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The inception, achievements, and implications of the China GAVI Alliance Project on Hepatitis B Immunization
Vaccine 31S (2013) J15–J20
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
The inception, achievements, and implications of the China GAVI Alliance Project on Hepatitis B Immunization夽 M.A. Kane a,∗ , S.C. Hadler b , L. Lee c , C.N. Shapiro d , F. Cui e , X. Wang f,1 , R. Kumar g a
Consultant on Immunization Policy, Mercer Island, WA, United States Division of Bacterial Diseases, NCIRD, Centers for Disease Control and Prevention, Atlanta, GA, United States Consultant, Bethesda, MD, United States d Office of Global Affairs, Department of Health and Human Services, Washington, DC, United States e Chinese Center for Disease Control and Prevention, Beijing, China f WHO Regional Office for the Western Pacific, Manila, Philippines g The GAVI Alliance, Geneva, Switzerland b c
a r t i c l e
i n f o
Article history: Received 11 December 2012 Received in revised form 13 March 2013 Accepted 26 March 2013
a b s t r a c t The China GAVI Hepatitis B Immunization Project was initiated in 2002 with the signing of a Memorandum of Understanding between GAVI and the Government of China. The Project was one of the three (China, India, and Indonesia) GAVI-initiated special projects done to support countries too large to receive full GAVI support for hepatitis B vaccine and safe injections. The Project in China was designed by the Chinese Government and partners to deliver free hepatitis B vaccine and safe injections to all newborns in the 12 Western Provinces and Poverty Counties in 10 Provinces of Central China (1301 Counties with approximately 5.6 million births per year), eliminating the gap in immunization coverage between wealthier and poorer regions of China. The project budget (USD 76 million) was equally shared by GAVI and the Chinese Government. Initially planned for 5 years, two no cost extensions extended the project to 2011. Although China produced hepatitis B vaccine, before the project the vaccine was sold to parents who were also charged a “user fee” for the syringe and vaccine administration. Basic Expanded Program on Immunization (EPI) vaccines such as BCG, DTP, Polio, and measles vaccines were provided free to parents, although they were charged a user fee. Vaccines were sold by China CDC Offices at provincial, prefecture, county level and township hospitals, and village doctors received a substantial portion of their income from the sale of hepatitis B and other vaccines. The result of charging for hepatitis B vaccine was that coverage was relatively high in Eastern and wealthier counties in Central China (∼80–90%), but was much lower (∼40%) in Western China and Poverty Counties where parents could not afford the vaccine. The Project was administered by the China MOH and China CDC EPI program, and two Project Co-managers, one from the Chinese Government and the other an international assignee, were chosen. The project had an oversight Operational Advisory Group composed of the Chinese Government, WHO, UNICEF, and GAVI. The initial targets of the project as delineated in the initial MOU for the Project areas (HepB3 coverage will reach 85% at the county level, >75% of newborns at the county level will receive the first dose of hepatitis B within 24 h of birth, and all immunization injections will be with auto disable [AD] syringes) were substantially exceeded. The differential in vaccine coverage between wealthier and poorer parts of China was eliminated contributing to a great improvement in equity. With additional contributions of the Chinese Government the Project was accomplished substantially under budget allowing for additional catch up immunization of children under 15 years of age. More than 5 million health workers were trained in how to deliver hepatitis B vaccine, timely birth dose (TBD), and safe injections, and public awareness of hepatitis B and its prevention rose significantly. TBD coverage was expedited by concurrent efforts to have women deliver in township clinics and district hospitals instead of at home. The effective management of the Project, with a Project office sitting within the China EPI and an Operational Advisory Group for oversight, could serve as a model for other GAVI projects worldwide. Most importantly,
夽 This commentary attempts to put the China GAVI Project into perspective with respect to the landscape of immunization at the inception of the Project, the achievements of the Project, and the implications of the Project for the future of hepatitis B control and introduction of future vaccines in China. It is written from the perspective of the authors and does not necessarily represent the official views of the GAVI Alliance, The Government of China, or institutions to which the authors are currently affiliated. ∗ Corresponding author. E-mail address: [email protected] (M.A. Kane). 1 Co-manager of China GAVI Project (2002–2005). 0264-410X/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.vaccine.2013.03.045
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the carrier rate in Chinese children less than 5 years of age has fallen to 1%, from a level of 10% before the inception of the Project. Liver cancer, one of the major cancer killers in China (250,000–300,000 annual estimated deaths), will dramatically decline as immunized cohorts of Chinese children age. While hepatitis C and non-alcoholic liver disease also exist in China and can lead to liver cancer and cirrhosis, the majority of liver disease in China is hepatitis B related and therefore preventable. The authors believe that China’s success in preventing hepatitis B is one of the greatest public health achievements of the 21st century. Work remains to be done in several key areas. There are still pockets of home births in rural provinces where a TBD is difficult to deliver, and China is strengthening its policy of screening pregnant women for HBsAg and delivering HBIG plus vaccine to newborns of HBV carrier mothers. Approximately 10% of the adult population of China remain chronic carriers of hepatitis B virus and cannot be helped by the vaccine, so prevention of liver cancer and cirrhosis in those groups remains a future challenge for China. © 2013 Published by Elsevier Ltd.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
The immunization landscape that led to the creation of GAVI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B vaccination in China prior to the China GAVI HepB Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inception of the Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of the Project on hepatitis B vaccine coverage in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B vaccine and production in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Project and changes in vaccine financing in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of the Project on timely birth dose and safe injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Injection safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. The immunization landscape that led to the creation of GAVI The success of global immunization efforts led by the Expanded Program for Immunization (EPI) during the 1970s and 1980s culminated in the achievement of Universal Childhood Immunization (UCI) in 1990, where the routine coverage of the basic 6 “EPI” vaccines (BCG, DTP, Polio, and Measles vaccines) increased from 5% in the mid 1970s to 80% by 1990 [1]. This effort, one of the greatest successes in global public health, represented a global partnership of National Immunization Programs in every country, WHO, UNICEF, civil society, non-governmental organizations (NGOs) such as Rotary International, bilateral donors, academia, technical institutes, and the vaccine industry. The underlying paradigm in global health at that time was “Child Survival”, and under that paradigm immunization sat near the top of the list of priorities for countries, UN Agencies, and donors. During that period the basic infrastructure for infant immunization was developed or strengthened in every country and deaths from vaccine preventable diseases fell dramatically in every country. It is important to remember that 80% coverage was a global average and that coverage in sub-Saharan African countries and India remained closer to 50–70%. The basic EPI vaccines were inexpensive: the vaccine cost to fully immunize a child was less than one US Dollar. The cost to deliver the vaccines largely fell to the countries and global donors at the country level. However, during the 1990s several factors converged that largely stalled the progress of global immunization. The underlying paradigm of global public health shifted to “health reform” and “decentralization” [2] and many major donors shifted funding to other activities some feeling that immunization was largely “done”. Health reform advocates often felt that immunization represented the poster child for old style “vertical programs” and blamed the relatively high funding and energy put into immunization for the failure of other less well funded health programs [3,4]. In addition,
