乙型肝炎疫苗低无应答婴儿再次免疫9年抗体水平分析

Antibody persistence after revaccination with three doses of hepatitis B vaccine among infants with non-and low-response following primary vaccination:9-year of follow-up

目的分析乙型肝炎疫苗(HepB)初次免疫(初免)低无应答婴儿再次免疫(再免)9年抗体持久性。方法2009-08-2009-09,在山东省济南、潍坊、烟台和威海4个市,按照分层整群抽样方法抽取75个乡镇,对抽取乡镇中所有按照"0-1-6"程序接种5μg重组酿酒酵母HepB的4147名婴儿,于第3剂次后1~6个月时采集静脉血2mL,经化学发光微粒子免疫分析法(CMIA)检测抗-HBs水平<100mIU/mL者共796名,即低应答和无应答者(低无应答)为入组对象;2个月后,对上述低无应答者分别使用5μg重组酿酒酵母HepB和10μg重组汉逊酵母HepB进行3剂次再免,共有555名婴儿完成再免和免后血标本采集(T0);2014年6-7月(T1)、2019年6-7月(T2),采集静脉血3~5mL使用CMIA法检测抗-HBs和抗-HBc,排除自行接种者,共随访到296名低无应答者。分析T2时抗-HBs阳性率和几何平均浓度(GMC);分别采用多因素非条件Logistic回归模型和多因素线性逐步回归模型分析T2时抗-HBs阳性率和GMC的影响因素。结果T0时296名调查对象抗-HBs阳性率(抗-HBs≥10mIU/mL者所占的比例)为100%,T2时降为59.46%(95%CI为53.63%~65.10%),总降幅达40.54%,T0~T29年间抗-HBs阳性率年均递减率为5.61%;T0时抗-HBs的GMC为906.22(95%CI为800.13~1026.37)mIU/mL,T2时降为17.79(95%CI为14.93~21.19)mIU/mL,T0~T29年间抗-HBs GMC年均递减率为35.39%。多因素分析结果显示,T2时抗-HBs阳性率和GMC与T0时抗-HBs水平与性别有关,与T0时抗-HBs<1000mIU/mL者相比,T0时抗-HBs≥1000mIU/mL者T2时抗体阳性率和GMC均较高,OR(95CI)为3.92(92.33~6.63),b(95%CI)为1.00(0.87~1.14);与男性相比,女性T2时抗体阳性率和GMC较低,OR(95%CI)为0.57(0.35~0.94),b(95%CI)为-0.35(-0.68~-0.01)。结论HepB低应答婴儿再免后9年仍有>50%抗-HBs保持在保护水平以上,低应答婴儿再免后抗体持久性和再免后1个月抗体水平均与性别有关;突破性感染率较低。

Objective To assess the 9-year Immune persistence after revaccination with 3-dose of hepatitis B vaccine(HepB)among infants with non-and low-response following primary HepB vaccination.Methods According to stratified cluster sampling,a total of 4147 infants were enrolled and primarily vaccinated with 5μg HepB derived in Saccharomyces Cerevisiae(HepB-SC)at 0-,1-,6-months schedule from 75 towns of Jinan,Weifang,Yantai,Weihai prefectures,Shandong province,China in August and September 2009.Blood samples were collected one to six months after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay(CMIA).A total of 796 infants were non-and low-responders whose anti-HBs were lower than 100 mIU/ml.The non-and low-responders were revaccinated with 3-dose of HepB.Blood samples were collected from a total of 296 infants one month(T0),four years(T1)and nine years(T2)after revaccination and antiHBs,antibody against hepatitis B core antigen(anti-HBc)were detected by CMIA,not including those self vaccinated.Positive rate and geometric mean concentration(GMC)of anti-HBs at T2 was calculated.The risk factors associated with positive rate of anti-HBs,GMC of anti-HBs were identified by multiple non-conditional Logistic regression analysis and multifactor linear regression model analysis,respectively.Results Among 296 children,positive rate of anti-HBs was 100%at T0 and decreased to 59.46%(176/296,95%CI:53.63%-65.10%)at T2,and the average annual decline rate was 5.61%.The corresponding GMC decreased from 906.22(95%CI:800.13-1026.37)mIU/ml to 17.79(95%CI:14.93-21.19)mIU/ml,and the average annual decline rate was 35.39%.Multivariable analysis showed the positive rate and GMC of anti-HBs at T2 were associated with anti-HBs titer at T0 and gender.The positive rate at T2 were significantly higher among the children whose anti-HBs titer≥1000 mIU/ml at T0 than those whose anti-HBs titer at T0 was less than 1000 mIU/ml,and the OR(95%CI)was 3.92(2.33-6.63).The same trend was found for GMC of anti-HBs at T2.The b value(95%CI)was 1.00(0.87-1.14).The positive rate and GMC among boys were significantly higher than girls at T2.The OR(95%CI)of the association of positive rate and gender was 0.57(0.35-0.94).The b value(95%CI)of the association of GMC and gender was-0.35(-0.68--0.01).Conclusions More than half children with non-or low-response to HepB primary immunization still have anti-HBs above protective level 9 years after three-dose revaccination.The anti-HBs persistence after revaccination is mainly associated with gender of vaccinee and anti-HBs level at one month after revaccination.The breakthrough rate is low.