Expert Review of Vaccines
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Chinese vaccine products go global: vaccine development and quality control Miao Xu, Zhenglun Liang, Yinghua Xu & Junzhi Wang To cite this article: Miao Xu, Zhenglun Liang, Yinghua Xu & Junzhi Wang (2015) Chinese vaccine products go global: vaccine development and quality control, Expert Review of Vaccines, 14:5, 763-773 To link to this article: http://dx.doi.org/10.1586/14760584.2015.1012503
Published online: 19 Feb 2015.
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Article views: 52
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View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierv20 Download by: [University of California Santa Barbara]
Date: 14 September 2015, At: 12:21
Review
Chinese vaccine products go global: vaccine development and quality control Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
Expert Rev. Vaccines 14(5), 763–773 (2015)
Miao Xu, Zhenglun Liang, Yinghua Xu and Junzhi Wang* Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, No.2, Tiantan Xili, Dongcheng District, Beijing 100050, People’s Republic of China *Author for correspondence: Tel.: +86 106 709 4993 Fax: +86 106 705 1912 [email protected]
Through the continuous efforts of several generations, China has become one of the few countries in the world that is capable of independently addressing all the requirements by the Expanded Program on Immunization. Regulatory science is applied to continuously improve the vaccine regulatory system. Passing the prequalification by WHO has allowed Chinese vaccine products to go global. Chinese vaccine products not only secure disease prevention and control domestically but also serve the needs for international public health. This article describes the history of Chinese vaccine development, the current situation of Chinese vaccine industry and its contribution to the prevention and control of infectious diseases. We also share our experience of national quality control and vaccine regulation during the past decades. China’s experience in vaccine development and quality control can benefit other countries and regions worldwide, including the developing countries. KEYWORDS: China . infectious diseases . quality control . regulatory science . vaccine . WHO prequalification
Epidemics of infectious diseases once led to high mortality of humans. Even today with advanced science and technology, as well as continuously improved health conditions, emerging infectious diseases still pose major threats to public health. Examples are the 2003 SARS epidemic in China [1], 2009 H1N1 influenza pandemic [2], H7N9 avian influenza [3] and 2014 Ebola virus disease [4]. It is generally accepted that vaccine immunization is the most effective means to prevent infectious diseases. China has one-fifth of the world’s population. How infectious diseases are managed in China could directly affect the prevalence of infectious diseases in other countries. China started to implement the Expanded Program on Immunization (EPI) in 1978. The EPI vaccines have expanded from those preventing six diseases to the current 14 varieties against 15 diseases [5,6]. Through the continuous efforts of EPI in the past 30 years, China has reduced the incidences of major infectious diseases (such as measles, whooping cough, diphtheria and tetanus, epidemic meningitis, Japanese encephalitis (JE), hepatitis B and hepatitis A) to historically low levels and has a poliomyelitis-free status since
informahealthcare.com
10.1586/14760584.2015.1012503
2000 [7–9]. Infectious disease prevention and control with vaccines play an important role in protecting the population and increasing the average life expectancy of Chinese. China’s average life expectancy has increased from 35 years in the 1950s to the current 75 years in 2012 [10]. The achievements in infectious disease prevention and control have not only improved the health condition of Chinese people but also benefited public health worldwide [5]. The history of Chinese vaccine development is a history of infectious disease prevention. Chinese vaccine manufacturers have evolved from a few that were only capable of producing smallpox and typhoid vaccines to the current 41 companies manufacturing 55 types or kinds of vaccines. Currently, the annual production of vaccines in China reaches approximately 700 million doses for prevention and control of 27 infectious diseases. Because vaccines are used in healthy populations, they are under the highest level of regulation, which is essential to ensure the safety and efficacy of marketed vaccines. Since the 21st century, vaccine management has advanced from empirical management with simple sample inspection to comprehensive whole-process
2015 Informa UK Ltd
ISSN 1476-0584
763
Review
Xu, Liang, Xu & Wang
Box 1. List of vaccine products included by Chinese pharmacopoeia (2010 edition) [40]. . . . . . . . .
