乙型肝炎疫苗初次免疫成年无应答者再次免疫后4年抗体持久性观察论文

·乙型肝炎疫苗·乙型肝炎疫苗初次免疫成年无应答者再次免疫后4年抗体持久性观察张丽颜丙玉吕静静刘甲野冯艺吴文龙曹传昭陈士玉周立波梁晓峰崔富强王富珍张国民徐爱强【摘要】目的评价乙型肝炎疫苗（HepB）初次免疫成年无应答者再次免疫后4年的免疫持久性。

方法于2009年9月，以山东省章丘市3个乡镇共79个村为研究现场，选取既往无乙型肝炎病毒（HBV）感染史和/或HepB免疫史、居住6个月以上、健康状况良好的18~49岁居民，共24237名。

采集其血标本，采用ELISA方法检测乙型肝炎表面抗原（HBsAg）、乙型肝炎表面抗体（抗-HBc）和乙型肝炎核心抗体（抗-HBc）。

经检测以上3项指标均为阴性者11590名，采用整群随机抽样方法，将其分为4组，按照0-1-6免疫程序分别接种3剂次20μg重组酵母HepB（HepB-SC）、20μg重组中国仓鼠卵巢细胞（HepB-CHO）、10μg HepB-SC和10μg重组汉逊酵母HepB(HepB-HP）进行初次免疫后，对其中的无应答者进行随访（调查基本情况、HBV感染史、HepB免疫史、吸烟史、饮酒史、慢性病史等）并按照相同程序再次免疫，于再次免疫后1个月（T1）和4年（再免后4年），采用化学发光微粒子免疫分析法检测抗-HBs、HBsAg和抗-HBc。

再免后4年，645名初次免疫无应答者中，共随访了356名对象，随访率为55.2%，分别采用多因素非条件logistic回归模型和多因素线性回归模型分析抗-HBs阳性和抗体GMC水平的影响因素。

结果356名随访对象中，男性占48.3%（172名），女性占51.7%（184名）。

T1时抗-HBs阳性率为90.4%（322例），再免后4年为55.9%（199例）；T1时抗-HBs的GMC为240.5（95%CI：186.4~310.4）mU/ml，再免后4年为15.0（95%CI：12.2~18.5）mU/ml。

与T1时抗-HBs的GMC为0~99mU/ml者相比，GMC为100~999或≥1000mU/ml者的抗-HBs阳性率均较高，其OR（95%CI）值分别为7.14（3.90~13.05）和28.40（13.16~61.30）；与T1时抗-HBs的GMC为0~99mU/ml者相比，GMC为100~999或≥1000mU/ml者抗-HBs的GMC亦均较高，其b（95%CI）值分别为1.66（1.26~2.05）和3.16（2.72~3.60）。