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a major effort to eradicate polio was begun and supported by major donors and UN agencies. Polio eradication became the top priority of WHO and some donors, and the introduction of new vaccines often became a secondary priority. At the same time the “Biotechnology Revolution”, using new tools from genetic engineering, was developing a new generation of important vaccines. These new vaccines, still coming online today, initially included DNA recombinant hepatitis B vaccine, conjugated Hib vaccines, and rotavirus vaccines, later followed by pneumococcal conjugate vaccines, newer generations of rotavirus vaccines, human papillomavirus (HPV) vaccines, and new vaccines against cholera, typhoid, and meningococcal meningitis. These vaccines are more complex technically, generally much more expensive than the older EPI vaccines, and start out as protected intellectual property. Unfortunately, during the 1990s the underlying financial infrastructure of global immunization was incapable of funding these new vaccines. This inability to fund new vaccines for the poorest countries plus the inability to sustain and improve general immunization delivery and infrastructure in these countries was the impetus that led to the creation of GAVI. While this is not the venue for a review of the founding of GAVI, it is useful to discuss aspects of early GAVI that relate to the origins of the China GAVI Project [5]. One important decision made by the early GAVI Board and Vaccine Fund was to not make financial commitments beyond funds firmly committed to GAVI. At that time, GAVI was offering eligible countries hepatitis B vaccine as a monovalent or combination vaccine (DTP-HepB) free for 5 years, auto-disable (AD) syringes for three years, and yellow fever and Hib vaccines to some countries. In addition cash grants for infrastructure development (Immunization Services Support (ISS)) were given on a “reward” basis: countries were given an initial investment payment but further funding depended on the country increasing its immunization coverage. Seventy-five countries were initially eligible based on their having a per capita GNP of US$ 1000 or less. However, GAVI could
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not afford to offer free hepatitis B vaccine and ISS support for all children in China, India, and Indonesia, which represented roughly one-third of the world’s children. Therefore, special grants were designed for those countries totaling up to $40 million each. The countries were free to choose the work done under those grants with GAVI approval. All three countries chose projects to enhance the delivery of hepatitis B vaccine, but in different ways. India chose to deliver HB vaccine in 30 pilot areas, Indonesia chose to focus on birth dose delivery, and China chose to deliver vaccine free to parents in Western Provinces and Poverty Countries in Central China. 2. Hepatitis B vaccination in China prior to the China GAVI HepB Project China currently has two classes of vaccines: routine EPI vaccines (class 1) are delivered free of charge to parents, but a second tier of vaccines (class 2) are sold to parents and used if the parents can afford them. Thus, the vaccines a child receives are partially a function of the socio-economic level of the parents. At the time the Project was initiated this resulted in significant disparity in coverage for hepatitis B vaccine (class 2 at that time): in wealthier cities and provinces in Eastern China coverage was high (in the range of 90%) but in poorer Western Provinces and Poverty Counties in Central China the coverage was much lower (in the range of 40%) [6]. Estimated coverage in Tibet was below 10%. Hepatitis B vaccine was sold to parents by the township clinics or by village doctors who added on a service charge for the syringe and for administering the vaccine. The sale of this vaccine provided a significant proportion of the money earned by the clinics and village doctors. In addition, Provincial, Prefect, and County EPS could each add a fee as they passed the vaccine to lower levels of the system. Thus, the potential loss of income at many levels of the system was a significant impediment to making hepatitis B vaccine free to the parents as a routine EPI vaccine. 3. Inception of the Project During the 1990s, within the China MOH and Chinese Academy of Preventive Medicine (CAPM) that became the China CDC, as well as within academia, an influential group of forward thinking leaders began to conceive how hepatitis B vaccine might be included into immunization programs across China. These leaders included (positions are at that time): Dr. Wang Zhao, Director, DDC; Dr. Shao Ruitai, Deputy Director, Department of Disease Control; Dr. Yu Jingjin, Head of EPI; Dr. Wang Kean, Director CAPM; Dr. Zhou Jun, Director of EPI Division MOH; Professor Wang Longde, Vice-Minister of Health; Professor Zhuang Hui, Professor, Department of Microbiology, Beijing Medical University; Professor Zhao Kai, Beijing Institute of Biological Products; and Professor Xu ZhiYi, Shanghai Medical College. With the encouragement of a highly regarded Minister of Health Dr. Chen Minzhang many prominent Chinese physicians in Government and Academia formed the China Hepatitis Foundation, which became an important advocate and technical advisor to China at the inception of the China/GAVI Hepatitis Project. The availability of support from GAVI for hepatitis B vaccine, in combination with new Central and Provincial level funds from China, provided the financial and political opportunity, as well as a management structure to strengthen hepatitis B vaccine coverage in western China and National Poverty Counties in central China. At the inception of the Project in 2002 China had been polio free since 1997, had moderately high immunization coverage nationally but with poorer coverage in western and poverty areas, and funding for vaccines and immunization was provided primarily at
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provincial and lower levels. The Project was consistent with the 2001–2005 plan for the EPI in China, in which the Ministry of Health had established goals in four key areas: (1) achieving maximum coverage among all children for routine immunizations; (2) reducing morbidity and mortality due to vaccine preventable diseases, placing the highest priority on maintaining China polio-free; (3) accelerating hepatitis B control and reducing the prevalence of chronic HBV infection among children <5 years of age; and (4) ensuring immunization injection safety. In addition, the State Council had approved in 2001, in part as a result of the requirements of the Project, a statement from the MOH and the Ministry of Finance that hepatitis B vaccine was to be integrated into routine EPI throughout all of China. However, this statement did not provide guidelines to reduce levels of allowable charges and the fees charged were still too high for many poor families to afford. GAVI asked the Children’s Vaccine Program (CVP) at PATH to work with China to develop a detailed Memorandum of Understanding (MOU) that would delineate the goals and milestones of the project, a management structure, a budget and means for accountability, and methods for monitoring and evaluation such as annual implementation plans and progress reports, specific performance indicators and milestones, and midterm and final project reviews. Dr. Janet Vail from PATH worked with the Chinese Government and GAVI to develop the MOU. The Chinese Government offered to match the GAVI contribution with an equal amount, allowing for a $76 million dollar budget. The project team sat within the National Immunization Program at the China CDC with oversight from the Ministry of Health (MOH). The protocol called for both a Chinese (Dr. Xiaojun Wang, followed by Dr. Fujiang Cui) and an International Project Co-manager (Dr. Craig Shapiro, followed by Dr. Stephen Hadler, and Dr. Yvan Hutin) who was assigned to live in China. The International Project Co-managers were funded by the US CDC Division of Viral Hepatitis and sat at the CAPM (subsequently the China CDC, Dr. Shapiro) or were assigned to WHO China (Drs. Hadler and Hutin). The project was managed by the China CDC National Immunization Program (NIP) office directed by Dr. Liang Xiaofeng. The GAVI Project manager and staff were the Hepatitis Division Chief, NIP, and his staff ensuring Chinese ownership of the project and integration of the project into the day job of their staff. This was critical to the success of the project since the China CDC EPI works closely with the vast network of CDC staff at Central, Provincial, Prefecture, and County levels. A strong monitoring system was built into the project allowing for feedback to all levels of the system strengthening management. It also allowed for effective implementation of large sero-surveys to evaluate the effectiveness and impact of the project [7]. The project was overseen by an Organizational Advisory Group (OAG) composed of stakeholders in the Immunization program chaired by the MOH, which met several times per year. The OAG approved work plans and budgets for the project, assessed progress, and gave advice to the project. Members included the China CDC and MOH, WHO, UNICEF, and a representative of GAVI Geneva. Staff from the China Ministry of Finance, Regulatory Agencies, and others (e.g. the World Bank and JICA) were invited to meetings on an ad hoc basis. The overall management structure of the project proved highly effective throughout the project, which exceeded its milestones for immunization coverage and impact. This success could not have occurred without the exceptional national commitment invested in the project. The establishment of a project office within the National Immunization Program, the international project comanager, and the OAG with diverse stakeholders was unlike how GAVI operates in any other country. It may be a useful model for management of other GAVI projects, as well as other cooperative projects between International or Bilateral donors and National Programs.
