母婴隐匿性乙型肝炎病毒感染及传播机制研究

Due to its routine non-identifiability, occult hepatitis B virus infection (OBI) threatens populational health for its silent transmission and epidemic. Based on overt hepatitis B infection, the efficacy of hepatitis B vacccination has been widely acknowledged; but a not-infrequnt portion of OBI still exists in both mothers and infants. Thus it's hypothesized that mother-to-infant transmission by OBI may not be effectively blocked by current vaccination strategies. Centering on mother-to-infant transmission by OBI, a hospital-based, matched, large cohort of the mothers and their newborns will be set up. Blood screening on HBsAg and HBV DNA and sequential follow-up will be done. Based on basic characteristics of the mothers and their infants with overt HBV infection or OBI, the effectiveness of HBV vaccine on the infants will be evaluated. HBV sequences variants will be compared between groups of overt HBV infection and OBI, matched mother-infant, vaccine-blocked and unblocked. We expect to obtain: basic characteristics, vaccine efficacy, OBI transmission and its mechanism; differential sequential variants between overt HBV infection and OBI will be obtained. Our results will form a basis for studying OBI biology, developing new OBI kits and vaccines, and designing new strategies for OBI prevention and control.

隐匿性乙型肝炎病毒感染(OBI)常规不易识别，而呈现的静默传播和流行威胁着人群健康。基于显性HBV感染评估的HBV疫苗有效性得到广泛认可，但母婴仍存在相对较高比例的OBI，提示着现有HBV疫苗免疫策略阻断OBI母婴传播仍存在问题。本研究围绕母婴OBI感染及传播机制，建立以医院为基础、匹配、大样本的孕妇及其新生儿队列，进行血液HBsAg和定量HBV DNA的检测筛选并随访；在获知母婴显性和隐匿性HBV感染特征的基础上，重新评估现有HBV疫苗免疫策略对OBI、显性HBV感染母婴传播的免疫保护效果；并比较各组间(显性和隐匿性、匹配母婴间、疫苗阻断和不可阻断等)HBV序列变异规律。研究预期获知母婴人群OBI的基本特征、免疫策略有效性、母婴传播风险及其机制，获得可有效区分显性和和隐匿性HBV的序列变异特征，为OBI病毒生物学特性、新型检测试剂和疫苗研制及防控策略的制定奠定基础。

系统研究母婴显性与隐匿性乙型肝炎病毒感染（Occult Hepatitis B infection, OBI）感染规律、序列变异情况及可能的传播机制。4226例孕妇HBV显性和OBI感染率分别为10.5%和1.4%，显性孕妇HBV 病毒载量高于OBI孕妇（568.0 IU/mL vs 322.0 IU/mL）。330例免疫后新生儿人群中HBV显性和OBI感染率分别为0.6%及0.9%。免疫后新生儿中，母亲为HBV感染者占18.5%，母婴传播率为6.6%。母亲为显性HBV感染的新生儿中，显性HBV及 OBI感染率分别为1.9%和5.7%。325例免疫后非HBV新生儿HBsAb阳性率为85.2%，应答率（HBsAb ≥10 IU/L）为80.9%。其中， 母亲HBV显性感染组HBsAb阳性率为94.0%, OBI组为100.0%，非HBV感染组为83.2%，三者间差异无统计学显著性。获得孕妇HBV S区、PreS 区、PreC/C区以及X区序列分别为255株（基因B型218株、C型37株）、79株（基因B型62株、C型17株）、46株（基因B型38株、C型8株）以及130株（基因B型116株、C型14株）。OBI病毒株中，基因C型病毒株所占比例高于基因B型（30.8% vs. 10.3%）。基因B型病毒株中，除X区外，各基因片段区在显性株与 OBI株之间的核苷酸变异率均存在差异。其中，在S区、PreS 区与X区分别发现7处、4处及3处非同义氨基酸替换。基因C型病毒株中，S基因区显性株与OBI株核苷酸替换率间存在统计学显著性（4.64‰ vs. 2.50‰）, 但未发现存在统计学差异的核苷酸替换位点。61对匹配母婴用于HBV MTCT序列分析，获得35株HBV母亲 S基因区序列。在发生MTCT的显性HBV病毒株中发现4个非同义氨基酸替换位点，但未发现与非MTCT组间存在统计学显著性差异。获得母亲HBV全长基因组序列20株，新生儿HBV全长基因组序HBV全长基因组序列2株，其HBV母婴传播模式均为母亲显性HBV感染—新生儿OBI。其中1例新生儿OBI病毒株序列与母亲序列高度同源，可确定为母婴传播，但另1例与母亲序列之间变异较大，尚不能确定其来源。总体上，现有的乙肝疫苗免疫策略有效，但仍无法完全阻断HBV母婴传播，尤其针对是母亲显性HBV感染—新生儿OBI的传播模式。