中国儿童用联合疫苗免疫策略的探讨
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摘要
自2007年起,中国开始扩大国家免疫规划(National Immunization Program, NIP)范围,疫苗种类由原来的6种扩大到14种,预防的传染病由7种增加至15种,这是中国免疫规划史上的一个重要里程碑。随着已经上市或将要上市的"新疫苗"越来越多,绝大多数针对婴幼儿和儿童的疫苗为儿童预防疾病带来福音的同时,也增加了儿童接种疫苗的剂次。儿童要完成全部免疫接种,在2岁之前需要接种疫苗20余剂次,如果再选择一些"新疫苗"来预防NIP之外的其他疾病,则需要接种更多剂次。接种针次过多,不但增加了为完成接种所需的服务和社会成本,还增加了发生疑似预防接种异常反应的风险。联合疫苗可以减少接种剂次,提高接种率,其应用在国外已成为主流。目前国外联合最多的是能同时预防百日咳、白喉、破伤风、脊髓灰质炎、乙型肝炎(乙肝)及b型流感嗜血杆菌引起的感染这6种疾病的六联疫苗,而国内目前只有五联疫苗在上市使用。新型联合疫苗(如含乙肝疫苗的联合疫苗)在中国上市使用可能会遇到其包含的单苗成分与NIP中单苗程序不一致的问题。是否允许联合疫苗在接种程序上有一定的灵活度,未来含乙肝疫苗的联合疫苗是否可以在中国使用,国内外有何借鉴经验,尚需深入讨论。笔者结合2018年11月在北京召开的"联合免疫研讨会"专家们的意见,对联合疫苗的使用从不同角度提出思考,为今后联合疫苗的研发上市及未来应用策略提供参考。
Since 2007, China has begun to expand the scope of its National Immunization Program(NIP), expanding the number of vaccines from 6 to 14, and increasing the number of infectious diseases from 7 to 15, which was a great milestone in the history of China′s immunization program.At the same time, there are more and more new vaccines on the market, most of which are for infants and children.Though these vaccines bring many benefits for children to prevent diseases, the doses of injection increase as well.A child have to accept more than 20 doses of vaccines before 2 years old to complete the vaccination of NIP.If some new vaccines are selected to prevent diseases uncovered by NIP, more doses are needed.This not only increases the service and social costs for the completion of vaccination, but also increases the risk of adverse events following immunization.Combined vaccines can reduce the number of vaccinations and improve the vaccination rate, and their application has been mainstreamed in foreign countries.At present, the hexavalent vaccine can prevent most kinds of diseases including pertussis, diphtheria, tetanus, poliomyelitis, hepatitis B and infection caused by haemophilus influenzae type b.It is used widely in foreign countries, while only pentavalent vaccine is currently used in domestic market.The problem that inconsistent schedules between new combined vaccines(such as those containing hepatitis B vaccine) and standalone vaccine might be met when they are put on the market in China.In the future, whether the combined vaccines can be allowed to have certain flexibility about the schedule,whether the combined vaccines containing HepB can be used in China,and what lessons we can learn from abroad are of great interest to us and need depth discussion.Based on expertise and comments made by experts who attended the "Seminar on the Immunization Strategy of Combination Vaccine" held in November 2018 in Beijing,we put forward thoughts from different perspectives to provide reference for the future development,application and immunization strategy of combined vaccine.
Since 2007, China has begun to expand the scope of its National Immunization Program(NIP), expanding the number of vaccines from 6 to 14, and increasing the number of infectious diseases from 7 to 15, which was a great milestone in the history of China′s immunization program.At the same time, there are more and more new vaccines on the market, most of which are for infants and children.Though these vaccines bring many benefits for children to prevent diseases, the doses of injection increase as well.A child have to accept more than 20 doses of vaccines before 2 years old to complete the vaccination of NIP.If some new vaccines are selected to prevent diseases uncovered by NIP, more doses are needed.This not only increases the service and social costs for the completion of vaccination, but also increases the risk of adverse events following immunization.Combined vaccines can reduce the number of vaccinations and improve the vaccination rate, and their application has been mainstreamed in foreign countries.At present, the hexavalent vaccine can prevent most kinds of diseases including pertussis, diphtheria, tetanus, poliomyelitis, hepatitis B and infection caused by haemophilus influenzae type b.It is used widely in foreign countries, while only pentavalent vaccine is currently used in domestic market.The problem that inconsistent schedules between new combined vaccines(such as those containing hepatitis B vaccine) and standalone vaccine might be met when they are put on the market in China.In the future, whether the combined vaccines can be allowed to have certain flexibility about the schedule,whether the combined vaccines containing HepB can be used in China,and what lessons we can learn from abroad are of great interest to us and need depth discussion.Based on expertise and comments made by experts who attended the "Seminar on the Immunization Strategy of Combination Vaccine" held in November 2018 in Beijing,we put forward thoughts from different perspectives to provide reference for the future development,application and immunization strategy of combined vaccine.