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Typhoid vaccine Typhoid and paratyphoid A combined vaccine Typhoid and paratyphoid A & B combined vaccine Vi polysaccharide typhoid vaccine Dysentery vaccine (live) of Shigella flexneri and S. sonnei, oral Group A meningococcal polysaccharide vaccine Group A and C meningococcal polysaccharide vaccine Haemophilus influenzae Type B conjugate vaccine Diphtheria vaccine, adsorbed Diphtheria vaccine for adults and adolescents, adsorbed Tetanus vaccine, absorbed Diphtheria and tetanus combined vaccine, adsorbed Diphtheria and tetanus combined vaccine for adults and adolescents, adsorbed Diphtheria and pertussis combined vaccine, adsorbed Diphtheria and tetanus and pertussis combined vaccine, adsorbed Diphtheria and tetanus and acellular pertussis combined vaccine, adsorbed Plague vaccine (live) for percutaneous scarification Anthrax vaccine (live) for percutaneous scarification Brucellosis vaccine (live) for percutaneous scarification BCG vaccine for intradermal injection Leptospira vaccine Japanese encephalitis vaccine, live Japanese encephalitis vaccine (Vero cell), inactivated Tick-borne encephalitis vaccine, inactivated Hemorrhagic fever with renal syndrome vaccine (Vero cell), inactivated Hemorrhagic fever with renal syndrome vaccine (hamster kidney cell), inactivated Hemorrhagic fever with renal syndrome vaccine (gerbil kidney cell), inactivated Rabies vaccine (Vero cell), for human use Rabies vaccine (Vero cell), for human use, freeze-dried Rabies vaccine (hamster kidney cell), for human use Hepatitis A (live) vaccine, freeze-dried Hepatitis A vaccine (human diploid cell), inactivated Recombinant hepatitis B vaccine (Saccharomyces cerevisiae) Recombinant hepatitis B vaccine (CHO cell) Recombinant hepatitis B vaccine (Hansenula polymorpha) Hepatitis A and B combined vaccine Measles vaccine, live Mumps vaccine, live Rubella vaccine (human diploid cell), live Rubella vaccine (rabbit kidney cell), live Measles and mumps combined vaccine, live Measles and rubella combined vaccine, live Measles, mumps and rubella combined vaccine, live Influenza vaccine (whole virion), inactivated Influenza vaccine (split virion), inactivated Poliomyelitis (live) vaccine (monkey kidney cell), oral Poliomyelitis vaccine in dragee candy (human diploid cell), live Poliomyelitis vaccine in dragee candy (monkey kidney cell), live
764
scientific management. The concept of ‘regulatory science’ has been gradually formulated during the development of a variety of new vaccines and the handling of associated regulatory issues [11]. Nowadays, many infectious diseases are well controlled, largely as a result of effective vaccination. Yet, vaccine-related incidences do occur and may often cause public anxiety. In this context, a common challenge faced by China and many other countries is how to manufacture safe and effective vaccines through scientific and stringent management. This article describes the development history of Chinese vaccine industry and its contribution to infectious disease prevention and control. We share our experiences of national quality control and regulation of vaccines during the past decades and discuss the difficulties and challenges in quality control and development of Chinese vaccine products. These experiences in China may benefit other developing countries. Sustainable development of Chinese vaccine industry
As early as 1919, vaccine-manufacturing research institutions had been established in China. At that time, the vaccine products included a limited number of varieties, such as those for typhoid and smallpox. The quality was low, and the quantity was small. After the founding of People’s Republic of China in 1949, six large-scale institutes for developing biological products were established in cities such as Beijing and Shanghai. Through half a century, Chinese vaccine business has gradually embarked on the track of healthy development and continued to develop and manufacture a variety of biologics that are urgently needed for the prevention and treatment of related diseases [12]. To date, China has become one of the few countries in the world that is able to independently address all the requirements of EPI. A total of 41 vaccine manufacturers are established and produce 55 varieties of vaccines for effective prevention of 27 infectious diseases. The vaccines manufactured in China cover most of the vaccine types on the market in developed countries, such as Europe and America (BOX 1). The total Expert Rev. Vaccines 14(5), (2015)
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
Chinese vaccine products go global