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4. Impact of the Project on hepatitis B vaccine coverage in China The initial targets of the project as delineated in the initial MOU (HepB3 coverage will reach 85% at the county level, >75% of newborns at the county level will receive the first dose of hepatitis B within 24 h of birth, and all immunization injections will be with Auto Disable (AD) syringes that cannot be re-used) were substantially exceeded. The progress of the Project was relatively smooth but interrupted by the 2003 SARS epidemic that took the time of all MOH and CDC staff. By 2005 more than 90% of newborns who had received the third dose of DTP (DTP3) had also received the third dose of HB vaccine (HB3), and by 2006 more than 80% of children who had received a first dose of DTP (DTP1) had received a timely birth dose of HB vaccine [8]. The differential in vaccine coverage between wealthier and poorer parts of China was eliminated contributing to a great improvement in equity [9]. The Project was accomplished substantially under budget because the Chinese Government decision to nationally fund Hep B vaccine applied to the project areas and freed up project funds that were reprogrammed to conduct large scale catch-up campaigns to reach children up to 15 years of age who were missed or were too old to have benefited from the routine newborn immunization and for other purposes [9]. The Project, using the CDC network trained 5–6 million health workers about hepatitis B and hepatitis B vaccine, perinatal transmission, and in injection safety and safe disposal of used injection equipment, using information materials developed by the project [10]. Public awareness of hepatitis B and its prevention rose significantly. TBD coverage was expedited by concurrent efforts to have women deliver in township clinics and district hospitals instead of at home. Most importantly, the carrier rate in Chinese children less than 5 years of age has fallen to 1%, from a level of 10% before the inception of the Project.
5. Hepatitis B vaccine and production in China Hepatitis B related liver cancer and cirrhosis is estimated to kill approximately 600,000 people per year and one of the major killers of mankind [11]. Globally, the most common pattern of infection occurs during early childhood where young children are infected either from their carrier mothers (perinatal transmission) or from infection from other family or community contacts (horizontal transmission). Infection during early childhood usually leads to development of a lifelong chronic carrier state which progresses to chronic hepatitis and often death from either cirrhosis or liver cancer. Liver cancer is the first or second cause of cancer death in most of sub-Saharan Africa and eastern Asia. Globally, China (250,000–300,000 yearly deaths) accounts for approximately 50% of hepatitis B related liver cancer deaths. The first of the new vaccine products of the biotechnology revolution was hepatitis B vaccine, first developed as an inactivated product from human plasma, but by the mid 1980s produced by recombinant DNA technology. In Western Countries the new hepatitis B vaccines were expensive (∼$100 per person) and initially targeted to adult high risk groups and to prevent perinatal transmission of the virus. By 1990 it was clear to health officials that the only way to impact community rates of chronic hepatitis and liver cancer globally was to make hepatitis B vaccine a routine part of the National Immunization Program in all countries and deliver it to all infants. In 1992 the World Health Assembly, the governing body of WHO, called for this to happen. The development of hepatitis B vaccines in South Korea that were offered at US $1 per dose for public sector programs put great downward pressure on the cost
of the vaccine from all producers, allowing the vaccine to be used in the developing world. Liver cancer and cirrhosis are such prevalent diseases in China that all major hospitals had liver cancer wards through which most doctors in training rotated. Therefore, when it became clear that chronic hepatitis B infection was the cause of most liver cancer and that a vaccine given at birth could prevent the infection, Chinese doctors and health officials were eager to use it. Since the early 1980s China has developed and produced a number of plasma derived and recombinant hepatitis B vaccines, and a Merck/Government of China partnership built two large factories to produce Merck DNA recombinant vaccine in China [12]. Soon after these production facilities were built and certified the ownership and management of these factories were transferred to the Chinese Government and they are still the source of a significant proportion of the hepatitis B vaccine used in China today. Another significant benefit of the China GAVI project is that it stimulated the Chinese National Control Authorities to work with WHO to improve regulation of all vaccines. Because the project agreement required use of Chinese vaccines which were not “prequalified” by WHO there was initial resistance from some GAVI Partners concerned that this might set a precedent for GAVI that had never before purchased non “pre-qualified” vaccines. WHO pre-qualification requires approval of both the manufacturer and the national control authority [13], and the China State Food and Drug Authority (SFDA) agreed to work with WHO to implement six critical national regulatory authority functions as a pre-requisite for pre-qualifying specific vaccines for UN procurement. This is an essential step in developing an export market for Chinese vaccines and in 2011 WHO certified that the SFDA had successfully implemented the criteria.
6. The Project and changes in vaccine financing in China At initiation of the China GAVI Project, most funding for immunization was provided by Provincial and lower level governments, with limited financial support by the national government. In addition, substantial revenue was generated for clinics and providers through user fees and other administrative charges, as described above. The GAVI requirement for a Financial Sustainability Plan FSP in 2004 provided the incentive for WHO China to invite Dr. Don Shepard of Brandeis University to conduct a detailed evaluation of vaccine financing in China. The 2004 International EPI review focused on immunization costing and financing information and the experiences (GAVI) with hepatitis B, with implications for equity, impact, and new vaccine introduction [14]. The China GAVI Project likely helped to redirect national thinking toward national level funding of vaccines. On March 2005, Premier Jiabao Wen issued a new set of laws on immunizations that addressed many of the key issues raised in the reports, including requirements for government to pay for all costs of the routine immunization program. The Ministry of Health Immunization Advisory Group was also strengthened and in early 2007, MOH announced that the government would fund addition of MMR, DTaP (DPT to be discontinued), Japanese Encephalitis, hepatitis A, hepatitis B, meningococcal A, C and Td to the routine immunization schedule. As well as charging parents for Hep B vaccine, “user fees” for delivery and the cost of the syringe were initially charged to parents as well [15], and these were an important incentive for village doctors to administer the vaccine as well as a source of revenue for Township health centers. Although the GAVI Board was uncomfortable with user fees for any vaccine, believing them to be significant impediments to immunization, the initial MOU allowed for user fees to be charged at the same level as those for other EPI vaccines, and these fees had to be widely advertised. As the GAVI project
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evolved, China began moving away from having the village doctors administer vaccines to encourage parents in rural areas to visit township immunization clinics. The 2003 SARS epidemic was a watershed event for China’s public health system highlighting problems within the system [16]. WHO China played a key role in coordinating the international response to the outbreak. The WHO Report and Recommendations, including recommendations on immunization user fees, was submitted to the MOH and State Council. On 28 August 2004, a new law on infectious diseases was passed, and included elimination of user-fees for routine immunizations nationwide. Following the SARS epidemic, strengthening China’s public health system became a top priority and government investment in CDC’s at all levels greatly expanded including strengthening disease surveillance. The success of the China GAVI project in dramatically raising coverage of both a timely birth dose and full hepatitis B immunization by making the vaccine free to parents was an important factor in the Chinese Government decision to make the vaccine free for all newborns in China in 2005 and likely contributed to the government decision to centrally fund all EPI vaccines in 2007. Reciprocally, these Chinese Government decisions also had major implications for the budget of the Project, since vaccine and syringes were now paid for by the Chinese Government in the GAVI areas as well. This decision freed up funds for other work supporting hepatitis B control, such as operational funds for poor counties to better implement the project, funds to conduct serosurveys, additional training, and funds for catch-up immunization of children under 5 who had not been immunized, and later catch-up immunization of children under 15 years of age. Other factors that led to significant budget savings included fewer births and lower vaccine and syringe prices than had been predicted at the inception of the project. Finally, unspent funds at the end of the project were approved for strengthening the immunization information system. The previous system did not allow seamless transmission of information from the Township CDC office through Prefecture, Provincial, and National level offices, delaying the receipt of timely information that could be used for real time management of the immunization system.