引文
[1] National Health and Family Planning Commission of the People′s Republic of China.Immunization schedules and instructions for vaccines of the National Immunization Program(2016 Version)[J].Zhongguo Bingdubing Zazhi,2017,7(2):5-10.(in Chinese)中华人民共和国国家卫生和计划生育委员会.国家免疫规划疫苗儿童免疫程序及说明(2016年版)[J].中国病毒病杂志,2017,7(2):5-10.
[2] Pellissier JM,Coplan PM,Jackson LA,et al.The effect of additional shots on the vaccine administration process:results of a time-motion study in 2 settings [J].Am J Managed Care,2000,6(9):1038.
[3] Koslap-Petraco MB,Judelsohn RG.Societal impact of combination vaccines:experiences of physicians,nurses,and parents[J].J Pediat Health Care,2008,22(5):300-309.
[4] Lei ZL,Li QL,Li L.Looking back on the achievements of national immunization program,fully aware of the challenges facing us and be confident and down-to-earth to do a good job in the future[J].Zhongguo Yimiao He Mianyi,2014,20(5):385-388.(in Chinese)雷正龙,李全乐,李黎.回顾免疫规划工作成绩斐然清醒认识面临的挑战充满信心脚踏实地做好今后工作[J].中国疫苗和免疫,2014,20(5):385-388.
[5] Hadler SC,de Monzon MA,Lugo DR,et al.Effect of timing of hepatitis B vaccine doses on response to vaccine in Yucpa Indians[J].Vaccine,1989,7(2):106-110.
[6] Middleman AB,Kozinetz CA,Robertson LM,et al..The effect of late doses on the achievement of seroprotection and antibody titer levels with Hepatitis B immunization among adolescents[J].Pediatrics,2001,107 (5):1065-1069.
[7] Yang JY,Xu ZY.Study on the different immunization schedule of hepatitis B vaccine after introduced into expanded programme on immunization (EPI)[J].Guangxi Yixue,1994,16(3):281-283.(in Chinese)杨进业,徐志一.乙肝疫苗纳入计划免疫(EPI)不同免疫程序的研究[J].广西医学,1994,16(3):281-283.
[8] Xiao M.Immune response in infants after universal high-dose hepatitis B vaccination:a community-based study in Beijing,China[D].Beijing:Peking Union Medical College,Tsinghua Uninversity,2015.(in Chinese)肖敏.北京市新生儿高剂量乙肝疫苗免疫效果及其影响因素研究[D].北京:北京协和医学院中国医学科学院清华大学医学部,2015.
[9] Tharmaphornpilas P,Rasdjarmrearnsook AO,Plianpanich S,et al.Increased risk of developing chronic HBV infection in infants born to chronically HBV infected mothers as a result of delayed second dose of hepatitis B vaccination[J].Vaccine,2009,27(44):6110-6115.
[10] Chen HF,Guo ZH,Gu YZ,et al.Study on the relationship between the immune effect and the second injection interval of hepatitis B vaccine in newborns[J].Zhonghua Liuxingbingxue Zazhi,1994,14(6):349-350.(in Chinese)陈惠峰,郭志宏,顾云忠,等.新生儿乙肝疫苗第2针接种时间与免疫效果关系研究[J].中华流行病学杂志,1994,14(6):349-350.
[11] Cui FQ,Shen LP,Li L,et al.Prevention of chronic hepatitis B after 3 decades of escalating vaccination policy,China[J].Emerg Infect Dis,2017,23(5):765-772.
[12] Liang X,Bi S,Yang W,et al.Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination[J].Vaccine,2009,27(47):6550-6557.
[13] Zheng H,Cui FQ,Gong XH,et al.Status of the hepatitis B virus surface antigen and e antigen prevalence among reproductive women in China[J].Zhongguo Yimiao He Mianyi,2010,16(6):496-499.(in Chinese)郑徽,崔富强,龚晓红,等.我国育龄期妇女乙型肝炎病毒表面抗原及e抗原流行情况分析[J].中国疫苗和免疫,2010,16(6):496-499.