production capacity of domestic vaccine manufacturers reaches approximately 700 million doses per year. These domestic vaccine products account for more than 95% of the inoculated vaccines and are therefore able to meet the needs of national prophylactic vaccination. Meanwhile, some imported vaccines from other countries such as diphtheria, tetanus, acellular pertussis, inactivated poliovirus and Haemophilus influenzae Type B combination vaccine, pneumococcal 7-valent conjugate vaccine, have been licensed and available in China and only comprise of less than 5% of all vaccines used every year in China. Furthermore, Chinese vaccine industry has always strived to develop new vaccines. As early as 1950s, Chinese scientists started to develop attenuated JE vaccine [13]. With nearly 30 years of work on strain screening, cultivation and selection, as well as the establishment of criteria for attenuation and quality control, an attenuated JE virus strain (SA14-2) was generated in 1988. Compared with the parental virulent strain SA14, this attenuated strain has 57 nucleotide substitutions across its genome, with 24 amino acid mutations in vial [14]. Further characterization showed that this mutant strain had T minus property, was nonpathogenic in the mouse and formed small plaques in hamster kidney cells [15]. Safety of the live vaccine prepared from the SA14-2 strain was further confirmed in vaccination of several hundred million children. The effectiveness of one-dose vaccination was 80% (95% CI: 44–93%), two-dose vaccination conferred 97.5% protection efficacy (95% CI: 86–99.6%) [16,17]. This live vaccine has also been widely used in JE endemic areas in Southeast Asia [18,19]. The vaccine seed and vaccine production technology have been documented in the WHO Guidelines for the production and control of human-use JE vaccine (live). Since then, China has successfully developed a variety of new vaccines, including attenuated hepatitis A vaccine [20,21] and the world’s first genetically engineered Helicobacter pylori [22] and hepatitis E vaccines [23]. Phase II clinical trials have been completed for the Sabin IPV vaccine, which was developed by the Institute of Medical Biology (Kunming, China) [24]. A number of 449 infants were given IPV; no serious adverse events were reported. After 3 doses, the seroconversion rates reached more than 90%. IPV is expected to address the issues for the oral vaccine-associated paralytic poliomyelitis. Chinese vaccine industry is also committed to develop vaccines against the emerging infectious diseases including H1N1 [25] and EV71 [26,27]. When the H1N1 pandemic occurred in 2009, China took the lead in developing the world’s first H1N1 vaccine. Clinical trials enrolled 95,244 participants between 4 and 60 years of age. This H1N1 vaccine showed an 87.3% (95% CI: 75.4–93.4) protection, had a safety profile similar to those of the seasonal influenza vaccines and was effective against confirmed H1N1 virus infection in school-age children [28]. In addition, Phase III clinical trials of EV71 vaccine have been completed in 30,000 infants. Three EV71 vaccines with different dosage (such as 400, 320 or 100 U) were developed by three Chinese vaccine companies and is expected to help control the severe hand-foot-and-mouth informahealthcare.com
Review
disease, and good safety profile and more than 90% protection efficacy were reported [29–31]. These EV71 vaccines will be a valuable tool in the prevention and control of hand-foot-andmouth disease epidemic in China and other countries. Since the Chinese vaccine regulatory system passed the assessment by WHO in 2011, a few Chinese vaccine companies have begun to apply for WHO prequalification. The WHO vaccine prequalification involves an assessment of manufacturing facilities, quality management systems and products of the vaccine manufacturers. The goal of this process is to ensure that the quality, safety and efficacy of the vaccine products meet the international standards and are suitable for use in the target populations. Vaccines that are recommended for the UN agencies such as the UNICEF must be products that have passed the strict WHO prequalification. With the help of international agencies such as the Bill & Melinda Gates Foundation and the Program for Appropriate Technology in Health of the USA, the Chengdu Institute of Biological Products has improved its vaccine quality assurance system and established the pharmacovigilance system that have met WHO requirements since 2006. With 7 years of efforts, this institute developed the live-attenuated JE vaccine, which became China’s first vaccine product that was prequalified by the WHO in October 2013 [32]. Both dosages (single and five human doses per vial) of JE vaccines are prequalified with more to come. Since 2014, all eligible countries can apply for funds from the Global Alliance for Vaccines and Immunization (GAVI) to purchase the JE vaccine manufactured by China. China has a strong vaccine production capacity covering a wide range