7. Impact of the Project on timely birth dose and safe injections A key issue in China was how to deliver hepatitis B vaccine at birth. This is especially important in China since approximately 30% of Chinese carrier mothers are HBeAg positive and have high titers of circulating virus. Untreated, 90% of children of such mothers become chronic carriers of hepatitis B through perinatal transmission. In 2002, at the inception of the project, approximately 22% of Chinese infants were born at home and births in Township clinics and Hospitals were done by medical staff who were administratively unrelated to the CDC immunization staff and were not trained to deliver vaccines. At the village level village doctors often lacked refrigerators to store vaccines and usually visited the CDC weekly to pick up supplies of vaccines. This made timely birth dose (TBD) within 24 h of delivery difficult or impossible for most home births. A number of studies, some pre-dating the China GAVI Project, were undertaken to study the feasibility of storing the vaccine without refrigeration in the homes of the village doctors for up to a month, and the results of these studies showed this to be an effective strategy with safety and immunogenicity in the infants similar to that obtained with refrigerated vaccine [17,18]. However, the National Regulatory Authorities in China never licensed the vaccine for use in this way. Two important solutions to this problem emerged. First, China strongly encouraged and financially supported women to deliver their babies in Township clinics and hospitals. For China
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as a whole the hospital delivery rate increased from 58% in 2002 to 93% by 2009. The incentive for this was primarily to reduce perinatal and maternal mortality and neonatal tetanus, and it has been effective. An important additional benefit is that infants born in clinics and hospitals can be more easily immunized at birth. Second, part of the success of the GAVI project was to get permission for and train delivery staff to deliver the vaccine at birth, and to ensure that refrigerated vaccine was available and that adequate records were kept. This has been done very successfully and became a model for the Region in the WPRO guidelines for timely birth doses [19]. However, there are still a significant number of home births in some Provinces in China and work to solve this problem must continue after the GAVI project. A third related issue is that of how to deal with infants of HBsAg positive carrier mothers. Although giving a TBD within 24 h is approximately 90% effective in preventing perinatal transmission, studies show some benefit of adding HBIG [20]. However, maternal testing and use of HBIG was not a part of the China GAVI Project. Use of HBIG requires the delivery staff to know the HBsAg status of the mother at the time of delivery. It is common in China to test pregnant women prenatally for HBsAg, but at the time of the project HBIG was expensive, the parents paid for it, it was often unavailable in rural areas, and it was usually not delivered in the hospital [21]. However, since 2011 HBIG is provided free to all infants of HBsAg positive mothers, fully funded by the central government. 8. Injection safety GAVI is also committed to help to solve the problem of unsafe injections, which is responsible for millions of cases of hepatitis B and C and a significant number of HIV infections throughout the developing world. At the time GAVI was started it was estimated that about 12 billion injections per year occurred in the developing world, 40–60% of them unsafe [22]. While immunization accounts for less than 10% of injections, and immunization injections are safer than curative injections because EPI had made safe immunization an important part of its program from its inception, training health workers and the public on the importance of safe injections will have benefits beyond immunization. GAVI supported eligible countries with free AD syringes for three years, and UNICEF and WHO supported supplying only AD syringes for all immunizations [23]. In the China GAVI hepatitis project an AD syringe was shipped with each dose of Hep B vaccine, and project areas were required to purchase AD syringes for all other EPI injections, subsidized in poverty counties with national or provincial funds. The Chinese government now recommends AD syringes for all immunization injections and provides funding to purchase all syringes, but does not require use of AD syringes. Most syringes used in Eastern China are disposable plastic syringes, and curative injections throughout China are given with disposable syringes since sterilizable glass and metal and sterilizable plastic syringes have been phased out as per WHO recommendations. Since the AD syringes are supplied by the Provincial level, it will be important to monitor that Provinces continue to supply AD syringes following the end of the GAVI project. The demand for AD syringes has also led to the development of AD syringe production in China, and the cost of AD syringes has fallen to within a cent of the cost of a disposable syringe [24]. 9. Conclusion The initial targets of the project as delineated in the initial MOU were substantially exceeded. The success of the project was made possible by the synergies between the project goals and larger Chinese Government goals and programs, the ability of the Chinese Government to effectively implement mass immunization
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programs and changes to those programs, and concurrent changes in government policy with financial commitments that will ensure the sustainability of high immunization coverage with HB vaccine and other antigens into the future. The future control of liver cancer and cirrhosis in China through routine hepB immunization is one of the most important global public health achievements of the 21st century and one of the greatest successes of GAVI. It also serves as a model for how other cancers such as cervical cancer can be controlled in the future. More than 90% of countries now use HepB vaccine as a routine part of their National Immunization Programs, a success that could not have happened in the poorest countries without the help of GAVI. China has now “graduated” from GAVI since its per capita GDP is higher than US $1500 and is no longer eligible for GAVI financial support. However, China has much to teach the world about hepatitis B control and how to prevent perinatal transmission and should remain engaged with GAVI as an important partner in the Alliance. The success of hepatitis B immunization in China and globally will in time greatly reduce the burden of liver cancer and cirrhosis, but immunization will not benefit the estimated 300 million chronic carriers of hepatitis B who remain at high risk of death from liver disease. Substantial progress is being made in reducing the risk of liver disease in carriers with anti-viral drugs, but these drugs remain relatively expensive, require trained physicians to administer them properly, and require screening to identify carriers that carries with it risk of discrimination [25]. Although many patients in China are being screened and treated for liver disease in individual clinics, there is no comprehensive government led programs or guidelines for screening or treatment of chronic hepatitis B, and no program to try to make affordable anti-viral drugs available to those that need them. This is an important next step for China in the control of all aspects of hepatitis B.
[3]
[4]
[5] [6] [7]
[8]
[9]
[10] [11] [12] [13]
[14]
[15]
[16]
[17]
Acknowledgements [18]
The authors would like to acknowledge a number of people who made major contributions to the success of the Project. They include: Drs. Liang Xiaofeng, Yvan Hutin, Tore Godal, Alex Palacios, Bai Huqun, Zhou Jun, Lei Zhonglong, Yang Weizhong, Cui Gang, Su Haijun, Feng Zijian, Zhu Xu, Janet Vail, Wang Lixia, David Hipgrave, and Ray Yip. Most importantly, many thousands of individuals working on immunization from the Provincial level to the Village Doctors made this project happen. Conflict of interest statement: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
[19]
[20]
[21]
[22]
[23]
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Geneva, 9–11 June 1998. Document reference GPV-CVI/SAGE.98/WP.13. Geneva: World Health Organization; 1998. Levine R. Should all vertical programs just lie down? Center for Global Development; 2007, October http://blogs.cgdev.org/globalhealth/2007/10/ should-all-vertical-programs-j.php (accessed 14.08.12). Msuya J. Horizontal and vertical delivery of health services: what are the trade offs? The World Bank; 2005 http://www-wds.worldbank.org/external/default/ WDSContentServer/WDSP/IB/2003/10/15/000160016 20031015125129/ additional/310436360 200502761000211.pdf (accessed 14.08.12). GAVI. Origins of GAVI; 2012 http://www.gavialliance.org/about/mission/origins/ (accessed 25.08.12). MOH. National review on national immunization programme in 2004. People Health Express; 2005. Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, et al. Evaluation of the impact of hepatitis B vaccination among children born during 1992–2005 in China. J Infect Dis 2009;200(1):J39–47. Cui F, Luo H, Wang F, Zheng H, Gong X, Chen Y, et al. Evaluation of policies and practices to prevent mother to child transmission of hepatitis B virus in China: results from China GAVI project final evaluation. Vaccine 2013;31: J36–42. Cui FQ, Liang XF, Gong XH, Chen YS, Wang FZ, Zheng H, et al. Preventing hepatitits B through universal vaccination: reduction of inequalities through the China GAVI Project. Vaccine 2013;31:J29–35. Liang X, Cui F, Hadler S, Wang X, Luo H, Chen Y, et al. Origins, design and implementation of the China GAVI project. Vaccine 2013;31:J8–14. WHO. Hepatitis B. Fact sheet N◦ 204 July 2012. http://www.who.int/ mediacentre/factsheets/fs204/en/ (accessed 13.08.12). Vagelos PR, Galambos L. The moral corporation: Merck experiences. Cambridge, UK: Cambridge University Press; 2006. WHO. A system for the prequalification of vaccines for UN supply. http:// www.who.int/immunization standards/vaccine quality/pq system/en/index. html (accessed 27.09.12). World Health Organization China. International Review of the Expanded Programme on Immunizations in China. Beijing: Beijing Reizhe Publishing House; 2005. England S, Kaddar M, Nigam A, Pinto M. Practice and policies on user fees for immunization in developing countries. WHO/V&B/01.07. Geneva: World Health Organization; 2001. Xu X. The impact of SARS on China. Seton Hall Journal of Diplomacy and International Relations 2003 http://www.isn.ethz.ch/isn/Digital-Library/ Publications/Detail/?ots591=0c54e3b3-1e9c-be1e-2c24-a6a8c7060233&lng= en&id=29725 (accessed 15.08.12). Wang SS, Xu ZY, Maynard JE, Prince AM, Beasley RP, Yang JY, et al. Evaluation of the hepatitis B model immunization program in Long’an County, China. J Guangxi Prev Med (Chin) 1995;1:1–4. Wang L, Li J, Chen H, Li F, Armstrong GL, Nelson C, et al. Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out-of-cold-chain delivery strategy. Bull World Health Organ 2007;85:688–94. World Health Organization Regional Office for the Western Pacific. Preventing mother-to child transmission of hepatitis B. Operational field guidelines for delivery of the birth dose of hepatitis B vaccine. Manila, Philippines: World Health Organization Regional Office for Western Pacific; 2006. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database of Syst Rev 2006;2:CD004790 (Online). Hu Y, Zhang S, Luo C, Liu Q, Zhou Y-H. Gaps in the prevention of perinatal transmission of hepatitis B virus between recommendations and routine practices in a highly endemic region: a provincial population-based study in China. BMC Infect Dis 2012;12:221. Simonsen L, Kane A, Lloyd J, Zaffran M, Kane M. Unsafe injections in the developing world and transmission of bloodborne pathogens: a review. Bull World Health Organ 1999;77(10):789–800. Levin A, Pyle D, Dia O, Rock M, Callahan R. Evaluation of GAVI’s injection safety support. Arlington, VA: JSI R&T; 2008. Wu Z, Cui F, Chen Y, Miao N, Gong X, Luo H, et al. Evaluation of immunization injection safety in China, 2010: achievements, future sustainability. Vaccine 2013;31:J43–8. European Association for the Study of the Liver. Revised Clinical Practice Guidelines on the Management of Chronic Hepatitis B. Issue 8 (April 2012). http://www.easl.eu/ clinical-practice-guideline/issue-8-april-2012-revisedclinical-practice-guidelines-on-the-management-of-chronic-hepatitis-B (accessed 17.08.12).