[14] Xin X,Wang Y,Cheng J,et al.Seroepidemiological survey of hepatitis B virus infection among 764,460 women of childbearing age in rural China:a cross-sectional study[J].J Clin Virol,2016,81:47-52.
[15] Marcy SM.Pediatric combination vaccines:their impact on patients,providers,managed care organizations,and manufactures[J].Am J Manag Care,2003,9(4):314-320.
[16] WHO.Hepatitis B vaccines:WHO position paper,July 2017[J].Weekly Epidemiol Record,2017,7(92):369-392.
[17] Blumberg EA.Prevention of hepatitis B virus infection in the United States:recommendations of the advisory committee on immunization practices:a summary of the MMWR report[J].Am J Transplantat,2018,18(5):1285-1286.
[18] Xia GL,Gong J,Wang JJ,et al.Efficacy of recombinant hepatitis B vaccine and low-dose hepatitis B immune globulin in preventing mother-infant transmission of hepatitis B virus infection[J].Zhonghua Liuxingbingxue Zazhi,2003,24(5):362-365.(in Chinese)夏国良,龚健,王继杰,等.重组乙型肝炎疫苗阻断乙型肝炎病毒母婴传播方案的保护效果评价[J].中华流行病学杂志,2003,24(5):362-365.
[19] Chinese Society of Hepatology,Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B(2015 version)[J].Zhongguo Ganzangbing Zazhi(Dianzi Ban),2015,19(5):1-18.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年版)[J].中国肝脏病杂志(电子版),2015,19(5):1-18.
[20] Obstetrics section,Chinese Society of Obstetrics and Gynecology,Chinese Medical Association.Clinical guidelines for prevention of mother-to-child transmission of hepatitis B virus(first version)[J].Zhonghua Fuchanke Zazhi,2013,48(2):151.(in Chinese)中华医学会妇产科学分会产科学组.乙型肝炎病毒母婴传播预防临床指南(第1版)[J].中华妇产科杂志,2013,48(2):151.
[21] Wang FZ,Zheng H,Zhang GM,et al.Sero-epidemiological analysis on hepatitis B among children aged 1-14 years old born to HBsAg positive mother in China,2014[J].Zhonghua Liuxingbingxue Zazhi,2017,38(4):457-461.(in Chinese)王富珍,郑徽,张国民,等.中国2014年HBsAg阳性母亲所生1～14岁儿童乙型肝炎血清流行病学特征分析[J].中华流行病学杂志,2017,38(4):457-461.
[2] Pellissier JM,Coplan PM,Jackson LA,et al.The effect of additional shots on the vaccine administration process:results of a time-motion study in 2 settings [J].Am J Managed Care,2000,6(9):1038.
[3] Koslap-Petraco MB,Judelsohn RG.Societal impact of combination vaccines:experiences of physicians,nurses,and parents[J].J Pediat Health Care,2008,22(5):300-309.
[4] Lei ZL,Li QL,Li L.Looking back on the achievements of national immunization program,fully aware of the challenges facing us and be confident and down-to-earth to do a good job in the future[J].Zhongguo Yimiao He Mianyi,2014,20(5):385-388.(in Chinese)雷正龙,李全乐,李黎.回顾免疫规划工作成绩斐然清醒认识面临的挑战充满信心脚踏实地做好今后工作[J].中国疫苗和免疫,2014,20(5):385-388.
[5] Hadler SC,de Monzon MA,Lugo DR,et al.Effect of timing of hepatitis B vaccine doses on response to vaccine in Yucpa Indians[J].Vaccine,1989,7(2):106-110.
[6] Middleman AB,Kozinetz CA,Robertson LM,et al..The effect of late doses on the achievement of seroprotection and antibody titer levels with Hepatitis B immunization among adolescents[J].Pediatrics,2001,107 (5):1065-1069.
[7] Yang JY,Xu ZY.Study on the different immunization schedule of hepatitis B vaccine after introduced into expanded programme on immunization (EPI)[J].Guangxi Yixue,1994,16(3):281-283.(in Chinese)杨进业,徐志一.乙肝疫苗纳入计划免疫(EPI)不同免疫程序的研究[J].广西医学,1994,16(3):281-283.
