HBV感染母亲所生儿童3岁时乙肝疫苗免疫应答情况及影响因素

The immune response and influencing factor of hepatitis B virus vaccine on 3-year-old children born to mothers infected with HBV

目的探讨乙型肝炎病毒(hepatitis B virus,HBV)感染母亲所生儿童3岁时的乙肝疫苗免疫应答情况及其影响因素。方法以2017年1月1日至2018年5月1日于首都医科大学附属北京地坛医院产检并分娩的HBV感染孕妇及其分娩的婴儿为研究对象,婴儿完成规范的乙肝疫苗接种及乙肝免疫球蛋白注射,并对婴儿随访至3岁。1岁及3岁时检测婴儿乙型肝炎病毒表面抗原(hepatitis B virus surface antigen,HBsAg)、乙型肝炎病毒表面抗体(hepatitis B virus surface antibody,HBsAb)滴度、肝功能及血红蛋白等,通过医院HIS系统和LIS系统收集孕妇孕产期临床生物化学指标、HBV DNA、孕期抗病毒治疗情况及孕产期并发症等。按儿童3岁时HBsAb水平将母亲及儿童分为无/弱应答组(HBsAb<100 mIU/ml)和强应答组(HBsAb≥100 mIU/ml)。采用Logistic回归分析3岁儿童对乙肝疫苗免疫应答的影响因素。结果共纳入符合条件的HBV感染孕妇及其分娩婴儿各155例,孕期未应用抗病毒药物行母婴阻断者39例,用药者116例(其中拉米夫定30例,替比夫定86例),用药组孕中期(用药前)HBV DNA为(7.35±0.57)lg IU/ml,未用药组孕中期HBV DNA为(7.26±0.71)lg IU/ml,差异无统计学意义(t=-0.856,P=0.393);用药组分娩前HBV DNA为(3.69±0.88)lgIU/ml,未用药组分娩前HBV DNA为(6.77±1.22)lgIU/ml,差异有统计学意义(t=17.04,P<0.001)。23例儿童出生后7个月~3岁曾补种乙肝疫苗,3岁时HBsAb中位滴度为208.84 mIU/ml;132例未补种,3岁时HBsAb中位滴度为94.07 mIU/ml,较1岁时(370.66 mIU/ml)显著降低(z=-0.607,P<0.001),补种疫苗儿童3岁时HBsAb滴度显著高于未补种疫苗儿童(z=-2.402,P=0.016)。未补种乙肝疫苗儿童1岁时乙肝疫苗无/弱应答率为25.75%(34/132),3岁时无/弱应答率为51.52%(68/132),补种乙肝疫苗儿童3岁时无/弱应答率为21.74%(5/23)。155例母婴阻断成功儿童至3岁时无1例感染HBV。多因素Logistic回归分析表明补种乙肝疫苗是3岁儿童乙肝免疫应答效果的独立保护因素(OR=0.259,95%CI:0.09~0.741,P=0.012)。结论孕期应用乙型肝炎抗病毒药物可显著降低HBV DNA水平,不影响婴儿对乙肝疫苗的免疫应答,补种乙肝疫苗是3岁儿童乙肝疫苗免疫应答效果的独立保护因素。

Objective To investigate the immune response and influencing factor of hepatitis B virus vaccine on 3-year-old children born to mothers infected with hepatitis B virus(HBV).Methods HBV-infected pregnant women and their babies delivered in Beijing Ditan Hospital,Capital Medical University from January 1st,2017 to May 1st,2018 were collected.The infants received standard hepatitis B virus vaccine and immunoglobulin injection,and were followed up to 3 years old.Hepatitis B virus surface antigen(HBsAg),hepatitis B virus surface antibody(HBsAb)titer,liver function and hemoglobin of the infants were detected at 1 year and 3 years old.Clinical biochemical indexes,HBV DNA,antiviral treatment during pregnancy and complications were collected through HIS system and LIS system.Mothers and children were divided into no/weak response group(HBsAb<100 mIU/ml)and strong response group(HBsAb≥100 mIU/ml)according to children’s HBsAb level at 3 years old.Logistic regression was used to analyze the influencing factors of immune response to hepatitis B virus vaccine for 3-year-old children.Results A total of 155 eligible HBV-infected pregnant women and their delivered infants were included.A total of 39 cases did not take antiviral drugs during pregnancy and 116 cases took antiviral drugs(lamivudine:30 cases;tibivudine:86 cases).In the middle of pregnancy(before treatment),HBV DNA load of pregnant women in treatment group was(7.35±0.57)lg IU/ml,which was(7.26±0.71)lg IU/ml in untreated group,the difference was not statistically significant(t=-0.856,P=0.393).There was statistical difference in HBV DNA load before delivery between pregnant women in treatment group and untreated group[(3.69±0.88)lg IU/ml vs(6.77±1.22)lg IU/ml;t=17.04,P<0.001].Total of 23 infants(reseed group)were vaccinated again with hepatitis B virus vaccine between 7 months and 3 years old after birth,the median value of HBsAb of children at 3 years old was 208.84 mIU/ml.There were 132 cases who were not vaccinated again with hepatitis B virus vaccine,the median value of HBsAb of children at 3 years old was 94.07 mIU/ml,which was significantly lower than that at 1 year old(370.66 mIU/ml,z=-0.607,P<0.001).HBsAb titer of children at 3 years reseed group was significantly higher than that in unreseed group(z=-2.402,P=0.016).The rates of no/weak response to hepatitis B virus vaccine of children in unreseed group were 25.75%(34/132)at the age of 1 year and 51.52%(68/132)at the age of 3 years,respectively,which was 21.74%(5/23)at the age of 3 years in reseed group.None of the 155 children with successful mother-to-child blockade was infected with HBV at the age of 3 years old.Multivariate Logistic regression analysis showed that hepatitis B virus vaccine supplementation was an independent protective factor for the effect of immune response in 3-year-old children(OR=0.259,95%CI:0.09~0.741,P=0.012).Conclusions Treatment with antiviral drug during pregnancy could reduce HBV load significantly and not affect the immune response of infants to hepatitis B virus vaccine.Hepatitis B virus vaccine reseeding was an independent protective factor of hepatitis B immune response in 3 years old children.