of varieties, including those in urgent need internationally, and Chinese vaccine products have competitive prices in the international market and the reliable quality. International organizations, including WHO, GAVI and UNICEF, have turned their attention to China’s vaccine industry and established extensive cooperation with government departments and related manufacturing companies. These partnerships have improved the international reputation of Chinese vaccine companies, and quality management and staff quality. On the contrary, several Chinese vaccine products are entering the international vaccine market by applying for the license in some countries, such as for meningococcal polysaccharide vaccine in Guinea, Zambia and Pakistan, rabies vaccine in Thailand, India and Philippines. In the same period, China has continuously substantiated national policy support for vaccine industry. In the ‘12th FiveYear’ Initiatives, biotechnology is recognized as one of the strategic and emerging industries, and vaccine-associated projects have received strong support. In 2011, the State Council executive meeting approved the Vaccine Supply System Construction Plan. Implementation of this plan has led to updated manufacturing facility for vaccine industry, improved the current vaccine quality inspection system and expanded the vaccine manufacturing capacity and physical reserves. These progresses will continue to accelerate the development of Chinese vaccine industry, especially the production of new vaccine varieties that are urgently needed [33]. 765
Review
Xu, Liang, Xu & Wang
1400000
100 90
1200000
Reported cases
1000000 800000
Measles
60
Polio
50
DTP3
600000
40
MCV
30
Pol3
400000
20 200000 10 0
0 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
70
Pertussis
Immunization coverage
80
Figure 1. A number of reported infectious disease cases and its vaccination coverage in China from 1980 to 2013. These data are based on the official reports [8]. DTP3: Third dose of diphtheria toxoid, tetanus toxoid and pertussis vaccine; MCV: Measles-containing vaccine; Pol 3: Third dose of polio vaccine.
Chinese vaccine immunization program & its contribution to infectious disease prevention & control
During the past 60 years, the immunization program in China has made rapid progress. Since the 1950s, nationwide smallpox vaccination have been carried out. In 1978, China introduced EPI, including the attenuated measles vaccine, live-attenuated poliomyelitis vaccine, whole-cell diphtheria, tetanus, and pertussis combined vaccine, and BCG vaccine. This process reached the goal of ‘4 vaccines against 6 diseases’. A series of other vaccines were gradually included in the national immunization program, including hepatitis B vaccine in 2002; hepatitis A vaccine; meningococcal meningitis vaccine; JE vaccine; and measles, mumps and rubella combined vaccine in 2007. Moreover, the adsorbed diphtheria–tetanus–acellular pertussis vaccine was used to replace the whole-cell diphtheria–tetanus–pertussis vaccine [5,6]. To better control certain infectious diseases, it is recommended that vaccination be given to vulnerable population with epidemic hemorrhagic fever in some targeted areas. When having anthrax and leptospirosis outbreaks or being possible leptospirosis outbreak caused by flood, emergency immunization plan launches to protect high-risk populations. To date, the number of EPI vaccines has reached 14 varieties against 15 infectious diseases. All of these vaccines are available for free vaccination as supported by the Chinese government (BOX 1). Furthermore, the target population of EPI has been expanded from children to adults. Through the successful implementation of EPI, China has eradicated smallpox and substantially reduced the incidences of diphtheria, JE, pertussis and meningococcal meningitis [7]. In October 2000, the WHO’s Western Pacific Region, which covers China, successfully achieved the poliomyelitis-free goal, 766
indicating that China has entered a poliomyelitis-free state [9,34] (FIGURE 1). China frequently performed measles supplementary immunization and regularly monitored measles patients, thereby significantly reducing the incidence of this disease. The 2013 National Report only recorded 27,646 patients with measles [8,35]. After many years of efforts, it was confirmed by the WHO in May 2012 that
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Chinese vaccine products go global: vaccine development and quality control Miao Xu, Zhenglun Liang, Yinghua Xu & Junzhi Wang To cite this article: Miao Xu, Zhenglun Liang, Yinghua Xu & Junzhi Wang (2015) Chinese vaccine products go global: vaccine development and quality control, Expert Review of Vaccines, 14:5, 763-773 To link to this article: http://dx.doi.org/10.1586/14760584.2015.1012503
Published online: 19 Feb 2015.