再免后4年HBsAg阳转率为0，抗-HBc阳转率为11.0%。

结论HepB初次免疫成年无应答者再免4年后抗-HBs阳性率和GMC均下降，但仍维持在保护水平之上；随访对象的抗体持久性主要与再次免疫后抗体水平有关。

【关键词】成年人；肝炎疫苗，乙型；无应答者；免疫；抗体持久性基金项目：科技重大专项（2012ZX10002001、2013ZX10004902）；山东省医药卫生科技发展计划（2009QZ017、2014WS0373）；山东省泰山学者工程（ts201511105）Anti-HBs persistence after revaccination with three doses of hepatitis B vaccine amongnon-responsive adults:a4-year of follow-up study Zhang Li*,Yan Bingyu,Lyu Jingjing,Liu Jiaye,Feng Yi,Wu Wenlong,Cao Chuanzhao,Chen Shiyu,Zhou Libo,Liang Xiaofeng,Cui Fuqiang,Wang Fuzhen,Zhang Guomin,Xu Aiqiang.*Division of Expanded Immunization Program,Shandong Provincial Center forDisease Control and Prevention,Shandong Provincial Key Laboratory of Infectious Disease Control andPrevention,Jinan250014,ChinaCorresponding author:Xu Aiqiang,Email:aqxuepi@【Abstract】Objective To explore anti-HBs persistence four years after revaccination with hepatitisB vaccine(HepB)among adults who were non-responsive to HepB primary immunization.Methods A totalof24237healthy adults who had no history of hepatitis B infection and hepatitis B vaccination,resided inDOI：10.3760/cma.j.issn.0253-9624.2016.06.005作者单位：250014济南，山东省疾病预防控制中心免疫预防管理所山东省传染病控制重点实验室（张丽、颜丙玉、吕静静、刘甲野、冯艺、吴文龙、徐爱强）；山东省章丘市疾病预防控制中心计划免疫科（曹传昭、陈士玉、周立波）；中国疾病预防控制中心免疫规划中心（梁晓峰、崔富强、王富珍、张国民）通信作者：徐爱强，Email：aqxuepi@the local area for more than six months and aged18-49years were selected from79villages of Zhangqiu County,Shandong Province,China in2009.Blood samples were obtained and hepatitis B surface antigen (HBsAg),antibody against hepatitis B surface antigen(anti-HBs)and antibody against hepatitis B core antigen(anti-HBc)were detected using ELISA method.A total of11590persons who were negative for all of these indicators were divided into four groups by cluster sampling methods.Each group was vaccinated with one of the following four types of HepB at0-1-6months schedule:20μg HepB derived in Saccharomyces cerevisiae(HepB-SC),20μg HepB derived in Chinese hamster ovary cell(HepB-CHO),10μg HepB-SC and 10μg HepB derived in Hansenula polymorpha(HepB-HP).Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay(CMIA).The non-responders were followed up and their basic information and the histories of hepatitis B infection,HepB vaccination,smoking and drinking were investigated.Then they were revaccinated with three doses of HepB with the same schedule as the primary immunization.Blood samples were collected from all of them one month(T1),two years and four years after revaccination and anti-HBs, anti-HBc and HBsAg were detected by CMIA.A total of356participants were followed up from645 low-responders four years after revaccination,and the ratio was55.2%.The risk factors associated with the positive rate and geometric mean concentration(GMC)of anti-HBs after four years of revaccination were analyzed using multivariate unconditional logistic regression model and multivariate linear regression model, respectively.Results Among356participants,172(48.3%)were males and184(51.7%)were females. The anti-HBs positive rate was90.4%(322cases)at T1and was55.9%(199cases)four years after revaccination.The GMC of anti-HBs was240.5(95%CI:186.4-310.4)mU/ml at T1and decreased to15.0 (95%CI:12.2-18.5)mU/ml four years after revaccination.The average annual decreasing rate of GMC was 50.63%from one month after revaccination to four years after revaccination.The corresponding rate was 64.89%in the first two years,which was2.12times the rate in the latter two years(30.57%).When compared with those whose anti-HBs titer was less than99mU/ml at T1,the significantly higher anti-HBs four years after revaccination was observed in those whose anti-HBs titer at T1was100-999mU/ml and those whose anti-HBs titer at T1was≥1000mU/ml.The OR(95%CI)was7.14(3.90-13.05)and28.40(13.16-61.30)respectively.When compared with those whose anti-HBs titer was≤99mU/ml at T1,the GMC of anti-HBs four years after revaccination was also significantly higher among those whose anti-HBs titer at T1 was100-999mU/ml and those whose anti-HBs titer at T1was≥1000mU/ml.The b(95%CI)was1.66(1.26-2.05)and3.16(2.72-3.60),respectively.Conclusion The positive rate and GMC of anti-HBs decreased four years after revaccination among non-responsive adults,but still kept anti-HBs above protective level. The immunity durability after revaccination is mainly associated with anti-HBs titer one month after revaccination.【Key words】Adult;Hepatitis B vaccine;Non-responder;Vaccination;Immune persistence Fund program:Major Project of National Science and Technology(2012ZX10002001, 2013ZX10004902);Shandong Medical and Health Science and Technology Development Programs (2009QZ017,2014WS0373);Taishan Scholar Program of Shandong Province(ts201511105)中国是乙型肝炎流行区，虽然儿童乙型肝炎病毒（hepatitis B virus，HBV）感染已得到有效控制，但成年人乙型肝炎表面抗原（hepatitis B surfaceantigen,HBsAg）阳性率仍在8%以上的较高水平[1]。