[8] Xiao M.Immune response in infants after universal high-dose hepatitis B vaccination:a community-based study in Beijing,China[D].Beijing:Peking Union Medical College,Tsinghua Uninversity,2015.(in Chinese)肖敏.北京市新生儿高剂量乙肝疫苗免疫效果及其影响因素研究[D].北京:北京协和医学院中国医学科学院清华大学医学部,2015.
[9] Tharmaphornpilas P,Rasdjarmrearnsook AO,Plianpanich S,et al.Increased risk of developing chronic HBV infection in infants born to chronically HBV infected mothers as a result of delayed second dose of hepatitis B vaccination[J].Vaccine,2009,27(44):6110-6115.
[10] Chen HF,Guo ZH,Gu YZ,et al.Study on the relationship between the immune effect and the second injection interval of hepatitis B vaccine in newborns[J].Zhonghua Liuxingbingxue Zazhi,1994,14(6):349-350.(in Chinese)陈惠峰,郭志宏,顾云忠,等.新生儿乙肝疫苗第2针接种时间与免疫效果关系研究[J].中华流行病学杂志,1994,14(6):349-350.
[11] Cui FQ,Shen LP,Li L,et al.Prevention of chronic hepatitis B after 3 decades of escalating vaccination policy,China[J].Emerg Infect Dis,2017,23(5):765-772.
[12] Liang X,Bi S,Yang W,et al.Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination[J].Vaccine,2009,27(47):6550-6557.
[13] Zheng H,Cui FQ,Gong XH,et al.Status of the hepatitis B virus surface antigen and e antigen prevalence among reproductive women in China[J].Zhongguo Yimiao He Mianyi,2010,16(6):496-499.(in Chinese)郑徽,崔富强,龚晓红,等.我国育龄期妇女乙型肝炎病毒表面抗原及e抗原流行情况分析[J].中国疫苗和免疫,2010,16(6):496-499.
[14] Xin X,Wang Y,Cheng J,et al.Seroepidemiological survey of hepatitis B virus infection among 764,460 women of childbearing age in rural China:a cross-sectional study[J].J Clin Virol,2016,81:47-52.
[15] Marcy SM.Pediatric combination vaccines:their impact on patients,providers,managed care organizations,and manufactures[J].Am J Manag Care,2003,9(4):314-320.
[16] WHO.Hepatitis B vaccines:WHO position paper,July 2017[J].Weekly Epidemiol Record,2017,7(92):369-392.
[17] Blumberg EA.Prevention of hepatitis B virus infection in the United States:recommendations of the advisory committee on immunization practices:a summary of the MMWR report[J].Am J Transplantat,2018,18(5):1285-1286.
[18] Xia GL,Gong J,Wang JJ,et al.Efficacy of recombinant hepatitis B vaccine and low-dose hepatitis B immune globulin in preventing mother-infant transmission of hepatitis B virus infection[J].Zhonghua Liuxingbingxue Zazhi,2003,24(5):362-365.(in Chinese)夏国良,龚健,王继杰,等.重组乙型肝炎疫苗阻断乙型肝炎病毒母婴传播方案的保护效果评价[J].中华流行病学杂志,2003,24(5):362-365.
[19] Chinese Society of Hepatology,Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for chronic hepatitis B(2015 version)[J].Zhongguo Ganzangbing Zazhi(Dianzi Ban),2015,19(5):1-18.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年版)[J].中国肝脏病杂志(电子版),2015,19(5):1-18.
[20] Obstetrics section,Chinese Society of Obstetrics and Gynecology,Chinese Medical Association.Clinical guidelines for prevention of mother-to-child transmission of hepatitis B virus(first version)[J].Zhonghua Fuchanke Zazhi,2013,48(2):151.(in Chinese)中华医学会妇产科学分会产科学组.乙型肝炎病毒母婴传播预防临床指南(第1版)[J].中华妇产科杂志,2013,48(2):151.
[21] Wang FZ,Zheng H,Zhang GM,et al.Sero-epidemiological analysis on hepatitis B among children aged 1-14 years old born to HBsAg positive mother in China,2014[J].Zhonghua Liuxingbingxue Zazhi,2017,38(4):457-461.(in Chinese)王富珍,郑徽,张国民,等.中国2014年HBsAg阳性母亲所生1～14岁儿童乙型肝炎血清流行病学特征分析[J].中华流行病学杂志,2017,38(4):457-461.