Submit your article to this journal
Article views: 52
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierv20 Download by: [University of California Santa Barbara]
Date: 14 September 2015, At: 12:21
Review
Chinese vaccine products go global: vaccine development and quality control Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
Expert Rev. Vaccines 14(5), 763–773 (2015)
Miao Xu, Zhenglun Liang, Yinghua Xu and Junzhi Wang* Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, No.2, Tiantan Xili, Dongcheng District, Beijing 100050, People’s Republic of China *Author for correspondence: Tel.: +86 106 709 4993 Fax: +86 106 705 1912 [email protected]
Through the continuous efforts of several generations, China has become one of the few countries in the world that is capable of independently addressing all the requirements by the Expanded Program on Immunization. Regulatory science is applied to continuously improve the vaccine regulatory system. Passing the prequalification by WHO has allowed Chinese vaccine products to go global. Chinese vaccine products not only secure disease prevention and control domestically but also serve the needs for international public health. This article describes the history of Chinese vaccine development, the current situation of Chinese vaccine industry and its contribution to the prevention and control of infectious diseases. We also share our experience of national quality control and vaccine regulation during the past decades. China’s experience in vaccine development and quality control can benefit other countries and regions worldwide, including the developing countries. KEYWORDS: China . infectious diseases . quality control . regulatory science . vaccine . WHO prequalification
Epidemics of infectious diseases once led to high mortality of humans. Even today with advanced science and technology, as well as continuously improved health conditions, emerging infectious diseases still pose major threats to public health. Examples are the 2003 SARS epidemic in China [1], 2009 H1N1 influenza pandemic [2], H7N9 avian influenza [3] and 2014 Ebola virus disease [4]. It is generally accepted that vaccine immunization is the most effective means to prevent infectious diseases. China has one-fifth of the world’s population. How infectious diseases are managed in China could directly affect the prevalence of infectious diseases in other countries. China started to implement the Expanded Program on Immunization (EPI) in 1978. The EPI vaccines have expanded from those preventing six diseases to the current 14 varieties against 15 diseases [5,6]. Through the continuous efforts of EPI in the past 30 years, China has reduced the incidences of major infectious diseases (such as measles, whooping cough, diphtheria and tetanus, epidemic meningitis, Japanese encephalitis (JE), hepatitis B and hepatitis A) to historically low levels and has a poliomyelitis-free status since
informahealthcare.com
10.1586/14760584.2015.1012503
2000 [7–9]. Infectious disease prevention and control with vaccines play an important role in protecting the population and increasing the average life expectancy of Chinese. China’s average life expectancy has increased from 35 years in the 1950s to the current 75 years in 2012 [10]. The achievements in infectious disease prevention and control have not only improved the health condition of Chinese people but also benefited public health worldwide [5]. The history of Chinese vaccine development is a history of infectious disease prevention. Chinese vaccine manufacturers have evolved from a few that were only capable of producing smallpox and typhoid vaccines to the current 41 companies manufacturing 55 types or kinds of vaccines. Currently, the annual production of vaccines in China reaches approximately 700 million doses for prevention and control of 27 infectious diseases. Because vaccines are used in healthy populations, they are under the highest level of regulation, which is essential to ensure the safety and efficacy of marketed vaccines. Since the 21st century, vaccine management has advanced from empirical management with simple sample inspection to comprehensive whole-process
2015 Informa UK Ltd
ISSN 1476-0584
763
Review
Xu, Liang, Xu & Wang
Box 1. List of vaccine products included by Chinese pharmacopoeia (2010 edition) [40]. . . . . . . . .