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
The inception, achievements, and implications of the China GAVI Alliance Project on Hepatitis B Immunization夽 M.A. Kane a,∗ , S.C. Hadler b , L. Lee c , C.N. Shapiro d , F. Cui e , X. Wang f,1 , R. Kumar g a
Consultant on Immunization Policy, Mercer Island, WA, United States Division of Bacterial Diseases, NCIRD, Centers for Disease Control and Prevention, Atlanta, GA, United States Consultant, Bethesda, MD, United States d Office of Global Affairs, Department of Health and Human Services, Washington, DC, United States e Chinese Center for Disease Control and Prevention, Beijing, China f WHO Regional Office for the Western Pacific, Manila, Philippines g The GAVI Alliance, Geneva, Switzerland b c
a r t i c l e
i n f o
Article history: Received 11 December 2012 Received in revised form 13 March 2013 Accepted 26 March 2013
a b s t r a c t The China GAVI Hepatitis B Immunization Project was initiated in 2002 with the signing of a Memorandum of Understanding between GAVI and the Government of China. The Project was one of the three (China, India, and Indonesia) GAVI-initiated special projects done to support countries too large to receive full GAVI support for hepatitis B vaccine and safe injections. The Project in China was designed by the Chinese Government and partners to deliver free hepatitis B vaccine and safe injections to all newborns in the 12 Western Provinces and Poverty Counties in 10 Provinces of Central China (1301 Counties with approximately 5.6 million births per year), eliminating the gap in immunization coverage between wealthier and poorer regions of China. The project budget (USD 76 million) was equally shared by GAVI and the Chinese Government. Initially planned for 5 years, two no cost extensions extended the project to 2011. Although China produced hepatitis B vaccine, before the project the vaccine was sold to parents who were also charged a “user fee” for the syringe and vaccine administration. Basic Expanded Program on Immunization (EPI) vaccines such as BCG, DTP, Polio, and measles vaccines were provided free to parents, although they were charged a user fee. Vaccines were sold by China CDC Offices at provincial, prefecture, county level and township hospitals, and village doctors received a substantial portion of their income from the sale of hepatitis B and other vaccines. The result of charging for hepatitis B vaccine was that coverage was relatively high in Eastern and wealthier counties in Central China (∼80–90%), but was much lower (∼40%) in Western China and Poverty Counties where parents could not afford the vaccine. The Project was administered by the China MOH and China CDC EPI program, and two Project Co-managers, one from the Chinese Government and the other an international assignee, were chosen. The project had an oversight Operational Advisory Group composed of the Chinese Government, WHO, UNICEF, and GAVI. The initial targets of the project as delineated in the initial MOU for the Project areas (HepB3 coverage will reach 85% at the county level, >75% of newborns at the county level will receive the first dose of hepatitis B within 24 h of birth, and all immunization injections will be with auto disable [AD] syringes) were substantially exceeded. The differential in vaccine coverage between wealthier and poorer parts of China was eliminated contributing to a great improvement in equity. With additional contributions of the Chinese Government the Project was accomplished substantially under budget allowing for additional catch up immunization of children under 15 years of age. More than 5 million health workers were trained in how to deliver hepatitis B vaccine, timely birth dose (TBD), and safe injections, and public awareness of hepatitis B and its prevention rose significantly. TBD coverage was expedited by concurrent efforts to have women deliver in township clinics and district hospitals instead of at home. The effective management of the Project, with a Project office sitting within the China EPI and an Operational Advisory Group for oversight, could serve as a model for other GAVI projects worldwide. Most importantly,
夽 This commentary attempts to put the China GAVI Project into perspective with respect to the landscape of immunization at the inception of the Project, the achievements of the Project, and the implications of the Project for the future of hepatitis B control and introduction of future vaccines in China. It is written from the perspective of the authors and does not necessarily represent the official views of the GAVI Alliance, The Government of China, or institutions to which the authors are currently affiliated. ∗ Corresponding author. E-mail address: [email protected] (M.A. Kane). 1 Co-manager of China GAVI Project (2002–2005). 0264-410X/$ – see front matter © 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.vaccine.2013.03.045
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the carrier rate in Chinese children less than 5 years of age has fallen to 1%, from a level of 10% before the inception of the Project. Liver cancer, one of the major cancer killers in China (250,000–300,000 annual estimated deaths), will dramatically decline as immunized cohorts of Chinese children age. While hepatitis C and non-alcoholic liver disease also exist in China and can lead to liver cancer and cirrhosis, the majority of liver disease in China is hepatitis B related and therefore preventable. The authors believe that China’s success in preventing hepatitis B is one of the greatest public health achievements of the 21st century. Work remains to be done in several key areas. There are still pockets of home births in rural provinces where a TBD is difficult to deliver, and China is strengthening its policy of screening pregnant women for HBsAg and delivering HBIG plus vaccine to newborns of HBV carrier mothers. Approximately 10% of the adult population of China remain chronic carriers of hepatitis B virus and cannot be helped by the vaccine, so prevention of liver cancer and cirrhosis in those groups remains a future challenge for China. © 2013 Published by Elsevier Ltd.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
The immunization landscape that led to the creation of GAVI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B vaccination in China prior to the China GAVI HepB Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inception of the Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of the Project on hepatitis B vaccine coverage in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hepatitis B vaccine and production in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Project and changes in vaccine financing in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of the Project on timely birth dose and safe injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Injection safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. The immunization landscape that led to the creation of GAVI The success of global immunization efforts led by the Expanded Program for Immunization (EPI) during the 1970s and 1980s culminated in the achievement of Universal Childhood Immunization (UCI) in 1990, where the routine coverage of the basic 6 “EPI” vaccines (BCG, DTP, Polio, and Measles vaccines) increased from 5% in the mid 1970s to 80% by 1990 [1]. This effort, one of the greatest successes in global public health, represented a global partnership of National Immunization Programs in every country, WHO, UNICEF, civil society, non-governmental organizations (NGOs) such as Rotary International, bilateral donors, academia, technical institutes, and the vaccine industry. The underlying paradigm in global health at that time was “Child Survival”, and under that paradigm immunization sat near the top of the list of priorities for countries, UN Agencies, and donors. During that period the basic infrastructure for infant immunization was developed or strengthened in every country and deaths from vaccine preventable diseases fell dramatically in every country. It is important to remember that 80% coverage was a global average and that coverage in sub-Saharan African countries and India remained closer to 50–70%. The basic EPI vaccines were inexpensive: the vaccine cost to fully immunize a child was less than one US Dollar. The cost to deliver the vaccines largely fell to the countries and global donors at the country level. However, during the 1990s several factors converged that largely stalled the progress of global immunization. The underlying paradigm of global public health shifted to “health reform” and “decentralization” [2] and many major donors shifted funding to other activities some feeling that immunization was largely “done”. Health reform advocates often felt that immunization represented the poster child for old style “vertical programs” and blamed the relatively high funding and energy put into immunization for the failure of other less well funded health programs [3,4]. In addition,
