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

Anti-HBs persistence after revaccination with three doses of hepatitis B vaccine among non-responsive adults：a 4-year of follow-up study

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0~99 mU/ml者相比，GMC为100~999或≥1000 mU/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0~99 mU/ml者相比，GMC为100~999或≥1000 mU/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。

Objective To explore anti-HBs persistence four years after revaccination with hepatitis B vaccine （HepB） among adults who were non-responsive to HepB primary immunization. Methods A total of 24 237 healthy adults who had no history of hepatitis B infection and hepatitis B vaccination, resided innbsp;the local area for more than six months and aged 18-49 years were selected from 79 villages of Zhangqiu County, Shandong Province, China in 2009. 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 of 11 590 persons 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 at 0-1-6months schedule： 20 μg HepB derived in Saccharomyces cerevisiae （HepB-SC）, 20μg HepB derived in Chinese hamster ovary cell （HepB-CHO）, 10μg HepB-SC and 10 μg 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 of 356 participants were followed up from 645 low-responders four years after revaccination, and the ratio was 55.2%. 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 Among 356 participants, 172 （48.3%） were males and 184 （51.7%） were females. The anti-HBs positive rate was 90.4% （322 cases） at T1 and was 55.9% （199 cases） four years after revaccination. The GMC of anti-HBs was 240.5 （95%CI： 186.4-310.4）mU/ml at T1 and decreased to 15.0 （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 was 2.12 times the rate in the latter two years （30.57%）. When compared with those whose anti-HBs titer was less than 99 mU/ml at T1, the significantly higher anti-HBs four years after revaccination was observed in those whose anti-HBs titer at T1 was 100-999 mU/ml and those whose anti-HBs titer at T1 was≥1 000 mU/ml. The OR （95%CI） was 7.14 （3.90-13.05） and 28.40 （13.16-61.30） respectively. When compared with those whose anti-HBs titer was ≤99 mU/ml at T1, the GMC of anti-HBs four years after revaccination was also significantly higher among those whose anti-HBs titer at T1 was 100-999 mU/ml and those whose anti-HBs titer at T1 was≥1 000 mU/ml. The b （95%CI） was 1.66 （1.26-2.05） and 3.16 （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.