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Typhoid vaccine Typhoid and paratyphoid A combined vaccine Typhoid and paratyphoid A & B combined vaccine Vi polysaccharide typhoid vaccine Dysentery vaccine (live) of Shigella flexneri and S. sonnei, oral Group A meningococcal polysaccharide vaccine Group A and C meningococcal polysaccharide vaccine Haemophilus influenzae Type B conjugate vaccine Diphtheria vaccine, adsorbed Diphtheria vaccine for adults and adolescents, adsorbed Tetanus vaccine, absorbed Diphtheria and tetanus combined vaccine, adsorbed Diphtheria and tetanus combined vaccine for adults and adolescents, adsorbed Diphtheria and pertussis combined vaccine, adsorbed Diphtheria and tetanus and pertussis combined vaccine, adsorbed Diphtheria and tetanus and acellular pertussis combined vaccine, adsorbed Plague vaccine (live) for percutaneous scarification Anthrax vaccine (live) for percutaneous scarification Brucellosis vaccine (live) for percutaneous scarification BCG vaccine for intradermal injection Leptospira vaccine Japanese encephalitis vaccine, live Japanese encephalitis vaccine (Vero cell), inactivated Tick-borne encephalitis vaccine, inactivated Hemorrhagic fever with renal syndrome vaccine (Vero cell), inactivated Hemorrhagic fever with renal syndrome vaccine (hamster kidney cell), inactivated Hemorrhagic fever with renal syndrome vaccine (gerbil kidney cell), inactivated Rabies vaccine (Vero cell), for human use Rabies vaccine (Vero cell), for human use, freeze-dried Rabies vaccine (hamster kidney cell), for human use Hepatitis A (live) vaccine, freeze-dried Hepatitis A vaccine (human diploid cell), inactivated Recombinant hepatitis B vaccine (Saccharomyces cerevisiae) Recombinant hepatitis B vaccine (CHO cell) Recombinant hepatitis B vaccine (Hansenula polymorpha) Hepatitis A and B combined vaccine Measles vaccine, live Mumps vaccine, live Rubella vaccine (human diploid cell), live Rubella vaccine (rabbit kidney cell), live Measles and mumps combined vaccine, live Measles and rubella combined vaccine, live Measles, mumps and rubella combined vaccine, live Influenza vaccine (whole virion), inactivated Influenza vaccine (split virion), inactivated Poliomyelitis (live) vaccine (monkey kidney cell), oral Poliomyelitis vaccine in dragee candy (human diploid cell), live Poliomyelitis vaccine in dragee candy (monkey kidney cell), live
764
scientific management. The concept of ‘regulatory science’ has been gradually formulated during the development of a variety of new vaccines and the handling of associated regulatory issues [11]. Nowadays, many infectious diseases are well controlled, largely as a result of effective vaccination. Yet, vaccine-related incidences do occur and may often cause public anxiety. In this context, a common challenge faced by China and many other countries is how to manufacture safe and effective vaccines through scientific and stringent management. This article describes the development history of Chinese vaccine industry and its contribution to infectious disease prevention and control. We share our experiences of national quality control and regulation of vaccines during the past decades and discuss the difficulties and challenges in quality control and development of Chinese vaccine products. These experiences in China may benefit other developing countries. Sustainable development of Chinese vaccine industry
As early as 1919, vaccine-manufacturing research institutions had been established in China. At that time, the vaccine products included a limited number of varieties, such as those for typhoid and smallpox. The quality was low, and the quantity was small. After the founding of People’s Republic of China in 1949, six large-scale institutes for developing biological products were established in cities such as Beijing and Shanghai. Through half a century, Chinese vaccine business has gradually embarked on the track of healthy development and continued to develop and manufacture a variety of biologics that are urgently needed for the prevention and treatment of related diseases [12]. To date, China has become one of the few countries in the world that is able to independently address all the requirements of EPI. A total of 41 vaccine manufacturers are established and produce 55 varieties of vaccines for effective prevention of 27 infectious diseases. The vaccines manufactured in China cover most of the vaccine types on the market in developed countries, such as Europe and America (BOX 1). The total Expert Rev. Vaccines 14(5), (2015)
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
Chinese vaccine products go global