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a major effort to eradicate polio was begun and supported by major donors and UN agencies. Polio eradication became the top priority of WHO and some donors, and the introduction of new vaccines often became a secondary priority. At the same time the “Biotechnology Revolution”, using new tools from genetic engineering, was developing a new generation of important vaccines. These new vaccines, still coming online today, initially included DNA recombinant hepatitis B vaccine, conjugated Hib vaccines, and rotavirus vaccines, later followed by pneumococcal conjugate vaccines, newer generations of rotavirus vaccines, human papillomavirus (HPV) vaccines, and new vaccines against cholera, typhoid, and meningococcal meningitis. These vaccines are more complex technically, generally much more expensive than the older EPI vaccines, and start out as protected intellectual property. Unfortunately, during the 1990s the underlying financial infrastructure of global immunization was incapable of funding these new vaccines. This inability to fund new vaccines for the poorest countries plus the inability to sustain and improve general immunization delivery and infrastructure in these countries was the impetus that led to the creation of GAVI. While this is not the venue for a review of the founding of GAVI, it is useful to discuss aspects of early GAVI that relate to the origins of the China GAVI Project [5]. One important decision made by the early GAVI Board and Vaccine Fund was to not make financial commitments beyond funds firmly committed to GAVI. At that time, GAVI was offering eligible countries hepatitis B vaccine as a monovalent or combination vaccine (DTP-HepB) free for 5 years, auto-disable (AD) syringes for three years, and yellow fever and Hib vaccines to some countries. In addition cash grants for infrastructure development (Immunization Services Support (ISS)) were given on a “reward” basis: countries were given an initial investment payment but further funding depended on the country increasing its immunization coverage. Seventy-five countries were initially eligible based on their having a per capita GNP of US$ 1000 or less. However, GAVI could
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not afford to offer free hepatitis B vaccine and ISS support for all children in China, India, and Indonesia, which represented roughly one-third of the world’s children. Therefore, special grants were designed for those countries totaling up to $40 million each. The countries were free to choose the work done under those grants with GAVI approval. All three countries chose projects to enhance the delivery of hepatitis B vaccine, but in different ways. India chose to deliver HB vaccine in 30 pilot areas, Indonesia chose to focus on birth dose delivery, and China chose to deliver vaccine free to parents in Western Provinces and Poverty Countries in Central China. 2. Hepatitis B vaccination in China prior to the China GAVI HepB Project China currently has two classes of vaccines: routine EPI vaccines (class 1) are delivered free of charge to parents, but a second tier of vaccines (class 2) are sold to parents and used if the parents can afford them. Thus, the vaccines a child receives are partially a function of the socio-economic level of the parents. At the time the Project was initiated this resulted in significant disparity in coverage for hepatitis B vaccine (class 2 at that time): in wealthier cities and provinces in Eastern China coverage was high (in the range of 90%) but in poorer Western Provinces and Poverty Counties in Central China the coverage was much lower (in the range of 40%) [6]. Estimated coverage in Tibet was below 10%. Hepatitis B vaccine was sold to parents by the township clinics or by village doctors who added on a service charge for the syringe and for administering the vaccine. The sale of this vaccine provided a significant proportion of the money earned by the clinics and village doctors. In addition, Provincial, Prefect, and County EPS could each add a fee as they passed the vaccine to lower levels of the system. Thus, the potential loss of income at many levels of the system was a significant impediment to making hepatitis B vaccine free to the parents as a routine EPI vaccine. 3. Inception of the Project During the 1990s, within the China MOH and Chinese Academy of Preventive Medicine (CAPM) that became the China CDC, as well as within academia, an influential group of forward thinking leaders began to conceive how hepatitis B vaccine might be included into immunization programs across China. These leaders included (positions are at that time): Dr. Wang Zhao, Director, DDC; Dr. Shao Ruitai, Deputy Director, Department of Disease Control; Dr. Yu Jingjin, Head of EPI; Dr. Wang Kean, Director CAPM; Dr. Zhou Jun, Director of EPI Division MOH; Professor Wang Longde, Vice-Minister of Health; Professor Zhuang Hui, Professor, Department of Microbiology, Beijing Medical University; Professor Zhao Kai, Beijing Institute of Biological Products; and Professor Xu ZhiYi, Shanghai Medical College. With the encouragement of a highly regarded Minister of Health Dr. Chen Minzhang many prominent Chinese physicians in Government and Academia formed the China Hepatitis Foundation, which became an important advocate and technical advisor to China at the inception of the China/GAVI Hepatitis Project. The availability of support from GAVI for hepatitis B vaccine, in combination with new Central and Provincial level funds from China, provided the financial and political opportunity, as well as a management structure to strengthen hepatitis B vaccine coverage in western China and National Poverty Counties in central China. At the inception of the Project in 2002 China had been polio free since 1997, had moderately high immunization coverage nationally but with poorer coverage in western and poverty areas, and funding for vaccines and immunization was provided primarily at
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provincial and lower levels. The Project was consistent with the 2001–2005 plan for the EPI in China, in which the Ministry of Health had established goals in four key areas: (1) achieving maximum coverage among all children for routine immunizations; (2) reducing morbidity and mortality due to vaccine preventable diseases, placing the highest priority on maintaining China polio-free; (3) accelerating hepatitis B control and reducing the prevalence of chronic HBV infection among children <5 years of age; and (4) ensuring immunization injection safety. In addition, the State Council had approved in 2001, in part as a result of the requirements of the Project, a statement from the MOH and the Ministry of Finance that hepatitis B vaccine was to be integrated into routine EPI throughout all of China. However, this statement did not provide guidelines to reduce levels of allowable charges and the fees charged were still too high for many poor families to afford. GAVI asked the Children’s Vaccine Program (CVP) at PATH to work with China to develop a detailed Memorandum of Understanding (MOU) that would delineate the goals and milestones of the project, a management structure, a budget and means for accountability, and methods for monitoring and evaluation such as annual implementation plans and progress reports, specific performance indicators and milestones, and midterm and final project reviews. Dr. Janet Vail from PATH worked with the Chinese Government and GAVI to develop the MOU. The Chinese Government offered to match the GAVI contribution with an equal amount, allowing for a $76 million dollar budget. The project team sat within the National Immunization Program at the China CDC with oversight from the Ministry of Health (MOH). The protocol called for both a Chinese (Dr. Xiaojun Wang, followed by Dr. Fujiang Cui) and an International Project Co-manager (Dr. Craig Shapiro, followed by Dr. Stephen Hadler, and Dr. Yvan Hutin) who was assigned to live in China. The International Project Co-managers were funded by the US CDC Division of Viral Hepatitis and sat at the CAPM (subsequently the China CDC, Dr. Shapiro) or were assigned to WHO China (Drs. Hadler and Hutin). The project was managed by the China CDC National Immunization Program (NIP) office directed by Dr. Liang Xiaofeng. The GAVI Project manager and staff were the Hepatitis Division Chief, NIP, and his staff ensuring Chinese ownership of the project and integration of the project into the day job of their staff. This was critical to the success of the project since the China CDC EPI works closely with the vast network of CDC staff at Central, Provincial, Prefecture, and County levels. A strong monitoring system was built into the project allowing for feedback to all levels of the system strengthening management. It also allowed for effective implementation of large sero-surveys to evaluate the effectiveness and impact of the project [7]. The project was overseen by an Organizational Advisory Group (OAG) composed of stakeholders in the Immunization program chaired by the MOH, which met several times per year. The OAG approved work plans and budgets for the project, assessed progress, and gave advice to the project. Members included the China CDC and MOH, WHO, UNICEF, and a representative of GAVI Geneva. Staff from the China Ministry of Finance, Regulatory Agencies, and others (e.g. the World Bank and JICA) were invited to meetings on an ad hoc basis. The overall management structure of the project proved highly effective throughout the project, which exceeded its milestones for immunization coverage and impact. This success could not have occurred without the exceptional national commitment invested in the project. The establishment of a project office within the National Immunization Program, the international project comanager, and the OAG with diverse stakeholders was unlike how GAVI operates in any other country. It may be a useful model for management of other GAVI projects, as well as other cooperative projects between International or Bilateral donors and National Programs.
