A. Efficacy of the quadrivalent HPV vaccine against HPV 6/11/16/18-related genital infection in young men. Presented at the 2008 Conference of the European Research Organization on Genital Infection and Neoplasia (EUROGIN); 2008 Nov 12-15; Nice, France. Abstract PS 1-3a. [4] Esposito S, Bosis S, Pelucchi C, Begliatti E, Rognoni A, Bellasio M, et al. Pediatrician knowledge and attitudes regarding human papillomavirus disease and its prevention. Vaccine 2007;25:6437–46.
M.A. Kane / Gynecologic Oncology 117 (2010) S32–S35 [5] Centers for Disease Control and Prevention [homepage on the Internet]. Vaccines for Children Program (VFC). Available from: http://www.cdc.gov/vaccines/ programs/vfc/default.htm. [6] Kane MA, Sherris J, Coursaget P, Aguado T, Cutts F. Chapter 15: HPV vaccine use in the developing world. Vaccine 2006;24(Suppl 3):S132–9. [7] World Health Organization (WHO). Human papillomavirus vaccines. WHO position paper. Wkly Epidemiol Rec 2009;84:118-31. Available from: http:// www.who.int/wer/2009/wer8415.pdf. [8] Jit M, Choi YH, Edmunds WJ. Economic evaluation of human papillomavirus vaccination in the United Kingdom. BMJ 2008;a769:337. [9] Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ 2009;b3884:339. [10] Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007;13:28–41. [11] Infectious Diseases Society of America (IDSA) [homepage on the Internet]. Patient care and science. ACIP makes recommendations for HPV vaccine use in males. IDSA News 2009 October;19(10). Available from: http://news.idsociety.org/idsa/ issues/2009-10-31/3.html. [12] Brabin L, Greenberg DP, Hessel L, Hyer R, Ivanoff B, Van Damme P. Current issues in adolescent immunization. Vaccine 2008;26:4120-34. [13] WHO, UNICEF, World Bank. State of the world's vaccines and immunization. 3rd ed. Geneva: WHO; 2009. Available from: http://www.unicef.org/media/files/ SOWVI_full_report_english_LR1.pdf. [14] Gavi Alliance [homepage on the Internet]. Innovative funding. Available from: http://www.gavialliance.org/about/in_finance/index.php. [15] Andrus JK, Sherris J, Fitzsimmons JW, Kane MA, Aguado MT. Introduction of human papillomavirus vaccines into developing countries—international strategies for financing and procurement. Vaccine 2008;26(Suppl 10):K87–92. [16] Merck and Co., Inc. Merck's plan to accelerate access to vaccines in the developing world. 20951760(1) – 07/09. Available from: http://www.merck.com/corporate-responsibility/docs/DW_Backgrounder062909.pdf. [17] Medical News Today [homepage on the Internet]. Global Vaccine Alliance Board approves $3.5B investment strategy that includes HPV vaccine; 2008 Jun 27. Available from: http://www.medicalnewstoday.com/articles/113026.php. [18] International Federation of Pharmaceutical manufacturers and Associations (IFPMA). HPV vaccine and cervical cancer. Available from: http://www.ifpma. org/index.php?id=2134. [19] Goldstein ST, Alter MJ, Williams IT, Moyer LA, Judson FN, Mottram K, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982–1998: implications for vaccination programs. J Infect Dis 2002;85:713–9.
S35
[20] Alter MJ, Hadler SC, Margolis HS, Alexander WJ, Hu PY, Judson FN, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies. JAMA 1990;263:1218–22. [21] Bonanni P, Pesavento G, Bechini A, Tiscione E, Mannelli F, Benucci C, et al. Impact of universal vaccination programmes on the epidemiology of hepatitis B: 10 years of experience in Italy. Vaccine 2003;21:685–91. [22] Kane MA, Brooks A. New immunization initiatives and progress toward the global control of hepatitis B. Curr Opin Infect Dis 2002;5:465–9. [23] Van Damme P, Kane M, Meheus A. Integration of hepatitis B vaccination into national immunisation programmes. Viral Hepatitis Prevention Board. BMJ 1997;314:1033–6. [24] World Health Organization [homepage on the Internet]. Immunization, vaccines and biologicals. Hepatitis B. Available from: http://www.who.int/immunization/ topics/hepatitis_b/en/index.html. [25] McMahon BJ, Bruden DL, Petersen KM, Bulkow LR, Parkinson AJ, Nainan O, et al. Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up. Ann Intern Med 2005;142:333–41. [26] Bonanni P, Boccalini S, Bechini A. Efficacy, duration of immunity and cross protection after HPV vaccination: a review of the evidence. Vaccine 2009;27 (Suppl 1):A46–53. [27] Clements CJ, Baoping Y, Crouch A, Hipgrave D, Mansoor O, Nelson CB, et al. Progress in the control of hepatitis B infection in the Western Pacific Region. Vaccine 2006;24:1975–82. [28] van der Sande MA, Waight PA, Mendy M, Zaman S, Kaye S, Sam O, et al. Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence. PLoS One 2007; e753:2. [29] Chongsrisawat V, Yoocharoen P, Theamboonlers A, Tharmaphornpilas P, Warinsathien P, Sinlaparatsamee S, et al. Hepatitis B seroprevalence in Thailand: 12 years after hepatitis B vaccine integration into the national expanded programme on immunization. Trop Med Int Health 2006;11:1496–502. [30] Centers for Disease Control and Prevention (CDC). Progress in hepatitis B prevention through universal infant vaccination—China, 1997–2006. MMWR Morb Mortal Wkly Rep 2007;56:441–5. [31] Centers for Disease Control and Prevention (CDC). Hepatitis B Information for Health Professionals. Statistics and Surveillance. Available from: http://www.cdc. gov/hepatitis/HBV/StatisticsHBV.htm#section1. [32] Chang MH, You SL, Chen CJ, Liu CJ, Lee CM, Lin SM, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst 2009;101:1348–55.