production capacity of domestic vaccine manufacturers reaches approximately 700 million doses per year. These domestic vaccine products account for more than 95% of the inoculated vaccines and are therefore able to meet the needs of national prophylactic vaccination. Meanwhile, some imported vaccines from other countries such as diphtheria, tetanus, acellular pertussis, inactivated poliovirus and Haemophilus influenzae Type B combination vaccine, pneumococcal 7-valent conjugate vaccine, have been licensed and available in China and only comprise of less than 5% of all vaccines used every year in China. Furthermore, Chinese vaccine industry has always strived to develop new vaccines. As early as 1950s, Chinese scientists started to develop attenuated JE vaccine [13]. With nearly 30 years of work on strain screening, cultivation and selection, as well as the establishment of criteria for attenuation and quality control, an attenuated JE virus strain (SA14-2) was generated in 1988. Compared with the parental virulent strain SA14, this attenuated strain has 57 nucleotide substitutions across its genome, with 24 amino acid mutations in vial [14]. Further characterization showed that this mutant strain had T minus property, was nonpathogenic in the mouse and formed small plaques in hamster kidney cells [15]. Safety of the live vaccine prepared from the SA14-2 strain was further confirmed in vaccination of several hundred million children. The effectiveness of one-dose vaccination was 80% (95% CI: 44–93%), two-dose vaccination conferred 97.5% protection efficacy (95% CI: 86–99.6%) [16,17]. This live vaccine has also been widely used in JE endemic areas in Southeast Asia [18,19]. The vaccine seed and vaccine production technology have been documented in the WHO Guidelines for the production and control of human-use JE vaccine (live). Since then, China has successfully developed a variety of new vaccines, including attenuated hepatitis A vaccine [20,21] and the world’s first genetically engineered Helicobacter pylori [22] and hepatitis E vaccines [23]. Phase II clinical trials have been completed for the Sabin IPV vaccine, which was developed by the Institute of Medical Biology (Kunming, China) [24]. A number of 449 infants were given IPV; no serious adverse events were reported. After 3 doses, the seroconversion rates reached more than 90%. IPV is expected to address the issues for the oral vaccine-associated paralytic poliomyelitis. Chinese vaccine industry is also committed to develop vaccines against the emerging infectious diseases including H1N1 [25] and EV71 [26,27]. When the H1N1 pandemic occurred in 2009, China took the lead in developing the world’s first H1N1 vaccine. Clinical trials enrolled 95,244 participants between 4 and 60 years of age. This H1N1 vaccine showed an 87.3% (95% CI: 75.4–93.4) protection, had a safety profile similar to those of the seasonal influenza vaccines and was effective against confirmed H1N1 virus infection in school-age children [28]. In addition, Phase III clinical trials of EV71 vaccine have been completed in 30,000 infants. Three EV71 vaccines with different dosage (such as 400, 320 or 100 U) were developed by three Chinese vaccine companies and is expected to help control the severe hand-foot-and-mouth informahealthcare.com
Review
disease, and good safety profile and more than 90% protection efficacy were reported [29–31]. These EV71 vaccines will be a valuable tool in the prevention and control of hand-foot-andmouth disease epidemic in China and other countries. Since the Chinese vaccine regulatory system passed the assessment by WHO in 2011, a few Chinese vaccine companies have begun to apply for WHO prequalification. The WHO vaccine prequalification involves an assessment of manufacturing facilities, quality management systems and products of the vaccine manufacturers. The goal of this process is to ensure that the quality, safety and efficacy of the vaccine products meet the international standards and are suitable for use in the target populations. Vaccines that are recommended for the UN agencies such as the UNICEF must be products that have passed the strict WHO prequalification. With the help of international agencies such as the Bill & Melinda Gates Foundation and the Program for Appropriate Technology in Health of the USA, the Chengdu Institute of Biological Products has improved its vaccine quality assurance system and established the pharmacovigilance system that have met WHO requirements since 2006. With 7 years of efforts, this institute developed the live-attenuated JE vaccine, which became China’s first vaccine product that was prequalified by the WHO in October 2013 [32]. Both dosages (single and five human doses per vial) of JE vaccines are