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4. Impact of the Project on hepatitis B vaccine coverage in China The initial targets of the project as delineated in the initial MOU (HepB3 coverage will reach 85% at the county level, >75% of newborns at the county level will receive the first dose of hepatitis B within 24 h of birth, and all immunization injections will be with Auto Disable (AD) syringes that cannot be re-used) were substantially exceeded. The progress of the Project was relatively smooth but interrupted by the 2003 SARS epidemic that took the time of all MOH and CDC staff. By 2005 more than 90% of newborns who had received the third dose of DTP (DTP3) had also received the third dose of HB vaccine (HB3), and by 2006 more than 80% of children who had received a first dose of DTP (DTP1) had received a timely birth dose of HB vaccine [8]. The differential in vaccine coverage between wealthier and poorer parts of China was eliminated contributing to a great improvement in equity [9]. The Project was accomplished substantially under budget because the Chinese Government decision to nationally fund Hep B vaccine applied to the project areas and freed up project funds that were reprogrammed to conduct large scale catch-up campaigns to reach children up to 15 years of age who were missed or were too old to have benefited from the routine newborn immunization and for other purposes [9]. The Project, using the CDC network trained 5–6 million health workers about hepatitis B and hepatitis B vaccine, perinatal transmission, and in injection safety and safe disposal of used injection equipment, using information materials developed by the project [10]. Public awareness of hepatitis B and its prevention rose significantly. TBD coverage was expedited by concurrent efforts to have women deliver in township clinics and district hospitals instead of at home. Most importantly, the carrier rate in Chinese children less than 5 years of age has fallen to 1%, from a level of 10% before the inception of the Project.
5. Hepatitis B vaccine and production in China Hepatitis B related liver cancer and cirrhosis is estimated to kill approximately 600,000 people per year and one of the major killers of mankind [11]. Globally, the most common pattern of infection occurs during early childhood where young children are infected either from their carrier mothers (perinatal transmission) or from infection from other family or community contacts (horizontal transmission). Infection during early childhood usually leads to development of a lifelong chronic carrier state which progresses to chronic hepatitis and often death from either cirrhosis or liver cancer. Liver cancer is the first or second cause of cancer death in most of sub-Saharan Africa and eastern Asia. Globally, China (250,000–300,000 yearly deaths) accounts for approximately 50% of hepatitis B related liver cancer deaths. The first of the new vaccine products of the biotechnology revolution was hepatitis B vaccine, first developed as an inactivated product from human plasma, but by the mid 1980s produced by recombinant DNA technology. In Western Countries the new hepatitis B vaccines were expensive (∼$100 per person) and initially targeted to adult high risk groups and to prevent perinatal transmission of the virus. By 1990 it was clear to health officials that the only way to impact community rates of chronic hepatitis and liver cancer globally was to make hepatitis B vaccine a routine part of the National Immunization Program in all countries and deliver it to all infants. In 1992 the World Health Assembly, the governing body of WHO, called for this to happen. The development of hepatitis B vaccines in South Korea that were offered at US $1 per dose for public sector programs put great downward pressure on the cost
of the vaccine from all producers, allowing the vaccine to be used in the developing world. Liver cancer and cirrhosis are such prevalent diseases in China that all major hospitals had liver cancer wards through which most doctors in training rotated. Therefore, when it became clear that chronic hepatitis B infection was the cause of most liver cancer and that a vaccine given at birth could prevent the infection, Chinese doctors and health officials were eager to use it. Since the early 1980s China has developed and produced a number of plasma derived and recombinant hepatitis B vaccines, and a Merck/Government of China partnership built two large factories to produce Merck DNA recombinant vaccine in China [12]. Soon after these production facilities were built and certified the ownership and management of these factories were transferred to the Chinese Government and they are still the source of a significant proportion of the hepatitis B vaccine used in China today. Another significant benefit of the China GAVI project is that it stimulated the Chinese National Control Authorities to work with WHO to improve regulation of all vaccines. Because the project agreement required use of Chinese vaccines which were not “prequalified” by WHO there was initial resistance from some GAVI Partners concerned that this might set a precedent for GAVI that had never before purchased non “pre-qualified” vaccines. WHO pre-qualification requires approval of both the manufacturer and the national control authority [13], and the China State Food and Drug Authority (SFDA) agreed to work with WHO to implement six critical national regulatory authority functions as a pre-requisite for pre-qualifying specific vaccines for UN procurement. This is an essential step in developing an export market for Chinese vaccines and in 2011 WHO certified that the SFDA had successfully implemented the criteria.
6. The Project and changes in vaccine financing in China At initiation of the China GAVI Project, most funding for immunization was provided by Provincial and lower level governments, with limited financial support by the national government. In addition, substantial revenue was generated for clinics and providers through user fees and other administrative charges, as described above. The GAVI requirement for a Financial Sustainability Plan FSP in 2004 provided the incentive for WHO China to invite Dr. Don Shepard of Brandeis University to conduct a detailed evaluation of vaccine financing in China. The 2004 International EPI review focused on immunization costing and financing information and the experiences (GAVI) with hepatitis B, with implications for equity, impact, and new vaccine introduction [14]. The China GAVI Project likely helped to redirect national thinking toward national level funding of vaccines. On March 2005, Premier Jiabao Wen issued a new set of laws on immunizations that addressed many of the key issues raised in the reports, including requirements for government to pay for all costs of the routine immunization program. The Ministry of Health Immunization Advisory Group was also strengthened and in early 2007, MOH announced that the government would fund addition of MMR, DTaP (DPT to be discontinued), Japanese Encephalitis, hepatitis A, hepatitis B, meningococcal A, C and Td to the routine immunization schedule. As well as charging parents for Hep B vaccine, “user fees” for delivery and the cost of the syringe were initially charged to parents as well [15], and these were an important incentive for village doctors to administer the vaccine as well as a source of revenue for Township health centers. Although the GAVI Board was uncomfortable with user fees for any vaccine, believing them to be significant impediments to immunization, the initial MOU allowed for user fees to be charged at the same level as those for other EPI vaccines, and these fees had to be widely advertised. As the GAVI project
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evolved, China began moving away from having the village doctors administer vaccines to encourage parents in rural areas to visit township immunization clinics. The 2003 SARS epidemic was a watershed event for China’s public health system highlighting problems within the system [16]. WHO China played a key role in coordinating the international response to the outbreak. The WHO Report and Recommendations, including recommendations on immunization user fees, was submitted to the MOH and State Council. On 28 August 2004, a new law on infectious diseases was passed, and included elimination of user-fees for routine immunizations nationwide. Following the SARS epidemic, strengthening China’s public health system became a top priority and government investment in CDC’s at all levels greatly expanded including strengthening disease surveillance. The success of the China GAVI project in dramatically raising coverage of both a timely birth dose and full hepatitis B immunization by making the vaccine free to parents was an important factor in the Chinese Government decision to make the vaccine free for all newborns in China in 2005 and likely contributed to the government decision to centrally fund all EPI vaccines in 2007. Reciprocally, these Chinese Government decisions also had major implications for the budget of the Project, since vaccine and syringes were now paid for by the Chinese Government in the GAVI areas as well. This decision freed up funds for other work supporting hepatitis B control, such as operational funds for poor counties to better implement the project, funds to conduct serosurveys, additional training, and funds for catch-up immunization of children under 5 who had not been immunized, and later catch-up immunization of children under 15 years of age. Other factors that led to significant budget savings included fewer births and lower vaccine and syringe prices than had been predicted at the inception of the project. Finally, unspent funds at the end of the project were approved for strengthening the immunization information system. The previous system did not allow seamless transmission of information from the Township CDC office through Prefecture, Provincial, and National level offices, delaying the receipt of timely information that could be used for real time management of the immunization system.
