新生儿HBV血清标志物及免疫状态与乙型肝炎疫苗无／弱应答的关系

Relationship between the mode of HBV marker and immune status in neonates and non-/ hypo-response to hepatitis B vaccine

目的 探讨新生儿HBV血清标志物及免疫状态对乙型肝炎（乙肝）疫苗无/弱应答的影响。方法 选择2011年7月至2013年7月太原市第三人民医院妇产科HBsAg阳性孕产妇及其足月新生儿386对，按我国0-1-6月免疫接种程序对新生儿进行乙肝疫苗接种并随访至12月龄。采用化学发光法检测孕产妇、新生儿及其12月龄（婴儿）的外周血HBV血清标志物HBsAg、抗-HBs、HBeAg、抗-HBe和抗-HBc水平；利用流式细胞术及ELISA检测新生儿及婴儿的外周血TLR3蛋白表达量及T淋巴细胞亚群、B淋巴细胞、树突状细胞（DCs）数量和Th1/Th2型细胞因子水平。结果 新生儿HBV血清标志物以“HBeAg^＋抗-HBe^＋”、“HBsAg^＋HBeAg^＋抗-HBe^＋”、“HBsAg^＋”和“HBV血清标志物全阴，HBVM-”为主；“HBeAg^＋抗-HBe^＋”模式下婴儿乙肝疫苗无/弱应答率为5.2%，低于其他3种模式的20.0%、40.0%和22.5%。4种主要HBV血清学模式下婴儿的CD4^＋ T淋巴细胞和CD8^＋ T淋巴细胞数量、新生儿及婴儿IL-6水平差异有统计学意义。“HBeAg^＋抗-HBe^＋”模式下新生儿及婴儿的IL-6水平均高于“HBVM-”模式；新生儿及婴儿的IL-6水平均与抗-HBs水平呈正相关；血清IL-6水平〉1 112.0 pg/ml的新生儿发生乙肝疫苗无/弱应答的风险下降了61.4%（OR=0.386，95% CI：0.266～0.561，P〈0.001）。结论 新生儿“HBeAg^＋抗-HBe^＋”模式及高水平IL-6者的乙肝疫苗无/弱应答率较低，新生儿各血清学标志物组合模式与免疫状态的关系有待进一步研究。

Objective A prospective study was conducted to explore the influence of neonatal modes of HBV marker （HBVM） on non-/hypo-response to hepatitis B vaccine in infants. Methods From July 2011 to July 2013, a total of 386 pregnant women who showed serum HBsAg positive with their neonates at birth and another 227 infants at 12 months admitted in the Third People＇s Hospital of Taiyuan in Shanxi province, China. All infants received hepatitis B vaccine with the 0-1-6 month schedule. Maternal, neonatal and infantile HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc were measured by chemiluminescence-immunoassay. The neonatal/infantile PBMC TLR3 expression level and the quantities of T cell subsets, B cells, DCs were measured by Flow Cytometry. The neonatal/infantile Th1/Th2 cytokines were measured by ELISA. Results Four types of common neonatal modes of HBVM appeared as ＂HBeAg^＋anti-HBe^＋＂, ＂HBsAg^＋HBeAg^＋anti-HBe^＋＂, ＂HBsAg^＋＂ and ＂HBVM-＂, respectively. The overall rate of non-/hypo-response to hepatitis B vaccine in neonatal mode of ＂HBeAg^＋anti-HBe^＋＂ was 5.2%, lower than that seen in the other three types of mode （20.0%, 40.0% and 22.5%, respectively）. The frequencies of circulating CD4^＋ T cells and CD8^＋ T cells were significantly different among four common modes of HBVM in infants. Meanwhile, the level of IL-6 in mode of ＂HBeAg^＋anti-HBe^＋＂ was higher than that in the mode of ＂HBVM-＂ at two points. There was a positive correlation appeared between the level of IL-6 and the level of anti-HBs. It was quite unlikely to show non-/hypo-response to hepatitis B vaccine, when neonates were at the level as IL-6〉1 112.0 pg/ml （OR=0.386, 95%CI：0.266-0.561, P〈0.001）. Conclusions Neonates who were with the mode of ＂HBeAg^＋anti-HBe^＋＂ and high level of IL-6 showed a lower non-/hypo-response rate on hepatitis B vaccine. It is necessary to further study the relationship between neonatal mode of HBVM and the immune status.