prequalified with more to come. Since 2014, all eligible countries can apply for funds from the Global Alliance for Vaccines and Immunization (GAVI) to purchase the JE vaccine manufactured by China. China has a strong vaccine production capacity covering a wide range of varieties, including those in urgent need internationally, and Chinese vaccine products have competitive prices in the international market and the reliable quality. International organizations, including WHO, GAVI and UNICEF, have turned their attention to China’s vaccine industry and established extensive cooperation with government departments and related manufacturing companies. These partnerships have improved the international reputation of Chinese vaccine companies, and quality management and staff quality. On the contrary, several Chinese vaccine products are entering the international vaccine market by applying for the license in some countries, such as for meningococcal polysaccharide vaccine in Guinea, Zambia and Pakistan, rabies vaccine in Thailand, India and Philippines. In the same period, China has continuously substantiated national policy support for vaccine industry. In the ‘12th FiveYear’ Initiatives, biotechnology is recognized as one of the strategic and emerging industries, and vaccine-associated projects have received strong support. In 2011, the State Council executive meeting approved the Vaccine Supply System Construction Plan. Implementation of this plan has led to updated manufacturing facility for vaccine industry, improved the current vaccine quality inspection system and expanded the vaccine manufacturing capacity and physical reserves. These progresses will continue to accelerate the development of Chinese vaccine industry, especially the production of new vaccine varieties that are urgently needed [33]. 765
Review
Xu, Liang, Xu & Wang
1400000
100 90
1200000
Reported cases
1000000 800000
Measles
60
Polio
50
DTP3
600000
40
MCV
30
Pol3
400000
20 200000 10 0
0 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Downloaded by [University of California Santa Barbara] at 12:21 14 September 2015
70
Pertussis
Immunization coverage
80
Figure 1. A number of reported infectious disease cases and its vaccination coverage in China from 1980 to 2013. These data are based on the official reports [8]. DTP3: Third dose of diphtheria toxoid, tetanus toxoid and pertussis vaccine; MCV: Measles-containing vaccine; Pol 3: Third dose of polio vaccine.
Chinese vaccine immunization program & its contribution to infectious disease prevention & control
During the past 60 years, the immunization program in China has made rapid progress. Since the 1950s, nationwide smallpox vaccination have been carried out. In 1978, China introduced EPI, including the attenuated measles vaccine, live-attenuated poliomyelitis vaccine, whole-cell diphtheria, tetanus, and pertussis combined vaccine, and BCG vaccine. This process reached the goal of ‘4 vaccines against 6 diseases’. A series of other vaccines were gradually included in the national immunization program, including hepatitis B vaccine in 2002; hepatitis A vaccine; meningococcal meningitis vaccine; JE vaccine; and measles, mumps and rubella combined vaccine in 2007. Moreover, the adsorbed diphtheria–tetanus–acellular pertussis vaccine was used to replace the whole-cell diphtheria–tetanus–pertussis vaccine [5,6]. To better control certain infectious diseases, it is recommended that vaccination be given to vulnerable population with epidemic hemorrhagic fever in some targeted areas. When having anthrax and leptospirosis outbreaks or being possible leptospirosis outbreak caused by flood, emergency immunization plan launches to protect high-risk populations. To date, the number of EPI vaccines has reached 14 varieties against 15 infectious diseases. All of these vaccines are available for free vaccination as supported by the Chinese government (BOX 1). Furthermore, the target population of EPI has been expanded from children to adults. Through the successful implementation of EPI, China has eradicated smallpox and substantially reduced the incidences of diphtheria, JE, pertussis and meningococcal meningitis [7]. In October 2000, the WHO’s Western Pacific Region, which covers China, successfully achieved the poliomyelitis-free goal, 766
indicating that China has entered a poliomyelitis-free state [9,34] (FIGURE 1). China frequently performed measles supplementary immunization and regularly monitored measles patients, thereby significantly reducing the incidence of this disease. The 2013 National Report only recorded 27,646 patients with measles [8,35]. After many years of efforts, it was confirmed by the WHO in May 2012 that