7. Impact of the Project on timely birth dose and safe injections A key issue in China was how to deliver hepatitis B vaccine at birth. This is especially important in China since approximately 30% of Chinese carrier mothers are HBeAg positive and have high titers of circulating virus. Untreated, 90% of children of such mothers become chronic carriers of hepatitis B through perinatal transmission. In 2002, at the inception of the project, approximately 22% of Chinese infants were born at home and births in Township clinics and Hospitals were done by medical staff who were administratively unrelated to the CDC immunization staff and were not trained to deliver vaccines. At the village level village doctors often lacked refrigerators to store vaccines and usually visited the CDC weekly to pick up supplies of vaccines. This made timely birth dose (TBD) within 24 h of delivery difficult or impossible for most home births. A number of studies, some pre-dating the China GAVI Project, were undertaken to study the feasibility of storing the vaccine without refrigeration in the homes of the village doctors for up to a month, and the results of these studies showed this to be an effective strategy with safety and immunogenicity in the infants similar to that obtained with refrigerated vaccine [17,18]. However, the National Regulatory Authorities in China never licensed the vaccine for use in this way. Two important solutions to this problem emerged. First, China strongly encouraged and financially supported women to deliver their babies in Township clinics and hospitals. For China
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as a whole the hospital delivery rate increased from 58% in 2002 to 93% by 2009. The incentive for this was primarily to reduce perinatal and maternal mortality and neonatal tetanus, and it has been effective. An important additional benefit is that infants born in clinics and hospitals can be more easily immunized at birth. Second, part of the success of the GAVI project was to get permission for and train delivery staff to deliver the vaccine at birth, and to ensure that refrigerated vaccine was available and that adequate records were kept. This has been done very successfully and became a model for the Region in the WPRO guidelines for timely birth doses [19]. However, there are still a significant number of home births in some Provinces in China and work to solve this problem must continue after the GAVI project. A third related issue is that of how to deal with infants of HBsAg positive carrier mothers. Although giving a TBD within 24 h is approximately 90% effective in preventing perinatal transmission, studies show some benefit of adding HBIG [20]. However, maternal testing and use of HBIG was not a part of the China GAVI Project. Use of HBIG requires the delivery staff to know the HBsAg status of the mother at the time of delivery. It is common in China to test pregnant women prenatally for HBsAg, but at the time of the project HBIG was expensive, the parents paid for it, it was often unavailable in rural areas, and it was usually not delivered in the hospital [21]. However, since 2011 HBIG is provided free to all infants of HBsAg positive mothers, fully funded by the central government. 8. Injection safety GAVI is also committed to help to solve the problem of unsafe injections, which is responsible for millions of cases of hepatitis B and C and a significant number of HIV infections throughout the developing world. At the time GAVI was started it was estimated that about 12 billion injections per year occurred in the developing world, 40–60% of them unsafe [22]. While immunization accounts for less than 10% of injections, and immunization injections are safer than curative injections because EPI had made safe immunization an important part of its program from its inception, training health workers and the public on the importance of safe injections will have benefits beyond immunization. GAVI supported eligible countries with free AD syringes for three years, and UNICEF and WHO supported supplying only AD syringes for all immunizations [23]. In the China GAVI hepatitis project an AD syringe was shipped with each dose of Hep B vaccine, and project areas were required to purchase AD syringes for all other EPI injections, subsidized in poverty counties with national or provincial funds. The Chinese government now recommends AD syringes for all immunization injections and provides funding to purchase all syringes, but does not require use of AD syringes. Most syringes used in Eastern China are disposable plastic syringes, and curative injections throughout China are given with disposable syringes since sterilizable glass and metal and sterilizable plastic syringes have been phased out as per WHO recommendations. Since the AD syringes are supplied by the Provincial level, it will be important to monitor that Provinces continue to supply AD syringes following the end of the GAVI project. The demand for AD syringes has also led to the development of AD syringe production in China, and the cost of AD syringes has fallen to within a cent of the cost of a disposable syringe [24]. 9. Conclusion The initial targets of the project as delineated in the initial MOU were substantially exceeded. The success of the project was made possible by the synergies between the project goals and larger Chinese Government goals and programs, the ability of the Chinese Government to effectively implement mass immunization
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programs and changes to those programs, and concurrent changes in government policy with financial commitments that will ensure the sustainability of high immunization coverage with HB vaccine and other antigens into the future. The future control of liver cancer and cirrhosis in China through routine hepB immunization is one of the most important global public health achievements of the 21st century and one of the greatest successes of GAVI. It also serves as a model for how other cancers such as cervical cancer can be controlled in the future. More than 90% of countries now use HepB vaccine as a routine part of their National Immunization Programs, a success that could not have happened in the poorest countries without the help of GAVI. China has now “graduated” from GAVI since its per capita GDP is higher than US $1500 and is no longer eligible for GAVI financial support. However, China has much to teach the world about hepatitis B control and how to prevent perinatal transmission and should remain engaged with GAVI as an important partner in the Alliance. The success of hepatitis B immunization in China and globally will in time greatly reduce the burden of liver cancer and cirrhosis, but immunization will not benefit the estimated 300 million chronic carriers of hepatitis B who remain at high risk of death from liver disease. Substantial progress is being made in reducing the risk of liver disease in carriers with anti-viral drugs, but these drugs remain relatively expensive, require trained physicians to administer them properly, and require screening to identify carriers that carries with it risk of discrimination [25]. Although many patients in China are being screened and treated for liver disease in individual clinics, there is no comprehensive government led programs or guidelines for screening or treatment of chronic hepatitis B, and no program to try to make affordable anti-viral drugs available to those that need them. This is an important next step for China in the control of all aspects of hepatitis B.
[3]
[4]
[5] [6] [7]
[8]
[9]
[10] [11] [12] [13]
[14]
[15]
[16]
[17]
Acknowledgements [18]
The authors would like to acknowledge a number of people who made major contributions to the success of the Project. They include: Drs. Liang Xiaofeng, Yvan Hutin, Tore Godal, Alex Palacios, Bai Huqun, Zhou Jun, Lei Zhonglong, Yang Weizhong, Cui Gang, Su Haijun, Feng Zijian, Zhu Xu, Janet Vail, Wang Lixia, David Hipgrave, and Ray Yip. Most importantly, many thousands of individuals working on immunization from the Provincial level to the Village Doctors made this project happen. Conflict of interest statement: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
[19]
[20]
[21]
[22]
[23]
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